CHIP Annual Report 2012 by Louise Klit Thomsen

D:A:D

Interviews with Lene Ryom, MD and StĂŠphane De Wit, MD, PhD

CHIP Annual Report 2012

INSIGHT FLU 002 and 003. Tracking one of the most serious influenza seasons of the past decade

MATCH

Results presented at ICAAC 2012 in San Francisco

HIV in Europe &

Guidance on Indicator Condition Guided HIV Testing Annual Report . 1

Contents Foreword, Andrew Phillips. From the Director.

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From the Director of Administration. .

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The D:A:D study is supervised by a steering committee with representation from each cohort, EMEA, patient community and industry. The steering committee is vital to the continued success and quality science generated by the study.

The D:A:D study coordinator, Lene Ryom, MD, is responsible for the adjudication of all D:A:D events received at the coordinating centre.

We spoke with Stéphane De Wit... a member of the D:A:D Steering Committee, to learn more about his role in D:A:D and the study’s efforts in the field of HIV research. What is your role in D:A:D? I am responsible for the Brussels Saint-Pierre HIV Cohort and as such I am a member of the D:A:D Steering Committee and have been for about 10 years. What impact has D:A:D made in the field of HIV medicine? D:A:D has generated major contributions in the field of HIV medicine: risk factors for cardiovascular disease now take into account HIV-specific factors such as exposure to some antiretrovirals. The D:A:D equation for cardiovascular disease has become a very useful tool which takes in to account these specificities.

D:A:D has also generated original data on cancer, illustrating the new epidemic of non-AIDS defining cancers and their link with immunodeficiency, further supporting the concept of early treatment.

What can we expect to see from D:A:D in the next few years? We still lack data both in the fields which D:A:D already explores, but also in systems such as bone disease, neurological involvement and maybe other metabolic complications.

More recently, data have been I sincerely hope that D:A:D will generated on nephrotoxicity of drugs, which will certainly impact pursue this magnificent work, clinical practice as renal disorders and I will be more than happy to further contribute to this exciting are becoming more prevalent in adventure. the HIV population. Has D:A:D fulfilled the expectations you had for it when you first joined the study? D:A:D has exceeded the expectations we had when it started; data which have been generated have led to major changes in our current practice. Moreover, when compared to the initial scope of the study, D:A:D now covers an impressive variety of fields.

Stéphane De Wit, MD, PhD As Clinical Coordinator of the Brussels Saint-Pierre Cohort with more than 2500 patients in active follow up, Stéphane De Wit represents the cohort on the D:A:D, EuroSIDA and NEAT Steering Committees. Stéphane is a senior physician with over 25 years experience, associate professor of Infectious Diseases, Master of Conference, and author or co-author of more than 140 articles in peer-reviewed journals, 290 presentations at international meetings and 11 chapters of books contributing to the study of HIV.

D:Amet:Dwith We Lene

The scientific results produced knowledge on this condition and by the D:A:D questions regarding the study. study have With an aging HIV-positive popula- its predictors. greatly enhanced our knowledge tion, several age-related diseases My work within about predictors and time trends are becoming to learn more about for cardiovascular disease, meta- increasingly comthe current D:A:D activities and Lene Ryom took over coordinabolic syndrome, cancers, and renalmon. Many of these diseases her experience as the study coortion of the D:A:D study in 2010, diseases. At CROI this year, we prerequire a large dinator. when she started her PhD at sented important new data on the cohort like D:A:D CHIP. Her PhD focuses on longrelation between certain non-AIDS to provide reliable What is your role in D:A:D? term adverse effects of antiretdefining malignancies and immunoestimations of As study coordinator I am, among roviral drugs, specifically investigating whether suppression (pX in publications), the occurrence and to other things, responsible for the cumulative exposure to anti-retroviral drugs associations between nephrotoxic disentangle the central validation of all events contribute to the development and progression anti-HIV drugs and development of possible relation received from the participating of different stages of chronic renal failure. renal impairment from initial normal cohorts. This process is carried out to immunosuprenal function, and the lack of an pression, HIV in accordance with the validation association between use of atazanamanual created by the D:A:D study itself and to HIVvir and cardio- and cerebro-vascular treatment relative to other risk fac- D:A:D has enabled me to establish group and also involves external events. The results from these and a world-wide network. For instance tors. Many of these chronic condiexperts for additional review. other D:A:D analyses are possible tions have very high morbidity and I’ve had the unique opportunity All D:A:D events are regularly thanks to the extensive scope of the mortality rates, making new insight to work at Mt. Sinai Hospital in monitored for completeness and study, and can be directly translated New York with Dr. Mike Ross, a accuracy. Our annual data merger, in to their predictors crucial. into clinical care. a procedure which merges all information received on events and other clinical data on the patients under follow-up, is an extensive process focusing on validating and cleaning all data before it is sent to the statistical department in London for further analysis. In close collaboration with the rest of the D:A:D working and study groups, I participate in developing and facilitating new research projects and assist statisticians and cohort investigators with

10 . CHIP 2012

What impact has D:A:D had on your research? The scientific environment I am surrounded by, including colleagues from the scientific committee, the working groups and the statistical department, are very inspiring to work with and their expertise in many different fields is overwhelming. My PhD project primarily concerns chronic kidney disease and D:A:D has, given its size and heterogeneity, provided an important platform for further

leading nephrologist and an external expert in the D:A:D kidney working group. The frequency of HIV-related renal failure is relatively low in Europe, so visiting a higher prevalence area gave me the chance to enhance my understanding of these patients. I also met with Dr. Christine Wyatt, who works with the INSIGHT network on renal insufficiency. This was an amazing opportunity, made possible because D:A:D is such a respected, high caliber programme.

Info

Annual Report . 11

The study had 3 oral presentations and 5 poster presentations at international conferences. An additional 3 projects were accepted for presentation at CROI 2013. Please visit www.cphiv.dk/D:A:D/ for presentation/publication details.

D:A:D

The Data Collection on Adverse Events of Anti-HIV Drugs

D:A:D is a prospective multi-cohort study of HIV-infected persons under active follow up. The study was initiated in 1999, and now includes follow-up of › 49.000 persons. While the original purpose of the study was to assess the incidence of myocardial infarction among HIV/AIDS patients receiving anti-retroviral therapy, the study has now expanded its efforts to cover other cardiovascular diseases, AIDS and non-AIDS defining cancers, end-stage renal and liver disease and death. In 2012 five articles were accepted for publication in peer- reviewed journals and another two

were submitted. They covered ART-related liver mortality among non-hepatitis co-infected over the lack of an association between atazanavir use and CV events and also short-term diabetes prediction. Another paper concerned sudden death/non-hem0rragic stroke with protease inhibitor use while yet another looks at the relationship between use of antiretrovirals and the risk of chronic renal impairment among persons with an initially normal renal function. One paper investigated the relation between ALAT levels and risk of MI and finally one concerned the association between cardiovascular disease and immune suppression.

D:A:D at a glance Patients enrolled Number of clinics Total person-years of follow-up Laboratory measurements CD4 counts Total Cholesterol Creatine Glucose Centrally validated endpoints MI Fatal cases ESLD NADM /ADM

49,731 215 339,108

1.365,666 718,566 760,946 577,131 893 4,098 204 1,091 /1,151

Annual Report . 9

D:A:D/CoDe page 9-12 FLU. .

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HIV in Europe The HIV in Europe Copenhagen 2012 Conference was held on 19-20 March 2012 at the University of Copenhagen. More than 300 participants from 46 countries participated, including the Danish Minister for Health, representatives from the European Commission, the European Parliament, WHO Europe, the European Center for Disease Prevention and Control, the EATG, AIDS Action Europe and other leading NGOs. Some 25% of conference participants were clinicians; while 37% were community representatives; 15% policy-makers; 15% social scientists, epidemiologist and statisticians and the rest from the mass media and private sector. The conference received financial support from the European Commission as part of the Health Programme 2008-2013.

HIV in Europe

Hepatitis..

Working Together for Optimal Testing and Earlier Care Copenhagen 2012 Conference

presenters. While ART has expanded in most countries the supply in EECA lags far behind the demand. A draft guide to routine testing in response to indicator conditions was presented to conference participants in March. Thanks in large part to findings from the HIV Indicator Diseases across Europe Study (HIDES) the list of medical conditions that should trigger an automatic HIV test now stands at more than 50. More generally numerous studies demonstrated the cost-effectiveness and broad acceptance of routine testing for all health care clients in a wide variety of settings, including emergency departments and primary care clinics.

HIV in Europe Call to Action, 2012-2014 All of us - people living with HIV, civil society representatives, health professionals and decision-makers, policy workers, European Union and national institution representatives and researchers - need to continue to closely collaborate in order to save lives by decreasing the number of people starting HIV treatment late. The HIV in Europe Initiative is working to:

2. Stimulate the scientific development of activities and events to inform the European agenda on optimal testing and earlier care;

START. .

3. Review data and studies on the impact of counselling and HIV/STI testing on risk behaviour and support a consensus process to agree on optimal counselling practices;

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4. Facilitate the implementation and assessment of HIV indicator condition guided testing; 5. Stimulate an evidence base on and reduce barriers to testing that include human rights, stigmatisation, discrimination and criminalisation; 6. Continue supporting the implementation of novel models to estimate the number of infected but not yet diagnosed individuals;

7. Investigate linkages and collaboration between HIV testing and hepatitis testing and access to care; and 8. Support the international institutions and agencies (European Commission, European Centre for Disease Prevention and Control (ECDC), WHO Regional Office for Europe, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and UNAIDS) to increase their engagement in working for optimal testing and earlier care and reinforce collaborative links.

The conference proceedings, evaluation and press coverage are available at

www.hiveurope.eu

Although HIV testing in EECA is on the rise the benefits of the expansion are minimal since risk group members still constitute less than 1% of those tested. More than half the PLHIV in the European Region are still classified as late 20 . CHIP 2012

Publications. .

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Teaching and Outreach. .

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Hiv in Europe page 20 Hides page 22 Funding. .

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1. Monitor and share research and best practices on HIV testing standards in order to improve practice and policy;

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Acknowledgements page 32

Acknowledgements After more than 12 years of dedicated service, Karoline B. Jensen, the manager of our monitor function has decided to leave CHIP by the end of 2012. The Nørrebro Social Psychiatric Centre has been so lucky as to attract Karoline, offering her a staff function with responsibility for implementation of quality standards, monitoring of adverse episodes/events and development of health related aspects of the operation of housing institutions and day centres in collaboration with the centre management and the management at the single institutions. It is a new position and part of the focused effort for the group of people that often are in need of the most care and attention. We and the INSIGHT network will miss Karoline; she has worked very diligently and collaborated with great commitment whilst developing and maintaining the CHIP spirit. We wish Karoline all the best and are sure she will keep in touch so we do not risk sliding off our cultural base.

We would also 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.

Justyna Kowalska finalized her research education and returned to her base in Warsaw. We have been very pleased to be able to contribute to the education of a young researcher such as Justyna. We have benefitted not only from Justyna’s research effort and achievements (especially her streamlining of the CoDe initiative) but also from her knowledge of local and regional conditions, cultural and political differences. We are certain that the team in Warsaw now benefits from the competences Justyna developed and we are confident that they will contribute to building even stronger bonds between CHIP and Andrzej Horban’s site and staff in Warsaw.

32 . CHIP 2012

Editors: Maria Campbell and Jesper Grarup Photographer: Andreas Mikkel · Layout: Kandrups Bogtrykkeri A/S

Foreword Andrew Phillips

counterpart with focus on the clinical aspects of the research questions and in Jens Lundgren and CHIP we have partnered up with a team with whom we work closely in discussing research ideas and obtaining funding. For me, there is no better source of new research ideas, or person to talk through thoughts with, than Jens. CHIP has the perfect set-up to put in to operation these joint research plans.

The collaboration between Jens Lundgren/ CHIP and the HIV Epidemiology and Biostatistics Group at University College London has been central to our groups’ research portfolio over the years, and has been very fruitful – our groups have co-authored over 220 peer-reviewed papers

Peer reviewed co-published papers by year 40 36 35

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and more than 10 PhDs have benefited from shared supervision across the North Sea. Our collaboration started in 1992 focusing on the observational research methodology in the EuroSIDA study and later expanded to include partnership in the global network INSIGHT, focusing on randomized controlled trials as well as the D:A:D cohort collaboration study. Our collaboration has also extended to modelling. For an academic group of statisticians and epidemiologists it has been crucial to have a skilled

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In 2009 we began working together on a study on HIV transmission risk. The aim of the study is to precisely estimate the rate of transmission of 6 HIV in couples prac5 4 3 3 ticing ongoing con2 1 dom-less sex where the HIV-positive person has a well controlled infection. During initiation of the study we all were challenged with the conflict of asking patients detailed question regarding condom-less sex and at the same time reminding patients about condom use – highlighting the importance of a broad project team drawing on experience not only from the scientists, but also from nurses and project leaders.

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Recently our group has developed prediction models for the development of the HIV-epidemic – a good example where complex statistical modelling uses the data from observational studies and clinical trials and the compiled biological Annual Report . 3

and clinical knowledge to interpret the data for use in the models. In this way we hope to be able to contribute with results not only guiding the treatment and management of patients, but also providing tools for evaluation of planned health systems interventions, which already has been utilized in collaboration with WHO. As seen, our collaboration has a broad range of scientific methodologies in play, ranging from observational research and epidemiology, to randomized controlled trials and mathematical modeling for prediction use. One of the major milestones our groups have been involved in is the INSIGHT START study that is currently close to being fully enrolled. We consider this to be a critical study that will provide the missing evidence we all need on the risks and benefits of very early initiation of ART. CHIP has many other achievements that we have only contributed to in relatively small way. The

HIV in Europe initiative has had a real influence on the HIV testing agenda in Europe and CHIP continues to take initiatives such as the Masterâ&#x20AC;&#x2122;s course, the Health Systems Global initiative, the prospective TB:HIV study whilst the IT department at CHIP has played an important role in the Probe-C acute hepatitis C study by developing the electronic CRF. We really appreciate being involved in generating new ideas as well as relevant and interesting research questions within these areas. We also prioritize the possibility to be able to develop new fields and approaches related to new research areas which our groups collaborate on, like sepsis and viral infections in transplant patients. We wish CHIP every continuing success in playing a leading role in HIV and infection research.

From the Director, Jens Lundgren Time to move on 2012 was another exciting year for CHIP. Our research sets out to inform and improve the care of people suffering from infectious disease in general and HIV in particular; there are several examples of results published in 2012 which will do exactly this. In D:A:D, the study of kidney function impairment associated with the use of certain types of antiretroviral therapy and the evolving focus on cancer as an important cause of morbidity and mortality in HIV-positive people should show exciting results and lead to discussions on more personalized care in the years to come (p. 9). EuroSIDA continues to document the marked diversity of standards of care across the European continent (p. 24). In 2012, for example, the establishment of indicators to benchmark care across the continent documented substantial differences in approaches to initiating medical treatment and the use of laboratory measurements to assess their effects. Further, the indicator that focuses on the ability to maintain full control of HIV replication showed marked regional differences, suggesting that the ability of health systems to ensure proper use varies markedly. We already know that correct use is critically important to optimize an individualâ&#x20AC;&#x2122;s health. Scandinavia is among the best performing regions in Europe in this respect, and an unmet research need is to elucidate a better understanding of the reasons for this best practice in order to share it abroad. Moreover, the HIV:TB study, building on the network established in EuroSIDA, has generated indicators for care in HIV-positive people infected with tuberculosis, and again showed marked regional differences in how those suffering from this life-threatening

infection are managed (p.25). There is significant room for improvement in care for people living with HIV, and we trust that our research findings will assist government and international organizations that advise government (e.g. WHO/ Europe and the ECDC) in doing so. We are ready and able to assist in this effort. CHIP has already expressed our desire to further strengthen the collaboration with WHO/Europe and the ECDC on other fronts. We organized the HIV In Europe conference in 2012 (p. 20). And we have spearheaded the research required to formulate guidelines on HIV testing performed proactively by health professionals for people presenting for care with certain medical conditions. As a result, the HIV indicator-diseases testing guidance was released in 2012. We will closely follow the implementation of this guideline document across the continent (and elsewhere), and at the same time continue HIDES (HIV Indicator Diseases across Europe Study) providing evidence for which conditions to include as an indicator for an HIV test. CHIP co-founded Health Systems (HS) Global in 2012 and now manages its secretariat (p. 31). This is the first global scientific society for research on health systems. I wish HS Global the best of luck in their important task of improving our understanding of how health systems can be organized to provide the best care in the varying settings around the world. The MATCH (Management of Post-Transplant Infections in Collaborating Hospitals) programme continues to expand its focus, including strengthening collaborations domestically and internationally (p. 16). It is well recognized that viral diseases are serious and frequent Annual Report . 5

complications in the period after organ transplantation. Preventive and therapeutic interventions to reduce risk from this type of disease are hence core business to CHIP. We have worked for five years to establish a cohort of transplant recipients at Rigshospitalet, and this significant effort is now starting to pay off. The identification of four critical mutations (and ultimately likely only 5-7 of the more than 35 described mutations) in the UL97 gene of Cytomegalovirus (CMV) rendering this virus resistant to treatment with the key antiviral drug ganciclovir is one example. Another was the demonstration of a more than 70% reduction in risk of contracting serious CMV infection from the complete renovation of the infrastructure at the hospital, in terms of approach to using antiviral drugs and screening for emerging infection. The current status of international collaboration related to transplant infectious diseases is comparable to the situation in HIV back in the mid-1990s. CHIP served a critical role in improving the situation for HIV over the last 20 years, and we have made a strategic decision to transfer that knowledge to transplantation infectious disease.

formed the basis for classifying cases of death in HIV+ persons (CoDe), and the HICDEP format (HIV Collaboration Data Exchange Protocol) used when preparing two datasets to be merged. In 2012, the DDT data exchange format was released, which allows for a “one-click” merging of data. These “behind the scenes” activities normally require significant personnel resources and were done manually by data managers in each participating cohort study. All three activities are recognized and used globally to facilitate collaboration.

Important research takes time to complete. In addition to the aforementioned studies, there are ongoing efforts seeking to clarify the following research questions: are people living with HIV and on fully suppressive antiretroviral therapy infectious? (the PARTNER study); has the poor prognosis of HIV/TB co-infected persons in Eastern European documented improved since 2009? (the HIV:TB prospective study); is cooling of body temperature to 32° C able to improve change of survival from septic shock? (the CASS study); and when should antiretroviral therapy be started in the course of the HIV infection? (the START study). We project that the first set of results from these studies will be announced between 2014 and 2016.

CHIP moved from Hvidovre Hospital to Rigshospitalet in 2007. We are currently part of the Institute for International Health, Immunology and Microbiology (ISIM), Faculty of Health Sciences, at the Panum Institute, University of Copenhagen. In collaboration with the directors of Rigshospitalet, we recently decided to move back to Rigshospitalet. Together with the dean of the faculty, we decided that our future academic link will be with the Institute of Clinical Medicine (ICM). The move is rationalized by the need to reduce cost and at the same time make better use of CHIP’s various capabilities to support the overall vision of Rigshospitalet. We want to thank the leadership of ISIM for their support to CHIP over the years, and at the same time we look forward to a constructive and collegial collaboration with the leadership and colleagues at ICM and at Rigshospitalet.

In addition to producing research results, CHIP is also maintaining focus on expanding the research methodology we use. For example, we 6 . CHIP 2012

CHIP is physically located in Copenhagen, but the network we coordinate involves more than 1500 colleagues. As of the end of 2012, CHIP collaborated with 269 clinics in Europe and Latin America. Additionally, we have strong and long-standing collaborations with other academic institutions involved in the coordination of the research effort including University College of London (UCL), the trial unit at the UK Medical Research Council, University of Minnesota, Georgetown University and the Kirkby Institute at the University of New South Wales.

From the Director of Administration, Jesper Grarup CHIP contributes to answering 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 evidenced in this and previous annual reports. Allow me to focus a bit on examples of CHIP’s operational set-up, which make this research possible. Our monitors have developed a relationship with our important partners at research sites, encouraging a “we are in this together” rather than “we will tell you how to do it” attitude. An important achievement following this spirit is

the successful set-up of the endpoint review procedure within the NEAT001 trial which included sorting out the complex logistical flow between sites, CTUs, sponsor, and statistician. Another good is example is the PARTNER study: after exchanging experience with clinical sites, information material was produced to aid PARTNER investigators in breaking the ice when it comes to talking with potential study participants about their partners and having unprotected sex. From both a scientific and a logistic perspective, the management and coordination of the HIV in Europe Conference, held in March of this year, 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 I study into testing guidelines, covering a variety of specialities, is a

major and well recognized achievement. The D:A:D team has managed to streamline the operations so we now have an integrated CoDe/D:A:D process. This includes a smoother data clarification process, allowing for the possibility to draw data on site performance to further improve the quality and procedures of the study. This also allows for continued support for the maintenance and refinement of the internationally used Coding of Causes of Death (CoDe) methodology. The IT group continued to break new ground this year by developing electronic data capture solutions for the Probe-C, HIDES II and CASS studies. On top of this, the Distributed Data Management tool allowing cohorts to control quality and share data via a web-based portal has been tested and fine-tuned in order to manage the COHERE merger in 2013. The most outstanding development however, is the second generation of the complex MATCH database to manage viral infections in transplant patients. In collaboration with the transplanting departments and labs at Rigshospitalet, the tool has now been expanded to include web-based access for clinical staff to follow results over time. We hope to be able to contribute further by expanding MATCH to other hospitals both domestically and internationally in the coming year. CHIP contributes substantially to the INSIGHT operations, supporting Jens Lundgren in his role as chair of the Scientific Steering Committee to oversee the process of the more than 50 ongoing scientific projects, evaluation of proposals and writing groups. A project management database developed by CHIP keeps track of these processes and procedures and manages e-mail reminders. This tool will be applied in the coming year to projects in other collaborations, like COHERE. Likewise CHIP supports INSIGHTâ&#x20AC;&#x2122;s Operational Steering Committee as well as its Quality Oversight and Performance Oversight Committee, which I currently chair, and support

8 . CHIP 2012

the network with tools and reports to improve the quality of research and performance at all levels. Working with more than 100 collaborating sites within the EuroCoord umbrella is a challenge from a contractual perspective; however, we have had very good experience with investigators acting as ambassadors to ensure smooth contract negotiations. We cannot emphasize enough that PI support and interaction continues to be of key importance to CHIP. When CHIP moved to the University of Copenhagen in 2007 it was done as part of a three-way agreement with Rigshospitalet, the university and CHIP, with the hope to become a bridge between the university and the hospital. We are happy to see that Rigshospitalet has been open and granted CHIP the possibility to unfold capabilities within the hospital framework: setting the MATCH programme into production and being awarded a MATCH research grant, and allowing us to contribute scientifically by granting us a one-year INSIGHT research assistance and a three year HIV-TB PhD position. From the above, I hope it is clear that CHIP continues to contribute beyond our own activities in collaboration with colleagues nationally as well as with institutions and networks internationally, offering them to take advantage of our experience and competences.

D:A:D

The Data Collection on Adverse Events of Anti-HIV Drugs

D:A:D is a prospective multi-cohort study of HIV-infected persons under active follow up. The study was initiated in 1999, and now includes follow-up of â&#x20AC;ş 49.000 persons. While the original purpose of the study was to assess the incidence of myocardial infarction among HIV/AIDS patients receiving anti-retroviral therapy, the study has now expanded its efforts to cover other cardiovascular diseases, AIDS and non-AIDS defining cancers, end-stage renal and liver disease and death. In 2012 five articles were accepted for publication in peer- reviewed journals and another two

49,731 215 339,108 1,365,666 718,566 760,946 577,131 893 4,098 204 1,091/1,151

Annual Report . 9

As a member of the D:A:D Steering Committee... we spoke to Stéphane De Wit a member of the D:A:D Steering Committee, to learn more about his role in D:A:D and the study’s efforts in the field of HIV research. What is your role in D:A:D? I am responsible for the Brussels Saint-Pierre HIV Cohort and as such I am a member of the D:A:D Steering Committee and have been for about 10 years. What impact has D:A:D made in the field of HIV medicine? D:A:D has generated major contributions in the field of HIV medicine: risk factors for cardiovascular disease now take into account HIV-specific factors such as exposure to some antiretrovirals. The D:A:D equation for cardiovascular disease has become a very useful

tool which takes in to account these specificities. D:A:D has also generated original data on cancer, illustrating the new epidemic of non-AIDS defining cancers and their link with immunodeficiency, further supporting the concept of early treatment.

current practice. Moreover, when compared to the initial scope of the study, D:A:D now covers an impressive variety of fields. What can we expect to see from D:A:D in the next few years? We still lack data both in the fields which D:A:D already explores, but also in systems such as bone disease, neurological involvement and maybe other metabolic complications.

More recently, data have been generated on nephrotoxicity of drugs, which will certainly impact clinical practice as renal disorders I sincerely hope that D:A:D will pursue this magnificent work, are becoming more prevalent in and I will be more than happy to the HIV population. further contribute to this exciting adventure. Has D:A:D fulfilled the expectations you had for it when you first joined the study? D:A:D has exceeded the expectations we had when it started; data which have been generated have led to major changes in our

10 . CHIP 2012

Incident cases of D:A:D events are reported real-time to the coordinating centre in Copenhagen using designated event forms. In addition to data on demographics, risk factors for cardiovascular disease and laboratory measurements are updated and sent electronically to the coordinating centre every eight months. The D:A:D study coordinator, Lene Ryom, MD, is responsible for the adjudication of all D:A:D events received at the coordinating centre.

We met with Lene

to learn more about the current D:A:D activities and her experience as the study coordinator. What is your role in D:A:D? As study coordinator I am, among other things, responsible for the central validation of all events received from the participating cohorts. This process is carried out in accordance with the validation manual created by the D:A:D study group and also involves external experts for additional review. All D:A:D events are regularly monitored for completeness and accuracy. Our annual data merger, a procedure which merges all information received on events and other clinical data on the patients under follow-up, is an extensive process focusing on validating and cleaning all data before it is sent to the statistical department in London for further analysis. In close collaboration with the rest of the D:A:D working and study groups, I participate in developing and facilitating new research projects and assist statisticians and cohort investigators with

knowledge on this condition and questions regarding the study. With an aging HIV-positive popula- its predictors. My work within tion, several age-related diseases are becoming increasingly common. Many of Lene Ryom took over coordinathese diseases tion of the D:A:D study in 2010, require a large when she started her PhD at cohort like D:A:D CHIP. Her PhD focuses on longto provide reliable term adverse effects of antiretestimations of roviral drugs, specifically investigating whether occurrence and to cumulative exposure to anti-retroviral drugs disentangle the contribute to the development and progression possible relation of different stages of chronic renal failure. to immunosuppression, HIV itself and to HIVtreatment relative to other risk fac- D:A:D has enabled me to establish a world-wide network. For tors. Many of these chronic conditions have very high morbidity and instance had the unique opportumortality rates, making new insight nity to work at Mt. Sinai Hospital in New York with Dr. Mike Ross, a in to their predictors crucial. leading nephrologist and an external expert in the D:A:D kidney What impact has D:A:D had on working group. The frequency of your research? HIV-related renal failure is relaThe scientific environment I am tively low in Europe, so visiting a surrounded by, including colhigher prevalence area gave me leagues from the scientific comthe chance to enhance my undermittee, the working groups and the statistical department, are very standing of these patients. I also met with Dr. Christine Wyatt, who inspiring to work with and their works with the INSIGHT network expertise in many different fields on renal insufficiency. This was an is overwhelming. My PhD project amazing opportunity, made posprimarily concerns chronic kidney sible because D:A:D is such a redisease and D:A:D has, given its spected, high caliber programme. size and heterogeneity, provided an important platform for further

Annual Report . 11

D:A:D

The scientific results produced by the D:A:D study have greatly enhanced our knowledge about predictors and time trends for cardiovascular disease, metabolic syndrome, cancers, and renal diseases. At CROI this year, we presented important new data on the relation between certain non-AIDS defining malignancies and immunosuppression (p.40), the associations between nephrotoxic anti-HIV drugs and development of renal impairment from initial normal renal function, and the lack of an association between use of atazanavir and cardio- and cerebro-vascular events. The results from these and other D:A:D analyses are possible thanks to the extensive scope of the study, and can be directly translated into clinical care.

Info

FLU

The current 2012-2013 influenza season in the Northern Hemisphere kicked off at the end of the year, becoming perhaps one of the more serious that we have seen over the past decade.

some areas represents a degree of antigenic drift within that subtype, or perhaps reflects instead just differential host susceptibility within populations having different degrees of vaccine uptake since 2009. One of the many strengths of our INSIGHT FLU 002 and 003 studies is that we capture prior vaccination histories and other pertinent demographic information at enrollment that we can then correlate with the indepth sequencing of viral isolates obtained from our study participants, thus facilitating this type of causal analysis. This season the Copenhagen ICC region enrolled 180 participants in FLU002 and 24 in FLU003. Enrollment by Country (01 Jan 2012 to present)

Why the FLU studies continues to be important While data are still limited, the distribution of influenza isolates between Europe and North America is showing some early discordance, with the A(H1N1)pdm09 subtype having â&#x20AC;&#x153;re-emergedâ&#x20AC;? and co-circulating in Europe at a higher frequency than presently seen in the United States and Canada, where H3N2 and influenza B continue to be the predominant subtypes isolated to date. If persistent, it will be important to learn whether this relative resurgence of A(H1N1)pdm09 in

300 250

FLU 002 Top Enrollers Argentina 247 Belgium 224 Peru 112

FLU 003 Top Enrollers US 74 Peru 63 Australia 20

200 150 100 50 USA

Thailand

Peru

Spain

Estonia

Germany

China

Denmark

Belgium

Australia

0 Argentina

A heavy volume of new cases flooding hospital emergency rooms in some regions or cities prompted some public health authorities to declare an increase in emergency level. The number of pediatric deaths attributable to influenza in the United States has risen this season from prior low levels.

FLU 003 FLU 002

Patients

The European Centre for Disease Prevention and Control reported activity in 16 of 20 countries in the last week of 2012. Countries in northern and western Europe were most affected. Of 734 sentinel specimens tested across 20 countries, 44% were positive for influenza virus. Of those 44% were type A (of those 51% A(H3N2) and 49% A(H1N1)pdm09) and 56% type B.

Publication updates for the FLU 002 and 003 studies 1 The association between serum biomarkers and disease outcome in Influenza A(H1N1)pdm09 virus infection: Results of two international observational cohort studies. Accepted at Plos One. 2 Sequence Analysis of in vivo defective-interfering (DI)-like RNA of Influenza A(H1N1) pandemic virus. Submission planned Q1 2013. Manuscript preparation, targeted for spring 2013 1 Bacterial and Viral Co-Infection in A(H1N1)pdm09 Patients 2 Serologic Analysis of A(H1N1)pdm09 Patients

Annual Report . 13

NEAT

European AIDS Treatment Network

NEAT 001/ANRS 143 An open-label randomized comparative two-year trial comparing two first-line regimens in HIV-infected antiretroviral na誰ve subjects: darunavir/r + tenofovir/emtricitabine vs. darunavir/r + raltegravir In October 2011 the enrollment into the NEAT 001 study was completed and the goal of including 800 participants at 93 different clinics in 14 European countries was met before expected. The Independent Data Monitoring Committee (IDMC) performed a Week 32 interim analysis in June 2012 and had no safety concerns, but recommended continuation of the study as planned. In preparation for the next IDMC meeting in January 2013, the CHIP monitor group put great effort and diligence in ensuring high data quality by visiting and monitoring all participating NEAT sites during the months of September/ October 2012. This was a busy but rewarding time for our monitors to meet up with all our colleagues in the countries CHIP coordinates: Austria, Belgium, Denmark, Germany, Poland, Portugal and Sweden - 20 monitor visits performed in two months. All 91 NEAT sites have been very successful in maintaining follow-up of their study participants. The graph below illustrates the percentage of completed follow-up visits until week 48 among the 4 clinical trials units; Amsterdam (AMC), Bordeaux (BDX), Copenhagen (CHIP) and London (MRC):

14 . CHIP 2012

At this point in time, the last study participant enrolled has reached the week 48 follow-up visit. For the remainder of the study, study participants will be seen every 3 months until trial closure in September 2013. This is the first clinical study conducted by NEAT and as with all new initiatives there have been challenges in making the scientific and operational procedures work on all levels. However, knowledge sharing across the network has proven to be most rewarding.

AMC BDX

CHIP MRC

100 95 90 85 80 75 70 w00

w02 w04

w08

w12

w18

w24 w32 w48 Follow-up Visit

MATCH

Management of Post-Transplant Infections in Collaborating Hospitals MATCH was developed and implemented in 2011 in order to optimize monitoring procedures and insure timely diagnosis and treatment of viral infections in organ transplant patients. On average a new patient is included in MATCH every other day. Currently 340 patients have been included and are following the programme, but patients transplanted prior to 2011 have also been retrospectively registered in MATCH. To evaluate the performance of MATCH, key indicators for monitoring and presentation of cytomegalovirus (CMV) infection (a virus monitored in MATCH) were analyzed in three calendar periods: prior to, during and after the implementation of MATCH. CMV infection was defined as either two consecutive plasma CMV-DNA results above the lower limit of detection (300 copies/mL), or one CMVDNA > 3000 copies/mL. The severity of infection at the time of diagnosis was categorized according to the CMV-DNA level as: Mild < 10.000 copies/mL, Moderate from 10.000-29.999 copies/ mL or Severe â&#x2030;Ľ 30.000 copies/mL. For patients diagnosed via pathology reports the infection was categorized as severe. A hospital admission

16 . CHIP 2012

was considered to be related to CMV infection when CMV was the primary cause of admission. A total of 809 patients were included in the analysis and 148 (18%) were diagnosed with CMV infection. The incidence of CMV infection did not vary over the three calendar periods. At the time of diagnosis of CMV infection the prevalence of moderate to severe infection decreased from 49% to 41% to 10% over calendar time (Figure 1). As a consequence the rate of admission due to CMV decreased from 44% and 52% to 13% over calendar time (Figure 1). We were able to improve the clinical outcome of CMV infection through a rational approach towards when and how to monitor for the infection. The results mentioned above were presented as a late breaker at this yearâ&#x20AC;&#x2122;s ICAAC in San Francisco [1]. The presentation was mentioned on Medscape (http://www.medscape. com/viewarticle/771482) and the medical news site Renal and Urology News (http:// www.renalandurologynews.com/novel-programme-cuts-cmv-related-admissions-in-transplant-patients/article/258626/). A future area of focus within the programme will be Epstein Barr virus which can cause B-cells to undergo

can be implemented at any transplant unit and that the platform used could be adapted for management of other clinical challenges regardless of the setting.

malignant transformation and cause cancer in transplant patients. While focusing on new areas we will also continue to further optimize procedures and monitoring plans included in programme. We believe this novel programme

Figure 1. Severity of infection at the time of CMV diagnosis and rate of CMV-related hospital admission

Mild Moderate Severe Hospital admission

100 51%

59%

90%

52%

15% 44%

12%

34% 29%

13%

4% 6%

0 2007-2008

2009-2010

2011

Figure 1. da Cunha-Bang, C., et al. Evaluation of novel programme aimed at reducing the risk of severe viral infections, including cytomegalovirus, following solid organ transplantation. in 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy. 2012. San Francisco.

Annual Report . 17

ICU division

The Organ Failure Studies – Cohort and biobank studies

The PASS

i pass

(Procalcitonin And Survival Study) trial was finalized in 2009. Throughout the trial, 1200 critically ill patients were recruited from nine intensive care units (ICU) across Denmark. A wide range of clinical and laboratory data were collected and are available for analysis in the PASS-database. Additionally, serum and plasma was collected from all patients on all study days, and genetic material has been extracted in vials for 1000 patients. Currently, the biobank is being processed for further analysis (six aliquots per patient-day). The following analyses are ongoing or planned for the next 12 months: 1 COM:PASS (Coagulation caused Organ Malfunction:Prediction Associated with Sepsis Survival): A PhD study identifying an association between elements of the blood and the development of circulatory failure in sepsis. A full description of the study is available on page 19. 2 ALIDA study: Sepsis, antibiotics and Liver failure in ICU-patients.

3 ALUDA study: Sepsis, antibiotics and Lung damage in ICU patients. This study has the primary objective to determine whether lung injury occurs more frequently in intensive care patients highly exposed to broad-spectrum antibiotics, as done in the ‘high-exposure-arm’ in the PASS-trial, and the secondary objective is to clarify if certain antibiotics are responsible for this difference. This project is in collaboration with Professor Jørgen Vesbo and Professor Else Tønnesen. 4

This is a research project to elucidate the frequency and clinical impact of liver cell dysfunction in severe sepsis, measured by elevated hyaluronic acid levels and to determine the clinical impact of liver failure in intensive care patients with severe sepsis and to determine if certain antibiotics are responsible for liver failure in these patients. 18 . CHIP 2012

RENAL study

A PhD study with the aim to 1) identify predictors of renal recovery in ICU patients with kidney failure, 2) to optimize the model using dynamic changes in two recently discovered biomarkers of renal function and 3) to test a renal replacement intervention by selecting the trial participants using the model developed in 1+2.

CASS

COM:PASS

(The Cooling And Surviving Septic Shock study) Circulatory failure in sepsis (septic shock) increases mortality significantly and is a major cause of death worldwide. The aim of the CASS study is to determine if Mild Induced Hypothermia (cooling to 32-34ºC for 24 hours) reduces mortality and organ failure in patients diagnosed with septic shock.

(Coagulation caused Organ Malfunction:Prediction Associated with Sepsis Survival) This study focuses on identifying an association between elements of the blood and the development of circulatory failure in sepsis.

The target recruitment is 560 patients. Detailed data are collected daily from all participants. In addition extensive analyses are done regarding biochemistry, microbiology, physiological and daily clinical assessment by the treating physician; age, sex, height, weight and acute and chronic diagnosis are collected. All data are registered by project nurses and entered in an electronic data base. Biobank material in the form of plasma and whole blood is collected from all study participants. The first patient was enrolled in the CASS study. in 2012 and throughout the year two safety analyses were carried out – continuation was recommended by the Data and Safety Monitoring Board. Twelve ICUs across Denmark have engaged to recruit patients into this trial. Hypothermia treatment of septic shock has never been done systematically before. If Mild Induced Hypothermia has a positive effect on organ failure and survival in septic shock, it will have great impact on patient therapy and prognosis worldwide. The results from the study will further clarify a number of questions regarding the physiological and molecular effect of cooling on infections, including gene-activation and inhibition and the activity of the cold shock proteins, coagulation proteins etc. Several sub-studies have already been initiated.

COM:PASS

Septic shock is the ultimate consequence of bacterial infection and mainly due to a dysfunction of the coagulation system, including platelets and the endothelium. The COM:PASS study is focusing on identifying changes in biomarkers leading to homeostatic dysfunction in patients with septic shock. Improving of our understanding of the pathogenesis of septic shock increases the opportunity to stratify patients by risk or a poor outcome. Blood samples (day 1-28) from 1200 critically ill patients with sepsis have been collected during the PASS study. 9 biomarkers focusing on coagulation, fibrinolysis and endothelial dysfunction have been selected. In 2012 measurements of biomarker levels by Enzyme-Linked Immunosorbent Assay were started and completion is expected in 2013. The preparation of identifying genetic biomarkers (Single Nucleotide Polymorphisms) prediction poor outcome in sepsis is under way and is expected to start in 2013.

Collaborators Transfusion Medicine, Rigshospitalet, Capital Region Blood Banks, Skejby University Hospital Blood Bank, Department of Clinical Microbiology, Hvidovre University Hospital, Center of Genomic Medicine, The Intensive Care Units at the below mentioned university hospitals: Hillerød, Gentofte, Bispebjerg, Herlev, Skejby, Århus, Roskilde, Køge, Horsens , Nykøbing Falster and Rigshospitalet.DAKO Denmark A/S, Glostrup, Denmark. Bioporto, Gentofte, Denmark.

Annual Report . 19

HIV in Europe The HIV in Europe Copenhagen 2012 Conference was held on 19-20 March 2012 at the University of Copenhagen. More than 300 participants from 46 countries participated including the Danish Minister for Health, representatives from the European Commission, the European Parliament, WHO Europe, the European Center for Disease Prevention and Control, the EATG, AIDS Action Europe and other leading NGOs. Some 25% of conference participants were clinicians; 37% were community representatives; 15% policy-makers; 15% social scientists, epidemiologist and statisticians and the rest from the mass media and private sector. The conference received financial support from the European Commission as part of the Health Programme 2008-2013.

More than 100 presentations were made at the conference in both oral and poster format. Some of the key issues raised during the conference were that there were an estimated 2.3 million people living with HIV (PLHIV) in the WHO European Region in 2010, including 1.5 million in eastern and central Europe. Although HIV testing in EECA is on the rise the benefits of the expansion are minimal since risk group members still constitute less than 1% of those tested. More than half the PLHIV in the European Region are still classified as late 20 . CHIP 2012

HIV in Europe

Working Together for Optimal Testing and Earlier Care Copenhagen 2012 Conference

The conference proceedings, evaluation and press coverage are available at

www.hiveurope.eu

HIV in Europe Call to Action, 2012-2014 All of us - people living with HIV, civil society representatives, health professionals, decision-makers, policy workers, European Union and national institution representatives and researchers - need to continue to closely collaborate in order to save lives by decreasing the number of people starting HIV treatment late. The HIV in Europe Initiative is working to: 1. Monitor and share research and best practices on HIV testing standards in order to improve practice and policy 2. Stimulate the scientific development of activities and events to inform the European agenda on optimal testing and earlier care 3. Review data and studies on the impact of counselling and HIV/STI testing on risk behaviour and support a consensus process to agree on optimal counselling practices 4. Facilitate the implementation and assessment of HIV indicator condition guided testing 5. Stimulate an evidence base on and reduce barriers to testing that include human rights, stigmatisation,Â discrimination and criminalisation 6. Continue supporting the implementation of novel models to estimate the number of infected but not yet diagnosed individuals 7. Investigate linkages and collaboration between HIV testing and hepatitis testing and access to care 8. Support the international institutions and agencies (European Commission, European Centre for Disease Prevention and Control (ECDC), WHO Regional Office for Europe, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and UNAIDS) to increase their engagement in working for optimal testing and earlier care and reinforce collaborative links

Hides

Guidance on Indicator Condition Guided HIV Testing

“HIV Indicator Conditions: Guidance for Implementing HIV Testing in Adults in Health Care Settings” was developed by a panel of medical specialists and experts from theEuropean Centre for Disease Prevention and Control (ECDC) and WHO Europe. It explains how to diagnose people earlier and avoid late presentation. The guidance in part builds on results from the HIDES I Study (HIV Indicator Conditions across Europe Study), which aimed to define the methodology of a European-wide study of HIV prevalence in individuals presenting with one

HIV Indicator Conditions: Guidance for Implementing HIV Testing in Adults in Health Care Settings

22 . CHIP 2012

of eight indicator conditions/diseases and to identify those with an HIV prevalence of › 0.1%, a level determined to be cost effective. Twenty percent reported previously having potential HIV-related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy’s efficacy in diagnosing HIV at an earlier stage. All eight ID fulfilled the › 0.1% criterion for cost-effectiveness, with the prevalence details in the Figure 1.

The HIDES study is being implemented in a phase II (2012-2013), allowing for more robust prevalence data and regional comparisons including a number of additional potential indicator conditions. www.hiveurope.eu

Figure 1 Feasibility and Effectiveness of Indicator Condition-Guided Testing for HIV: Results from HIDES I (HIV Indicator Diseases across Europe Study) Results â&#x20AC;&#x201C; HIV diagnoses per Indicator Condition HIV test HIV+ Prevalence (95% CI) Total 3588 66 4.06 (2.78-5.71) Malignant lymphoma 344 1 0.29 (0.01-1.61) Cevical or anal dysplasia 542 2 0.37 (0.04-1.32) Herpes Zoster â&#x20AC;š 65yo 207 6 2.89 (1.07-6.21) Hepatitis B/C 1099 4 0.36 (1.10-0.93) On-going mononucleosis 441 17 3.85 (2.26-6.10) Leuko/thrombocytopaenia 94 3 3.19 (0.66-9.04) Seborrheic dermatitis/exanthema 97 2 2.06 (0.25-7.24) Manuscript under review in Plos ONE

HIV Indicator Conditions is available at www.hiveurope.eu and a summary is available in French, German, Spanish and Russian.

EuroCoord

Quite a number of the activities that CHIP coordinates belong under the umbrella of the EU-funded EuroCoord Network of Excellence established by the four founding networks CASCADE, COHERE, PENTA and EuroSIDA. The EuroCoord structure aims to ensure integration and synergy and avoid duplication of research, but from a research site perspective it can sometimes be difficult to identify the roles and responsibilities related to the research topics you are involved in. In brief, the training and e-learning activities in WP2 are operationally coordinated by CHIP, all of the cohort hepatitis co-infection activities are lead by CHIP in WP3, and in WP4 our IT group has implemented the Distributed Management platform used for data mergers in COHERE. EuroSIDA comprise WP9 and WP10, COHERE WP11 and WP12, and the HIV-TB study WP13.

COHERE

Several important new initiatives in improving data quality and process of the annual mergers were taken. The data management SOP was finalised, timelines and processes became aligned between CASCADE and COHERE, the HIV Distributed Data Management tool was agreed upon for the 2013 merger and the first cohort visits were done at the MASTER, AHIVCOS and FHDH cohorts. These process optimisations and quality improving efforts will continue into 2013 when a new data merger for several scientific projects will be conducted. COHERE also performed two additional mergers on hepatitis and socio-economic data and finalized the treatment change episode database. As part of WP4 data managers continue to collaborate with the IeDEA data harmonization group to ensure synergy between the two networks.

24 . CHIP 2012

EuroSIDA

The focus of the EuroSIDA study remains to address yet unsolved issues of clinical relevance for HIV-positive patients, and the primary objective of EuroSIDA remains to prospectively study the long-term virological, immunological and clinical outcome for HIV-positive persons across Europe. During 2012 EuroSIDA has enrolled another cohort of approximately 2500 new HIV-positive patients to ensure that the population followed in the study remains as representative as possible for HIV-positive patients in Europe. In 2012, we have involved 9 new HIV-clinics in Denmark, France, Iceland, Russia, Spain, Switzerland, and Ukraine. EuroSIDA has now published a total of 170 articles in peer-reviewed journals, of which 10 were published in 2012. These articles are the results of activities within EuroSIDA alone or - when relevant - in research collaborations with other cohorts as in the D:A:D, ART-CC, PLATO and COHERE studies. Within the last year EuroSIDA has reported on a diverse area of topics including

mortality, risk of AIDS and non-AIDS disease, risk of death in relation to long-term exposure to antiretroviral therapy, role of HIV drug resistance and of hepatitis B and C (HBV/HCV) co-infection. At the recent 11th International Congress on Drug Therapy in HIV Infection in Glasgow, EuroSIDA had 5 oral presentations on temporal changes and regional differences in HCV seroconversion and HCV treatment, development of advanced chronic or end stage kidney disease, role of immune-virological disorder and drug specific effects on the clinical prognosis at a given CD4 and HIV-RNA level. An important feature of the EuroSIDA study remains the ability to report on regional differences within Europe and Argentina and especially the unique ability to report on the HIV epidemic in Eastern Europe. Of note a 2012 article on regional differences in AIDS and non-AIDS mortality was published as was an article discussing various approaches of bench-marking HV health care allowing comparisons of HIV health care across countries and regions.

TB:HIV

(Tuberculosis among HIV-positive patients: an international prospective observational study) Tuberculosis (TB) among HIV-positive patients continues to be a significant clinical and public health challenge, particularly in resource-limited settings. The TB:HIV study is a scientific non-profit collaboration of TB and HIV clinicians aiming to address yet unanswered questions on the most optimal management of TB/HIV co-infected patients including the influence of resistance to anti-TB therapy and related epidemiological issues. This is the first large international, prospective cohort study on TB/HIV co-infected patients, collecting clinical data on more than 1400 TB/HIV co-infected patients from 15 countries across Eastern Europe, Western Europe and Latin America. The uniqueness of the study is that it collects clinical information on TB/HIV co-infected

Annual Report . 25

TB:HIV study Number of patients enrolled per region. November 2012

no. of patients enrolled

600 500

TB:HIV study Enrolled over time and trend

1200

492

1000

400

706

800

300

600

200

400

145

100

0 Eastern Europe

Western Europe

525 658 415 493

Latin America

200

250

0 Eastern Europe

patients as well as linked bacteriological characterization of Mycobacterium tuberculosis (Mtb). The collected Mtb samples will undergo centralized resistance testing and genotyping and will then be linked to clinical outcome data, allowing for identification of microbial factors impacting on poor disease outcome. The study further seeks to explore the role of biomarkers among HIV-positive individuals with active TB disease. A subproject of plasma sample collection is currently being implemented allowing us to establish a central plasma sample bio-bank and thus address important research questions within the TB/HIV biomarker field. TB/HIV co-infected patients may experience significant differences in health care for many reasons. In order to evaluate and compare health care provided to TB/HIV co-infected patients in different countries and clinics, an online health care survey was sent to all participating sites in November 2012.

26 . CHIP 2012

Western Europe

Latin America

Training

As part of EuroCoord work package 2, CHIP has been actively involved in developing online training modules. Modules on CoDe and HICDEP were both completed in 2012. Additional modules will be developed in 2013, based on results of training assessment surveys which were distributed to clinicians, data managers and statisticians from the four founding networks. Once completed, these modules will be available on the EuroCoord website.

Hepatitis CHIP has addressed hepatitis as part of its HIV co-infection research for almost two decades now. During this time the extent of HIV co-infection with hepatitis B (HBV) and hepatitis C (HCV) has become increasingly better documented. Attention across Europe has intensified on the issue as evidenced by the holding of the first World Hepatitis Awareness Day in 2006 at WHO Europe. Four years later a global resolution on hepatitis was passed by the World Health Assembly, followed by a strategy for countries around the world to better prevent and treat viral hepatitis. CHIP is proud to be the institution undertaking the first global survey on viral hepatitis policy on behalf of the WHO and the World Hepatitis Alliance. This survey will set the baseline for the monitoring of global hepatitis for decades to come. The data generated will also contribute to the writing of the Hepatitis Reader that CHIP is managing for the European HepC Initiative, a new major European Commission project. CHIP, first and foremost, is a clinical research unit. Via our oldest cohort study, EuroSIDA, we are investigating the relationship between HBV resistance, virological failure and the risk of progression of liver disease in HIV/HBV co-infected patients. Although effective HBV treatment has been available for a decade for co-infected patients, many patients in Europe still receive suboptimal therapy that puts them at risk of developing drug-resistant hepatitis B and liver-related complications. In 2012 two of our students sequenced HBV-DNA for drug mutations and measured a liver fibrosis biomarker in plasma samples which will enable us to describe longterm risk factors for liver-related complications in this population. This study is particularly relevant for the millions of HIV/HBV co-infected patients

in resource-limited countries that do not have access to the best anti-HBV drugs. EuroSIDA takes advantage of the detailed HBV and HCV co-infection information collection via the standardized data collection form and the large plasma repository. In 2012, an article reporting on the association between HCV viremia and chronic kidney disease was published, and several other hepatitis subprojects are ongoing at present, including those presented at the European AIDS conference in November as well as above mentioned projects on progression of liver disease in HIV/HBV co-infected patients and the role of HBV resistance to antiviral drugs.

In EuroCoord, the EuroSIDA hepatitis agenda together with the COHERE hepatitis projects (”Sustained virological response in hepatitis C co-infection”, “Effect of NRTI and pegylated interferon in hepatitis C co-infected”, “Hepatocellular carcinoma in HIV patients”) form the Network Portfolio of hepatitis research that CHIP is leading. CHIP has recently explored the incidence of acute HCV, risk groups and regional differences in EuroSIDA, and results were presented at the European AIDS conference in November. Factors associated with the risk of sexual transmission of hepatitis C and the optimal strategy for the treatment of acute HCV are, however, still not well defined. Together with the European AIDS Treatment Network (NEAT), CHIP is participating in the PROBE-C Study which follows HIV-positive patients with acute HCV infection to learn more about risk factors for sexual transmission, the natural history of the infection and to define the best treatment strategy. The results could help in the formulation of better prevention and treatment strategies for hepatitis C. Annual Report . 27

Partner What is the PARTNER Study

The PARTNER study is enrolling couples where one partner is HIV-positive and the other is HIV-negative. This new study is looking at the risks of HIV transmission when someone is taking effective HIV treatment.

The PARTNER study particularly focuses on partnerships that do not always use a condom when having sex. The study is also looking at why condoms are not always used.

Partners of people on ART: a New Evaluation of the Risks

HIV Treatment Sexual Transmission Condom Use

Study Coordinating Centre contact: Tina Bruun, RN

Study Coordinator Copenhagen HIV Programme University of Copenhagen, Faculty of Health Sciences The Panum Institute/Building 21.1 Blegdamsvej 3B 2200 Copenhagen N Denmark tbr@cphiv.dk Tel: +45 35 45 57 57 Fax: +45 35 45 57 58

The PARTNER Study: a new study for sero-discordant couples

HIV Treatment Sexual Transmission Condom Use

www.partnerstudy.eu

For information in your country, please contact:

The aim of the PARTNER study is to estimate transmission risk in partnerships that are not using condoms consistently and where the HIV positive partner is on ART and has a viral load â&#x20AC;š50.

www.partnerstudy.eu

1200

1000

800

600

400

200

10 0

Inclusion by month

As the majority of sero-different couples in studies so far are heterosexual there is a lack of data from observational cohorts or RCTs following sero-different MSM couples to determine risk of HIV transmission through anal intercourse when the HIV-positive partner is on ART. While the PARTNER study contributes data on sero-different couples having condom-less vaginal sex with suppressed VL on ART, the data the study collects following the MSM couples are especially important.

People on ART with low viral load have clearly reduced infectiousness but the extent of the reduction is uncertain. There is increased interest in ART as a prevention tool following the results of the HPTN 052 which showed a reduction in HIV transmission risk due to ART use of 96%; however it still remains unclear what the risk of HIV transmission is with ART when condoms are not used. In most of the studies to date sero-different couples have used both condoms and ART so

nov/12

sep/12

jul/12

may/12

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nov/11

sep/11

jul/11

may/11

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sep/10

28 . CHIP 2012

The PARTNER Study: a new study for sero-discordant couples

the low observed transmission risk is partly due to www.partnerstudy.eu consistent condom use. In the PARTNER study the risk analysis will be done exclusively in partnerships that have unprotected sex and where the HIV positive partner has a viral load â&#x20AC;š50 copies/mL.

As of December 2012 the study has enrolled 879 sero-different couples, 314 of whom are MSM couples.

Cumulative & Goal Inclusion

The PARTNER study is an international collaborative study taking place in several European countries. It is funded by the National Institute for Health Research in England and is coordinated by Copenhagen HIV Programme (CHIP), in collaboration with University College London (the sponsor) and The Royal Free Hampstead NHS Trust, London.

Start

Strategic Timing of AntiRetroviral Treatment

The START study is a randomized controlled trial that will provide critical data about the benefits and risks of starting antiretroviral treatment over 500 cells versus deferring initiation of antiretroviral treatment until the CD4 count is 350 cells/μL.

Hereafter excellent follow-up and adherence to the randomization arms are of great importance in order to be able to answer one of the most important research questions within treatment of HIV/AIDS: when is the right time to initiate ART?

The START study is being conducted at 232 sites in 35 countries across the world. In November 2012 an important milestone was reached, namely the enrollment of patient number 3200 corresponding to 80% of the enrollment goal of 4000 participants in total.

There have been updates to numerous HIV treatment guidelines since the initiation of the START study. These include modifications to guidelines issued by the World Health Organization, as well as country and region specific guidelines in Europe, the United Kingdom, the United States, and Brazil amongst others. While guidelines for initiation of antiretroviral treatment have changed based on information from ongoing studies and on changing expert opinion, it is important to stress that there have been no new data to inform these changes that address the population being studied in START – that is, asymptomatic persons with CD4+ counts over 500 cells and naïve to antiretroviral treatment.

The majority of the established START sites have recruited well and lately countries like India, Uganda and South Africa have contributed successfully to the enrollment numbers. The projected interim recalculation of the sample size was finalized by 15 February 2013 and resulted in a revised sample size of 4600 participants and a follow-up of at least three years for all enrolled participants.

In particular, none of the changes in these guidelines and recommendations are based on new The enrollment rate and expected finalization of data from randomized trials that demonstrate enrollment is illustrated below: improved survival or decreased morbidity in asymptomatic individuals starting therapy 5000 at higher CD4+ counts. 4500 Rather, the most recent4000 ly released data from 3500 HPTN 052, for example, 3000 suggested that delaying 2500 antiretroviral treatment 2000 Observed to when the CD4 count 1500 Projected has decreased to below 1000 250 cells/μl is likely 500 harmful, consistent 0 Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec with current world-wide 2012 2013 consensus. 4600 expected in Dec

CHIP MRC

4000 expected in May

AMC BDX

Annual Report . 29

Teaching and Outreach CHIP continued its tradition of organizing teaching and outreach activities, both within and outside the university system through lectures, conference presentations and the supervision of medical and public health students. In total CHIP staff supervised six medical students, a master thesis of a Human Biology student and five international health masters theses, and chaired a PhD defense committee.

CHIP developed the e-learning module ‘HIVrelated diseases, treatment and care’ which was a successful addition to the Copenhagen School of Global Health’s Master of International Health programme, with participation from students with various educational backgrounds from all over the world. CHIP also contributed to two courses at the Danish Institute for Study Abroad.

Health Systems Global On 3 November 2012, with more than 350 people in attendance, the newly elected board of Health Systems Global launched the world’s first international professional society on health systems research. A leader in global health initiatives In early 2012, CHIP expanded its work to address health systems more explicitly. The first step was a big one: CHIP became a co-founder of Health Systems Global. The creation of the society was inspired by the Montreux Statement (2010), which called on health systems research stakeholders to build a society that would focus on “science to accelerate universal health coverage to build credibility, constituency and capacity”.

Voices” and plenary talks by two ministers of health and WHO’s Assistant Director General on health systems innovation. The central theme was universal health coverage, and important

HS Global, with its 1500 members, sets out to catalyze research and convene researchers, decision-makers and implementers to create and utilize health systems research for improved health systems performance. CHIP hosts the secretariat (led by Professor Jeffrey Lazarus) and, together with an international working group, organized its launch at the Second Global Symposium on Health Systems Research (Beijing, Nov 2012).

consultations such as the role of health in the post-Millennium Development Goal era were debated. Key documents including WHO’s health policy and systems research strategy were launched. Webcasts of the plenary sessions can be viewed via the HSG website: www.healthsystemsglobal.org. HS Global will manage future symposia, including in Cape Town (2014), and engage members as it consolidates its central role in health systems research.

Professor Jeffrey Lazarus at the Beijing Symposium, 2012

The Symposium, which brought together nearly 1800 experts, included more than 190 scientific sessions, the innovative participation of “Emerging

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Annual Report . 31

Acknowledgements After more than 12 years of dedicated service, Karoline B. Jensen, the manager of our monitor function has decided to leave CHIP by the end of 2012. The NĂ¸rrebro Social Psychiatric Centre has been so lucky as to attract Karoline, offering her a staff function with responsibility for implementation of quality standards, monitoring of adverse episodes/events and development of health related aspects of the operation of housing institutions and day centres in collaboration with the centre management and the management at the single institutions. It is a new position and part of the focused effort for the group of people that often are in need of the most care and attention. We and the INSIGHT network will miss Karoline; she has worked very diligently and collaborated with great commitment whilst developing and maintaining the CHIP spirit. We wish Karoline all the best and are sure she will keep in touch so we do not risk sliding off our cultural base. Justyna Kowalska finalized her research education and returned to her base in Warsaw. We have been very pleased to be able to contribute to the education of a young researcher such as Justyna. We have benefitted not only from Justynaâ&#x20AC;&#x2122;s research effort and achievements (especially her streamlining of the CoDe initiative) but also from her knowledge of local and regional conditions, cultural and political differences. We are certain that the team in Warsaw now benefits from the competences Justyna developed and we are confident that they will contribute to building even stronger bonds between CHIP and Andrzej Horbanâ&#x20AC;&#x2122;s site and staff in Warsaw.

32 . CHIP 2012

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.

Publications 1 Evaluation of HIV protease inhibitor use and the risk of sudden death or nonhemorrhagic stroke. SW Worm, DA Kamara, P Reiss, E Fontas, S De Wit, W El-Sadr, A D´Arminio Monforte, M Law, A Phillips, L Ryom, NF Dabis, R Weber, C Sabin, JD Lundgren on behalf of the D:A:D Study Group. J Infect Dis. 2012 Feb;205(4):535-9. 2 Projected life expectancy of people with HIV according to timing of diagnosis. F Nakagawa, RK Lodwick, CJ Smith, R Smith, V Cambiano, JD Lundgren, V Delpech, AN Phillips. AIDS. 2012 Jan 28;26(3):335-43. 3 Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes : A cohort study. D Costagliola, R Lodwick, B Ledergerber, C Torti, A van Sighem, D Podzamcer, A Mocroft, et al. The Pursuing Later Treatment Option II (PLATO II) project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Group. Lancet Infect Dis. 2012 Jan 28;26(3):315-323. 4 Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy. JD Kowalska, J Reekie, A Mocroft, P Reiss, B Ledergerber, J Gatell, AD Monforte, A Phillips, JD Lundgren, O Kirk; for the EuroSIDA Study Group. AIDS. 2012 Jan 28;26(3):315-32. 5 Dampening the effect of drug resistance in HIV: a leap forward. JD Lundgren, JV Lazarus. Lancet Infect Dis. 2012 Feb;12(2):91-2.

34 . CHIP 2012

6 CD4 cell count and the risk of AIDS or death in HIV-infected adults on cART with a suppressed viral load: A longitudinal cohort study from COHERE. J Young, M Psichogiou, L Meyer, S Ayayi, S Grabar, F Raffi, P Reiss, B Gazzard, M Sharland, F Gutierrez, N Obel, O Kirk, JM Miro, H Furrer, A Castagna, S De Wit, J Muñoz, J Kjær, C Colin, J Grarup, G Chêne, H Bucher. PLoS Med. 2012 Mar;9(3):e1001194. 7 All-cause mortality in treated HIV-infected adults with CD4 ›=500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. C Lewden, V Bouteloup, S De Wit, C Sabin, A Mocroft, JC Wasmuth, A van Sighem, O Kirk, N Obel, G Panos, J Ghosn, F Dabis, M Mary-Krause, C Leport, S Perez-Hoyos, P Sobrino-Vegas, C Stephan, A Castagna, A Antinori, A d’Arminio Monforte, C Torti, C Mussini, V Isern, A Calmy, R Teira, M Egger, J Grarup, G Chêne. Int J Epidemiol. 2012 Apr;41(2):433-445. 8 Partners of people on ART - a New Evaluation of the Risks (The PARTNER study): design and methods. A Rodger, A Phillips, T Bruun, M Weait, P Vernazza, S Collins, V Estrada, J Van Lunzen, GM Corbelli, J Lundgren. BMC Public Health. 2012 Apr 20;12(1):296. 9 HIV Therapies and the Kidney: Some Good, Some Not So Good? L Ryom, A Mocroft, JD Lundgren. Curr HIV/AIDS Rep. 2012 Jun;9(2):111-20.

10 The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI(*). A Cozzi-Lepri, R Paredes, AN Phillips, B Clotet, J Kjaer, V Von Wyl, G Kronborg, A Castagna, Jr Bogner, JD Lundgren for EuroSIDA in EuroCoord. HIV Med. 2012 Jan;13(1):62-72. 11 HIV in men who have sex with men in sub-Saharan Africa. ML Sabin, JV Lazarus, L Frescura, W Gill, M Mahy. Lancet Infect Dis. 2012 Jul;12(7):505-6. 12 Population mobility and the changing epidemics of HIV-2 in Portugal. A Carvalho, E Valadas, T Branco, MJ Aleixo, J Mendes, M Doroana, R Marques, C Carvalho, MJ Águas, A Sarmento, R Sarmento e Castro, F Antunes, JV Lazarus, H Barros. HIV Med. 2012 Apr;13(4):219-25. 13 Mapping Global Fund investments in harm reduction from 2002 to 2009. J Bridge, BM Hunter, R Atun, JV Lazarus. Int J Drug Policy. 2012 July;23(4):279-85. 14 Regional differences in AIDS and non-AIDS related mortality in HIV-positive individuals across Europe and Argentina: The EuroSIDA Study. J Reekie, JD Kowalska, I Karpov, J Rockstroh, A Karlsson, A Rakhmanova, A Horban, O Kirk, JD Lundgren, A Mocroft; for EuroSIDA in EuroCoord. PLoS One. 2012;7(7):e41673. 15 “E” is for everything else, not least for expanding HIV testing in Europe. JV Lazarus, JD Lundgren. Bulletin World Health Organ. 2012;90:634-634A.

16 HIV replication, inflammation, and the effect of starting antiretroviral therapy on plasma asymmetric dimethlarginine, a novel marker of endothelial dysfunction. JV Baker, J Neuhaus, D Duprez, M Freiberg, JI Bernardino, AD Badley, DE Nixon, JD Lundgren, RP Tracy, JD Neaton; INSIGHT SMART Study Group. J Acquir Immune Defic Syndr. 2012 Jun 1;60(2):128-34. 17 Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. JU Jensen, L Hein, B Lundgren, MH Bestle, T Mohr, MH Andersen, KJ Thornberg, J Løken, M Steensen, Z Fox, H Tousi, P SøeJensen, AO Lauritsen, DG Strange, N Reiter, K Thormar, PC Fjeldborg, KM Larsen, NE Drenk, ME Johansen, LR Nielsen, C Ostergaard, J Kjær, J Grarup, JD Lundgren; The Procalcitonin And Survival Study (PASS) Group. BMJ Open. 2012 Mar 11;2(2). 18 Health Systems Global, the new international society for health systems research. D Kraushaar, MP Kieny, JV Lazarus, R Bermejo 3rd, S Abimbola, N Prashanth, W Flores, F Ssengooba, D Maceira. Health Policy Plan. 2012 Oct;27(7):535-40. 19 Predicting the short-term risk of diabetes in HIV-positive patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. K Petoumenos, SW Worm, E Fontas, R Weber, S De Wit, M Bruyand, P Reiss, W El-Sadr, A d’Arminio Monforte, N Friis-Møller, JD Lundgren, MG Law on behalf of the D:A:D Study Group. Journal of the International AIDS Society 2012, 15:17426.

Annual Report . 35

20 Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. R Weber, M Ruppik, M Rickenbach, A Spoerri, H Furrer, M Battegay, M Cavassini, A Calmy, E Bernasconi, P Schmid, M Flepp, J Kowalska, B Ledergerber and the Swiss HIV Cohort Study (SHCS). HIV Med. 2012 Sep 24. 21 Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. DA Duprez, J Neuhaus, LH Kuller, R Tracy, W Belloso, S De Wit, F Drummond, HC Lane, B Ledergerber, J Lundgren, D Nixon, NI Paton, RJ Prineas, JD Neaton for the INSIGHT SMART Study Group. PLoS One. 2012;7(9):e44454. 22 Benchmarking HIV health care: from individual patient care to health care evaluation. An example from the EuroSIDA study. D Podlekareva, J Reekie, A Mocroft, M Losso, A Rakhmanova, E Bakowska, IA Karpov, JV Lazarus, J Gatell, JD Lundgren, O Kirk. BMC Infect Dis. 2012 Sep 25;12(1):229. 23 HCV viremia increases the incidence of chronic kidney disease in HIV-infected patients. L Peters, D Grint, JD Lundgren, JK Rockstroh, V Soriano, P Reiss, A Grzeszczuk, H Sambatakou, A Mocroft, O Kirk; for EuroSIDA in EuroCoord. AIDS. 2012 Sep 24;26(15):1917-1926. 24 Long-term effects of intermittent IL-2 in HIV infection: Extended follow-up of the INSIGHT STALWART Study. N Markowitz, G Lopardo, D Wentworth, D Gey, A Babiker, L Fox, J Tavel; STALWART Study Group. PLoS One. 2012;7(10):e47506.

27 System to classify cause of deaths in HIV-positive persons: time to harmonize. JD Kowalska, C Smith, JD Lundgren. AIDS. 2012 Sep 10;26(14):1835-6. 28 The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1infected patients with and without complete viral suppression. A Mocroft, WP Bannister, O Kirk, JD Kowalska, P Reiss, A dâ&#x20AC;&#x2122;Arminio Monforte, J Gatell, M Fisher, H Trocha, A Rakhmanova, JD Lundgren; the EuroSIDA Study in EuroCoord. Antivir Ther. 2012;17(7):1291-1300. 29 Key barriers affecting the use of modern contraceptives among women in Albania - a qualitative study. KK Nielsen, SF Nielsen, R Butler, JV Lazarus. Reproductive Health Matters. 2012;20(40):160-167. 30 Making the first global society for health systems research truly global. JV Lazarus, D Balabanova, M McKee. Cent Eur J Public Health 2012; 20 (4): 299-304. 31 Collaboration in the provision of mental health care services: a cross-sectional survey of Lithuanian general practitioners. L Jaruseviciene, JV Lazarus, N Zemaitiene, G Jarusevicius, L Valius. Healthmed. 2012; 6(5):1583-1589. 32 A study of antibiotic prescribing: the experience of Lithuanian and Russian GPs. L Jaruseviciene, R Radzeviciene, JV Lazarus, A Jurgutis, I Ovhed, EL Strandberg, L Bjerrum. Central European Journal of Medicine. 2012 (6 September 2012), pp. 1-10.

25 Refinement of prompts for rapid response teams. JU Jensen, M Bestle, JD Lundgren. Crit Care Med. 2012 Jul;40(7):2241-2. 26 Aging with HIV in Africa: the challenges of living longer. J Negin, T BĂ¤rnighausen, JD Lundgren, EJ Mills. AIDS. 2012 Jul31;26 Suppl 1:S1-5.

Annual Report . 37

Presentations

11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012, Glasgow Oral 1 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 Jetovic, V Soriano, JD Lundgren, JK Rockstroh, O Kirk, A Mocroft for EuroSIDA in EuroCoord. 2 CD4 count and viral load specific rates of AIDS, non-AIDS and deaths according to current antiretroviral use. A Mocroft, A Phillips, J Gatell, A Horban, B Ledergerber, K Zilmer, D Jevtovic, F Maltez, O Kirk, JD Lundgren et al for the EuroSIDA study in EuroCoord. 3 Increases in acute hepatitis C (HCV) incidence across Europe: which regions and patient groups are affected? JK Rockstroh, D Grint, C Boesecke, V Soriano, JD Lundgren, A dâ&#x20AC;&#x2122;Arminio Monforte, VM Mitsura, O Kirk, A Mocroft and L Peters for EuroSIDA in EuroCoord. 4 Immuno-virological discordance (ID) is associated with a higher frequency of fatal and non-fatal AIDS and non-AIDS. A Zoufaly, A Cozzi-Lepri, O Kirk, JD Lundgren, P Reiss, D Jetovic, L Machala, R Zangerle, A Mocroft, J van Lunzen on behalf of EuroSIDA in EuroCoord. 5 Advanced chronic kidney disease, end-stage renal disease and renal death in HIV-positive individuals in Europe. L Ryom, O Kirk, JD Lundgren, C Pedersen, P Reiss, S De Wit, S Buzunova, J Gasiorowski, JM Gatell and A Mocroft on behalf of EuroSIDA in EuroCoord. Poster 1 Impact of antiretroviral therapy (ART), viraemia and immunosuppression on lipid levels: the D:A:D Study. DA Kamara, C Sabin, P Reiss, M Rickenbach, C Smith, S De Wit, M Law, A Mocroft, C Pradier, JD Lundgren.

XXXIII Nordic Congress in Clinical Chemistry, June 12th - 15th 2012, Reykjavik Oral Procalcitonin use in infections in different settings - The need for clinical trials. JU Jensen.

38 . CHIP 2012

52nd ICAAC, San Francisco, September 2012 Oral The time course of development and impact from viral resistance against ganciclovir in cytomegalovirus infection complicating course after transplantation. C da Cunha-Bang. Poster Evaluation of novel programme aimed at reducing the risk of severe viral infections including cytomegalovirus, following solid organ transplantation. C da Cunha-Bang, N Kirkby, SS Sørensen, M Iversen, H Sengeløv, A Rasmussen, F Gustafson, J Hilsted, J Kjær, RS Brandt, C Matthews, L Peters, O Kirk, J Grarup, JD Lundgren.

XIX International AIDS Conference, Washington DC, July 2012 Oral 1 Characteristics of individuals with HIV presenting late for care across Europe. JD Lundgren for the Late Presenters working group of COHERE in EuroCoord. 2 Trends over time in underlying causes of death in the D:A:D study from 1999 to 2011. CJ Smith, L Ryom, R Weber, P Morlat, C Pradier, P Reiss, J Kowalska, N Friis-Møller, AN Phillips, CA Sabin, JD Lundgren for the D:A:D Study Group. 3 The START Trial: On the shoulders of SMART. JD Lundgren. Poster 1 Factors associated with elevated D-dimer levels in HIV-positive individuals. A Borges, J O’Connor, A Phillips, J Baker, M Vjecha, M Losso, H Klinker, G Lopardo, I Williams, JD Lundgren for the INSIGHT SMART, ESPRIT and SILCAAT Study Groups.

XIX International Workshop on Co-morbidities and Adverse Drug Reactions in HIV, Washington DC, July 2012 Oral 1 Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. A Borges, MJ Silverberg, D Wentworth, A Grulich, G Fätkenheurer, R Mitsuyasu, G Tambussi, C Sabin, J Neaton, JD Lundgren for the INSIGHT SMART, ESPRIT and SILCAAT Study Groups.

Annual Report . 39

19th Conference on Retroviruses and Opportunistic Infections, Seattle, March 2012 Oral 1 Non-AIDS defining malignancies (NADM) and immunosuppression: The D:A:D study. SW Worm, M Bower, P Reiss, A Grulich, E Fontas, F Bonnet, G Faetkenheuer, M Law, A Phillips, HJ Furrer, W El-Sadr, O Kirk, L Ryom, D Abrams, A D’Arminio Monforte, S De Wit, C Sabin, JD Lundgren on behalf of the D:A:D Study Group. Poster 1 Exposure to antiretrovirals (ARVs) and the risk of renal impairment among HIV+ persons with normal baseline renal function: the D:A:D Study. L Ryom, A Mocroft, SW Worm, DA Kamara, P Reiss, M Ross, C Fux, P Morlat, O Moranne, C Smith, O Kirk and JD Lundgren on behalf of the D:A:D Study Group. 2 Atazanavir (ATV)-containing antiretroviral treatment is not associated with an increased risk of cardio- or cerebro-vascular events (CVE) in the D:A:D study. A d’Arminio Monforte, P Reiss, L Ryom, W El-Sadr, F Dabis, S De Wit, SW Worm, A Phillips, JD Lundgren, and C Sabin. 3 Associations between markers of immunosuppression and the risk of cardiovascular disease (CVD): the D:A:D study C Sabin, SW Worm, M Law, W El-Sadr, P Reiss, M Bruyand, E Fontas, A d’Arminio Monforte, R Weber, O Kirk, S de Wit, JD Lundgren on behalf of the D:A:D Study Group. 4 The effect of interleukin-2 in HIV-1 patients with HBV and HCV co-infection: Associations between fibrosis biomarkers at baseline and clinical outcomes in the ESPRIT study. L Peters, S Bhagani, M Klein, JD Lundgren, N Markowitz, V Soriano, J Rockstroh, J Neaton, W Stohr, D Dunn, M Danta, C Boesecke, P de la Torre, F Zamora, M Landrum, E Page, S Rizza, A Rodger, D Wentworth for the INSIGHT ESPRIT Study Group.

40 . CHIP 2012

Financial Contributors 2012 Study/activity EuroSIDA

D:A:D

Public EU Commission

Private Bristol-Myers Squibb GlaxoSmithKline Merck & Co Inc Pfizer Inc Tibotec/Janssen Research & Development, Pharmaceutical Companies of Johnson & Johnson The Oversight Committee for The Evaluation of The Oversight Committee sponsors: Metabolic Disorders of HAART Abbott Laboratorie EMeA Boehringer-Ingelheim Pharmaceuticals Inc FDA Bristol-Myers Squibb Gilead Sciences GlaxoSmithKline Merck & Co Inc Pfizer Inc Roche Pharmaceuticals Tibotec/ Janssen-Cilag International NV

INSIGHT Network INSIGHT START

National Institutes of Health, USA (NIH) 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

INSIGHT FLU NEAT

NIAID, NIH EU Commission

Monitoring Medicines, WHO TB:HIV

EU Commission EU Commission

EUROCOORD-CHAIN COHERE PARTNER

EU Commission EU Commission National Institute for Health Research, UK (NIHR)

Health Systems Global (CHIP is secretarial) Public health consultancies

WHO

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

Study drug sponsors: Gilead Sciences Janssen-Cilag International NV Abbott Laboratories Ltd Merck Inc. Bill & Melinda Gates Foundation Mærsk McKinney Møller og hustru Chastine McKinney Møller’s Fond til almene Formaal Gilead Sciences

Rockefeller Foundation

UNICEF: Children and AIDS: 6th Stocktaking Report The World Hepatitis Alliance: Global Hepatitis Strategy Review

Annual Report . 41

Study/activity IWHOD

Public NIH Office of AIDS Research

Private Boehringer-Ingelheim Pharmaceuticals Inc ANRS, Agence nationale de recherches sur le Gilead Sciences GlaxoSmithKline sida HCDCP (Hellenic Centre for Disease Control & Pfizer Inc Roche Pharmaceuticals Prevention) Tibotec/ Janssen-Cilag International NV

HIV in Europe

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

CASS PASS and derived projects

COM:PASS

42 . CHIP 2012

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

Danish Research Council Capital Region of Denmark

The Idella Foundation Lundbeckfonden Mærsk McKinney Møller og hustru Chastine McKinney Møller’s Fond til almene Formaal Lundbeckfonden

Copenhagen University Hospital & University of Copenhagen Copenhagen HIV Programme 路 Faculty of Health Sciences The Panum Institute/Building 21.1 Blegdamsvej 3B 2200 Copenhagen N Denmark

Printed in Denmark by Kandrup

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