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The Panum Institute/Building 21.1 Blegdamsvej 3B 2200 Copenhagen N Denmark

Tel: +45 35 45 57 57 Fax: +45 35 45 57 58 www.cphiv.dk chip@chip.dk

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i pass

Annual Report 2011

Copenhagen University Hospital & University of Copenhagen Copenhagen HIV Programme Faculty of Health Sciences

Annual Report

2011


Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 From the Director .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 From the Director of Administration .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Randomized Clinical Trials START .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NEAT .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FLU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intensive Care Division .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12 13 14 15 16

Observational Research DAD .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EuroSIDA .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TB/HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CoDe .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PARTNER .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Editors: Maria Paulsen, Karen Skov Hansen, Jesper Grarup Photographer: Andreas Mikkel Layout: Louise Klit Schou, Kandrups Bogtrykkeri A/S

20 21 24 26 28


Content IT & Bioinformatics .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Projects HIV in Europe .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OST .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MATCH .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EuroCoord .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34 36 37 38

Teaching & Outreach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Acknowledgements .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Publications 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Presentations 2011 .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55


4 · CHIP 2011


Foreword · 5

Foreword

Impact: the role of philosophy The theme of CHIP’s annual report is “Impact”. From the history of philosophy it appears that philosophy never attains final conclusions about anything. Even though philosophy takes its subject-matter both from our everyday experience and the sciences, it constantly remains on the level of conceptual analysis, critical examination, new ideas, so time and again it fails to produce definitive “positive results”. Philosophers claim: “Those questions that are already capable of definite answers are placed in the sciences, while those only to which, at present, no definite answers can be given, remain to form the residue which is called philosophy.”1 In other words, many scientifically established truths have started as philosophic questions, but once they received definite answers they get moved to the realm of science. If one is not familiar with the historical development of science – and the fact that the first modern scientists viewed themselves as natural philosophers, we miss the important role of philosophy in generating ideas for new research. CHIP has continuously been able to evolve from the philosophical flowerbed due to many new ideas nursed by mutual inspiration and debate.Therefore CHIP continues to have impact, in the meaning of a significant or strong influence; an effect. CHIP’s impact is clear through the changes to treatment and related clinical guidelines. The influence on research itself by supporting and developing strong collaborative networks for clinicians with shared challenges as transplant virology, establishing international networks for cohort as well as randomized clinical studies is evident. And lately CHIP demonstrates a strong impact placing the philosophy of early testing and treatment on the agenda by the HIV in Europe initiative and conference. At the clinical department of infectious diseases, we are proud to be a part of one end of the bridge CHIP builds between the University and Rigshospitalet – University of Copenhagen.

Peter Skinhøj, Professor, D.M.Sc. Chair, Department of Infectious Diseases Rigshospitalet

1 Bertrand Arthur William Russell, (18 May 1872 – 2 February 1970)


6 · CHIP 2011

From

the Director Impact: long-term research leading to long-lasting change The Copenhagen HIV Programme was founded when the HIV epidemic was still accelerating in the 1990s and antiretroviral therapy was first being introduced. We were privileged at the time to be able to form a strong and long-standing collaborative network across Europe at a time when international collaborations on the continent were still in their infancy. It started with the EuroSIDA study, which is now in its seventeenth year and still providing crucial evidence on the longer-term outcome of antiretroviral therapy. EuroSIDA also provided the foundation for the D:A:D collaboration, which aims to elucidate possible adverse drug reactions to ART and focused initially on cardiovascular disease, and subsequently viral hepatitis-related liver disease, renal disease and cancers. This vibrant collaboration is now in its twelfth year. The network formed around EuroSIDA was further enhanced by the opportunity to form a strong trans-atlantic collaboration with the National Institutes of Allergy and Infectious Disease and the University of Minnesota and led to the formation of the INSIGHT network. This network focused initially on resolving whether adjunctive interleukin-2 was clinically helpful for people living with HIV and later on whether ART was required continuously or whether it could be used intermittently. Today, it looks at when antiretroviral therapy should be first initiated in the course of the HIV infection. Building on these networks, a healthy research focus on viral hepatitis has emerged. These efforts contribute markedly to international guidelines on best practices to treat the underlying HIV infection and prevent various types of organ disease in people living with HIV. CHIP’s early research was clearly heavily focused on optimizing care for the individual infected with HIV. However, we also made three critical public health observations from the data we collected: 1) patients in eastern Europe were not benefitting from antiretroviral therapy to the extent observed in Central and Western Europe; 2) also in the East, there was an unchecked coexisting epidemic of tuberculosis resistant to most first-line drugs; and 3) throughout Europe a significant proportion of patients enter care too late for them to fully benefit from ART. These observations led to the first major strategic expansion of our scope of work, in 20042007. We needed to engage in professional networks aimed more broadly at public health/ healthcare systems. Collaboration with WHO and agencies within the European Commission (such as the ECDC) was developed. The HIV in Europe initiative was launched in 2007, bringing together health policy-makers, patient advocacy groups and physicians to try to get more HIVpositive people diagnosed and into care earlier in the course of their HIV infection. Studies to document the exact reasons for the poor outcome among people living with HIV in Eastern Europe who are co-infected with tuberculosis and the detrimental impact in that region of lack of access to ART were initiated. We are determined to maintain and expand this strategic direction of our research.


From the Director 路 7

However, our diversification of focus has also expanded into other areas of infectious disease and beyond. We now study severe bacterial infections in the general population admitted to intensive care and viral infections in post-transplant recipients, as well as continuing to track the 2009 influenza A(H1N1) pandemic and other influenza types. Most recently, we launched research focused on behaviours and risks linked to the acquisition of HIV and viral hepatitis: the PARTNER study assesses the risk of acquisition of HIV from persons on antiretroviral therapy and we have a knowledge centre on health in opioidJens D. Lundgren dependent persons. We have also developed state-of-the-art bioinformatics and abilities to disseminate knowledge through e-learning. These expansions made sense to us because of our interest in the area of infectious diseases, our interest in providing an environment for research education for infectious disease clinicians, and because we have the capabilities inhouse and within our networks to undertake this research. Being a research coordinating centre, we rely on the collegiality and collaborative spirit of investigators in our network. In particular, our research efforts could not have prospered without the collaboration initiated two decades ago with the department of public health at University College London. But in the end, CHIP would not be where we are now without the longstanding commitment and hard work of the staff featured in this annual report. But what lies in store for CHIP? We will continue to conduct multicentre infectious disease research and expand our related work in public health and health systems. We will work hard to further strengthen the integration of CHIP in the overall strategy of the Department of Infectious Diseases, Rigshospitalet (Copenhagen University Hospital), and in the newly created Faculty of Health and Medical Sciences at the University of Copenhagen. And as we assess our programme in the light of the changing context around us, we may find a new name. After all, the Copenhagen HIV Programme does much more than HIV research - see for yourself!


8 · CHIP 2011

From

the Director of Administration CHIP has developed into a rather complex organization in order to be able to address the many diversified projects and tasks we are engaged in. From an administrative and operational perspective, however, it is a great pleasure to observe that even through times where it would be easy to get distracted, our ambitious flagship projects like EuroSIDA (p. 21) and D:A:D (p. 20) are sailing steadily – and continue to have a steady impact on our scientific results. The many new endpoint types in D:A:D generate numerous queries and that process has been streamlined throughout the year in parallel with the process of evaluating causes of deaths in the CoDe study (p. 26). For EuroSIDA, the main operational achievement is the transfer of activities to be continued under EuroCoord, which among other things has required us to enter new third party contracts with our more than one hundred sites – a major achievement though we still have a number of agreements pending. A new election for the EuroSIDA Steering Committee is likewise following the new funding round – we are glad once again to have such an engaged and professional Committee. The retrospective HIV-TB project was launched as a prospective study and we have been lucky to attract Anne Marie Werlinrud as a PhD student to collaborate with Daria Podlekareva on this project under the EuroCoord funding – we are proud to be engaged in this as evidence to impact the treatment and care standards is urgently needed. The INSIGHT activities and achievements have been plentiful. Jens Lundgren, supported by Mette Brandt-Madsen and Lars Peters, has launched an efficient procedure for submission and evaluation of new projects within INSIGHT, managed by the Scientific Steering Committee and the 30 writing groups were formed throughout the year. Maintaining a smooth operating process at the SSC to a large extent impacts the productivity of the network. We are very glad that Alvaro Borges from Brazil has joined us as a new PhD student working on the INSIGHT inflammatory marker data. On the operational side, we have served as the secretariat for the Operational Steering Committee and managed the Quality Oversight and Performance evaluation Committee, with a completely revised site quality management procedure implemented. After the implementation of the START study (p. 12), we soon found ourselves engaged in pulling off the second definitive phase of the study. So parallel to supporting existing sites and monitoring their activities, we have managed to double the number of sites involved – our monitoring group did an outstanding work in the first phase of the START study and we believe this will heavily impact the desire to know the definitive answer to the question of ‘When to START’ . For the FLU studies (p. 14), we not only ensure site coordination but also serve as an investigational site ourselves, visiting participants at home throughout the influenza season. In addition, our bioinformatics team is deeply involved in phylogenetic analysis of viral mutations.


From the Director of Administration · 9

Serving as one of four clinical trial units in the NEAT001 trial has been a huge success (p. 13). In our region our sites managed to enroll 120% of the enrolment goal in the competitive enrolment. This was a huge accomplishment for our Jesper Grarup sites and the monitoring team who supported them while also being responsible for the compiling of the monitoring manual, the safety reporting procedure and the endpoint review procedure. We are glad that we have strengthened our monitoring team by engaging Christiane Pahl and Zillah Joensen. Our IT group (p. 32) continues to develop procedures and tools: eCRF solutions for the PARTNER study, the HIV-TB study, the indicator disease project, the CASS study, the ProbeC study (NEAT acute hepatitis study) and more on the way. Further, they have been heavily supporting the implementing of our new project management system, EazyProject, with the launch of a very efficient timesheet function that links to our financial management system. CHIP’s IT activities have been taken to a completely new level (pg x), positively impacting the quality of the collected data and limiting the time consumption for query resolution. The “doctor’s office” has been translating the content of the HIV treatment and care module from the Master of HIV education into an interactive e-module and the Cohort and IT groups developed a 4-week online pilot course which was successfully launched in November (p. 41). CHIP welcomed Torben Weide to our IT group this year and we are already benefiting from his web programming experience. As more and more of our activities have elements of public health and health systems, we found it was a good opportunity to formalize our collaboration with Jeffrey Lazarus – and we are very happy to have Jeff onboard part-time as associated professor. Maria Egede joined us as a PhD student with the CASS study (p. 16),–a follow-up activity to PASS, which studies the possible benefits from cooling sepsis patients. It is amazing how fast Maria, supervised by Jens- Ulrik Jensen, has been able to initiate the study – as we go to press five participants have already been enrolled. Early in 2011 we successfully finalized the revision of the WHO Europe guidelines for HIV management and treatment of adults, chaired by Jens Lundgren, and the guidelines for the treatment of hepatitis B patients, chaired by Lars Peters. We owe many thanks to the dedicated collaborators in our network who contributed to the revisions. Likewise, during the spring and summer Jens Lundgren chaired the revision of the EACS co-morbidity treatment guidelines,


10 · CHIP 2011

>

From

the Director of Administration

transforming research results into highly efficient and user-friendly guidelines. It is always a pleasure to experience how the hard-earned results and experiences from the clinical research we conduct directly impact the way patients are managed. COHERE (p. 38), similar to the EuroSIDA study, is now running under the EuroCoord funding umbrella. The Copenhagen RCC is responsible for the operational work package and we developed an operations manual and operative procedures in 2011. To further support the project groups, a set of reporting tools was developed. The activities under the HIV in Europe Initiative (p. 34), – in particular the Indicator Disease Project, HIDES I, received much deserved attention at the EACS conference in Belgrade and gave a boost to the HIDES II implementation. We are honored that the European Commission granted us co-funding for the third HIV in Europe conference, to be held in Copenhagen (March 2012) – we are proud to contribute so actively to improving early testing and treatment to impact the spread of the epidemic. Dorthe Raben and Maiken Mansfeld have been the drivers of a report compiling the current evidence and highlighting the gaps in knowledge related to opioid substitution therapy for people who inject drugs (p. 36). From working with HIV and hepatitis patients we realize that this is a major problem and the report clearly identifies the need for prospectively collected data. CHIP has initiated collaboration with the Danish Society for Addictive Medicine to try to raise funds for such a project. We are glad that one of our new PhD students, Christian Tjagvad, is experienced in this field and is willing to take part in the project. In the PARTNER study (p. 28), Tina Bruun managed almost singlehandedly to involve more than 70 sites in the study – a huge achievement. Tina and Maria Paulsen developed eye-catching new leaflets to inform participants and we now rely on the sites to enroll the projected number of discordant couples in the study. In April we successfully passed a financial site visit from NIH – a rather detailed audit of our grant management and operational procedures and skills. The MATCH programme (p. 37) has been in operation since 2010. Additional funding for the programme is under discussion, and if support is ensured, we are ready to move forward with a roll-out of the individual data reporting tool as well as implementing an online access tool for transplant responsible clinicians. Throughout the year interest in the programme from Germany and Switzerland developed and an INSIGHT transplant virology interest group has been established. Again a good example of translating experience from one field into another to positively impact the quality of treatment and the quality of life of patients. Finally, as a research unit, we are very pleased that in spite of our many operational tasks, we continue to maintain our impact by producing so many peer-reviewed articles and conference posters and oral presentations.


Randomized Clinical Trials 路 11

Randomized Clinical Trials


12 · CHIP 2011

Start

 

As the international coordinating centre, CHIP has been very busy preparing regulatory submission packages for the many new sites we had to enroll for the definitive phase of the study and we are happy that all new sites are trained and have passed the regulatory approval. Throughout the spring and summer we saw a relatively low recruitment rate in our region. By surveying and interviewing sites we experience that many of the existing sites have exhausted their pool of naïve patients and now rely on new naïve patients as START participants. Further, the discussions throughout the patient community, triggered by the DHHS guidelines with regard to early treatment as prevention, have resulted in reluctance by participants to enroll in some sites. However, in the last part of 2011 the enrollment rate picked up some of the lost momentum. We encourage sites to keep the focus on doing their utmost to include, on average, two participants per month throughout 2012. Participant consent by month, Copenhagen ICC

45 40 35 30 25 20 15 10 5 0 Jan 11

Feb 11

Mar 11

Apr 11 May 11

Jun 11

Jul 11

Aug 11

Sep 11

Oct 11

Nov 11

Dec 11

The substudy co-enrolment rates are: Genomics 97.4; Neurology 54.5; Arterial Elasticity 66.1; Pulmonary 58.5; and BMD 71.4, a little above the network average for Genomics and Pulmonary.


Randomized Clinical Trials ¡ 13

NEAT In October 2011, the NEAT001 study was fully enrolled. As seen in the table, the Copenhagen region did extremely well, with enrollment 20% above the goal – a result of the hard work by our sites supported by the professionalism of our monitor group directly impacting the success of the study. Percentage of Number of CTU CPH

BDX

MRC

AMC

Total

Country A B D D P P S CPH F E BDX G G I I MRC N B H AMC

sites 2 1 8 2 3 1 4 2 2 1 3 8 3 2 2 3 3 4 1 8 9

goal core Screening 6 3 12 2 2 1 3 26 25 9 35 11 8 1 14 27 6 2 6 3 92

Core trial 4 3 10 2 2 1 3 22 21 7 29 9 6 1 11 22 6 2 6 3 78

trial 22 355 140 133 92 122 86 120 121 65 99 138 22 66 62 77 22 55 66 44 91

Viral and ImmunoPharmaco logic genomics Dynamics consent sub-study 3 0 2 0 9 1 0 0 1 0 1 0 2 0 17 1 17 1 6 1 26 3 7 4 0 0 9 0 4 0 13 4 36 0 2 0 6 4 3 4 60 6

Neurocognitive Bone sub- function study sub-study 0 0 2 1 0 2 6 1 0 0 0 0 0 0 2 1 2 1 9 3 8 16 0 7 0 0 0 5 3 8 3 16 1 0 0 0 0 0 1 0 14 33

In addition to supporting the sites in our region, the Copenhagen CTU is responsible for the Endpoint Review procedure (ERC). It has been a major challenge to manage this role. The data forming the basis for the event evaluation from the electronic adverse event CRFs have been very difficult to interpret since contradictory information could be entered and multiple event types indicated for a single event. It has taken some effort and many meetings to agree on a revised procedure in order to ensure that the different CTU take on the responsibility to sort out the information entered before the data are submitted to our ERC coordinator, Per Jansson. The procedure is now well functioning, not least due to the very engaged reviewers in the ERC, chaired by Ferdinand Wit.


14 · CHIP 2011

FLU The INSIGHT influenza studies FLU002 and FLU003 had their protocols revised and we have successfully assisted our sites with the submission of the new protocol versions for regulatory approval. Some additional follow-up information is now collected, which is also reflected in the increased funding for the studies. Besides the coordination of the studies, we run our own investigational site in FLU002. We have a nice collaboration with Copenhagen general practitioners and have a team of MDs from CHIP visiting participants in their home. This set-up has proven highly efficient. Further, our bioinformatics group is involved with the phylogenetic analysis, producing fascinating trees to gain knowledge of the spread of influenza and viral mutations – a unique endeavor directly impacting our understanding of the global spread of influenza and improving the management of the infection.


Randomized Clinical Trials · 15

Laboratory Even though CHIP manages specimens from many sites and stores more than 100,000 samples in our 10 freezers, the team behind the activities is small. Ruth Kjærsgaard mainly manages and quality assures the INSIGHT samples and advises regarding the NEAT specimen shipment and lab procedures. Annette Fischer supports the EuroSIDA sites and manages the EuroSIDA repository. Very few samples are analyzed in Copenhagen with most analysis managed by our partners at the laboratory in Badalona, Spain. We consider the repository our treasure box – the stored samples are valuable resources for supporting future research and are often the element which adds the crucial impact to the clinical data collected.


16 · CHIP 2011

Intensive Care Division CASS The Cooling And Surviving Septic shock study Severe bacterial infection with circulatory collapse (septic shock) is a major cause of death affecting 1/5 of all ICU patients with a mortality rate of around 50%. The CASS study investigates whether Mild Induced Hypothermia (cooling to 32-34°C for 24 hours) can reduce organ failure and mortality in septic shock. Mild induced hypothermia results in the following effects in severe bacterial infection: 1) substantially reduced metabolism, 2) anti-thrombosis and preserved tissue perfusion, 3) anti-apoptosis, 4) reduced bacterial and toxin activity and 5) reduced endothelial stiffness.   In 2011 the CASS study group has been focusing on patient safety and implementation of the trial. Several safety initiatives have been taken including the measurement of coagulation status on whole blood by thrombelastography (TEG) during the first 3 days of study participation. Furthermore, an electronic Case Report Form (https://www.crf.cass-studiet.dk) has been developed; investigators log on to a web page with username and password and enter patient data, which allows the data to be compiled directly without being delayed by fax and secondary keying.   Participation agreements with 12 intensive care units across all 5 regions in Denmark have been made and the CASS study group is collaborating with various departments including clinical microbiology, biochemistry and blood banks with a wide range of personnel groups involved. It is expected that the first 50 patients will be included before summer 2012 and the study will be open for enrollment to the rest of the participating ICUs in the summer, 2012.   PASS The Procalcitonin and Survival Study The primary result from the PASS study was published (JU Jensen et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011 Sep;39(9):2048-58.) and a secondary analysis was presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The Organ Failure Studies The randomized design and the large sample size of the PASS study allows for several important studies about the effect and toxic properties of some of the most used antimicrobial drugs in ICU settings.


Randomized Clinical Trials · 17

Impact 2011 The Data and Safety Monitoring Board (DSMB) has been formed consisting of international experts in different fields within randomized controlled trials. The first patient was successfully included in November 2011. Due to the safety of the study the first 50 patients will be included at 6 of the 12 hospitals. After inclusion of the 50 patients, recruitment is opened to all participating intensive care units.   The CASS study has been met with broad interest both within and outside the health sector and internationally, and the CASS study group has presented the study details on several occasions. Trygfonden made a donation of 2 million Danish kroner and The Lundbeck Foundation made a donation of 1 million Danish kroner.


18 · CHIP 2011

The Organ Failure Studies will focus on the effects and side effects of antimicrobial drugs on renal, pulmonary, liver and cardiac functions, as well as fungal infections. Two of these studies have been completed in 2011 and have been submitted for publication, while several others will be conducted in 2012. COM:PASS The Coagulation caused Organ Malfunction: Prediction Associated with Surviving Sepsis study Septic shock is mainly due to formation of multiple blood clots and breakdown in the microcirculation. The risk of developing the breakdown in the microcirculatory system varies among the patients as does the risk of dying. In COM:PASS the relationship between proteins involved in the formation of blood clots and the tendency for patients to develop septic shock and die from the condition is investigated. This is done by using a biobank established during the PASS study consisting of whole blood, plasma and serum from 1200 patients with different levels of sepsis. The possibility to predict outcome in sepsis by measuring biomarkers (including both conventional biomarkers from plasma and serum plus Single Nucleotide Polymorphism (SNPs)) is investigated. We then prevent organ failure by measuring biomarkers, which show who will most likely develop circulatory failure, and then target treatment towards restoring the circulatory system and by adjusting the treatment to the individual patient, over- or undertreatment can be avoided. Detection of genetic variations, Single Nucleotide Polymorphisms (SNPs), responsible for alterations in protein levels makes it possible to make the risk assessment even before the protein levels are measurable. The DNA has already been extracted from the whole blood samples and the planned analysis of SNPs in genes involved in the coagulation process are scheduled to take place in 2012 together with the measurement of biomarkers in the collected plasma and serum samples.  

Vision of the PASS/CASS group:

i pass COM:PASS

To improve survival, organ function and quality of life for critically ill patients by investigating new and old treatment strategies in ‘state-ofthe-art’ randomized trials, observational studies and biobank/gene-studies.


Observational Research 路 19

Observational Research


20 · CHIP 2011

D:A:D The D:A:D study (Data Collection on Adverse events of Anti-HIV Drugs) is a prospective multicentre cohort study of more than 49,000 HIV-positive persons. The main study objective is to assess the incidence and risk of myocardial infarction (MI) and other cardiovascular (CV) endpoints in relation to antiretroviral treatment. In recent years focus has been expanded to also include endpoints such as non-AIDS-defining malignancies (NADM), end-stage renal disease (ESRD) and chronic liver disease. Study at a glance Patients enrolled

49,734

Number of clinics Total person-years of follow-up

215 304,694

CD4 count measurements Triglycerides measurements Creatine measurements Glucose measurements

1,280,827 661,619 671,675 526,381

Centrally validated endpoints, MI Centrally validated endpoints, NADM Centrally validated endpoints, ESRD

844 931 93

In 2011 the study had 2 oral presentations and 3 posters at international conferences. Please visit www.cphiv.dk/dad/ for presentation/publication details. Focus in 2012 will be on assessing associations between individual antiretrovirals and risk of NADM and ESRD as well as analyses of mortality trends over time, including liver-related deaths.

Impact 2011 Four articles were published in peer- reviewed journals and another 2 were submitted. They covered topics of CV disease after smoking cessation; risk of MI in relation to triglyceride levels and fasting state. One paper concerned protease inhibitors use and sudden death/ non-hem0rragic stroke. Another paper characterized NADMs and finally one focused on short-term diabetes prediction.


Observational Research 路 21

EuroSIDA The primary objective of EuroSIDA is to prospectively study the long-term virological, immunological and clinical outcome for HIV-positive persons across Europe. 2011 has been another active and productive year for the study. EuroSIDA entered a new funding period as one of four partners in EuroCoord. In the spring a new Steering Committee (SC) was elected for a 5-year term. New EuroSIDA SC members Regions Western

Northern

Eastern

Southern

Other SC members

Name of members

Country

J眉rgen Rockstroh (Chair)

Germany

Stephane de Wit (Co-chair)

Belgium

Bruno Ledergerber

Switzerland

Court Pedersen

Denmark

Matti Ristola

Finland

Brian Gazzard

UK

Igor Karpov

Belarus

Andrzej Horban

Poland

Aza Rakhmanova

Russia

Marcelo Losso

Argentina

Antonella Monforte

Italy

Jose Gatell

Spain

Jens Lundgren

Denmark

Andrew Phillips

UK

Peter Reiss

Netherlands

We would like to express our profound appreciation for the dedicated work Bruno Ledergerber and Peter Reiss carried out during their 8 years as chair and vice-chair for the SC, and would also like to acknowledge the long-standing commitment and important work by other SC members who did not continue in the new SC: Christine Katlama, Francisco Antunes, Bonaventura Clotet, Nathan Clumeck, Dan Duiculescu and Anders Karlsson.


22 · CHIP 2011

At the end of 2011, 2500 new patients were enrolled into EuroSIDA Cohort IX and 12 new clinics were invited into the collaboration. Of the patients recruited, 1250 are from Eastern Europe. This will bring the number of patients participating in EuroSIDA to more than 19,000 and there will be 30 participating clinics from Eastern Europe. EuroSIDA would like to welcome new investigators and thank all investigators for their engagement and hard work which has provided the solid basis for the continued success of this study.

Impact 2011 EuroSIDA has now published a total of 158 articles in peer–reviewed journals, of which 16wwere published in 2011. Within the last year, EuroSIDA has reported on a diverse area of topics such as cause of death, HIV drug resistance, hepatitis B and C coinfection, vitamin D insufficiency, non-AIDS disease and tuberculosis and several papers reported on the differences between HIV-positive persons in Eastern and Western Europe. By addressing areas of clinical relevance for HIVpositive patients, EuroSIDA continues to have large impact on clinical management of HIV-positive patients in Europe and elsewhere. In 2011 EuroSIDA had 5 oral presentations and 2 posters at international conferences. At the European conference (EACS) in Belgrade in October 2011, EuroSIDA had 5 presentations on topics of high clinical relevance namely non-AIDS bacterial infections, non-AIDS malignancies and various aspects of hepatitis B and C co-infection, underlining the continued aim to address topics of high clinical relevance for the HIV-positive patients.


Observational Research 路 23

Countries participating in EuroSIDA, 2011


24 · CHIP 2011

TB:HIV The “Tuberculosis among HIV-positive patients: an international prospective observational study” was initiated in the beginning of 2011. The TB:HIV study is a prospective extension of the retrospective phase which was completed in 2010. The study is funded by the European Commission FP7 through the EuroCoord application (work package 13). The overall objective is to prospectively study the long-term clinical prognosis of HIV-positive patients with active TB disease, and the temporal changes and regional differences hereof. The specific objectives are: 1) epidemiology of HIV/TB co-infection and 2) clinical aspects and management of HIV/TB patients. As of December 2011, 3 HIV cohorts and 54 HIV and TB clinics from across Europe and Latin America have agreed to participate in the study. Nearly 300 HIV/TB patients have been enrolled and during 2012 we plan to continue patient enrollment and collect follow-up information on those already enrolled.

Figure 1. The crude mortality rate in HIV/TB patients stratified by time from TB diagnosis Crude incidence rate per 100 PYFU (95% Confidence Intervals)

100

Figure 2. Incidence rate ratios (IRR) for TB-related death

better worse WEA vs EE

‹3 months 61.4

3-12 months

0.05 (0.03-0.09) 0.15 (0.06-0.39)

IDU vs. not

›12 months

HCVpos vs. neg

26.5 18.6

0.30 (0.22-0.42) 0.42 (0.19-0.93) 0.34 (0.25-0.45) 0.33 (0.16-0.68) 3.69 (2.66-5.12) 1.97 (0.82-4.71)

Started cART vs. not*

17.4

10

Initial RHZ-treatment

6.4

Rifamycin-resistance vs. not

p ‹0.0001 1

EE WEA

p ‹0.0001 EE WEA

p ‹0.0001

1.9

EE WEA

N under FU

585 493 N deaths

81

22

IRR (95% CI)

493 461 83

21

363

412

120

20

CD4 cell count per 100 cells* increase

Univariable Multivariable

HIV-RNA per log10 increase*

0.01

0.1

* Time updated

1

Indicence rate ratio


Observational Research 路 25

Impact 2011 In 2011 we continued to address scientific questions within data obtained during the retrospective phase of the study (2006-2010). Comparative analysis of mortality rates in Eastern Europe vs. Western Europe and Argentina revealed that mortality in both regions were highest within the first 3 months after TB diagnosis and subsequently decreased. However, mortality rates in Eastern Europe remained significantly higher at any time after TB diagnosis compared to the other regions (figure 1). Detailed analysis of causes of death showed that patients in Eastern Europe were more likely to die of TB whereas patients from other regions were more often dying of other causes than TB at any time point after TB diagnosis. Among other factors significantly associated with TBrelated mortality were: failure of cART initiation, failure to start TB treatment with standard anti-TB drugs (rifamycin, isoniazid and pyrazinamide) and presence of resistance to at least rifamycin (figure 2). These data were presented at the EACS 2011 conference in Belgrade, Serbia and a manuscript is currently under development.


26 · CHIP 2011

The CoDe Project The Coding Causes of Death in HIV (CoDe) project is a uniform coding system, applicable to studies of individuals with HIV infection. The project was initiated in 2004 out of a need to harmonize and standardize the approach taken when collecting data and reviewing the causes of death of HIV-1-infected individuals. As of December 2011, 2772 CRFs have been registered in the CoDe database (418 in 2011). Of these, a total of 2403 cases (613 in 2011) have gone through the review process and have received a final classification of death. The CoDe methodology is widely implemented by various studies including the D:A:D, EuroSIDA, TB:HIV Project, clinical trials of the INSIGHT collaborative network and the Antiretroviral Therapy Cohort Collaboration (ART-CC) as presented in the table below. The methodology and study documents are free to use and accessible online at the CHIP website (www.cphiv.dk/CoDe) and the project coordinating centre is available to advise individual studies on how they can implement the methodology in to their projects.

Study

Title

Publication

HIV/TB Project

Mortality rate, TB recurrence and causes of death in HIV/TB coinfected patients: Results from the HIV/TB collaborative study

13th European AIDS Conference 2011

Spanish AIDS Research Cohort (CoRIS)

Differences in the causes of death in HIV-infected patients in the Spanish AIDS Research Cohort (CoRIS) according to data sources and coding algorithms

13th European AIDS Conference 2011

D:A:D

The Coding Causes of Death in HIV (CoDe) Project – Initial results and evaluation of methodology

Epidemiology 2011

EuroSIDA

A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: Results from the EuroSIDA study

HIV Clinical Trials 2011

EuroSIDA

Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy

AIDS 2011


Observational Research 路 27

Impact 2011 Several manuscripts and presentations in 2011 were based on CoDe data or methodology. The CoDe project formed the basis for the PhD thesis Assessing the risk and benefit of combination antiretroviral therapy for HIV-1 infection with a special focus on cause-specific mortality, which was successfully defended by Justyna D. Kowalska in October, 2011 (p. 48). The dissertation is available on the CHIP website (www. cphiv.dk). In 2012, CoDe will continue to collect and analyze data on causes of death in the HIV-positive population, further contributing to better insight in both methodological and clinical aspects of this important field.


28 · CHIP 2011

PARTNER The PARTNER study assesses the risk of HIV transmission to HIV-negative partners, in partnerships which consistently do not use condoms and where the HIV-positive partner is on ART with a viral load <50. The study also looks at why some partnerships do not use condoms, determines the proportion of partnerships which begin to adopt consistent condom use and the consequences associated with these issues. Community Leads and Outreach: a new initiative In order to increase enrollment in the PARTNER study, each country has been asked to appoint a Community Lead to help promote the study in the HIV and gay community by informing community stakeholders and increasing the study profile by using networks and social media. The Community Lead will work closely together with the National Coordinator and country sites. Some of the tasks are to interact with community stakeholders and increase the profile of the study by using networks and social media. Some Community Leads have taken the initiative by placing advertisements for the PARTNER study in local magazines which target the gay community.

Homosexual number: 174 (33%)

Heterosexual number: 347 (67%)

Country Austria Belgium Denmark Finland France Germany Ireland Italy Portugal Spain Sweden Switzerland The Netherlands UK Total

Number of Sites 4 3 4 1 4 8 1 3 1 12 2 5 1 24 73

Projected Enrollment 60 45 61 15 90 99 20 60 20 285 40 90 15 382 1282

Current Enrollment 27 7 35 11 31 58 8 18 0 128 30 70 12 93 528

Percentage of Projected Goal 45 15.6 57.3 73.3 34.4 58.6 40 30 0 55 75 77.8 80 24.3 41.2


Observational Research 路 29

HIV-positive with a negative partner? HIV-negative with a positive partner?

Help make a difference by joining this study

Impact 2011 There has been an increasing global interest in the PARTNER study in 2011 because of the large population of MSM partnerships in the study and because PARTNER is investigating transmission risk in sero-different couples who do not use condoms.

The PARTNER Study Partners of people on ART: a New Evaluation of the Risks

A new study is looking at the impact HIV treatment has on reducing the risk of HIV transmission. While everyone wants to know these risks, there are hardly any accurate studies.

The PARTNER study is looking for couples where one partner is HIV-negative and the other is HIV-positive and on treatment. The study will also look at the different patterns of condom use. All information from the study will be anonymised and will be in confidence.


30 · CHIP 2011


IT 路 31

IT & Bioinformatics


32 · CHIP 2011

IT & Bioinformatics

CHIP’s IT group had a fruitful 2011 with many new developments and improvements on existing solutions.   As part of EuroCoord, the HICDEP (HIV Cohorts Data Exchange Protocol) platform was developed as a wiki in order to allow participants to navigate through the various versions of HICDEP (www.hicdep.org ) and was developed with help from our Swiss colleagues and faciliated the release of HICDEP 1.5.   At the IWHOD workshop in Prague three posters specifically on improvement in data management were presented: ”How to identify patients enrolled in multiple cohorts exemplified by the D:A:D study”, ”Improving data quality in HIV cohort collaborations – exemplified by the D:A:D study” and ”Simplifying and automating cohort study feasibility, quality assurance and data management - a distributed approach to data management”. The latter was also presented at both the European and subsequently the International Resistance workshop with special focus on using the tool for creating a cross-European sample repository database. Work within these areas will accelerate during 2012 and onwards in part due to the outside interest in what these tools, algorithms and best practices can be used for on a global scale. In addition to this work, another two EuroSIDA datasets were gathered, the 12th D:A:D merger and a COHERE merger for more than 280,000 patients and more than 75,000 resistance tests were completed and transformed into seven different project datasets together with our colleagues in Bordeaux.   The IT group also improved on existing projects, developed new eCRFs and planned for further eCRF solutions. The CoDe project was further improved; eCRFs were developed and released for HIV in Europe, and solutions for CASS, PROBE-C studies, HIV-TB and EuroSIDA solutions are in the making.   Version 1 of the MATCH database was finalized, allowing us to scale this up into a web-based version 2 with a new visual approach to bring together heterogeneous data sources from Rigshospitalet into a single and coherent informative overview.   Of final note, the IT work within the INSIGHT network on both START resistance tests and influenza full sequences data management and phylogeny and also investigation of CMV resistance mutations and phylogeny is all done locally at CHIP.


Projects 路 33

Projects


34 · CHIP 2011

HIV in Europe The HIV in Europe Initiative The HIV in Europe Initiative has influenced, and in some cases dictated, the policy and normative discourse on testing and early access to care in Europe through the research projects it has initiated, the scientific conferences it has organized and its policy & advocacy work.

The 3rd HIV in Europe Conference will be held at the Panum Institute, University of Copenhagen 19-20 March 2012. The Conference is financially supported by the European Commission.

The initiative has established itself as a HIV in Europe pan-European platform for sharing ideas and Working Together for Optimal knowledge and is recognized as an important Testing and Earlier Care stakeholder in the fight against HIV/AIDS. It has Copenhagen 2012 Conference generated numerous abstracts and articles to a large number of conferences and journals during the last 3 years. One of the aims set forth and achieved by the initiative was to put the issue on the agenda of European agencies and the European Commission. As a result, the initiative has experienced a cascading of its messages during 2010-2011 through the strong collaboration with all key HIV policy relevant organizations, namely WHO Europe and ECDC, both of which sit as observers to the Steering Committee and the European Commission. Millions of people are being treated for HIV every year, but many millions more do not even know they are infected. Our job with the HIV in Europe Initiative is to raise awareness about the importance of early testing and care. Next, we have to work with health systems, in Europe and abroad, to ensure that they can provide optimal treatment and care - and that no population group is overlooked. HIDES I HIV Indicator Diseases across Europe Study, Phase 1 The objectives of HIDES I were to define the methodology of a Europe-wide survey of HIV prevalence in eight indicator diseases or conditions (ID) and to identify those ID with an HIV prevalence of >0.1 %.


Projects · 35

Impact 2011 A total of 3588 individuals were included in HIDES I. Sixty-six were found to be HIV positive, giving an overall HIV prevalence of 1.8% [95% CI:1.4-2.3] and all 8 ID exceeded an HIV prevalence of 0.1%. HIDES I describes an effective strategy to detect undiagnosed HIV infection. By employing indicator condition-guided HIV testing, eight conditions were identified which exceeded the 0.1% prevalence proposed for cost effectiveness. Therefore, all individuals presenting to any health care setting with one of these ID should be recommended an HIV test.

HIDES II 2011-2013 • Roll out pilot ID to other settings and initiate surveys for other ID • Europe-wide audit of HIV testing in patients presenting with conditions for which routine HIV testing is already indicated • Convene a panel to develop indicator condition targeted HIV testing guidelines; to include representatives from relevant medical specialties and European Health Agencies (ECDC and WHO) Results – HIDES I: HIV diagnoses per Indicator Condition Total STI Malignant lymphoma Cervical or anal dysplasia Herpes Zoster <65yo Hepatitis B/C On-going mononucleosis-like illness Leuko/thrombocytopaenia Seborrheic dermatitis/exanthema

HIV-tests

HIV +

Prevalence (95%CI)

3588 764 344 542 207 1099 441 94 97

66 31 1 2 6 4 17 3 2

1.84 (1.42-2.34) 4.06 (2.78-5.71) 0.29 (0.01-1.61) 0.37 (0.04-1.32) 2.89 (1.07-6.21) 0.36 (0.10-0.93) 3.85 (2.26-6.10) 3.19 (0.66-9.04) 2.06 (0.25-7.24)


36 · CHIP 2011

OST Medical practice for people living with HIV with opioid dependence including the use of OST (opioid substitution therapy) More than 1 million HIV+ individuals living in Europe (in particular in Eastern Europe) are opioid-dependent. To address this issue and discuss the best medical practice guidelines for individuals, including people living with HIV with opioid dependence including the use of OST, in 2011 Copenhagen HIV Programme (CHIP) initiated a process of reviewing the literature, discussing the situation within the CHIP network (in particular in the Eastern European region) and explore how the issue is approached in Denmark/Scandinavia.  The discussion has focused on: • How do European health systems manage HIV patients on OST? What are the obstacles? • How can we use the experience from Western/Central Europe to guide intervention, including OST, of opioid-dependent individuals in Eastern Europe? • Could we benefit from establishing a European dialogue forum to further focus the issue in collaboration with established organizations that have this topic as their articulated priority (e.g., EMCDDA and WHO/Europe)? The area of concern will be further developed in 2012 with the introduction of a PhD programme.

Impact 2011 In 2012 CHIP will join the European Health Management Association, a membership organization which aims to build the capacity and raise the quality of health management in Europe. Over 160 institutional members from over 30 countries in the WHO region and beyond have joined this organization, and CHIP is proud to be one of them.


Projects 路 37

MATCH

Management of Post-Transplant Infections in Collaborating Hospitals Following solid organ or bone marrow transplantation, immunosuppressive drugs used to prevent rejection also cause an increased risk of opportunistic infections. In collaboration with the respective clinical departments at Rigshospitalet, the prospective transplantation database MATCH has been in operation since October 2010 and currently 227 patients have been registered and are being followed. The database serves as a tool for central registration and stratification of post-transplant virological screening for all solid organ transplantations. In 2012 the collected data will be subject to statistical analysis evaluating the risk of developing viral infections following transplantation with a solid organ at Rigshospitalet. The collective intentions of these efforts are to provide clinicians with evidence-based knowledge in the area of post transplant infections and thereby improve clinical management and patient care.

MATCH

Impact 2011 Quality assurance and safety is implemented via continuous feed back with the clinical departments regarding adherence to stratification and development of viral infections. As a measure of impact within the first year of operation the proportion of patients diagnosed with a serious viral infection has been kept as low as 1%.


38 · CHIP 2011

EuroCoord By establishing EuroCoord as the umbrella for the four founding networks, CASCADE, COHERE, EuroSIDA and PENTA, we have formed a platform to impact development within observational research. We have now concluded the first of the five years of funding and are currently deeply engaged in the reporting procedure. It has been a challenge to enter contracts with the many third parties we collaborate with and a few sites have pending contracts. It is important to emphasize that we are not able to distribute funding for third parties unless the third party is approved by the European Commission and we have a signed agreement with the site. Apart from the administrative activities, for EuroSIDA the new structure does not influence much the daily activities. For COHERE the funding and kick-off of the planned projects have opened a good opportunity to streamline the procedures and reporting structure. We have now established regular meetings between the two RCCs and developed manuals and a procedures tool. The prospective HIV-TB study is likewise funded through EuroCoord as Workpackage 13 and has successfully engaged sites to enroll participants in the prospective study.

EuroCoord

EuroSIDA

COHERE

HIV-TB

CHAIN

IWHOD The 14th cohort workshop (IWHOD) was successfully completed in March 2011, in Prague – the workshop is a unique closed forum for researchers to share ideas and early results, greatly contributing to networking and generating new ideas. CHIP acts as the financial and contractual secretariat for the Society behind the conference. We are happy that the collaborative effort has been able to continue the workshop after we took it over in 2008. In order to find affordable and adequate venues for the conference, we need to work with at least a two-year future horizon, which therefore requires a constant effort to ensure funding.


Teaching and Outreach 路 39

Teaching & Outreach


40 · CHIP 2011

Teaching and Outreach Throughout 2011 CHIP continued its teaching and outreach efforts, both at the University of Copenhagen as well as outside the university system. The dissemination and application of scientific results is an important component to research and for CHIP, it’s a priority. Among the many teaching activities in 2011, CHIP personnel lectured, presented at international conferences, supervised medical students (bachelor candidates), and launched an online pilot course for HIV-related diseases, treatment and care. Bachelor Candidates Management of HIV-infected patients with tuberculosis: A literature review to identify the most common obstacles to overcome. Isabelle Lodding. Supervisors: Jens D. Lundgren and Daria Podlekareva How does chronic infection with hepatitis C cause liver disease? Anna Olsson. Supervisor: Lars Peters The blood-brain-barrier in HIV infection. Iva Claudia Ralbovsky. Supervisor: Lars Peters PhD Students In recent years, the group of MDs has expanded; a total of 16 doctors work at CHIP, 5 of whom are following a PhD programme while 2 are currently preparing PhD project descriptions. It continues to be a high priority to engage and educate PhD students at CHIP. The CHIP organization provides an excellent infrastructure for PhD programmes, having the administrative and organizational back-up which allows the PhD students to focus on obtaining a detailed knowledge of the design and structure of the studies they are involved in. This creates a solid basis for gaining experience in performing observational and randomized trials, and for developing their own scientific projects. Conversely, CHIP also gains from hiring ambitious young MDs who, with fresh eyes and lots of energy, assist in coordinating and running many of CHIP’s projects. The PhD programmes are related to large ongoing international projects such as EuroSIDA and D:A:D as well as national studies such as the MATCH project and the PASS and CASS studies. The PhD students at CHIP are supervised by senior staff at CHIP as well as by colleagues from the HIV Epidemiology and Biostatistics Group at University College London Medical School, Royal Free Campus (RFH) under the leadership of professors Andrew Phillips, Amanda Mocroft and Caroline Sabin, with whom CHIP has an extremely fruitful and long-lasting collaboration. It is a high priority to create possibilities for PhD students to keep involved after obtaining


Observational Research 路 41

Master of HIV e-Learning After serious considerations, the launch of the Master of HIV programme planned to take place in September 2011 was postponed for an undefined period of time, despite having almost 70 qualified candidates applying for the course. Unfortunately, most of the applicants, coming from low- and middle-income countries, could not afford the tuition fee and especially the cost of living in Denmark for a year. The need for education on HIV-related diseases, their treatment and care, especially in lowand middle-income countries, is very high. CHIP, in collaboration with the Copenhagen School of Global Health, decided to launch a 10-week, 100% on-line, interactive course from the Master of HIV curriculum in April 2012. In this way we hope to be able to bring the knowledge to the students, allowing those with fewer means and in countries where this knowledge is of major importance, to have a chance to develop their skills in this area. The course has been accredited by Trop-Ed and is part of the Master of International Health. The course aims to provide the students with an in-depth understanding of the state-of-the-art treatment and prevention of HIV, opportunistic infections, co-morbidities and co-infections. To ensure a high-quality course, CHIP implemented a 4-week pilot course on HIV-related diseases, treatment and care. The course was received very well by the participants who came from various professional and cultural backgrounds.


42 · CHIP 2011

their PhD degrees, thus benefitting from the experience and expertise the PhD students have gained and enabling them to further develop their scientific skills and careers. Several doctors are working in post-doc positions or are part-time affiliated to CHIP while they are completing their medical specialization: Justyna D. Kowalska, MD, PhD, returning to Warsaw in early 2012, but will remain involved in CHIP activities Daria N. Podlekareva, MD, PhD, post-doc; EuroSIDA and HIV-TB studies Signe Worm, MD, PhD, post-doc, D:A:D study Jens-Ulrik Jensen, MD, PhD, part-time, PASS and CASS studies Nina Friis-Møller, MD, PhD, part-time ID specialist, COHERE study Ulrik Bak Dragsted, MD, PhD, part-time ID specialist, Master and educational activities Lars Peters, MD, research fellow and coordinator, EuroSIDA and INSIGHT studies Ole Kirk, MD, DMSc, ID specialist, research coordinator, EuroSIDA and HIV-TB studies Internal Education Sessions CHIP continues to prioritize employee training and has, for the last 6 years, provided a weekly internal education and update session. The topics, identified by staff, are presented by CHIP personnel as well as other guest lecturers, both national and international. Danish Institute for Study Abroad (DIS) Drs. Lars Peters and Signe Worm from CHIP have been active in teaching at DIS (affiliated with Copenhagen University). Lars coordinates the “A Biomedical Exploration of HIV and AIDS” course, which is offered in the spring and autumn. This course includes an overview of understanding of the complexity of HIV/ AIDS from a biological and medical perspective. The course also includes biological characterization of HIV (virology, immunology and epidemiology), and medical and clinical aspects of HIV/AIDS (development of HIV infection, opportunistic infections, treatments, complications and co-infections).

Currently Active in the PhD Programme Lene Ryom, MD, PhD student, CHIP, D:A:D and EuroSIDA Anne Marie Werlinrud, MD, PhD student, CHIP, HIV-TB study Maria Egede Johansen, MD, PhD student, CHIP, CASS study Caspar da Cunha-Bang, MD, PhD student, CHIP, MATCH project Joanne Reekie, PhD student, RFH, EuroSIDA Daniel Grint, PhD student, RFH, EuroSIDA and HIV-TB studies David Alim Kamara, PhD student, the D:A:D study. Alvaro Humberto Diniz Borges and Christian Tjagvad both recently joined the group in Copenhagen and are currently preparing their PhD project descriptions.


Acknowledgements 路 43

Acknowledgements


44 · CHIP 2011

Acknowledgements Michelle Ellefson moved to a newly established position in the Steno Foundation managing scientific support to diabetes researchers. We are of course very sad to see Michelle leave us, but also very thankful for the enormous effort and dedication Michelle offered us throughout her seven years at CHIP – talk about impact! We posted a new position, to start in early 2012, with even more focus on cross-functional project management utilizing the skills and experiences across the cohort and monitoring groups. After 6 and 7 years, respectively, as monitors and study coordinators in CHIP, Heidi Juncher and Birgitte Jensen left to join a contract research organization. Heidi and Birgitte were valuable and dynamic collaborators and have contributed substantially to the success of the monitor group – many thanks. Nanna Lange, our ‘missing link’ between the project manager, monitors and the IT group, unfortunately had to move back to Jutland. Nanna will be hard to replace as a unique mediator understanding where both IT users and IT supporters come from. Funding CHIP is entirely dependent on external project-specific funding; only one university position is actually funded by Copenhagen University. EU EuroCoord FP7 funding is a major contribution for our activities. The continuation of EuroSIDA and COHERE is funded under EuroCoord as is the prospective HIV-TB study. CHIP is likewise involved as a partner in three additional EU projects: CHAIN, NEAT and the WHO project Monitoring Medicines. NIH CHIP receives limited network funding as International Coordinating Centre in the INSIGHT Network. However, the START study has been granted funding until its completion in 2014 and the FLU002/003 studies are ensured funding at least throughout 2012. Pharmaceutical Industry CHIP is happy to be able to continuously attract private funding and grateful for the many contributions. It is, however, important for us that our activities are driven by an academic research agenda supported by public funding and that CHIP is a strictly non-profit research organization working solely for the benefit of patients by conducting high quality research. We emphasize that the private co-funding we raise is encouraged by and in line with the policies of our public sponsors and the University of Copenhagen.


Acknowledgements 路 45

The EuroSIDA grant does not cover all proposed activities and therefore industry funding for the analytical work related to resistance mutations, toxicities and co-infections is an invaluable contribution. Sponsorship agreements are only entered if the scientific question to be investigated under the agreement is scientifically sound and valuable for patient safety and treatment as evaluated by the Scientific Steering Committee. The resulting reports are often used for regulatory submission as the response to requests from regulatory authorities. The D:A:D study has been and continues to be funded by the HAART Oversight Committeeincluding merger 13 in 2012. In December 2011, the Committee decided to fund for an additional year. The Oversight Committee was originally formed based on requests from the EMEA, which closely follows the D:A:D results and funding. Together with the University of Bordeaux, CHIP administers the activities of the legal entity established to take care of the International Workshop on HIV Observational Databases (IWHOD). The HIV in Europe Initiative is coordinated by CHIP and is a pan-European multidisciplinary initiative working for optimal testing and care for HIV in Europe. Eight pharmaceutical companies sponsor the initiative (p. 46) and the European Commission granted support for the 3rd HIV in Europe conference, to be held in March 2012, in Copenhagen.


46 · CHIP 2011

Financial Contributors 2011 Study/activity

Public

Private

EuroSIDA

EU Commission

Merck & Co Inc Pfizer Inc Tibotec

D:A:D

The Oversight Committee for The Evaluation of Metabolic Disorders of HAART

The Oversight Committee sponsors:

EMeA

Boehringer-Ingelheim Pharmaceuticals Inc

FDA

Bristol-Myers Squibb

Abbott Laboratorie

Gilead Sciences GlaxoSmithKline Merck & Co Inc Pfizer Inc Roche Pharmaceuticals Tibotec/ Janssen-Cilag International NV INSIGHT Network

National Institutes of Health, USA (NIH)

INSIGHT START

Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS), Australian National Health and Medical Research Council (NHMRC); Bundesministerium fur Bildung und Forschung (BMBF), Division of Clinical Research, NIAID, NIH; National Institute for Mental Health (NIMH), NIH; National Institute of Neurological Disorders and Stroke (NINDS), NIH; National Cancer Institute (NCI), NIH; European AIDS Treatment Network (NEAT); Department of Bioethics, NHI, Clinical Center

Study drug sponsors: Gilead Sciences Bristol-Myers Squibb Merck & Co Inc Abbott Laboratorie GlaxoSmithKline Tibotec/ Janssen-Cilag International NV

INSIGHT FLU

NIAID, NIH

NEAT

EU Commission

Study drug sponsors: Gilead Sciences Janssen-Cilag International NV Abbott Laboratories Ltd Merck Inc.

Monitoring Medicines, WHO

EU Commission

HIV-TB

EU Commission

Bill & Melinda Gates Foundation

EUROCOORD-CHAIN

EU Commission

COHERE

EU Commission

PARTNER

National Institute for Health Research, UK (NIHR)

IWHOD

NIH Office of AIDS Research

Boehringer-Ingelheim Pharmaceuticals Inc

NEAT

Gilead Sciences

ANRS, Agence nationale de recherches sur le sida

Gilead Sciences

GlaxoSmithKline Pfizer Inc Roche Pharmaceuticals Tibotec/ Janssen-Cilag International NV

HIV in Europe

EU Commission (2012 conference)

Abbott Laboratorie

Endorsed by

Boehringer-Ingelheim Pharmaceuticals Inc

AIDS Action Europe WHO Europe European AIDS Treatment Group (EATG) University of Copenhagen

Bristol-Myers Squibb Gilead Sciences GlaxoSmithKline Merck & Co Inc Schering-Plough Tibotec/ Janssen-Cilag International NV

CASS

TrygFonden Lundbeck Foundation


Publications 2011 路 47

Publications 2011


48 · CHIP 2011

Assessing the risk and benefit of combination antiretroviral therapy for HIV-1 infection with a special focus on cause-specific mortality Summary of PhD thesis defended successfully 28 October 2011 Justyna Kowalska, MD, PhD Combination antiretroviral therapy (cART) has dramatically improved the prognosis of HIV-positive persons. The effect of cART is achieved by suppressing the HIV replication, thereby allowing the person’s immune system to regenerate, as indicated by an increasing CD4 lymphocyte count. This response leads to a marked decreased risk of developing an AIDS event and of all cause mortality. Among the various causes of death, the decline in non-AIDS death has been less pronounced than the decline in AIDS-related death. Consequently, the proportion of non-AIDSrelated deaths - such as death due to cardiovascular diseases, accelerated liver cirrhosis or chronic kidney disease - has substantially increased in the last decade after cART was widely used. Besides the traditional risk factors for non-AIDS death, untreated HIV-infection, as well as adverse drug reactions from cART, may contribute to the risk of such deaths. The latter contribution is not likely to affect overall net cART benefit on a population level, but may translate into net harm for certain subgroups of persons. Identifying these subgroups and ensuring that research circumvents this problem is of clinical relevancy. Although rational use of any treatment needs to be weighed against its potential risks, scientific methods for such assessment are limited. Hence, it is challenging to differentiate potential negative effects from the use of cART from those that HIV infection by itself may contribute with and that cART is potentially correcting. Despite these challenges, further investigation of whether - and if so in whom - long-term cART toxicities may limit the overall treatment benefit is necessary in order to further guide the most appropriate use of cART. This challenge was a major objective for this PhD thesis. In the first step we investigated whether it is possible to identify patients where the risk of serious adverse events is high and may compromise the beneficial effect of the drug. We discussed how to balance risk and benefit in practical terms, using an example of the recently reported increased risk of myocardial infarction associated with abacavir. By translating relative risk to an absolute risk increase and number needed to harm, we illustrated how to identify patients


Publications 2011 路 49

who could remain on abacavir-containing regimens and those for whom such an approach would result in an unacceptably high risk of myocardial infarction. We created an on-line tool designed to help clinicians assess patient risk (www.cphiv.dk). It is still unknown whether and how the adverse effects of cART translate into cause-specific mortality. Analyzing changes in cause of death with cumulative exposure to treatment is necessary to further understand this issue. The EuroSIDA study, following large numbers of patients across Europe since 1994, is in a unique position to investigate the issue. Further investigation requires accurate assessments of the causal link between the disease or condition and death, followed by establishing the underlying cause of death. Such procedures have been developed at the Copenhagen HIV Programme, namely the Coding Causes of Death in HIV (CoDe) project and in 2004 the procedures were included into the EuroSIDA study methods. For all events collected before 2004, an algorithm was developed and tested to unify accessible information and classify all deaths as either AIDS or non-AIDS-related. Finally, we analysed the incidence of causespecific death in relation to cumulative exposure to cART. We did not find any association between prolonged exposure to treatment and dying from any cause, after accounting for the latest CD4 count, viral load and other factors. This suggests that adverse effects of cART do not compromise the overall benefit received from treatment at a population level. With increasing patient survival, new antiretrovirals approved for routine care and earlier initiation of antiretroviral treatment, surveillance of the rate of cause-specific deaths remains a vital tool in monitoring long-term treatment benefit and drug safety. Future research should continue to provide insight into groups of patients with pre-existing unfavourable risk profiles and focus on adding a harm perspective to treatment choice.

Info A pdf version of the thesis is available at www.chip.dk (publications/dissertations).


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Publications 2011 In 2011 a total of 45 articles were published in peer-reviewed journals, with an average impact factor of eight. Scientific articles are one of the main outcomes for CHIP as an organization and are key to the impact CHIP research has in the field of infectious disease research. The articles published in 2011 illustrate the diversity of the projects either coordinated or executed here at CHIP. 1 Estimating prevalence of accumulated HIV-1 drug resistance in a cohort of patients on antiretroviral therapy. W Bannister, A Cozzi-Lepri, J Kjær, B Clotet, A Lazzarin, JP Viard, G Kronborg, D Duiculescu, M Beniowski, L Machala, A Phillips. J Antimicrob Chemother. 2011 Apr;66(4):901-11. 2 Rates of cardiovascular disease following smoking cessation in patients with HIV infection: Results from the D:A:D study. K Petoumenos, S Worm, P Reiss, S de Wit, A d’Arminio Monforte, C Sabin, N Friis-Møller, R Weber, P Mercie, C Pradier, W El-Sadr, O Kirk, JD Lundgren, M Law; for the D:A:D Study Group. HIV Med. 2011 Aug;12(7):412-21. 3 Risk factors for fatality in HIV-infected patients with dideoxynucleoside-induced severe hyperlactataemia or lactic acidosis. A Arenas-Pinto, A Grant, K Bhaskaran, A Copas, A Carr, SW Worm, E Martinez, P Reiss, D Dunn, R Weber, J Hoy, I Weller, the Lactic Acidosis International Study Group. Antivir Ther. 2011;16(2):219-26. 4 Factors associated with the development of cytomegalovirus infection following solid organ transplantation. C da Cunha-Bang, SS Sørensen, M Iversen, VH Sengel, JG Hillings, A Rasmussen, SA Mortensen, ZV Fox, NS Kirkby, CB Christiansen, JD Lundgren. Scand J Infect Dis. 2011 May;43(5):360-5. 5 Regarding: Humar et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. C da Cunha-Bang, M Iversen, SA Mortensen, A Rasmussen, H Sengeløv, SS Sørensen, J Lundgren. Am J Transplant. 2011 Feb;11(2):408. 6 A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: Results from the EuroSIDA study. JD Kowalska, A Mocroft, B Ledergerber, E Florence, M Ristola, J Begovac, H Sambatakou, C Pedersen, JD Lundgren, O Kirk, for the EuroSIDA Study Group. HIV Clin Trials. 2011 Mar-Apr;12(2):109-17.


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7 HIV-1-related Hodgkin lymphoma in the era of combination antiretroviral therapy: Incidence and evolution of CD4+ T cell lymphocytes. J Bohlius, K Schmidlin, F Boué, G Fätkenheuer, M May, AM Caro-Murillo, A Mocroft, F Bonnet, G Clifford, V Paparizos, JM Miro, N Obel, M Prins, G Chêne, M Egger. Blood. 2011 Jun 9;117(23):6100-8. 8 Acute hepatitis C in HIV-infected individuals- recommendations from the NEAT consensus conference. JK Rockstroh; The European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel. AIDS. 2011 Feb 20;25(4):399-409. 9 Risk of triple-class virological failure in children with HIV: A retrospective cohort study. Pursuing Later Treatment Options II (PLATO II) project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE), H Castro, A Judd, DM Gibb, K Butler, RK Lodwick, A van Sighem, JT Ramos, J Warsawski, C Thorne, A Noguera-Julian, N Obel, D Costagliola, PA Tookey, C Colin, J Kjær, J Grarup, G Chene, A Phillips. Lancet. 2011 May 7;377(9777):1580-7. 10 HIV in hiding: methods and data requirements for the estimation of the number of people living with undiagnosed HIV. Working Group on Estimation of HIV Prevalence in Europe. AIDS. 2011 May 15;25(8):1017-23. 11 Impact of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy - a European multi-cohort study. The EuroCoord-CHAIN joint project. L Wittkop, HF Günthard, F de Wolf, D Dunn, A Cozzi-Lepri, A de Luca, C Kucherer, N Obel, V von Wyl, B Masquelier, C Stephan, C Torti, A Antinori, F Garcia, A Judd, K Porter, R Thiébaut, H Castro, AI van Sighem, C Colin, J Kjær, JD Lundgren, R Paredes, A Pozniak, B Clotet, A Phillips, D Pillay, G Chêne. Lancet Infectious Diseases. 2011 May;11(5):363-371. 12 A comparison of the long-term durability of nevirapine, efavirenz and lopinavir in routine clinical practise across Europe: A EuroSIDA study. J Reekie, P Reiss, B Ledergerber, D Sedlacek, M Parczewski, J Gatell, C Katlama, G Fatkenhaeur, JD Lundgren, A Mocroft. HIV Med. 2011 May;12(5):259-68. 13 The Coding Causes of Death in HIV (CoDe) Project- Initial Results and Evaluation of Methodology. JD Kowalska, N Friis-Møller, O Kirk, W Bannister, A Mocroft, C Sabin, P Reiss, J Gill, C Lewden, A Phillips, A d’Arminio Monforte, M Law, J Sterne, S De Wit, JD Lundgren, the CoDe Working Group and the D:A:D Study Group. Epidemiology. 2011 Jul;22(4):516-523. 14 Tuberculosis among HIV-postive patients across Europe: Changes over time and risk factors. A Kruk, W Bannister, D Podlekareva, N Chentsova, A Rakhmanova, A Horban, P Domingo, A Mocroft, J Lundgren, O Kirk; on behalf of the EuroSIDA Study Group. AIDS. 2011 Jul 31;25(12):1505-13. 15 Vitamin D and clinical disease progression in HIV infection: Results from the EuroSIDA study. JP Viard, JC Souberbielle, O Kirk, J Reekie, B Knysz, M Losso, J Gatell, C Pedersen, JR Bogner, JD Lundgren, A Mocroft for the EuroSIDA Study Group. AIDS. 2011 Jun 19;25(10):1305-1315.


52 · CHIP 2011

16 The metabolic syndrome in HIV. SW Worm, JD Lundgren. Best Pract Res Clin Endocrinol Metab. 2011 Jun;25(3):479-86. 17 Elevated triglycerides and risk of MI in HIV-positive persons, the D:A:D study. SW Worm, DA Kamara, P Reiss, O Kirk, W El-Sadr, C Fux, E Fontas, A Phillips, AD Monforte, S De Wit, K Petoumenos, N Friis-Møller, P Mercie, J Lundgren, C Sabin. AIDS. 2011 Jul 31;25(12):1497-504. 18 Antibiotics in intensive care: too little or too much? ME Johansen, JU Jensen, JD Lundgren. Crit Care Med. 2011 Jul;39(7):1849-51. 19 Mortality in enterococcal bloodstream infections increases with inappropriate antimicrobialtherapy. M Suppli, R Aabenhus, ZB Harboe, LP Andersen, M Tvede, JU Jensen. Clin Microbiol Infect. 2011 Jul;17(7):1078-83. 20 The impact of fasting on the interpretation of triglyceride levels for predicting myocardial infarction risk in HIV-positive individuals: The D:A:D Study. DA Kamara, SW Worm, P Reiss, M Rickenbach, A Phillips, O Kirk, AD Monforte, M Bruyand, M Law, S De Wit, C Smith, C Pradier, JD Lundgren, C Sabin. J Infect Dis. 2011 Aug;204(4):521-525. 21 Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial. JU Jensen, L Hein, B Lundgren, MH Bestle, TT Mohr, MH Andersen, KJ Thornberg, J Løken, M Steensen, Z Fox, H Tousi, P Søe-Jensen, AØ Lauritsen, D Strange, PL Petersen, N Reiter, S Hestad, K Thormar, P Fjeldborg, KM Larsen, NE Drenck, C Ostergaard, J Kjær, J Grarup, JD Lundgren; Procalcitonin And Survival Study (PASS) Group. Crit Care Med. 2011 Sep;39(9):2048-58. 22 HIV infection, aging and cardiovascular disease: Epidemiology and prevention. K Petoumenos, SW Worm. Sex Health. 2011 Nov;8(4):465-73. 23 Predictors of having a resistance test following confirmed virological failure of cART: Data from EuroSIDA. ZV Fox, A Cozzi-Lepri, A d’Arminio Monforte, A Karlsson, AN Phillips, G Kronborg, J Kjaer, B Clotet, JD Lundgren for EuroSIDA. Antivir. Ther. 2011;16(5):781-5. 24 Hepatitis delta in HIV-infected individuals in Europe. V Soriano, D Grint, A d’Arminio Monforte, A Horban, C Leen, E Poveda, F Antunes, S de Wit, J Lundgren, J Rockstroh, L Peters. AIDS. 2011 Oct 23;25(16):1987-92. 25 Fatal and non-fatal AIDS and non-AIDS events in HIV-1 positive individuals with high CD4 counts according to viral load strata. J Reekie, J Gatell, I Yust, E Bakowska, A Rakhmanova, M Losso, M Krasnov, P Francioli, J Kowalska, A Mocroft; EuroSIDA in EuroCoord. AIDS. 2011 Nov 28;25(18):2259-68. 26 Factors associated with HIV-1 virological failure in an outpatient clinic for HIV-infected people in Haiphong, Vietnam. DT Huong, W Bannister, PT Phong, O Kirk, L Peters. Int J STD AIDS. 2011 Nov;22(11):659-64.


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27 Hyaluronic acid levels predict increased risk of non-AIDS death in hepatitis-coinfected persons interrupting antiretroviral therapy in the SMART Study. SMART Study Group, L Peters, J Neuhaus, A Mocroft, V Soriano, J Rockstroh, G Dore, M Puoti, E Tedaldi, B Clotet, B Kupfer, JD Lundgren, MD Klein. Antivir Ther. 2011;16(5):667-75. 28 Procalcitonin-guided antibiotic treatment of respiratory tract infections in a primary care setting: Are we there yet? R Aabenhus, JU Jensen. Prim Care Respir J. 2011 Dec;20(4):360-7. 29 A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy. R Paredes, MC Puertas, W Bannister, M Kisic, A Cozzi-Lepri, C Pou, R Bellido, G Betancor, J Bogner, P Gargalianos, D Bánhegyi, B Clotet, J Lundgren, L Menéndez-Arias, J Martinez-Picado; The EuroSIDA Study Group. J Infect Dis. 2011 Sep 1;204(5):741-52. 30 Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations. EZ Soliman, JD Lundgren, MP Roediger, DA Duprez, Z Temesgen, M Bickel, JC Shlay, C Somboonwit, P Reiss, JH Stein, JD Neaton, INSIGHT SMART Study Group. AIDS. 2011 Jan 28;25(3):367-77. 31 Can linear regression modeling help clinicians in the interpretation of genotypic resistance data? An application to derive a lopinavir-score. A Cozzi-Lepri, MCF Prosperi, J Kjær, D Dunn, R Paredes, CA Sabin, JD Lundgren, AN Phillips, D Pillay, for the EuroSIDA and the United Kingdom CHIC/United Kingdom HDRD Studies. PLoS One. 2011;6(11):e25665. 32 Cardiovascular implications from untreated human immunodeficiency virus infection. JV Baker, JD Lundgren. Eur Heart J. 2011 Apr;32(8):945-51. 33 Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection. JV Baker, J Neuhaus, D Duprez, LH Kuller, R Tracy, WH Belloso, S De Wit, F Drummond, HC Lane, B Ledergerber, J Lundgren, DE Nixon, NI Paton, JD Neaton, INSIGHT SMART Study Group. J Acquir Immune Defic Syndr. 2011 Jan;56(1):36-43. 34 Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): A European multicohort study. L Wittkop, HF Günthard, F de Wolf, D Dunn, A Cozzi-Lepri, A de Luca, C Kücherer, N Obel, V von Wyl, B Masquelier, C Stephan, C Torti, A Antinori, F García, A Judd, K Porter, R Thiébaut, H Castro, AI van Sighem, C Colin, J Kjaer, JD Lundgren, R Paredes, A Pozniak, B Clotet, A Phillips, D Pillay, G Chêne, EuroCoord-CHAIN Study Group. Lancet Infect Dis. 2011 May;11(5):363-71. 35 Effect on transmission of HIV-1 resistance of timing of implementation of viral load monitoring to determine switches from first to second-line antiretroviral regimens in resource-limited settings. AN Phillips, D Pillay, G Garnett, D Bennett, M Vitoria, V Cambiano, J Lundgren. AIDS. 2011 Mar 27;25(6):843-50.


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36 Haemoglobin and anaemia in the SMART study. A Mocroft, AR Lifson, G Touloumi, J Neuhaus, Z Fox, A Palfreeman, MJ Vjecha, S Hodder, S De Wit, JD Lundgren, AN Phillips, INSIGHT SMART Study Group. Antivir Ther. 2011;16(3):329-37. 37 Prevention of HIV-1 infection with antiretroviral therapy. A Rodger, A Phillips, J Lundgren. N Engl J Med. 2011 Nov 17;365(20):1934; author reply 1935. 38 The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI. A Cozzi-Lepri, R Paredes, AN Phillips, B Clotet, J Kjaer, V Von Wyl, G Kronborg, A Castagna, Jr Bogner, JD Lundgren for EuroSIDA in EuroCoord. HIV Med. 2012 Jan;13(1):62-72. 39 Prevalence and prognostic significance of ECG abnormalities in HIV-infected patients: results from the Strategies for Management of Antiretroviral Therapy study. EZ Soliman, RJ Prineas, MP Roediger, DA Duprez, F Boccara, C Boesecke, C Stephan, S Hodder, JH Stein, JD Lundgren, JD Neaton. J Electrocardiol. 2011 Nov-Dec;44(6):779-85. 40 The Global Fund’s resource allocation decisions for HIV programmes: Addressing those in need. O Avdeeva, JV Lazarus, MA Aziz, R Atun. J Int AIDS Soc. 2011 Oct 26;14:51. 41 Critical interactions between the Global Fund-supported HIV programs and the health system in Ghana. R Atun, SK Pothapregada, J Kwansah, D Degbotse, JV Lazarus. J Acquir Immune Defic Syndr. 2011 Aug;57 Suppl 2:S72-6. 42 Attitude of Lithuanian residents to confidentiality of adolescent sexual and reproductive health care. L Jaruseviciene, JV Lazarus, A Zaborskis. Central European J Public Health, 2011; 19(4): 211-217. 43 Overcoming obstacles to late presentation for HIV infection in Europe. JV Lazarus, R Jürgens, M Weait, A Phillips, J Hows, J Gatell, T Coenen, A Sönnerborg, D Raben and JD Lundgren. HIV Med. 2011 Apr;12(4):264-9. 44 A comparison of the long-term durability of nevirapine, efavirenz and lopinavir in routine clinical practice across Europe: a EuroSIDA study. J Reekie, P Reiss, B Ledergerber, D Sedlack, M Parczewski, J Gatell, C Katlama, G Fätkenheuer, JD Lundgren, A Mocroft; for the EuroSIDA Study Group. HIV Med. 2011 May;12(5):259-68. 45 Acute hepatitis C in HIV-infected individuals – recommendations from the NEAT consensus conference. JK Rockstroh; The European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel. AIDS. 2011 Feb 20;25(4):399-409.


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Presentations 2011


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Presentations 2011 13th European AIDS Conference/EACS, Belgrade, October 2011 Oral presentations 1 Non-AIDS defining malignancies (NADM) in the D:A:D study: Time trends and predictors of survival. S Worm for the D:A:D Study Group. 2 Chronic hepatitis C (HCV) infection and chronic kidney disease (CKD) in HIV-infected patients in the EuroSIDA study. L Peters on behalf of the EuroSIDA study. 3 The incidence of serious non-AIDS defining infections in the EuroSIDA cohort. J Reekie on behalf of the EuroSIDA study. 4 Predictors of hepatitis C viremia in co-infected individuals. D Grint, A Phillips on behalf of the EuroSIDA study. 5 Hepatitis delta in HIV-infected individuals in Europe. V Soriano on behalf of the EuroSIDA study. 6 HIV Indicator Diseases across Europe Study (HIDES I): Results from the pilot phase. Ann Sullivan on behalf of the HIV Indicator Diseases Across Europe Study Group. 7 Mortality rate, TB recurrence and causes of death in HIV/TB co-infected patients: Results from the HIV/TB collaborative study. DN Podlekareva, D Grint, A Panteleev, A Rakhmanova, R Miller, M Bruyand, H Furrer, F Post, I Zeltina, A Skrahin, JM Miro, N Obel, E Girardi, MH Losso, J Toibaro, J Caylá, JD Lundgren, O Kirk, HIV/TB Collaboration Study Group.


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ICAAC, Chicago, September 2011 Poster presentations 1 Renal failure related to broad-spectrum antibiotics in critically ill patients. ME Johansen, JU Jensen, , L Hein, B Lundgren, M Bestle, T Mohr, MH Andersen, KJ Thornberg, J Loken, M Steensen, Z Fox, H Tousi, P Soe-Jensen, AO Lauritsen, D Strange, N Reiter, K Thormar, P Fjeldborg, KM Larsen, NE Drenck, L Ryom, C Ostergaard, J Kjaer, J Grarup, JD Lundgren. 2 Candida infections related to broad-spectrum antibiotics in critically ill patients. JU Jensen, K Reinholdt, L Hein, B Lundgren, M Bestle, T Mohr, MH Andersen, J Loken, H Tousi, P Soe-Jensen, AO Lauritsen, D Strange, N Reiter, K Thormar, KM Larsen, NE Drenck, ME Johansen, C Ostergaard, JK Møller, B Olesen, MC Arendrup, J Kjaer, J Grarup, JD Lundgren for the PASS Study Group. 3 Cytomegalovirus and the drugs used to prevent and treat this infection as risk factors for longer term deterioration of kidney function after solid organ and human stem cell transplantation. C da Cunha-Bang, S S Sørensen, M Iversen, H Sengeløv, A Rasmussen, F Gustafsson, Z Fox, JD Lundgren.

13th Int. Workshop on Adverse Drug Reactions and Co-morbidities in HIV, Rome, July 2011 Oral presentation Development of a definition for Rapid Progression (RP) of renal disease in HIV-positive. persons. L Ryom, DA Kamara, SW Worm, MJ Ross, P Reiss, CA Fux, P Morlat, O Moranne, O Kirk, C Smith and JD Lundgren for the D:A:D Study Group.

Int. Workshop on HIV & Hepatitis Virus Drug Resistance & Curative Strategies, Los Cabos, June 2011 Poster presentation Development of a cross European virtual sample repository and HIV resistance database. J Kjær, DK Kristensen, G Beheydt, S Imbrechts, M Rickenbach, I Fanti, F Incardona and A-M Vandamme.


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9th European Workshop on HIV & Hepatitis – Treatment Strategies & Antiviral Drug Resistance, Cyprus, March 2011 Poster presentation A semi-automated system to query distributed heterogeneous viral databases. G Beheydt, E Schülter, S Imbrechts, A Abecasis, FM Codoñer, D Paraskevis, A Sönnerborg, A-M Vandamme and J Kjær.

18th Conference on Retroviruses and Opportunistic Infections, Boston, February 2011 Poster Presentations 1 Risk of cause-specific deaths over calendar time and according to cumulative exposure to combination antiretroviral therapy (cART). JD Kowalska, A Mocroft, J Reekie, A Phillips, P Reiss, B Ledergerber, J Gatell, A d’Arminio Monforte, JD Lundgren and O Kirk for the EuroSIDA Study Group. 2 Predictors of virologic response to etravirine-based cART regimens in a large european cohort of HIV-infected patients. A Cozzi-Lepri, R Paredes, A Phillips, J Kjær, A Lazzarin, J van Lunzen, A Karlsson, M Johnson, and J Lundgren for the EuroSIDA Study Group. 3 Kinetics of platelet counts following interruption of ART: Results from the SMART Study. E Zetterberg, J Neuhaus, for SMART/INSIGHT Study Group. 4 HCV treatment and CD4 cell count decline in HIV/HCV co-infected patients: European Cohort Collaboration. C Smit, A d’Arminio, F de Wolf, M Puoti, F Dabis on behalf of the HCV working group of COHERE in EuroCoord.


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CHIP annual report 2011