Chip Annual Report 2014

Centre for

Health & Infectious Disease Research

Annual Report 2014

Centre for

Health & Infectious Disease Research

PERSIMUNE New Activities at CHIP

WHO Collaborating

Centre on HIV and Viral Hepatitis

CHIP

A Year of Transformation

EuroSIDA

Expanding the Study

Introduction CHIP last published an annual report in 2012. Since then, CHIP has gone through various changes, both physical and structural. To reflect these changes, we chose to focus this report on some of the main results since the 2012 annual report, as well as looking towards the future of CHIP. Professor Thomas Sinkjær, Director of the Danish National Research Foundation, provided the foreword for this report, highlighting that CHIP has recently been awarded a six-year grant to establish the Centre for Personalised Medicine Managing Infectious Complications in Immune Deficiency (PERSIMUNE). Structural changes at CHIP have resulted in a new management group. In this report you will find messages outlining CHIP’s areas of focus from the director, Jens D. Lundgren; Dorthe Raben, Director of Research Coordination; and Jesper Grarup, Director of Administration and IT Development.

Table of Contents Forewords From Professor Thomas Sinkjær. . . . . . . . . . . . . . . . . . . . . . . . 3 From the Director.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 From the Directors of Research Coordination & Administration & IT Development.. . . . . . . . . . . . . . . . . . . . . . 6

Focus on Results The PARTNER Study .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 START & INSIGHT .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Publications.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Presentations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Focus on the Future of CHIP New activities at CHIP: PERSIMUNE .. . . . . . . . . . . . . . . . . . 10

Acknowledgments Funding Contributors.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Acknowledgments.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Focus on Viral Hepatitis and HIV WHO Collaborating Centre on HIV and Viral Hepatitis .. 15 SACC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 EuroSIDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 HepHIV2014 Conference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Annual Report 2014 · 3

Foreword Jens Lundgren and his research colleagues are among the 12 new Centers of Excellence funded by the Danish National Research Foundation. They have been awarded a six-year grant to establish the Centre for Personalized Medicine Managing Infectious Complications in Immune Deficiency (acronym PERSIMUNE).

As director of the Danish National Research Foundation, I am pleased with the enormous amount of talent revealed in the ambitious and original ideas that this application round produced. I am convinced that the centers we have established will contribute considerably to growth and welfare in Denmark through their original and innovative approaches to a wide range of important research questions, including the questions related to personalized medicine that PERSIMUNE will pursue.

The foundation supports what may be called frontier research or front-line research. These terms can be translated as saying that the foundation expects its centres to carry out highly ambitious, original research of a high international calibre, research that may further be described as very creative, scientifically daring, and potentially ground breaking. The researchers at PERSIMUNE are expected to engage in pondering some of the large unsolved questions and to address the challenges that intrigue them the most. The philosophy is that when excellent people work on problems they are most passionate about, ground breaking results will follow. In other words, the foundation welcomes curiosity-driven research or what might be described

as exceptional researchers’ “dream projects.”

We are happy that Rigshospitalet has followed our recommendation and established PERSIMUNE as a joint physical entity, which will facilitate a large degree of daily interaction. We are also happy that the centre, as encouraged by the foundation, has pursued international collaborations with high-ranking researchers from Paris, Oxford and London.

All Centres of Excellence are headed by distinguished scientists who have not only shown excellence in their own research but also proven themselves as visionary leaders able to form a creative and dynamic research community. When assessing applications, the foundation puts emphasis on the qualifications of the proposed centre leader.

We are convinced that Professor Jens Lundgren will use his leadership skills to facilitate the pursuit of excellent results and will continue to set high standards for how exceptional research should be conducted. In addition, by serving as a hub for exceptional research, the center will provide an optimal environment for training the next generation of first-rate scientists.

The foundation is looking forward to working with Professor Lundgren and his colleagues as they successfully pursue their ambitious research agenda.

Professor Thomas Sinkjær Director, Danish National Research Foundation

4 · Annual Report 2014

From the Director

CHIP

A Year of Transformation (...yet again) CHIP is no stranger to change. In fact, we thrive on it - driving change and improving the fields of HIV and other infectious diseases as well as immune deficiency research by providing top quality research and initiating novel approaches for both new and persisting challenges alike. In 2014 we continued this tradition of embracing change by adapting our “look” and name to reflect the extensiveness of our research portfolio, which is better described by ‘Centre for Health and Infectious Disease Research’ added to our logo, rather than only ‘Copenhagen HIV Programme’. The original abbreviation, CHIP, is retained, and is the name we use in general communications.

To a large extent, our research focuses on identifying factors that determine outcome. Predicting

things, in particular those that will happen in the future, is not easy. It is not only a question of identifying predictive factors but also determining how effective these factors are.

This research intends to elucidate ways by which we can better guide care of infectious disease. When is the optimal time to commence antiretroviral therapy (ART) in chronic HIV infection, direct acting antiviral (DAA) therapy in chronic hepatitis C virus infection or antiviral therapy in transplant recipients in risk of cytomegalovirus infection?

Straightforward questions, but answers are complex and require diverse research efforts. Not only is this research assisting in optimising care, but it also assists in creating a better understanding of the underlying biological mechanisms which determine the risk of infection.

The infectious disease speciality has advanced in providing medicine that best fit the individual’s needs – personalised medicine. But we can do better still. Empiric antimicrobial, antifungal and antiviral therapy remains prominent as part of care, in particular among individuals with impaired immune function – which as a hallmark is a population at excess risk of infection. This infectious phenotype presents itself either directly (overt infection) or indirectly (organ dysfunction and cancers) as complications from this excess propensity. An intriguing area for us to engage in, and in doing so, create a synergy with the experiences we’ve gained from HIV and its resulting immune deficiency which CHIP has focused on for more than two decades.

Annual Report 2014 · 5

It was with great joy I received a call from the director of the Danish National Research Foundation, Professor Sinkjær, in early October, and learned that our application to establish a Centre of Excellence was accepted. This centre will aim to explore factors that determine the risk of the infectious phenotype in populations with impaired immune system. The “Centre of Excellence for Personalised Medicine of Infectious Complications in Immunodeficiency” (PERSIMUNE), opens on 1 February, 2015 and will engage a large, international team of researchers. Patients at Rigshospitalet, and elsewhere, with impaired immune systems will contribute with biological material, and I look forward to further strengthen the collaborative tires with clinical response for caring for patients with cancer, transplant recipients, autoimmune disease, HIV, congenital immunodeficiencies, etc.

CHIP and its collaborators have contributed with a number of important research observations in 2014. To

name a few, the first set of observations of the PARTNER study demonstrate zero HIV transmissions from HIV+ individuals to their HIV- partners engaged in condomless sex, provided that the HIV+ person is on ART. We demonstrated that the kinetic of CMV replication in transplant recipients was more protracted than believed, and that a simple set of chemical characteristics in liver transplant recipients at day 10 post transplantation was able to identify an exclusive subgroup at risk of death in subsequent months. Also, recruitment in the START trial was completed in December 2013. The characteristics of this large cohort (4685 participants) will enter the public domain while follow-up continues. These and other research outcomes were done in collaboration with colleagues at the University College of London (Prof Andrew Phillips’ team, including Prof Amanda Mocroft and Prof Caroline Sabin, et al), the INSIGHT network (Profs James Neaton, Abdel Babiker and Fred Gordin, et al) and many others at the 270+ network of infectious

disease clinics with which CHIP affiliates. Thank you for your continued collegially spirited and dedicated collaboration.

Finally, lots of ‘thank yous’ also go to the team at CHIP and my colleagues at Rigshospitalet in general and in particular the colleagues at the Department of Infectious Diseases and Rheumatology, and the Steering Committee members of the MATCH programme. Rigshospitalet is a great and inspiring place to work.

I hope to see many of you at the opening ceremony of the PERSIMUNE Centre of Excellence in February 2015.

Jens D. Lundgren, Director

6 · Annual Report 2014

From the Directors of Research Coordination & Administration and IT-development Since the last annual report in the spring of 2013, a lot of things have happened at CHIP. Hopefully, you as the reader of this annual report will realise that CHIP, despite the changes, continues to strive to answer important research questions directly impacting the way patients are managed, their quality of life as well as knowledge of risk factors contributing to their disease, as well the way patients timely enter care.

Since 2007, CHIP was located at the University of Copenhagen based on a three-party agreement with Rigshospitalet, the University and CHIP. Over the last few years, we have become more and more involved with activities at the hospital and therefore it was logical to fully integrate CHIP as part of the hospital. This was implemented by 1 January 2014, although the physical relocation was effective only from 1 February 2014. Our new facilities are at Parken, the national stadium, where we have very nice offices just opposite the hospital. In between our offices and the hospital lies Fælledparken, the most visited park in Copenhagen. From a contractual and legal perspective, this means that CHIP now belongs to The Capital Region of Denmark as our housing legal entity instead of the University of Copenhagen.

Another change has been Jesper Kjær’s decision to leave CHIP by the end of February 2014. Since early on in the life of CHIP, Jesper contributed to development of study databases and not least frontline tools to organise and merge large cohort data for which we are very thankful (see

acknowledgment section). CHIP management decided to use the opportunity to restructure the leadership group, involving Dorthe Raben as Director of Research Coordination, allowing Jesper Grarup to include the IT-function in his area of responsibility.

A number of activities have been implemented strengthening the involvement of CHIP in hepatitis and co-infected HIV and viral hepatitis patients. This has become increasingly interesting to follow as new drugs for treatment of hepatitis C has entered the market.

In July 2013, CHIP was designated WHO Collaborating Centre on HIV and Viral Hepatitis. In addition to reviewing and contributing to guideline development and participating on behalf of the WHO Europe office at high level meetings, CHIP has contributed to a number of country missions (Belarus, Estonia, Georgia, Tajikistan, and Kyrgyzstan) evaluating implementation of guidelines and monitoring of national HIV treatment and care programmes. We are happy to contribute to this important work and also happy that a number of skilled people throughout our network has offered their expertise and resources to fulfil these tasks.

We remain confident that the activity has an impact by allowing access to interact with involved stakeholders at national levels from health authorities, clinics to civil society organisations, striving to improve diagnosis, treatment and care of people living with HIV and viral hepatitis in the European Region, and in particular in the Eastern European and Central

Asian region mostly affected by the epidemic.

As another important hepatitis activity, the HIV in Europe initiative, with its secretariat based at CHIP since 2009, expanded the scope of the biennial conference to include earlier testing and care for HIV and viral hepatitis, recognising the high burden of undiagnosed hepatitis in the region. From both a scientific and a logistical perspective, the management and coordination of the HepHIV2014 Conference held in October 2014, Barcelona, Spain, the third coordinated by CHIP on behalf of the HIV in Europe Initiative, was a success. This success continues by translating and disseminating the brilliant contributions and discussions at the conference in a way that ensures this important event makes a lasting impact. Similarly, the encapsulation of experience from the HIDES study into testing guidelines, covering a variety of specialities, is a major and well recognized achievement that is now recognised as an important and innovative testing strategy. A three-year grant from the EU Commission under the Second Health Programme 2013 for the The OptTEST project (Optimising testing and linkage to care for HIV across Europe) will build on these past experiences by providing tools and assessment methods to analyse and effectively respond to late presentation for HIV care and treatment.

The MATCH programme principle, originally developed to monitor treatment and care of transplant patients at the hospital and ensuring automated feed of treatment data to the

D:A:D at a glance · 7

CHIP offices, Rigshospitalet: 5-7 floors, Tower F (Entrance at Øster Allé 56)

8 · Annual Report 2014

national quality assurance database, is now being developed to support a shared care model for monitoring and treatment of hepatitis at addiction care centres across Copenhagen (SACC). The project is supported by a grant from the Capital Region of Denmark and our MATCH-based database provides specialists at the central hospital with an overview of all participant data both from the hospital, labs and the addiction centres. This allows them to maintain treatment and care responsibility, while it is the local medical staff at the addiction centres that are directly interacting with the participants.

Drug users can then be screened, monitored and treated in a known and safe environment. Our IT group is skilfully supporting this development, and in addition is working on the further development of electronic data capture solutions (already in place for Probe-C, HIDES II, and the CASS studies) into EuroSIDA. As a result the new EuroSIDA cohort X is using e-data capture for enrolment data and when this report is published we will also have an e-data capture system for EuroSIDA follow-up data implemented. The system will allow sites to see their latest data in the e-form, enabling them to easily continue recording any newer data.

As featured in this report, the MATCH principle plays a major role in the successful implementation of the personalised medicine project (PERSIMUNE) we will be coordinating from 2015 and 6 years ahead.

Our monitors have achieved an important milestone by ensuring the successful completion of the NEAT001 study, documenting that dual therapy with a combination of an integrase inhibitor plus a boosted-PI was non-inferior at week 96 compared to PI-based triple therapy, but was less effective in patients starting with a high viral load.

Completion of NEAT001 included reconciliation of study data, site closure

and contribution to the publication of the main study results as well as producing a poster for the Glasgow HIV Drug Therapy conference in 2014 on the endpoint review process coordinated by CHIP. Maintaining participants in the treatment arm to which they are randomised in START and ensuring a low lost to follow-up rate is the current main focus in the START study. In addition, the group is getting ready for the yearly influenza season and the FLU002/003 Plus studies in parallel to setting up the new randomised influenza study investigating the effect and safety of treating influenza with specific hyper immune serum – the FLU-IVIG study.

For the last couple of years CHIP has housed the secretariat for the Health Systems Global organization. This year has been busy planning the symposium, held every two years, which successfully took place in Cape Town, South Africa in October, 2014. The meeting brings together society members with the full range of players involved in health systems and policy research to share new state-of-the-art evidence and review the progress and challenges towards implementation of the global agenda of priority research. An important area is working to strengthen the scientific rigour of health systems research including concepts, frameworks, measures and methods and facilitate greater research collaboration and learning communities across disciplines, sectors, initiatives and countries.

As part of CHIP’s contribution in the INSIGHT network, we were responsible for planning and hosting the annual International Coordinating Centre/Operational Steering Committee Retreat, which took place this year in Barcelona, Spain. As always, the retreat brings together dedicated and engaged operational and scientific staff from the entire

network, making it a rewarding task to plan and host the event.

In the area of cohort collaborations, the EuroCoord activities in EuroSIDA, COHERE and TB:HIV are continuing according to plan. An important undertaking is the decision to expand the 10th EuroSIDA cohort from 2500 to 5000 participants – all co-infected with hepatitis C. This is made possible via additional fundraising activities and we are all excited to be part of the effort to collect large scale data on the evidence on the hepatitis C treatment being rolled out throughout Europe. For COHERE, the operational workpackage is managed

by CHIP and we are proud that the effort invested in the development and implementation of operational procedures have paid off and ensured a smooth identification of research projects, definition of the data needed for the single projects, a successful data merger and quality assurance, as well as the successful analysis and publication of results.

For the TB:HIV study, the diversity of centres is large and it has been resourceful to have the many participating centres trained and focused on their performance to allow a seamless capture of quality data.

The process is now streamlined and a baseline publication is on its way.

The DAD study continues producing science of high quality and the group is working hard on the day-to-day coordination of the project and ensuring the quality of the data. We are happy to have new PhD students in both EuroSIDA and D:A:D. Another important milestone is the presentation of the first PARTNER data on the risk of HIV transmission in sero-different couples in a mixed population of homo- and heterosexual couples, at CROI in 2014 (p<XX>) and the successful raising of funds to continue the study in a phase II, focusing on gaining evidence on the transmission risk among homosexual couples where

Annual Report 2014 路 9

one is HIV positive and well treated.

A final large achievement worth mentioning is that the CASS study, investigating cooling of patients with septicaemia, has now successfully expanded internationally. The first centre outside of Denmark is a Dutch centre at the Amsterdam Medical Centre (AMC), which will hopefully be

followed by centres in the US. From the above, we hope you understand that we at CHIP are proud to contribute beyond our own activities in collaboration with colleagues nationally as well as with institutions and networks internationally, offering all to take advantage of our experience and competencies. The multi-

disciplinary team at CHIP is always ready to take on new challenges, which area a constant part of our daily work.

Dorthe Raben, Director of Research Coordination & Jesper Grarup, Director of Administration and IT Development

The CHIP management team Jens Lundgren, Dorthe Raben and Jesper Grarup

Focus on the Future of CHIP

Annual Report 2014 · 11

New Activities at CHIP PERSIMUNE We are proud to announce that Jens Lundgren’s application for a Centre of Excellence grant from the Danish National Research Foundation was successful. The application focused on the development of PERSIMUNE, a research centre for personalised medicine of infectious

complications in immune deficiency. The grant covers a 6-year period with the possibility for a 4-year extension with a start date in February 2015.

The multidisciplinary centre at Rigshospitalet works from the hypothesis that across patients with impaired immune function, there is a common pattern of un-discovered risk factors explaining the variation in risk of infectious complications.

PERSIMUNE aims to understand the mechanisms explaining the variation in risk using a diverse set

of methodologies, including pattern recognition from big data from routine care, studies of host and microbial genetics, imaging, and immunological characterization.

The discovery phase will likely identify novel mechanisms of host defence, which will be used to characterize groups of immune-compromised patients and identify clusters of factors associated with comparable types of infectious complications. From this, we will formulate a series of immunodeficiency indices encapsulating the variation in risk for infectious complications. The indices will be validated and used to personalise interventions aimed at reducing infectious complications.

One major problem is that the existing microbiological technologies rarely identify bacterial or fungal cause of these syndromes in contrast to the identified sensitive markers that exist for viral pathogens. PERSIMUNE will, as part of its core activities, apply molecular technology to address this shortcoming.

After the initial studies to improve sensitivity and specificity for microbial identification in situations of infectious-related clinical syndromes, the work will continue with the main project component being the identification of PERSIMUNE predictive factors (PPF) allowing for personalisation of medicine.

PERSIMUNE predictive factors that apply to one or more subgroup(s) of immune deficient hosts and for one or more categories of infectious phenotype(s) will be identified and categorised as: • Novel PPFs • Validation PPFs (validation of observation made by others) The scientific priorities of investigation into the different types of PPFs will be based on the principle that excellence takes priority. This includes the discovery of novel markers and the investigation into their biological mechanism, taking priority over the investigation of markers already identified and used as validation data, but in addition as a subject for further exploration of their biological mechanism.

12 · Focus area: CHIP in the future

The research investigates the interactions as depicted in Figure 2 below and does this in a discovery and evaluation flow as depicted in Figure 1.

Figure 1

Figure 2

The evaluation of PPFs will include: • Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPP), and population attributable fraction (PAF)* as high as possible across subgroups and categories of infectious phenotypes (the larger the number of subgroups and categories the better) • Independent predictive ability - Differentiate between statistical prediction vs pathophysiological PPFs. PPFs that reflect varied component of the same pathophysiological process may each be novel in their discovery, and hence a key beneficial output from PERSIMUNE, despite that only some of them are required to be included as part of the Immune Deficiency Index because only some of them are independently predicting the infectious phenotype in question.

- Confounders, both understood and available: initially the centre will conduct a series of analyses based on routinely available data in order to identify such confounders, which will be required to demonstrate the degree of independency for novel identified PPFs. However, these initial steps will by themselves generate a number of PPFs, many of which of the “validation” type but potentially also of the “novel” type.

The key measurable outputs from the PERSIMUNE centre will be: As a prerequisite for the scientific projects in PERSIMUNE, we will establish a classification of microbial causes of clinical syndromes seen frequently in immune-compromised hosts. The syndromes are 1. Fever 2. Sepsis and 3. Pneumonia

The biological mechanism(s) explaining the predictive ability of the PPF. As the PERSIMUNE unfolds its activities and starts to generate PPFs, it may choose to either further investigate the biological mechanisms, continue to search for other PPFs or a combination of the two.

The ambition for the centre is high, both regarding scientific achievements, but not least in the perspective of establishing a hospital-wide platform for performing frontline clinical immunology research.

Focus area: CHIP in the future 路 13

Focus on Viral Hepatitis and HIV

14 路 Annual Report 2014

Focus area: Viral hepatitis and HIV · 15

WHO Collaborating Centre on HIV and Viral Hepatitis In July 2013, CHIP was designated a WHO Collaborating Centre on HIV and Viral Hepatitis, formalising the longstanding collaboration between the World Health Organization Office for Europe and CHIP. The activities of the WHO Collaborating Centre for the next 4 years includes assisting WHO in the development of guidance, providing technical support on treatment and care of HIV and viral hepatitis (primarily to the countries of Central and Eastern Europe and central Asia (CEECA)), networking and the building of strategic partnerships, as well as promoting and disseminating evidence-based data on HIV, viral hepatitis treatment and care in the CEECA region.

The Collaborating Centre (CC) pursues the formation of strategic partnerships in the CEECA and dissemination of evidence-based approaches to HIV in order to optimise the prevention, treatment and management of patients within CEECA. The Collaborating Centre established a CC secretariat function in 2013 and constructed a WHO CC website. Initial partnership activities have involved encouraging Health Care Managers from CHIP’s network to engage in WHO CC and HQ Global activities. Additionally, Danish policy-makers and government officials have been encouraged to utilise the WHO CC and establish a formal cooperation.

The Collaborating Centre has carried out a number of country missions

to assess the strengths and weaknesses of national HIV/AIDS programmes: in Belarus (November 2013 and November 2014), Estonia (May 2014), Georgia (June 2014), Tajikistan (October 2014) and Kyrgyzstan (November 2014).

Debriefings were carried out with relevant country authorities like the Ministry of Health, and evaluation reports were prepared. The missions are an important strategic priority, facilitating knowledge sharing of the research performed at CHIP and capacity building in the region as well as awareness-raising among policy makers in these countries.

In addition to these activities, a proposal has been drafted to develop an e-learning course on HIV and

Centre for

Health +Infectious

Centre for Disease Research

Health & Infectious Disease Research

viral hepatitis, including modules on opportunistic infections and adverse events of ART in collaboration with EACS and focusing on Eastern European countries. The proposed course is structured according to the ‘train the trainers’ concept wherein course participants serve as moderators for subsequent generations of participants. To facilitate this concept, national representatives will be selected from the WHO network to contribute to the development of the course and receive training in both clinical work and e-learning moderation.

For a comprehensive list of WHO CC activities, please visit our website at http://www.cphiv.dk/WHO-CC/ CHIPs-CC-activitie

WHO Collaborating Centre on HIV and Viral Hepatitis

16 · Annual Report 2014

SACC

Developing and validating a shared care model for decentralised hepatitis C treatment of injection drug users The Shared Addiction Care Copenhagen (SACC) project was initiated in June 2014 and will run for a three-year period. SACC will develop and validate a model for decentralized testing, clinical evaluation and treatment of hepatitis C (HCV) at 12 counselling centres in Copenhagen offering drug treatment. The overall aim is to decrease transmission of HCV and HCV-related morbidity and mortality among injection drug users (IDUs) with the point of departure being that most IDUs in Denmark have never been tested for HCV infection, while few of those with chronic HCV infection have received HCV treatment.

The SACC database The essential working tool will be the SACC database that is currently under development. The database will gather data from relevant existing databases in a common patient chart. The data will be accessible to both the health professionals at counselling centres offering drug treatment and to the Department of Infectious Diseases & Rheumatology at Rigshospitalet. This development draws heavily from CHIP’s experience with database development and implementation from previous research projects.

The treatment model SACC’s treatment model will initially be implemented in three pilot counselling centres. The treatment model will thereafter be validated in the nine remaining counselling centres offering drug treatment.

An initial phase of strengthening teaching and information about hepatitis C will take place, aimed at both clients and staff. Thereafter, all direct contact to participating clients will take place locally at the counselling centres, including initial conversations with clients, HCV testing, non-invasive evaluation of liver fibrosis (fibro scanning) and further clinical evaluation of clients in order to identify their eligibility for HCV treatment.

The daily contact to patients and distribution of medicine lies with the counselling centres. The monitoring of treatment outcome and prescription of medicine lies with the Department of Infectious Diseases.

At the Department, assigned staff will monitor treatment outcomes, through the “online” database, and uphold dialogue with counselling centres. The database will be programmed to generate alarms if tests are not performed or if the results require an intervention.

Research An estimated 1800 to 2000 clients will be included in the project.

Collection of data on HCV infection, treatment and outcome from a large population of IDUs will enable the production of scientific publications and presentations on the health status of IDUs in general and HCVrelated disease and integrated hepatitis C treatment and care in particular. This is done as a means to strengthen research in health interventions aiming to secure inclusion of vulnerable and marginalized groups and reduce inequality in access to health.

A Project Steering Committee was established with representatives from: Social Services Administration, City of Copenhagen; counselling centres; CHIP and; Department of Infectious Diseases and Rheumatology, Rigshospitalet.

Shared Addiction Care Copenhagen

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Shared Addiction Care Copenhagen - from the point of view of the City of Copenhagen Throughout many years it has been of substantial importance to the City of Copenhagen to enable testing and evaluation followed by offer of treatment for hepatitis- and HIV-infected persons enrolled in the drug treatment system in accordance with the National Action Plan on Hepatitis C and the National Guidance on the Medical Treatment of Drug Users in Substitution for Opioid Dependence. For the treatment cascade, many barriers have been identified and they have been found hard to overcome.

They can manifest as individual barriers, barriers in the treatment system as well as systemic barriers, both in the region of the municipality as well as in the health care system.

By participating in this Shared Addiction Care project, the City of Copenhagen is looking forward to the opportunity to join efforts in order to overcome the barriers and bridge the gap, regarding qualifying existing knowledge as well as creating new knowledge regarding this vulnerable, not well-researched, group of citizens in order to facilitate testing and offer of treatment in order to decrease morbidity and mortality due to drug-related infections.

The inter-disciplinary approach is already an integrated part of

Helle Petersen, MD Head of Medical Section, Drug and Alcohol Addiction Treatment, City of Copenhagen the treatment setting (social and health aspects) and SACC is drawing upon the shared experiences as a means to develop appropriate handling of an important health issue in this group.

Focus area: Viral hepatitis and HIV · 19

EuroSIDA Expanding the Study The EuroSIDA study was initiated in 1994 and continues to expand in various ways. As an observational study, the type of data collected has diversified tremendously since 1994 as advances in the medical management of HIV have allowed for infected patients to anticipate a good life prognosis. The study continues to adapt to and accommodate these advances in medicine, with focus expanding to include liver disease, renal disease, nonAIDS cancers, and confounders relevant for predicting risk factors for their occurrence.

Liver-related death due to hepatitis C virus (HCV) is one of the leading causes of death among HIV patients. In the EuroSIDA observational HIV cohort about 30% of all patients are co-infected with HCV. In Eastern Europe, where HIV is predominantly acquired through injection drug use, more than half of all HIV patients are co-infected with HCV. Treatment options have, until recently, been limited to interferon-based therapy, which is both poorly tolerated and has a low cure rate among co-infected patients.

treatment seems to be equally effective in people who are co-infected with HIV. The main drawback of the new drugs is their high cost, which will require prioritization of candidates for treatment, and result in unequal access to treatment in different parts of the world.

In keeping with EuroSIDA’s tradition of expanding its research agenda to investigate important developments in the field of HIV, in 2014 EuroSIDA started the enrolment of a new cohort of 5000 HIV/ HCV co-infected patients. These patients will join the 2500 co-infected patients already followed in EuroSIDA. All patients will be followed for at least five years.

In addition to evaluating regional differences in uptake and virologic outcome of HCV treatment in a real-life clinical setting, the design of the study will enable a comparison of characteristics of patients who received HCV therapy with those

who did not, and evaluate the long term clinical benefit of HCV treatment, including the risk of HCV re-infection.

Seventy-three EuroSIDA centres, including two new centres in Poznan and Tbilisi, from 29 different countries have expressed interest in enrolling patients into the new cohort. EuroSIDA, which has played a similar key role in assessing the uptake and clinical outcomes of antiretroviral therapy in HIV–positive persons across Europe, is in a unique position to provide high-quality data from countries, in particular from Eastern Europe, that otherwise would not be available.

le of CHIP/collaborator oral presenta6on slides

With the advent of several potent and well-tolerated oral direct acting antivirals (DAA) against hepatitis C virus (HCV), 2014 is likely to become a watershed year for HCV treatment. Interferon-free combinations of DAA, taken for only around 12 weeks, will eradicate HCV in nearly all patients who receive the treatment. Furthermore, the

20 · Annual Report 2014

HepHIV2014 Conference:

HIV and Viral Hepatitis

Challenges of Timely Testing and Care Recognising the need to integrate research and intervention in HIV and viral hepatitis, the HIV in Europe initiative, with the Secretariat and co-chair based at CHIP since 2009, joined forces with leading hepatitis organisations to organise the first HIV and viral hepatitis conference on testing and access to treatment.

Over recent years, the need to address the ‘hidden’ burden of viral hepatitis has become more urgent within the fields of communicable diseases and public health. The HepHIV2014 conference brought together for

the first time stakeholders from the fields of viral hepatitis and HIV/AIDS, ranging from practitioners at the local level to top policymakers.

of the HepHIV2104 conference, succinctly raises long-standing public health concerns from both sides as a single document.

The HepHIV2014 Conference was a vital first step in bringing these two fields together at a European level.

Not only did it highlight how much the hepatitis and HIV fields can learn from each other, but also showed us that by working together, the two fields can present a united, stronger front with which to tackle these serious public health concerns. The Call for Action, developed as one outcome

HepHIV 2014

The Call for Action has been developed by the HIV in Europe Steering Committee and HepHIV2014 Scientific Committee based on input at the conference.

5-7 OCTOBER BARCELONA

The Steering Committee of the HIV in Europe initiative met after the conference and agreed to continue focusing on hepatitis and merge to produce a HepHIV initiative in 2016, when the next HepHIV Conference will be organised.

HepHIV 2014

5-7 OCTOBER BARCELONA

HIV and Viral Hepatitis: Challenges of Timely Testing and Care

Focus area: Viral hepatitis and HIV · 21

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8.

9.

Surveillance of viral hepatitis. Assess, nationally and regionally, how many people are infected with viral hepatitis (B and C, acute and chronic), their fibrosis stage, how many present late, and how many remain undiagnosed, over time and by key population, in order to monitor trends and to better target interventions.

Defining late diagnosis of viral hepatitis for medical care. Support further consultation to establish a simple and lasting consensus definition for late presentation of viral hepatitis to improve surveillance and enable monitoring of health systems and testing strategies.

Testing modalities and targeted testing and communication. Promote multiple testing platforms in community settings, healthcare facilities and in the home (self-testing), with special attention to cost and cost-effectiveness and the possibility of testing all three blood-borne viruses at the same time.

Involve key communities in the tailoring of testing and health promotion messages to their audiences.

Indicator-condition-guided testing. Broadly implement indicator-condition-guided HIV testing in healthcare settings, especially general practices.

Develop the evidence to support the concept of indicator-condition-guided testing for viral hepatitis.

Health policy strategies. Correlate national health policy strategies with public health outcomes for viral hepatitis, HIV and TB, comparing Eastern and Western European regions, as well as the European Union and the rest of the European Region. Advocate for expansion and support the funding of successful harm-reduction models, such as those developed by Ukraine, and adoption of international standards in national strategies.

Synergy of infectious disease efforts. Facilitate collaboration between HIV, HBV, HCV, STI and TB activities in research, policy, health promotion, surveillance, testing and education at regional, European Union and national levels and among civil society, including representatives of key populations.

Continuum of care. Develop robust data to inform each component of the continuum of care for viral hepatitis and for HIV, including linkages to affordable state-of-the-art treatment and interventions for prevention and testing.

Affordability. Make HIV and viral hepatitis (HBV and HCV) treatment affordable by working to lower drug prices and ensuring that both domestic and international funders contribute to financing the treatment of both conditions.

Political leadership. Renewed political leadership of governments, the European Union and international agencies in the European Region is crucial to address the important challenges in viral hepatitis and HIV. Policies and public health interventions need to be based on existing scientific evidence and validated guidelines are needed to inform viral hepatitis and HIV policies and programmes.

Barcelona 5-7 October 2014

Focus on Results

24 路 Annual Report 2014

PARTNER STUDY

First results and continuation until 2017 PARTNER study began recruiting sero-different couples in September 2010, funded by the National Institute of Health research in the UK. The aim of the study is to follow sero-different heterosexual and homosexual couples who report having had condomless vaginal or anal sex in order to study the risk of HIV transmission to partners, in particular in partnerships that continue not to use condoms consistently and where the HIV-positive partner is on therapy with a viral load < 200 copies/mL. Furthermore to study why some partnerships do not use condoms, to describe the proportion who begin to adopt consistent condom use, and factors associated with this. In June 2014 the heterosexual follow up ended and only the homosexual couples continued. The total number of recruited heterosexual couples was 693.

In March 2014 the first interim results were presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) in Boston, USA, 3rd-6th March 2014. The analysis showed no linked transmissions among the HIV negative partners that sero-converted. The number of condomless sex acts was more than 44.000 and shows that the risk of HIV transmission through condomless sex from HIV positive people on ART with plasma VL < 200 copies/mL is extremely low.

However, it also became clear that there are still uncertainties over the HIV risk in anal and especially

receptive anal sex since only 1/3 of the couples in the PARTNER study was homosexual men. To strengthen data on anal sex additional follow-up in MSM is needed to get more precise estimates for transmission risk to inform policy and also individual choice on condom use. The 2nd phase of PARTNER from 2014-2017 will follow 950 MSM couples until 2017.

The PARTNER 2 Study: a study for sero-different gay couples

Understanding the risk of HIV transmission when the HIV+ partner is on therapy www.chip.dk/partner

Link to articles: http://www.cphiv.dk/Ongoing-Studies/PARTNER/Press/ Links-to-media-coverage

Annual Report 2014 · 25

START When is the best time to start antiretroviral treatment in individuals diagnosed with HIV? This highly debated question is being explored in the START study; the first international randomized trial to determine whether starting antiretroviral therapy early, i.e., before CD4 cell count drops to less than 500 cells/ mm³, rather than waiting until CD4 count drops to less than 350 cells/ mm³, when evidence from randomized trials supports starting ART, reduces the risk of serious morbidity and mortality.

Initiated by the INSIGHT investigational network (http://insight.ccbr. umn.edu/index.php) the START study enrolled its first patient in April 2009. Enrollment was completed in December 2013, with 4,688 participants, and follow-up is expected to continue until December 2016 with an average of 4,5 years of follow-up on all participants. The study is currently being conducted at 222 clinical sites in 35 countries, on five continents, around the world.

Along with research teams in London, Washington and Sydney, CHIP is one of four International Coordinator Centers (ICC) administrating the START trial for the sponsor. With nine full-time employed Clinical Trial Associates (CRA), CHIP is responsible for the daily oversight of study data collection as well as on-site monitoring to assure excellent data quality. CHIP coordinates the trial conduct at 52 clinical sites in 13 European countries.

Despite changing HIV treatment guidelines around the world since the initiation of the START study no new evidence has been published from randomised clinical trials

that show improved survival or decreased morbidity in asymptomatic individuals starting antiretroviral treatment at higher CD4 cell counts. Therefore, START is still the only on-going randomised clinical trial that finally will be able to give a scientific answer to this question.

Once yearly unblinded data collected in START is closely reviewed by a Data Safety Monitoring Board (DSMB). At the most recent DSMB meeting in May 2014, the Board expressed they are pleased with the conduct and progress of START, and recommends continuation according to protocol for this study that will provide essential data to answer a very important question.

Owing to the size of the START trial, its diversity of recruitment, rigorous methodology and conduct, and the primary hypothesis under investigation, it is an ideal opportunity for the execution of hypothesis-driven substudies to investigate the effects of early vs. deferred ART in individuals infected with HIV. In START there are six proper substudies where eligible participants have consented to take part; Genomics substudy (2,565 participants) will look at extracted DNA and genetic variants to determine the risk of primary and secondary outcomes assessed in START; Neurology substudy (608 participants) will inform on the preservation of neurocognitive health; Arterial Elasticity (337 participants) will further explore the association between ART and enhanced risk of cardiovascular disease (CVD); Pulmonary substudy (1026 participants) will show whether early initiation of ART results in a slower rate of lung function decline compared to deferred ART; Bone Mineral

Density substudy (424 participants). The purpose of this study is to quantify the relative contributions of HIV and of antiretroviral treatment (ART) for HIV on rates of bone mineral density (BMD) loss leading to osteoporosis; Liver Fibrosis substudy (230 participants). START represents an ideal opportunity to examine the effect of early vs. delayed commencement of ART on liver fibrosis progression over an extended period in both HIV mono-infected and HIV-HCV co-infected participants.

In addition, there are two centrally randomised substudies, either per country or per site; the Informed Consent substudy and the Monitoring substudy. To learn more about these unique substudies please visit the INSIGHT web at: http://insight. ccbr.umn.edu/start/index.php?study=start&page=&menu=substudies The INSIGHT network acknowledge the immense and indispensable contribution of the 4,688 participants currently being followed in START, many of whom have also volunteered to be co-enrolled in one or more of the substudies.

Without their involvement this important study would not have been possible. With two more years of follow-up the main focus for all parties involved will be to assure excellent data collection, adherence to the allocated treatment arm, minimize the number of lost-to-followup and ensure all study endpoint are properly reported to finally be able to answer the question: When is the best time to start ART?

26 · Annual Report 2014

Clinical Publications and PhD Theses from 2013 – 2014

2014 1 Short and long term mortality and causes of death in HIV/TB patients in Europe. DN Podlekareva, AM Panteleev, D Grint, FA Post, JM Miro, M Bruyand, H Furrer, N Obel, E Girardi, A Vassilenko, MH Losso, A Arenas-Pinto, J Caylá, A Rakhmanova, I Zeltina, AM Welinrud, JD Lundgren, A Mocroft, O Kirk; the HIV/TB Study Group.

Eur Respir J. 2014 Jan;43(1):166-77. (IF: 7.125) 2 Development of a definition for Rapid Progression (RP) of renal function in HIV-positive persons: The D:A:D Study. DA Kamara/L Ryom*, M Ross, O Kirk, P Reiss, P Morlat, O Moranne, CA Fux, A Mocroft, C Sabin, JD Lundgren, CJ Smith.

BMC Nephrol. 2014 Mar 25;15(1):51. (IF: 1.52) 3 Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons in the D:A:D study. L Ryom, A Mocroft, O Kirk, M Ross, P Reiss, CA Fux, P Morlat, O Moranne, C Smith, W El-Sadr, M Law, JD Lundgren, et al. for the D:A:D Study Group.

AIDS. 2014 Jan 14;28(2):187-99. (IF: 6.557) 4 Increased incidence of antiretroviral drug discontinuation among patients with viremic HCV coinfection and high hyaluronic acid, a marker of liver fibrosis. D Grint, L Peters, J Rockstroh, S De Wit, VM Mitsura, B Knysz, C Pedersen, O Kirk, JD Lundgren, A Mocroft for EuroSIDA in EuroCoord.

AIDS. 2014 Feb 20;28(4):577-87. (IF: 6.557) 5 A comparison of estimated glomerular filtration rates using Cockcroft-Gault and the Chronic Kidney Disease Epidemiology Collaboration estimating equations in HIV infection. A Mocroft, L Ryom, P Reiss, H Furrer, A D’Arminio Monforte, J Gatell, S De Wit, M Beniowski, JD Lundgren, O Kirk; EuroSIDA in EuroCOORD. HIV Med. 2014 Mar;15(3):144-52. (IF: 3.454) 6 Hepatitis – a devastating epidemic in Europe. JV Lazarus, KA Fenton.

BMC Infectious Diseases. Oct 2014;14(Suppl 6):S1. (IF: 2.561) 7 Roundtable discussion: how lessons learned from HIV can inform the global response to viral hepatitis. JV Lazarus, JD Lundgren, J Casabona, L Wiessing, C Matheï, P Vickerman, M Prins, M Kretzschmar, M Kantzanou, I Giraudon, M Ferri, P Griffiths, M Harris, M Walker, L Chavdarova, E Schatz, K Schiffer, J Kools, J Farell, L Mendão.

BMC Infectious Diseases. Oct 2014;14(Suppl 6):S18. (IF: 2.561) 8 Health service delivery models for the provision of antiretroviral therapy in sub-Saharan Africa: a systematic review. JV Lazarus, K Safreed-Harmon, J Nicholson, S Jaffar.

TMIH. 2014 Oct;19(10):1198-215. (IF: 2.302) 9 Hepatitis C virus infection epidemiology among people who inject drugs in Europe: a systematic review of data for scaling up treatment and prevention. L Wiessing, M Ferri, B Grady, M Kantzanou, I Sperle, KJ Cullen; EMCDDA DRID group, A Hatzakis, M Prins, P Vickerman, JV Lazarus, V Hope, C Matheï.

PLoS One. 2014 Jul 28;9(7). (IF: 3.534) 10 Preparedness of Lithuanian general practitioners to provide mental healthcare services: a cross-sectional survey.

L Jaruseviciene, L Valius, G Jarusevicius, JV Lazarus.

Int J Ment Health Syst. 2014; 8(1):11. (IF: 0.963) 11 Public expectations concerning confidentiality protection of adolescents’ sexual and reproductive health care in Lithuania: findings of the surveys conducted in 2005 and 2012. L Jaruseviciene, A Zaborskis, JV Lazarus.

Eur J Contracept Reprod Health Care. 2014;19(2):102-7. (IF: 1.835)

Reception at the new CHIP office

28 · Annual Report 2014 12 Are there national strategies, plans and guidelines for the treatment of hepatitis C in people who inject drugs?

A survey of 33 European countries. M Maticic, J Videcnik Zorman, S Gregorcic, E Schatz, JV Lazarus.

BMC Infectious Diseases. Oct 2014;14(Suppl 6):S14. (IF: 2.561) 13 Policy responses to viral hepatitis B and C among people who inject drugs in Member States of the WHO European region: a sub-analysis of the WHO 2013 global hepatitis policy survey. A Spina, I Eramova, JV Lazarus.

BMC Infectious Diseases. Oct 2014;14(Suppl 6):S15. (IF: 2.561) 14 A systematic review of hepatitis C virus treatment access in people who inject drugs in the European region.

JV Lazarus, I Sperle, M Maticic, K Safreed-Harmon, L Wiessing.

BMC Infectious Diseases. Oct 2014;14(Suppl 6):S16. (IF: 2.561) 15 Serum and plasma Neutrophil Gelatinase Associated Lipocalin (NGAL) levels are not equivalent in patients admitted to intensive care. T Skovsgaard Itenov, K Bangert, PH Christensen, JU Jensen, MH Bestle; on behalf of the Procalcitonin and Survival Study (PASS) Study Group.

Journal of Clinical Laboratory Analysis. 2014 Mar;28(2):163-7. (IF: 1.144) 16 Multi-drug-resistant tuberculosis in HIV positive patients in Eastern Europe. FA Post, D Grint, AM Werlinrud, A Panteleev, V Riekstina, EA Malashenkov, A Skrahina, D Duiculescu, D Podlekareva, I Karpov, V Bondarenko, N Chentsova, J Lundgren, A Mocroft, O Kirk, JM Miro; HIV-TB Study Group.

J Infect. 2014 Mar;68(3):259-63. (IF: 4.017) 17 Biomarkers as point-of-care tests to guide prescription of antibiotics in patients with acute respiratory infections in primary care. R Aabenhus, JU Jensen, KJ Jørgensen, A Hróbjartsson, L Bjerrum.

Cochrane Database Syst Rev. 2014 Nov 6;11. (IF: 5.939) 18 Novel biomarkers of infection in critically ill cancer patients: certainties and doubts. JU Jensen, JD Lundgren.

Crit Care Med. 2014 Dec;42(12):2632-3. (IF: 6.147) 19 Delayed HIV diagnosis and initiation of antiretroviral therapy: inequalities by educational level, COHERE in EuroCoord. Socio-economic Inequalities and HIV Writing Group for Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord.

AIDS. 2014 Sep 24;28(15):2297-306. (IF: 6.557) 20 Factors associated with short-term changes in HIV viral load and CD4(+) cell count in antiretroviral-naive individuals. Natural History Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord.

AIDS. 2014 Jun 1;28(9):1351-6. (IF: 6.557) 21 Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. FN Engsig, R Zangerle, O Katsarou, F Dabis, P Reiss, J Gill, K Porter, C Sabin, A Riordan, G Fätkenheuer, F Gutiérrez, F Raffi, O Kirk, M Mary-Krause, C Stephan, PG de Olalla, J Guest, H Samji, A Castagna, A d’Arminio Monforte, A SkaletzRorowski, J Ramos, G Lapadula, C Mussini, L Force, L Meyer, F Lampe, F Boufassa, HC Bucher, S De Wit, GA Burkholder, R Teira, AC Justice, TR Sterling, H Crane, J Gerstoft, J Grarup, M May, G Chêne, SM Ingle, J Sterne, N Obel; Antiretroviral Therapy Cohort Collaboration (ART-CC) and the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord.

Clin Infect Dis. 2014 May;58(9):1312-21. (IF: 9.416) 22 Incorrect inclusion of individual studies and methodological flaws in systematic review and meta-analysis.

R Aabenhus, JU Jensen, JW Cals.

Br J Gen Pract. 2014 May;64(622):221-2. (IF: 2.356) 23 Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier cART will alter this risk. ÁH Borges, R Dubrow, MJ Silverberg.

Curr Opin in HIV and AIDS. 2014 Jan;9(1):34-40. (IF: 4.392)

Annual Report 2014 · 29 24 Factors associated with D-dimer levels in HIV-infected individuals. ÁH Borges, JL O’Connor, AN Phillips, JV Baker, MJ Vjecha, MH Losso, H Klinker, G Lopardo, I Williams, JD Lundgren; INSIGHT SMART Study Group; ESPRIT Study Group; SILCAAT Scientific Committee.

PLoS One. 2014 Mar 13;9(3):e90978. (IF: 3.534) 25 Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation. AD Nordell, M McKenna, ÁH Borges, D Duprez, J Neuhaus, JD Neaton; INSIGHT SMART, ESPRIT Study Groups; SILCAAT Scientific Committee.

J Am Heart Assoc. 2014 May 28;3(3):e000844. (IF: 2.882) 26 Markers of inflammation and activation of coagulation are associated with anaemia in antiretroviral-treated HIV disease. ÁH Borges, JI Weitz, G Collins, JV Baker, Y Lévy, RT Davey Jr, AN Phillips, JD Neaton, JD Lundgren, SG Deeks; INSIGHT SILCAAT Scientific Committee.

AIDS. 2014 Jul 31;28(12):1791-6. (IF: 6.557) 27 Thrombocytopenia is associated with an increased risk of cancer during treated HIV disease. ÁH Borges, JD Lundgren, A Ridolfo, C Katlama, F Antunes, A Grzeszczuk, A Blaxhult, VM Mitsura, M Doroana, M Battegay, P Gargalianos, A Mocroft; on behalf of EuroSIDA in EuroCOORD. AIDS. 2014 28(17) 2565-2571. (IF: 6.557) 28 Trends over time in underlying causes of death in the D:A:D study 1999-2011. CJ Smith, L Ryom, R Weber, P Morlat, C Pradier, P Reiss, JD Kowalska, S De Wit, M Law, W el Sadr, O Kirk, N Friis-Moller, A d’Arminio Monforte, AN Phillips, CA Sabin, JD Lundgren, D:A:D Study Group.

Lancet. 2014 Jul 19;384(9939):241-8. (IF: 39.207) 29 HIV and hepatitis C co-infection in Europe, Israel and Argentina: a EuroSIDA perspective. L Peters, A Mocroft, J Lundgren, D Grint, O Kirk, J Rockstroh on behalf of EuroSIDA in EuroCoord.

BMC Infect Dis. 2014;14 (Suppl 6):S13. (IF: 2.561) 30 Increased risk of cardiovascular disease (CVD) with age in HIV positive men: a comparison of the D:A:D CVD risk equation and general population CVD risk equations. K Petoumenos, P Reiss, L Ryom, M Rickenbach, C Sabin, W ElSadr, A d’Arminio Monforte, A Phillips, S De Wit, O Kirk, F Dabis, C Pradier, J Lundgren, M Law; D:A:D study group.

HIV Med. 2014 Nov;15(10):595-603. (IF: 3.454) 31 Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIVinfected persons. L Shepherd, JC Souberbielle, JP Bastard, S Fellahi, J Capeau, J Reekie, P Reiss, A Blaxhult, M Bickel, C Leen, O Kirk, JD Lundgren, A Mocroft, JP Viard, on behalf of EuroSIDA in EuroCOORD. J Infect Dis. 2014 Jul 15;210(2):234-43. (IF: 5.778) 32 Deteriorating renal function and clinical outcomes in HIV-positive persons. A Mocroft, L Ryom, J Begovac, Ad Monforte, A Vassilenko, J Gatell, E Florence, V Ormaasen, O Kirk, JD Lundgren, EuroSIDA in EuroCOORD. AIDS. 2014 Mar 13;28(5):727-37. (IF: 6.557) 33 High rate of hepatitic C virus (HCV) recurrence in HIV infected individuals with spontaneous HCV-RNA clearance. L Peters, A Mocroft, V Soriano, J Rockstroh, N Kirkby, P Reiss, C Katlama, N Zakharova, R Flisiak, J Lundgren; in EuroSIDA in EuroCoord.

HIV Med. 2014 Nov; 15(10):615-20. (IF: 3.454) 34 A survey of ATRIPLA use in clinical practice as first-line therapy in HIV-positive persons in Europe. A Mocroft, P Reiss, A Rakhmanova, D Banhegyi, AN Phillips, S De Wit, M Ristola, JD Lundgren, J Grarup, O Kirk, EuroSIDA in EuroCOORD. Infection. 2014 Aug;42(4):757-62. (IF: 2.864) 35 Relationship between inflammatory and coagulation biomarkers and cardiac autonomic function in HIV-infected individuals. LC Young, MP Roediger, G Grandits, J Baker, C Somboonwit, I Williams, JD Lundgren, JD Neaton, EZ Soliman.

Biomark Med. 2014 Oct;8(9):1073-83. (IF: 2.858)

30 · Annual Report 2014 36 Cost-effectiveness of HIV drug resistance testing to inform switching to second line antiretroviral therapy in low income settings. A Phillips, V Cambiano, F Nakagawa, T Magubu, A Miners, D Ford, D Pillay, A De Luca, J Lundgren, P Revill.

PLoS One. 2014 Oct 7;9(10):e109148. (IF: 3.534) 37 Potential future impact of a partially effective HIV vaccine in a southern African setting. AN Phillips, V Cambiano, F Nakagawa, D Ford, JD Lundgren, E Roset-Bahmanyar, F Roman, R Van Effelterre.

PLoS One. 2014 Sep 10;9(9):e107214. (IF: 3.534) 38 Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models. JW Eaton, NA Menzies, J Stover, V Cambiano, L Chindelevitch, A Cori, JA Hontelez, S Humair, CC Kerr, DJ Klein, S Mishra, KM Mitchell, BE Nichols, P Vickerman, R Bakker, T Bärnighausen, A Bershteyn, DE Bloom, MC Boily, ST Chang, T Cohen, PJ Dodd, C Fraser, C Gopalappa, J Lundgren, NK Martin, E Mikkelsen, E Mountain, QD Pham, M Pickles, A Phillips, L Platt, C Pretorius, HJ Prudden, JA Salomon, DA van de Vijver, SJ de Vlas, BG Wagner, RG White, DP Wilson, L Zhang, J Blandford, G Meyer-Rath, M Remme, P Revill, N Sangrujee, F Terris-Prestholt, M Doherty, N Shaffer, PJ Easterbrook, G Hirnschall, TB Hallett.

Lancet Global Health. 2014 Jan;2(1):e23-34.

39 Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies. R Lynfield, R Davey, DE Dwyer, MH Losso, D Wentworth, A Cozzi-Lepri, K Herman-Lamin, G Cholewinska, D David, S Kuetter, Z Ternesgen, TM Uyeki, HC Lane, J Lundgren, JD Neaton: INSIGHT Influenza Study Group.

PLoS One. 2014 Jul 8;9(7):e101785. (IF: 3.534) 40 Biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co-infected patients in the SMART study. L Peters, J Neuhaus, D Duprez, JD Neaton, R Tracy, MB Klein, A Mocroft, J Rockstroh, G Dore, JD Lundgren; INSIGHT SMART Study Group.

J Clin Virol. 2014 Jul;60(3):295-300. (IF: 3.466) 41 Update on HIV in Western Europe. F Nakagawa, AN Phillips, JD Lundgren.

Curr HIV/AIDS Rep. 2014 Jun;11(2):177-85.

42 Antiretroviral dose reduction: good for patients and rollout. JD Lundgren, A Phillips.

Lancet. 2014 Apr 26;383(9927):1442-3. (IF: 39.207) 43 Immuno-virological discordance and the risk of non-AIDS and AIDS events in a large observational cohort of HIVpatients in Europe. A Zoufaly, A Cozzi-Lepri, J Reekie, O Kirk, J Lundgren, P Reiss, D Jevtovic, L Machala, R Zangerle, A Mocroft, J Van Lunzen; EuroSIDA in EuroCoord.

PLoS One. 2014 Jan 31;9(1):e87160. (IF: 3.534) 44 Predicted levels of HIV drug resistance: potential impact of expanding diagnosis, retention, and eligibility criteria for antiretroviral therapy initiation. V Cambiano, S Bertagnolio, MR Jordan, D Pillay, JH Perriëns, F Venter, J Lundgren, A Phillips.

AIDS. 2014 Jan;28 Suppl 1:S15-23. (IF: 6.557) 45 Determinants of developing widened spatial QRS-T angle in HIV-infected individuals: results from the Strategies for Management of Antiretroviral Therapy [SMART] Study. FZ Dawood, MP Roediger, G Grandits, D Miller, M Fisher, ZM Zhang, S Hodder, JF Hoy, JD Lundgren, JD Neaton, EZ Soliman; INSIGHT SMART Study Group.

J Electrocardiol. 2014 Mar-Apr;47(2):264-71. (IF: 1.363) 46 Antiretroviral therapy recommendations for the global community: aspiration versus reality. AN Phillips, P Munderi, PA Revill, WM El-Sadr, JD Lundgren.

AIDS. 2014 Apr 24;28(7):939-41. (IF: 6.557) 47 Antiretroviral therapy, immune suppression and renal impairment in HIV-positive persons. L Ryom, A Mocroft, JD Lundgren.

Curr Opin HIV AIDS. 2014 Jan;9(1):41-7. (IF: 4.392) 48 People with HIV are at increased risk of acute myocardial infarction. JD Lundgren.

Evid Based Nurs. 2014 Apr;17(2):43-4.

Annual Report 2014 · 31 49 Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naïve adults infected with HIV-1: 96 week results from the NEAT001/ANRS142 randomised non-inferiority trial. F Raffi, AG Babiker, L Richert, JM Molina, EC George, A Antinori, JR Arribas, J Grarup, F Hudson, C Schwimmer, J Saillard, C Wallet, PO Jansson, C Allavena, R Van Leeuwen, JF Delfraissy, S Vella, G Chêne, A Pozniak; NEAT001/ANRS143 Study Group.

Lancet. 2014 Nov 29;384(9958):1942-51. (IF: 39.207) 50 Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based antiretroviral therapy: A multi-cohort European case-control study using centralized ultrasensitive 454 pyrosequencing. A Cozzi-Lepri, M Noguera-Julian, F Di Giallonardo, R Schuurman, M Däumer, S Aitken, F Ceccherini-Silberstein, A d’Arminio Monforte, A Geretti, C Booth, R Kaiser, C Michalik, K Jansen, P Bellecave, B Masquelier, R Kouyos, E Castro, H Furrer, A Schultze, H Günthard, F Brun-Vézinet, R Paredes, K Metzner.

Journal of Antimicrobial Chemotherapy. 2014 Oct 21. Epub ahead of print (IF: 5.439) 51 Invasive candida infections and the harm from antibacterial drugs in critically ill patients - Data from a randomised, controlled trial to determine the role of ciprofloxacin, piperacillin-tazobactam, meropenem and cefuroxime.

JU Jensen, L Hein, B Lundgren, MH Bestle, T Mohr, MH Andersen, J Løken, H Tousi, P Søe-Jensen, AØ Lauritsen, D Strange, JA Petersen, K Thormar, KM Larsen, NE Drenck, J Helweg-Larsen, ME Johansen, K Reinholdt, JK Møller, B Olesen, MC Arendrup, C Østergaard, A Cozzi-Lepri, J Grarup, JD Lundgren.

Crit Care Med. Accepted for publication 2014. (IF: 6.147) 52 Cancer risk and use of cART: the D:A:D study. M Bruyand, L Ryom, L Shepherd, P Reiss, S De Wit, A d’Arminio Monforte, M Rickenbach, A Phillips, C Pradier, M Law, A El-Sadr, J Lundgren, C Sabin for the D:A:D Study Group.

JAIDS. Accepted for publication 2014. (IF: 4.394)

2013 1 An internationally generalizable risk index for mortality after one year of antiretroviral therapy. JP Tate, AC Justice, MD Hughes, F Bonnet, P Reiss, A Mocroft, J Nattermann, FC Lampe, HC Bucher, TR Sterling, HM Crane, MM Kitahata, M May, J Sterne.

AIDS. 2013 Feb 20;27(4):563-572. (IF: 6.557) 2 Predictors of CD4+ T-cell counts of HIV type 1-Infected persons after virologic failure of all 3 original antiretroviral drug classes. D Costagliola, B Ledergerber, C Torti, A van Sighem, D Podzamczer, A Mocroft, M Dorrucci, B Masquelier, A de Luca, K Jansen, S De Wit, N Obel, G Fätkenheuer, G Touloumi, C Mussini, A Castagna, C Stephan, F García, R Zangerle, X Duval, S Perez-Hoyos, L Meyer, J Ghosn, C Fabre-Colin, J Kjær, G Chêne, J Grarup, A Phillips, R Lodwick, C Torti, M Dorrucci, HF Günthard, C Michalik, G Chrysos, and the Pursuing Later Treatment Option II (PLATO II) Project Team of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE).

J Infect Dis. 2013 Mar;207(5):759-67. (IF: 5.778) 3 Severe bacterial non-AIDS infections in HIV-positive persons: incidence rates and risk factors. OS Søgaard, J Reekie, M Ristola, D Jevtovic, I Karpov, M Beniowski, S Servitskiy, P Domingo, P Reiss, A Mocroft, O Kirk for EuroSIDA in EuroCoord.

J Infect. 2013 May;66(5):439-46. (IF: 4.017) 4 Atazanavir is not associated with an increased risk of cardio or cerebrovascular disease events. AD Monforte, P Reiss, L Ryom, W El-Sadr, F Dabis, S De Wit, SW Worm, MG Law, R Weber, O Kirk, C Pradier, AN Phillips, JD Lundgren, CA Sabin.

AIDS. 2013 Jan 28;27(3):407-15. (IF: 6.557) 5 Health care index score and risk of death following tuberculosis diagnosis in HIV-positive patients. DN Podlekareva, D Grint, FA Post, A Mocroft, AM Panteleev, RF Miller, JM Miro, M Bruyand, H Furrer,V Riekstina, E Girardi, MH Losso, JA Caylá, EA Malashenkov, N Obel, AM Skrahina, JD Lundgren, O Kirk; HIV-TB Study Group.

Int J Tuberc Lung Dis. 2013 Feb;17(2):198-206. (IF: 2.756)

32 · Annual Report 2014 6 Electrocardiographic spatial QRS-T angle and incident cardiovascular disease in HIV-infected patients (from the Strategies for the Management of Antiretroviral Therapy [SMART] study). FZ Dawood, F Khan, MP Roediger, ZM Zhang, A Swaminathan, H Klinker, J Hoy, JD Lundgren, JD Neaton, EZ Soliman; INSIGHT SMART Study Group.

Am J Cardiol. 2013 Jan 1;111(1):118-24. (IF: 3.425) 7 Platelet count kinetics following interruption of antiretroviral treatment. E Zetterberg, J Neuhaus, JV Baker, C Somboonwit, JM Llibre, A Palfreeman, M Chini, JD Lundgren; INSIGHT SMART Study Group.

AIDS. 2013 Jan 2;27(1):59-68. (IF: 6.557) 8 Stability of hepatitis C virus (HCV) RNA levels among interferon-naïve HIV/HCV-coinfected individuals treated with combination antiretroviral therapy. D Grint, L Peters, J Reekie, V Soriano, O Kirk, B Knysz, O Suetnov, A Lazzarin, B Ledergerber, J Rockstroh, A Mocroft A; EuroSIDA in EuroCoord.

HIV Med. 2013 Jul;14(6):370-8. (IF: 3.454) 9 Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: The D:A:D Study. L Ryom, A Mocroft, O Kirk, SW Worm, DA Kamara, P Reiss, M Ross, CA Fux, P Morlat, O Moranne, C Smith, JD Lundgren; on behalf of the D:A:D study group.

J Infect Dis. 2013 May;207(9):1359-1369. (IF: 5.778) 10 Considerations in the rationale, design and methods of the strategic timing of antiretroviral treatment (START) study. AG Babiker, S Emery, G Fätkenheuer, FM Gordin, B Grund, JD Lundgren, JD Neaton, SL Pett, A Phillips, G Touloumi, MJ Vjecha.

Clin Trials. 2013;10(1 Suppl):S5-S36. (IF: 1.944) 11 Hyaluronic acid levels predict risk of hepatic encephalopathy and liver-related death in HIV/viral hepatitis coinfected patients. L Peters, A Mocroft, V Soriano, J Rockstroh, A. Rauch, A Karlsson, B Knysz, C Pradier, K Zilmer, JD Lundgren, for EuroSIDA in EuroCoord.

PLoS One. 2013 May 27;8(5):e64283. (IF: 3.534) 12 When to start antiretroviral therapy: the need for an evidence base during early HIV infection. JD Lundgren, AG Babiker, FM Gordin, ÁH Borges, JD Neaton.

BMC Med. 2013 Jun 14;11:148. (IF: 7.276) 13 Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. ÁH Borges, MJ Silverberg, D Wentworth, AE Grulich, G Fätkenheuer, R Mitsuyasu, G Tambussi, CA Sabin, J Neaton, JD Lundgren; for the INSIGHT SMART, ESPRIT, SILCAAT Study groups.

AIDS. 27(9):1433-1441, June 1, 2013. (IF: 6.557) 14 Association between ALT level and the rate of cardio/cerebrovascular events in HIV-positive individuals: The D:A:D Study. CA Sabin, L Ryom, H Kovari, O Kirk, S De Wit, M Law, P Reiss, F Dabis, C Pradier, W El Sadr, AD Monforte, D Kamara, AN Phillips, JD Lundgren JD. JAIDS. 2013 Aug 1;63(4):456-63. (IF: 4.394) 15 Advanced chronic kidney disease, end-stage renal disease and renal death among HIV-positive individuals in Europe. L Ryom, O Kirk, J Lundgren, P Reiss, C Pedersen, S De Wit, S Buzunova, J Gasiorowski, JM Gatell and A Mocroft on behalf of EuroSIDA in EuroCoord.

HIV Medicine. 2013 Sep;14(8):503-8. (IF: 3.454) 16 Risk factors and outcomes for late presentation for HIV-positive persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE). A Mocroft, JD Lundgren, M Sabin, A d’Arminio Monforte, N Brockmeyer, J Casabona, A Castagna, D Costagliola, F Dabis, S De Wit, G Fätkenheuer, H Furrer, AM Johnson, O Kirk, for the Late Presenters Working Group, on behalf of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study in EuroCoord.

PLoS Med. 2013 10(9): e1001510. (IF: 14) 17 World Hepatitis Day 2013: Know it, confront it. JV Lazarus, C Gore, T Nguyen, K Safreed-Harmon, I Sperle, RJJ Peck, H Harmanci, S Wiktor.

Lancet Global Health. 2013 Sept. Vol 1, Issue 3; e127-128.

Annual Report 2014 · 33 18 Unnecessary injecting of medicines: a global challenge. C Gore, JV Lazarus, I Sperle, K Safreed-Harmon.

Trop Med & Int’l Health. 2013 Sept. Vol 18, Issue 9;1157-1159. (IF: 2.302) 19 Primary healthcare providers’ views on improving sexual and reproductive health care for adolescents in Bolivia, Ecuador, and Nicaragua. L Jaruseviciene, M Orozco, M Ibarra, FC Ossio, B Vega, N Auquilla, J Medina, AC Gorter, P Decat, SD Meyer, M Temmerman, AB Edmonds, L Valius, JV Lazarus.

Global Health Action. 2013;6:10.3402/gha.v6i0.20444. (IF: 1.646) 20 Enabling factors for prescribing antibiotics for upper respiratory tract infections: the perspectives of Lithuanian and Russian general practitioners. L Jaruseviciene, R Radzeviciene-Jurgute, JV Lazarus, A Jurgutis, G Jarusevicius, L Bjerrum.

Uppsala Journal of Medical Sciences. 2013 May;118(2):98-104. (IF: 1.708) 21 Non-AIDS defining cancers in the D:A:D Study - time trends and predictors of survival: a cohort study. SW Worm, M Bower, P Reiss, F Bonnet, M Law, G Fätkenheuer, A d’Arminio Monforte, DI Abrams, A Grulich, E Fontas, O Kirk, H Furrer, S De Wit, A Phillips, JD Lundgren, CA Sabin.

BMC Infect Dis. 2013 Oct 9;13(1):471. (IF: 2.651) 22 Temporal changes and regional differences in treatment uptake of hepatitis C therapy in EuroSIDA. D Grint, L Peters, C Schwarze-Zander, M Beniowski, C Pradier, M Battegay, D Jevtovic, V Soriano, JD Lundgren, JK Rockstroh, O Kirk and A Mocroft for EuroSIDA in EuroCoord.

HIV Medicine. 2013 Nov;14(10):614-23. (IF: 3.454) 23 Associations between immune depression and cardiovascular events in HIV infection. CA Sabin, L Ryom, S De Wit, A Mocroft, AN Phillips, SW Worm, R Weber, AD Monforte, P Reiss, D Kamara, W El-Sadr, C Pradier, F Dabis, M Law, J Lundgren.

AIDS. 2013 Nov 13;27(17):2735-48. (IF: 6.557) 24 Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resourcelimited settings. V Cambino, S Bertagnolio, MR Jordan, JD Lundgren, A Phillips.

J Infect Dis. 2013 Jun 15;207 Suppl 2:S57-62. (IF: 5.778) 25 The potential of antimicrobials to induce thrombocytopenia in critically ill patients: data from a randomized controlled trial. ME Johansen, J-U Jensen, MH Bestle, L Hein, AØ Lauritsen, H Tousi, KM Larsen, J Løken, T Mohr, K Thormar, PI Johansson, A Cozzi-Lepri, JD Lundgren.

PLoS One. 2013 Nov 28;8(11):e81477. (IF: 3.534) 26 TB Meningitis in HIV-positive patients in Europe and Argentina: clinical outcome and factors associated with mortality. AM Werlinrud Efsen, A Panteleev, D Grint, DN Podlekareva, A Vassilenko, A Rakhmanova, I Zeltina, MH Losso, R Miller, E Girardi, J Caylá, F Post, JM Miro, M Bruyand, H Furrer, N Obel, JD Lundgren, A Mocroft, O Kirk, and the HIV/TB study group.

Biomed Res Int. 2013;2013:373601.

27 Antiretroviral drug-related liver mortality among HIV-positive persons in the absence of hepatitis B or C virus coinfection: the data collection on adverse events of anti-HIV drugs study. H Kovari, CA Sabin, B Ledergerber, L Ryom, SW Worm, C Smith, A Phillips, P Reiss, E Fontas, K Petoumenos, S De Wit, P Morlat, JD Lundgren, R Weber.

Clin Infect Dis. 2013 Mar;56(6):870-9. (IF: 9.416) 28 Biomarker-guided clinical decisions: for patients, health economists or neither? JU Jensen.

Eur Resp J. 2013 Oct;42(4):895-7. (IF: 7.125) 29 The time course of development and impact from viral resistance against ganciclovir in cytomegalovirus infection.

C da Cunha-Bang, N Kirkby, M Sønderholm, SS Sørensen, H Sengeløv, M Iversen, A Rasmussen, F Gustafsson, CM Frederiksen, J Kjaer, AC Lepri, JD Lundgren.

Am J Transplant. 2013 Feb;13(2):458-66. (IF: 6.19)

34 · Annual Report 2014 30 The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies. RT Davey Jr, R Lynfield, DE Dwyer, MH Losso, A Cozzi-Lepri, D Wentworth, HC Lane, R Dewar, A Rupert, JA Metcalf, SL Pett, TM Uyeki, JM Bruguera, B Angus, N Cummins, J Lundgren, JD Neaton; INSIGHT FLU 002 & 003 Study Groups.

PLoS One. 2013;8(2):e57121. (IF: 3.534) 31 Encephalitis in primary HIV infection: challenges in diagnosis and treatment. M Helleberg, O Kirk.

Int J of STD and AIDS. 2013 Jun;24(6):489-93. (IF: 1.037) 32 The case for indicator condition-guided HIV screening. JV Lazarus, M Hoekstra, D Raben, V Delpech, T Coenen, JD Lundgren; HIV in Europe Initiative Steering Committee.

HIV Med. 2013 Aug;14(7):445-8. (IF: 3.454) 33 Editorial commentary: universal antiretroviral therapy for HIV infection? JD Lundgren, R Wood.

Clin Infect Dis. 2013 Sep;57(6):888-90. (IF: 9.416) 34 CD4 cell count and viral load-specific rates of AIDS, non-AIDS and deaths according to current antiretroviral use.

A Mocroft, AN Phillips, J Gatell, A Horban, B Ledergerber, K Zilmer, D Jevtovic, F Maltez, D Podlekareva, JD Lundgren; EuroSIDA study in EuroCOORD. AIDS. 2013 Mar 27;27(6):907-18. (IF: 6.557) 35 The incidence of AIDS-defining illnesses at a current CD4 count ≥ 200 cells/μL in the post-combination antiretroviral therapy era. A Mocroft, HJ Furrer, JM Miro, P Reiss, C Mussini, O Kirk, S Abgrall, S Ayayi, B Bartmeyer, D Braun, A Castagna, A d’Arminio Monforte, B Gazzard, F Gutierrez, I Hurtado, K Jansen, L Meyer, P Muñoz, N Obel, P Soler-Palacin, A Papadopoulos, F Raffi, JT Ramos, JK Rockstroh, D Salmon, C Torti, J Warszawski, S de Wit, R Zangerle, C Fabre-Colin, J Kjaer, G Chene, J Grarup, JD Lundgren; Opportunistic Infections Working Group on behalf of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study in EuroCOORD. Clin Infect Dis. 2013 Oct;57(7):1038-47. (IF: 9.416) 36 Conclusions from the HIV in Europe Copenhagen 2012 Conference and ways forward: working together for optimal HIV testing and earlier care. D Raben, V Delpech, J de Wit, A Sullivan, JV Lazarus, N Dedes, T Coenen, J Lundgren; HIV in Europe Steering Committee.

HIV Med. 2013 Oct;14 Suppl 3:1-5. (IF: 3.454) 37 Does hepatitis C viremia or genotype predict the risk of mortality in individuals co-infected with HIV? JK Rockstroh, L Peters, D Grint, V Soriano, P Reiss, Ad Monforte, M Beniowski, MH Losso, O Kirk, B Kupfer, A Mocroft; EuroSIDA in EuroCoord.

J Hepatol. 2013 Aug;59(2):213-20. (IF: 10.401) 38 Further research needed to support a policy of antiretroviral therapy as an HIV prevention initiative. AJ Rodger, T Bruun, P Vernazza, S Collins, V Estrada, J Van Lunzen, GM Corbelli, AN Phillips, JD Lundgren; PARTNER Study Group.

Antivir Ther. 2013;18(3):285-7. (IF: 3.143) 39 Feasibility and effectiveness of indicator condition-guided testing for HIV: results from HIDES I (HIV indicator diseases across Europe study). AK Sullivan, D Raben, J Reekie, M Rayment, A Mocroft, S Esser, A Leon, J Begovac, K Brinkman, R Zangerle, A Grzeszczuk, A Vassilenko, V Hadziosmanovic, M Krasnov, A Sönnerborg, N Clumeck, J Gatell, B Gazzard, Ad Monforte, J Rockstroh, JD Lundgren.

PLoS One. 2013;8(1):e52845. (IF: 3.534) 40 The need for evidence-based use of antiretroviral therapy. JD Lundgren, AG Babiker, FM Gordin, ÁH Borges, JD Neaton.

BMC Medicine, 2013 Jun 14;11:148. (IF: 7.276)

41 The natural history of HIV infection. CA Sabin, JD Lundgren.

Curr Opin HIV AIDS. 2013 Jul;8(4):311-7. (IF: 4.392) 42 Are antiretrovirals enough for people living with HIV? A Phillips, J Baker, J Lundgren.

Lancet. 2013 Nov 2;382(9903):1466-7. (IF: 39.207)

43 Comparison of two HIV testing strategies in primary care centres: indicator-condition-guided testing vs. testing of those with non-indicator conditions. I Menacho, E Sequeira, M Muns, O Barba, L Leal, T Clusa, E Fernandez, L Moreno, D Raben, J Lundgren, JM Gatell, F Garcia, L Cayuelas, V Aragunde, M Vergara, M Catalan, MA Moreno, G Hormigo, A Siso, Z Herreras, L Sebastian, L Benito, A Picas, J Hoyo, MJ Giner, D Cararach, E Moles, ML Moro, P Arrabal, D Roca, S Prego, X Ferrer, A Egido, C Ventosa, S Garcia, S Muñoz, A Massana, J Sole, M Curiel, F Heras, A Leon.

HIV Med. 2013 Oct;14 Suppl 3:33-7. (IF: 3.454) 44 Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons. M Rotger, TR Glass, T Junier, J Lundgren, JD Neaton, ES Poloni, AB van ‘t Wout, R Lubomirov, S Colombo, R Martinez, A Rauch, HF Günthard, J Neuhaus, D Wentworth, D van Manen, LA Gras, H Schuitemaker, L Albini, C Torti, LP Jacobson, X Li, LA Kingsley, F Carli, G Guaraldi, ES Ford, I Sereti, C Hadigan, E Martinez, M Arnedo, L Egaña-Gorroño, JM Gatell, M Law, C Bendall, K Petoumenos, J Rockstroh, JC Wasmuth, K Kabamba, M Delforge, S De Wit, F Berger, S Mauss, M de Paz Sierra, M Losso, WH Belloso, M Leyes, A Campins, A Mondi, A De Luca, I Bernardino, M Barriuso-Iglesias, A Torrecilla-Rodriguez, J Gonzalez-Garcia, JR Arribas, I Fanti, S Gel, J Puig, E Negredo, M Gutierrez, P Domingo, J Fischer, G Fätkenheuer, C Alonso-Villaverde, A Macken, J Woo, T McGinty, P Mallon, A Mangili, S Skinner, CA Wanke, P Reiss, R Weber, HC Bucher, J Fellay, A Telenti, PE Tarr; MAGNIFICENT Consortium; INSIGHT; Swiss HIV Cohort Study.

Clin Infect Dis. 2013 Jul;57(1):112-21. (IF: 9.416) 45 Increased HIV incidence in men who have sex with me despite high levels of ART-induced viral suppression: analysis of an extensively documented epidemic. AN Phillips, V Cambiano, F Nakagawa, AE Brown, F Lampe, A Rodger, A Miners, J Elford, G Hart, AM Johnson, J Lundgren, VC Delpech.

PLoS One. 2013;8(2):e55312. (IF: 3.534) 46 Køling af sepsis patienter. Hvorfor dog det? JU Jensen.

Bestpractice Infektionsmedicin. 2013 May. Nr. 03.

47 Procalcitonin: Er evidens fra store randomiserede kliniske studier nødvendigt før indførelse af biomarkører for sepsis? TS Itenov, JU Jensen.

Klinisk Biokemi i Norden. 2013; 3(25):8-13.

PhD Theses 1 Chronic kidney disease in HIV-positive persons; contribution of traditional risk factors, HIV and antiretrovial agents.

Lene Ryom. 2013. Copenhagen 2 Prevention of CMV disease among transplant recipients - what is the optimal strategy?

Caspar da Cunha-Bang. 2013. Copenhagen *Shared first authorship Impact factors are accurate at time of printing

36 · Annual Report 2014

Presentations 2014 European Public Health Association, UK, 19-22 November 2014, Glasgow Oral presentations Policy responses to viral hepatitis B and C among people who inject drugs in Member States of the WHO European region: a sub-analysis of the WHO 2013 global hepatitis policy survey. J Lazarus on behalf of WHO.

HIV Drug Therapy 2014, 2-6 November 2014, Glasgow Oral presentations 1 A clinically useful risk-score for chronic kidney disease (CKD) in HIV infection. A Mocroft on behalf of the D:A:D Study group.

2 Gender differences in the use of cardiovascular disease-related interventions among HIV-positive persons: D:A:D Study. CI Hatleberg on behalf of the D:A:D Study Group.

3 Predictive value of Prostate Specific Antigen for prostate cancer: a nested case control study in EuroSIDA. L Shepherd on behalf of EuroSIDA in EuroCoord.

4 Regional differences in self-reported HIV care and management in the EuroSIDA study. K Laut on behalf of EuroSIDA in EuroCoord.

5 Detection of resistance mutations and CD4 slopes in individuals experiencing sustained virological failure. A Schultze on behalf of EuroSIDA in EuroCoord.

6 The prevalence and predictive value of dipstick protein (DUP) in HIV-positive persons in Europe. A Mocroft on behalf of EuroSIDA in EuroCoord.

7 Factors associated with IL-6 levels during HIV infection. ÁH Borges on behalf of the INSIGHT study 8 Major challenges in clinical management of TB/HIV coinfected patients in Eastern Europe compared with Western Europe and Latin America. AMW Efsen on behalf of the TB:HIV Study Group in EuroCoord.

ID-week, 8-12 October 2014, Philadelphia Oral presentations 1 Elevation in liver Transaminase (ALT-flares) in Transplant (TX) Recipients: Risk factors and consequences. L Lundgren on behalf of the MATCH Study 2 Clinically applied variation in replication kinetics during episodes of post-transplant cytomegalovirus (CMV) infections. PI Lodding on behalf of the MATCH Study 3 Systematic review and meta-analysis of RCTs comparing initial NNRTI- versus PI/r-based ART. ÁH Borges, A Lundh, B Tendal, TB Huedo-Medina, JA Bartlett, D Costagliola, N Clumeck, ES Daar, P Echeverría, M Gisslén, M Hughes, KH Hullsiek, P Khabo, S Komati, P Kumar, S Lockman, RD MacArthur, F Maggiolo, A Matteelli, JM Miró, S Oka, K Petoumenos, RL Puls, SA Riddler, PE Sax, J Sierra-Madero, C Torti and JD Lundgren.

HepHIV 2014 Conference: HIV and Viral Hepatitis: Challenges of Timely Testing and Care, 5-7 October 2014, Barcelona Oral presentation Regional differences in hepatitis testing, vaccination and treatment in the EuroSIDA study. J Lazarus on behalf of EuroSIDA in EuroCoord.

Annual Report 2014 · 37

European Society of Intensive Care Medicine (ESICM) 27th Annual Congress, 27 September – 1 October 2014, Barcelona Oral presentation A model to predict recovery from acute kidney injury in ICU patients. JU Jensen

5th International Hypothermia Symposium, 7-10 September 2014, Edinburgh Oral presentation 1 Mild induced hypothermia: Effects on sepsis-related coagulopathy - Results from a randomized controlled trial. ME Johansen on behalf of CHIP/the Cooling And Surviving Septic shock trial group (CASS group).

2 Update on evidence in sepsis/encephalopathy. M Bestle, M Egede, J Lundgren, JU Jensen and the Cooling And Surviving Septic shock trial group (CASS group).

World AIDS Conference, 20-25 July 2014, Melbourne Oral Presentation Impact of short-term change in body mass index after antiretroviral therapy initiation on subsequent risk of cardiovascular disease and diabetes in HIV-positive individuals: the D:A:D study. AC Achhra, A Mocroft, P Reiss, C Sabin, L Ryom, S De Wit, C Smith, A d'Arminio Monforte, A Phillips, R Weber, J Lundgren, MG Law, The D:A:D Study Group.

American Thoracic Society (ATS) Annual Meeting, 16 – 21 May 2014, San Diego Oral presentation The Cooling And Surviving Septic shock study (CASS) in: Time 0 – 6 hours – revisiting the Golden Hours. JU Jensen on behalf of CHIP/ the Cooling And Surviving Septic shock trial group (CASS group), Copenhagen

21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014, Boston Oral presentation HIV transmission risk through condomless sex if the HIV positive partner is on suppressive ART: PARTNER study. A Rodger, V Cambiano, T Bruun, P Vernazza, S Collins, V Estrada, J Van Lunzen, GM Corbelli, AM Geretti, D Asboe, P Viciano, F Gutiérrez, C Pradier, K Westling, R Weber, H Furrer, J Prins, J Gerstoft, A Phillips and J Lundgren for the PARTNER Study Group.

Poster presentations 1 Association between Dideoxynucleoside Analogues (d-drugs) and End-Stage Liver Disease (ESLD).

L Ryom on behalf of DAD Study Group 2 Predictors of progression, stabilisation or improvement of eGFR after chronic renal impairment. L Ryom on behalf of D:A:D Study Group 3 Is there continued evidence for an association between abacavir and myocardial infarction risk? C Sabin on behalf of D:A:D Study Group 4 Liver-related death among HIV/HCV coinfected individuals, implications for the era of directly acting antivirals. D Grint on behalf of EuroSIDA in EuroCoord.

38 · Annual Report 2014

Presentations 2013 14th European AIDS Conference, 16-19 October 2013, Brussels, Belgium Oral presentations 1 Infection related and unrelated malignancies, HIV and the aging population. L Shepherd on behalf of EuroSIDA in EuroCoord.

2 The spectrum of clinical disease and relationship with measures of deteriorating renal function. A Mocroft on behalf of EuroSIDA in EuroCoord.

3 Prevalence of detected drug resistance across different regions of Europe: Data from EuroSIDA 1997-2012. A Schultze on behalf of EuroSIDA in EuroCoord.

4 Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers in HIVinfected persons. JP Viard, A Mocroft, JD Lundgren, O Kirk, C Leen, et al. on behalf of EuroSIDA in EuroCoord.

5 Organisation and delivery of healthcare for HIV/TB coinfected patients in Europe. M Mansfeld on behalf of the TB:HIV study in EuroCoord.

6 Response to combination antiretroviral treatment in HIV-positive individuals in Europe: variation by educational level. J del Amo, O Kirk, A Mocroft, et al. for the Socio-economic Inequalities Working Group of COHERE in EuroCoord.

7 Mortality in migrants living with HIV in Western European countries: differences by geographical origin and gender.

S Monge, O Kirk, A Mocroft, et al. on behalf of the Migrants Working Group of COHERE in EuroCoord.

8 Prediction of global CVD risk in HIV-positive persons. N Friis Møller, L Ryom, C Smith, R Weber, P Reiss, F Dabis, S De Wit, A D´Arminio Monforte, O Kirk, E Fontas, C Sabin, A Phillips, J Lundgren, M Law for the D:A:D Study Group.

Poster presentations 1 Development of thrombocytopenia and risk of AIDS and serious non-AIDS events in Europe. ÁH Borges et al. on behalf of EuroSIDA in EuroCoord.

2 Estimation of percentage of HIV-infected people with limited future drug options in a closed observational setting over the period 2007-2011 and beyond. A Cozzi-Lepri, et al. for EuroSIDA in EuroCoord.

3 Management of cardiovascular risk in HIV positive individuals in Europe. M Shahmanesh, A Schultza, JD Lundgren et al. on behalf of EuroSIDA in EuroCoord.

4 A survey of ATRIPLA use in clinical practice among treatment-naïve HIV-positive patients in Europe. O Kirk, et al. for EuroSIDA in EuroCoord.

8th European Congress on Tropical Medicine and International Health, 10-13 September 2013, Copenhagen Oral presentations 1 Health service delivery models for the provision of antiretroviral therapy in sub-Saharan Africa: A systematic review.

J Lazarus.

2 The Global WHO/Hepatitis Alliance Survey and Hepatitis and drug use in Europe - a systematic review. J Lazarus.

Annual Report 2014 · 39

13th International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies, 4-8 June 2013, Toronto Oral presentation Low-frequency drug-resistant HIV-1 and risk of virological failure to firts-line NNRTI-based ART: a multi-cohort European case-control study using centralized ultrasensitive 454 sequencing. A Cozzi-Lepri, M Noguera-Julian, F Di Giallonardo, R Schuurman, M Däumer, S Aitken, HF Günthard, F Brun-Vezinet, KJ Metzner, R Paredes, and the CHAIN Minority HIV-1 Variants Working Group.

th

20 International HIV Dynamics and Evolution Conference, 8-11 May 2013, Utrecht Poster presentation

The Colombian epidemic is dominated by HIV-1 subtype B: A molecular epidemiology and phylodynamic study. AC Pineda, NR Faria, FJ Diaz, P Olaya, CM Frederiksen, L Guangdi, A Gomez-Lopez, P Lemey, AM Vandamme.

20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta Oral presentation Increased risk of cardiovascular disease (CVD) with age in men: a comparison of D:A:D with HIV negative CVD risk equations. K Petoumenos, W El-Sadr, A d’Arminio Monforte, C Sabin, P Reiss, L Ryom, S De Wit, M Rickenbach, JD Lundgren and MG Law for the D:A:D Study Group.

Poster presentations 1 Cancer Risk and Use of PI or NNRTI-based Combination Antiretroviral Therapy (cART): The D:A:D Study. M Bruyand, L Ryom, L Shepherd, P Reiss, S De Wit, A d’Arminio Monforte, M Rickenbach, A Philips, C Pradier, M Law, W El-Sadr, J Lundgren, C Sabin for the D:A:D Study Group.

2 Predictors of Advanced Chronic Kidney Disease and End-Stage Renal Disease in HIV-Positive Persons in D:A:D. L Ryom, A Mocroft, O Kirk, M Ross, P Reiss, W El-Sadr, S De Wit, P Morlat, O Moranne, CA Fux, A d’Arminio Monforte, M Law and JD Lundgren for the D:A:D Study Group.

3 Improvements in short-term mortality following myocardial infarction (MI): the D:A:D Study. C Sabin, L Ryom, M Law, W El-Sadr, O Kirk, M Bruyand, P Reiss, C Pradier, B Ledergerber, A d’Arminio Monforte, S De Wit, JD Lundgren on behalf of the D:A:D Study Group.

4 The incidence of AIDS defining events (ADEs) at a current CD4 count ≥ 200/mm3 in the post combination antiretroviral therapy era. Amanda Mocroft on behalf of the Opportunistic Infections Working Group of COHERE in EuroCoord.

5 Inflammation and coagulation markers are predictive of anemia in antiretroviral-treated HIV disease. ÁH Borges, J Weitz, G Collins, JBaker, Y Levy, R Davey, A Phillips, J Neaton, J Lundgren, S Deeks for the INSIGHT SILCAAT Study Group. (themed discussion and poster)

40 路 Annual Report 2014

Acknowledgments

Financial Contributors 2014 Study/activity

Public

Private

EuroSIDA

EU Commission

D:A:D

The Oversight Committee for The Evaluation of Metabolic Disorders of HAART EMeA FDA

Bristol-Myers Squibb GlaxoSmithKline Merck & Co Inc Pfizer Inc Tibotec/Janssen Research & Development, Pharmaceutical Companies of Johnson & Johnson The Oversight Committee sponsors: AbbVie Laboratories Inc. Bristol-Myers Squibb Company, Gilead Sciences Inc. GlaxoSmithKline Research & Development Ltd Merck & Co Inc. Janssen Pharmaceuticals GmbH

INSIGHT Network

National Institutes of Health, USA (NIH)

INSIGHT START

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

INSIGHT FLU

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 NIAID, NIH

NEAT

EU Commission

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

Monitoring Medicines, WHO HIV-TB

EU Commission

COHERE

EU Commission

PARTNER

National Institute for Health Research, UK (NIHR) WHO

Health Systems Global (CHIP is secretarial) Public health consultancies

IWHOD

EU Commission

UNICEF: Children and AIDS: 6th Stocktaking Report The World Hepatitis Alliance: Global Hepatitis StrategyReview ANRS, Agence nationale de recherches sur le sida

A.P. Møller-fonden Kathrine og Vigo Skovgaards Fond Augustinus Fonden ViiV Healthcare Rockefeller Foundation Welcome Trust Open Society Institute

Gilead Sciences GlaxoSmithKline Tibotec/ Janssen-Cilag International NV Abbvie Mylan

42 路 Annual Report 2014

Study/activity

Public

Private

HIV in Europe

EU Commission (2012 conference) UNICEF Endorsed by AIDS Action Europe WHO Europe European AIDS Treatment Group (EATG) University of Copenhagen

Abbott Laboratorie Boehringer-Ingelheim Pharmaceuticals Inc Bristol-Myers Squibb Gilead Sciences GlaxoSmithKline Merck & Co Inc Schering-Plough Tibotec/ Janssen-Cilag International NV ViiV Healthcare

OptTEST

The Consumers, Health and Food Executive Agency (Chafea), European Commission Danish Research Council

CASS

PASS (stored specimens)

TrygFonden Kivex Lundbeckfonden Corgenix DAKO BioPorto

Annual Report 2014 · 43

Acknowledgments After more than a decade of dedicated service, Jesper Kjær, the manager of our IT and bioinformatics function, decided to leave CHIP in early 2014.

NovoNordisk has been so lucky as to attract Jesper, offering him a central position in developing tools for data capture and management. We and our entire network will miss Jesper and his ability to be on the forefront of developments in data management and mergers of large datasets. Jesper has shown us the meaning of the saying “work smarter, not harder.”

Knowing the results of clinical research is no better the quality of the data, Jesper focused on letting computers take over where it made sense and saved human resources for the quality checks. Our distributed data management tool and the concept of MATCH would not have seen the light of day without him.

Two of our PhDs finalised their research education and returned to clinical specialisation: Caspar da Cunha-Bang and Lene Ryom Nielsen.

We have been very pleased to be able to contribute to the education of the young researchers and we have highly benefitted from their energy and efforts in developing their areas of interest. Caspar has been a driver of the day-to-day achievements of the MATCH programme and Lene has professionally led the DAD coordination.

In addition, Lene contributed and still contributes to the coordination of the European AIDS Clinical Society guidelines coordinated by CHIP. We are certain that the clinics, being so fortunate to have Caspar and Lene on board, now benefit from the competences they developed and we are confident that both will contribute to further develop their research areas.

We would also like to acknowledge the many years of service to EuroSIDA and DAD/CoDe provided

by Jette Elfvig Nielsen and Nick Giordano’s contribution to managing the HIV in Europe testing weeks and the OptTEST coordination, before both continues on their own to pursue new challenges.

We would especially like to thank and acknowledge the patients who participate in the trials and studies coordinated at CHIP. It is for and because of them that we continually strive to produce high quality research

Centre for

Health & Infectious Disease Research

Centre for

Health & Infectious Disease Research