Issuu on Google+

HIV i-Base

treatment

training for advocates

Part One: Introduction to HIV Section 1: The immune system and CD4 count Section 2: Virology, HIV and viral load Section 3: Introduction to ARVs Section 4: Side effects of ARVs Section 5: OIs and co-infections Section 6: HIV and pregnancy Section 7: Drug users and ARVs Section 8: Clinical trials and research Section 9: Learning resources Appendices

3rd Edition: January 2008

HIV i-Base: 3rd Floor East,Thrale Hse, 44-46 Southwark St, London SE11UN. Tel: +44 (0)20 7407 8488 admin@i-Base.org.uk www.i-Base.info


www.i-Base.info

HIV i-Base

Treatment training for advocates Part One: Sections 1-9

Section 1: The immune system and CD4 count Section 2: Virology, HIV and viral load Section 3: Introduction to ARVs Section 4: Side effects of ARVs Section 5: OIs and co-infections Section 6: HIV and pregnancy Section 7: Drug users and ARVs Section 8: Clinical trials and research Section 9: Learning resources: science support modules Appendices

Third edition January 2008 Second edition June 2005 First edition November 2004

Written and edited by: Simon Collins, Polly Clayden, Mauro Guarinieri, Svilen Konov, Roman Dudnik, Ben Cheng and Sipho Mthathi, Matt Williams.

HIV i-Base: basic training for advocates



January 2008


www.i-Base.info

Contents

Treatment training for advocates: January 2008 HIV i-Base. http://www.i-Base.info

page

Contents Introduction to this resource Introduction to course outline

ii vii viii

Section 1 - The immune system and CD4 count 1.1 Introduction to Section 1

1

1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.12 1.13 1.14 1.15 1.16

Aims for Section 1 Definition of AIDS (SIDA) Basic organs in the body How the immune system works How HIV specifically interacts with immune system CD4 count as ‘surrogate marker’ How quickly does HIV progress in different people Interpreting CD4 results: CD4 count and CD4 percentage Differences between adults and children Different stages of infection CD4 level cut-offs for opportunistic infections Use of CD4 count in guidelines for starting therapy Glossary: Section one Questions: Section 1 Course evaluation for Section 1

Section 2:Virology, HIV and viral load 2.1 Introduction to Section 2 2.2 Aims for Section 2 2.3 Definition of HIV 2.4 Other causes of illness 2.5 HIV and infection 2.6 Viral dynamics of early and chronic infection 2.7 Reinfection with HIV 2.8 What is a viral load test 2.9 History of viral load technology 2.10 Impact of coinfections on viral load 2.11 Compartments and sanctuary sites 2.12 Importance of viral load on-treatment and off-treatment 2.13 Viral lifecycle, drug resistance and adherence

16

2.14 How CD4 and viral load are related 2.15 Glossary: Section 2 2.16 Questions: Section 2 2.17 Course evaluation for Section 2 HIV i-Base: basic training for advocates

ii

January 2008


www.i-Base.info

Contents

Section 3: Introduction to ARVs 3.1 Introduction to Section 3 3.2 Aims for Section 3 3.3 What is combination therapy? 3.4 Do the drugs really work? 3.5 How HIV drugs work - main types of drugs 3.6 Treatment guidelines 3.7 When to start treatment 3.8 Why three or more drugs are used 3.9 Reducing viral load to less than 50 copies/mL 3.10 Treatment choice 3.11 Side effects 3.12 Can I change treatments? 3.13 Can I take a break in my treatment? 3.14 Recreational drugs, alcohol and complementary therapy 3.15 Adherence - and why it is so important 3.16 Tips to help adherence... 3.17 What if I forget to take my pills? 3.18 Resistance to ARVs 3.19 Treatment failure 3.20 Glossary: Section 3 3.21 Questions: Section 3 3.22 Course evaluation for Section 3

27

Section 4: Side effects of ARVs 4.1 Introduction to Section 4 4.2 Aims for Section 4 4.3 General questions 4.4 General side effects 4.5 More serious side effects associated with WHO combinations 4.6 Other side effects 4.7 How to report side effects 4.8 How side effects are graded 4.9 Side effects diary 4.10 Glossary: Section 4 4.11 Questions: Section 4 4.12 Course evaluation for Section 4

42

HIV i-Base: basic training for advocates

iii

January 2008


www.i-Base.info

Contents

Session 5: Opportunistic Infections (OIs) and important co-infections 5.1 Introduction to Section 5 5.2 Aims for Sections 5 5.3 Approach to each OI 5.4 GI infections: giardia, cryptosporidia, microsporidia

5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15

5.16 Summary table of OIs and effect of ARV treatment

67

Candida (candidiasis) and other skin problems PCP TB MAI and MAC Hepatitis B and C CMV Toxoplasmosis Cryptococcal meningitis Cancer: lymphoma, and sarcoma Wasting and weight loss Malaria

5.17 Glossary: Section 5 5.18 Questions: Section 5 5.19 Course evaluation for Section 5

Section 6: HIV and pregnancy 6.1 Introduction to Section 6 6.2 Aims for Section 6 6.3 General questions 6.4 Mother’s health and pregnancy 6.5 Prenatal care and treatment 6.6 Safety of HIV drugs in pregnancy 6.7 Side effects and pregnancy 6.8 Resistance in pregnancy 6.9 Other screening and tests 6.10 Other infections 6.11 Drugs and the baby’s health 6.12 Choices for delivery and use of C-section 6.13 When the baby is born 6.14 Breastfeeding 6.15 Mother’s health after the baby is born 6.16 Other useful information 6.17 Glossary: Section 6 6.18 Questions: Section 5 6.19 Course evaluation for Section 6

HIV i-Base: basic training for advocates

iv

80

January 2008

OIs


www.i-Base.info

Contents

Section 7: Drug users and ARVs 7.1 Introduction to Section 7 7.2

Aims for Section 7

7.3

General questions

7.4

Comprehensive and accessible care

7.5

Interactions between recreational drugs and antiretrovirals

93

7.6 Why this theoretical information is not as useful as controlled interaction studies in humans 7.7

Interactions with other ARVs

7.8

Interactions with methadone

7.9

Table I: Interactions between antiretrovirals and rave drugs

7.10 Questions: Section 7 7.11 Course evaluation of Section 7 Section 8: Clinical trials and research 8.1 Introduction to Section 8

8.2

Aims for Section 8

8.3

Why trials are important

8.4

Developing a new treatment: Phase I, II, III and IV studies

8.5

Hypothesis and endpoints

8.6

Three main types of trial design

8.7

Randomised, double-blind, placebo-controlled trials

8.8

Other types of studies

8.9

Grading given to different types of evidence

8.10 Glossary of terms

8.11 How studies are reported

8.12 Patient involvement in clinical studies and research

8.13 Issues of confidentiality for advocates involved in research

8.14 Summary of different advocacy roles

8.15 Multiple choice test questions

8.16 Course evaluation of Section 8

102

Section 9: Learning resources & science support modules 9.1 Introduction to Section 9 9.2 How to read a graph

123 123 124

9.3

What is an average

126

9.4

What happens when you take a drug

128

9.5

Drug levels, drug activity and side effect

130

9.6

Common mathematical signs, symbols, statistical and medical terms 132

9.7 Units of measurement

133

9.8

135

Log value conversion table

HIV i-Base: basic training for advocates



January 2008


www.i-Base.info

Contents

Appendices

Appendix I 1993 CDC AIDS surveillance case definition

136

Appendix II WHO classification system for HIV infection

137

Appendix III OIs listed by disease type

138

Appendix IV Drugs and doses of European licensed ARVs

139

Appendix V Further reading

141

Appendix VI Answers to questions for each section

142

HIV i-Base: basic training for advocates

vi

January 2008


www.i-Base.info

Introduction

Introduction to this resource This training resource uses eight work units for the basic course. The format is very simple. Other units can be added if they are more appropriate to different situations. This resource is part of a copyright-free project that is available on the i-Base website to download in various formats, or to work online. As with other treatment information produced by i-Base we encourage translations into other languages. It is written for people who do not have a scientific background or medical training. For people who already have a basic understanding of the way HIV and treatment works we plan to extend this modules to produce an intermediate course. Some of the sessions are very short, and have simple questions. This is so that anyone can start learning about treatment, and in turn pass that information on to others. Even if you are not very academic, and this training is difficult, you can still be a very effective advocate and activist. This training will help you understand the background to traetment issues. The training material has been written in a way that makes it easier for you to then explain the information again to other people without a medical background. As community advocates and trainers, it is important to understand and explain things that people may not be initially very interested in. And explain them in a way that makes the new information relevant to getting better care. Most people don’t want to know about science - they just want to get on with their lives. But you will need to explain the science behind how things work. It means getting people to believe in things that they can’t see, and getting them to trust in things that are too small to see with their own eyes. We can’t see a virus, or a CD4 cell or any of the things that are tested in blood with the naked eye. We can’t see whether one pill or another will work better or at all. But understanding a bit about how treatment works does empower people to have more control over their treatment and their choices. This course is written by treatment advocates who have had no formal medical training and who are mostly HIV-positive – and we’ve tried to remember the biggest surprises that we found as we developed our own treatment knowledge. Sometimes it’s the surprises that keep you learning – because they show how different thing are to how you imagined them. Hopefully some of these will be helpful in developing your own treatment interest – once you start, you realise there is always more to learn.

HIV i-Base: basic training for advocates

vii

January 2008


www.i-Base.info

Introduction

Introduction to course programme Sections 1-9 – Introduction to HIV The first six sections are to introduce the most important aspects of treatment to an intermediate standard. The aim for each section is to provide a general understanding for each area. This will form the structure for more advanced training and your own research in the future. Understanding and completing this would enable a good grasp of 90% of the issues involved in HIV and treatment. Although this course presents a structure for what you need to learn about HIV, the approach to learning will be more practical than just reading or taking notes. Advocacy is based on a problem-solving. This involves an approach to new information. You will never reach a point where you suddenly know everything. You will always need to use research to confirm the things you think that you know, and to find out new things that you don’t. This is also because information itself changes very quickly. Each section then has around 15-20 questions that you should be able to answer. The aim for the first section of basic training is to get familiar with the most important terms and concepts. You do not need to know everything about each area in detail, and it will be too much to deal with if you try to learn everything straight away. These first eight sections are to provide the basic structure to build on.

HIV i-Base: basic training for advocates

viii

January 2008


www.i-Base.info

Section 1: Immune system and CD4 counts

Section 1:The immune system and CD4 count

1.1 Introduction to Section 1 If you understand CD4 and viral load you will be able to understand: •

the risk for HIV-related illnesses

when and why treatment is recommended at different times, and

whether treatment is working properly

The first section starts with your body and the way that it fights infections using the immune system. For example: HIV is a virus and you need to know how your body reacts to a virus. HIV is a virus that attacks the immune system – so you need to understand how your body is damaged. Sections 2 links closely to Section 1.

1.2 Aims for Section 1 After reading and completing this section, advocates will have a basic understanding of: •

the ways a scientist or doctor understands the immune system

CD4 cells and CD4 tests and what they mean

how the CD4 count is used to monitor HIV infection

use of CD4 count in treatment decisions and guidelines

HIV i-Base: basic training for advocates

S1:1

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1

1.3 Definition of AIDS AIDS stands for Acquired Immune Deficiency Syndrome Acquired

because it is largely an infection that people catch

Immune

because it relates to your immune system

Deficiency

because it reduces your immune system

Syndrome –

because it describes a collection of different infections and illness caused by HIV

Learning about HIV will involve learning lots of new terms that you do not know yet. Every time you see a word you don’t understand, write it down and find out the meaning. After a while you will find you have learnt things you would never have expected. For many HIV-positive people the meaning of the words that make up AIDS do not mean very much until they are explained clearly.

1.4 Basic organs in the body

It is easy to know the bits on the outside of your body, but most people don’t know where their thymus, or kidneys or lungs are, or what these organs do. Understanding treatment is much easier if you know the way the major systems in your body work. Heart - The heart is between the two lungs. The heart muscles continually circulate blood around your body.You know your heart is working because you can feel your heart beat and you can feel the blood at your pulse. The heart pumps oxygen to every part of your body and pumps the oxygen-depleted blood back through the lungs to be re-oxygenated.

HIV i-Base: basic training for advocates

S1:2

January 2008


www.i-Base.info

Section 1: Immune system and CD4 counts

Lungs - your lungs are sponge-like organs and every time you breathe they filter oxygen from the air where it passes through tiny vessels into the blood - and is then carried to the heart to be pumped round your body. The lungs filter carbon dioxide from your body when you breath out. Liver - your liver is the organ below the lungs that acts like a filter for the blood. Chemicals and impurities - such as drugs and medications - are filtered out by the liver. Important other activities occur in the liver including production and processing of many body fats. The liver is the only internal organ that can regrow. Kidneys - the kidneys also act like a filter. Some drugs are filtered more by the kidneys than the liver. Waste products are filtered by the kidneys and leave the body as urine.You have two kidneys and they are at the back of your body. Any blockage to your kidneys is extremely painful and can cause permanent damage. Although you are born with two kidneys, many people survive very well with just one. Stomach and intestines - The stomach is where food, drink and oral medications start to be broken down and processed in the body. Nutrients and drugs are absorbed through the stomach and small intestine walls. The small intestines are about 5 metres long. The large intestines are about 1.5 metres long. Thymus - this is a small gland high in the chest where CD4 cells and other lymphocytes develop. CD4 cells are sometimes called T-cells (‘Thymus-cells’). The thymus is very active in children and adolescents, and becomes much less active as you grow older. Pancreas - your pancreas is a pistol shaped gland below the liver that releases digestive enzymes into the small intestine and hormones that control sugar levels in your blood.You can live without a pancreas but you need to take insulin to regulate blood sugar levels and take supplementary digestive enzymes. Skin - your skin is the largest organ in the body and makes up 16% of your body weight. It stops your body from drying out and is the main barrier against infection. Bone - your bones are a living material and about 10% of bone cells die and are replaced each year. If bone cells are not replaced quickly enough, bones becomes brittle and break more easily. Bone marrow is the soft tissue inside bones and is the source of all blood cells. Blood is the fluid pumped by your heart to deliver oxygen and nutrients to every part of your body and carries waste products away. Blood contains cells (red cells, white cells, platelets etc) and plasma. Plasma is the fluid part of blood that contains nutrients, glucose, proteins, minerals, enzymes, and other substances but with the blood cells taken out. Lymph is a clear fluid that contains white blood cells and antibodies and is distributed round your body through a series of lymph vessels, nodes, and organs. The lymph system supports the blood in removing waste products from the body. Although a lot of information about your health and HIV comes from blood tests, only 2% of the HIV in your body is in your blood. Most of the other 98% is in the lymph system. Lymph nodes are the little lumps that sometimes get enlarged in your neck, under your arms, and in the crease between your legs and your body.

HIV i-Base: basic training for advocates

S1:3

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

Web resources: There are hundreds of sites on the internet that explain basic biology, immunology and other medical terms. The following sites may be useful: In the US, a 39-year-old man on death row donated his body to science. After he was executed, his body was frozen, cut into one-millimetre-thick slices, and photographed. The data were made available in 1994 on the Internet by the US National Library of Medicine. To view two- and three-dimensional representations of the human body based on these data, visit these sites: http://www.nlm.nih.gov/research/visible/visible_human.html BodyQuest - a site designed to explain human anatomy to students ages 11–16. Try starting with the tour, which gives you an overview of the human body and allows you to find more detailed information: http://library.thinkquest.org/10348/?tqskip1=1&tqtime=0326 The Atlas of the Body - An interactive exploration of muscles, internal organs, and skeleton of the human body from the American Medical Association. http://www.ama-assn.org/ama/pub/category/7140.html

HIV i-Base: basic training for advocates

S1:4

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.5 How the immune system works (before HIV infection) Some ways of protection from infection are straightforward: •

Your skin is a major barrier

If your skin is damaged - for example through a tiny cut or tear (in the case of a virus like HIV) or is breathed in (in the case of TB) then your body uses different cells to attack and break down this new infection. Two medical words are often used when talking about the immune system: •

Antigen is a word for small particles of infectious material broken down in the body, that are recognised by the immune system.

Antibody is a type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen.

Cellular and humoral immunity There are two main ways that your body deals with different infections: i)

Humoral immune responses are based on antibodies.

HIV is routinely diagnosed using an antibody test that looks for the body’s response to HIV. This usually takes 2-3 weeks to develop, but can take several months and occasionally longer. ii)

Cellular immunity is based on CD4 and CD8 responses

T-cells are a type of white blood cells (lymphocytes). The two main types of T-cells are CD4 cells and CD8 cells. CD4 cells are sometimes called helper cells because they help the immune response by sending signals to CD8 cells. CD8 cells are sometimes called killer cells because they recognise and kill cells that are infected with a virus Sometimes these processes and functions overlap Generally your body uses cellular immunity to fight viruses, and to fight HIV. Macrophages are another type of larger white blood cell that engulf or swallow up infectious organisms or waste material from dead cells. They also signal other cells in the immune system.

HIV i-Base: basic training for advocates

S1:5

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.6 How HIV interacts with the immune system HIV is an especially difficult virus for the body to deal with. This is because the cells that the virus uses to reproduce itself are the cells that the body uses to fight infection. HIV infection makes infected cells die more quickly, and it also makes infected cells signal to other cells to die more quickly. These two factors are like a dog chasing its tail! • HIV infection makes the body produce more CD4 cells to fight this new virus •

These new cells provide more target cells for HIV to infect and reproduce

The body responds by making more cells to fight the new virus

After a while the HIV-specific T cells get worn out and disappear (in most people within 6 months after infection). After many years the body gets very tired and the rest of the immune system is worn down.

This is a difficult page to understand. The main point is that HIV makes the immune system go into overdrive - producing more and more cells. These cells also die very quickly though and over time the immune system loses out. This is why your CD4 cells, as measured by your CD4 count, drops. ARV treatment blocks HIV from reproducing as quickly, and returns your immune system back to an almost normal state.

HIV i-Base: basic training for advocates

S1:6

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.7 CD4 count as ‘surogate marker’ Pattern of CD4 count after HIV infection without treatment. The CD4 count (full name: CD4+ T-lymphocyte count, but also called CD4+ T-cell or T4 count) is the result of a blood test that tells you how many of these cells are in a cubic millimetre of blood. A surrogate marker is when one factor is used to indirectly measure something else. The CD4 count­ is a good surrogate marker for how much HIV has damaged your immune system. It can tell you your risk of infections and when you need to start treatment. The average CD4 count for an HIV-negative person is usually between 600 and 1600 - but a few people have naturally lower or higher levels than this. HIV treatment

HIV infection 1500 600

200

2 - 10 years after HIV infection CD4 count drops a bit and then recovers

CD4 count then drops quickly in a few people, but most people take 4-7 years to drop down to 200

after treatment, your CD4 count should rise again to higher levels

A few weeks after infection with HIV the CD4 count falls

Then as the body’s immune system begins to fight back, it goes back up again though not to the levels that it was before HIV infection

This level is sometimes called the CD4 set point and usually takes about 3- 6 months after infection to stabilise, but it can take much longer

Then the trend for the CD4 count is to gradually go down over several years. The average rate that CD4 counts fall is about 50 cells/mm3 every year. In some people this will be much faster and in some people much slower.

Everyone should have a CD4 test soon after they are diagnosed with HIV. If this is under 200 cells/mm3 is is an indication to start treatment. CD4 monitoring should be done every three months. Sometimes due to lack of resources it may only be done every six months.

Most people’s immune system controls HIV very successfully without needing drugs for many years.

HIV i-Base: basic training for advocates

S1:7

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.8 How quickly does HIV progress in different people The time it takes for the CD4 count to drop (for example to 200 cells/mm3) varies a lot between different people

CD4 set point

1500 600

slow progressor fast progressor (ARV after 2-3 years) average progressor (ARV after 7-8 years)

200

primary infection (approx 6 months)

2

3

4

5

6

7

8

9

10

Time (years)

Approximate time for CD4 count to drop to 200 cells/mm3:

<5% people take 1-2 years (fast progressors)

10% people will take 3-4 years

70% people will take 5-9 years

10% people will take 10-12 years

<5% people will not see any drop in their CD4 count even after 10-15 years (long term slow progressors) Sometimes people who have very serious illness when they are first infected (during seroconversion) will lose CD4 cells more quickly. There is no way to guess how quickly HIV will progress, other than by monitoring their CD4 count over time. People who progress more quickly, and who lose CD4 cells more quickly, will still get as good and as strong a response to treatment, as people who progress more slowly.

HIV i-Base: basic training for advocates

S1:8

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.9 Interpreting CD4 results: CD4 count and CD4 percentage A single CD4 count doesn’t mean very much.You really need to get several results over time to see what the trend is. When you have several results you can see whether the trend is going up or down and how quickly it is changing - or whether it is generally stable. CD4 counts can go up and down depending on the time of day, whether you have eaten a fatty meal, if you have just been running up and down stairs, whether you have oher infections or even if there were just more or fewer cells in that sample of blood. This is why the trend looks at the average results.

CD4 count

1500 600

Average CD4 count

200

Actual CD4 counts 2 - 10 years

Each point on the dotted line shows an individual ‘absolute’ CD4 count. This is the number of CD4 cells in a cubic millimetre (cells/mm3) or microlitre (cells/uL) of blood. In scientific papers this is sometimes written as ‘cells x106/L’. The solid line shows the average of these results. In this example it shows that the trend is for the CD4 count to fall over time. If you ever get an unexpectedly high or low count, then if possible, this should be confirmed with a second test. The CD4 percentage (CD4%) is sometimes a more stable indication of whether there has been a change in the immune system. It is the percentage of total lymphocytes that are CD4 cells. A CD4% of 12-15% is about the same as a count of under 200 cells/mm3. A CD4% of 29% is about the same as a count of over 500 cells/mm3, but there is a wider range for higher values. An HIV-negative person has a percentage of about 40%. Absolute CD4 counts are not used for children, who are monitored by CD4%.

1.10 Differences between adults and children •

Children generally have much higher CD4 counts than adults.

Babies have higher CD4 counts than children.

Over time, and as we age our CD4 count drops gradually.

• Because the differences are so much higher in children though, children with HIV are monitored by CD4% rather than absolute CD4 count. HIV i-Base: basic training for advocates

S1:9

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.11 Different stages of infection Stages of HIV infection are described in slightly different ways by different organisations like the WHO and the US medical system, etc. Now that there are effective treatments, these stages are less important. The WHO definition relies on symptoms only and not test results. The US-based definition relies on symptoms and lab results. WHO staging categories: The WHO categories do not include CD4 counts. A list of the related symptoms are included in Appendix II. These symptoms are used with the following performance stages: Performance Stage 1: asymptomatic, normal activity Performance Stage 2: symptoms, but nearly fully ambulatory Performance Stage 3: in bed more than normal but < 50% of normal daytime during the previous month Performam Stage 4:  in bed > 50% of normal daytime during previous month US CDC ­staging categories: Clinical categories are determined with the letters A, B and C. CD4 count is determined by numbers: 1, 2 or 3. A No symptoms, inc primary infection CD4 count

Clinical categories B

C

Symptoms AIDS (if not A or C) defining * infections **

1 = 500 or over

A1

B1

C1

2 = 200-499

A2

B2

C2

3 = less than 200

A3

B3

C3

* Less serious or early symptoms include: candida (thrush) in the mouth, or vagina if not responding to treatment, fever (over 38.5 degrees C) or diarrhoea lasting >1 month, cervical abnormalities or cancer, pelvic inflammatory disease (PID) ** AIDS defining infections include all the most serious infections including: oesophagal candida, CMV disease, many active lymphoma, pulmonary TB, KS, MAI, PCP, weight loss >10%, bacterial pneumonia, PML, toxoplasmosis. See Appendix I for a full list. In the US (but not Europe) a CD4 count under 200 cells/mm3 is an AIDS diagnosis. Before there were effective treatments, people were categorised based on how ill they were and their life expectancy. This system is used less now where treatment is available. People did not generally get better, so that the progression through stages A, B and C was a ‘one-way’ direction. For more information on classification of HIV see: http://hivinsite.ucsf.edu/InSite?page=kb-01-01#S3X

HIV i-Base: basic training for advocates

S1:10

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.12 CD4 level cut-offs for opportunistic infections An ‘opportunistic infection’ or OI is the name given to HIV-related illnesses that your body would normally be able to fight off, but which take advantage of the fact that your immune system is damaged. The lower a person’s CD4 count, the higher the risk that they will develop HIV-related illnesses. This is why monitoring of CD4 levels is important when you are not on treatment. You can still be well and healthy with a CD4 count that is below 200, below 100, below 50 or even below 10 - but it is much more likely that you will have serious health-related problems. Different illnesses become more likely at different CD4 counts. Many serious and life threatening illnesses become a risk when the CD4 count drops to under 200 cells/mm3.

When the count drops below 300:

Diarrhoea from microsporidia and cryptosporidia

Skin problems - candida (thrush), dry skin, etc

When the count drops below 200:

PCP (pneumonia) and chest infections

Toxoplasmosis - parasitic infection that commonly causes brain lesions

When the count drops below 100:

MAI / MAC - bacterial infections similar to TB Cryptococcus infection - fungal infection that can cause meningitis in the brain and PCP-like symptoms in the lungs

When the count drops below 50: CMV (cytomegalovirus) - a viral infection that can cause permanent vision loss and blindness

More detailed information on these opportunistic infections are given later in the course. The main point is that the lower your CD4 count the higher the risk of these and other illnesses. When your CD4 count increases after starting HIV treatment, your immune system is often able to deal with these infections by itself again.

HIV i-Base: basic training for advocates

S1:11

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1.13 Use of CD4 count in guidelines for starting therapy The main use of the results from CD4 tests is to know when to start HIV treatment. If HIV drugs were perfect - with no side effects and no resistance - then everyone would use treatment as soon as they were diagnosed. However, they are not perfect. This means you need to decide when the risk of not using treatment becomes outweighed by the risk of using treatment. Or when the benefits of treatment are greater than the risks of treatment. In general, people are unlikely to have HIV-related illnesses when their CD4 count is over 200 cells/mm3. Several large studies have also shown that people who start treatment with a CD4 count of 200 compared to people starting at 350 or above, get the same benefit. WHO and UK treatment guidelines therefore recommend starting treatment in people who have no other symptoms, before the CD4 count falls below 200. US treatment guidelines recommend starting treatment before CD4 counts falls below 350. Several years ago both UK and US treatment guidelines recommended starting at higher levels, and they may change again in the future - especially if better and easier to tolerate drugs become available. If you have any HIV related symptoms or illnesses, then treatment is recommended, even if your CD4 count is over 350. Remember that any one count is just a general figure. It doesnâ&#x20AC;&#x2122;t matter very much whether you start treatment at 180 or 220 - but generally around 200 is better than waiting much longer. In practice, many people start treatment at much lower levels - and they will still do very well. Many people are only diagnosed with HIV when they have HIV-related illness and CD4 counts that are under 200.

HIV i-Base: basic training for advocates

S1:12

January 2008

1


www.i-Base.info

Section 1: Immune system and CD4 counts

1

1.14 Glossary: Section 1 acute infection

early infection (first few months with HIV)

antibody

cells in your immune system that recognise antigens

antigen infectious material produced by a virus or bacteria TB

tuberculosis - bacterial infection that commonly infections the lungs but which can affect other organs

CD4 cell

cell (lymphocyte) in your immune system that signals CD8 cells to destroy a virus. CD4 cells are also used by HIV as factories to reproduce in

CD8 cell

cell (lymphocyte) in your immune system that kills cells that are infected with HIV

chronic infection

established infection (everything after the first 6 months)

CMV

cytomegalovirus - infection that can produce permanent loss of sight. Occurs mainly with CD4 count under 50. Can also affect other organs.

immune system

different parts of your body used to fight infections

MAC / MAI

bacterial infection similar to TB called MAI in Europe and MAC in the US

opportunistic infections

also called â&#x20AC;&#x2DC;OIsâ&#x20AC;&#x2122; - infections that occur after your immune system has been damaged by HIV

prophylaxis

a drug that you take in order to prevent a future illness

surrogate marker

an indirect measure for something else that can not be easily measured directly (i.e. a CD4 count is an indirect marker for HIV disease)

toxoplasmosis (toxo) infection that affects the brain (can cause fits and memory loss). Risk increases with CD4 under 100. Co-trimoxazole (Septrin) can protect from toxo. WHO

World Health Organisation

HIV i-Base: basic training for advocates

S1:13

January 2008


www.i-Base.info

Section 1: Immune system and CD4 counts

1

1.15 Questions: Section 1 1.

Immune system and immunology basics

Give simple explanations: 1.

What does AIDS stand for?

2.

What is a CD4 T cell?

3.

What is a CD8 T cell?

4.

What is the range of a CD4 count for an HIV-negative adult?

5.

Give other names for each of these cells

6.

What is CD4% and when is it used?

7.

What is the difference between cellular and humoral immune responses? Which responses are used by the body to fight HIV?

8.

What is a ‘surrogate marker’?

9.

How often should a CD4 test be done? (describe several different circumstances)

10.

How does CD4 test results relate to when to start treatment?

11.

Describe the general pattern of what happens to your CD4 after HIV infection, in early infection and through chronic infection?

12.

Draw a graph to show this.

13.

Which OI’s become more likely after your CD4 count falls below these levels: 300, 200, 100, 50?

14.

What is the main difference between children’s and adults’ CD4 counts?

15.

What is an antigen?

16.

What is an antibody?

Now write 1000 words about the immune system including this and other information you learnt about CD4 cells and CD4 cells counts. (i.e. a basic leaflet that you would send to someone who wanted to know about this).

HIV i-Base: basic training for advocates

S1:14

January 2008


www.i-Base.info

Section 1: Immune system and CD4 counts

1.16 Course evaluation for Section 1 Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation.

Session One: How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

HIV i-Base: basic training for advocates

S1:15

January 2008

1


www.i-Base.info

Section 2:Virology, HIV and viral load

Section 2:Virology, HIV and viral load

2 2.1 Introduction to Section 2 The second section provide information about HIV as a virus: what kind of infection is HIV; what happens after you are infected and how is the virus monitored.

2.2 Aims for Section 2 After this section you should understand: •

Definition of HIV

Difference between different causes of illness: viruses, bacteria, fungi and parasites.

Viral dynamics of early and chronic infection (the natural history of HIV)

Impact of co-infections on viral load

Brief history of viral load technology and accuracy

The importance of viral load whether you are on-treatment or off-treatment

Viral lifecycle

Basic theory of resistance

Recap CD4 and viral load graphs and superimpose them

HIV i-Base: basic training for advocates

S2:16

January 2008


www.i-Base.info

Section 2:Virology, HIV and viral load

2.3

Definition of HIV

HIV stands for Human Immunodeficiency Virus. Immunodeficiency means â&#x20AC;&#x2DC;reduced immunityâ&#x20AC;&#x2122;. A virus is genetic organism that can only reproduce inside cells of another living organism. Some viruses are harmless and others can cause illness. Antiviral drugs are used to treat viral infections. Examples of viral infections that affect people with HIV include hepatitis A, B and C; cytomegalovirus (CMV); herpes (HSV).

2.4

Other causes of illness

Other causes of illness include bacteria, fungal parasites and protozoa - and different types of treatment are used for each cause. For example, antibiotics do not work against a viral infection. Sometimes this is complicated because the differences between viruses and bacterial infections are not always clear. Bacteria - bacteria are single-cell micro-organisms. Some bacteria are healthy and help your body and some cause disease. Antibiotic drugs are used to treat bacterial infections. Examples of bacterial infections that affect people with HIV include tuberculosis, bacterial pneumonia, sinusitis, gonorrhoea and some skin infections. Fungi - fungal infections Examples of fungal infections that affect people with HIV include candida (thrush); cryptococcosis. Anti fungal drugs are used to treat fungal infections. Parasites - Parasite-related infections: cryptosporidium, microsporidium and protozoa like toxoplasmosis.

2.5

HIV and infection

HIV is actually a difficult virus to catch, but at the same time people can become HIV-positive after only one exposure to the virus. HIV dies within a minute or so in blood and other bodily fluids once they are outside the body. HIV is not infectious in saliva. Levels of HIV are measured using viral load tests and these are discussed in more detail later in this Section. The risk of catching HIV is related to the risk of the virus coming into contact with broken skin or through cells that are close to the surface of the skin. The risk is highest when viral load levels are high. The majority of people with HIV stay well for many years after they are infected. Some people (less than 5%) will become ill within a few years and a few people (also less than 5%) can go for 15 years or more before they need treatment. Although a lot of information about your health and HIV comes from blood tests, only 2% of the HIV in your body is in your blood. Most HIV is in your lymph system and lymph nodes. These are the little lumps that sometimes get enlarged in your neck, under your arms, and in the crease between your legs and your body. HIV i-Base: basic training for advocates

S2:17

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.6

Viral dynamics of early and chronic infection

The â&#x20AC;&#x2DC;natural historyâ&#x20AC;&#x2122; of any illness is the term to describe how that illness normally progresses if left untreated. It is very important to understand the natural history of HIV. With HIV infection there are several different periods including infection, seroconversion, primary infection, chronic infection and late-stage illness. Fig. 1: What happens to your viral load after infection

Infection - this is the point when the virus infects the first cells. It then takes several hours for these newly infected cells to be carried with the virus to the lymph nodes.

During the next few days or weeks the virus continues to multiply. Over this time the levels of viral load will be going up very high and very quickly.

Seroconversion - as viral load increases, this high level of viral activity produces symptoms in 50-80% people that include sweating, fevers, temperature, weakness and tiredness, etc.

The body produces an immune reaction to this new infection, and starts to produce antibodies to fight the virus. It can take 1-3 months after infection for this immune response (antibodies to HIV) to be strong enough to be detected on an HIV-antigen test.

Primary HIV Infection (PHI) - also called early infection or acute infection. Primary infection is usually used to describe the first six months after infection. Chronic infection - chronic infection is the term given to HIV infection after the first six months. Chronic infection can last for many years. It can take anything from 2 - 10 years until the majority of people need treatment. With treatment, chronic infection can be lifelong - ie 20, 30, or 40 or more years. Late stage infection - AIDS - this is the term used to describe the most serious stage. This is usually in people who do not have access to treatment, who are only diagnosed very late, or whose treatment has stopped working.

HIV i-Base: basic training for advocates

S2:18

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.7 Reinfection with HIV There have been several recent reports of cases of reinfection with HIV. This is where someone who is already diagnosed with HIV, is exposed to, and infected with, a second different strain of HIV. The reason that this is controversial, is that for many years it was assumed that once you had been infected with HIV, reinfection was not a risk. It is not clear how often this occurs, or the risk factors for reinfection. Some recent studies have not indicated that the risk is very high, but the fact it has been reported is something to be aware of. Many of these case reports have included people in early infection. They have also included examples where someone whose treatment was working effectively has been reinfected by someone with drug resitant HIV, and where the treatment then stopped working. This is the real risk of reinfection. Two people with the same non-resistant virus, or with the same resistant virus would not risk the same difficulties from reinfection, as someone who is reinfected with drugresistant virus.

2.8 What is a viral load test A viral load test measures how much HIV is in a sample of blood. After infection, viral load levels are very high, but then your body fights back and it drops to much lower levels. Over time though, usually over several years, the levels of virus increase again. It is usually very high (around 50,000 - 200,000 copies/mL) by the time that your CD4 count drops to around 200 cells/mm3. A viral load test is used after starting treatment to check that the drugs are working. If ARV treatment brings viral load down to less than 50 copies/mL, then treatment can last for many years. These tests are used in many countries but are difficult to get in many others. In some countries, viral load and CD4 tests cost much more than the drugs. New research is also looking at developing new tests that will be just as good but which are not so expensive or difficult to run. Even if you do not have access to these tests, it makes a difference that you understand how CD4 and viral load change. These two tests tell any doctor 95% of what they need to know about the risk of HIV to your health and how well your treatment is working.

HIV i-Base: basic training for advocates

S2:19

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.9 History of viral load technology Without viral load tests it is possible that combination therapy would never have been developed or understood. This was a new technology that was only being developed as a research tool during the 1990s. Viral load tests showed that HIV was never a dormant infection. It is a gradually progressive viral infection that is always active.

2

There are three main types of viral load tests: i) PCR - polymerase chain reaction (written as PCR RNA) ii) bDNA - branched DNA iii) NASBA These tests multiply a small sample of virus many times so that it can be more easily counted. But this means that the individual results from any one test are not very accurate and can have a 3-fold margin of error. So, if your viral load result is 30,000 - the real result could potentially be anywhere between 10,000 and 90,000 copies/mL. As with CD4 test results, it is important to look at the trend of results over several tests to get a picture of whether there is any change. •

Never make any treatment decision based on the result of one test.

Different tests are also sensitive down to different minimum levels.

For example the first tests in 1995 could only measure down to 10,000 copies/mL. By 1996-7 the next tests were able to measure down to 400 or 500 copies/mL. Since 1998 the most routinely used tests now measure down to 50 copies/mL although some tests used for research are even more sensitive (down to 5 copies).

When viral load tests were first developed many doctors thought that it would be impossible to measure the progress of a disease on an individual level.

2.10 Impact of co-infections on viral load Other infections can have an impact on HIV viral load. Sexually transmitted infections like herpes, gonorrhoea and syphilis increase the levels of HIV in sexual fluids (semen and vaginal fluids). Viral infections like the flu can increase your viral load while the infection is active. Responses to some vaccinations may also increase viral load temporarily.

HIV i-Base: basic training for advocates

S2:20

January 2008


www.i-Base.info

Section 2:Virology, HIV and viral load

2.11 Compartments and sanctuary sites Although we measure viral load in blood, which is one compartment, several other important places in the body have barriers that limit both HIV and HIV drugs from moving freely. These are sometimes referred to as compartments or sanctuary sites. They include the genital tract, the CSF - Cerebral Spinal Fluid - the fluid that circulates around the brain and spinal column, and the brain itself. HIV can develop differently in these compartments. Some drugs get into these compartments better than others. Resistance can be different in different compartments - it will usually develop in one compartment but can then travel to other sites.Viral load levels can be different in each compartment. This makes HIV a very complicated illness - although in practice, because blood is used for most tests, you are unlikely to know exactly what is going on in other compartments.

2.12 Importance of viral load on-treatment and off-treatment When not on-treatment: When not taking ARVs, then the CD4 count is more important than viral load. Viral load tests are still useful, but they are not as important at predicting the risk of infections or when you should start treatment. The one exception may be if your viral load is very high. If your viral load is over 100,000 or perhaps over 500,000, this would be seen as a reason to start treatment at a higher CD4 count than 200. When on-treatment: If you are using HIV treatment, then viral load tests are probably more important than a CD4 test. This is because on treatment, your CD4 count is probably already increasing. Your viral load when on-treatment is a good measure of how long you can expect treatment to last. Sometimes viral load tests are used to check adherence. If your viral load goes to below 50 copies/mL then treatment can last for many years. When viral load is this low, resistance usually only develops if you are late or miss taking your medication. If it is reduced, but only gets down to for example 500 copies/mL, then there is enough HIV reproducing each day for resistance to develop to the drugs in your combination. If you do not have access to a viral load test, then your doctor will manage you based either on CD4 tests or on clinical symptoms. Viral load is higher in children than in adults when not using ARV treatment, but it is just as important for children on treatment to reduce their viral load to less than 50 copies/mL. It is not clear how often you need to have your viral load tested. UK and US guidelines recommend a viral load test every 3-6 months when not on treatment, and every 3 months when on treatment. They also recommend a viral load test one month after starting treatment or after making any treatment change.

HIV i-Base: basic training for advocates

S2:21

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.13 Viral lifecycle, drug resistance and adherence Everyone who is HIV-positive and not on-treatment produces several billion new viral copies of HIV every day. In making this vast number of copies of itself, the virus also makes lots of very small mistakes. These are called mutations. When you are not taking treatment there is no reason for any particular mutation to be produced because they are usually not as strong as the original wild-type HIV. However, when you are on treatment, some mutations that develop will not be affected by drugs you are taking. These resistant mutations will continue to reproduce and eventually become the major type of your HIV.You then become more resistant to these drugs, as well as to other similar drugs. This is called cross-resistance. The higher your viral load when you are on treatment, the more likely that you are developing resistance. This is why it is so important to get your viral load as low as possible, as quickly as possible, and ideally below 50 copies/mL. Resistance and adherence are closely related. If you miss, or are late, taking one or all of your drugs, you increase the chance of developing resistance. This is because drug levels fall below a minimum safe level during this period. Drug interactions can also affect the levels of ARV drugs. ARVs can interact with other HIV and OI medications (especially with treatment for TB). They can also interact with some recreational drugs, and complementary and herbal drugs. Always tell your doctor and pharmacist about any other medications or treatments that you are taking. In order to make sure that you get the correct level of each drug, it is important to follow any special instructions relating to whether treatment needs to be taken with food or on an empty stomach. The mutations that occur when you only have low concentrations of your drugs can stop the drugs working. Adherence is therefore critical. Resistance and adherence are discussed in detail in Section 3.

HIV i-Base: basic training for advocates

S2:22

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.14 How CD4 and viral load are related Although they measure completely different things, the pattern of viral load and CD4 results are usually related: â&#x20AC;˘

Generally when viral load is low, CD4 counts will be high.

â&#x20AC;˘

In a similar way, when CD4 counts are low, viral load will be high.

A few weeks after infection when HIV levels go up to very high levels, CD4 counts drop. Then as the immune system brings viral load levels down, CD4 counts go back up again. There is sometimes a lag period between viral load and CD4 changes: i)

after starting treatment viral load drops very quickly, but CD4 counts sometimes take several months before they start to increase

ii) if treatment fails and viral load levels start to rebound, CD4 count may still continue to rise for a while, although as viral load gets higher CD4 count then usually starts to fall. You can now see how the CD4 count and viral load curves fit together. Firstly without treatment:

And then when on treatment:

HIV i-Base: basic training for advocates

S2:23

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.14 Glossary for Section 2

ARV

antiretroviral - a drug used to treat a retrovirus (i.e. anti-HIV drug)

bacteria

single-cell micro-organisms without a nucleus

lymph system

vessel, nodes, organs and clear fluid, that are part of the immune system

natural history

the pattern a disease takes if it is not treated

nucleus

the central part of some cells that contains DNA

parasite

an animal or plant that get nutrients and support from another species

protozoa

single-cell creatures with a nucleus, with similar characteristics to animals

resistance

when the genetic structure of an organism changes in ways that stops a drug from working

seroconversion

the period when the body generates an immune response to HIV (usually 2-3 weeks after infection, occasionally much longer)

viral load test

test that look at the amount of virus. This is usually in a small sample of blood, but viral load test can also be used to check viral levels in other compartments like genital fluid, semen or spinal fluid

virus infectious organism that can only reproduce inside the cell of another plant or animal

HIV i-Base: basic training for advocates

S2:24

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.15 Questions: Section 2 1.

What is HIV, what does HIV stand for?

2.

What percentage of HIV virus is circulating in the blood?

3.

Where is the rest?

4.

Why are blood tests used for CD4 and viral load?

5.

What are â&#x20AC;&#x2DC;sanctuary sitesâ&#x20AC;&#x2122; ?

6.

How can viral load behave differently in these sites?

7.

List four main causes of infections and illness

8.

Explain the viral dynamics of early and chronic infection, with approximate ranges for viral load levels and times (ie 2 weeks, 2 month, 2 years after infection) and after treatment (after 1 week, 1 month, 6 months).

9.

Draw a simple graph for the answer to question 8.

10.

Give a brief history of viral load technology and levels of sensitivity.

11.

Name three types of viral load tests

12.

What is the margin of error for viral load tests?

13.

What is the importance of viral load results for someone who is taking HIV treatment?

14.

What is the importance of viral load results for a patient who is not yet taking HIV treatment?

15.

Explain in simple language how HIV can become resistance to treatment.

HIV i-Base: basic training for advocates

S2:25

January 2008

2


www.i-Base.info

Section 2:Virology, HIV and viral load

2.16 Course evaluation for Section 2 Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation.

2

Section 2: How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

HIV i-Base: basic training for advocates

S2:26

January 2008


www.i-Base.info

Section 3: Introduction to ARVs

Section 3: Introduction to ARVs

2

3.1 Introduction to Section 3 The third section is a basic introduction to treatment of HIV infection. It includes information about the medical approach to treatment as well as how to approach this as an HIV-positive person. Combination therapy with ARVs is more complicated than many other medical conditions, and every person starting treatment needs to understand something about this if they are to have the best chance of long term benefit.

3.2

Aims for Section 3

After completing this section you should have a basic understanding of: •

How ARV drugs work

Treatment guidelines - using 3 or more drugs and getting viral load undetectable

Main drugs that are used and generic combinations

Treatment choice and side effects

Adherence and drug levels: including practical aspects (late with dose, missed dose, being sick, tips to remember, importance of good habits, etc)

Resistance and failing treatment

HIV i-Base: basic training for advocates

S3:27

January 2008


www.i-Base.info

Section 3: Introduction to ARVs

3.3 What is combination therapy? Combination therapy is the term for using three or more ARV drugs to treat HIV. ARV stands for Antiretroviral. This is because HIV is a retrovirus. It is also called triple therapy, ‘potent’ or ‘effective’ therapy, or HAART (Highly Active AntiRetroviral Therapy). The treatment only works because there are three different drugs all fighting the virus. If you miss doses or are late taking them, then they may not work at all, or will only work for a few months. HIV is a difficult disease to treat.

3.4 Do the drugs really work? Yes! In every country that uses ARVs, AIDS-related deaths and illnesses drop dramatically. Treatment works for women, men and children. It works no matter how you were infected with HIV. Whether this was sexually, through IV drug use, or by blood transfusion. Taking HIV drugs, exactly as prescribed, will reduce the virus in your body to tiny amounts. This then lets your immune system recover and get stronger by itself. Now that there are treatments for HIV, this is an important reason to know whether you are HIV-positive. Generic drugs work as well as brand-name drugs and sometimes they are available in formulations that are easier to take.

HIV i-Base: basic training for advocates

S3:28

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.5 How HIV drugs work - main types of drugs Like everything that is living, HIV has to be able to reproduce itself. It does this inside CD4 cells. This involves many different stages, and HIV drugs work by interfering with some of these stages. There are four main parts of the HIV life-cycle where different HIV drugs work. The four families of drugs are: •

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) - ‘nucleosides’ or ‘nukes’

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Protease Inhibitors (PIs)

Entry Inhibitors (EIs)

3

Fig 1: HIV drugs work in different ways HIV virus

entry inhibitors work by stopping HIV getting into the CD4 cell

CD4 cell nukes & non-nukes (NNRTIs)

protease inhibitors

work by stopping any new HIV virus from leaving the CD4 cell

both work by stopping one of the main ways that HIV reproduces inside the CD4 cell

HIV uses CD4 cells as factories to make hundreds of copies of itself. Different drugs work at different stages of the HIV life cycle.

3.6 Treatment guidelines Many countries already have guidelines for how treatment should be used. They include guidelines for treatment of adults, but also separate documents for treating children for treatment during pregnancy, for TB or hepatitis co-infection, for adherence, and for treating opportunistic infections. Guidelines are only useful though if they are up-to-date - so always look at the date first. Many guidelines are also available online. They are generally written for doctors in a more technical language. They present a consensus opinion, for example, on when to start treatment, which drugs to use, how to manage side effects, etc and are updated regularly. WHO guidelines:

http://www.who.int/3by5/publications/documents/arv_guidelines/en/

US guidelines (for prevention, treatment, OIs, children and pregnancy):

http://www.hivatis.org/

UK guidelines are updated every two years.

http://www.bhiva.org

HIV i-Base: basic training for advocates

S3:29

January 2008


www.i-Base.info

Section 3: Introduction to ARVs

3.7 When to start treatment There are several areas to consider before starting treatment. i)

Firstly - someone has to be ready to start treatment.

This involves:

• understanding that treatment will help your health

• understanding that 100% adherence means taking every dose

• understanding that 100% adherence means following any food recommendations

• understanding that side effects will usually be mild and can be managed

All these ‘non-medical’ aspects are very important. Someone has to want to actively be committed to treatment before they start. Otherwise adherence will not be good, resistance will develop and treatment will fail. ii)

Secondly, anyone with any HIV-related symptoms is usually recommended to start treatment (at any CD4 count).

iii)

Thirdly, people with or without symptoms are recommended to start before their CD4 count falls to below 200 cells/mm3.

See section 1 for more details about CD4 counts and starting treatment.

3.8 Why three or more drugs are used When HIV drugs were first developed, people used each drug by itself, or used them in combinations of two drugs. In both these cases the benefit from treatment only lasted a few months, perhaps a year or two at the most, and resistance to the drugs developed quickly. Three or more drugs are used in HIV combinations, because none of the drugs are powerful enough to use on their own. Some combination therapies include three drugs in a single pill - but it is important to remember that there are three drugs involved.

3.9 Reducing viral load to less than 50 copies/mL Although people start treatment to improve their health, and to stay healthy, one of the main goals of treatment in most guidelines is to reduce viral load to undetectable levels (less than 50 copies/mL). Combinations using 3 or more drugs are able to do this for 50-80% of people starting treatment for the first time - even if resistance tests are not available to test this. If you get viral load this low, and you take all the drugs on time, you are unlikely to develop resistance.You can then use the same drugs for many years.

HIV i-Base: basic training for advocates

S3:30

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.10 Treatment choice There are over 20 HIV drugs, but not all drugs are available in every country. Lists of WHO-approved drugs and all licensed drugs in Europe and the USA are included in Appendices IV and V. Also, although there are many hundreds of possible combinations with these individual drugs, there are a few combinations that are recommended in treatment guidelines. This usually involves either:

2 x RTIs (nukes) plus an NNRTI or

2 x RTIs (nukes) plus a PI (preferably a PI boosted with ritonavir)

3

The WHO recommends four similar NNRTI-based combinations:

3TC + d4T + nevirapine

3TC + d4T + efavirenz

3TC + AZT + nevirapine

3TC + AZT + efavirenz

Fixed Dose Combinations (FDCs) are where these three drugs are combined into one pill. Generic manufacturers produce combination treatments that are not available to all countries. There are different advantages and disadvantage of each combination: •

nevirapine-based combinations are preferred in women who are pregnant.

efavirenz-based combinations are preferred in people who need TB treatment at the same time.

efavirenz-based combinations are used if people are intolerant to, or have side effects with nevirapine.

efavirenz-based combinations should not be used by women who want to become pregnant.

d4T-based combinations are generally recommended because this is a very inexpensive drug - but if you get side effects like neuropathy, the d4T needs to be changed to AZT.

d4T-based combinations are generally recommended in people who develop AZTrelated side effects.

AZT-based combinations are not recommended if you have anaemia.

HIV i-Base: basic training for advocates

S3:31

January 2008


www.i-Base.info

Section 3: Introduction to ARVs

3.11 Side effects Everyone is worried about side effects before they start treatment. In practice though, most people manage to lead a very normal life when taking medications. If side effects occur, they are often easy to manage: • Most side effects are usually mild. • They can often be reduced with other medication that is easy to use. • There is a small risk of more serious side effects, but these should be picked up by routine monitoring from your doctor. More information about these side effects is included below. Many people, however, also put up with side effects when they could change to another treatment and that is not good. If you experience any side effects, then contact your doctor as soon as possible. You have to make sure that your doctor understands exactly how the side effects affect you. More serious side effects can usually be avoided by changing to alternative drugs. Before starting treatment, learn about the side effects that can occur with the drugs you are going to use. Ask your doctor, nurse, or HIV pharmacist about how likely they are to occur. Ask how many people stop treatment because of them (usually very few). Even rough estimates will give you a good idea of what is involved. This way you will know what to look out for. The most common side effects associated with drugs recommended in the WHO first-line combinations are included in detail in Section 4: Side effects with ARVs.

HIV i-Base: basic training for advocates

S3:32

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.12 Can I change treatments? If your first combination is too difficult to follow, or if any initial side effects have not improved after the first few weeks or months then there may be an alternative drug or combination that you can change to. If this is your first combination, you have more choice.You should not put up with difficult side effects for months on end.

3.13 Can I take a break in my treatment? Once you start treatment it is best not to take any break or interruption unless your doctor recommends this. To benefit from HIV treatment you need to take every dose on time. The longer you stay on treatment the longer the benefit should continue. If you get a very good response to treatment and start to feel better, it is still important to continue taking every dose of treatment on time. • Stopping treatment for any short period is not recommended. Levels of HIV in your blood - your viral load - can increase again very quickly (from undetectable to several thousand in as little as a few days). Each interruption of treatment also carries a risk of developing drug resistance. • An interruption may be reasonable if you have a very strong CD4 count or have very difficult side effects. • If you want to take a treatment break, it is essential to talk to your doctor first. Some drugs have to be stopped all together, and others need to be stopped at different times. Nevirapine, efavirenz and 3TC all stay in the blood for longer than d4T or AZT. They are also easy drugs to develop resistance to. Stopping all three drugs at the same can give the virus several weeks to develop resistance.

3.14 Recreational drugs, alcohol and complementary therapy Some HIV drugs interact with recreational drugs, street drugs, methadone and complementary or traditional herbal therapies. The interactions can be complicated. Sometimes the interactions will increase the amount of recreational drugs found in blood to dangerous levels. Some recreational drugs can reduce the levels of ARVs, increasing the risk for resistance. It is therefore very important that your doctor and pharmacist know about any other drugs or supplements that you use. Even if you use them rarely.Your doctor should treat this information in confidence. Alcohol does not interact with HIV medications. However, heavy alcohol use, as with recreational drug use, may reduce adherence. It would help if your healthcare workers know about this.

HIV i-Base: basic training for advocates

S3:33

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.15 Adherence - and why it is so important See the ‘Science Support’ section 3: ‘What happens when you take a drug’ and ‘Science Support’ section 4: ‘Drug levels, drug activity and side effects’.

What is adherence? Adherence is a word to describe taking your drugs exactly as prescribed. This includes taking them at the right time. It also includes following any special diet restrictions. This ensures that you have a constant minimum level of each drug - 24 hours a day, 7 days a week, 365 day a year! Every time that the levels of a drug fall below this minimum level, you are at risk of the virus developing resistance to the drugs in your combination. It is important that you develop a routine. Treatment for HIV involves a complicated daily schedule.You may need some support to get used to the changes it makes in your life. Adherence can be very difficult. This is the most important thing you have to think about when you start taking a new combination. Start treatment when you can give yourself the extra time and space you may need to adjust. During the first few weeks, nothing else should take priority over getting your treatment right. Many treatment centres now have an adherence clinic or an adherence nurse.

How much is enough? Taking medication exactly on time is very important. However, there is usually a window period of about an hour that is still okay. Some drugs, and some people, have a wider window period than others. Because of this variation, it is still better to aim for the same time each day. Diet restrictions are very important. Ignoring these can be like only taking half a dose.You will not absorb enough of the drug for it to work. Resistance is then more likely to occur. The next question is: ‘exactly how close to perfect adherence do you have to get?’ Unfortunately, the answer is ‘almost 100%’... Many studies have shown that even missing one or two doses a week can have a big impact on the chances of a successful treatment. One early study showed that even with 95% adherence only 81% people achieved undetectable viral load. That is only one in every 20 doses that was missed or late. [1]

Adherence rates % of people undetectable over 95% 81% 90-95% 64% 80-90% 50% 70-80% 25% under 70% 6%

Adherence also directly impacts HIV-related mortality. In another study of 950 people starting treatment for the first time, for every 10% decrease in adherence there was a 16% increase in HIV-related death. [2] On the other hand, a US study of people in prison who took every dose showed much better results. [3]

HIV i-Base: basic training for advocates

S3:34

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

Because these patients were in prison, every dose was supervised. All had viral loads below 400 copies/ml after a year and 85% were below 50 copies/ml. This result was more impressive than nearly every clinical trial. Most of these people had already failed previous treatments and so were even less likely to get a good result. The point is not that you need to be in prison. It is that if you find a way to take all your drugs as prescribed, you will get good results. • Be strict with yourself in assessing how adherent you are through a regular week. • If it’s not looking so good, you need more support.You will need to ask. • Talk to your doctor! References: 1. Paterson DL et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 133-21-30 (2000). 2. Hogg RS et al. Non-adherence to triple combination therapy is predictive of AIDS and death in HIV-positive men and women. 7th CROI, 2000. Abstract 73. 3. Fischl M et al. Impact of Directly Observed Therapy (DOT) on outcomes in clinical trials. 7th CROI, 2000. Abstract 71.

3.16 Tips to help adherence... The following tips will be helpful in different situations: • Choice of treatment. Get all the information on what you will need to do before you start treatment: How many tablets? How big are they? How often do you need to take them? How exact do you have to be with timing? Are there food or storage restrictions? Can they be taken with any other current medications Are there easier choices? • Use a daily chart to plan your timetable and use it to get used to the routine. For the first few weeks mark off each dose and the time that you took it. • Make sure that you contact your hospital or clinic if you have difficulties with side effects. They can prescribe additional medication to help. They can also change the treatment if necessary. • Divide up your day’s drugs each morning and use a pillbox. Then you can always check if you think you have missed a dose. • Use a pill beeper or alarm watch. Use it for both morning and evening doses. • Take extra drugs if you go away for a few days. • Keep a small supply where you may need them in an emergency. This can be in a cool place in your car, at work or at a friend’s house. • Get friends to help you remember difficult dose times. Ask them to remind you when you are out at night. • Ask friends who are already on treatment what they do. Ask them how well they are managing. Ask your treatment centres if you can talk to someone who is already taking the same treatment if you think this will help. • Ask your doctor for a supply of medications to control nausea and diarrhoea. These side effects are the most common when starting therapy. • Most combinations are twice-daily regimens. This usually means taking them every 12 hours. However,­ several drugs only need to be taken once a day. This usually means taking them every 24 hours. • Completely missing a once-daily dose may be more serious than forgetting a dose from a twice-daily regimen. Adherence is especially important with once daily regimens. HIV i-Base: basic training for advocates

S3:35

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.17 What if I forget to take my pills? Almost everyone will forget or be late with their drugs at some time. There is a difference though between occasionally missing a dose, and regularly forgetting on a daily or weekly basis.You need to aim to take all your doses at approximately the right time. You may be regularly taking them late or missing doses completely. If this is the case it may be better to talk to your doctor about stopping treatment altogether. This would at least limit your risk of resistance.You can restart treatment later when you are more able to cope with the regimen. There may be an easier combination that you can use. Some people hate lots of pills. Some hate fatty foods or having to eat breakfast. Some people will always have trouble with taking medicine at work during the day. All these things are important in deciding which combination will suit you best. You have to follow your regimen everyday. This includes both during the weekend, and in the different situations involved in life. Taking days off your regimen is a very dangerous way of using treatment. There are always things that can help you to avoid missing doses, whatever your lifestyle. If you realise you have missed a dose; take it as soon as you remember. BUT, if you only realise when youâ&#x20AC;&#x2122;re going to take your next dose, do not take a double dose.

HIV i-Base: basic training for advocates

S3:36

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.18 Resistance to ARVs What is resistance? Resistance to ARVs occurs when the structure of the virus makes tiny changes. These changes are called mutations. This can mean that the drugs no longer work as well or even at all. You can also be infected with a strain of HIV that is already resistant to some or all HIV drugs. How does resistance occur? Mutations that lead to drug resistance are generally only produced when you continue taking a treatment with a detectable viral load. If your viral load is still above 400 copies/ml after 2-3 months, or above 50 copies/ml after 6 months you may need to change your treatment. Your doctor should look closely at why the results are not as good as they could be. They will want to discuss how you are managing adherence and side effects. They should also test for resistance and possibly drug levels. Resistance can develop even at low viral load levels between 50 and 500 copies/ml. Ideally, it is recommended to have a viral load test four weeks after starting or changing treatment. This should then be checked at least every 3 months when on treatment. Get the results when they are ready (usually after two weeks). Donâ&#x20AC;&#x2122;t just wait until your next visit. What is cross-resistance? Some drugs are cross-resistant to others. This means that if you become resistant to one drug you will also be resistant to other similar drugs, even if you have never taken them before. This is particularly true of drugs in the same class. There are also varying degrees of cross-resistance. Sometimes you may still get some benefit from the second drug but the response is less likely to be as strong or as durable. What are resistance tests Resistance tests can show if you have these resistance mutations. These tests are not available in every country. Because some drugs are very vulnerable to resistance - such as nevirapine, efavirenz and 3TC. If you have a detectable viral load on these treatments, or your viral load rebounds to levels above 2000 copies/mL, you would assume that you have resistance to one or more ARV drugs in your combination. How do I avoid resistance? Avoiding resistance is one of the most important conditions for using combination therapy. You need to use a combination that is potent enough to minimise the risk of getting resistance to any of the drugs you take. The best chance you have of stopping resistance involves reaching and maintaining undetectable on viral load tests that measure down to 50 copies/ml. HIV i-Base: basic training for advocates

S3:37

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.19 Treatment failure Treatment failure is defined in different ways, and sometimes this relates to the different treatments that are available in a country. Virological failure If viral load levels never reach undetectable, or rebound and become detectable, this is called ‘virological failure’. The drugs are not working to suppress the virus. With virological failure, you will not necessarily feel more ill in the short term. Clinical failure Clinical failure is when you get symptoms - ie other illnesses mean that the drugs are not preventing you from getting ill. How to manage treatment failure depends on the choice of alternative drugs that are available in any country. Virological failure usually occurs first - and it can sometimes take months or even years for this to lead to clinical failure. This is why management of treatment failure depends on which treatments are available. •

For people who have several good options for a new regimen, virological failure is used to decide when to change treatment.

For people who have limited options for a new regimen, clinical failure is used to decide when to change treatment.

Low level increases in viral load (up to 2000) often are just ‘blips’ and often go down by themselves. Before making any decision to change treatment it is important to identify why the treatment failed. It may be for a simple reason that the person has stopped taking treatment altogether, or that they have not been taking treatment on time, or in the way prescribed. It may be because of resistance or because the treatment was not potent enough, or because the drugs were being poorly absorbed. When there are new treatment options, then changing all 3 drugs to a new regimen is recommended when it is confirmed that the viral load has rebounded and it is not a ‘blip’. Management of treatment failure is a specialised area, and approaches changes based on new research.

HIV i-Base: basic training for advocates

S3:38

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.20 Glossary: Section 3 adherence

the term to describe taking medication exactly as it is prescribed - both at the right time and following any special diet recommendations

DNA

genetic material inside every living cell that contains the information and code for how that cell grows, functions and reproduces

EI

entry inhibitor - family of drugs that target HIV before it enters a cell

HAART

Highly Active Anti-Retroviral Therapy - a term for HIV combination therapy using at least three drugs

lactic acidosis

life threatening side-effect, mainly associated with d4T when it is used in combination with ddI (didanosine)

lipoatrophy

side effect that reduces subcutaneous fat on the arms, legs or face

lipodystrophy

name for a set of side effects relating to the way your body processes fats and sugars. Symptoms include lipoatrophy, fat accumulation and increased blood cholesterol and triglycerides

NRTI

Nucleoside Reverse Transcriptase Inhibitor - family of anti-HIV drugs that work when HIV is in the cell, but before it is integrated into the cells DNA

NNRTI

Non-Nucleoside Reverse Transcriptase Inhibitor - family of anti-HIV drugs, similar to NRTIs, that work when HIV is in the cell, but before it is integrated into the cells DNA

PI

Protease inhibitor - family of anti-HIV drugs that stop new viral material being cut into smaller sections. This prevents new assembled HIV from leaving the cell.

peripheral neuropathy

this is a term for damage to the nerves in your hands and/or feet. Symptoms start gradually in your fingers and toes as tingling or numbness, or increased sensitivity. If allowed to continue it can become very painful and debilitating.It can be caused by HIV, and is also a common side effect of some ARVs.

HIV i-Base: basic training for advocates

S3:39

January 2008

3


www.i-Base.info

Section 3: Introduction to ARVs

3.21 Questions: Section 3 1.

What does ARV stand for?

2.

How many drugs are usually used in ARV combination therapy?

3.

Name four families of drugs

4.

Which drug family is active before HIV enters a CD4 cell?

5.

How many drugs are approved in the US to treat HIV?

6.

How many combinations are recommended as first-line treatment by the WHO?

7.

Name the individual drugs used in the WHO combinations

8.

Give at least three reasons to delay starting treatment

9.

What can affect the levels of ARVs in the blood?

10.

What is adherence?

11.

Give six examples of things that could help with adherence.

12.

What is drug resistance?

13.

What is clinical failure?

14.

What is virological failure?

15.

How low does viral load need to go to prevent resistance developing?

16.

Write 500 words about adherence?

HIV i-Base: basic training for advocates

S3:40

3

January 2008


www.i-Base.info

Section 3: Introduction to ARVs

3.22 Course evaluation for Section 3 Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation.

Section 3: How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

HIV i-Base: basic training for advocates

S3:41

January 2008

3


www.i-Base.info

Section 4: Side effects of ARVs

Section 4: Side effects of ARVs

Regular blood tests will check for some side effects. If you have any difficulties make sure your doctor takes these seriously... Nausea and fatigue can be very serious... 4.1 Introduction to Section 4 This is a very important section of the training resource. Treatment for most people can become an easy routine part of life so long as any side effects are managed effectively. This can involve treatment for the side effect, dose adjustments or changing to alternative HIV drugs. To get to this stage, you need to take your quality of life seriously, and may need to become active in your own care. A minority of side effects can be extremely serious, and it is important to be able to know which of these are associated with different drugs.

4.2 Aims for Section 4 This section will provide an overview of the following areas: •

overview of risk of side effects

difference between major and minor side effects

how to reduce side effects, including switching treatment

main side effects linked to WHO combinations

HIV i-Base: basic training for advocates

S4:42

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.3 General questions What are side effects? Drugs are generally tested on, and licensed, to help with specific illnesses. When they affect the body in other ways, these are called side effects. They are also called adverse events (a/eâ&#x20AC;&#x2122;s) or drug toxicity. In this booklet we will focus on unwanted side effects of HIV treatments. It is important to realise that many of the symptoms of side effects are similar to symptoms of illnesses. Different treatment are needed when related to illnesses. Why do side effects occur? Although drugs are designed to work against specific illnesses, they sometimes interfere with other ways that your body works. It is difficult enough to develop a drug that works against HIV, and any drug that reaches the market has undergone a lot of research trying to minimise toxicity. Often, very promising drugs have their development stopped because of toxicity. The aim is always to develop safer and more tolerable, as well as better drugs. Most people â&#x20AC;&#x201C; people living with HIV, doctors and researchers â&#x20AC;&#x201C; recognise that the current drugs available to treat HIV are far from perfect and hopefully new drugs in the future will be easier to tolerate. Do all drugs have side effects? Most drugs have side effects of some sorts, although in the majority of cases they are mild and easily manageable. Sometimes side effects are so mild that they are rarely noticed. Sometimes they only affect a small proportion of people that use the drug. Sometimes side effects only become apparent after the drugs have been licensed and approved, when many more people use them over a much longer period than the original studies. All drugs have side effects, but not all people taking drugs will experience the same effects and to the same extent. The leaflet included in the packaging with your drugs (called the Summary of Product Characteristics, SPC) lists all the reported range of possible side effects associated with each drug. This booklet also includes other useful information including how the drug needs to be taken, possible interactions with other medications, etc. How are side effects for drugs reported? When drugs are first studied, every side effect that occurs is recorded, even if it only affects a few people, and even if it cannot be directly linked to the drug being studied. This means that if you look at the SPC leaflet you usually find a long list of potential side effects. Side effects that are serious or occur most frequently are also usually discussed in more detail. If side effects only become apparent after the drug has been approved, as with lipodystrophy, the SPC may not have this information and the leaflet will usually be changed later to reflect this.

HIV i-Base: basic training for advocates

S4:43

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

Starting treatment for the first time Risk of side effects can be a big worry if you are about to start HIV treatment for the first time. It will help if you know what to expect from different drugs before choosing your combination. Ask for information about each of the drugs you might take, including the likelihood of side effects occurring. For example, what percentage of people had side effects related to those drugs and how serious they were? You may be asked to consider entering a study looking at side effects in different combinations and these studies are important to define the extent of side effects in different combinations. Can I change drugs easily? If starting treatment for the first time, you will usually have a lot of flexibility in choosing and changing drugs until you find a combination that works and is tolerable. There are already 20 approved ARV drugs, and while you can’t quite mix and match them all, you have a lot of choice. If one or more of the drugs in your combination are difficult to tolerate, you can change it for another. Often people are not given a choice when starting treatment. However, the fewer drugs you have used previously, the more choice you have to change. If you change a drug because of tolerability, you can usually go back and use it later if you need to. Just because you used a drug once, doesn’t mean you have ‘used up your option’ of using it again in the future. The only drug you can not do this with is abacavir. If you have a hypersensitivity reaction to abacavir you must never take it again. Sometimes side effects improve after the first few weeks or months, but sometimes they don’t. Read the sections on individual side effects for more recommendations for how long you should put up with them before changing. You do not have to continue with a drug to prove anything to yourself or to please your doctor. If you know something is wrong, ask your doctor to change it to something else. Some drugs are just not for everyone. Can I predict the side effects I may get? Generally you cannot predict how difficult or easy you will find it to take any particular drug beforehand. Sometimes, if you already have similar symptoms related to the side effects, these may make the risk of side effects greater. For example, if results of routine liver tests show that you have raised liver enzymes, this may increase higher still if you use nevirapine. If you have high cholesterol or triglycerides before treatment, these are more likely to increase if you use protease inhibitors. Are side effects different in men and women? Many trials in the past enrolled far too few women to be able to study differences adequately. Sometimes differences in side effects between men and women are reported later. Women have shown higher rates of side effects in some nevirapine studies (both liver toxicity and rash), which highlights the importance of careful monitoring. With lipodystrophy (fat loss in your arms, legs or face; or fat gain in abdomen, breasts, and shoulders), women are more likely to report symptoms of fat accumulation rather than fat loss. HIV i-Base: basic training for advocates

S4:44

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

What about side effects and adherence? Whether you are starting your first treatment or have been using HIV drugs for a long time, your doctor should have talked to you about the importance of adherence. This is the term that describes taking the meds in your combination exactly as they are prescribed - ie on time and following any diet advice. There is special section about adherence and side effects in Section 3. Getting your doctor to do something… Unfortunately it is true that: • some doctors generally think that their patients overestimate side effects. Doctors generally think that their patients exaggerate side effects, and that they are not really as bad as their patients say. It is also true that: • most patients actually underestimate side effects. Patients generally say that side effects are less inconvenient or less difficult than they really are, or often forget to mention them at all. This means there can be a big difference between what is actually going on and what doctors think is going on – and this is why side effects are often under treated. What happens if side effects persist? If the first treatment you are given to help with a side effect does not work, there are usually others that you can use that may be more tolerable. This is why we have listed a range of options, including alternative treatments, for each of the main symptoms. If one doesn’t work – try the other options. Changing or stopping treatment are important options that you can discuss with your doctor.

4.4 General side effects Nausea (feeling sick), diarrhoea and tiredness are the most common general side effects. These often become easier after the first few weeks.Very rarely, nausea and tiredness can be very serious. This is why you should tell your doctor of any problems. Ask your doctor or pharmacist for anti-nausea and diarrhoea medications when you first start therapy so you can use these if you need them. If these medications aren’t effective, ask your clinic for stronger or more effective drugs. If this still doesn’t help you may be able to change to a different treatment.

HIV i-Base: basic training for advocates

S4:45

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.5 Side effects associated with WHO combinations The following pages deal in more detail with more serious side effects that are particularly associated with drugs recommended as first-line treatment in WHO guidelines. These are summarised in the table below, and more detail is provided in the text afterwards.

Table 1: Serious side effects from WHO recommended firstline combinations Symptoms in bold are urgent to describe to your doctor. Drug Name

Side Effect

Symptoms

d4T

Peripheral neuropathy (PN)

Loss of feeling (numbness) OR pain in fingers and/or toes

Lactic acidosis

Feeling sick, vomiting, no appetite, extreme tiredness

Lipoatrophy

Loss of fat in face, arms, legs or buttocks. Veins become more prominent.

3TC

Hair loss (rare)

Hair thinning or falling out

(lamivudine)

PN (rare)

Loss of feeling (numbness) OR pain in fingers and/or toes

AZT

Anaemia

Feeling tired or weak

(zidovudine)

Lipoatrophy

Loss of fat in face, arms, legs or buttocks. Veins become more prominent.

nevirapine

Liver toxicity

Feeling sick, vomiting, poor apetite, yellow eyes or skin, light coloured stool or dark coloured urine, tenderness or swelling in your liver Redness or small rash on skin

(stavudine)

Rash

efavirenz

Severe rash

Any rash over more than 10% of body, any broken skin

CNS side effects

Mood changes, feeling disorientated or anxious, vivid or disturbing dreams, change in sleep pattern. If severe then urgent to see doctor.

Liver toxicity

Feeling sick, vomiting, poor apetite, yellow eyes or skin, light coloured stool or dark coloured urine, tenderness or swelling in your liver

Rash

Redness or small rash on skin

Severe rash

Rash over more than 10% of body, any broken skin

HIV i-Base: basic training for advocates

S4:46

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

• Liver toxicity: nevirapine, efavirenz Although liver toxicity with nevirapine (or efavirenz) is not very common it can be very serious and life-threatening if it does occur. Less than 5% people have to change treatment for this reason, but because nevirapine is included in Fixed Dose Combinations (FDCs) it is very important to know about these symptoms. If you have a rash with nevirapine, it is important that you have a blood test to check whether your liver is being affected. These tests are usually for levels of liver enzymes called ALT or AST. If this is not available, other symptoms include: • Feeling sick (nausea) or being sick (vomiting) • Poor appetite • If your eyes or skin looks more yellow • Light coloured stool or dark coloured urine • Tenderness or swelling in your liver - your liver is just below your stomach If you have any of these symptoms, you should contact your doctor straight away. Liver toxicity usually occurs in the first 6 weeks of treatment, but can also occur later. If you are co-infected with hepatitis then the risk of liver toxicity is much higher, and another choice of drug would be more appropriate. • Rash: nevirapine, efavirenz About 10-15% people who use nevirapine or efavirenz get a low level rash that is not serious, and about 5% people discontinue the drug because of this. However, 2-3% people can be at risk of a much more serious rash, especially using nevirapine. Nevirapine should be given at a reduced dose of 200mg once-daily for the first two weeks that it is used. If there in no rash at the end of these two weeks then the dose increases to 200mg every 12 hours. The nevirapine dose should NEVER be increased if you still have a rash. If the rash covers more than 10% of your body or breaks the skin at all, you must see your doctor immediately. In these rare cases, nevirapine has to be stopped very quickly to reduce the risk of a severe reaction that can be fatal. The staggered dose is just as important with Fixed Dose Combinations, but sometimes in practice it is ignored. This is something you should check and ask your doctor about.

HIV i-Base: basic training for advocates

S4:47

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

â&#x20AC;˘ Peripheral neuropathy: d4T, rarely 3TC Peripheral neuropathy is the term for damage to the nerves in your hands or feet. Sometimes this starts as a tingling or numbness, but if it is allowed to develop it can become very painful and permanent and move up your limbs. Although it is sometimes caused by HIV, it can also be a side effect from some HIV drugs. It is also more likely if you start treatment with a very low CD4 count. The main drugs linked to neuropathy are ddC (which is rarely used), d4T, ddI and to a lesser extent, 3TC. d4T is one of the drugs in Triomune, and d4T is currently recommended in first-line therapy in many countries. This means that you have to be very aware of any tingling or pain in your hands or feet and report this to your doctor. Because there is no cure for neuropathy, the best choice is to stop using d4T and change it to another drug. Many people are also able to reduce the dose of just the d4T part of your combination. Triomune for example comes with a dose of either 30mg or 40mg of d4T. If you can get each drug prescribed separately, then you may be able to reduce to dose even further to 20mg twice a day. Reducing the dose of d4T can be enough to stop further nerve damage. If neuropathy continues and there are no other treatment choices, then it may be better to stop your treatment for a period.You could only do this if you are doing well now and your lowest ever CD4 count never dropped much below 200 cells/mm3.You could restart treatment later if you need it again or when an alternative ARV becomes available.. Neuropathy can reverse by itself when you stop the drug that is causing it, but only if you stop the drug before serious damage has been caused.You and your doctor should manage this important side effect very carefully.

HIV i-Base: basic training for advocates

S4:48

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

â&#x20AC;˘ Lipodystrophy: d4T, AZT, nevirapine, efavirenz, protease inhibitors Lipodystrophy refers to changes in fat cells and the distribution of body fat. This can result in losing fat from your arms, legs and face or gaining fat in your abdomen, breasts or shoulders. It also includes changes in blood fat and blood sugar levels. Different drugs may be responsible for fat gain than those responsible for fat loss. Fat accumulation, to the stomach or breasts and/or across the shoulders, has been more linked to protease inhibitors and NNRTIs. Fat loss, from arms, legs, face and buttocks, has been linked mainly to d4T, and to a lesser extent to AZT. d4T and AZT are both drugs that are included in recommended first line therapy in the WHO guidelines. We do not know what causes lipodystrophy. Symptoms can occur rarely in HIV-positive people who are not on treatment. Lipodystrophy usually, but not always, develops slowly over many months or years. Early symptoms may reverse if you switch to different HIV drugs. Exercise and dietary changes can also help. Careful body measurements by a dietician, by DEXA scan, or photographs can monitor changes. Regular blood tests will check for other side effects. If you have any difficulties, make sure your doctor takes them seriously and does something about it.

HIV i-Base: basic training for advocates

S4:49

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

• Mood changes, paranoia, strange dreams, nervousness: efavirenz Efavirenz is linked to one set of side effects that are different to all the other drugs. This is because it can affect your mood and feelings.You may feel disorientated or anxious when you start taking efavirenz and you may have vivid or disturbing dreams. This is a side effect of this drug. Most people get some changes when they first start to take efavirenz, but this also reduces after the first few weeks, and is much easier to manage. However, some people get very serious problems and should contact their doctor to switch to another drug. Efavirenz can make your worries or depression worse and you need to be aware of this if you start a combination that includes this drug. • Anaemia: AZT Anaemia is a shortage of oxygen-carrying red blood cells whose symptoms are extreme tiredness, and it is caused by AZTs effect on bone marrow. Lower doses of AZT may be just as effective against HIV, but this is not possible in the currently available Fixed Dose Combinations. If you are using AZT and become extremely tired or weak, you need to see your doctor who should perform a blood test or change this treatment. • Lactic acidosis: d4T, ddI, AZT Lactic acidosis is a term for a dangerous build up of lactate in the blood. The symptoms include feeling sick and/or very tired and muscle weakness. The risk of lactic acidosis is much higher when d4T is used with ddI - and these two drugs are not recommended to be used together in most guidelines. If you have these symptoms, it is essential to contact your doctor.

4.6 Other side effects This booklet has focused on the more serious side effects that also occur more rarely. However anything that makes you feel unwell - even if they are not classed as serious is something you should tell your doctor about. If you are using drugs that are not included in the WHO first line recommended combinations then use the internet to find out information about the drugs you will be using. Sites with good information (in English) on other drugs include: Basic easily explained factsheets on every drug

www.aidsinfonet.org

More detailed factsheets:

www.tpan.com/publications/drug_guide/drug_guide_2004.html

Website of the European regulatory agency. This site is very difficult to navigate but it includes the full prescribing information for every EU-approved drugs in different European languages.

www.emea.eu.int

HIV i-Base: basic training for advocates

S4:50

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.7 How to report side effects If you want your doctor to be able to understand your side effects and how they are affecting you, you will need to be able to describe them very clearly. This will be important for your doctor to check for other causes (ie that diarrhoea is not related to food poisoning or low sex drive to low testosterone levels). The best way to do this is to keep a side effects diary from when you start a new treatment until you next see your doctor. Information about how to describe symptoms is given in detail in the following sections. It generally includes information about the following areas: Frequency: • How often do you get symptoms? • Once or twice a week? Once every day, or 5 – 10 times a day etc? • Do they occur at night as well as during the day? Duration: • How long do the symptoms last? • If you feel sick or get headaches, do they last for 20 minutes or for 3 – 4 hours, or for different times? • Is there a pattern to when they occur – ie when you take your medications or at a regular time afterwards? Severity: • How bad are the symptoms? • Often it helps to rate them on a scale (from 1 for very minor to 10 for very severe). • A scale is a useful tool for describing anything that involves pain. • Recording how severe side effects are when they occur is better than recording them later. • Have you noticed anything that helps to reduce or stop them. Quality of life: This can really help your doctor understand how difficult the side effects are for you. Many people put up with chronic diarrhoea without explaining to their doctor that it stops them ever going to the pub or the cinema. If you are feeling more anxious or nervous, are not sleeping properly, have a lower sex drive, have experienced taste changes, or are too nauseous to eat proper meals, it is important that your doctor understands this. Symptoms of lipodystrophy are difficult to evaluate. Although minor changes may not be a problem, some people find that more severe symptoms can change their whole outlook on life, and become a cause for underlying depression. If side effects are affecting adherence (ie you are not taking all your meds at the correct time) and how you take your treatment, you must tell your doctor about this. A side effects diary is included in Section 4.9. Use this for any changes that you notice after you start treatment. Take this diary with you when you see your doctor at your next appointment.

HIV i-Base: basic training for advocates

S4:51

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.8 How side effects are graded Most information about the risk of side effects comes from the original studies when the drugs were first being developed. This is why it is very important to report to your doctor all side effects if you take part in any trials. These studies collect information about frequency and severity of all side effects – although studies for new HIV drugs generally only use small groups of people for relatively short periods of time. Some side effects only become apparent after the drugs have been approved and have been used by thousands more people over a longer period of time. Knowing what the risk of side effects are for a particular drug ­– ie what percentage of people get these side effects – can help you to make an informed decision about which drugs to choose. Where a side effect is very common, knowing what percentage of people who needed to change therapy because of it, is useful too. More accurate information may be provided by your doctor, or from a community treatment organisation. It is usually also included in the information that you should get with all HIV drugs. Although there are slightly different details for reporting the severity of each side effect, they are graded from 1 to 4. Grade 1 is very mild and grade 4 is very serious ­– life threatening or requiring hospitalisation. GRADE 1 (Mild): Transient (goes away after a short time) or mild discomfort; no limitation in activity; no medical intervention/therapy required. GRADE 2 (Moderate): Your daily activity is affected mild to moderately – some assistance may be needed; no or minimal medical intervention/therapy required. GRADE 3 (Severe): Your daily activity is markedly reduced – some assistance usually required; medical

intervention/therapy required, hospitalisation or hospice care possible. GRADE 4 (Potentially life threatening): Extreme limitation to daily activity, significant assistance required; significant medical intervention/therapy, hospitalisation or hospice care very likely.

4

A general indication of grading (based on US NIH Division of AIDS) is shown below together with specific details for some of the most common side effects. Side effect

Grade 1

Grade 2

Grade 3

Grade 4

Diarrhoea 3–4 loose stools a day 5–7 loose stool a day OR mild diarrhoea lasting OR diarrhoea lasting less than one week more than one week

Bloody diarrhoea OR Hospitalisation over 7 loose stools a day required (possible OR needing IV treatment OR also for Grade 3) feeling dizzy when standing

Fatigue Liver toxicity: AST or ALT levels

Normal activity reduced Normal activity by less than 25% reduced by 25–50 %

Normal activity reduced by over 50 %; cannot work

Unable to care for yourself

1.25–2.5 Upper Limit Normal >2.5–5.0 ULN

5.0–7.5 ULN

> 7.5 ULN

Mood disturbance Mild anxiety, able to continue daily tasks

Moderate anxiety/dist- Severe mood changes Acute psychosis, urbance, interfering with requiring medical treatment suicidal thoughts ability to work, etc Unable to work

Nausea Mild OR transient reasonable food intake

Moderate discomfort Severe discomfort OR OR intake decreased for minimal food intake for less than 3 days more than 3 days

Hospitalisation required

Rash Redness or itchy skin on part or whole body

Rash that breaks skin, hard or soft pimples OR light peeling/scaling

Blistering, open ulcers, wet peeling, serious rash over large areas

Severe rash, Stevens Johnson syndrome. Severe broken skin, etc

Severe vomiting of all food and fluids over 24 hours OR needing IV treatment OR feeling dizzy when standing

Hospitalisation for IV treatment (possibly also for Grade 3)

Vomiting 2–3 episodes a day 4–5 episodes a day OR mild vomiting for OR mild vomiting for less than one week more than one week

HIV i-Base: basic training for advocates

S4:52

January 2008


www.i-Base.info

Section 4: Side effects of ARVs

4.9 Side Effects Diary Use this page to record any changes in your health that could be related to side effects. You may not get any side effects but if you do, then this diary will be useful. The most common side effects are listed below but include others even if they are not listed here. 1 2 3 4 5 6 7 8 9

Tingling or pain in hands/feet Pain in hands/feet Nausea/vomiting Headache Feeling tired Dry skin Rash Diarrhoea Stomach pains

Side effect symptom

10 11 12 13 14 15 16 17

Day

Hair loss Body shape changes Weight gain Weight loss Changes in taste or appetite Sexual problems Sleep disturbance Vivid dreaming

Time(s)

18 19 20 21 22

Feeling anxious/nervous Changes to your eyesight Mood swings Feeling depressed Other(s) specify

Scale: 1= very mild 5 = very bad

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

Other comments and questions to ask your doctor:

HIV i-Base: basic training for advocates

S4:53

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.10 Glossary: Section 4 anaemia

low or reduced red blood cells - this reduces the amount of oxygen distributed to the body

ALT

alanine transaminase - a liver enzyme which, if raised, can be an indication of liver disease or liver toxicity

AST

aspartate transaminase - a liver enzyme which, if raised, can be an indication of liver disease or liver toxicity

CNS

Central Nervous System. Consists of the brain and the spinal cord - the parts of the body that process and conduct sensory information

DEXA scan

Dual Energy X-ray Absorptiometry, is a type of X-ray that can measures the proportion of fat, muscle and bone in a body and can also measure bone mineral density

liver toxicity

side effects that damage the liver or reduce liver function

side effects

secondary effect of a drug other than the reason it is prescibed. Side effects are usually related to negative effects. Some side effects can be positive and lead to new uses for that drug

SPC

Summary of Product Characteristics - the leaflet included in the packaging with your drugs

Stevens Johnson syndrome (SJS) Severe life-threatening skin reaction toxicity

harmful effects of a substance

ULN

Upper Limit of Normal

HIV i-Base: basic training for advocates

S4:54

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.11 Questions: Section 4 1.

What are side effects?

2.

Are side effects different in men and women?

3.

Should you stop your treatment, or change it because of side effects? Give examples of each situation.

4.

Which are the mildest and the most serious grades for side effects?

5.

What is the difference between lipodystrophy and lipoatrophy?

6.

What is peripheral neuropathy?

7.

Which drug/drugs are most commonly associated with peripheral neuropathy?

8.

Which is the medication from the ARVs that is most common associated with anaemia?

9.

Which drug/drugs are most commonly associated with liver toxicity?

10.

Name two symptoms associated with liver toxicity.

11.

Which drug/drugs are most commonly associated with serious rash?

12.

How is a â&#x20AC;&#x2DC;severe rashâ&#x20AC;&#x2122; defined?

13.

Give an example of any two grade 4 side effects.

14.

When is the risk of lactic acidosis higher?

15.

Which medication is associated with mood changes, paranoia and strange dreams?

HIV i-Base: basic training for advocates

S4:55

January 2008

4


www.i-Base.info

Section 4: Side effects of ARVs

4.12 Course evaluation for Section 4 Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation.

Session One: How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section?

4

Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

HIV i-Base: basic training for advocates

S4:56

January 2008


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

Section 5: Opportunistic Infections (OIs) and important co-infections

OIs OIs 5.1 Introduction to Section 5 This section provides an overview of the most common opportunistic infections and coinfections related to HIV. Opportunistic Infections (OIs) are illnesses that your body is not able to fight because of the damage caused by HIV to your immune system. This information is just an introduction.You will need to research more detailed information yourself after you have understood these basic notes.

5.2 Aims for Sections 5 To understand the main symptoms and ways to prevent and treat the following infections and co-infections: • Candida and other skin problems • GI infections: giardia, cryptosporidia/microsporidia • PCP • TB • MAI and MAC • Hepatitis C • CMV • Toxoplasmosis • Cryptococcal meningitis • Cancer: lymphoma and sarcoma, including NHL, KS • Wasting and weight loss

HIV i-Base: basic training for advocates

S5:57

January 2008

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.3 Approach to each OI There are about 10 main OIs that advocates should know about. There are at least another 10 other important OIs but which are less common. The full list of AIDS-defining infections is included in Appendix I. All AIDS-defining OIs are potentially fatal, but the majority also improve dramatically when ARVs are available. For basic training you should learn about the OIs that are most common in your country. For each OI aim to know: •

Type of infection: whether viral, bacterial etc, how it is contracted and avoided and whether it is infectious to other people.

Main symptoms: how you or your doctor might diagnose this OI - note that many symptoms overlap for many of these infections. This is further complicated by the fact that most OIs can cause primary disease in a wide range of organs.

Diagnosis: how is the infection confirmed. Sometimes this involves either testing blood, saliva or sputum (fluid from the lungs) or trying to grow a culture from one of these samples (which can take several weeks).

Sometimes symptoms alone are sufficient to start treatment, based on a ‘best guess’.

Because a definite diagnosis can be difficult or impossible to confirm, you may only know afterwards whether the suspected illness was a correct guess, if symptoms improve after treatment.

Treatment: which drugs or choices or drugs can be used to treat and the success rate for each one. Can treatment be stopped afterwards? Most OIs, but not all of them, resolve after successful ARV treatment for HIV has enabled CD4 counts to raise to higher levels.

Prophylaxis: whether treatment is appropriate in order to prevent infection in the first place. Secondary prophylaxis is where you continue a treatment after the illness has been treated in order to prevent it occurring again in the future. At what CD4 count can prophylaxis treatment be stopped (after ARV treatment)?

Future research: are better tests or drugs being developed that could help in the future?

This structure will help you build your knowledge of HIV-related complications. The summaries in this section of the training course on each OI are very brief. You will need to undertake further reading and research to get more detailed information on each of these infections. There are many sources of information on these OIs on the internet, because they were the first focus of HIV research, before ARV drugs were available. The recommendations in Appendix VI for further reading are internet resources available in English. They provide more detail on the full range of OIs in both simple, intermediate and advanced levels of medical detail.

HIV i-Base: basic training for advocates

S5:58

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.4 GI infections: giardia, cryptosporidia and microsporidia Weight loss can be caused by many factors and illnesses. •

Type of infection: Giardia, cryptosporidia and microsporidia are tiny parasites (protozoa) that can cause stomach upset and severe diarrhoea. Diarrhoea and weight loss are often linked because the body is less able to absorb nutrition from food. Severe diarrhoea can also reduce absorption of medication.

Weight loss in HIV-positive people, that is not explained by a change in diet, can be very serious. Unexplained weight loss of 10% over a year is an AIDS-defining illness.

Several studies have suggested that unexplained weight loss of 5% over a shorter period is predictive of 10% weight loss later, and therefore any weight loss should be taken seriously.

Main symptoms: persistent diarrhoea that does not resolve within a few weeks. Microsporidia can also cause inflammation in other parts of the body including the lungs, bladder, bowel, sinuses, ears, eyes, brain and pancreas.

Diagnosis: Laboratory analysis of a stool sample can look for causes of diarrhoea, but sometimes the cause of diarrhoea is difficult to identify.

Infection is almost always the result of drinking unfiltered water, swallowing contaminated water when swimming or eating raw vegetables that were contaminated by infected or infested food handlers.

Cryptosporidia infections may also result from drinking unpasteurised milk. Exposure to diapers, daycare facilities, pets, livestock, and other people must be considered as well.

Treatment: In people with strong immune systems (HIV-negative people, or HIV-positive people with CD4 counts over 300) the body usually flushes out these parasitic causes of diarrhoea without treatment within a few weeks. In people with CD4 counts under 300 this doesn’t always happen and diarrhoea can become chronic.

There are no universally effective treatments for these infections, although albendazole and thalidomide have been used to treat some kinds of microsporidia. HIV treatment with ARVs to increase CD4 count is likely to be the most effective direct treatment.

It is important to drink plenty of fluids to help prevent dehydration caused by diarrhoea.

Prophylaxis: Ways to minimise risk of these infections for HIV-positive people with lower CD4 counts is to drink bottled water, to wash vegetables carefully and cook meat thoroughly, and not to eat foods washed in unbottled water. Hygiene (especially washing your hands) is important to reduce the risk of becoming infected or spreading infection. Many parasites that cause GI (gastro-intestinal) upset are linked to pet or human faeces, and so hygiene when caring for children is especially important if you are HIV-positive.

HIV i-Base: basic training for advocates

S5:59

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.5 Candida (candidiasis) and other skin problems Minor skin problems can be one of the first symptoms of HIV and are an indication that CD4 count is less than 300 cells/mm3. Often these can be relatively minor, like dry skin, but sometimes it can be the result of an infection that your immune system is no longer strong enough to fight effectively. Candida is also called thrush and it is very common in people with CD4 counts under 300, and it becomes more common the lower the CD4 count. •

Type of infection: Candida is a fungal yeast infection that frequently affects the mouth and throat (oral candida), gullet (oesophagus), sinuses, genital organs and much more rarely, the brain

Main symptoms: Oral thrush appears as white or red patches (especially in the mouth) that can sometimes be scraped off, and can include cracks at the corners of the mouth. In the sinuses it can cause headaches and difficulty breathing, and a build up of mucus. Oesophageal candida can make eating difficult and result in vomiting.

Diagnosis:Visual examination (for oral candida) or swap biopsy for candida in other areas.

Treatment: Some diet approaches include reducing or cutting down on foods that contain refined sugars and wheat.

Live unpasteurised yoghurt that contains lactobacillus bacteria can be eaten or applied directly to the vagina.

Anti-fungal medications are available in different formulations - as creams, lozenges (pastilles), syrup, patches and tablets.

These include: co-trimoxazole lozenges nystatin or itraconazole syrup fluconazole oral solution miconazole patch (for the inside of the mouth) ketaconazole, fluconazole and itraconazole tablets (fluconazole may be better if using rifampicin for TB treatment).

Anti-HIV treatment (HAART) should increase CD4 counts and reduce the occurrence of candida.

Prophylaxis: the possible benefit from prophylaxis has to be balanced against the risk of developing resistance.

Future research: Several experimental treatment are in development, and these would help people who develop resistance to existing anti-fungals.

HIV i-Base: basic training for advocates

S5:60

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.6 PCP •

Type of infection: PCP stands for Pneumocystis carinii pneumonia. PCP is caused by a relatively common organism that behaves more like a fungi than a protozoa (this is an area of recent research).

As with other opportunistic infections, PCP only becomes a problem in people who have a damaged immune system. A CD4 count of under 200 cells/mm3 puts you at higher risk of PCP. It only rarely occurs at higher CD4 counts. Most cases of PCP occur in people with a CD4 count under 100 cells/mm3.

Main symptoms: PCP is predominantly a lung infection and symptoms include difficulty breathing (shortness of breath), dry cough, tightness in the chest, fatigue, fever and weight loss. The organisms can sometimes grow in other area of the body like the lungs, bones and eye, though this is much more rare.

Diagnosis: Symptoms in an HIV-positive person with a low CD4 count are often sufficient to start treatment. Analysis of sputum from either bronchoscopy or ‘induced’ sputum - after breathing salty mist which brings up fluid from deeper in the lungs - is used for definite diagnosis.

Treatment: First-line treatment for PCP is with Co-trimoxazole (Septrin, Bactrim, TMP-SMX). Co-trimoxazole is made up of two drugs trimethoprim (TMP) and sulphamethoxazole (SMX). Standard doses are TMP 15-20 mg/kg/day and SMX 75 mg/kg/day by continuous drip or injection (three to four injections daily) for 3-4 days, and then switch to tablet.

Other treatments include trimethoprim plus dapsone, pentamidine, trimetrexate, atovaquone and clindamycin plus primaquine.

Prophylaxis: Prophylaxis against PCP, at a lower dose that used for treatment, is recommended for anyone with a CD4 count below 200 cells/mm3 whether or not they are using ARVs. Co-trimoxazole (Septrin or Bactrim) at 960mg/day is the most widely used prophylaxis. The other treatments that are listed below are used when co-trimoxazole causes side effects or if resistance has developed.

Dapsone is often associated with side effect in people who cannot tolerate cotrimoxazole. Other treatments used as prophylaxis include aerosolised pentamidine (with treatment every 2-4 weeks), atovaquone, sulphadiazine plus pyrimethamine and dapsone plus pyrimethamine.

Prophylaxis for PCP with TXP-SMX provides protection against other infections including toxoplasmosis. Prophylaxis can usually be safely stopped after CD4 counts rise over 200 cells/mm3 after successful response to ARV treatment.

HIV i-Base: basic training for advocates

S5:61

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.7 Tuberculosis (TB) TB and HIV are closely linked in many parts of the world. Where there is a high rate of one infection this is often driven by a high rate of the other. TB infection is more serious and more common and harder to treat in HIV-positive people. TB can also make HIV progress more quickly. •

Type of infection: TB (Tuberculosis) is a bacterial infection that is most widely known as an infection of the lungs (pulmonary TB). It can more rarely affect other parts of the body including the brain, lymph nodes, stomach, liver, bones and even muscles. The majority of people are exposed to TB in childhood, when the spores are breathed in, but then stay dormant, usually in the lungs for many years. The risk of TB becoming active again is less than 10% over the lifetime of an HIV-negative adult, but is about 10% per year in an HIV-positive person who does not have access to ARVs.

TB is transmitted from someone with active infection when they sing, shout, sneeze (without covering their mouth) and people can have active infection for 1-2 years before they develop symptoms.

Main symptoms: Symptoms of pulmonary TB include chronic productive cough, shortness of breath, fatigue, fever, night sweats and weight loss. Symptoms of TB in other part of the body are different (ie TB in the brain leads to confusion, etc).

Diagnosis: The distinction between active and inactive disease is very important to understand. Inactive disease is not infectious but diagnosis of latent (inactive) TB is not straight-forward. Skin tests that show previous exposure to TB are not accurate or effective in HIV-positive people who have a CD4 count under 400 cells/ mm3.

Active TB can be grown in the lab from a sample of spit or blood and is accurate if the result is positive, but not if the result is negative as infection can be missed in these tests. Pulmonary TB will show on X-ray. There is currently no simple blood test for TB.

Treatment: TB treatment requires a 2-month course of a combination of four antibiotics (i.e. isoniazid, rifampicin, pyrazinamide and ethambutol), followed by a 4-month course of a combination of two antibiotics (i.e. isoniazid and ethambutol). Adherence is so critical that TB treatment is often given in DOT (Directly Observed Therapy) where a nurse or other healthcare worker is responsible for seeing you take every dose. Even though you will feel better after a few weeks, the complet six-month course needs to be completed, otherwise: i) infection will return ii) resistance to these drugs will develop

TB that is resistant to TB medication requires longer treatment (sometimes for two years) and selection of different, usually less effective drugs.

Is HIV treatment the same for people with TB coinfection?

HIV treatment is recommended for anyone who also has active TB infection, even if the CD4 count is higher than 200.

Because of the interaction between rifampicin-based TB treatment and ARVs, different HIV drugs are recommended.

The dose of efavirenz is higher (800mg rather than 600mg) when using TB treatment, although a recent study in Thailand suggested that the dose change may not be needed in people who have a lower body weight (less than 50 kg).

HIV i-Base: basic training for advocates

S5:62

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

HIV only: nevirapine +2 RTIs efavirenz + 2 RTIs

www.i-Base.info

HIV + TB: efavirenz + 2 RTIs abacavir + 2 other RTIs saquinavir+ritonavir + RTIs

Efavirenz should not be used in pregnant woman (who should use pyrazinamide in their TB regimen) or in women who may become pregnant. Children with low weight are recommended to use abacavir + 2 RTIs.

Summary of drug interactions •

rifampicin should not be taken with any PI or nevirapine because rifampicin reduces these drugs to very low levels

rifabutin should not be taken with ritonavir, saquinavir or nevirapine

rifabutin interacts with indinavir, nelfinavir, amprenavir, saquinavir (Fortovase and Invirase) and efavirenz, but appropriate dose adjustments can be made.

rifabutin levels are increased by PIs

rifampicin may also interact with other drugs taken by people with HIV

risk of neuropathy with izoniazid is likely to be increased in people using d4T

When to use ARVs with active TB infection

There are very few trials of how to treat TB in HIV coinfection, so recommendations are based on expert guidelines.

People with a CD4 count under 100, can start TB meds for 2-3 weeks and then start ARVs.

People with a CD4 count between 100 - 200, can usually wait until after the first 2 months TB treatment before starting ARVs.

People whose CD4 count is over 200 can usually finish the 6-month course of TB treatment before starting ARVs.

A serious side effect of the TB-drug izoniazid is peripheral neuropathy (PN). PN can also be caused by HIV and by ARV drugs including d4T, ddI, and 3TC - and this risk increases when both isoniazid and these ARVs are used over the same period.

Sometimes ARV treatment for HIV, especially in people with very low CD4 counts, can cause an immune response that complicates the management of TB (such as IRIS disease). This requires specialist management.

Prophylaxis: Prophylaxis treatment for TB is usually only recommended in specific circumstances, usually where people share the same confined living or working space - ie family members will often receive treatment if a member of their family is diagnosed with active TB. Secondary prophylaxis, to prevent either TB coming back, or reinfection with a new strain of the virus, is rarely recommended. This is mainly because treatment is difficult to tolerate, and the risk of resistance is high.

Future research: There is an urgency for new accurate tests for TB and these may become available in the future. This would dramatically improve management and care of HIV-positive people co-infected with TB.

Other antibiotics and regimens are also being studied.

HIV i-Base: basic training for advocates

S5:63

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.8 MAI/MAC •

Type of infection: Mycobacterium avium and Mycobacterium intracellulare are two bacterial organisms closely related to Mycobacterium tuberculosis which causes TB. Illness from these bacteria is generally called MAI in Europe and MAC in the US, but they are the same.

MAI can spread throughout the body, and can affect almost any organ, especially the blood, lymph nodes, liver, spleen and bone marrow. The cells infected by these bacteria include macrophages (the cells that engulf infectious material).

Route of infection: Infection comes from soil, dust or contaminated water, but is not infectious between individuals. Like other OIs, MAI only becomes a problem in people with suppressed immune systems. If your CD4 count is under 100 cells/mm3 you are at risk for MAI. The lower your CD4 count the higher the risk.

Symptoms: Fever, night sweats, weight loss, loss of appetite, and weakness. MAI in the gut can cause diarrhoea and abdominal pain due to ulcers. In the lymphatic system, MAI will cause swollen lymph nodes, liver and spleen. Blood tests can show low levels of red blood cells and platelets (anaemia, neutropenia).

Diagnosis: MAI can be confirmed by growing culture from blood or biopsy samples (from the affected organ or gland), but this can take up to four weeks. An ‘acid smear’ test is much quicker but cannot differentiate between bacteria that cause MAI and TB.

Treatment: Treatment involves a combination of two or more antibiotics in order to reduce the risk of resistance; usually clarithromycin or azithromycin, plus ethambutol. People who develop resistance to clarithromycin will have cross resistance to azithromycin and vice versa. Other drugs used in combinations include rifabutin (see section on interactions with HIV drugs in the section on TB), rifampicin, gentamicin, amikacin, ciprofloxacin and sparfloxacin.

Treatment is lifelong, unless ARV treatment for HIV has increased CD4 count back above 100 cells/mm3, in which case MAI treatment can be safely stopped after a year.

Prophylaxis: Whether prophylaxis should be recommended in people with CD4 counts under 50 cells/mm3 is not clear. Recommendations vary in different countries. The risk of developing resistance to these antibiotics is the main caution against using prophylaxis. If ARV drugs are available they are likely to be more protective against MAI, than using MAI prophylaxis, as ARVs will increase the CD4 count to a protective level.

Azithromycin may also help protect against toxoplasmosis.

HIV i-Base: basic training for advocates

S5:64

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.9 Hepatitis B and C Type of infection • Hepatitis is a name for any infection that causes liver inflammation or damage. • Three main causes of liver infection are hepatitis A (HAV), hepatitis B (HBV) and hepatitis C (HCV) virus. These are all very different viruses with different treatment. • This section mainly deals with HBV (which is acquired sexually including through saliva) and HCV (acquired by blood contact through infected needles, and more rarely sexually). With HIV, these are considered coinfections rather than OIs. Main symptoms • Some of the symptoms of acute (early) or active liver infection, like nausea, vomiting, fatigue, diarrhoea, jaundice (yellow eyes or skin), are similar for any viral infection to the liver. Not everyone will get symptoms or even know they are infected. Intolerance to fatty foods or alcohol, a swollen or tender liver or ‘liver spots’ on the skin are other symptoms of hepatitis. Hepatitis B (HBV) • Hepatitis B can be transmitted by sexual exposure including oral sex and sharing injecting drug equipment, and is more infectious than HIV. • Up to 90% of HIV-positive people have already been exposed to HBV, with the majority clearing the virus without treatment. • HIV probably makes HBV a more serious illness, and complications of managing HIV/ HBV coinfection are largely related to some common HIV treatment having activity against both viruses. Diagnosis

Blood tests can screen for either previous exposure to viral hepatitis or active infection. The symptoms listed above should prompt a doctor to test for HBV.Viral load (PCR) tests for hepatitis are used similar to HIV viral load tests, and can confirm an infection when immunological tests are either negative or unclear.

Previous exposure to HBV is shown by testing positive for HBV core antibodies (HBcAb+) or HBV surface antibodies (HBsAb+).

2-10% of people exposed to HBV become chronic carriers and remain infectious, shown by a positive test result for HBV surface antigen (HBsAg+).

Treatment

HIV and hepatitis B coinfection needs care from a doctor with experience of both infections.

Several drugs used to treat HIV also are active against HBV. These include 3TC, tenofovir and FTC. HBV is also treated with adefovir, a drug developed for HIV, but now used just for HBV.

These drugs have to be used very carefully. • The drugs 3TC, tenofovir, FTC and entecavir should only be used in HIV-positive people as part of a 3-drug ARV combination because of the risk of HIV resistance developing to both HIV and HBV.

HIV i-Base: basic training for advocates

S5:65

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

• HBV treatment in people with HIV is recommended to include 2 drugs that are active against HBV in order to reduce the risk of resistance (and 3 drugs that are active against HIV). • Adefovir can be used as single treatment if ARV treatment is not needed, but is not a preferred choice. • Resistance to HIV and HBV treatment are different and occur independently. • There is a serious risk of HBV reactivation, and severe or fatal liver toxicity, if the drugs active against HBV are stopped in someone who has not cleared the infection. • Interferon was the first treatment for HBV and needs to be given by a course of injections (usually for 6-12 months). This is now used less often because oral drugs are much easier to take and to tolerate. Pegylated interferon can still be used by HIV-positive people who do not need HIV treatment. HBV can be successfully treated in most people. Sometimes life-long treatment is needed. Long-term HBV coinfection is a specialist area of disease management. If HBV is cleared, you are usually immune to reinfection. Prophylaxis Effective vaccinations are available for hepatitis A and hepatitis B. Response to vaccines are related to CD4 count, and some clinics use higher doses in HIV-positive patients in order to improve the response rate. There is no vaccination against hepatitis C. Research Research into new drugs to treat hepatitis B is ongoing. Some of these will be available in the next 5-10 years. Hepatitis C (HCV) • Hepatitis C is mainly transmitted by sharing injecting drug equipment, and is more infectious than HIV. Although it is rare for HCV to be transmitted sexually, especially in heterosexual couples, sexually transmitted HCV in gay men and MSM in European cities has been reported and a new and increasing health risk. • HCV can take 20-25 years in HIV-negative people to progress to liver damage (scarring and liver cancer). Coinfection with HIV seems to approximately double the speed of HCV progression (ie taking form 10-15 years). Continued high use of alcohol is a major risk factor for faster HCV progression. Chronic (long-term) HCV is also associated with mental difficulties and depression. • Up to 20% of HIV-positive people clear HCV in the first months after infection, without needing HCV treatment. Diagnosis Blood tests can screen for either previous exposure to viral hepatitis (many people clear the virus without knowing they were infected, and produced antibodies) or active infection. The symptoms listed above should prompt a doctor to test for HCV. Viral load (PCR) tests for hepatitis are used similar to HIV viral load tests, and can confirm an infection when immunological tests are either negative or unclear. If you are diagnosed with HCV, then you need to have an ‘HCV genotype test’ to find out which type of HCV you have (genotype 1, 2, 3 or 4). Treatment HIV and hepatitis C coinfection needs care from a doctor with experience of both infections and is highly specialised. Combination HCV treatment with interferon or PEG

HIV i-Base: basic training for advocates

S5:66

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

interferon, plus ribavirin, for 48-weeks is current standard of care, but people with HCV coinfection may need longer treatment. Response rates to treatment vary by HCV genotype. The proportion of people who clear HCV ranges from 30% for HCV genotype 1 or 4 to 60-70% for genotype 2 or 3. Response rates after 12 weeks may be an early sign of the effectiveness of treatment. Treatment is mainly used after long-term infected with HCV, when a liver biopsy or other test have shown that liver damaged has progressed. If HCV is diagnosed in acute infection (within 6 months of infection) then early treatment can result in higher response rates. A successful response is defined as undetectable HCV viral load, six months after stopping HCV treatment. Most people who get this response have been cured of HCV. Even if HCV is not cleared, treatment may improve liver damage and delay disease progression. If HCV is cleared, you are not immune to reinfection – and it is very easy to catch it again if you put yourself at risk. Prophylaxis Effective vaccinations are available for hepatitis A and hepatitis B. There is no vaccination against hepatitis C. Research There is extensive research into new drugs that work in other ways and which have less side effects than interferon, including oral drugs. Some of these will be available in the next 5-10 years. Other areas of research include: •

Risks from low levels of alcohol use

Use of non-invasive test to monitor liver damage (other than needle biopsies

Duration of treatment needed with different HCV genotypes

Earlier access to experimental HCV drugs for people coinfected with HIV

Further reading: i-Base Guide to Hepatitis C for HIV-positive people. http://www.i-base.info/guides/hepc This guide has been translated into other languages including Italian, Portuguese, Russian and Spanish. See the i-Base website for details.

HIV i-Base: basic training for advocates

S5:67

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.10 CMV (cytomegalovirus) •

Type of infection: CMV is a viral infection that only becomes serious when CD4 levels drop below 50. So although it is widespread (over 50% general population, over 60% in IDU and over 90% in gay men), it only becomes a problem when the immune system is reduced - mainly people with HIV or having an organ transplant.

Main symptoms: CMV infection can affect many different organs. CMV retinitis can cause progressive and permanent loss of sight. Early symptoms include floaters, blind-spots, blurred or dark area of vision, flashing lights or any vision loss. Sometimes active disease can affect peripheral vision without this being clear so it is essential that everyone with a CD4 count under 50 has regular eye examinations (every 1-3 months).

CMV can affect other organs: GI tract, stomach, bowel, rectum (all of which can cause diarrhoea and bleeding); lungs (often with PCP); brain and the central nervous system.

Diagnosis: CMV retinitis is diagnosed by eye examination. CMV in other organs usually requires diagnoses from a biopsy sample.

Treatment: With CMV retinitis, immediate treatment is essential, as damage to the eyes is permanent. The three main treatments are ganciclovir, foscarnet and cidofovir, usually given by slow IV delivery, twice-daily, started on the day of diagnosis. Ganciclovir and foscarnet are first line options. Local treatment (ie to the affected eye) can be given by a direct injection into the eye or slow delivery implants.Valganciclovir is available in an oral formulation, which is replacing the previous oral formulation of ganciclovir.

ARV treatment for HIV that brings CD4 counts back over 50 cells/mm3 is the best medium and long-term treatment. Once the CD4 count has been raised over 100 cells/mm3 (perhaps even over 50) for several months, CMV treatment can usually be safely stopped. Otherwise this difficult treatment is lifelong.

Sometimes ARV treatment for HIV can cause an immune response that complicates the management of CMV. This requires specialist management.

The same IV and oral formulations are used to treat CMV in other organs.

Prophylaxis: There may be a role for primary or secondary prophylaxis with oral proganciclovir (valganciclovir) in people with CD4 counts under 50 cells/mm3 who are not responding to HIV treatment. This has to be balanced against the side effects of the drugs and the risk of developing resistance.

Future research: Several other compounds for treating CMV are in development. However, much of the urgency for this research, is now reduced due to the huge impact that ARVs had on reducing the incidence of CMV retinitis.

HIV i-Base: basic training for advocates

S5:68

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.11 Toxoplasmosis •

Type of infection: Toxoplasmosis (‘toxo’) is an illness caused by a protozoa. It is mainly transmitted by eating raw or under-cooked meat; or through exposure to cat faeces. Although many adults have been exposed to toxo, the risk of it causing illness only usually occurs when CD4 levels are below 200 cells/mm3.

Main symptoms: Toxoplasmosis most commonly causes lesions in the brain. Symptoms include fever, headache, disorientation, confusion, memory loss and vision loss. If this progresses it can lead to behaviour change. If untreated toxo can be fatal.

Diagnosis: Diagnosis is difficult because blood tests for antibodies, and even viral load tests in CSF (cerebrospinal fluid) are not always positive. MRI or CT brain scans can highlight any damaged to the brain, but rarely provide sufficient information to diagnose the cause of the damage.

Symptoms are often sufficient to start treatment, and if symptoms improve within a two weeks then toxoplasmosis will have been the cause. Lesions should start to reduce on an MRI or CT scan by three weeks.

Treatment: Treatment is effective and usually straight forward using antibiotics pyrimethamine plus sulphadiazine, usually in oral tablet, sometimes IV in severe disease. Other antibiotics - clindamycin, clarithromycin or azithromycin can be used if there is a reaction against sulphadiazine, but they are not as effective.

After a successful response to treatment (usually three weeks) maintenance therapy is continued with low dose pyrimethamine plus either sulphadiazine or clindamycin.

Treatment is lifelong as long as your CD4 count remains below 200. As with many other OIs, a successful response to ARV treatment for HIV which brings CD4 count back over 200, means that treatment for toxo can usually be stopped. This depends on the severity of the previous illnes and is dependent on the CD4 count staying above 200.

Prophylaxis: Co-trimoxazole (trimethoprim plus sulfamethoxazole) - Bactrim, Septrin - in people with CD4 counts under 200 is widely used - mainly because this is the same prophylaxis used to prevent PCP. In people who can not tolerate cotrimoxazole, either atovaquone or dapsone can be used as prophylaxis against both toxoplasmosis and PCP.

Future research: Alternative antibiotics like atovaquone, azithromycin and doxycycline are the subject of future research.

HIV i-Base: basic training for advocates

S5:69

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.12 Cryptococcal meningitis •

Type of infection: Cryptococcus is a fungal infection found in soil from bird droppings, that can be breathed in as dust. It can not be passed in the air from one infected person to another. Infection can be dormant for many years. As with other OIs this only becomes a problem as an active disease if your CD4 count drops to below 100 cells/mm3. Smokers and people who work out of doors have higher risk of cryptococcus.

Main symptoms: If cryptococcus infects the blood, it can cause cryptococcal meningitis which can be very serious. Sypmtoms of cryptococcal meningitis include headache, neck-ache, nausea, fever, confusion and disorientation, sensitivity to light and can lead to stroke and coma. In the lungs, symptoms can be similar to PCP and include coughing and shortness of breath, fever and fatigue.

Diagnosis: Diagnosis is made by testing spinal fluid or blood either for antigens, or by growing the fungus in culture. A successful response to treatment is confirmed using the same tests. Spinal fluid is more difficult to test and requires a lumbar puncture or ‘spinal tap’.

Treatment: Moderate to severe initial infection (when there are brain-related symptoms) is treated with amphotericin B, or liposomal (fat-coated) amphotericin B. Treatment is through a central line (Hickman or Portacath) into a deep vein. This is a more complicated and difficult and can last up to six weeks. Oral fluconazole or itraconazole are active against cryptococcus but are not as effective, and are only used in cases of mild infection. If the meningitis has caused high pressure in the spinal fluid this may also be drained periodically as part of treatment to reduce the risk of brain damage. Once the infection is cleared a second stage of maintenance treatment (secondary prophylaxis) is essential to prevent the infection returning. This is with oral fluconazole capsules at 400 mg/day for the first eight weeks, reduced to 200 mg/day for as long as CD4 count remains below 100-200. Maintenance therapy can be stopped after a successful response to ARV treatment that increases CD4 levels above 100. As with other maintenance therapy, if CD4 counts drop again in the future, secondary prophylaxis should be restarted.

Prophylaxis: If you are in a country where the incidence of cryptococcus is high, then prohylaxis with fluconazole (200mg/day) or itraconazole if you have a CD4 count under 100 may protect you from infection. This has to be balanced against the risk of resistant infections and cost. ARV therapy to raise your CD4 count to a safer level would be much better value if this is available.

HIV i-Base: basic training for advocates

S5:70

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.13 Lymphoma, including Kaposi’s Sarcoma (KS), Non-Hodgkins Lymphoma (NHL), Hodgkins Disease (HD) Several important cancers are linked to HIV, and are listed as AIDS-defining illnesses. These include NHL, KS and cervical cancer. Even though many other cancers occur more frequently in HIV-positive individuals compared to the general population (i.e. anal cancer, lung cancer, Hodgkins Disease) they have not been categorised as AIDS-defining. This may change in the future. Some cancers (i.e. breast cancer) do not appear to occur at higher rates in HIV-positive people. The definition of cancer is a disease caused by uncontrolled growth and spread of abnormal cells. Benign (or ‘in situ’) cancers are contained to the original cells and as long as they do not spread, they are not dangerous. Malignant cancers spread to other parts of the body and are much more serious. If the spread is not controlled, they can be fatal. Lymphoma are cancers that develop in the lymphatic system. The most common type of lymphoma is Hodgkins Disease (HD). All other lymphomas are called non-Hodgkins lymphomas (NHL). Sarcoma are cancers of the bone, cartilage, fat, muscle, blood vessels, skin or other connective or supportive tissue. The most common Sarcoma associated with HIV is Kaposi’s Sacroma (KS). Carcinoma is the name for a form of cancer that develops in tissues covering or lining organs of the body, such as the skin, the uterus, the lung, or the breast. Each cancer has different characteristics, symptoms and treatment. All cancers have a better prognosis if the earlier they are detected. Apart from KS, in general, HIV-related cancers are the one type of illnesses that do not dramatically improve and resolve as a response to ARV therapy. This is why screening and early monitoring is so important. Recent research has linked many HIV-related cancers to other viral infections: •

KS is skin cancer that can also affect other organs and is associated with HHV-8 (Human Herpes Virus-8).

Cervical and anal cancer are both linked to HPV (Human Papilloma Virus). HPV is a large family of viruses that also cause genital and anal warts. Some strains (16, 18, 31, 33, 35) have a stronger link to cancer than others.

Epstein-Barr virus is associated with NHL.

Liver cancer is associated with Hepatitis C virus (HCV).

HIV i-Base: basic training for advocates

S5:71

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.14 HIV-related weight loss and HIV-related wasting Weight loss can be a symptom of many infections, including HIV itself. It may be caused by more than one factor, and may need more than one approach to diagnose and treat. Even people using ARV treatment can have difficulty regaining and maintaining higher weight. Severe weight loss or wasting is life threatening, although is usually reverses if ARV treatment are used. In someone with diarrhoea and weight loss, the cause of the diarrhoea needs to be found. The same is true if nausea or vomiting are factors. As well as treating the cause of weight loss, you need to look at diet changes to reduce diarrhoea and improve nutrition. If diarrhoea is a factor,this should be treated. Often the best long term response is to get effective ARV treatment. With nausea and vomiting, anti-nausea and anti-sickness medication should be prescribed. •

Type of illness: Weight loss is a symptom of most of the other OIs discussed in this section. It can also be a side effect of any illness or treatment that reduces your appetite. Weight loss or wasting are also caused by HIV itself, because the energy that you generate from nutrition (food and drink) is being used by the virus to over-activate your immune system. The amount of energy from diet that your body needs to function even when just sitting or lying down (called Resting Energy Expenditure, REE) is higher in HIV-positive people. It becomes higher still as HIV disease progresses. Other infections and illnesses also increase the amount of energy the body needs in order to fight infection.

Main symptoms: Weight loss is general reduction in weight.

HIV-related wasting specifically includes muscle wasting and loss of lean body mass. Food is basically a source of energy. If you eat less calories each day than your body needs to do the things it needs to, then the extra energy is taken from stores of body fat. If body fat levels are already low, then this extra energy will be taken from protein that is used to build and maintain muscle.

Diagnosis: Diagnosis of weight loss is easy and straight-forward because it only requires a pair of scales. Weight loss of 10% from normal body weight that can not be explained by other factors (ie change of diet, increased exercise, other infections or medications) becomes an AIDS-defining illness.

Unexplained weight loss of 5% of body weight over six months is predictive of continued loss to 10%, and therefore should be taken seriously.

When lipoatrophy and wasting occur in the same person diagnosis and treatment becomes more complicated. Loss of subcutaneous fat as a side effect of ARV drugs (called lipoatrophy or lipodystrophy) is different to HIV wasting.

Treatment: In very simple terms, regaining weight should just be a matter of increasing the amount of calories that you get in your daily diet. Achieving this can be complicated though. Depending on the cause of weight loss, things that may seem common sense - like eating more high calorie foods may not always be appropriate. For example, increasing high calorie fatty foods in someone with diarrhoea, will increase the diarrhoea and reduce the likelihood that any nutrition will be absorbed by the body. Special dietary advice should always be sought.

If the cause of diarrhoea, nausea and vomiting are other OIs, the ARV treatment should help these symptoms improve. Also, people starting ARV treatment generally put on weight as they find they have a stronger appetite and more energy.

HIV i-Base: basic training for advocates

S5:72

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

If oral or oesophagal thrush or mouth ulcers had made eating difficult or painful, then ARVs will similarly help resolve those problems.

Steroid use (with exercise), testosterone replacement (for both men and women) and appetite stimulants like Dronabinol (medicinal marijuana) are often used to help regain weight.

â&#x20AC;˘

Prophylaxis: If you are HIV-positive and not using ARVs, it is easier to loose weight than it is to put weight back on again. Earlier interventions are easier and more successful.

OIs

5

HIV i-Base: basic training for advocates

S5:73

January 2008


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.15 Malaria Type of illness • Malaria is a parasitic infection of red blood cells. • Malaria is transmitted to humans by a bite from a female Anopheles mosquito. There can be a delay of 1 week to 1 year between getting infected and having symptoms. • Most people who grow up in malarial areas have some immunity to the illness. Malaria is usually an acute (short-term) illness, but for some people it becomes a chronic (life-long) problem. • The risk of malaria is related to where you live and whether this is in a high-risk country or region, and by season. Malaria is the one of the leading causes of death in children under 5 who live in areas affected by malaria. In people with HIV: • acute infection is not an OI • chronic malaria is considered a coinfection Main symptoms • Shaking chills • High fever and sweating

OIs

• Dizziness, nausea, vomiting, abdominal cramps, diarrhoea • Headache and back ache

5

• Tiredness • Sometimes jaundice (yellowing of skin and eyes) Malaria attacks happen over 4 to 6 hours, and occur every 2 or 3 days. If malaria affects the brain, it can be fatal within 24 hours. Malaria can cause anaemia. Malaria and HIV HIV-positive people are at a higher risk of malaria infection, and the disease is more severe. HIV makes malaria worse. • There is a higher density of parasites • The symptoms last for longer • A low CD4 count and high viral load increases this risk • There is an increased risk of reinfection (with a new infection) within 28 days of treatment • Malaria can contribute to anaemia • Malaria increases HIV viral load which may affect long term health • It is not like a typical OI because childhood immunity is often retained in adults Malaria, pregnancy and anaemia Pregnant women are three times more likely to catch malaria compared to non-pregnant women. HIV i-Base: basic training for advocates

S5:74

January 2008


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

The increase in viral load from malaria coinfection increases the risk of HIV transmission in HIV-positive pregnant women, and causes lower birth weight in the baby. Haemoglobin levels are lower in coinfected pregnant women and the risk of anaemia is higher. This has to be taken very seriously and managed appropriately. This usually means that the risks from not treating malaria are greater than the difficulties from treatment (ie drug interactions). Diagnosis Malaria is diagnosed by physical examination and blood tests. Information about travel history and symptoms are important. Treatment Malaria can be treated with inexpensive drugs and can usually be cured. The choice of drugs depends on whether the malaria in your region has developed resistance to treatment. Malaria is usually treated with a combination of drugs. Several anti-malarial drugs and combinations are available and used. • choroquine-based treatment used to be the most widely-used first line therapy, and the most effective therapy, but is now one of the drugs to which there is most resistance • artemisinin + lumefantrine are now more widely used in choroquine-resistant regions Drugs interactions with HIV drugs are complicated.

5

• halofantine - don’t give with PIs • artemether - don’t give with PIs • lumefantine - don’t give with PIs • artemether – levels reduced by nevirapine & efavirenz • lumefantine – levels reduced by nevirapine & efavirenz • quinine - unclear if there are PI or NNRTI interactions Prophylaxis One of the most effective ways to stop malaria is to use insecticide-treated bed nets, which cost less than $5 and can reduce all-cause child mortality by 25%. This is part of a major international campaign to reduce infant mortality from malaria. Oral prophylaxis is with co-trimoxazole (Septrin), which also protects against PCP and toxoplasmosis. Research Research on malaria is looking at the following areas: •

Resistance to treatment is a serious problem. New drugs are being looked at.

More research is needed on the effect of malaria in HIV-positive children?

Does better malaria treatment improve HIV?

Implications of cotrimoxazole treatment for protection and the risk of resistance

On drug interactions between malaria treatment and ARVs?

Vaccine research

HIV i-Base: basic training for advocates

S5:75

OIs

January 2008


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.16 Summary table of OIs and effect of ARV treatment This table summarises the OIs and co-infections discussed in this section, together with the impact of ARV treatment. Prophylaxis None, care with food and water etc

Protection returns after ARV increases CD4 Yes

None *

Yes

PCP

Under 200

Yes

Yes

TB (pulmonary)

Under 500

Not generally *

No

MAI / MAC

Under 100

Not generally *

Yes

Hepatitis B and C

Any CD4

None

CMV

Under 50

Not generally

No, but response to HCV treatment is stronger Yes

Toxoplasmosis

Under 200

Yes

Yes

Cryptococcal meningitis

Under 100

Sometimes *

Yes

Cancer: lymphoma and sarcoma

Varies.Can be at any CD4 NHL usually under 200

No

Varies depending on lymphoma, KS can resove on ARV treatment alone

Infection/OI Gut infections: giardia, cryptosporidia/ microsporidia Candida and other skin problems. Herpes.

CD4 risk level (cells/mm3) Under 300 Under 300

Wasting syndrome

Usually under No Yes 300 * Although drugs can be used as prophylaxis, the risks or side effects and developing resistance usually outweigh the benefit of protection for infection.

HIV i-Base: basic training for advocates

S5:76

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.17 Glossary: Section 5 biopsy

The removal of cells or tissues for examination under a microscope.

bronchoscopy

This test uses a thin, flexible lighted tube called a bronchoscope to look inside your lungs.

cirrhosis

Chronic injury to the liver can result in scar tissue. This scarring distorts the normal structure and regrowth of liver cells. The flow of blood through the liver from the intestine is blocked and the work done by the liver, such as processing drugs becomes much more difficult. Cirrhosis is Stage 4 on Metavir and Knodell disease staging and Stage 6 on Ishak score.

CSF (cerebrospinal fluid) A clear, colourless fluid surrounding the central nervous system. GI (gastro intestinal) The gastro-intestinal system includes the stomach, bowel and colon. prophylaxis

Taking a drug to prevent an infection. This is most important at lower CD4 counts and/or when there is no access to ARVs. Continuing to take medication (often at a lower dose) after an illness has already been treated, in order to reduce the risk of re-infection or reactivation, is called secondary prophylaxis..

protozoa

Small parasites that can cause upset stomach and serious diarrhoea.

vaccination

A low dose, or inactivated version of an infectious organism that is given as an injection to stimulate the body to produce antibodies. These anitbodies provide protection against future infection. It is important that HIV-positive people are not generally given vaccinations that are made of live viruses. Inactivated alternatives are available and should be used if you are HIV-positive.

HIV i-Base: basic training for advocates

S5:77

January 2008

OIs

5


Section 5: Opportunistic Infections (OIs) and important co-infections

www.i-Base.info

5.18 Questions: Section 5 1.

What are protozoa? Name three that cause gastric infections.

2.

At what CD4 count are you at greater risk for gastric infections?

3.

Name three ways to minimise the risk of gastric infections?

4.

What is candida?

5.

What are the main symptoms of candida?

6.

Name three anti-fungal medications.

7.

What is PCP?

8.

At what CD4 are you more at risk for PCP?

9.

Which drugs are used as prophylaxis?

10.

What is first-line treatment for PCP?

11.

What other treatments can be used for PCP?

12.

What is TB?

13.

What is the difference between active and inactive TB?

14.

What is the first-line treatment for TB?

15.

What ARVs should not be taken with rifampicin?

16.

When is TB prophylaxis recommended?

17.

What is MAI/MAC?

18.

What treatment is recommended?

19.

What is hepatitis?

20.

How long does hepatitis C take to progress to liver damage in HIV negative people?

21.

What is the treatment for hepatitis B?

22.

Below what CD4 count does the risk of CMV become active dramatically increase?

23.

How is CMV diagnosed?

24.

How is toxoplasmosis transmitted?

25.

How long does toxoplasmosis need to be treated?

26.

Which are the main AIDS-defining cancers?

27.

Do cancers improve with ARV treatment?

28.

What cancer is associated with hepatitis C?

29.

What is AIDS wasting?

HIV i-Base: basic training for advocates

S5:78

OIs

January 2008

5


www.i-Base.info

Section 5: Opportunistic Infections (OIs) and important co-infections

5.19 Course evaluation for Section 5 Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation.

Session 5 How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones?

OIs

Did the questions relate to the information you found yourself?

5

What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

HIV i-Base: basic training for advocates

S5:79

January 2008


www.i-Base.info

Section 6: HIV and pregnancy

Section 6: HIV and pregnancy

6.1 Introduction to Section 6 Section 6 provides an overview of HIV and pregnancy. This section is particularly important as over half of new HIV diagnoses are in young women and many will want to have children in the future.

6

6.2 Aims for Section 6 After completing this section you should have a basic understanding of: •

Why maternal health is important for a healthy baby

Where treatment in pregnancy differs from that for non-pregnant adults

Which HIV drugs are safest to use in pregnancy for the mother’s and baby’s health

Some treatment strategies for different situations

Resistance, monitoring and other tests

Choices for delivery and use of C-section

Baby’s diagnosis

Feeding the baby

HIV i-Base: basic training for advocates

S6:80

January 2008


www.i-Base.info

Section 6: HIV and pregnancy

6.3 General questions Can HIV-positive women safely become mothers without risks to their babies? Yes. Using antiretroviral (ARV) drugs, an HIV positive woman can safely become pregnant with very little risk of transmitting the virus to her baby. Many thousands of women have taken therapy during pregnancy without complications to their babies. This has resulted in many HIV-negative babies. How is HIV transmitted to a baby? Without treatment, about 25% of babies born to HIV-positive women will be HIV-positive. The exact way that transmission from mother to baby happens is still unknown. However, the majority of transmissions occur near the time of or during labour and delivery. Transmission can also occur through breastfeeding. Certain risk factors seem to make transmission during labour much more likely. The strongest of these is the mother’s viral load. If a woman has a high viral load the risk of transmission to her baby is much greater than if it is very low or “undetectable”, so the aim of the HIV drugs is to make sure that her viral load is as low as possible, particularly at the time of delivery. This will also give the most benefit to the mother herself if she needs treatment for her own HIV. Other risk factors include premature birth, lack of prenatal HIV care and the time between when the mothers waters’ break and the actual delivery. This time is called ‘duration of ruptured membranes’. •

The mother’s health directly relates to the HIV status of the baby

Whether the baby’s father is HIV-positive will not affect whether the baby is born HIV-positive

Do HIV drugs protect the baby? Reducing the risk of a baby becoming HIV-positive was an early benefit of ARVs. PACTG 076 is the name of a famous HIV trial. This was the first study to show that using the drug AZT could protect the baby from HIV. Mothers took AZT before and during labour. The baby received AZT for six weeks after birth. This reduced the risk of the baby becoming HIV-positive from 25% to 8%. From 1994, this strategy was recommended for all HIV-positive pregnant women in Western Europe and North America. But even further advances have been made over the last few years. Transmission rates with combination therapy of three or more drugs are now less than 1%.

HIV i-Base: basic training for advocates

S6:81

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

6.4 Mother’s health and pregnancy A mother’s own health (and her own treatment) is the most important consideration to ensure a healthy baby. Overall, treatment for an HIV positive pregnant woman will be the same as for any HIV positive adult. Differences in treatment strategies will be discussed later in this section. It is important that the mother receives support from an experienced healthcare team during her pregnancy. Some discrimination still exists against HIV-positive people deciding to have children but although situations vary throughout the world things are generally better than they used to be. •

HIV - Pregnancy does not make a woman’s own health related to HIV get any worse. It will not make HIV progress any faster.

CD4 - Pregnancy may cause a drop in a woman’s CD4 count. This is usually about 50 cells/mm3 but it can vary a lot. This drop is only temporary. Her CD4 count will normally return to her pre-pregnancy level soon after the baby is born.

This is not a concern unless her CD4 falls below 200 cells/mm3. Below this level, she is at a higher risk from opportunistic infections. These infections could affect both the mother and the baby.

OIs - In general, pregnant women need the same treatment to prevent opportunistic infections as women who are not pregnant (see Section 6.10 and all of Section 5).

6.5 Prenatal care and treatment Prenatal or antenatal care is all the extra care that you receive during your pregnancy in preparation for your baby’s birth. Treatment in pregnancy - Recommendations will vary depending on the mother’s situation and her own treatment needs when she becomes pregnant. Most guidelines now recommend treating adults at around a CD4 count of 200 cells/mm3. Pregnancy is one situation where ARVs are used differently to the way they are used in treatment of other HIV-positive adults. This is because there is a risk of transmission, even with mothers who have low viral loads that are less than 1000 copies/ml before they start treatment. Transmission drops from almost 10% in untreated women to less than 1% in women treated with anti HIV drugs. We will look at different situations and treatment strategies: i) If a woman is pregnant and does not need HIV treatment for her own health: In this situation a woman will most likely be offered a short course of triple combination therapy after the second trimester (6 months into pregnancy) at 24 to 28 weeks OR to use AZT monotherapy to mother and baby - as in the 076 study - and have an elective Caesarean (C-)section (see Section 6.12). She will need to carefully consider these two options. •

Using three drugs will be more likely to reduce her viral load to undetectable levels. This has shown the lowest transmission risk to date.

Using three drugs will also protect her from the possibility of developing resistance. This will protect her options for future treatment.

HIV i-Base: basic training for advocates

S6:82

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

C-sections are major surgery. They can carry risks for the mother.

The baby will be exposed to a greater number of drugs with combination therapy.

The risk of the mother developing resistance is higher using AZT monotherapy than triple combination therapy.

ii) If a woman is HIV-positive and needs treatment for her own HIV? If someone is diagnosed during pregnancy and needs treatment for her own HIV she should be prescribed appropriate combination therapy. If she is diagnosed early on in her pregnancy, she may wish to delay starting treatment until the end of the first trimester. This is the first 12 to 14 weeks from her last missed period. She may also want to delay treatment if she already knows her HIV status but has not yet started treatment. There are two main reasons for delaying treatment. •

The baby’s main organs develop in the first 12 weeks in the womb. This is called organogenesis. The baby may therefore be vulnerable to any effects the medicines could have during this time.

Nausea or ‘morning sickness’ in the early stage of pregnancy. This is very normal, but symptoms of morning sickness are very similar to the nausea that can occur when starting HIV treatment.

If an HIV-positive pregnant woman either wants to begin treatment immediately, or urgently needs to start because she has a low CD4 count, this should be recommended by her doctor. iii) If she discovers she is HIV-positive late in pregnancy Late in pregnancy, there is still a benefit to using treatment. Even after 36 weeks, it will reduce the mother’s viral load to very low levels. Even using treatment for one week with combination therapy will reduce viral load levels very quickly by a large amount. iv) If she is already using HIV treatment when she becomes pregnant Many women decide to have a baby when they are already using HIV treatment. Unless there are very particular circumstances she should remain on her treatment (see Section 6.4).

HIV i-Base: basic training for advocates

S6:83

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

6.6 Safety of HIV drugs in pregnancy Which drugs to use: •

As with all treatment decisions there are no hard and fast rules.

AZT is the only drug licensed for use in pregnancy and there is much experience with its use so it is likely that it will be recommended as part of her combination.

The second NRTI is likely to be 3TC as there is also much experience with this drug in pregnancy.

The third drug will be either a protease inhibitor - and there is most experience with nelfinavir - or an NNRTI such as nevirapine – but there are some cases where this drug would not be appropriate.

Drugs and situations where drugs are not recommended: •

Efavirenz is not recommended in pregnancy and the caution is strongest during the first trimester (12 weeks), because of possible risk to the baby. If someone finds that she is pregnant and using efavirenz she will need to have some extra tests. After the first trimester there is no point in switching efavirenz.

Nevirapine is not recommended for women with CD4 counts above 250 cells/ mm3 (not just during pregnancy), because of risk of liver toxicity. It is very safe for women with CD4 counts below 250 cells/mm3.

There is a strong warning against using d4T and ddI - the ‘d’ drugs – together. There have been several reports of fatal side effects in pregnant women using these drugs together. d4T is no longer recommended for first line therapy in Western Europe and North America.

6

HIV i-Base: basic training for advocates

S6:84

January 2008


www.i-Base.info

Section 6: HIV and pregnancy

6.7 Side effects and pregnancy Side effects should be carefully monitored in pregnancy. These are a few important points about side effects in pregnancy (see also Section 4: Side effects of ARVs). Similar to non-pregnant adults - Approximately 80% of pregnant women using combination therapy with ARVs will experience some side effects. This is similar to the percentage of women using ARVs who are not pregnant. Usually minor - Most side effects are minor and include nausea, feeling tired and diarrhoea. Sometimes, but more rarely, they can be very serious. ARV side effects and pregnancy changes - Some effects of HIV medicines are very similar to the changes that happen during pregnancy e.g. morning sickness and the nausea caused by ARVs. This can make it harder to tell whether treatment or pregnancy is the cause. Anaemia (low red blood cells) can cause tiredness. It is a very common side effect of both AZT and pregnancy. A simple blood test checks for this. If someone has anaemia they may need to take iron supplements. Diabetes - There is a risk of developing diabetes during pregnancy. And women taking protease inhibitors in pregnancy may have a higher risk of this common complication. They should have glucose levels monitored and be screened for diabetes during pregnancy. Lactic acidosis -Pregnancy may be an additional risk factor for raised levels of lactic acid. Your liver normally regulates this. Lactic acidosis is a rare but potentially fatal side effect of nucleoside analogues. Using d4T and ddI together in pregnancy appears to be particularly risky. This combination is now not recommended in pregnancy.

6.8 Resistance in pregnancy Resistance is an important issue during pregnancy. Some strategies to reduce mother-to-child transmission can also easily lead to resistance. Using only one drug (monotherapy) or two drugs (dual therapy) is not as good as the minimum treatment for an HIV-positive person. Of these strategies, AZT used alone is less likely to induce resistance than AZT plus 3TC or nevirapine alone. Resistance can also develop when a personâ&#x20AC;&#x2122;s viral load is detectable with three or more drugs. This will affect their long-term health.Viral load at time of delivery is also strongly linked with risk of transmission from mother to child. It is also possible to transmit resistant virus. The expectation for outcome of a baby born with drug resistant HIV virus is very poor as their HIV will be much harder to treat. See also Section 3.18 on Resistance to ARVs.

HIV i-Base: basic training for advocates

S6:85

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

6.9 Other screening and tests HIV care in pregnancy should include screening for hepatitis, syphilis and other sexually transmitted diseases, anaemia and TB. Sexually transmitted diseases and vaginal infections can increase HIV transmission. Screening for toxoplasmosis and CMV may also be necessary. These are two common viruses that can be transmitted to a baby. The tests should be performed as early as possible in pregnancy, and treated if necessary. A clinic should provide a gynaecological check up. This will include a cervical smear. This is particularly important if a woman’s CD4 is below 200 cells/mm3. Tests to be avoided by HIV-positive pregnant women Generally HIV-positive pregnant women are advised to avoid the following tests unless they are essential: •

Amniocentesis

Chorionicvillus sampling

Fetal scalp sampling

Cordocentis

Percutaneous umbilical cord sampling

Internal fetal labour monitoring (external ultrasound and fetal monitoring are perfectly okay).

6.10 Other infections Treatment and prophylaxis for most opportunistic infections (OIs) during pregnancy is broadly similar to that for non-pregnant adults. Only a few drugs are not recommended. PCP, MAC,TB - Prophylaxis and treatment of pneumocystis carinii pneumonia (PCP), mycobacterium avium complex (MAC) and tuberculosis (TB) infections are recommended if necessary during pregnancy. CMV -Prophylaxis against cytomegalovirus (CMV), candida infections, and invasive fungal infections is not routinely recommended because of drug toxicity. Treatment of very serious infections should not be avoided because of pregnancy. Herpes - A large number (about 75%) of women with HIV also have genital herpes. HIVpositive mothers are far more likely to experience an outbreak of herpes during labour than negative mothers. To reduce this risk prophylaxis treatment for herpes with acyclovir is often recommended. Herpes is very easily transmitted from mother to child. Even if HIV viral load is below detection on ARVs, herpes sores contain high levels of HIV. The herpes virus can also be released from the sores during labour. This will put the baby at risk from neonatal herpes and at increased risk of HIV. Prophylaxis and treatment with acyclovir is safe to use during pregnancy

HIV i-Base: basic training for advocates

S6:86

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

6.11 Drugs and the baby’s health Today, even children who were first exposed to AZT monotherapy during their mothers’ pregnancy will not be older than fifteen. Children first exposed to combination therapy will not be more than six years old now. So this is the limit of long-term follow up of children of mothers who have used these drugs in pregnancy. But careful follow-up of children exposed to AZT has not shown any differences to other children so far. However, the biggest risk, to a baby born to a mother with HIV, is HIV itself. Combination therapy can prevent this. Prematurity -There was initial caution over the use of protease inhibitors. This was over possible links to prematurity (delivery before 37 weeks) and low birth rate. Abnormality - No particular abnormality in children has so far been linked to exposure to HIV treatments. Development -So far no adverse effects on these children’s development have been reported either. Mitochondrial toxicity -There have been a small number of reports that the use of 3TC and AZT in pregnancy may be linked to mitochondrial damage in children. Mitochondria are the ‘energy producing factories’ that live within our cells. But a large study failed to show evidence of fatal mitochondrial damage in children exposed to these drugs during their mothers’ pregnancy.

6.12 Choices for delivery and use of C-section Caesarean or C-section is a procedure to deliver a baby that involves making a cut through the abdominal wall to surgically remove the infant from the uterus. The way a baby is born and whether to have a vaginal birth or Caesarean section is controversial for HIV-positive women. Several early studies showed that an elective Caesarean (C-) section significantly reduced mother-to-child transmission compared to vaginal birth. But these studies were before combination therapy and viral load testing were routinely used. Whether or not elective Caesarean delivery offers any benefit to babies born to mothers using combination therapy is unknown. The operation must be carried out before the onset of labour and ruptured membranes. This is called ‘elective’ or ‘scheduled’ C-section. Complications, particularly infections, are more common in woman having C-sections than woman having vaginal delivery. There is such a low risk of transmission if a woman’s viral load is undetectable associated with either mode of delivery that it may never be possible to show an advantage in transmission risk either way. Interestingly, HIV transmission to the baby is rare among mothers who are taking ARV triple therapy, even when their viral load is greater than 50 copies/mL. It is very important that a woman makes her own informed decision in association with her healthcare team concerning mode of delivery. HIV i-Base: basic training for advocates

S6:87

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

6.13 When the baby is born The baby’s diagnosis Babies born to HIV-positive mothers will always test HIV-positive at first. This is because they have their mother’s immune system and share her antibodies. If a baby is not infected with HIV these will gradually disappear. This can sometimes take as long as 18 months. The best test for HIV in babies is very similar to a viral load test. This is an HIV PCR DNA test. It looks for virus in the baby’s blood rather than at immune responses. To check the baby is HIV negative: • HIV PCR DNA is a polymerase chain reaction (PCR) test and is a highly sensitive test that detects tiny amounts of HIV DNA in blood plasma. • The test will “amplify” or multiply the DNA so that HIV can be more easily detected. Good practice is to test babies the day they are born, and when they are one month and three months old. It will be possible to show that the baby no longer has the mother’s antibodies when he or she is 18 months old. This is called seroreversion. If all these tests are negative, and the mother is not breast-feeding the baby, then the baby is not HIV-positive. The baby’s treatment A baby will need to take HIV drugs for probably four to six weeks following his or her birth. This is most likely to be AZT, which must be taken either two or four times a day. In a few cases a baby may be given another drug or combination therapy.

6.14 Breastfeeding The risk of transmitting HIV from mother-to-baby via breast milk can be as high as 28%. HIV-positive mothers living in industrialised countries can easily avoid this by using bottles and formula milk. Bottle-feeding is strongly recommended for all HIV-positive mothers. It is also strongly recommended that a woman does not breastfeed occasionally. In fact one study showed that ‘mixed feeding’ may carry an even higher transmission risk than exclusive breastfeeding.

HIV i-Base: basic training for advocates

S6:88

January 2008

6


www.i-Base.info

Section 6: HIV and pregnancy

6.15 Motherâ&#x20AC;&#x2122;s health after the baby is born A motherâ&#x20AC;&#x2122;s own adherence after the baby is born is critical. New mothers often neglect their own health. Many women have excellent adherence during their pregnancy. After the baby is born it is easy to forget their own health. Having a new baby can be a huge shock. In serious cases, women can have postnatal depression. So they will need lots of extra support from their family, friends and healthcare team. She may also find a community group very helpful. Many mothers find the best way to remember to take their own medication is if they link it to the dosing schedule of their new baby.

6.16 Other useful information i-Base pregnancy booklet

http://www.i-Base.info

International Community of Women (ICW)

http://www.icw.org

WORLD

http://www.womenhiv.org

Project Inform

6

http://www.projinf.org

British (BHIVA) pregnancy and treatment guidelines

http://www.bhiva.org/

US pregnancy guidelines

http://www.aidsinfo.nih.gov/guidelines/

Pregnancy registry

http://www.apregistry.com

So far, the registry has not seen any increase in the type or rate of birth defects.

HIV i-Base: basic training for advocates

S6:89

January 2008


www.i-Base.info

Section 6: HIV and pregnancy

6.17 Glossary: Section 6 Caesarean or C-section

A procedure to deliver a baby that involves making a cut through the abdominal wall to surgically remove the infant from the uterus. This can be either a planned or scheduled C-section or an emergency Csection. An emergency C-section offers no reduction in transmission to women receiving no therapy or monotherapy.

Mother-tochild-transmission Transmission of HIV is when the virus passes from one person to another. When this is from mother to baby it is called mother-to-child transmission (MTCT) or perinatal or vertical transmission. Pre-natal

The period before a baby is born during which the foetus (developing baby) develops and grows in the uterus.

Post-natal

The period after a baby is born.

Prophylaxis

When you take a drug to prevent an infection or reinfection before it occurs.

â&#x20AC;&#x153;Treat as nonpregnant adultâ&#x20AC;?

This is a very commonly used phrase. This means that generally your HIV is treated as if you are not pregnant. There are some exceptionsparticularly when you do not need treatment for your own HIV and concerning some of the commonly used HIV drugs.

6

HIV i-Base: basic training for advocates

S6:90

January 2008


www.i-Base.info

Section 6: HIV and pregnancy

6.18 Questions: Section 6

1.

What percentage of babies will be born HIV-positive if their mothers receive no treatment?

2.

What is the most important factor in preventing mother to child transmission?

3.

Does the fatherâ&#x20AC;&#x2122;s HIV status relate to the baby being born HIV positive?

4.

Does pregnancy influence the CD4 count of the pregnant woman? If yes, how?

5.

What are the risks for the mother if she uses only AZT monotherapy for reducing mother to child transmission?

6.

What is the current mother to child transmission rate when a pregnant woman receives a combination therapy of three or more drugs?

7.

What should be the advice to an HIV positive pregnant woman who does not need ARVs for her own HIV infection yet?

8.

List the pros and cons of the C-section as a means of delivery for an HIV positive pregnant woman.

9.

Which ARVs, or combinations of ARVs, are not recommended in pregnancy, or in particular circumstances in pregnancy. List them and explain why.

10.

To which conditions can pregnancy contribute?

11.

Which tests should an HIV-positive pregnant woman avoid?

12.

When would you recommend prophylaxis with acyclovir during pregnancy?

13.

When and how should the babyâ&#x20AC;&#x2122;s HIV status be checked?

14.

Can HIV-positive women breastfeed? Please explain?

15.

For how long should a baby take ARVs ?

16.

What is particularly important for an HIV positive woman to remember after her baby is born?

6

HIV i-Base: basic training for advocates

S6:91

January 2008


www.i-Base.info

Section 6: HIV and pregnancy

6.19 Course evaluation for Section 6 Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation.

Session 6 How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

HIV i-Base: basic training for advocates

6

S6:92

January 2008


www.i-Base.info

Section 7: Drug users and ARVs

Session 7: Drug users and ARVs

“All patients who meet eligibility criteria and want treatment should receive it, including IDUs, sex-business workers and other populations. Access to HIV treatment should not be artificially restricted due to political or social constraints. Specifically there should be no categorical exclusion of injection drug users from any level of care.” WHO’s 2004 Protocols for HIV/AIDS

7.1 Introduction to Section 7 Transmission of HIV through injecting drug use accounts for the majority of new infections in: Russia, Ukraine, Central Asia, some of Eastern Europe, South East Asia, North Africa, Iran, Afghanistan, Pakistan, Nepal, Indonesia, Portugal and the Southern Cone of Latin America. People at risk of becoming HIV positive through injection drug use are often among the poorest and most marginalised sections of society: ethnic minorities, unemployed, youth, migrants, and sex workers. Additionally - although there has been little or no research to address this - there are potential interactions between injection and non-injection recreational drugs, substitution therapies and ARVs.

HIV i-Base: basic training for advocates

S7:93

January 2008

7


www.i-Base.info

Section 7: Drug users and ARVs

7.2 Aims for Section 7 This section provides an overview of three key areas: •

Beliefs and realities around treatment for drug users with HIV

Known and potential interactions between recreational drugs and ARVs

Known and potential interactions with methadone

7.3 General questions Why are drug users sometimes excluded from ARV treatment programmes? In many countries drug users are routinely excluded from ARV treatment programmes due to widespread belief that they are less likely to be adherent to treatment and less likely to have a good response to treatment. Reluctance to offer ARV to drug users includes not only injection drug users (IDUs), but also those on medically prescribed substitution treatment such as methadone, users of non-injection drugs, and former drug users. Is this appropriate? No. Beliefs that drug users are non-adherent and untreatable are based on prejudice rather than science. However, several studies suggest that drug users—particularly when HIV treatment is delivered with adherence, social and medical support—can achieve high levels of adherence and benefit from treatment just like any other group of people with HIV. •

A large Western European study of people receiving ARVs found no significant difference between IDUs and non-drug users in CD4 or treatment response.

Another study in Canada found that drug users who were adherent to treatment gained the same increases in CD4 count as adherent non-drug users.

In an American mobile syringe exchange programme, 77% of drug users offered peer support along with ARVs achieved reduction of viral load to less than 400 copies/ml and a 25% increase in CD4 after six months.

A French study of people receiving ARVs found that those also receiving buprenorphine achieved higher levels of adherence (78.1%) than either former drug users (65.5%) or active IDUs not on buprenorphine (42.1%).

7 HIV i-Base: basic training for advocates

S7:94

January 2008


www.i-Base.info

Section 7: Drug users and ARVs

7.4 Comprehensive and accessible care Including as many health and social services as possible at a single site has been shown to improve both adherence and treatment outcomes for IDUs. Drug users are often unwilling to come forward, and there is a need for appropriate support. Services need to be located somewhere accessible to IDUs and within the HIV clinic setting. Comprehensive, multi disciplinary services should include: •

Access to ARVs

Access to substitution therapy: methadone or buprenorphine

OI prophylaxis and treatment

Accessible, non-judgemental healthcare team

Needle exchange

Adherence support and counselling

Strong links with community based programmes

Food programmes and public transport

Outreach strategies

7.5 Interactions between recreational drugs and antiretrovirals There is much research and information about interactions between antiretrovirals and other prescribed medications, but little reliable information about interactions between ARVs and recreational drugs. In 1996 a young HIV positive British man died after taking ecstasy while using ritonavir. His death was caused by an overdose, and the level of ecstasy in his blood was nearly ten times the level that is expected to cause serious toxic effects, ie roughly the level after taking 22 ecstasy tablets. The patient had taken ecstasy previously with no such ill effects. This was the first time that he had taken ecstasy since adding ritonavir – taken full dose ie 600mg twice daily – to his ARV combination, which is why his doctors concluded that this interaction was the culprit. Following interventions by activists, the company – Abbott - produced some theoretical interaction information for ritonavir and commonly used recreational drugs. Predicted interactions with ritonavir and street drugs: •

2 to 3 fold increase in ecstasy levels

About 50% decrease in blood levels of heroin

2 to 3 fold increase in levels of amphetamines

No serious interactions with cocaine

Note: this information is based on using full dose ritonavir; this drug is now most commonly used to boost other protease inhibitors.

HIV i-Base: basic training for advocates

S7:95

January 2008

7


www.i-Base.info

Section 7: Drug users and ARVs

7.6 Why this theoretical information is not as useful as controlled interaction studies in humans? Because these drugs are illegal, predicted interactions are not based on studies in humans but based on theory, experiments in test tubes (in vitro) or animal studies. There are a number of difficulties both with conducting proper studies and using the theoretical information: •

Clinical trials using illegal drugs would require permission from the (American) government, which has been exceedingly reluctant to allow such studies for fear of being perceived as “soft on drugs”.

Finding supplies of pure drugs would, in some cases, be difficult. There are no approved versions of drugs such as cocaine. For legal and ethical reasons, drug companies are unwilling to manufacture test versions of such drugs in their own laboratories, even if the government granted permission.

Illegal drugs are seldom pure, are often contaminated by other substances, and may contain very little or none of the actual ingredient.

Illegal drugs rarely have standardised doses: what could be a relatively minor interaction at one dose could be serious at another.

There is little financial incentive for drugs companies to do this work.

Some protease inhibitors have been found to have effects in real life opposite to those predicted in the test tube (eg, there have been instances of decreased methadone levels in human users where test tube experiments had predicted such levels would increase).

Manufacturers are concerned about legal liability should they offer advice based on uncertain or potentially incomplete information.

7 HIV i-Base: basic training for advocates

S7:96

January 2008


www.i-Base.info

Section 7: Drug users and ARVs

7.7 Interactions with other ARVs All protease inhibitors are processed by the body in a similar way to ritonavir, as is the NNRTI efavirenz, so there is potential for interaction with any of these drugs. A comprehensive overview summarising interactions between ARVs and recreational drugs (and methadone) lists the following potential interactions and observed interactions from case studies and makes recommendations. See Table 1 in Section 7.9. Ecstasy -

Potential for an interaction with PIs or efavirenz. Advised to take appropriate precautions: use 25% of the usual amount of ecstasy, take breaks from dancing, ensure rave or party has medical team on site, drink lots of water and avoid combining with alcohol.

Other amphetamines â&#x20AC;&#x201C; Potentially dangerous interactions with ritonavir and this combination should be avoided if possible. GHB

Potential interaction with PIs (especially ritonavir) and possibly efavirenz.

KETAMINE There are no studies or reports describing interactions between ketamine and antiretroviral agents. People using PIs may be at risk for ketamine toxicity due to drug accumulation. PCP (angel dust) Potential that use of PCP with PIs, and possibly efavirenz may result in elevated PCP concentrations and resultant toxicity. People using PCP who are also receiving treatment with ARVs should be cautioned to use less than what they would normally use given the potential for a drug interaction. LSD

It is not very clear how this drug works, therefore anticipating drug interactions with LSD is extremely difficult. People who use LSD recreationally and who use ARVs should be warned about the possibility of an interaction and to be familiar with signs of LSD toxicity, and perhaps consider using a smaller amount than normal.

Cocaine

Interactions between cocaine and antiretrovirals have not been described. It is thought that interactions with nevirapine or efavirenz may possible increase the risk of liver toxicity but there is no research to support this.

Heroin

There may be concern that heroin is more rapidly metabolized producing symptoms of withdrawal when used with PIs and efavirenz.

7 HIV i-Base: basic training for advocates

S7:97

January 2008


www.i-Base.info

Section 7: Drug users and ARVs

7.8 Interactions with methadone There have been more studies of interactions between ARVs and methadone. •

People using methadone and efavirenz or nevirapine will have a reduced dose of methadone (of up to 60% in blood concentration) and may require an increase in their methadone dose to overcome symptoms of methadone withdrawal.

There was a decrease of methadone of 36% in a human study of interaction with ritonavir. This was interesting as a previous study in the test tube found a 30% increase in methadone.

Reduced concentrations of methadone have been found with PIs nelfinavir and lopinavir/ritonavir. Some people may need a dose increase of methadone.

AZT concentrations are increased by approximately 2-fold and so a dose reduction of 50% of this drug is recommended with methadone.

In contrast, methadone appears to decrease concentrations of d4T and ddI – there are currently no guidelines for dose adjustment.

Reduced methadone concentrations are not always accompanied by symptoms of withdrawal. It can be difficult to distinguish between symptoms of ARV toxicity and symptoms of withdrawal (eg nausea, vomiting). It is likely that symptoms that develop within 2-3 days may be due to ARV toxicity, and those that develop after 6 days are more likely to be associated with withdrawal.

7 HIV i-Base: basic training for advocates

S7:98

January 2008


www.i-Base.info

Section 7: Drug users and ARVs

7.9 Table 1 â&#x20AC;&#x201C; Interactions Between Antiretrovirals and Rave Drugs Drug

Metabolism

Actual/ Theoretical Interaction

Potential Significance

Recommendation

Amphetamines

CYPD6

Possible _ concentration with ritonavir

Hypertension, hyperthermia, seizures, arrhythmias, tachycardia, tachypnea

Avoid combination with ritonavir if possible: alternatively, start with 25-50% of initial amount of amphetamine used

GHB

Expired breath as CO2 : first pass metabolism

Possible increased concentrations/ prolonged effect with antiretrovirals, expecially ritonavir

1 case of GHB toxicity with ritonavir/ saquinavir: myoclonic or seizure activisty, bradycardia, respiratory depression, loss of consciusness

Ketamine

CYP2B6 (main) 3A, 2C9 (both to lesser extent)

Possible increased concentration with antiretrovirals, especially ritonavir, nelfinavir and efavirenz

Respiratory depression, loss of conscousness, hallucinations

LSD

Unknown

Possible increased LSD concentration

Hallucinations, agitation, psychosis, flashbacks

MDMA, Ecstasy

CYP2D6 (main) 1A2, 2B6, 3A4 (to lesser extent)

Possible increase with ritonavir, other PIs, efavirenz

1 death reported; hyponatremia, hyperthermia, arrhythmias, tremor, hyperreflexia, sweating, seizures, tachycardia, rhabdomyolysis

PCP

CYP3A, CYP2C11, inhibits CYP2B1

Possible increased concentrations with antiretrovirals

Seizures, hypertension, rhabdomyolysis, hyperthermia

Use cautiously with CYP450 inhibitors (i.e. PIs, delavirdine, efavirenz,): become aware of signs/ symptoms of GHB toxicity

Use cautiously with CYP450 inhibitors, especially ritonavir nelfinavir, and efavirenz: become aware of signs/symptoms of ketamine toxicity Use cautiously with CYP450 inhibitors; become aware of signs/symptoms of LSD toxicity Avoid combination with ritonavir if possible; alternatively use 25% - 50% of usual amount and watch for signs of MDMA toxicity; stay well hydrated, avoid alcohol Use cautiously with CYP450 inhibitors; become aware of signs/symptoms of PCP toxicity

From: T Antoniou and A Lin-in Tseng. Interactions Between Recreational Drugs and Antiretroviral Agents. The Annals of Pharmacotherapy. 2002, October;Volume 36 HIV i-Base: basic training for advocates

S7:99

January 2008

7


www.i-Base.info

Section 7: Drug users and ARVs

7.10 Questions: Section 7 1.

Why are drug users frequently excluded from ARV treatment?

2.

Is this based on scientific evidence?

3.

What treatment and services would be ideally included in a system of comprehensive care for IDU?

4.

Is there an interaction between ritonavir and ecstasy?

5.

Is there an interaction between ritonavir and heroin?

6.

Is there an interaction between efavirenz and methadone?

7.

What is dose changes, if any, are recommended in each case?

8.

Is there an interaction between efavirenz and AZT?

9.

What is recommended?

10.

How could you distinguish between symptoms caused by ARVs toxicity and symptoms of drug withdrawal?

7 HIV i-Base: basic training for advocates

S7:100

January 2008


www.i-Base.info

Section 7: Drug users and ARVs

7.11 Course evaluation of Section 7

Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation as we can develop this into an online resource. Session 7 How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

7 HIV i-Base: basic training for advocates

S7:101

January 2008


Section 8: Clinical trials and research

www.i-Base.info

Chapter 8: Clinical trials and research

8.1 Introduction to Section 8 Section 8 provides information about clinical trials and research. This section of the manual aims to provide a key grounding for advocates interested in this subject. It also includes information about how research is presented and how to analyse and interpret trial results. Community involvement in HIV research is important. Advocates have always argued for active patient and community representation and involvement at all stages of our health care, including research. This includes being involved on the type of research and the design of trials. It helps make sure: •

That trials are run properly,

That all patients receive at least current standard-of-care treatment,

That we are able to monitor and follow both enrolment, and

That we are able to monitor and follow early results.

As patients and advocates we have a good idea on how latest treatment advances may affect the standard of care in the future. This will help plan trials that will still be relevant when they come to enrol. Even after a study is finalised, it will often take a year or longer before any patients are enrolled, and then several years for the study to run. Trials need to therefore be designed based on what we expect the standard of care to be for the duration of the study. For community advocates to be actively involved, and not just included to show good clinical practice, or for researchers to get grant approved, most advocates will need training and support.

HIV i-Base: basic training for advocates

S8:102

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

8.2 Aims for this section After reading this section advocates will have an understanding of: •

How trials are designed to produce reliable and accurate information

Why research is needed to inform treatment choices

The basic concepts used in trials

The main types of trials and quality of different types of studies

Advantages and disadvantages of different studies

Common features of all studies

Informed consent and patient care

Interpreting study results

The different roles advocates can take

Examples: 6 key studies (separate section)

8.3 Why trials are important Modern medicine is often called ‘evidence-based medicine’. This is because it is based on treatments or strategies that have been proven to show an advantage compared to other approaches. Well-designed studies can produce results that can be carefully studied, and often repeated in similar studies. Without trial results, treatment decisions would only be based on guesswork, on the hope that a treatment works, on untypical results or on commercial marketing. Hard evidence is needed to know how to improve care. Trials can show which drugs are better than others. For example, the higher risk of side effects when using d4T compared to tenofovir in first-line therapy. Trials can show which strategies are better than others – for example that combinations that include three drugs are better that combinations with two drugs.

8 HIV i-Base: basic training for advocates

S8:103

January 2008


Section 8: Clinical trials and research

www.i-Base.info

8.4 Developing a new treatment: Phase I, II, III and IV studies When a new drug is being developed, there are four main ‘phases’ of clinical research. These studies are run in order – you have to start with Phase I, then II etc Pre-clinical research is the term used to describe the whole range of studies, including test-tube and animal studies, that are carried out before a drug enters human trials. Phase I studies Phase I studies are the first human studies. This includes single-dose studies that are often called Phase Ia trials. A small group of patients (5-10) will take one dose and be carefully monitored. 1-2 patients will usually get a placebo. Short-term multi-dose studies, perhaps for 1-2 weeks, are called Phase Ib. This is where a slightly larger group (perhaps 10-20 patients) will take multiple doses and be carefully followed. These studies are usually in ‘healthy volunteers’ - ie for an HIV drug, the first people to take it are HIV-negative. Phase II studies Phase II studies are usually the first study to look at activity – whether the investigational compound is actually active. These are short-term and in HIV-positive people. Phase IIa studies usually enrol 20-50 HIVpositive people. Phase IIb studies also look at different doses of a drug – called ‘dose-finding’ studies. In which case they may enrol 200-300 people. Phase III studies Phase III studies are the large trials that are used by regulatory agencies to decide whether a drug will be approved. For an HIV drug this is usually 1000 – 2000 patients. If the same people from the Phase II study, continue to be followed in the Phase III study, the study is sometimes called Phase II/III. If one study leads into another study, it is called a ‘roll-over’ study. Phase IV studies Phase IV studies are usually referred to as ‘post-marketing’ studies. They involve longer follow-up of patients looking at side effects and other safety concerns. Sometimes a rare side effect, or a side effect that takes years to develop, are unlikely to be seen in Phase III studies. Phase IV studies are usually recommended by the regulatory agencies. Although, in the past, the European regulatory agency (called the EMEA) had very little power to make sure companies followed through on these commitments, recent legislation has strengthened these powers. Phase IV studies are now compulsory and the EMEA can withdraw a medication if safety commitments are not followed.

HIV i-Base: basic training for advocates

S8:104

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

8.5 Hypothesis and endpoints Several key concepts are important in research. Trial question â&#x20AC;&#x201C; the hypothesis This is the theory the trial aims to either prove or disprove. Every trial or study needs to start with a question: -

Is something happening?

-

Can doing something improve health?

-

Is one treatment better (or as good as) another?

Primary endpoint This is the main ways that the results of a trial will be assessed. It should be decided in the study design before any patients are enrolled. A primary endpoint decides what level of evidence or results will be accepted to prove or disprove the study question. What endpoints are chosen can determine in how useful the final results are. For example, with a new drug, the primary endpoint is often the percentage of people who have an undetectable viral load at a certain point. This could be 8 weeks for an early effect or 48 weeks for a longer effect. But it could also be the average drop in viral load or the average increase in CD4 count. Or a direct measure of health in how many people see improved or reduced health. Secondary endpoints Secondary endpoints can look at everything else: the safety of a drug, side effects, the impact on CD4 count, the impact on quality of life, the cost-effectiveness of treatment and many other factors. Community involvement in trail design can help ensure that important secondary endpoints are included when the study is first planned.

8 HIV i-Base: basic training for advocates

S8:105

January 2008


Section 8: Clinical trials and research

www.i-Base.info

8.6 Three main types of trial design There are three main categories that cover all trials. Each type of study has specific advantages and disadvantages. They all provide different types of information. Observational vs experimental (or interventional) An observational study either looks for evidence that something has happened, or follows people to see whether something happens. The trial doesnâ&#x20AC;&#x2122;t involve a specific intervention other than normal standard care. Examples of an observational study include: - Looking at a group of patients to see how many people have lipodystrophy - Following a group of patients to see how many people develop lipodystrophy An experimental (or interventional) study is where something specific is done in the study â&#x20AC;&#x201C; ie using a treatment, strategy, or other intervention, that is recorded and analysed. Examples of an experimental study include: - Comparing whether switching one drug for another improves diarrhoea, or - Seeing whether diet or exercise can improve fat accumulation Cross-sectional vs longitudinal A cross-sectional study looks at collecting information at one point in time. Examples of a cross-sectional study include: - Looking at a group of patients to see how many people have osteoporosis (bone disease) at one time point, or - Finding out what percentage of HIV-positive patients are smokers A longitudinal study follows individuals to see how things change over time. Examples of a longitudinal study include: - Following a group of patients to see how many develop lipodystrophy, or - Following a group of patients to see whether an intervention to quit smoking could reduce the percentage of patients at risk of heart disease Retrospective vs prospective A retrospective study looks backwards in time. Examples of a retrospective study include: - Analysing a database to find out what percentage of patients failed their first combination, or - Looking back at medical records to see whether a recently reported side effect has happened in other patients A prospective study decides on what is going to be studied and then follows people over time to see what happens.

HIV i-Base: basic training for advocates

S8:106

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

Examples of a prospective study include: - Comparing a new HIV drug to an existing drug - A trial of New-fill to treat facial fat loss (lipoatrophy) - Following a group of patients to see whether heart disease is linked to HIV treatment In describing a study one of each of these three terms should be included, ie - An observational, longitudinal, prospective study - An interventional, longitudinal, prospective study - An observational, cross-sectional, retrospective study

8.7 Randomised, double-blind, placebo-controlled trials The most reliable evidence – often referred to as the ‘gold standard’ – is ‘ a prospective randomised, double-blind, placebo-controlled study. Randomisation Randomising patients in a study is the best proven way to allow for the fact that some things in a trial – and in life - can happen by chance. Patients in a study are often randomised when two or more groups are studied. Randomisation is designed to balance factors in each group that could affect the study results. This includes known factors, such as sex, smoking status or social differences, and unknown factors such as genetic differences that we may not know anything about. Randomising people, if done correctly, and especially with larger groups, should normally result in an approximate balance of all these factors. This is a very difficult concept, but it is one of the most important things to understand. It also stops bias. For example, it prevents a doctor putting patients who are most ill and in need of treatment into the group that receives an active drug rather than a placebo (dummy pill). If this happened, although this may sound more ‘fair’, the two groups would be different at the start, so you couldn’t compare the results accurately at the end. Clinical research, by definition, involves different people getting different treatment. Often the people to get first access to a treatment in a trial, do not get the best results compared to people after the drug is approved. The balance though, is that by getting earlier access to treatment, they can benefit from other later research. Randomisation has to be done in a way that doesn’t select a certain group over another. The most common example for randomising a patient to one of two groups is to toss a coin for each patient – heads they join one group and tails they join the other. This is because tossing a coin is random and can’t be predicted. Over time, the more a coin is tossed, the more likely that approximately 50% will be heads and 50% will be tails.

HIV i-Base: basic training for advocates

S8:107

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

An example of bad randomisation would be assigning patients who come to clinic on a Monday to one group and patients who come on a Tuesday to another. In this example, people who come on Mondays may be different from people who come on a Tuesday, for social reasons. They may be more organised people, or less likely to have a hang over from the weekend. This could represent important differences between the two groups – ie alcohol use – and this could affect the study results. When a study reports its results they also report the characteristics of people being studied. Sometimes, even with randomisation, you may see that one group may have different characteristics. This is sometimes adjusted for in the final analysis, or needs to be considered when interpreting the study results. Blind and double-blind studies Blinding (sometimes called ‘masking’) is the term to describe a doctor, patient or researcher not knowing which study group a patient has been assigned to. A blinded study is where the patient doesn’t know which group they are in, or which treatment they are getting. A double-blinded study is where neither the doctor nor the patient know which group the patient is in. Blinding prevents different care or treatment being given based on what either the doctor or patient believes. An example of why blinding is important is that if someone know they are getting an active drug, both doctors and patients may be more likely to report side effects. It could also affect how likely a patient is adherent to treatment. Placebo A placebo is the term for a dummy pill, ie a pill that looks, smells and tastes like the drug that is being studied, but which has no active ingredient. Using a placebo helps find out whether the active drug is really active. It also helps interpret side effects. If 10% of people in the active drug group report having a headache and 2% of people in the placebo group report a headache, then it is reasonable to think that the active drug can cause headaches. If 10% of the placebo group also reported a headache, then it is reasonable to think that the active drug doesn’t cause a headache. An example of why placebo trails are still important was shown in the development of an NNRTI called capravirine. In an early (Phase IIb) study people using capravirie plus a background regimen did no better than people using the same regimen plus a placebo. This stopped further development of the study drug without putting any further patients at risk from using an ineffective treatment in later trials.

HIV i-Base: basic training for advocates

S8:108

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

Control group A control group refers to a group of patients in a study, that any intervention is compared to. This helps to show that the intervention actually caused what was seen and that it wouldnâ&#x20AC;&#x2122;t have happened anyway. One common type of control group is to use a placebo. 250 patients get best treat

500 patients

ment + trial drug

Follow for

24 weeks

and compare

Randomise

250 patients

results

get best treat-

ment + placebo

Although all patients get the best treatment with or without the new drug, if, for example, this is a new HIV drug and the best treatment already includes 3 active drugs, then it could be difficult to see any difference between the new drug and the placebo â&#x20AC;&#x201C; because both groups will already do very well. Another type of control group is a group where no intervention takes place.

250 patients get trial drug

500 patients

Randomise

250 patients get

no intervention

Follow for

24 weeks

and compare results

This example might be used where there is something about the trial drug that makes using a placebo difficult â&#x20AC;&#x201C; perhaps because it is given by injection. The difficulty of not randomising the control group to having a placebo is that you can never be sure whether some of the things (both good and bad) that happened to patients in the active drug arm, are not due to chance. More importantly, people in each arm may behave differently because they know they are getting active drug, for example, by reporting more side effects. Another type of control group is to use a drug or combination that has already been studied. 250 pts: tenofovir +FTC + trial drug 500 patients

Follow for

Randomise

HIV i-Base: basic training for advocates

24 weeks

250 pts: tenofovir

+ FTC + efavirenz

S8:109

and compare results

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

This is still generally the type of trial design used for studying a new HIV drug in people who are treatment-naïve. This is generally ok, so long as the new drug turns out to be better than, or at least as good as, the current standard of care (ie tenofovir+FTC+efavire nz). For this reason, early trials with this design should not enrol people who have advanced HIV (for example with CD4 counts less than 100 cells/mm3) as these people will need to depend on a proven treatment. Randomising patients should mean that important factors – known and unknown – are likely to be distributed between each group. For example, having the similar numbers of women, Caucasians, smokers, CD4 counts etc.

8.8 Other types of studies Although we referred earlier to randomised, double-blind, placebo-controlled studies as the gold standard, other types of studies are very common, and are often needed first in order to justify the expense of running a randomised controlled study. Randomised controlled trial (RCT) These are usually experimental and prospective, and compare two or more groups. Randomisation is the most important factor, as it should make sure each group is similar at the start. The control group helps confirm whether a real effect is seen, rather than just happening by chance, or from other external factors. All potential new drugs have to be studied in RCTs before they can be approved. Cohort study Cohort studies are usually observational and longitudinal. They can either follow a group of people prospectively to see the incidence of whatever is being looked for or look backwards (retrospectively) to look for an effect. They can also look as other factors that can contribute to an effect. Cohort studies may include all patients at one or more hospitals (such as the MACS or WIHS cohorts in the US), or patients in one country (such as the UK-CHIC cohort), or can include international collaborations of national cohorts, such as the EuroSIDA or D:A: D studies in Europe. Cohorts can provide different types of results to an RCT. They can report on what happens in a regular clinic setting, in a wider group of patients than are usually selected for clinical trials. People can be followed for longer, and they can look at more than one or two options. However, because patients are not randomised to different treatments and know which treatment they receive (ie are not blinded), results have to be interpreted carefully to try to rule out other things that might explain the results (called ‘confounding factors’).

HIV i-Base: basic training for advocates

S8:110

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

Case-control study These studies are usually observational and retrospective. A group of patients with a symptom (cases) are compared to similar patients without the symptom (controls) in order to try and identify what factors either caused the symptom or protected against it. A case-control study could look at a group of people with lipodystrophy compared to a similar group (similar age, gender, duration of HIV infection, smoking status, etc) and see whether there was a pattern in different HIV drug use; or look to see whether genetic factors could be identified. Cross-sectional study These studies are usually quick studies to look at the scale of a problem: what percentage of a population are HIV-positive; what percentage of people have lipodystrophy etc. They can identify prevalence of an illness (how many people have a disease at any one point in time) but not the incidence of an illness (how many people will develop an illness over time). The results from cross-sectional studies are limited by not being followed in time. We can see what is seen at and analyse what factors are related or associated to what is seen, but they cannot prove that one thing causes another or what intervention improves it. Case study and case-note review This is not a strong type of evidence, but can be used to collect data that might lead to other types of studies. A case study is where an individual patient report is included as evidence. Even though all sorts of other factors could have caused what was seen, case studies can alert researchers, doctors and patients to something new. Case note review is where a group of patient notes are reviewed retrospectively, and are limited by quality of the data that is recorded. Literature review and systematic literature review A literature review can report collected results of selected studies, A systematic review has to include all relevant studies in the area being looked at. Meta analysis This refers to analysing and comparing collected results from several studies. These results have to be carefully interpreted as different studies usually involve different types of patients and it is not straightforward to just compare a final end result. Both literature reviews and meta analysis are reliant on the types of studies that are published. For the results to be reliable you need to see the range of studies that were included in the analysis.

8 HIV i-Base: basic training for advocates

S8:111

January 2008


Section 8: Clinical trials and research

www.i-Base.info

8.9 Grading given to different types of evidence Different types of trials are given a different weight when making recommendations in treatment guidelines. UK Treatment guidelines use the following system to rate the different importance of different types of evidence. Table 1: Grading of recommendations and levels of evidence (www.BHIVA.org) Recommendation

Quality of evidence for recommendations

A

Required, should always be followed

B

Recommended, should usually be followed

C

Optional

(I)

At least one randomised trial with clinical endpoints

(II)

At least one randomised trial with surrogate markers

(III)

Observational cohort data

(IV)

Expert opinion based on other evidence

A recommendation A (1) should alwasy be followed and is supported by the most reliable evdence form clincal trials. Recommendation A (IV) should be followed, but this is based on expert opinion and has not been proven by any studies (perahps because they would be unethical to run).

8 HIV i-Base: basic training for advocates

S8:112

January 2008


Section 8: Clinical trials and research

www.i-Base.info

8.10 Glossary of other terms Cross-over study

Where patients in a study â&#x20AC;&#x2DC;roll-overâ&#x20AC;&#x2122; to a second related study. For example, this can be after a fixed period in a study (ie after 48 weeks) or after another event (for example, not having a treatment response).

Intent-to-treat (ITT) vs Observed/on-treatment (OT)

These are two important ways that drug trial results are analysed. ITT includes all patients when calculating the response rates. OT only calculates the response rates for people still on the randomised treatment.

For example:

100 people use a trial drug in one arm of a study

25 stop treatment before the end of the study for various reasons

50 have an undetectable viral load after 48 weeks

25 have a detectable viral load after 48 weeks

In an ITT analysis 50% of people got an undetectable viral load using the study drug (50 out of 100 patients).

In an OT analysis, 66% of people got an undetectable viral load using the study drug (50 out of 75 patients).

ITT analyses are more conservative but arguable are most important when looking at overall effectiveness and safety. OT analyses always make a drug look more effective, so you need to check which analysis is being presented.

In-vitro

A study in a test tube.

In-vivo

A study in humans.

Matched sample ie each group has similar age, gender, ethnicity, health, etc Null hypothesis

This sometimes just refers to the hypothesis in a study, but more specifically it refers the idea that any difference between to study groups has only occurred by chance.

Open label

Where a patient in a trial knows which treatment they are taking.

Publication bias

Refers the tendency for published results to be different to other trials. For example, trials that show a positive effect are more likely to be reported and published, than trials that find no effect.

Qualitative

Where what is being measured either fits one of several categories, or includes descriptive results.

HIV i-Base: basic training for advocates

S8:113

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

Quantitative

Where what is being measured has a numerical value or fits a pre-defined scale or range of responses.

Study population

This is a term of the group of people in a study. What happens in study population overall is not guaranteed to happen in every individual.

8.11 How studies are reported Most studies are reported using a similar format or structure. This involves 5 main sections: Background – the context for the study – what is already known about this area of research and why the study is being run. Method – the study design – what exactly was studied and how it was preformed. Results – what was seen or demonstrated. Discussion – this can include a discussion about the strengths and weaknesses of the study: cautions about interpretation, what could have been done better, and the implications for clinical practice, treatment guidelines or for further research. Conclusion – the final summary results – what was learned and how it can affect care. Sometimes researchers jump from their results to conclusions that are not supported by their evidence. This is important to look out for. Abstract A study abstract is a reduced summary of the main points of a study and is usually limited to around 500 words. There is not usually enough information in the abstract to be able to discuss the quality and significance of the findings. Poster A poster presentation at a medical conference should usually include many more details and is the format used to give more information when the study is presented at a conference. Peer-reviewed publication A peer-reviewed publication is the most detailed presentation of a study, where other experts in the field have examined the methods, results, and conclusions – in order to verify that the study was conducted properly and that the results stand up to scrutiny. Peer-reviewed publications takes longer. Many studies presented at conferences are never followed through to publication. Results seen in a trial are often different to the results you would expect to see out of a trial – for example, after a drug has been approved. Results are often better, because people in studies may be more organised and committed to treatment, and because they receive more care and time at the hospital, When looking at a study it is important to look at the authors, where they work and if they have a declared conflict of interest

HIV i-Base: basic training for advocates

S8:114

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

8.12 Patient involvement in clinical studies and research Clearly, studies need patients. But patients are real people, not just the subjects of research. Any clinical study should follow guidelines to ensure that the trial is ethical. Factors include ensuring that: •

Patients are willing to be part of the research and freely consent to this.

- This is why non-technical information about any study has to be available for discussions with doctors and researchers AND as written material in a patients’ first language. Community advocates should be involved in writing and approving this material. Patients understand the risks and benefits of a study.

- This is why patients need to sign an ‘informed consent’ form before entering a study. This is a form which every participant needs to sign before entering a study. In theory, it should mean that every patient understands the risk and benefits of the study, and voluntary agrees to take part in the research. In practice, informed consent forms can be difficult to understand, and many patients are happy to sign whatever their doctor recommends.

- informed consent can be withdrawn by a patient at any time, and this should not affect his or her future health care

Patients are not knowingly harmed as part of the research.

- this involves all patients receiving at least the minimum standard of care when the trial is designed, and that the trial is changed to reflect any changes in the standard of care over the duration of the study.

- that a study is discontinued early if one arm is found to be much better than another.

- that a study design is changed or amended if results from other research have an impact on the current trial.

- that studies should have pre-planned reviews of study results (either blinded or unblinded), preferably by independent experts who are not connected with running the study. This group is called the DSMB (Data and Safety Monitoring Board).

This is why patient advocates need to be included in following the conduct and early results from a trial, and included in trial steering committees and at investigators meeting.

Patients taking part in a study will be able to benefit from the results of a study.

- ie that a company can’t run an inexpensive study in a poor country but not then make the drug available to patients in that country afterwards A study answers a relevant medial question.

- this includes making sure that new studies are not designed, for which we already know the answer.

- with randomised studies, it involves making sure at the start that each group in the study has the potential to be the best option. The study should have been approved by an ethics committee linked to that research centre.

HIV i-Base: basic training for advocates

S8:115

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

8.13 Issues of confidentiality for advocates involved in research For advocates to be actively involved in research usually involves understanding the importance of confidentiality in relation to study results, especially if you are seeing early trial results before they are made public. This can sometimes include formally signing a confidentiality agreement. Most studies will result in one group in a trial doing better than another. As an advocate you may get to see these results before they are presented in public. Often the early results though are not the same as the results seen at the end of the study. As long as the study continues to be run ethically and as long as the study question hasnâ&#x20AC;&#x2122;t been answered, it is important that early results stay confidential to the research group. Making early results public could cause an important study to never reach a final result. This does not stop you raising any serious concern you have on the safety of a study with the researchers involved in the study, or with other community colleagues that agree to the same level of confidentiality. Only as a last resort should confidentiality within a study be taken to the wider community.

8.14 Summary of different advocacy roles Advocates can be involved in many different roles. These include: - in trial design before the study is finalised - in wording of patient information sheets and informed consent - in publicising good research to help study enrolment - in highlighting poor or inappropriate research - in an educational role to explain benefits and risks of a study - being an independent advisor for whether a trial is appropriate for an individual patient - on the trial steering committee â&#x20AC;&#x201C; following enrolment, trial practice and early results - on the Data and Safety Monitoring Board (DSMB) - reporting and critically commenting on results when they are publicly presented at medical meetings or when final results are published - suggesting additional analysis of study results - ensuring study participants are informed of the results of the research that they have been involved in

HIV i-Base: basic training for advocates

S8:116

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

Section 8.15 Multiple choice questions For each question you can tick more than one answer. Please tick/check all that you think apply. 1.

Community advocates should be involved in research because… ¢ It can help with grant applications. ¢ Advocates need jobs too. ¢ Advocates can help design a study today that will still be providing good treatment in a years time. ¢ Advocates can independent represent patient interests if a study isn’t running well. ¢ If advocates understand the research they can give independent information about the risks and benefits to individual patients who may want to join the study.

2. Why is research important for advocates? ¢ Because if designed well, it can provide reliable information about how effective and/or harmful as treatment of drug is. ¢ Because it will help a company sell more drugs. ¢ Because it can prove a new treatment may be better than an older treatment. ¢ Because without evidence, you can only guess at whether something works. ¢ Because without evidence people are vulnerable to false claims about miracle drugs. 3. Which of these statements about different trials in drug development are true? ¢ Phase IV studies are run to get a drug approved. ¢ Phase II studies are run before Phase I studies. ¢ Phase I studies are run in animals. ¢ Phase 3 studies are the main large studies that a company runs to get a new drug approved. ¢ Phase II studies look at different doses of a drug to find the best one.

HIV i-Base: basic training for advocates

S8:117

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

4. Which of these statements about a trial hypothesis are true? ¢ Every trial needs to start with a question, which is called a ‘hypothesis’. ¢ The hypothesis is a question that a study is designed to either prove or disprove. ¢ The hypothesis has to be true from the start of the study. ¢ A hypothesis has to say that one thing is better than another. ¢ Some trials do not need a hypothesis. 5. Which of these statements about a trial design are true? ¢ A primary endpoint of a study is always seen in the group that does the best. ¢ A primary endpoint is decided before the study starts. ¢ A secondary endpoint is only used for studies in older children. ¢ A primary endpoint decides what level of evidence or results will be acceptable to prove or disprove the study question. ¢ Secondary endpoints can look at a wide range of important things like side-effects and quality of life. 6. Which of these statements about studies are true? ¢ A prospective study looks backwards in time to see what happened in the past. ¢ An new drug is tested in an interventional study. ¢ A retrospective study look backwards in time. ¢ A cross-sectional study looks at something happening at one point in time. ¢ A longitudinal study looks at how tall people are. 7. Which of the following statements describe a study that randomises patients to receive a new drug or a placebo and then follows them? ¢ A prospective, observational study. ¢ A prospective interventional study. ¢ A retrospective, cross-sectional study.

8

¢ A prospective, longitudinal study. ¢ A cross-sectional, longitudinal study.

HIV i-Base: basic training for advocates

S8:118

January 2008


Section 8: Clinical trials and research

www.i-Base.info

8. Which of the following describes a cross-sectional, retrospective study? ¢ A study that give people a new drug to see if it has less side effects. ¢ A study that decides to see how many people have lipodystrophy at their next clinic appointment. ¢ A study that looks at hospital records to see how many patients are smokers. ¢ A study that looks at hospital records to see how many patients had a heat attack last year. ¢ A study to see whether combination therapy with 4 drugs in young children is better than starting with three drugs. 9. Which of the following statements about randomisation are true? ¢ Randomisation helps make sure that people who are more ill stand a better chance of getting a new active drug. ¢ Randomisation will help make sure that each arm has the same proportion of women are in each arm, which similar ages and CD4 count. ¢ Randomisation will help make sure that equal proportion of Gemini, Aries, and Librans are in each arm. ¢ Randomisation is likely to be effective if people are chosen by tossing a coin. ¢ Randomisation is likely to be effective if people are chosen by the day that the visit the clinic. 10. Which of the following statements about terms used in trials are true? ¢ A placebo is a drug that works well but has no taste. ¢ A placebo has no active drug and is used to compare results to an investigational drug. ¢ Blinding makes sure that a patient knows which drug they get. ¢ Double-blinding means that neither the doctor nor patients know which arm they are in. ¢ A control group is the name for study arm that is used to compare the results of a new intervention.

8 HIV i-Base: basic training for advocates

S8:119

January 2008


Section 8: Clinical trials and research

www.i-Base.info

11. Which statements about these different types of trial are true? ¢ A cohort study is usually an observational study that follows a group of people over time. ¢ A cohort study is the best way to see if a new drug works. ¢ Prospective, randomised, placebo-controlled, studies are the ‘goldstandard’ for getting the most reliable evidence about an intervention. ¢ A cross sectional study can give you a re quick answer to whether a new side effect is being seen in a clinic. ¢ A meta-analysis compares results from different studies. 12. Which of the following five terms relates to each of the longer descriptions below. Give each description 1 - results, 2 - method, 3 - discussion, 4 - background, 5 - conclusion ___ The final summary results - what was learned and how it can affect care. ___ The strengths and weaknesses of the study: cautions about interpretation, what could have been done better, and the implications for clinical practice, treatment guidelines or for further research. ___ What exactly was studied and how it was preformed.

___ What is already know about this area of research and why the study is being run. ___ What was seen or demonstrated.

13. Which of these statements about informed consent are true ¢ The ‘main’ reason for informed consent is to protect a researcher from legal claims in the future ¢ The ‘main’ reason for informed consent is to make sure patients understand the potential risks and benefits of a study before they agree to take part ¢ Informed consent should be written in simple language and carefully explain any technical terms ¢ Informed consent should be in a language that a patient understands ¢ Even after someone has signed an informed consent form, they can with draw from the study at any time

HIV i-Base: basic training for advocates

S8:120

January 2008

8


Section 8: Clinical trials and research

www.i-Base.info

14. Advocates can be involved in the following roles in research ¢ Following study recruitment and seeing early results with investigators ¢ Suggesting additional analysis of study results

¢ Being an independent advisor for whether a trial is appropriate for an individual patient ¢ Helping design the trial before the study is finalised ¢ Highlighting poor or inappropriate research

8 HIV i-Base: basic training for advocates

S8:121

January 2008


Section 8: Clinical trials and research

www.i-Base.info

8.16 Course evaluation of Section 8

Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation as we can develop this into an online resource. Session 8 How much of the information was new? None

1

2

3

4

5

All

How useful was the source material?

1

2

3

4

5

Not

Very

How much support time did you need in 1-2-1 questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve?

.

8 HIV i-Base: basic training for advocates

S8:122

January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

9.0 Learning resources & science support modules

9.1 Introduction The following five 2-page sections provide summaries of some of the technical, medical or scientific aspects related to HIV and treatment. If you want to be able to review results from studies - either to see whether a treatment is appropriate, or to follow latest research, then you will find this easier if you can understand the terms involved.

LEARNING RESOURCES HIV i-Base: basic training for advocates

S9:123

January 2008


www.i-Base.info

Section 9: Learning resources & science support modules

9.2 How to read a graph This short section explains how to read and understand information from a graph. A graph is a way of showing complicated information in a clear easy to understand way. They are used to summarise complicated results.

_ _ _ _

_ _ _ _ _ _

Y-axis

CD4 count (cells/mm3)

A graph usually has two axis - vertical (y-axis) and horizontal (x-axis), and anything can be measured on either axis.

12 13 14 etc

1 2 3 etc

X-axis

Time (months)

If time is one of the variables that is being compared, then ‘time’ is always measured on the x-axis. Each axis need to be clearly marked with what is being measured: ie Time, CD4 count etc. All graphs should have a clear title. If the graph is being used to show data rather than just a general trend or idea, then the units being measured need to be included: ie hours or years for time and cells/mm3 for CD4 counts. This scale needs to be shown in even measurements. If all the results cannot be fitted on the same scale, then the axis can be broken as in the second graph above, and the scale shown on each section. An example of how one persons CD4 results after starting treatment could be plotted is shown in Figure 1.

500 400 x

300 200 -x

x

x

x

x

jul 04 -

apr 04 -

jan 04 -

oct 03 -

jul 03 -

0-

apr 03 -

100 -

Time (months)

The only difference in a graph that is showing more HIV i-Base: basic training for advocates

x

x

jan 03 -

You can also plot the average results of much larger amounts of data. For example the ‘average’ CD4 counts of a group of 100 people after treatment could look exactly the same.

600 -

oct 02 -

Although the actual counts go up and down a lot, the average trend in the example above shows CD4 count increasing by about 200 copies/mm3 over 18 months.

Figure 1: CD4 count changes in Patient A after starting treatment in October 2002 CD4 count (cells/mm3)

To make results clearer, a line showing an ‘average’ of the results is often added to make the general trend appear more clearly.

S9:124

January 2008

LEARNING RESOURCES


www.i-Base.info

Section 9: Learning resources & science support modules

jul 04 -

apr 04 -

jan 04 -

oct 03 -

jul 03 -

apr 03 -

jan 03 -

Time (months) N

100 99

99

98

97

97

92

91

Figure 3: Median CD4 count and IQR change in 100 patients after starting treatment in Oct 2002 600 500 400 300 200 -x

x

x x

x

x

x

x

100 0-

oct 02 -

The graph should state which range is being shown.

0-

N

100 99

Time (months) 99

98

97

97

jul 04 -

iii) the middle 95%.

100 -

apr 04 -

ii) the range of the middle 50% (called the Inter-Quartile Range: IQR); or

x

x

x

x

jan 04 -

i) the full range of the results

x

oct 03 -

This can either show:

300 200 -x

x

x

jul 03 -

The top and bottom of these lines often have a small horizontal line to make this clearer

400 -

apr 03 -

They show this by vertical lines that go up from and down from the average result that is plotted - see Figure 3.

500 -

jan 03 -

Graphs should also really show the variation within a group (see also the next module on scientific terms and averages).

600 -

oct 02 -

Although the results are for a group of 100 people, in this example either not all the people have completed the study and it is an early analysis, or some people have dropped out of the study.

CD4 count (cells/mm3)

‘N’ is the mathamatical term for ‘number’

Figure 2: Average (median) CD4 count change in 100 patients after starting treatment in Oct 2002

CD4 count (cells/mm3)

than one set of results, is that the numbers of people at each time point should also be included underneath each time. See Figure 2.

92

91

Caution:Just as graphs can make information much clearer they can also be used to show make things look better or worse than they really are. i) Scales - always check the scale on a graph. If it doesn’t start at zero, then the change shown may look more impressive than it really is. ii) Numbers of people or results at any time point. If a study started with 100 people, then any average results plotted in a graph should be an average of all 100 people. If early or preliminary results of a study are being shown, the numbers at each time point may much lower after further time points. Further reading: Caroline Sabin- Statistics part 1 HIV i-Base: basic training for advocates

S9:125

http://www.i-Base.info/ukcab January 2008

LEARNING RESOURCES


www.i-Base.info

Section 9: Learning resources & science support modules

9.3 What is an ‘average’? Study results are nearly always based on finding a pattern from lots of individual observations. In order to see any trend the average results are then presented. The average can be used to be able to generalise results for larger groups of people or larger sets of results. You always need to remember when looking at average results that some results will have been higher and lower than the average. This is especially important when looking at studies related to healthcare. There are two most commonly used ways to calculated the average, that can give very different results. Mean average - this is where all the results are added together, and then divided by the number of results. ie CD 4 increases after 6 months treatment in 10 people could be:

+20 +40 +15 -20

-5

+120 +250 +30 +50

+100

Most people had increase but some peoples count was lower after 6 months. The mean average from these results would be 20 + 40 + 15 -20 etc divided by 10 people: ie 600 / 10 = 60. Median average - this is where the results are all arranged in numerical order and the most the results in the centre is taken as the median. In the same example this would be:

-20

-5

+15 +20 +30 +40 +50 +100 +120

+250

The median CD4 increase would be the middle point - ie half way betwen the 5th and 6th result - ie an increease of +35. ‘Even distribution’ is a term to describe data where most results are in the middle and a roughly similar number of results fall either side. It is also called a bell-shaped distribution . If results are evenly distributed then the mean average is appropriate, When the results are not evenly distributed this is called a skewed distribution. For example the majority os results may be higher or lower than the middle range and skewed to the right or the left, then it is important to use the median average. (see Figure 1). In the example above, the result of one person that was much higher than the rest (+250) had a disproportianate effect on the mean average.

LEARNING RESOURCES HIV i-Base: basic training for advocates

S9:126

January 2008


www.i-Base.info

Section 9: Learning resources & science support modules

When thinking about averages, you also need to know how much variation there is in any collection of results. This will help you decide how much you want to rely on the results.

For example the mean of 48 + 49 + 50 + 50 + 51 + 52 is 300/6 = 50

But the mean of 0 + 25 + 50 + 50 + 75 + 100 is also 300/6 = 50

You can see that completely different patterns of results give you the same mean average. Different ways to show variation are used depending on whether the results are evenly or unevenly distributed. If distribution is even and you are using the mean average, then variation is usually calculated as being twice the â&#x20AC;&#x2DC;standard deviationâ&#x20AC;&#x2122; - and shown in brackets with a +/- sign in front of the result. One x standard deviation gives you the middle range of 50% of the results. Two x standard deviations give you the middle range of 95% of the results. If the results are not evenly distributed - like the example of CD4 counts earlier - then the median average is used. Variation with the median average is easier to understand, and is shown is two main ways: i ) either the full range of results - ie the lowest and the highest ie for the same example:

-20 -5

+15 +20 +30 +40 +50 +100 +120

Median = 35 (range -20, +250)

+250

ii) or the middle section of results - called the Inter Quartile Range (IQR) The Inter-Quartile Range is sometimes given instead of the full range, toreduce the impact of very high or very low results. This is the range of the middle 50% of result with the highest 25% and lowest 25% not included. The IQR for the above example would be midway between -5 and +15 = 10 for the lowest 25% and midway between 100 and 120 for the highest 25% = 110. The median and IQR for the same results would be shown as:

Median = 35 (IQR 10, 110)

Further reading: Caroline Sabin- Statistics part 2

LEARNING RESOURCES

http://www.i-Base.info/ukcab

HIV i-Base: basic training for advocates

S9:127

January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

9.4 What happens when you take a drug

If you understand what happens when you take a drug through the following graphs, you will understand the science behind adherence. When you take a drug, it can be absorbed by your body into the blood in different ways depending on how it is taken. â&#x20AC;˘

A pill is usually absorbed through the stomach walls after it is swallowed - these can become active in a few minutes but usually take an hour or two to reach the highest concentration in the blood.

â&#x20AC;˘

IV drugs are injected directly into the blood work much faster - sometimes in seconds or minutes.

However a drug is taken though, it will reach a peak level and then these levels will go down as the body breaks down the active ingredients, usually as the circulating blood is filtered by the liver or kidneys. This basic process happens with every drug - alcohol, nicotine, aspirin, HIV drugs.... Drugs are always absorbed more quickly than the body can break them down, so the highest concentration is reached relatively quickly, and then it takes longer to leave the body.

The maximum concentration is called the Cmax. The total exposure to drug over the dosing period is call the Area Under the Curve (AUC) The time taken to get to the maximum concentration is called the Tmax

LEARNING RESOURCES HIV i-Base: basic training for advocates

S9:128

January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

The time taken to reduce the maximum concentration by half (by 50%) is called a drugs ‘half-life’ or T1/2. It takes approximately 5 = half life for a drug to be cleared to negligible levels, but in theory, tiny quantities can be in the system for much longer. When a drug is taken routinely as treatment, the minimum concentration just before the next dose is called the Cmin or Ctough (trough level).

Remember that all these results are ‘averages’.

Some people absorb drugs more quickly or more slowly than the average.

Some people clear drugs more quickly or more slowly than the average.

These results are usually only calculated in blood and blood levels do not always relate to how active a drug is. With nucleoside analogues, the level on the active drug inside the cell is more important than blood levels. The graphs showing drugs levesl inside cells would follow a similar pattern. Pharmocokinetics is the name for ways that drugs are absorbed and eliminated by the body. Although drug levels can behavein different compartments: blood, brain, benital fluids, inside different cells etc the bacic principles of absortion and elimination are often very similar.

LEARNING RESOURCES HIV i-Base: basic training for advocates

S9:129

January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

9.5 Drug levels, drug activity and side effects On a very basic level, if drug levels are too low, then the drug will not be active enough to have any effect. If drug levels are too high, then the risk of some side effects is likely to be higher.

Doses of a drug and how often you need to take a medication are designed to keep you in this target range.

Different drugs have different target ranges.

Drugs that leave your body quickly have to be taken more frequently and drugs that are processed more slowly can have longer dosing intervals.

Some drugs - including HIV drugs, TB drugs, antibiotics and anti-fungal drugs have to be above a certain concentration, so that resistance doesn’t occur (see next section for more on this).

It is important to remember that there isoften a very wide range of variability between different people who take the same dose of a drug. Some people will process the drug more quickly and get lower than average drug levels. Some people will process drugs more slowly and get higher than average levels. Just to make things even more complicated, there can be differences in drug levels in the same person, even if the levels are measured at the same time after each dose. Some drug levels are different 12 hours after a morning dose compared to 12 hours after an evening dose.

LEARNING RESOURCES HIV i-Base: basic training for advocates

S9:130

January 2008


www.i-Base.info

Section 9: Learning resources & science support modules

Again, althogh the details are complicated the simple picture is important to grasp: you are aiming to have a constant safe levels on drug whenever you are on treatment. You can see that a graph of drug levels can give you information about adherence and what happens if you are late with a dose or if you miss a dose completely. If you remember that average figure invole a range of higher and lowere actual concentrations, that people who absorb lower levels of drugs are at higher risk of resistance if they are late or miss a dose.

Minimum level Dose

Risk of resistance

Dose

Each time you take a drug on time, the levels of the drug stay above the minimum level needed

MISSED dose If you are late with a dose, or completely miss it altogether, the drug level in your blood falls below the safe minimum level. Resistance to the drug can then develop.

Occasionally missing or being late with a dose (say once a month) may not make very much difference. If you are missing or being late with a dose even once a week though, this will increase the time the virus has to develop resistance, and will increase the chance you will develop resistance over time. Adherence is not about doing things on time just because your doctor says so. It is about keeping minimum levels of each drug in your body 100% of the time that you are on treatment.

LEARNING RESOURCES HIV i-Base: basic training for advocates

S9:131

January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

9.6 Common mathematical signs, symbols, statistical and medical terms Signs +

plus

<

less than

-

minus

<

less than or equal to

/

divided by

infinity

x

multiplied by

~

approximately

=

equals

±

‘plus or minus’ – this is use to show the range of group of values (Standard Deviation) when the ‘mean’ is used to calculate the average – ie SD ± 0.45 etc.

is not equal to

>

greater than (ie >500 means ‘more than 500’)

>

greater than or equal to (ie >500 means ‘500 and over’)

Commonly used Greek characters α

alpha (alfa)

= ‘a’

β

beta

= ‘b’

δ or Δ delta

= ‘d’ – this is the abbreviation for ‘change’

γ

gamma

= ‘g’

μ

mu

= ‘m’ – this is the abbreviation for ‘micro’; μL = micro litre

Greek letter are commonly used for names of immune-related chemicals. ie interferon-alpha (IFN-a; IFN-α) or interferon-beta (INF-b, IFN-β) to treat hepatitis C. Delta is used as a short cut for ‘change’ ie delta CD4 (δ CD4 or ΔCD4) means ‘change in CD4’. Common medical abbreviations Medical abbreviations that are commonly used include: qd or QD

once daily

bd or BD or BID

twice daily

td or TD or TID

three times daily

q12h or q12H

every 12 hours

q25h or q24H

every 24 hours

Note: when people talk about once-daily or twice-daily HIV drugs, they really mean q12H or q24H because you need to take them at the same time each day, with the same interval between each dose. Other abbreviations commonly used as notes or in presentations Bx biopsy Rx resistance Tx

LEARNING RESOURCES

treatment

HIV i-Base: basic training for advocates

S9:132

January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

9.7 Units of measurement There are two basic units used to count CD4 cells and viral load: Cubic millimetre – mm3 A cubic millimetre measures a very small volume. The length, depth and height of the volume are all 1 millimetre (mm) long. In scientific papers cubic millimetre are sometimes shown as microlitres (µL) or million parts per litre (106/L). CD4 count is measured as number of cells in a mm3. One cubic millimetre is about a drop of blood. Millilitre – mL A millilitre measures a volume of liquid. Viral load is measured as number of copies in a mL. 1,000 mm3 = 1 mL. 1,000 mL = 1 litre. And two advanced units often used in studies:: Log value – log10 A log value shows a number as a factor of 10. Log values make it easier to deal with big numbers. Measuring viral load using logs Viral load is often measured using a log value.

A 1 log drop in viral load means the amount of HIV has gone down by 90%

A 2 log drop means it has gone down by 99%

If your viral load was 20,000 then a 1 log drop equals a 10-fold (10 times) decrease to 2,000. A 2 log drop equals a 100-fold decrease (10 x 10 times) to 200.

A 1 log drop in viral load can mean different things.

A drop from 20,000 to 2,000 and from 2,000 to 200 are both drops of 1 log.

Table: log = number 1 log10 = 10

4 log10 = 10,000

1.5 log = 30

4.5 log = 30,000

1.7 log = 50

4.7 log = 50,000

2 log10 = 100

5 log10 = 100,000

2.5 log = 300

5.5 log = 300,000

2.7 log = 500

5.7 log = 500,000

3 log10 = 1,000

6 log = 1,000,000

3.5 log = 3,000

6.5 log = 3,000,000

3.7 log = 5,000

6.7 log = 5,000,000

HIV i-Base: basic training for advocates

S9:133

LEARNING RESOURCES January 2008


Section 9: Learning resources & science support modules

www.i-Base.info

Percentage – % A percentage shows a number as a proportion of 100 – the number of parts in 100 parts. 1% = 1 in 100 Percentages are often used to compare proportions from different samples. CD4 cells are sometimes counted as a percentage – the proportion of lymphocytes (white blood cells) that are CD4 cells. A CD4% of 12.5 usually equals a CD4 count of 200 in adults. Percentages can be made easier to understand by turning them into fractions: 20% = 20 in 100 = 20/100 Sometimes percentages are shown as a decimal fraction of 1 (100% = everything you count = 1). To make a percentage into a decimal fraction, divide it by 100. 20% = 20/100 = 0.20 Table: common percentages and what they mean 5% = 0.05 = 1 in 20 10% = 0.10 = 1 in 10 12.5% = 0.125 = 1 in 8 16.5% = 0.165 = 1 in 6 20% = 0.20 = 1 in 5 25% = 0.25 = 1 in 4 = a quarter 33% = 0.33 = 1 in 3 = a third 50% = 0.50 = 1 in 2 = half 66% = 0.66 = 2 in 3 = two thirds 75% = 0.75 = 3 in 4 = three quarters 80% = 0.80 = 4 in 5 90% = 0.90 = 9 in 10 95% = 0.95 = 19 in 20 Percentages can deceive! Percentages show proportions, not actual numbers. It is sometimes difficult to see the whole picture: A study reports: 80% of people using our new drug had an undetectable viral load at the end of the study. Questions: how many people completed the study? Was it many people, or only a few? Maybe lots of people dropped out because of side effects!? The report suggests the new medicine worked for 8 in 10 people who took the drug – when it really worked for 8 in 10 people who completed the study.

LEARNING RESOURCES

When looking at percentages, remember to ask ‘percentage of what?’

HIV i-Base: basic training for advocates

S9:134

January 2008


www.i-Base.info

Section 9: Learning resources & science support modules

9.8 Log value conversion table Numbers that can span a wide numerical range â&#x20AC;&#x201C; ie from 10 to 10,000,000 can be clumsy to use and compare. They are easier to manage when converted to a log scale. A log scale can be made for any base number, and viral load results are often converted to a factor (log) of 10:

1 log = 10;

2 logs = 10x10 = 100;

3 logs = 10x10x10 = 1,000 etc

This table gives a rough guide for translating numbers into log scale and vice versa. i.e.

- a viral load result of around 20,000 copies/mL is 4.3 logs

- a viral load of 5.6 logs is about 398,000 copies/mL

Note: numerical figures above 4 logs have been rounded to nearest practical number. Table: HIV RNA viral load log valueâ&#x20AC;&#x201C;number conversion Log 10

Copies/mL

Log 10

Copies/mL

1.0 logs 1.1 logs 1.2 logs 1.3 logs 1.4 logs 1.5 logs 1.6 logs 1.7 logs 1.8 logs 1.9 logs

10 13 16 20 25 32 40 50 63 79

4.0 logs 4.1 logs 4.2 logs 4.3 logs 4.4 logs 4.5 logs 4.6 logs 4.7 logs 4.8 logs 4.9 logs

10,000 12,600 15,800 20,000 25,100 31,600 39,800 50,100 63,100 79,400

2.0 logs 2.1 logs 2.2 logs 2.3 logs 2.4 logs 2.5 logs 2.6 logs 2.7 logs 2.8 logs 2.9 logs

100 126 158 200 251 316 398 501 631 794

5.0 logs 5.1 logs 5.2 logs 5.3 logs 5.4 logs 5.5 logs 5.6 logs 5.7 logs 5.8 logs 5.9 logs

100,000 126,000 158,000 200,000 251,000 316,000 398,000 501,000 631,000 794,000

3.0 logs 3.1 logs 3.2 logs 3.3 logs 3.4 logs 3.5 logs 3.6 logs 3.7 logs 3.8 logs 3.9 logs

1,000 1,260 1,580 1,990 2,510 3,160 3,980 5,010 6,310 7,940

6.0 logs 6.1 logs 6.2 logs 6.3 logs 6.4 logs 6.5 logs 6.6 logs 6.7 logs 6.8 logs 6.9 logs

1,000,000 1,260,000 1,580,000 2,000,000 2,510,000 3,160,000 3,980,000 5,010,000 6,310,000 7,940,000

HIV i-Base: basic training for advocates

S9:135

LEARNING RESOURCES January 2008


www.i-Base.info

Appendix I

Appendix I Conditions included in the 1993 CDC AIDS surveillance case definition • • • • • • • • • • • • • • • • • • • • • • • • •

Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal (thrush) Cervical cancer, invasive Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (greater than 1 month’s duration) Cytomegalovirus disease (CMV) (other than liver, spleen, or nodes) Cytomegalovirus retinitis (CMV) (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (greater than 1 month’s duration); or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (greater than 1 month’s duration) Kaposi’s sarcoma (KS) Lymphoma, Burkitt’s (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis (TB), any site (pulmonary or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis carinii pneumonia (PCP) Pneumonia, recurrent Progressive multifocal leukoencephalopathy (PML) Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV

Source: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm

APPENDICES HIV i-Base: basic training for advocates

App:136

January 2008


www.i-Base.info

Appendix II

Appendix II: WHO Classification System for HIV Infection Clinical Stage 1 1.  Asymptomatic infection 2.  Persistent generalized lymphadenopathy 3.  Acute retroviral infection Performace Stage 1  Asymptomatic, normal activity Clinical Stage 2 4.  Unintentional weight loss <10% body weight 5.  Minor mucocutaneous manifestations (e.g. dermatitis, prurigo, fungal nail infections, angular cheilitis) 6.  Herpes zoster within previous 5 years 7.  Recurrent upper respiratory tract infections Performance Stage 2  Symptoms, but nearly fully ambulatory Clinical Stage 3 8.  Unintentional weight loss >10% body weight 9.  Chronic diarrhea >1 month 10.  Prolonged fever >1 month (constant or intermittent) 11.  Oral candidiasis 12.  Oral hairy leukoplakia 13.  Pulonary tuberculosis within the previous year 14.  Severe bacterial infections 15.  Vulvovaginal candidiasis Performance Stage 3 In bed more than normal but <50% of normal daytime during the previous month Clinical Stage 4 16.  HIV wasting syndrome 17.  Pneumocystis carinii pneumonia 18.  Toxoplasmosis of the brain 19.  Crytosporidiosis with diarrhea > 1 month 20.  Isosporiasis with diarrhea > 1 month 21.  Cryptococcosis, extrapulmonary 22.  Cytomegalovirus disease of an organ other than liver, spleen or lymph node 23.  Herpes simplex virus infection, mucocutaneous 24.  Progressive multifocal leukoencephalopathy 25.  Any disseminated endemic mycois (e.g., histoplasmosis) 26.  Candidiasis of the esophagus, trachea, bronchi, or lung 27.  Atypical mycobacteriosis, disseminated 28.  Non-typhoid Salmonella septicemia 29.  Extrapulmonary tuberculosis 30.  Lymphoma 31.  Kaposi’s sarcoma 32.  HIV encephalopathy Performance Stage 4 In bed > 50% of normal daytime during previous month Source: HIV InSite Knowledge Base http://hivinsite.ucsf.edu/InSite?page=kb-01-01

HIV i-Base: basic training for advocates

App:137

APPENDICES January 2008


www.i-Base.info

Appendix III

Appendix III: OIs listed by disease type Bacterial Infections • Mycobacterium Avium Complex (MAI / MAC) • Mycobacterium Kansasii • Salmonellosis • Syphilis & Neurosyphilis • Tuberculosis (TB) Malignancies (Cancers) • Anal Dysplasia/Cancer • Cervical Dysplasia/Cancer • Kaposi’s Sarcoma (KS) • Lymphomas Viral Infections • Cytomegalovirus (CMV) • Hepatitis C • Herpes Simplex Virus (oral & genital herpes) • Herpes Zoster Virus (shingles) • Human Papiloma Virus (HPV, genital warts, anal/cervical dysplasia/cancer) • Molluscum Contagiosum • Oral Hairy Leukoplakia (OHL) • Progressive Multifocal Leukoencephalopathy (PML) Fungal Infections • Aspergillosis • Candidiasis (thrush, yeast infection) • Coccidioidomycosis • Cryptococcal Meningitis • Histoplasmosis Protozoal Infections • Cryptosporidiosis • Isosporiasis • Microsporidiosis • Pneumocystis Carinii Pneumonia (PCP) • Toxoplasmosis Neurological Conditions • AIDS Dementia Complex (ADC) • Peripheral Neuropathy Other Conditions and Complications • Aphthous Ulcers (Canker Sores) • Thrombocytopenia (low platelets) • Wasting Syndrome-

Source: http://www.aidsmeds.com

HIV i-Base: basic training for advocates

APPENDICES App:138

January 2008


www.i-Base.info

Appendix IV

Appendix IV: Drugs and doses of European licensed ARVs An illustrated chart of the most commonly used antiretroviral drugs licensed in Europe is included in the i-Base Introduction to Combination to Therapy. Please check this online linke for an up-to-date version of this information. http://www.i-base.info/manual/en/arvlist.html

APPENDICES HIV i-Base: basic training for advocates

App:139

January 2008


www.i-Base.info

Appendix V

Appendix V: Resources and further reading The following resources in English provide further information at a range of different levels. Basic and intermediate New Mexico AIDS Infonet The most comprehensive range of basic factsheets covering a wide range of HIVrealted subjects, including information on tests and monitoring, side effects, OIs and each HIV drug. Available in English and Spanish. This information is revised monthly, and is one of the few websites that doen not keep out-dated information online. http://www.aidsinfonet.org/topics.php HIV i-Base treatment guides Each of these guides is written in a similar format to this training manual. Emphasis is on non-technical language and up-to-date information. Produced by an HIV-positive led activist organsiation. Material is copyright-waived and free to copy or translate. Starting treatment: Introduction to combination therapy http://www.i-base.info/pub/guides/starting Changing treatment: guide to second-line and salvage therapy http://www.i-base.info/pub/guides/changing Guide to avoiding and managing side effects http://www.i-base.info/pub/guides/side HIV, pregnancy and womens health http://www.i-base.info/pub/guides/pregnancy

HIV and Hepatitis C http://www.i-base.info/pub/guides/HepC

Advanced and reference HIV Treatment Bulletin Monthly bulletin that includes reviews of medical journals and conference reports with an emphasis on clinical care. Distributed free in print, online and pdf format. Technical language but produced from an HIV-positive activist organisation. http://www.i-Base.info aidsmap UK based website with extensive information. All treatment information is referenced. Useful for overview of individual drugs and illnesses. Check the date for non-technical factsheets. http://www.aidsmap.com HIV inSite Knowledge Base Extensive online reference manual with chapters on every aspect of HIV treatment. Very technical site. New chapters are added or updated on a monthly basis, but check the last modified date at the top of information. http://hivinsite.ucsf.edu/

APPENDICES HIV i-Base: basic training for advocates

App:140

January 2008


www.i-Base.info

Appendix V

Medscape Professional website, with many aspects fo specialist care, including HIV. Free onetime online registration. Includes coference reports and free access to selected journal papers. http://www.medscape.com

Treatment guidelines WHO guidelines:

http://www.who.int/3by5/publications/documents/arv_guidelines/en/

UK guidelines are updated every two years.

http://www.bhiva.org

US guidelines (for prevention, treatment, OIs, children and pregnancy):

http://www.hivatis.org/

European guidelines fomr the European AIDS Clinical Society (EACS)

http://www.easc.eu

Internet sites with treatment information in Russian

http://www.aids.ru

http://www.positivenet.ru

http://www.infospid.ru

http://www.spid.ru

Internet sites about drug interactions and ARVs HIV Drug Interactions University of Liverpool

http://www.hiv-druginteractions.org/

APPENDICES HIV i-Base: basic training for advocates

App:141

January 2008


www.i-Base.info

Appendix VI

Appendix VI: Answers to questions The following answers are to the questions at the end of each Section. Section 1: The immune system and CD4 count 1.

AIDS stands for: - Acquired - Immune - Deficiency - Syndrome

2. A white blood cell (lymphocyte) that signals CD8 cells to destroy a virus. CD4 cells are a primary target for HIV, which uses these cells as factories to reproduce. 3. A white blood cell (lymphocyte) that kill cells that are infected with viruses (i.e. HIV). 4. In a HIV-negative adult this is usually between 500 and 1600, and occasionally outside this range 5. CD4 cell=helper cell (but also CD4+ T-lymphocyte, CD4+ T-cell, T4 cell); CD8=killer cell (but also CD8+ T-lymphocyte, CD8+ T-cell, T8 cell) 6. CD4% is the percentage of total lymphocytes that are CD4 cells. It is used as a more stable indication of whether there has been a change in the immune system and mandatory for monitoring HIV-positive children. A normal CD4% for an HIV-negative person is 40%. 7. Cellular immune responses are based on CD4 and CD8 responses. Humoral immune responses are based on antibodies. 8. A surrogate marker is the term for an indirect measure for something else that cannot be easily measured directly (i.e. the CD4 count as a measure for HIV disease progression). 9. Current guidelines recommend routine CD4 tests every 3-4 months in the UK. This may vary for different individuals: - Someone not on treatment with a very high and stable CD4 count and low viral load may be monitored less frequently. Some countries only provide test every 6 months for all patients. - Someone just starting or changing treatment should be monitored 2-4 weeks after the new treatment to look at the early response. 10. Some guidelines (WHO, UK) recommend starting treatment before the CD4 count has fallen below 200, while others (US) recommend before 350. As treatment becomes easier to take and tolerate, guidelines will probably tend towards earlier treatment, possibly even while CD4 counts are above 350. 11. A few weeks after the infection, the CD4 count usually falls, then the immune system fights back and the count goes back again but not to the levels that it was before HIV infection. From then on the CD4 count goes down gradually and it takes from 2 to 10 years usually to drop down to 200. 12. Please see graph on page 7.

http://www.i-base.info/manual/en/1-7.html

13. CD4 <300

-

diarrhoea from microsporidia and cryptosporidia

-

skin problems-candida (thrush), dry skin, etc.

HIV i-Base: basic training for advocates

App:142

APPENDICES January 2008


www.i-Base.info

CD4 <200

-

PCP (pneumonia) and chest infection

-

toxoplasmosis-a parasitic infection that commonly causes brain lesions

MAI/MAC-bacterial infection similar to TB

CD4 <100 -

-

Cryptococcus infection-fungal infection that can cause meningitis in the brain and PCP-like symptoms in the lungs

CD4 <50 -

CMV (cytomegalovirus)-a viral infection that can cause permanent vision loss or blindness

14. Children have much higher CD4 counts than adults. Babies have higher CD4 counts than children. Babies, infants and younger children are monitored by their CD4% rather than absolute CD4 count. Over time and as people age their CD4 count drops gradually, so a normal CD4 count for a 50 year old man would be lower than a normal count for a 20 year old man. 15. An antigen is any infectious material for example produced by a virus or bacteria, that is recongised by the bodies immune system as a treat. 16. Cells in the immune system that recognise antigens. Section 2: Virology, HIV and viral load 1. HIV is a virus. HIV stands for Human Immunodeficiency Virus. 2. Only 2% 3. Mostly in the lymph system and lymph nodes. 4. Blood is the most accessible compartment for regular monitoring. 5. Sanctuary sites are compartments of the body with barriers that limit both HIV and HIV drugs from moving freely. These compartments include the genital tract, the cerebral spinal fluid and the brain. 6. Yes, viral load levels can be different in each compartment (about 10% of people have different results in blood compared to other sites). 7. - Bacteria

- Fungi

- Viruses

- Parasites/protozoa

8. During the first few days and weeks after the infection, the viral load (VL) goes very high and very quickly. Its levels can reach 1,000,000 copies. Then, during the seroconversion, the immune system starts producing antibodies in order to fight back. As a result the viral load goes down (sometimes to below 50 copies). During chronic infection viral load progressively increase, usually over many years, to the point when ARV therapy is recommended. One of the main goals for treatment is for viral load to become â&#x20AC;&#x2DC;undetectableâ&#x20AC;&#x2122; (below 50 copies/mL). 9. Please see the graph on page 18.

http://www.i-base.info/manual/en/2-6.html

10. The viral load test was developed as a research tool during the 1990s. The first test in 1995 could only measure down to 10,000 copies/mL. By 1996-7 the tests were able to measure down to 400-500 copies/mL. Since 1998 the most routinely used test measure down to 50 copies/mL, although some tests are even more sensitive and can measure down to 5 copies/mL.

HIV i-Base: basic training for advocates

App:143

January 2008

APPENDICES


www.i-Base.info

11. - PCR-polymerase chain reaction

- bDNA-branched DNA

- NASBA

12. 3-fold margin (i.e. a result of 30,000 means that the real result could potentially be anywhere between 10,000 and 90,000) 13. The viral load test shows whether i) the drugs are active – ie whether after the first 24 weeks viral load have dropped, and ii) to check that viral load is low enough to know develop resistance (is getting to less than 50 copies/mL). 14. If the levels are very high (>100,000), then this would be seen as a reason to start treatment at a higher CD4 count than 200. Even though the VL is not as important at predicting the risk of opportunistic infections as the CD4 count, several studies have shown that it can predict the rate of HIV progression. 15. HIV makes mistakes when replicating. Those mistakes are called mutations. When on treatment, some mutations will not be affected by the drugs. These mutations will continue to reproduce and eventually will become the major type of HIV in the individual. He/she then becomes resistant to other similar drugs and this is called crossresistance. Section 3: Introduction to ARVs 1. Antiretroviral 2. All guidelines recommend using 3 drugs, but can be more. Some studies are looking at boosted PI-monotherapy (ie Kaletra) but this is not recommended in guidelines. 3. Any four from:

NRTI – Nucleoside Reverse transcriptase Inhibitors (‘nucleosides’ or ‘nukes’)

NNRTI – Non-Nucleoside Reverse Transcriptase Inhibitors

PI – Protease Inhibitors

EI – Entry Inhibitors

INI – Integrase Inhibitors

CCR5 Inhibitors

4. Entry inhibitors 5. Over 20 (22, in 2005) 6. 4 (in 2005) 7. 3TC, d4T, nevirapine, efavirenz, 3TC, AZT 8. - If the person is not ready to start treatment

- If the person does not suffer from Ois

- If the CD4 count has not fallen below 200

9. - Speed of a persons metabolism

- Individual characteristics of a drug

- Diet – food interactions can increase drug absorption for some drugs and reduce it for others. There can be many different mechanisms involved – some interactions are related to fat content of food, some to acid content in the stomach.

- Drug interactions with other drugs can increase or reduce drug levels

- Use of recreational drugs

- Timing – taking a dose late will result in lower levels

HIV i-Base: basic training for advocates

App:144

APPENDICES January 2008


www.i-Base.info

10. Taking the drugs exactly as they are prescribed-at the right time and following any special diet restriction. 11. - Daily chart

- Pillbox

- Pill beeper or alarm watch

- Have medications for the side effects

- Ask a friend to remind you

- Keep a small supply of drugs at an easy to reach place etc

12. When a virus has changed or mutated so that the drugs no longer work as well or even at all against HIV 13. When the HIV-positive person gets symptoms (i.e. other illnesses) – ie something that has a direct effect on your health 14. If viral load levels never reached undetectable or rebounds and become detectable – ie the result of a lab test. 15. to less than 50 copies/mL 16. Please imagine that you are a counsellor and need to explain to your client what is adherence, why adherence is important and how to improve adherence. Section 4: Side effects of ARVs 1. Secondary effects of a drug other than the reason it is prescribed. Side effects are also called adverse events or drug toxicity. 2. Generally there are not big differences. When differences occur they can be important (ie baseline CD4 count and risk of rash with nevirapine. 3. Both of these are possible but not without a discussion with the doctor. Numerous examples for switching treatments are possible – any side effect that impacts on quality of life should prompt a review of alternative treatments. The most serious reason to interrupt treatment relates to life threatening toxicity – for example on a major organ (liver, heart, kidney)., hypersensitivity reactions (SJS for nevirapine, or abacavir hypersensitivity reactions). Although treatment interruptions are not generally recommended (since results form the SMART trial), there may be individual situations where improvement in quality of life balances risk from stopping treatment) 4. Grade 1-mildest; grade 4-most serious. 5. Lipoatrophy relates to reduced subcutaneous fat on the arm; legs or face, while lipodystrophy has to do with the way the body processes fats and sugars. Symptoms of lipodystrophy include lipoatrophy, fat accumulation and increased blood cholesterol and triglycerides. 6. Damage to the nerves in the ‘periphery or the body’ ie hands or feet - that starts in the fingers and toes. It starts with tingling and numbness, or increased sensitivity. 7. d4T, ddI, more rarely 3TC 8. AZT 9. Nevirapine, efavirenz 10. Nausea, poor appetite, painful or tender liver 11. Nevirapine, efavirenz, abacavir, T-20, fosamprenavir 12. Rash is defined by extent – ie proportion of the body affected, and severity – is

HIV i-Base: basic training for advocates

App:145

January 2008

APPENDICES


www.i-Base.info

whether mild discolouration or whether the skin is broken. A guide to severe rash is when the rash covers more than 10% of the body or if it breaks the skin. 13. Any from the table. Diarrhoea requiring hospitalisation, liver toxicity with AST or ALT levels above 7.5 ULN 14. When d4T is used with ddI. risk is especially high during pregnancy when these drugs should not be used together. 15. Efavirenz Section 5: OIs and co-infections 1. Protozoa are tiny parasites. Giardia, cryptosporidia, and microsporidia. 2. Below 300 cells/mm3. 3. - Drink bottled water sourced from a deep spring - Wash vegetables thoroughly - Cook meat and fish thoroughly 4. Candida is a fungal yeast infection that commonly affects the mouth and throat, gullet, sinuses, genital organs, and much more rarely the brain. 5. Symptoms of Candida include white or red patches (especially in the mouth), sometimes cracks at the corners of the mouth, headaches and possible vomiting. 6. - Co-trimoxazole

- Itraconazole

- Fluconazole

7. Pneumocystis Carinii Pneumonia – since 2006 PCP has been renamed Pneumocystis Jirovecii Pneumonia (the acronym PCP because it can be read “Pneumocystis pneumonia”). 8. Below 200 cells/mm3 9. Co-trimoxazole or dapsone or aerosolised pentamidine, etc. 10. Co-trimoxazole by continuous drip or injection for 3-4 days and then switch to tablets. 11. Trimethoprim plus dapsone, pentamidine, trimetrexate, atovaquone and clindamycin plus primaquine. 12. Tuberculosis - a bacterial infection 13. A person with active TB is infectious to other people, while a person with inactive TB is not infectious. 14. A 2-month course of a combination of four antibiotics (I.e. usually - isoniazid, rifampicin, pyrazinamide and ethambutol), followed by a 4-month course of a combination of 2 antibiotics (i.e. usually - isoniazid and ethambutol) 15. Any PI or nevirapine. 16. When people share the same confined living or working place. 17. Mycobacterium avium /Mycobacterium intracellulare-bacterial organisms closely related to mycobacterium tuberculosis. 18. A combination of two or more antibiotics; usually clarithromycin or azithromycin plus ethambutol. 19. An infection that causes liver inflammation or damage.

APPENDICES

20. 20-25 years.

HIV i-Base: basic training for advocates

App:146

January 2008


www.i-Base.info

21. Adefovir if the person is not on anti-HIV drugs. Because many HepB drugs are also active against HIV (including 3TC, tenofovir, and FTC) it is possible to treat HIV and hepatitis with the some of the same drugs. This usually includes 2 drugs that work on both viruses (ie tenofovir plus either 3TC or FTC) pls a third drug to ensure there are 3 active drugs working against HIV. 22. Below 50 cells/mm3 23. CMV retinitis is usually diagnosed by eye examination while in other organs usually by biopsy sample. 24. By eating raw or undercooked meat or through exposure to cat faeces that is more than 1 day old. 25. Until the CD4 count goes back over 200 cells/mm3. 26. NHL (Non-Hodgkin Lymphoma), KS (Kaposi’s Sarcoma) and cervical cancer. 27. Incidence f some cancers have been improved by ARVs (ie KS) whilst others do not dramatically improve 28. Liver cancer 29. A symptom of different diseases including HIV infection and OIs that results in weight loss. Wasting is defined as unintentional weight loss (particularly muscle loss) of over 5% of body weight over 6 months. Section 6: HIV and pregnancy 1. About 25% 2. Ensuring that the viral load of the pregnant woman is as low as possible – at least under 1500 copies/mL but preferably undetectable (under 50 copies/mL) 3. No. The babys status is only related to the mother. An HIV-negative woman can not have an HIV-positive baby. 4. Pregnancy may cause a drop in a woman’s CD4 count. This is usually about 50 cells/ mm3 but it can vary a lot. 5. A risk of resistance (not very high) and the need to have a C-section as a mode of delivery (rather than natural birth). 6. Less than 1% 7. A short course of triple combination therapy after the second trimester at 24 to 28 weeks. 8. Cons:

- More probable complications like infections

- Having a natural birth after a C-section is more complicated and difficult

- Babies delivered by C-section are more likely to receive ventilatory support

Pros:

- Reduced risk of HIV transmission when the pregnant woman receives only AZT

- Protects against HCV if the mother also has Hepatitis C.

9. Efavirenz-generally in pregnancy and the caution is strongest during the first trimester (12 weeks); Nevirapine is not recommended for women with a high CD4 count (above 250 cells/mm3) because of risk of liver toxicity; ‘ d‘ drugs together (ie not to use d4T + ddI) as they can cause fatal side effects in pregnant women

APPENDICES

10. Morning sickness, nausea, anaemia, diabetes, lactic acidosis.

HIV i-Base: basic training for advocates

App:147

January 2008


www.i-Base.info

11. Amniocentesis, chorionicvillus sampling, foetal scalp sampling, cordocentis, percutaneous umbilical cord sampling, internal foetal labour monitoring. 12. During labour in order to avoid herpes. 13. Herpes 14. The day the baby is born, one month after that and three months after that, using HIV PCR DNA test. 15. No. The risk of transmitting HIV from mother-to-baby can be as high as 28%. 16. Four to six weeks. 17. Her own adherence and health.

Section 7: Drug users and ARVs 1. Due to the wrong but widespread belief that they are less likely to be adherent to treatment and less likely to have a good response to treatment. 2. No, several studies showed that drug users could achieve high levels of adherence and benefit from treatment just like any other group of people with HIV. 3. - Access to treatment

- access to substitution therapy

- OI prophylaxis and treatment

- accessible, non-judgemental healthcare team

- needle exchange

- adherence support and counselling

- strong link with community based programmes

- food programmes

- public transport

- outreach strategies.

4. Yes. 2 to 3 fold increase in ecstasy levels. 5. Yes. About 50% decrease in blood levels of heroin. 6. Yes. People using methadone and efavirenz will have a reduced dose of methadone (of up to 60 % in blood concentration) and may need to increase the dose of their methadone. 7. Yes. AZT concentrations are increased by approximately 2-fold. A dose reduction of 50% of the drug is recommended when used with methadone. 8. Symptoms that develop within 2-3 days are more likely to be a result of ARV toxicity, and those that develop after 6 days are more likely to be associated with opiate drug withdrawal. Section 8: Clincal trials and research 1.

Community advocates should be involved in research because....

• It can help with grant applications NO. Although including community members undoubtedly helps grant applications, this isn’t the primary reason for involving the community

APPENDICES

• Advocates need jobs too

HIV i-Base: basic training for advocates

App:148

January 2008


www.i-Base.info

NO. Although it is nice to have a job, this isn’t a primary reason advocates should be involved in research • Advocates can help design a study today that will still be providing good treatment in a years time YES. Studies designed today need to still be offering standard of care while the trial is running, and advocates can help here. • Advocates can independent represent patient interests if a study isn’t running well YES. Advocates have to focus on the safety of the study for every trial participant, whatever group they are in. • If advocates understand the research they can give independent information about the risks and benefits to individual patients who may want to join the study YES. Advocates can help people with information to decide whether a particular trial is right for them, and whether they are happy with the risks and benefits of enrolling in the study. This can help ensure only people who want to be in the study are enrolled, and this can help reduce ‘drop-out’ of patients leaving the study later. 2. Why is research important for an advocate? • Because if designed well, it can provide reliable information about how effective and/or harmful as treatment of drug is. YES. Good research can provides reliable information about a wide range of clinical choices • Because it will help a company sell more drugs NO. Although an effective drug may generate income for a company, from an advocates perspective we should focus on medical and scientific questions about getting the best information for patient choices • Because it can prove a new treatment may be better than an older treatment YES. New research will hopefully lead to better treatments. Although this isn’t always the case, this is a major reason for research. • Because without evidence, you can only guess at whether something works YES. Even the best expert opinion needs to be proven in practice. • Because without evidence people are vulnerable to false claims about miracle drugs YES. Only carefully designed trials can show if a treatment has a real effect, or whether it is just hype and marketing. 3. Which of these statements about different trials in drug development are true? • Phase IV studies are run to get a drug approved NO. Phase III studies are used for drug approval. Phase IV studies are usually additional safety studies run after a drug has been approved. • Phase II studies are run before Phase I studies NO. Phase I studies have to be run before Phase II studies. • Phase I studies are run in animals

APPENDICES

NO. All ‘Phase’ studies refer to human studies.

HIV i-Base: basic training for advocates

App:149

January 2008


www.i-Base.info

• Phase 3 studies are the main large studies that a company runs to get a new drug approved. YES. These are usually large randomised comparative studies. • Phase II studies look at different doses of a drug to find the best one YES, Phase II studies look at safety, efficacy, and also usually different doses, to decide the best formulation and dose for Phase III studies. 4. Which of these statements about a trial hypothesis are true? • Every trial needs to start with a question, which is called a ‘hypothesis’ YES. This is a fundamental idea to grasp. Every study starts with a question. • The hypothesis is a question that a study is designed to either prove or disprove. YES. The study starts with a question and is designed to test whether the idea is valid. • The hypothesis has to be true from the start of the study. NO. The study itself is designed to show whether the hypothesis is true or false. • A hypothesis has to say that one thing is better than another NO. A hypothesis can ask any question. It doesn’t have to compare one thing to another. Sometimes ‘by implication’ there can be a comparative group. • Some trials do not need a hypothesis. NO. All trials need to start with a hypothesis. 5. Which of these statements about a trial design are true? • A primary endpoint of a study is always seen in the group that does the best. NO. The the primary endpoint is assessed in all groups in the study • A primary endpoint is decided before the study starts YES. A study needs to decide how the results will be analysed to answer the study question BEFORE the study starts. • A secondary endpoint is only used for studies in older children NO. Secondary endpoint is the term for measuring all other factors in a study other than the primary endpoint. • A primary endpoint decides what level of evidence of results will be acceptable to prove or disprove the study question. YES. This is a essential concept to understand for all studies.

• Secondary endpoints can look at a wide range of important things like sideeffects and quality of life. YES. Secondary endpoints can look for a wide range of very important factors in any study. 6. Which of these statements about studies are true? • A prospective study looks backwards in time to see what happened in the past. NO. Prospective studies look forward in time.

APPENDICES

• An new drug is tested in an interventional study.

HIV i-Base: basic training for advocates

App:150

January 2008


www.i-Base.info

YES. Giving someone a new drug is an ‘intervention’ or ‘experiment’ compared to just ‘observing’ them. • A retrospective study look backwards in time. YES. Retrospective looks backwards. Prosepctive looks forwards. • A cross-sectional study looks at something happening at one point in time. YES. Cross-sectional studies take a ‘slice’ through data and report on what is found. • A longitudinal study looks at how tall people are. NO. A longitudinal study follows people over a period of time, and compares was it seen at the start of the period to what is seen at the end. 7. Which of the following statements describe a study that randomises patients to receive a new drug or a placebo and then follows them? • A prospective, observational study NO. Although this is a prospective study, it involves and intervention and is not observational • A prospective interventional study YES. The study follows people forwards in time and uses an intervention (giving a new drug) • A retrospective, cross-sectional study NO. Retrospective is looking backwards. Cross-sectional looks at a single time point. • A prospective, longitudinal study YES. The study follows people over time into the future. • A cross-sectional, longitudinal study NO. This is not cross-sectional. It is longitudinal. 8. Which of the following describes a cross-sectional, retrospective study? • A study that give people a new drug to see if it has less side effects NO. This is a prospective interventional study. • A study that decides to see how many people have lipodystrophy at their next clinic appointment NO. This is a prospective, cross-sectional study. • A study that looks at hospital records to see how many patients say they are smokers at their next clinic visit NO. Although this is cross-sectional, it is prospective and not retrospective. • A study that looks at hospital records to see how many patients had a heat attack last year. YES. This is taking a snapshot of one event recorded in past medical records. • A study to see whether combination therapy with 4 drugs in young children is better than starting with three drugs NO. This is a prospective, interventional, longitudinal study.

HIV i-Base: basic training for advocates

App:151

APPENDICES January 2008


www.i-Base.info

9. Which of the following statements about randomisation are true? • Randomisation helps make sure that people who are more ill stand a better chance of getting a new active drug NO. Randomisation means that however ill someone is, they have equal chance to going into whatever groups are being randomised. • Randomisation will help make sure that each arm has the same proportion of women are in each arm, which similar ages and CD4 count. YES. Randomisation should help to balance all these and other factors. • Randomisation will help make sure that equal proportion of Gemini, Aries, and Librans are in each arm YES. Although this is unlikely to be relevant to the study, proper randomisation should help balance any difference between different patients. • Randomisation is likely to be effective if people are chosen by tossing a coin YES. This is a good example - so long as the coin has not been weighted! • Randomisation is likely to be effective if people are chosen by the day that the visit the clinic NO. Social factors could results in differences between people who visit their clinic on a Monday compared to those that visit on a Friday, and these differences could affect the study results. 10. Which of the following statements about terms used in trials are true? • A placebo is a drug that works well but has no taste. NO. A placebo is matched closely to copy a study drug, but doesn’t include the active ingredient - so some placebo’s will taste horrible. • A placebo has no active drug and is used to compare results to an investigational drug. YES. This is the definition of a placebo drug in a trial. • Blinding makes sure that a patient knows which drug they get. NO. Blinding makes sure a patients does NOT know which drug they get. • Double-blinding means that neither the doctor nor patients know which arm they are in YES. Double-blinding means only a few researchers will know who gets which drug. • A control group is the name for study arm that is used to compare the results of a new intervention. YES. There are lots of different types of control group, but the aim is the same - to act as a comparison for an intervention group. 11. Which statements about these different types of trial are true? • A cohort study is usually an observational study that follows a group of people over time. YES • A cohort study is the best way to see if a new drug works

APPENDICES

NO. Because is is neither interventional HIV i-Base: basic training for advocates

App:152

January 2008


www.i-Base.info

• Prosepective, randomised, placebo-controlled, studies are the ‘gold-standard’ for getting the most reliable evidence about an intervention YES. The follow people forwards in time and randomise to balance arms and rule out bias. • A cross sectional study can give you a re quick answer to whether a new side effect is being seen in a clinic YES. This is often the best strength for a cohort study. • A meta-analysis compares results from different studies YES. Comparing studies is difficult though as they may involve people with very different characteristics - so interpretation of conclusions from a meta-analysis should be done cautiously. 12. Which of the following five terms relates to each of the longer descriptions below. Results, Method, Discussion, Background, Conclusion • The final summary results - what was learned and how it can affect care. = CONCULSION • The strengths and weaknesses of the study: cautions about interpretation, what could have been done better, and the implications for clinical practice, treatment guidelines or for further research. = DISCUSSION • What exactly was studied and how it was preformed. = METHOD • What is already know about this area of research and why the study is being run. = BACKGROUND • What was seen or demonstrated. = RESULTS 13. Which of these statements about informed consent are true • The ‘main’ reason for informed consent is to protect a researcher from legal claims in the future NO. Informed consent can be used this way but the PRIMARY aim is to PROTECT PATIENT CARE IN A STUDY. • The ‘main’ reason for informed consent is to make sure patients understand the potential risks and benefits of a study before they agree to take part YES. This is a good description of why informed consent was developed. • Informed consent should be written in simple language and carefully explain any technical terms YES. The is non point to informed consent if it is not clear and easy to understand. • Informed consent should be in a language that a patient understands YES. Especially if their first language is not the fiurst language of the country where the study is being run, • Even after someone has signed an informed consent form, they can with draw from the study at any time. YES. Any patient can withdraw consent at any time. HIV i-Base: basic training for advocates

App:153

January 2008

APPENDICES


www.i-Base.info

14. Advocates can be involved in the following roles in research... • Following study recruitment and seeing early results with investigators. YES. These are all good reasons to be involved in research. • Suggesting additional analysis of study results. YES. These are all good reasons to be involved in research. • Being an independent advisor for whether a trial is appropriate for an individual patient. YES. These are all good reasons to be involved in research. • Helping design the trial before the study is finalised. YES. These are all good reasons to be involved in research. • Highlighting poor or inappropriate research YES. These are all good reasons to be involved in research.

APPENDICES HIV i-Base: basic training for advocates

App:154

January 2008


Treat.Training-Manual-Jan-08_Final