Annual Report 2008 Table of Content

ANNUAL REPORT 2008 TABLE OF CONTENT

ISM WELCOMES CHIP 3 FROM THE DIRECTOR 5 GLOBAL COLLABORATION 8 WHO HIV INFORMATION WEBSITE 12 ORGANISATION 14 QUALITY MANAGEMENT 18 EDUCATION 20 BIOINFORMATICS 22 RANDOMISED CLINICAL TRIALS 23 INTERLEUKIN-2 STUDIES 24 ESPRIT 25 SILCAAT 26 STALWART 27 START 28 SMART 30 PASS 33 OBSERVATIONAL STUDIES 36 EUROSIDA 36 D:A:D 39 PROJECTS 43 THE CODE PROJECT 44 COHERE 46 HIV/TB PROJECT 47 EuroCOORD 48 ACTIVATE 49 NEAT 49 DISSERTATIONS IN 2008 50 FUNDING 53 ACKNOWLEDGEMENTS 55 AWARDS 55 OTHER CHIP ACTIVITES 56 PUBLICATIONS 2008 58 PRESENTATIONS 2008 61 ISIM welcomes CHIP

CHIP has now for little more than a year been a member of the colourful family at the Department of Interna- tional Health, Immunology and Microbiology. CHIP has added further to the strong research profile of ISIM and we appreciate CHIP’s impressive production that contributes to fulfill the vision of ISIM “to become a centre of excellence uniquely bridging research and education in the basic sciences of immunology, virology and microbiology with clinical and global health applied sciences, augmenting research outcome by collaboration”.

CHIP quickly engaged in collaboration with ISIM colleagues to develop a Master in HIV education. We look forward to CHIP’s development into the field of teaching and capacity building. Welcome to ISIM.

Carsten Geisler Head of Department

3 4 FROM THE DIRECTOR

The dean of the University of Copenhagen and the I would like to thank all staff at CHIP for their pro- medical director of Rigshospitalet (Copenhagen Uni- fessional attitude and commitment to ensure that versity Hospital) inaugurated the new CHIP offices the focus of CHIP – to improve the handling of infec- at the Panum Institute in November 2007. The CHIP tious diseases in general and HIV in particular – has staff eagerly occupied the completely renovated offi- been and will continue to be maintained. ces - designed to match the Institute and the needs of CHIP - ready to enter a new era of the research CHIP has progressed on many fronts in the last 1-2 group’s history. Two months earlier, we had to leave years. These are described in detail in this annual Hvidovre Hospital in a hurry – after having worked report, but allow me to emphasise some of them: there for 20 years – and were temporarily housed in a vacated building close to the Panum Institute. The Clinical research has to involve the conduct of ran- 30th November 2007, when we moved in to our new domised controlled trials. offices, was indeed a lovely day, and we are conti- CHIP has been heavily involved in further analysis nuously grateful to the University and to Rigshospi- of the data from the SMART trial, where follow-up talet for allowing this to happen. was completed in 2007. Three years ago the SMART results were unblinded and we expect that the num- Despite the “logistical turmoil” experienced by CHIP, ber of articles will at least be doubled in the next 1-2 the group was not thrown into “research turmoil”. years from the current tally of 30 articles. As a matter of fact, the research has never been as The ESPRIT Study was initiated in 1999, and follow- productive as it has been in the last couple of years. up was completed on 15th November 2008. The un- It continues to amaze me how critical key people, blinding of the results will occur in Buenos Aires in and how these people interact, are to whether early January 2009 – 10 years to answer a research research becomes productive or not. CHIP has been question and 2 minutes to hear the answer, but fortunate to attract unique persons with a drive that what a treat: “Those two minutes encapsulate what makes things happen and sees things through. research is all about”.

Of note, it is my strong belief that the temporal The PASS study has been another impressive achie- relationship between logistical turmoil and improvement – more than 950 patients have been rando- vement in research productivity has not been causal mised from 8 intensive care units across Denmark – rather, the fact that research productivity did not – an unprecedented academic collaboration; we will deteriorate merely shows the steadfast determinati- see the results of the PASS study in 2009. on to ensure that circumstances outside our control should not influence the purpose for why we work In 2009, the “Strategic Timing of Antiretroviral Treat- in the first place. A high price to pay, you may say- ment (START)” study will be initiated; the first (and and certainly in 2008, the cost has come in various likely the only) randomised clinical trial that will shapes and sizes. place the critical, strategic question: “When to start antiretroviral therapy?”. This question has been

5 debated and has caused controversy ever since the We have initiated this already, and will continue to first antiretroviral drugs became available in the end do so in the years to come. CHIP fully supports the of the 1980s – and now we have the chance to do vision of creating a “Copenhagen School of Global a randomised clinical trial to answer this question Health” together with our colleagues at the de- properly. An additional bonus is that the rationale partment of International Health, Immunology and for START derives from research-findings that CHIP Microbiology (ISIM). This school will create a com- either contributed to or led. prehensive educational platform for graduates from around the world. Only by continually expanding on The European HIV trials network (NEAT) will hopeful- this vision can we truly rely on low-resourced parts ly also in 2009 get its first trials underway. of the world being fully capable of developing their health infrastructure. The CHIP contribution to the The D:A:D study aroused the most excitement in vision is expertise in viral diseases and clinical re- 2008. Much to our surprise a new set of analysis of search methodology related to infectious diseases. this large collaborative project - initiated in 1999 - CHIP is e.g. working on the initiation of a “Master in demonstrated that the antiretroviral drug abacavir HIV”. Hopefully, resources will become available to was associated with an excess risk of cardiovascular support the vision. disease. We (and many others) did not believe this, but subsequent studies supported the finding, and Our collaboration with the WHO continued in 2008. various treatment guidelines have consequentially CHIP has participated in various meetings at WHO used this observation to change their advice. The headquarters and at regional levels. A publication abacavir story encapsulates what CHIP wants to in the Lancet on how to best monitor the effects of achieve. antiretroviral therapy in a poorly resourced environment started considerable discussion. In 2008 the EuroSIDA continues to produce a steady number of Gates Foundation and the European Commission publications. EuroSIDA extended its collaboration decided to fund a WHO-led development of phar- to involve hospitals in the Eastern region of Europe macovigilance research infrastructure in resource some 10 years ago and this has been a major asset. limited settings. CHIP will continue to support and Good and trusted collaborative relationships have contribute to these activities. Through the D:A:D been established and now facilitate new projects, study, CHIP is involved in similar projects with the e.g. the study of the negative interaction between European Medicines Evaluation Agency (EMEA). HIV and tuberculosis. In 2009 EuroSIDA will enter as one of 5 partners in a joint application to the Recently, CHIP has focused on a major question - European Commission under the working name how to reduce the number of persons infected but “EuroCOORD”. not yet diagnosed with HIV. In Europe (including Eastern Europe), half of the HIV-infected persons As CHIP is now part of the University of Copenha- fall into this category. The University of Copenhagen gen we are required to reach out to the educational co-chaired a meeting on early diagnosis and care component of the activities within the institution. for HIV-infected persons across Europe in November

6 2007. CHIP has subsequently followed up on this CHIP is related to Rigshospitalet in other ways, initiative in collaboration with European patient-ad- more specifically to the department of clinical vocacy groups and policy makers. A major achieve- microbiology (centre for viral diseases (CVD)) and to ment was the adoption by the European Parliament the department of infectious diseases. Attempts to of a resolution on the exact action points we had establish fruitful research collaborations to better identified. The adoption of the resolution took place understand viral disease management post-trans- on the 19th November 2008 by the vote of 480 for plantation have been the main focus. and 4 against (!). The main focus is now to hold the politicians accountable for the resolution´s trans- The future of CHIP is going to be interesting to formation into action. To assist and support this follow. In research, and in particular in research process, a European steering committee, co-chaired funded 100% from international sources, the future by CHIP, has been formed. The new projects include entirely depends on being able to continue to raise the creation of further evidence for how best to use new funds for new projects. This is done in direct the concept of “indicator-disease” guided testing competition with other international institutions. for HIV; better understanding of the adverse con- CHIP has benefited from this competition in the sequences of the expanded legislation across the last decade; it has allowed us to focus on the best continent that criminalises behaviour once a person research and our research productivity reflects that. is diagnosed HIV positive; and how best to reduce This strategy requires a lot of energy and momen- other non-governmental types of stigmatisation of tum in the group - and a lot of hours in airplanes. HIV positive persons. But most of all it requires “presence, focus, strategic planning and “rettidig omhu”” – virtues the A fully effective HIV vaccine will not be available any CHIP management team will continue to cultivate. time soon, and there is an urgent need to develop other new concepts for prevention. Men can protect themselves and their partner by using a condom Jens D. Lundgren and being circumcised, but women have no protec- Director of CHIP tive strategy of which they have sole control. Use of antiretroviral drugs in un-infected persons to prevent them from being infected is a possibility; either by taking a pill (and hence be systematically exposed to the drug), or by applying technologies to ensure a sufficient concentration of the drug in the vagina. CHIP will pursue the latter in collaboration with the department of gynaecology at Rigshospita- let and the International Partnership for Microbici- des (IPM).

7 GLOBAL COLLABORATION

The foundation of CHIP is to perform scientific Our other global collaborations include: research to improve patient care and outcome. In a small country like Denmark, this would not be EuroSIDA (p. 36) has been funded by the European possible without strong, professional, and collegial Commission since 1990, and has secured funding international collaboration. under Framework Programme 6 until February 2010. The EuroSIDA study group published its 100th CHIP has a history of successful collaborations and publication in peer-reviewed journals in September the list of contributing investigators, institutions, 2008! The EuroSIDA study is collecting data on over and countries is long. It is this dynamic interchange 10,000 patients twice annually in over 90 centres in between specialists and experts in the field that Eastern and Western Europe. drives the research process. D:A:D (p. 39) The D:A:D study has received support The research accomplishments at CHIP are a true from the Oversight Committee for Metabolic Compli- collaborative effort. CHIP has a combined network cations – an international syndicate of pharma- of over 100 investigators in 35 countries worldwide. ceutical companies, regulatory authorities, patient Some of these collaborations are well-established advocacy groups and academia – since 1999. In (for example the INSIGHT and D:A:D networks) December 2008, the study received funding until and some are new (for example the 9 new centres 2013 (thus including the 13th Merger). recently established in EuroSIDA). “International Network for Strategic Initiatives in CHIP has been fortunate in 2008 to begin some col- Global HIV Trials” (INSIGHT) is funded by the Na- laborations which we hope to continue in the future. tional Institutes of Allergy and Infectious Diseases, The 1st International ACTIVATE Course was held in National Institutes of Health from 2006-2011. The Minsk, Belarus, September 12-13th, 2008. Over 50 INSIGHT global network is responsible for conduc- participants from 15 Eastern European countries at- ting the SMART (p. 30), ESPRIT (p. 25), STALWART (p. tended the course in the beautiful city of Minsk. The 27) and START (p. 28) studies. CHIP serves as one of course was organised by CHIP together with our col- four international coordinating centres with over 50 leagues in Minsk, Igor Karpov and Anna Vassilenko. European centres. This course was significant in that it was comprised of short lectures from experts in the field as well as “The Network of European AIDS Treatment” (NEAT) small group sessions where delegates presented is funded by the European Commission from 2006 their own clinical cases for discussion with ex- - 2010. A total of 37 partners constitute NEAT, of pert colleagues. All sessions were conducted with which CHIP is one. CHIP serves as convener on the simultaneous Russian-English translation. The NEAT task for “ARV toxicity, complications of HIV infec- network awarded a teaching and education grant to tions” within the research work package and co- give financial scholarships to 50 participants to at- chairs the work package on EU networking. tend the day-and-a-half course. We hope to be able to repeat the success in Minsk again in 2009!

8 “The Collaboration of Observational HIV Epidemio- World Health Organisation (WHO) logical Research Europe” (COHERE) Formed in 2005, In addition to these internal research collabora- this European collaboration of adult and paediatric tions, CHIP has continued its long tradition of cohorts has data on over 200,000 HIV-infected engaging in collaboration with the WHO on various persons. The principle of collaboration is to conduct levels. In March 2008, the European Commission fa- epidemiological research on the prognosis and vourably reviewed a WHO application in which CHIP outcome of HIV-infected people and to focus on is a partner on workpackages looking at an informa- questions, requiring a large sample size of patients, tion repository and HIV-related pharmacovigiliance which the contributing cohorts cannot answer work in Europe. Additionally, throughout 2008, CHIP individually and which do not overlap with existing has been working with the WHO to establish closer collaborations. and more formal links.

EuroCOORD HIV in Europe 2008: Priorities and Vision EuroCOORD activities in 2008 were focused on In late November 2007, AIDS Action Europe and establishing a legal entity for the partners (CA- WHO Europe came together to organise a pan- SCADE, COHERE, EuroHIVResistance, EuroSIDA, and European conference entitled “HIV in Europe 2007: PENTA) and establishing an application steering Working together for optimal testing and earlier committee. The EuroCOORD group has moved seve- care” in anticipation of World AIDS Day 2007. For the ral collaborative projects forward in 2008, including first time, key pan-European HIV stakeholders inclu- ACTIVATE and CHAIN, as well as the coordination of ding advocates, clinicians and public health profes- the International Cohort Workshop. sionals as well as policy makers were convened to debate and take action in addressing critical issues Cohorts Workshop (International Workshop on HIV around HIV testing and care in a European setting. Observational Databases—IWHOD) In 2008, EuroCOORD, in partnership with the scientific committee of the IWHOD, began the process of taking over the organisation and administration of the IWHOD. The cohort workshop involves cohorts from Europe, Australia, North America and resource limited countries. The presented data at this workshop is not made public, thereby allowing for discussion of work-in-progress. The financial administration of the workshop has been established as an independent foundation in Copenhagen and the workshop secretariat is in Bordeaux.

9 To continue the momentum from this unprece- • Improvement in surveillance data. Legislation dented collaboration, this group outlined and was made in Italy in July 2008 that removed legal moved forward on the activities for 2008 which barriers for providing surveillance data to the included: European Centre for Disease Prevention and Con- trol, ECDC and WHO Europe and the ECDC has • Publishing conference proceedings in the peer- also rectified issues in Spain that prevented that reviewed journal HIV Medicine as a supplement country from submitting their data. in July 2008. • Release of testing guidelines. A first set of • A roundtable discussion in September 2008 indicator diseases have been released on the at the European Parliament with the EU Health European AIDS Clinical Society (EACS) web site Commissioner and several senior European Par- (http://www.eacs.eu/guide/index.htm). Lack of liament members. The outcome of the meeting opt-out testing of pregnant women was identi- was the formulation of a resolution, which was fied at the conference in several countries, and then adapted by the European Parliament on 19 a number of these have now modified national November 2008. testing guidelines to implement this (Denmark • Supporting national organisations to roll out for one). The British HIV Association released the national and/or regional activities as a follow-up first comprehensive national testing guidelines to the conference. in September 2008 (http://www.bhiva.org/ cms1222621.asp).

10 Focus on Early Diagnosis and Testing

Most patients living with HIV across the European Region remain undiagnosed; although the percen- tage of infected yet undiagnosed varies markedly from 15-80% depending on the country. Undiagnosed HIV is harmful to the person infected (as appropiate HIV-specific health interventions per definition are delayed until the HIV infection is diagnosed) and to society (as persons unaware of their HIV infection may transmit more frequently to others than persons that are aware of their HIV status).

A large proportion of persons continue to enter health care very late in the course of their chronic HIV infection throughout Europe. This situation has remained stationary for the last several years, without evidence of improvement.

Surveillance to identify the exact extent of the problem remains insufficient across Europe. Model-based tools to quantify the size of the “undiagnosed” population have yet to be developed for the European Region, although some countries have models to quantify the size within their borders. Finally, a technical issue is that a common definition has not been established for when a person enters care too late (late presenters), although the conference outlined the current sets of definitions applied in the literature.

In most Western countries, a large proportion of men who have sex with men (MSM) remain untested for HIV. Testing is not accepted as part of a comprehensive and routine health care approach. Persons from high-HIV-endemic areas of the world immigrating to Western Europe are only infrequently tested, despite several of the European countries are offering testing at the time of entry.

Multiple factors that may serve as obstacles for more widespread testing of at-risk groups include: • Lack of access to care for persons found HIV positive; • Persistent stigma and fear of discrimination associated with HIV infection; • Criminalisation of HIV infection; • Concern about reduced counselling for primary HIV prevention if testing is carried out more widely; • Lack of committed political interest; • Lack of research to guide rational increases in testing.

CHIP remains committed to address this important public health issue and is focusing on how we can best contribute to improve early testing and diagnosis among HIV-positive people. In 2008, several projects were initiated in this area and we anticipate more activity in the first half of 2009.

11 WHO HIV INFORMATION WEBSITE

Risk Score Calculation Tools

The CHIP website currently holds three different by Kathy Petoumenos at the 9th International Con- risk score calculators: The Framingham risk equa- gress on Drug Therapy in HIV Infection in Glasgow, tion calculator for calculating risk of cardiovascular Scotland in November 2008. The presentation was disease, the EuroSIDA risk score for estimating entitled: ”Predicting the short term risk of diabe- short clinical disease progression for HIV-1 posi- tes in HIV infected patients in the D:A:D cohort: tive patients on combination antiretroviral therapy The D:A:D study group”. It was also presented as a and the GFR/MDRD calculator to estimate glome- poster at the 14th Conference on Retroviruses and rular filtration rate/creatinine clearance. Opportunistic Infections in Los Angeles, USA in February 2007 with the title: ”Predicting the risk The website address is: of coronary heart disease (CHD) in HIV-infected http://www.cphiv.dk/tools.aspx. patients: The D:A:D CHD risk equation”. When the tools have been validated and the papers have The tools are currently listed in the ”Guidelines been published, the tools will be available on the for the Clinical Management and Treatment of CHIP website. HIV-infected Adults in Europe” published by the European AIDS Clinical Society (EACS). Following this, a website will be developed together with WHO that integrates these tools into New tools will be made publicly available in 2009 a portal that will provide these tools to healthcare based on new publications. The first presentation professionals and, in addition, be an information of research behind these new tools was presented site for providing treatment guidelines.

12 ORGANISATION ORGANISATION

CHIP has a solid organisation shaped to support its activities. Besides a strong scientific group, CHIP has a relatively large yet dynamic operational and administrative staff to secure the efficient implementation and coordination of sites, regulatory work, data capture and data entry, as well as monitoring and quality assurance. During our first year as a part of the University of Copenhagen we have tried to adjust the orga- nisational structure to reflect the two columns – science and operations – as well as incorporate the many new challenges CHIP is faced with.

Jens Lundgren Director

PA & CVD coordinator NN

Jesper Grarup Director of Administration

Cohort, Grants and Education Administrative IT & bioinformatics Mngt RCT Management Clinical Trials Manager Research Management Management Coordination JKJ KBJ DCG OKI MEL

Finance & personnell Bioinformatics Trial physician Ph.Ds Lab Databases Research & clinics Lars Peters Quality Management Data Entry NEAT Daria Podlekareva Achiever Form INSIGHT Signe Westring Worm development Safety officer Justyna Kowalska IT & web support Post Docs Nina Friis-Møller Ulrik Dragsted Education & Projects Research Assistants Cohort Team Academic Monitor group KSH Caspar da Chunha-Bang Services Team Majken Sønderholm CMA

NEAT project EuroSIDA e-learning content INSIGHT trials Contract management DAD Masters NEAT trials IWHOD EuroCOORD CSGH IPM and CVS RCT projects COHERE WHO CC activities trials Poster production Grant Management Training Regulatory coordination CODE Indicator diesease e-learning platform ACTIVATE

The scientific data analysis and interpretation of findings are the important and valuable outcomes of CHIP’s activities, corresponding to the tip of the iceberg. However, the labour intensive operational activities, like the biannual follow-up of more than 14,000 patients in EuroSIDA distributed between 93 sites in 33 countries, the merger of data comprising more than 150,000 patient years of follow-up in D:A:D, and the coordination of activities in more than a handful of large randomised controlled trials form the rest of the iceberg together with the new challenges like development of a new education: Master in HIV.

The structure of CHIP has been consolidated in the recent period. The coordinators from the operational functions of CHIP have been delegated the responsibility for operational and administrative personnel in their functions and have formed a management coordination group. Ole Kirk represents the scientific staff in the management group. This structure secures the necessary coordination and high level of information. The single functions have their group meetings to disseminate information, discuss and share experiences and bring up new ideas.

14 Scientific group with his HIV-hepatitis co-infection and diagnostic Besides Jens Lundgren, the scientific group com- markers using project with data from both EuroSIDA prises a number of long-term involved post-doc and the SMART study – already resulting in 6 publi- researchers, PhD students and research assistants. cations/manuscripts. Justyna Kowalska had her PhD After completing his specialty education, Ole Kirk project accepted and is now deeply engaged in her has been engaged in a half-time position to coordi- project implying a substantial amount of statistics nate and guide the activities of the scientific group developing models to evaluate risk and benefits of besides his continued primary responsibility for treatments based on clinical endpoints. Jens-Ulrik the EuroSIDA and TB activities; Nina Friis-Møller Jensen has coordinated the efforts to keep the continues her valuable involvement in D:A:D activi- motivation of the centres contributing patients to ties, and the CoDe project; Ulrik Bak Dragsted has the PASS study to investigate the diagnostic value been a leading character in the development of the of the plasma marker, procalcitonin, supposed to Master in HIV and secures a continued high level of specifically indicate ongoing bacteraemia in pa- HIV-training for the CHIP staff; Daniela Gey is the tients admitted to the intensive care units. Related responsible physician related to the NIH studies and to Jens Lundgren’s Viral Disease professor-ship, has been heavily involved in the central set-up of CHIP has engaged a research assistant, Caspar da the START study. In addition, CHIP houses five PhD Cunha-Bang, to establish a database and investi- students. Signe Westring Worm is currently respon- gate critical viral infections in immuno-suppressed sible for the day-to-day management of the D:A:D patients. Christian Brandt finalised his doctoral study and despite her involvement in event evaluati- dissertation supported by CHIP funding for the final on, she managed to submit her PhD thesis ahead of 6 months and submitted it for defence in 2009. Also schedule. Daria Podlekareva has finalised data col- Christian Holkmann Olsen finalised and defended lection related to her HIV/TB study in collaboration his PhD thesis focused on development and testing not only with HIV clinics but also TB clinics mainly in of the CoDe system. Eastern Europe. Lars Peters is moving ahead quickly

15 The monitoring group The cohort group Charlotte Matthews has with great enthusiasm very The cohort group has developed substantially due successfully managed the group of clinical moni- to the many new challenges at the university as well tors while Karoline Bo Jensen has been on parental as the applied science activities in which CHIP has leave. recently engaged. The operational activities of the Per Jansson is coordinating the STALWART activi- cohort group are managed by Michelle Ellefson ties, Heidi Juncher-Benzon the ESPRIT activities assisted by Jorunn Tverland, Maria Paulsen and An- and Mary Pearson the SILCAAT activities. Bitten nemette Borch. Very recently we have welcomed An- Aagaard is very dedicated to Poland and secures nette Hauberg Fischer back in a new position as pro- that the document management system is kept ject secretary and currently we are rolling Charlotte floating. Søren Stentoft Reilev is responsible for all Matthews over to the group. The cohort group has PASS activities after Mie Kofoed Djursner left CHIP. a number of student staff taking care of data forms´ Birgitte Gram Jensen sees to centres in Germany and logistics and quality assurance. Annemette’s main Scandinavia. Our monitor-staff outside of Denmark function is to secure the never-ending flow of forms. also has developed. In Germany, Klaus Tillman and Jorunn, as previous monitor, is handling EuroSIDA Dejan Adzic are hard at work and in daily contact monitoring and query resolution and Maria is doing with Copenhagen. In Spain, we changed collabora- a great job in compiling newsletters and keeping tive partner to Acoiba in Madrid and are very happy track of the many new activities related to CoDe lo- with our new, dedicated monitors: Begoña Portas gistics, ACTIVATE, EuroCOORD and CHAIN. The daily (already a long-term collaborator in SILCAAT) and work in the cohort group is the most complex in Patricia Herrero managed by Paco Lopez. Daniela CHIP: besides the operational staff it involves most Gey, our Clinical Trial Manager, is a valuable support of the scientists; the data-managers, data entry and for the RCT activities. The coming year will be chal- bioinformatics staff; CHIP´s statistical group at the lenging with the initiation of the long awaited START Royal Free Hospital in London; as well as investi- study, but also our involvement with the Interna- gators, partners and other collaborators form the tional Partnership for Microbicides and their phase many cohort collaborations. Besides managing all of II study investigating an intravaginal ring delivery this, Michelle has managed to be heavily involved in of antiretroviral drug. In addition, the two NEAT the Masters application. trials – one in treatment naïve patients and one in HIV-hepatitis co-infected patients are both expected to be initiated in 2009 and will keep the monitoring group busy.

16 The IT and bioinformatics group Finance and laboratory Jesper Kjær is managing the activities of the group. Helle Bo Duus has a challenging job as head of the Besides running the EuroSIDA database and finance function. Helle has worked very well to- securing the mergers of data from D:A:D, COHERE gether with Bjørn Lyngsøe, and therefore was espe- and CoDe, the group is responsible for the many cially affected by Bjørn’s cancer disease and death. administrative databases and tools as well as for To secure production, Helle has been assisted the functionality of the web-based portals and tools by temporary and student staff, but now Annette covering the activities of the whole of CHIP. Dennis Fischer will take over Bjørn’s EuroSIDA accounting Kristensen is mainly programming web interfaces, responsibilities. Helle also administers personnel Allen Sawitz is managing D:A:D mergers, to be taken and acts a work environment and safety officer. over by Rikke Salbøl Brandt in the coming year, and Ruth Kjærsgaard Pedersen has worked hard to keep a large staff of keyers takes care of data entry, scan- the laboratory function floating. She secures the ning and quality assurance. The group also admini- overview and handling of the more than 90,000 sters the flow of samples to and from the repository. samples in the research repository (mainly EuroSIDA Jesper Kjær continues to be productive in the field of samples) and also the logistics and coordination of bioinformatics – unfortunately Leif Høj, our second collection of samples from the randomised control- bioinformatic scientist, was offered a job in the led trials and the safe shipment of the samples to industry and left CHIP, but the position will be filled the US-based repository for these trials. By en- again, securing the strong bioinformatics profile of gaging Majken Sønderholm as research assistant the group. (50% funded by CHIP) the laboratory group has created the planned support for our PhD students. Secretariat The primary focus has been securing analysis capa- Karen Skov Hansen is coordinating the secretariat bilities related to the hepatitis co-infection project. function. Karen is unfortunately leaving us, she The finance and lab functions are staff groups under wants to challenge herself by starting a translation the Director of Administration. bureau on her own. Marianne Jeppesen is primarily assisting the monitoring group with travel arran- Management gements, courier, systems and shipment. Peer Jens Lundgren, Director, and Jesper Grarup, Director Aagaard is primarily ‘managing’ Jens Lundgren and of Administration, currently form the management translation tasks as well as guests and temporary of CHIP. To secure the continued development staff housing and permits. Additionally, cross func- of CHIP it will be important to free some of Jens’ tion projects are managed by the secretariat. resources from running the various projects, allowing him to focus on development. Therefore, the intention is to expand the group by more senior scientists with the ability to take on some of Jens’ many ongoing scientific obligations.

17 Q QUALITY MANAGEMENT

Being involved in clinical trials operations un- analysis, data management, information services mistakably involves ICH-GCP and Standard and the like. Our partners or customers are prima- Operating Procedures. CHIP is in the process of rily public sponsors like the EU commission and establishing a ‘holistic’ approach to SOPs, not only National Institutes of Health in USA, but also private describing the single procedure but trying to estab- sponsors, mostly medical companies and regula- lish a network and hierarchy of procedures and tory authorities. Our many investigators fit into the processes to manage and constantly improve the quality management system as partners/customers quality of our work. The following figure illustrates in many instances, but are also recognised as sup- the turning wheel of quality development that will pliers, in cases where we expect patient data from be the backbone of quality management in CHIP and them. On a second level, HIV patients and patient in interaction with our customers. organisation dependent on the results from the The scope of the Quality Management System is in trials can be viewed as customers. accordance with the ISO standards and specifies requirements if an organisation Citing the Helsinki declaration: “Involving human • needs to demonstrate its ability to consistently subjects in clinical research necessitates carefully provide services that meet customer and appli- planned and documented processes to protect cable regulatory requirements, and the life, health, privacy, and dignity of the human • aims to enhance partner satisfaction through subjects involved. Further, medical research must the effective application of the system, including conform to generally accepted scientific principles, processes for continual improvement of the be based on a thorough knowledge of the scientific system and the assurance of conformity to part- literature, other relevant sources of information, ners and applicable regulatory requirements. and on adequate laboratory and, where appropria- In CHIP products are clinical trials or coordination te, animal experimentation.” A quality management of clinical trials (or ultimately published results system securing quality and traceability of data is from such research), as well as performance of the best way to secure valid conclusions based on other services related to clinical trials e.g. statistical the medical research.

18 Key: Value-adding activities Information flow

19 EDUCATION

CHIP has developed markedly in the past year, reflecting the university environment we are now a part of, but also reflecting our wish to contribute to disseminating and applying the scientific results we have generated. The grand opening and kick-off was manifested last year on the 30th November where Jens Lundgren held his inauguration lecture related to the professorship in Viral Diseases at the University of Copenhagen. Jens gave an inspiring and easily understandable round-tour in the mechanisms of viral infections, their diagnosis, development and treatment with a natural focus on HIV and a strong personal touch by dedicating the lecture to his father that did not live long enough to take part despite his strong wish. A well-deserved celebration was preceded by dedicated speeches by Rector Ralf Hemmingsen, Dean Ulla Wewer, Hospital Director Jannik Hilsted and Professor Ian Weller.

Master in HIV ACTIVATE Part of the mutual strategic reflections related to In 2008, the first and second ACTIVATE trainings CHIP’s relocation to the university was to utilise were carried out. The first one was held in Minsk in CHIP’s strong scientific base to develop a Master September and the second in Glasgow in November in HIV with ability to attract international students. (p. 49). CHIP committed to take on the task and established a steering group in February to guide and advise on the EACS process. Ib Bygbjerg and the dynamic team at the In- CHIP has been pleased to host dr. Iwona Cielnak ternational Health Unit as well as Jeff Lazarus from the from Poland for four months under the EACS me- European WHO office, have been especially suppor- dical exchange programme. Iwona brought some tive. We managed to develop the application timely of her own data and worked actively to establish a despite the significantly increased requirements from good network at CHIP and we look forward to work- the ACE Denmark since the last round of applications. ing closely with Iwona in the future. ACE Denmark did not approve the education based on Jens is an EACS EC member and chaired the group details regarding the types and frequency of examina- that developed the guidelines on the prevention tion and the semantics around the skills and quali- and management of metabolic diseases in HIV, and fications that candidates will obtain. However, ACE Lars Peters is a panel member for the Guidelines for Denmark made a positive evaluation of 1) the need for the clinical management and treatment of chronic the education; 2) the job situation of candidates; 3) hepatitis B and C co-infection in HIV-infected adults. the education being research based; and 4) the quality of the research base. Therefore, we PhD students and research have not changed our minds about the establishment assistants of a Master in HIV at the University of Copenhagen, CHIP strives to maintain a critical mass of PhD and will submit a revised proposal prior to the April 1, students and clinical assistants associated with 2009 deadline. This will not allow us to initiate the full the ongoing research activities – mainly related to education in 2009, but we intend to launch at least EuroSIDA and D:A:D. It is important for the large some of the modules next fall. projects to have engaged and dynamic young

20 researchers involved to expand the points of view. It receive Ellen Moseholm in a project investigating is equally beneficial for PhD students to be involved differences across European regulatory authorities directly in and gain a thorough understanding of related to reporting requirements for suspected the day-to-day business of large research projects unexpected adverse drug reactions. and an experience of working in a large network of international researchers. Also, the direct involve- Internal education sessions ment with the statistical group at Royal Free and the Daniela Gey has for the last few years been the PhD students there is mutually inspiring. Currently, driver of the very popular programme for the weekly Signe Westring Worm, Daria Podlekareva, Lars internal education sessions for CHIP staff members. Peters and Justyna Podlekareva are PhD students Many subjects and teachers with closer or more located at CHIP, Jens Ulrik Jensen is a PhD student remote relation to CHIP have willingly contributed. located both at CHIP and Hvidovre Hospital, Cas- par da Cunha-Bang and Majken Sønderholm are Danish Institute for Study Abroad research assistants located at Rigshospitalet and (DIS) Joanne Reekie and Alim Kamara are located at Royal Lars Peters, Ulrik Bak Dragsted, Signe Westring Free. Within the last year Christian Holkmann Olsen, Worm and others from CHIP have been active in Wendy Bannister, and Zoe Fox successfully defen- teaching at DIS (affiliated with Copenhagen Univer- ded their PhD theses. Recently, Signe Westring sity). Ulrik and Lars are instructors and coordinators Worm submitted her thesis for defence in the year on the HIV/AIDS in Europe: Biomedical Perspectives to come and Christian Brandt submitted his doctoral course that ran in the Fall. This course included an dissertation also for defence in 2009. overview of understanding of the complexity of HIV/ AIDS from a biological and medical perspective. The OSVAL and other students course also included a biological characterisation of After relocation to the university CHIP has been HIV (virology, immunology and epidemiology), and approached by medical and public health students medical and clinical aspects of HIV/AIDS (develop- that want to do project work and internships at CHIP ment of HIV infection, opportunistic infections, and receive the related guidance from CHIP treatments, complications and co-infections). The staff. Currently, CHIP has no funding for such course featured distinguished guest lecturers from activities as we do not have a base funding from CHIP, including Ole Kirk, Nina Friis-Møller, and Daria the university, but we intend to establish funding Podlekareva. Additionally, Lars, Ulrik, and Signe and resources for an internship programme in the taught a short and intensive summer course on HIV/ near future. As a start, in the spring 2009, CHIP will AIDS.

21 BIOINFORMATICS

During 2008 the work entitled: “Prediction of phe- mechanisms that enables HIV-1 protease enzyme to notypic susceptibility to antiretroviral drugs using escape the amprenavir drug pressure. 2009 and the physiochemical properties of the primary enzymatic years to come will show further work along this path structure combined with artificial neural networks” for other drugs and also expand the work to other was accepted and published in HIV Medicine. This types of vira. first publication by the IT/bioinformatical group is The first work on using the prediction models for the culmination of the joint masters thesis made estimating the susceptibility of B vs. non-B subty- by Leif Høj and Jesper Kjær, defended in Septem- pes was presented on a poster at the 9th Interna- ber 2007. This work is a new approach to assess tional Congress on Drug Therapy in HIV Infection in the change in susceptibility of the drugs by using Glasgow, Scotland in November 2008. The poster physiochemical properties of the mutating amino was titled: “Are non-B subtypes less susceptible to acids in the protease and reverse-transcriptase antiretroviral drugs? - a bioinformatical approach enzymes targeted by the majority of the currently to prediction on non-B subtype susceptibility”. This available drugs. Previous work in this field has been work allowed us to use the ability of extrapolating of rather discretised approaches that look at spe- loss of susceptibility learned from B-subtypes to cific mutations where present or not. By using the the non-B subtypes using the continuous space of physiochemical approach, the amino acid mutations physiochemical amino acid properties. Currently are considered in a continuous space of changes in available drugs have been developed in the We- chemistry and physiology of the enzymes. stern world where subtype B is the most dominant versus the A, C, G and CRF_AE subtypes, which are As a consequence, we are able to extrapolate and the most common types in Africa. Further work on a dissect the models we have developed to further larger set of non-B subtypes sequences are planned understand the mechanisms of the HIV-1 enzymes to provide more robust estimates of drug susceptibi- when undergoing changes in the primary and lity that will give information about which drugs are secondary structure to escape drug pressure. The likely to work on non-B subtypes as well as they do first work on entangling these mechanisms in HIV-1 on B subtypes. was presented at the XVII International HIV Drug Resistance Workshop in Sitges, Spain in June 2008. Leif Høj, who played a key role in undertaking these The poster was titled: “In silico identification of computations, has taken on a position at Microsoft. physiochemical properties at mutating positions CHIP and the IT/bioinformatical group wish him relevant to reduced susceptibility to amprenavir”. good luck with the new challenges. A replacement This project headed by Leif Høj looked at which che- for Leif is currently being sought so that the many mical and physiochemical properties are the main exciting projects in the pipeline can be carried out.

22 RANDOMISED CLINICAL TRIALS INTERLEUKIN-2 STUDIES

Scientific purpose The following two studies were designed to investi- Potent antiretroviral drug combinations have consi- gate the effects of sc rIL-2 in patients with a conti- stently been shown to result in prolonged survival nuum of low CD4+ lymphocyte counts (the SILCAAT and less HIV-associated morbidity. The target of the- study) and medium to high CD4+ lymphocyte counts se drugs is the suppression of the HIV replication. (the ESPRIT study). An additional strategy for the management of HIV could be to stimulate the recovery of the immune A third study investigates the use of sc rIL-2 on function. Two long-term, large-scale studies are patients who are either treatment naïve or have not currently investigating an immunological response received anti-HIV therapy within one year prior to by selectively raising the CD4+ lymphocyte count ra- randomization (the STALWART study). ther than targeting the virus. The studies investigate this approach by assessing the effects of subcuta- Preliminary results make it likely that IL-2 with cART neous recombinant interleukin-2 (sc rIL-2) and no has a significant advantage over cART alone, but sc rIL-2 on HIV disease progression and death over the future use of IL-2 as part of a standard therapy a long-term follow-up period in patients who are can only be determined when in-depth analyses of taking combination antiretroviral therapy (cART). the ongoing studies have been completed which is expected to take place in 2009.

The results of the Interleukin-2 studies If rIL-2 is shown to be clinically effective in either or both of the two ongoing phase III studies ESPRIT and SILCAAT, rIL-2 could serve an important role as part of standard therapy. The results of STALWART as a phase II study evaluating the safety and im- munologic and virologic effects of rIL-2 in asymptomatic, treatment naïve HIV-infected patients will nicely complement these two trials and our knowledge on the best way to use rIL-2 in HIV-infected patients and its potential as an antiretroviral-sparing agent.

24 ESPRIT

Description proposal is an effort to have patients in the rIL-2 arm The study is a phase III, randomised, open-label, (who are currently not at their CD4 goal and without multi-centre study involving 4,150 study partici- medical contraindication towards rIL-2) continue pants at 255 sites in 25 countries around the world. using rIL-2 also towards the end of the study to CHIP is one of four International Coordinating maintain a difference in CD4 count in the two study Centres (ICCs) and coordinates the study in Austria, groups and hence to ensure a successful conduct of Belgium, Germany, Poland, Portugal, Spain, and the study. the Scandinavian countries with 982 patients under management. The collection of serious non-AIDS (SNA) events has been another focus during 2008. This initiative was Achievements (2008) and the future triggered by the increased recognition of the impact After nearly a decade of study conduct the ESPRIT of SNA events (like cardiovascular disease, liver study closed to patient follow-up on 15 November and renal disease) on morbidity and mortality in 2008 after the required number of events (320) had people with HIV infection. Therefore, SNAs occurring occurred. QOPEC (Quality Oversight and Perfor- in ESPRIT have been collected retrospectively and mance Evaluation Committee), the four ICCs and all prospectively for evaluation by the Endpoint Review ESPRIT sites worldwide are simultaneously securing Committee (ERC). the study closeout procedure. CHIP is coordinating that process for more than 40 sites in 9 countries As part of the study closeout procedure, a tremen- within Europe. dous amount of data cleaning and sample shipment is taking place worldwide. The site de-registration During this last year of study conduct the ESPRIT process will begin in early 2009 and by 31 May study group has continued its focus on ensuring 2009 all 255 sites around the world will be officially excellent data quality and on keeping study partici- de-registered. The unblinding of study data will take pants under active follow-up. Increased monitoring place at a closed meeting in Buenos Aires in January activities in 2008 reflect this main focus. 2009. It is planned to present study results to investigators and study participants early in 2009. Another area of focus has been the rIL-2 recycling proposal, which was introduced in early 2007. This

25 SILCAAT

Description decade of study conduct. QOPEC (Quality Oversight The study is a phase III, randomised, open-label, and Performance Evaluation Committee), the four multi-centre study involving 1,971 patients from 125 ICCs and all SILCAAT sites worldwide are simultane- sites in 11 countries on 4 continents. As in ESPRIT, ously securing the study closeout procedure. CHIP is the role of CHIP in SILCAAT is to be one of 4 Interna- coordinating that process for 30 sites in 3 countries tional Coordinating Centres (ICCs) coordinating sites within Europe. in Belgium, Germany and Spain with an overall of 418 randomised patients . During this last year of study conduct in SILCAAT, increased monitoring activities took place with the Achievements (2008) and the future main focus on ensuring good data quality and on The Data and Safety Monitoring Board (DSMB) re- keeping study participants under active follow-up. viewed SILCAAT at their most recent meeting in No- The rIL-2 recycling proposal has been another main vember 2007. There were no concerns arising from focus in 2008, as described under the ESPRIT study. either efficacy or safety data warranting a change in the conduct of SILCAAT. While the trial cannot meet Site de-registration will begin in early 2009 and its original design target of 300 primary endpoints, by 31 May 2009 all 125 sites around the world will at the time of study closure, the Board believed that be officially de-registered. Concurrently with the the additional data collected in 2008, especially the ESPRIT study, SILCAAT will be unblinded at a closed primary endpoints will be valuable to the overall po- meeting in Buenos Aires in January 2009. The study wer of SILCAAT, both on its own and for comparison results are planned to be presented to investigators to the results of ESPRIT. and study participants early in 2009.

SILCAAT closed to follow-up concurrently with the ESPRIT trial on 15 November 2008 after nearly a

26 STALWART

Description While it was planned to terminate enrolment to STALWART is an international, phase II, multi-centre, STALWART when the ESPRIT study would end (No- open label, randomised controlled trial. The purpo- vember 2008) STALWART closed patient enrolment se of the study is to compare the effects of sc rIL-2 prematurely on 30 June 2008. The premature administered with and without concomitant pericy- closure was due to a low (one digit) enrolment rate cle highly active antiretroviral therapy (HAART) to no over more than a 6-month period in late 2007/early therapy in patients with HIV-1 infection and CD4+ T 2008. One reason for the low enrolment rate was lymphocyte count ≥ 300 cells/mm3. Pericycle HAART difficulties with regulatory approvals, which limited is given only for a few days before, during and after the number of active sites to only about half of the each 5-day-cycle of IL-2. intended number. Also, the interest of potential participants declined as antiviral treatment came to The hypothesis being tested is that intervention at be initiated earlier and as the number of antiretro- an early stage of HIV infection with intermittent sc viral drug options available increased. Therefore, rIL-2 therapy, either alone or with pericycle HAART, the ending of enrolment acknowledged the unlikely can maintain or increase CD4+ T cell counts as com- prospect of approaching the target sample size, pared to controls that receive neither antiretroviral even with a long extension. therapy nor rIL-2. Although the original enrolment goal of 480 could STALWART opened in September 2005 and as of not be reached, valuable data has been collected June 2008, a total of 267 participants across 47 si- in STALWART and with the enrolment of 267 par- tes in 10 countries worldwide could be enrolled into ticipants, the study will still have an 80% power the study. As in ESPRIT and SILCAAT, CHIP is one of 4 to detect an 80% CD4 cell difference between the International Coordinating Centres (ICCs) coordina- treatment groups. ting sites in Poland, Portugal, Spain and Germany. All study participants will be followed-up until a Achievements (2008) and the future common closing date on 28 February 2009 - 32 The most recent Data Safety and Monitoring Board weeks after the last patient was randomised. This (DSMB) meetings took place in November 2007 and will allow all participants to reach the primary study May 2008. After reviewing safety and efficacy data outcome at week 32. The unblinding of study data from all sites the DSMB concluded, “no considera- will take place at a closed meeting in Bangkok in tion of early stopping based on safety or efficacy March 2009. The study results are planned to be data is indicated.” shared with investigators and study participants during 2009.

27 START START

Background and scientific purpose to HIV RNA suppression, higher CD4+ count, or With the exception of data from a small subgroup other beneficial effects of ART. of participants who were not taking antiretroviral therapy (ART) at the time of entry into the SMART However, a clear picture on the likely risk/benefits Study (Strategies for Management of AntiRetroviral of early ART in terms of hepatic, cardiovascular and Therapy, p. 30), evidence from randomised trials renal disease does not emerge when collectively does not exist to guide decisions about the initia- considering the data from epidemiological studies, tion of highly active ART regimens for HIV-infected laboratory studies, and the SMART study. A trial is individuals with CD4+ cell counts >200 cells/mm3. needed to provide definitive information on these Current guidelines are based largely on data from risks and benefits. cohort studies and recommend initiating ART between 201 and 350 cells/mm3. ART is usually not The purpose of START (Strategic Timing of Anti- initiated until the CD4+ cell count is <350 cells/mm3 Retroviral Therapy) is to determine whether the for various reasons. immediate initiation of ART in HIV-1 infected persons who are antiretroviral naïve with a CD4+ lymphocyte Current data indicate that morbidity and mortality count above 500 cells/mm3 is superior in terms of risk reduction with earlier use of ART may be greater reducing the occurrence of serious morbidity and than previously estimated. Furthermore, it is pos- mortality compared to deferral of ART until the CD4+ sible that any increased risk of non-AIDS morbidity lymphocyte count declines below 350 cells/mm3, as and mortality associated with use of ART may be current guidelines recommend. more than counter-balanced by a reduced risk due

START Schematic:

HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3

Early ART Group Deferred ART Group

Initiate ART immediately following Defer ART until the CD4+ count declines randomisation to < 350 cells/mm3 or AIDS develops

N=450 in pilot phase and N=450 in pilot phase and estimated as estimated as N=2,000 for definitive trial N=2,000 for definitive trial

28 Description funding in our region is granted from the German START is an international randomised trial com- Federal Ministry of Education and Research (Bun- paring early ART vs. deferred ART. The study will desministerium für Bildung und Forschung, BMBF) proceed in two phases: 1) a pilot phase and 2) a de- that supports the START Study by funding a total of finitive phase. In its initial phase, START will enroll 16 German sites in both phases of the study. 900 participants from 22 countries in the Americas, Europe, Africa, the Middle East, and Australia. If Achievements (2008) and the future the first phase is successful, enrolment will expand Extensive preparations for this worldwide project to include approximately 4,000 participants and have been ongoing throughout 2008. A main focus additional countries. The entire study is expected to was the finalisation of the START main protocol and take about 6 years. its substudies. Additional funding has been secured The pilot phase of START is expected to start in early from pharmaceutical companies, other organisa- 2009. Successful completion of the pilot phase re- tions and governments. Legal issues have been quires enrolment of at least 900 participants in one cleared including e.g. sponsor responsibilities, year by 70 designated sites supported by Division of insurance coverage, ensuring compatibility with the AIDS (DAIDS). Additional sites, funded by organisa- EU Directive and European Eudravigilance require- tions other than DAIDS, will also participate in the ments. pilot and definitive phase. Other areas of main focus in 2008 included the site Substudies selection and site establishment process. A ‘train Three substudies (Informed Consent, Neurology and the trainer’ session for the 4 ICCs took place at the Genomics Substudy) are part of the START protocol INSIGHT core center in Minneapolis, Minnesota in and will start at a subset of sites together with the June 2008. Training material has been developed as main study. A fourth substudy, the Arterial Stiffness well as CRFs, questionnaires, protocol instruction Substudy, is a separate protocol but is also ex- manual, monitoring manual, pharmacy plan and pected to start in conjunction with the main study patient information material. A central drug repo- at selected sites. Other substudies (e.g. a substudy sitory and drug distribution plan for 22 countries on pulmonary function and on bone density) are around the world was another challenging focus currently in the planning phase and may also be during 2008. launched during 2009. As soon as the final protocol is signed off, many START at the Copenhagen ICC activities will run in parallel in all participating CHIP serves as one of four International Coordina- countries around the world in early 2009, like e.g. ting Centres (ICCs) within the INSIGHT network (p. obtaining Ethics Committee approval, ensuring 8) and is responsible for the implementation of the compliance with national regulatory requirements, protocol across European countries. For the pilot etc. Protocol training for the site coordinating phase, this includes 16 sites from 6 countries centers (SCCs), monitors and sites are also plan- (Belgium, Denmark, Finland, Germany, Poland and ned for early/mid 2009 and thereafter there will be Spain). Additional countries and sites are expected a ‘grand opening’ of sites for enrolment of study to come on board in the definitive trial. External participants.

29 SMART

Scientific purpose ticipants were then followed for an additional 18 The purpose of the SMART (“Strategies for Manage- months until SMART closed to follow-up on 11 July ment of AntiRetroviral Therapy”) study was to com- 2007. The study close-out process was completed pare two strategies of antiretroviral management: end of 2007/early 2008. 1. The “viral suppression” (VS) strategy which aimed at continued use of antiretroviral therapy Results and Publications (ART) to maximally suppress HIV replication Reinitiating continuous ART in patients previously 2. The “drug conservation” (DC) strategy which assigned to episodic treatment reduced excess risk aimed at minimising exposure to ART as much for OD or death. However, an excess risk remained as possible while maintaining a reasonable which was mainly attributable to failure to reinitiate immune function. ART was used intermittently therapy by some participants and slow recovery of to maintain the CD4+ lymphocyte T cell count CD4+ cell counts for those who reinitiated therapy. above thresholds where ART would be indicated Follow-up was too short to assess the full effect of in patients who had not yet commenced it switching from episodic to continuous ART (12). In – namely >200 cells/μL general, the higher risk of OD/death in DC patients was associated with (a) spending more follow-up Study closure and initial results time with relative immunodeficiency and (b) living CHIP served as one of four International Coordina- longer with uncontrolled HIV replication even at ting Centres (ICCs) within the INSIGHT network (p. 8) higher CD4+ cell counts. Ongoing HIV replication at and was responsible for the SMART study conduct a given CD4+ cell count places patients at an excess and close-out process at 37 sites in 13 European risk of OD/death (11). countries. Besides these main results, the influence of the A total of 5,472 participants from 318 research sites CD4+ guided treatment interruption strategy as per in 33 countries around the world were enrolled into the SMART design has been analyzed thoroughly for the study which made SMART the largest global many organ diseases including cardiac events (CVD effort to address a strategic question in relation to (9), myocardial ischaemia (4), myocardial infarction, using ART. SMART was discontinued and unblinded (14) as well as bacterial pneumonia (6), renal function in January 2006 due to an increased risk of contrac- (1) and hepatitis (15). The role of biomarkers (hsCRP, ting opportunistic disease (OD) in patients rando- IL-6 and D-dimer) as potential predictor for all cause mised to the DC strategy, but also the risk of dying mortality (7) and opportunistic disease (submitted for from a non-AIDS related cause and contracting car- publication) were other surprising and very exciting diovascular, kidney and liver disease was increased findings within SMART. in this group of patients (18). Other analyses conducted within SMART include the After 11 January 2006, all participants assigned to risk of cancers (17), quality of life (3), HIV-transmission the DC group were advised to reinitiate ART, except (2) as well as visceral and subcutaneous adiposity from some who had remained ART-naïve. All par- measurements (16) and the choice of interrupting a

30 suppressive NNRTI-regimen, which influences resup- is the first evidence from a randomised trial to guide pression rates when restarting a similar regimen (5). decisions about the initiation of ART for HIV-infected individuals with CD4+ cell counts > 200 cells/mm3, Another essential finding within SMART is the these findings naturally require validation in a large, analysis of the subgroup of study participants who randomised clinical trial (8), (10) and p. 28). were either ART naïve (n=249) or who had not been receiving ART for ≥ 6 months (n= 228). Initiation of An overview of SMART publications is listed below. ART at CD4+ cell counts >350 cells/μL compared with This list is also available on the INSIGHT website <250 cells/μL may reduce both OD and serious non- where it is regularly updated: http://insight.ccbr. AIDS events (13). While this subgroup of participants umn.edu/

SMART Publications 2008 suppressive non-nucleoside reverse transcriptase inhibitor- 1. Mocroft A, Wyatt C, Szczech L, Neuhaus J, El-Sadr W, Tracy based regimen. AIDS 2008; 22:2279-2289. R, Kuller L, Shlipak M, Angus B, Klinker H, Ross M; for the 6. Gordin FM, Roediger MP, Girard PM, Lundgren JD, Miro JM, INSIGHT SMART study group. Interruption of antiretroviral Palfreeman A, Rodriguez-Barradas MC, Wolff MJ, Easterbrook therapy is associated with increased plasma cystatin C. PJ, Clezy K, Slater LN. Pneumonia in HIV infected persons: AIDS 2008; 23(1):71-82. increased risk with cigarette smoking and treatment inter- 2. Burman W, Grund B, Neuhaus J, Douglas J Jr, Friedland G, ruption. Am J Respir Crit Care Med 2008; 178(6):630-636. Telzak E, Colebunders R, Paton N, Fisher M, Rietmeijer C for Epub 2008 Jul 10. the SMART Study Group and INSIGHT. Episodic antiretrovi- 7. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane ral therapy increases HIV transmission risk compared with HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, continuous therapy: results of a randomized controlled trial. Neaton JD for the INSIGHT SMART Study Group. Inflammatory J Acquir Immun Defic Synd 2008; 49:142-150. and coagulation biomarkers and mortality in patients with 3. Burman WJ, Grund B, Roediger MP, Friedland G, Darbyshire HIV infection. PLoS Med 2008; 5(10):e203. doi:10.1371/jour- J, Wu AW for the SMART Study Group. The impact of episodic nal.pmed.005. CD4 cell count guided antiretroviral therapy on quality of life. 8. Neaton JD, Grund B. Earlier initiation of antiretroviral therapy J Acquir Immun Defic Synd 2008; 47(2):185-193. in treatment naïve patients: implications of results of tre- 4. Carr A, Grund B, Neuhaus J, El-Sadr WM, Grandits G, Gibert atment interruption trials. Current Opinion in HIV and AIDS C, Prineas RJ for the SMART Study Investigators. Asympto- 2008; 3:112-17. matic myocardial ischaemia in HIV-infected adults. 9. Phillips AN, Carr A, Neuhaus J, Visnegarwala F, Prineas R, AIDS 2008; 22(2):257-267. Burman WJ, Williams I, Drummond F, Duprez D, Belloso WH, 5. Fox Z, Phillips A, Cohen C, Neuhaus J, Baxter J, Emery S, Goebel F-D, Grund B, Hatzakis A, Vera J, Lundgren JD. Inter- Hirschel B, Huppler Hullsiek K, Stephan C, Lundgren J on ruption of antiretroviral therapy and risk of cardiovascular behalf of the SMART Study Group. Viral resuppression and disease in persons with HIV-1 infection: exploratory analyses detection of drug resistance following interruption of a from the SMART trial. Antivir Ther 2008; 13:177-187.

31 10. Phllips AN, Neaton J, Lundgren JD. The role of HIV in serious Therapy (SMART) study. Clin Infect Dis 2008; epub 27 Octo- disease other than AIDS. AIDS 2008; 22:2409-2418. ber. 11. SMART Study Group. Inferior clinical outcome of the CD4+ See also: Wyles DL. Hepatitis virus coinfection in the Stra- cell count guided antiretroviral treatment interruption tegic Management of Antiretroviral Therapy (SMART) study: strategy in the SMART study: role of CD4+ cell counts and HIV A marker for nonliver, non-opportunistic disease mortality. RNA levels during follow-up. J Infect Dis 2008; 197:1145-1155. (editorial) Clin Infect Dis 2008; epub 27 October. 12. SMART Study Group. Risk of opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients 2007 with HIV previously receiving episodic therapy, a randomized 16. Ellis KJ, Grund B, Visnegarwala F, Thackeray L, Miller CG, trial. Ann Int Med 2008; 149:289-299. Chesson CE, El-Sadr W, and Carr A for the Strategies for 13. SMART Study Group. Major clinical outcomes in antiretroviral Management of Anti-Retroviral Therapy (SMART) Study therapy (ART) naïve participants and in those not receiving Group. Visceral and subcutaneous adiposity measurements ART at baseline in the SMART study. in adults: Influence of measurement site. J Infect Dis 2008; 197:1133-1144. Obesity 2007; 15(6):1441-1447. See also: Hughes MD, Ribaudo HR. The search for data on 17. Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry when to start treatment for HIV infection. K, Hidalgo J, Lortau L, Neaton JD, Tambussi G, and Abrams DI. (editorial) J Infect Dis 2008; 197:1084-1086. Risk of cancers during interrupted antiretroviral therapy in 14. SMART/INSIGHT and D:A:D Study Groups. Use of nucleoside the SMART study. AIDS 2007; 21:1957-1963. reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008; 22:F17-F24. 2006 15. Tedaldi E, Peters L, Neuhaus J, Puoti M, Rockstroh J, Klein 18. SMART Study Group. CD4+ count-guided interruption of MB, Dore GJ, Mocroft A, Soriano V, Clotet B, Lundgren JD for antiretroviral treatment. N Engl J Med 2006; 355:2283-2296. the SMART Study Group and International Network for Stra- See also: Currier JS, Baden LR. Getting smarter – the toxicity tegic Initiatives in Global HIV Trials (INSIGHT). Opportunistic of undertreated HIV infection. disease and mortality in patients coinfected with hepatitis (editorial) N Engl J Med 2006; 355:2359-2361. B or C virus in the Strategic Management of Antiretroviral

32 THE PROCALCITONIN AND SURVIVAL STUDY: PASS

Scientific purpose nin start a relevant decrease within 24 hours when The Procalcitonin And Survival Study (PASS) is bacterial infection is controlled. We have shown designed to investigate whether daily procalcitonin that an increase in the procalcitonin level for just 24 measurements and timely and appropriate response hours in ICU patients is an independent predictor of to abnormal procalcitonin values, can reduce morta- mortality with a corresponding hazard ratio of 1.8 lity for critically ill patients. in patients with a 24 hours procalcitonin increase, Additionally, the study will show if it is possible to compared to a decreasing procalcitonin level. reduce the frequency of sepsis complications, the quantity of antimicrobial chemotherapy used and The hypothesis in the PASS study is, that by control- the length of the ICU stay. ling procalcitonin increases by means of intensi- fying antimicrobial diagnostics and therapy, when Description procalcitonin levels increase, infection-related Bacterial infection is a major cause of mortality in mortality can be reduced. the intensive care unit (ICU). The initial diagnosis of The PASS Study is a randomised, single-blinded, bacterial infection and the monitoring of the anti- multicentre interventional study with a 28-day mor- microbial treatment effect are complicated in ICU tality primary endpoint. The study has a calculated patients, since: 1) symptoms, 2) clinical signs and sample size of 1,000 critically ill patients and it 3) the traditionally most used biomarkers of infec- refers to ICH-GCP rules and guidelines. All relevant tion are often affected from other causes than infec- authorities, including the regional ethics board, ap- tion. Additionally, these parameters often give in- prove it. The study is registered at the USA National formation regarding the infection status with a Institutes of Health register (www.clinicaltrials.gov) significant time lack. The PASS Study is coordinated by Copenhagen HIV Delay of relevant antibiotics and antimicrobial Programme (www.cphiv.dk), and the Department of surgery in bacterially infected ICU patients carries a Clinical Microbiology 445, Copenhagen University high and increasing mortality rate. Hospital, Hvidovre. Procalcitonin is a marker of bacterial infection that Eight ICUs in Denmark participate and the database has been demonstrated to increase shortly after and biobank that will be formed by the PASS Study release of bacterial products to the blood stream. It will be used for investigating multiple purposes has also been shown that blood levels of procalcito- regarding the treatment of critically ill patients.

33 Achievements in 2005-2008 The future A. Protocol approved by ethics committee, data- Major aims for the PASS Study the following year. controlling authorities etc. A. Completion of inclusion of 1,000 ICU patients B. Establishment of Steering Committee and PASS- within January 2009 Study-group. B. Publication of the primary paper regarding the C. Establishment of the Procalcitonin bio-analysis survival in the two groups (primary endpoint) in the Department of Clinical Microbiology 445, C. Development of several hypotheses to be tested Hvidovre Hospital, including 365 days/ year real- using the biobank and database time analysis. D. Presentation of the main results in leading inter- D. Establishment of the Procalcitonin bio-analysis national fora in the Department of Clinical Biochemistry, E. Further consolidation of the scientific qualities of Århus University Hospital, Skejby, including 365 the group days/ year real-time analysis. F. Initiation of one new investigator initiated E. Establishment of 365 days /year transport of Randomised Controlled ICU study within the next biomaterial from recruiting sites to laboratories. year F. Recruitment at eight major intensive care units in G. Establishment of a Research Centre for the inve- Denmark, including education of all personnel. stigation of life threatening microbial diseases in G. All three planned interim analyses have been ICU patients: performed (250, 500, 750) and the DSMB re-  Copenhagen Research Initiative for Icu Trials commended the study to be completed with the (CRIIT) to lead and innovate landmark indepen- planned sample size. dent clinical trials in ICU settings H. 925 subjects of planned 1,000 included in the study (November 2008) I. Oral presentations of the PASS-study at 10 international meetings/congresses and at numerous occasions in Denmark. J. Six publications in international peer-reviewed journals & books (see page 58 for publications)

34 OBSERVATIONAL STUDIES EuroSIDA

Scientific purpose The primary objective of the EuroSIDA study is to Study Overview (status as of December 2008) prospectively study demographic, clinical, thera- Patients enrolled 17,200 peutic, virological and laboratory data from persons Number of countries 32 infected with HIV across Europe in order to determine the long-term virological, immunological and Number of clinics 103 clinical outcome. Total person-years of follow-up 75,009 The study is headed by a 12-member steering com- CD4 cell measurements 319,471 mittee, elected by the EuroSIDA investigators. The Viral load measurements 267,676 coordination of the study is carried out at CHIP. Plasma samples collected 65,202 The EuroSIDA study group has now been working on this study for 14 years and has several notable ac- The EuroSIDA study group continued in 2008 to complishments to date. This September, EuroSIDA participate in and further initiate international inter- reached the milestone of having 100 articles pub- cohort collaborations to address issues, which can- lished in peer-reviewed journals (including the New not be readily answered within the EuroSIDA study England Journal of Medicine and the Lancet among itself. Such collaborations include the D:A:D study, others). Sixteen new articles have been published COHERE, the ART Cohort Collaboration. or accepted for publication this year. EuroSIDA presented 10 orals and posters at major international HIV conferences in 2008, covering a variety of EuroSIDA Celebrates topics. For a full list, please see the CHIP website at 100 Publications! www.cphiv.dk. This September, EuroSIDA reached the milestone of having 100 articles published in peer-reviewed This year’s publications covered a large variety journals, including the New England Journal of of topics such as adverse events to antiretroviral Medicine and the Lancet among others. therapy (including participation in the DAD study), The 100th publication, ”Does less frequent rou- and frequency of routine monitoring. Several papers tine monitoring of patients on a stable, fully sup- have been published on the role of HIV drug resi- pressed cART regimen lead to an increased risk stance, as well as on hepatitis C epidemiology. The of treatment failure?”, was published in AIDS. first article on pharmacokinetics of HIV drugs was The cornerstone of EuroSIDA is the data provided also accepted in 2008. by the centres and study personnel twice annually. The study is a transnational collaboration, as can be seen by the study group on page 38.

36 As a supplement, data is also collected for resistan- The Future ce testing performed locally on patients participa- EuroSIDA will continue to address emerging questi- ting in EuroSIDA. Data from these two data sources ons regarding the clinical management of HIV-in- allows for analyses of the influence of resistance fected patients – also including the role of HIV drug mutations on the patients’ clinical prognosis. resistance, late-onset adverse event to antiretroviral treatment, co-infection with hepatitis B and C and The hepatitis workpackage of EuroSIDA is lead by tuberculosis. A special focus will be on the situation Dr. Jürgen Rockstroh and the work carried out in col- in Eastern Europe where EuroSIDA is in a unique laboration with Dr. Vincent Soriano in Madrid. position to address issues of special relevance for David Burger is the leader of the pharmacokinetics this region. workpackage which is located in Nijmegen, The Netherlands.

Co-infection with hepatitis B or C virus has become an increasingly important area of research within EuroSIDA. At CHIP, Lars Peters is investigating a promising serum biomarker, hyaluronic acid, as a predictor of liver disease progression. The aim is to provide clinicians with a new, non- invasive marker that can reduce the number of liver biopsies. Data from this work will be presented in 2009.

17,000 HIV-infected patients incl. 3,800 from Eastern Europe Cohort VIII >2,500 new patients of these, >1,250 from Eastern Europe. New Sites in Ukraine, Bosnia, Slove- nia, Austria, Belgium and Spain.

37 The EuroSIDA Study Group The multi-centre study group on EuroSIDA (national coordinators in parenthesis). Argentina: (M Losso), C Elias, Hospital JM Ramos Mejia, Buenos Aires. Austria: (N Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna; (R Zangerle) Medical University Innsbruck, Innsbruck. Belarus: (I Karpov), A Vassilenko, Belarus State Medical University, Minsk, VM Mitsura, Gomel State Medical University, Gomel; O Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N Clumeck) S De Wit, B Poll, Saint-Pierre Hospital, Brussels; R Colebunders, Institute of Tropical Medicine, Antwerp; (L Vandekerckhove) University Zie- kenhuis Gent, Gent. Bosnia: (V Hadziosmanovic) Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: K Kostov, Infectious Disea- ses Hospital, Sofia.Croatia ; J Begovac, University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L Machala) H Rozsypal, Fa- culty Hospital Bulovka, Prague; D Sedlacek, Charles University Hospital, Plzen. Denmark: (J Nielsen) G Kronborg,T Benfield, M Larsen, Hvidovre Hospital, Copenhagen; J Gerstoft, T Katzenstein, A-B E Hansen, P Skinhøj, Rigshospitalet, Copenhagen; C Pedersen, Odense University Hospital, Odense, L Oestergaard, Skejby Hospital, Aarhus. Estonia: (K Zilmer) West-Tallinn Central Hospital, Tallinn, Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M Ristola), Helsinki University Central Hospital, Helsinki. France: (C Katlama) Hôpital de la Pitié-Salpétière, Paris; J-P Viard, Hôpital Necker-Enfants Malades, Paris; P-M Girard, Hospital Saint-Antoine, Paris; JM Livrozet, Hôpital Edouard Herriot, Lyon; P Vanhems, University Claude Bernard, Lyon; C Pradier, Hôpital de l’Archet, Nice; F Dabis, D Neau, Unité INSERM, Bordeaux. Germany: (J Rockstroh) Universitäts Klinik Bonn; R Schmidt, Medizinische Hochschule Hannover; J van Lunzen, O Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; HJ Stellbrink, IPM Study Center, Hamburg; S Staszewski, JW Goethe University Hospital, Frankfurt; J Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J Kosmidis) P Gargalianos, G Xylomenos, J Perdios, Athens General Hospital; G Panos, A Filandras, E Karabatsaki, 1st IKA Hospital; H Sambatakou, Ippokration Genereal Hospital, Athens. Hungary: (D Banhegyi) Szent Lásló Hospital, Budapest. Ireland: (F Mulcahy) St. James’s Hospital, Dublin. Israel: (I Yust) D Turner, M Burke, Ichilov Hospital, Tel Aviv; S Pollack, G Hassoun, Rambam Medical Center, Haifa;S Maayan, Hadassah University Hospital, Jerusalem. Italy: (A Chiesi) Istituto Superiore di Sanità, Rome; R Esposito, I Mazeu, C Mussini, Università Modena, Modena; C Arici, Ospedale Riuniti, Bergamo; R Pristera, Ospedale Generale Regionale, Bolzano; F Mazzotta, A Gabbuti, Ospedale S Maria Annunziata, Firenze; V Vullo, M Lichtner, University di Roma la Sapienza, Rome; A Chirianni, E Montesarchio, M Gargiulo, Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli; G Antonucci, F Iacomi, P Narciso, C Vlassi, M Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A Lazzarin, R Finazzi, Ospedale San Raffaele, Milan; M Galli, A Ridolfo, Osp. L. Sacco, Milan; A d’Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan. Latvia: (B Rozentale) P Aldins, Infectology Centre of Latvia, Riga. Lithuania: (S Chaplinskas) Lithuanian AIDS Centre, Vilnius. Luxembourg: (R Hemmer), T Staub, Centre Hospitalier, Luxembourg. Netherlands: (P Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (J Bruun) A Maeland, V Ormaasen, Ullevål Hospital, Oslo. Poland: (B Knysz) J Gasiorowski, Medical University, Wroclaw; A Horban, E Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; D Prokopowicz, R Flisiak, Medical University, Bialystok; A Boron-Kaczmarska, M Pynka, Medical Univesity, Szczecin; M Beniowski, E Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H Trocha, Medical University, Gdansk; (E Jablonowska) E Malolepsza, K Wojcik, Wojewodzki Szpi- tal Specjalistyczny, Lodz. Portugal: (F Antunes) E Valadas, Hospital Santa Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Lisbon; F Maltez, Hospital Curry Cabral, Lisbon. Romania: (D Duiculescu) Spitalul de Boli Infectioase si Tropicale: Dr. Victor Babes, Bucarest. Russia: (A Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; E Vinogradova, St Petersburg AIDS Centre, St Peterburg; S Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M Mokráš) D Staneková, Dérer Hospital, Bratislava. Slovenia: (J Tomazic) University Clinical Centre Ljubljana, Ljubljana. Spain: (J González-Lahoz) V Soriano, L Martin-Carbonero, P Labarga, Hospital Carlos III, Madrid; (S Moreno) Hospital Ramon y Cajal, Madrid; B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, Hospital Germans Trias i Pujol, Badalona; JM Gatell, JM Miró, Hospital Clinic i Provincial, Barcelona; P Domingo, M Gutierrez, G Mateo, MA Sambeat, Hospital Sant Pau, Barcelona. Sweden: (A Karlsson), Karolinska University Hospital, Stockholm; PO Persson, Karolinska University Hospital, Huddinge; L Flamholc, Malmö University Hospital, Malmö. Switzerland: (B Ledergerber) R Weber, University Hospital, Zürich; P Francioli, M Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B Hirschel, E Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H Furrer, Inselspital Bern, Bern; M Battegay, L Elzi, University Hospital Basel. Ukraine: (E Kravchenko) N Chentsova, Kiev Centre for AIDS, Kiev; (G Kutsyna) Luhansk AIDS Center, Lu- hansk; (S Servitskiy), Odessa Region AIDS Center, Odessa; (S Antoniak) Kiev; (M Krasnov) Kharkov State Medical University, Kharkov. United Kingdom: (S Barton) St. Stephen’s Clinic, Chelsea and Westminster Hospital, London; AM Johnson, D Mercey, Royal Free and University College London Medical School, London (University College Campus); A Phillips, MA Johnson, A Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M Murphy, Medical College of Saint Bartholomew’s Hospital, London; J Weber, G Scullard, Imperial College School of Medicine at St. Mary’s, London; M Fisher, Royal Sussex County Hospital, Brighton; C Leen, Western General Hospital, Edinburgh.

Virology group: B Clotet, R Paredes(Central Coordinators) plus ad hoc virologists from participating sites in the EuroSIDA Study. Steering Committee: F Antunes, B Clotet, D Duiculescu, J Gatell, B Gazzard, A Horban, A Karlsson, C Katlama, B Ledergerber (Chair), A D’Arminio Montforte, A Phillips, A Rakhmanova, P Reiss (Vice-Chair), J Rockstroh Coordinating Centre Staff: J Lundgren (project leader), O Kirk, A Mocroft, N Friis-Møller, A Cozzi-Lepri, W Bannister, M Ellefson, A Borch, D Podlekareva, J Kjær, L Peters, J Reekie, J Kowalska

Statement of Funding: Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Fra- mework (QLK2-2000-00773) and the 6th Framework (LSHP-CT-2006-018632) programs. Current support also includes unrestricted grants by Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck and Co., Tibotec and Boehringer-Ingelheim. The participation of centres from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.

Updated 1 December 2008 38 D:A:D

Scientific purpose and query of events, and the preparation of draft The Data Collection on Adverse events of Anti-HIV research papers. The coordinating office organises Drugs (D:A:D) is a prospective multi-cohort study SC meetings with representatives from each cohort, of HIV-infected persons under active follow-up. the lead statistician, EMEA, the patient community The main objective of the study is to assess the and industry. The SC approves all analytic proposals incidence of myocardial infarction (MI) and other prior to their execution and has the overall responsi- cardiovascular disease endpoints in HIV-infected bility for the scientific conduct of the study. persons, and to investigate whether treatment with antiretroviral drugs is associated with development Results of cardiovascular disease as a late-onset adverse In 2008, the study presented numerous novel effect. analyses. On April 2nd 2008, key analyses from the study were presented in the Lancet on the risk of Description MI associated with drugs from the NRTI drug class. Eleven cohorts worldwide are participating, with Unexpectedly, abacavir (and to a lesser extent di- a total current enrolment of more than 33,000 danosine) was associated with an increased risk of patients from 212 clinics in 21 countries in Europe, MI. As none of these drugs are normally associated Argentina, USA and Australia. The original study po- with metabolic disturbances, several additional pulation of 23,437 patients were enrolled December analyses were conducted to explore this unexpected 1999 - April 2001, and is referred to as D:A:D Cohort finding. The risk for MI associated with abacavir I ; an additional 10,021 patients were enrolled in remained unchanged after adjustments for CVD risk D:A:D Cohort II throughout the Spring of 2004. As factors and metabolic parameters such as lipids and of February 1st 2008, the patients in Cohort I and II glucose. The 90% increased MI risk in those expo- have contributed with more than 178,000 person- sed to abacavir was evident: 1) when patients were years of follow-up. In 2009 an additional cohort of actually receiving the drug; 2) as well as shortly > 5000 patients is planned (cohort III). On average after they stopped taking the drug, but appeared patients are seen in the clinics every 3 months, and reversible within a few months after their cessation. specific data collection for D:A:D takes place at least The excess risks were most pronounced, in absolute every 8 months. Each cohort gathers and compute- terms, in patients with high underlying risk (Figure rises its own data; subsequently data is merged in a 1). Based on these results the DDHS guidelines database in Copenhagen. (November 2008) recommended that alternatives to abacavir should be given to those patients at high Organisation risk for developing coronary heart disease, i.e. a 10 The staff at the coordinating office at CHIP includes year predicted risk of > 20% (1) (2). the principal investigator, the study coordinators and the central data-manager. The coordinating Another paper from the D:A:D study group, publis- office has the overall responsibility, including the hed in Diabetes Care (3), investigated the incidence coordination, collection and cleaning of data, review and risk factors for new onset of diabetes. During

39 130,151 person-years of follow-up, 744 patients were Due to the known relationship between exposure to diagnosed with DM (incidence rate of 5.72 per 1,000 combination antiretroviral therapy and cardiovascu- PYFU (95% CI: 5.31-6.13)). The incidence of diabetes lar disease (CVD), it has become increasingly impor- mellitus (DM) increased with cumulative exposure tant to intervene against risk of CVD in HIV-infected to cART, the association remained significant after patients. In Clinical Infectious Diseseases (5) we adjustment for potential risk factors for DM. The evaluated changes in risk factors for CVD and strongest relationship with DM was exposure to the use of lipid-lowering therapy in HIV-infected stavudine; exposure to zidovudine and didanosine individuals and assessed the impact of any chan- were also associated with an increased risk of DM. ges on the incidence of myocardial infarction. The Time-updated measurements of total cholesterol, proportion of patients at high risk of CVD increased HDL-cholesterol and triglycerides were all associ- from 35.3% during 1999-2000 to 41.3% during 2005- ated with DM. While lipodystrophy was significantly 2006. Of 28,985 patients, 2,801 (9.7%) initiated associated with DM, adjustment for this did not mo- lipid-lowering therapy; initiation of lipid-lowering dify the relationship between cART and DM sugge- therapy was more common for those with abnormal sting the two thymidine analogues probably directly lipid values and those with traditional risk factors contribute to insulin resistance potentially through for CVD. After adjusting for these, use of lipid- mitochondrial toxicity. lowering drugs became relatively less common The purpose of another study from the D:A:D study over time. The incidence of myocardial infarction group, published in AIDS (4), was to evaluate deaths (0.32 cases per 100 person-years [PY]; appeared to from AIDS-defining malignancies (ADM) and non- remain stable. However, after adjusting for changes AIDS-defining malignancies (nADM) and to investi- in risk factors for CVD, the rate decreased over time gate the relationship between these deaths and im- (relative rate in 2003 [compared with 1999-2000], munodeficiency. Due to a malignancy, 298 patients 0.73 cases per 100 PY ; in 2004, 0.64 cases per 100 died prior to the cut-off for this analysis (ADM: n = PY; in 2005-2006, 0.36 cases per 100 PY ). 110; nADM: n = 188). The mortality rate due to ADM CONCLUSIONS: Although the CVD risk profile among decreased from 20.1/1,000 person-years of follow-up patients in the D:A:D Study has decreased since when the most recent CD4 cell count was <50 cells/ 1999, rates have remained relatively stable, possibly microliter to 0.1 /1,000 person-years of follow-up as a result of a more aggressive approach towards when the CD4 cell count was more than 500 cells/ managing the risk of CVD. microliter; the mortality rate from nADM decreased from 6.0 to 0.6 per 1,000 person-years of follow-up Future between these two CD4 cell count strata (Figure The study is projected to continue at least until 2). In multivariable regression analyses, a two-fold 2013, and provide more than 260,000 person-years higher latest CD4 cell count was associated with a of data. The D:A:D Study continues to follow pa- halving of the risk of ADM mortality. tients prospectively, focusing on monitoring the risk CONCLUSION: The severity of immunosuppression of cardiovascular disease, its association with more is predictive of death from both ADM and nADM in extended exposure to cART, and its relationship to HIV-infected populations. the specific drug classes used. Furthermore, the

40 study has started on a prospective collection of end- All cohorts taking part in the D:A:D collaboration stage liver disease, end-stage kidney disease and have implemented the standardised coding from non-fatal non-AIDS cancer diseases as the large size the CoDe Project (p. 44), which will assist the eva- of the D:A:D study will allow us to explore possible luation of causes of death. associations with ART and these rare outcomes.

A No recent didanosine Recent didanosine B No recent abacavir Recent abacavir

35 35

30 30

25 25

20 20

15 15 Rate (per 1000 PY) 10 10 Rate (per 1000 PY)

5 5

0 0

Overall Low Moderate High Not known Overall Low Moderate High Not known

Predicted 10-year CHD risk Predicted 10-year CHD risk

Events 393 124 78 24 86 26 134 34 95 40 Events 325 192 60 42 79 33 100 68 86 49 PY 130184 27728 59281 13102 14289 3383 6914 1474 49700 9770 PY 126581 31331 57628 14754 13372 4300 6293 2095 49288 10182

Figure 1. Rates of myocardial infarction, stratified by predicted 10-year risk of coronary heart disease, and recent use of either (A) didanosine or (B) abacavir. Reprinted from the Lancet 2008 Apr 26;371(9622):1417-26. E pub 2008 Apr 2 (2008DOI:10.1016/50140-6736(08)60423-7), “Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.” Writing group: CA Sabin, SW Worm, R Weber, P Reiss, W E l Sadr, F Dabis, S De Wit, M Law, A D´Arminio Monforte, N Friis-Møller, O Kirk, C Pradier, I Weller, AN Phillips, JD Lundgren; copyright 2008 with permission from Elsevier.

41 100 ADM Non - ADM

1 Event rate /1,000 PYFU

0,1 <50 50 -99 100 - 199 200 -349 350 - 499 > 500

Latest CD4 count (cells/mm3)

Figure 2. Rates of mortality from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) (with 95% Cl) stratified by (A) latest CD4 cell count and (B) latest HIV RNA. ADM, AIDS-defining malignancies; PYFU, person-years of follow-up. Reprinted form AIDS 2008 Oct 18;22(16):2143-53 HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. A Monforte, D Abrams, C Pradier, R Weber, P Reiss, F Bonnet, O Kirk, M Law, S De Wit, N Friis-Møller, AN Phillips, CA Sabin, JD Lundgren; Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. AIDS; copyright 2008 with permission from AIDS.

Reference List 1. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F et 4. Monforte A, Abrams D, Pradier C, Weber R, Reiss P, Bonnet al. Use of nucleoside reverse transcriptase inhibitors and risk F et al. HIV-induced immunodeficiency and mortality from of myocardial infarction in HIV-infected patients enrolled in AIDS-defining and non-AIDS-defining malignancies. the D:A:D study: a multi-cohort collaboration. AIDS 2008 October 18;22(16):2143-53. Lancet 2008 April 26;371(9622):1417-26. 5. Sabin CA, d’Arminio MA, Friis-Moller N, Weber R, El-Sadr WM, 2. Guidelines for the use of antiretroviral agents in HIV-1- in- Reiss P et al. Changes over time in risk factors for cardiova- fected adults and adolescents. DHHS 2008. scular disease and use of lipid-lowering drugs in HIV-infected 3. De Wit S, Sabin CA, Weber R, Worm SW, Reiss P, Cazanave individuals and impact on myocardial infarction. C et al. Incidence and risk factors for new-onset diabetes in Clin Infect Dis 2008 April 1;46(7):1101-10. HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care 2008 June;31(6):1224-9.

42 PROJECTS THE CODE (”CODING OF DEATH IN HIV”) PROJECT

Background The purpose of the data collection is to provide The CoDe project was initiated in 2004 based on sufficient information for the reviewers’ classifi- the realisation that there was a need to harmonise cation of the cause of death. The review of causes and standardise the approach taken when collec- of death in the CoDe project should be based on a ting data and reviewing the causes of death in HIV-1 synthesis of the information provided in the CoDe infected patients. This has become increasingly Case Reporting Form. The review should result in a necessary as a significant proportion of deaths in specific coding of the cause(s) of death (underlying, HIV-1 infected persons are now caused by non-AIDS contributing and/or immediate) as well as coding events, many AIDS defining illnesses are poorly of relatedness to immunodeficiency. For each of identified in the ICD system (International Classifi- these, the reviewer should also indicate the de- cation of Diseases), and some diseases (e.g. CNS gree of certainty by which the code is made, as the (Central Nervous System) diseases) have a different intention is to reduce the classification category of aetiology in HIV patients and are therefore not unknown, but at the same time allow for sensitivity covered by the ICD system, or at great risk of mis- analysis depending on degree of certainty. Each classification. case is reviewed by at least two reviewers. If the two reviewers cannot reach a consensus on the cause of Scientific purpose death, the case is then sent to an expert in the field The purposes of the CoDe project are: for additional review (Figure 1). 1) The development of an algorithm to classify deaths of HIV-infected persons. Status 2) Creating a surveillance system for emerging As of September 2008, a total of 1,401 Case Repor- trends in the causes of deaths based on this ting Forms had been received and entered in to the consensus algorithm. central CoDe database. Of these cases, two independent reviewers had coded 517. Currently, 152 are Methods in the review process and 577 are ready for review. The CoDe Project is a uniform coding system that can be applied to studies of individuals with HIV Implementation infection, including: In 2007/8 a number of improvements have been • A detailed data collection on the causes of death introduced to the daily routines and procedures of and contributing factors, and CoDe. The group of CoDe reviewers has been incre- • A centralised review process of the data col- ased and compensation for completing the reviewer lected. CoDe forms introduced. In addition, new IT tools have been developed for CoDe reviewers and CHIP’s staff to improve the flow of the review process.

44 Figure 1

CRF batch ready for review CRF is approved to be reviewed by MD

Reviewers agree to commit to current batch, are Assigning Group of Reviewers assigned in a database to 20 CRFs and e-mails send out with event ID list and instructions

CRF ready to review on-line

Consensus assessment Cases are reviewed on whether consensus was achieved

Discrepancy cases If the consensus cannot be reached an expert in the area is consulted

Reimbursement Twice annually, 25 USD per event coded

Figure 2 Site

Reviewer 1 Yes Coordinating Case Agreement Centre Coded

Reviewer 2 No Yes

• Registration Re-Evaluation • Keying • Pre approval No • Approval Expert in the field

CHIP’s role • Develops and maintains the database specifica- The coordinating office is located at CHIP and is tions responsible for receiving, registering, quality assu- • Organises teleconferences and meetings for the rance and archiving of CoDe CRFs (Figure 2), as well CoDe working group as the initiating, organising, and monitoring of the • Makes the CoDe study documents publicly avai- review process. lable These responsibilities use the resources of about 10 CHIP staff members: program coordinator and Evaluation and feed-back assistant, data managers, MDs, and keyers. CoDe is publicly available free of charge. Following In addition to the daily responsibilities, the coordi- the experience and evaluation of the CoDe pilot, this nating office also: method has been implemented widely in HIV cohorts, and will be subject for continuous evaluation. • Contributes to the continued development of the If studies wish for assistance in setting up the infra- CoDe methods structure for CoDe or to adapt the database specifi- • Supports the project with developing new IT cations, please contact the CoDe coordinating office tools (at [email protected]).

45 COHERE (Collaboration of Observational HIV Epidemiological Research Europe)

In 2008, COHERE published their first manuscript treated HIV-infected patients to reach the same mor- in AIDS entitled ”Response to combination antire- tality rates as those of the general population.” troviral therapy: variation by age”. Caroline Sabin headed the project. An additional merger for the PLATO II project was completed by the end of 2008. This project gathe- Three mergers of data were performed in 2008. red detailed HIV-1 sequence data for protease and The work of gathering the data from the 33 cohorts reverse transcriptase on the patients experiencing participating in COHERE is divided between the extensive triple class failure. regional coordination centre (RCC) in Bordeaux and Copenhagen. In addition, a minor additional merger on hepatitis co-infection and prophylaxis/treatment for opportu- The first merger of the year was for the PLATO II nistic infections was performed during late summer project. This project is lead by Andrew Phillips and for a project aiming to validate existing guidelines focuses on HIV-1 infected patients experiencing for discontinuation of prophylaxis for opportuni- extensive triple class virological failure. For the first stic infections (OI) and make recommendations for merger in this project, 30 cohorts across Europe amendment where appropriate. Additionally, the contributed data on a total of 96,423 patients and project aims to evaluate the extent to which clinici- a stunning total of 368,707 person years of follow- ans discontinue primary or secondary prophylaxis up while on combination antiretroviral treatment according to the criteria listed in the U.S. Public (cART). First results from the analysis were sub- Health Service (USPHS) and Infectious Diseases mitted to the 16th Conference on Retroviruses and Society of America (IDSA) recommendations and Opportunistic Infections (CROI) and accepted as a in national European guidelines in Europe since poster with the title: “Risk of extensive triple class January 2000. Hansjakob Furrer heads this project virological failure of the three original antiretro- and analyses are currently being initiated. viral drug classes among people followed from therapy initiation with NNRTI or ritonavir-boosted The COHERE collaboration has during 2008 received PI regimens.” Additionally, an abstract for the an- funding from ANRS (Agence nationale de recher- nual International Workshop on HIV Observational ches sur le sida et les hépatites virales), France and Databases (IWHOD) has been submitted entitled: the HIV Monitoring Foundation, The Netherlands. ”Viral load outcome after virological failure of the COHERE is currently drafting its scientific agenda three original antiretroviral drug classes in 2000- for research to be undertaken in the coming years 2007.” The same dataset is currently being used for as part of the EuroCOORD cooperation (The Euro- an additional project headed by Charlotte Lewden, pean Coordinating Committee for the Integration of investigating the hypothesis ”High values of CD4 Ongoing Coordination Actions Related to Clinical, attained after a certain period of time might allow Virological and Epidemiological HIV Research).

46 HIV/TB PROJECT

Co-infection with Mycobacterium tuberculosis in • Argentina (115 patients) HIV-infected patients is of a great research interest, • Southern Europe (SE): Italy and Spain (210 pa- as tuberculosis (TB) is a leading cause of mortality tients) in HIV-infected patients and there are many unresol- • Central/Northern Europe (CNE): France, Den- ved issues related to HIV/TB co-infection. CHIP has mark, Switzerland, United Kingdom (168 pa- initiated and coordinates an international collabo- tients) ration of HIV and TB clinicians from Europe and Ar- • Eastern Europe (EE): Belarus, Latvia, Romania, gentina entitled “Co-infection with Mycobacterium Russia, Ukraine (582 patients). tuberculosis among HIV-infected patients in Europe” In this analysis a special focus has been put on (the HIV/TB project). The project has been establis- Eastern Europe, where the situation of HIV/TB hed with a purpose to analyse regional diversity in co-infection is of particular concern due to rapid patients’ characteristics and management of HIV/TB increase in HIV prevalence as well as incidence of TB patients across Europe and Argentina and to assess among the HIV-infected population. risk factors associated with death in these patients. Results of the study demonstrate pronounced regional differences in the clinical characteristics Enrolment of patients was completed in April 2008 and management of HIV/TB patients across Europe and the rest of the year was dedicated to data clea- and Argentina. Most striking is the fact that HIV/TB ning, data verification and data analysis. The first patients in EE, compared to those in other regions, results from this study have been presented at the were at a three- to fivefold increased risk of death 15th Conference on Retroviruses and Opportunistic within the first year after diagnosis of TB. At the Infections (CROI 2008) as a poster presentation: ab- same time a higher proportion of patients from stract O-138 “Characteristics and clinical outcome of this region was infected with mycobacteria strains patients with HIV-associated tuberculosis (HIV/TB) resistant to main TB drugs, and significantly lower in Europe and Argentina”. More detailed results on proportion of patients were receiving combination patient characteristics and their clinical prognosis antiretroviral therapy (cART). were presented at the Ninth International Congress In 2009 we plan to continue with more detailed on Drug Therapy in HIV Infection in Glasgow as an analysis of such important and yet unresolved que- oral presentation: abstract O-412 “Factors associ- stions, as: ated with poor clinical outcome among HIV-infected • Safety and efficacy of TB treatment in HIV- patients with tuberculosis (TB) in Europe and Argen- infected patients and interactions with antiretro- tina”. viral drugs • Timing of cART: when to start cART in HIV/TB Analyses of regional differences in patients’ cha- co-infected patients racteristics, management and outcomes were • Causes of death among HIV/TB co-infected pa- performed on a cohort of 1,075 HIV-infected patients tients diagnosed with active TB disease between 2004 At the same time we explore the possibilities for and 2006. All participating countries were divided continuing the HIV/TB project and start a new pro- into four regions: spective study of patients with HIV/TB co-infection.

47 EuroCOORD

The EuroCOORD milestones in 2008 were met and in by Gilead. This project will markedly increase the November the Application Steering Committee (ASC) number of individuals with available information was established. The ASC consists of 22 members as compared to what each cohort or collaboration from 22 partner institutions in 16 countries as well would be able to achieve. Additionally, it will allow as 2 invitees for paediatric expertise. For Euro- us to answer important scientific questions that COORD, 2008 was largely spent preparing for the require data from large numbers because resistance collaborative approach to applying for the 7th EU profile and/or the outcome of interest is rare. Framework Program. The EuroCOORD group is collaboratively implemen- EuroCOORD CHAIN ting the ACTIVATE grant (p. 49), the CHAIN project The EU has favourably reviewed and funded the (described above), and administering the annual CHAIN project and approximately 85% of the Cohorts workshop (p. 9). Next year will be an extre- EuroCOORD resistance in naïves project. Additional mely busy and exciting year for EuroCOORD. money for this project has been kindly provided

48 ACTIVATE

CHIP is a partner on the ACTIVATE grant which is a field of HIV presented sessions on various topics, collaborative project through the EuroCOORD colla- including Drug-to-Drug Interaction by Jens Lund- boration. ACTIVATE (capACity building and Training gren, HIV-TB Co-infection by Frank Post, and Optimal in hIV/Aids Treatment and management across Treatment for HIV & HBV/HCV co-infection by Jürgen Europe) was awarded for 3 years (2007-2010) by Rockstroh. The course was a mixture of lecture ses- DG SANCO. In 2008, the first and second ACTIVATE sions and case presentations, many of which were trainings were carried out, the first one in Minsk in presented by course participants. September and the second in Glasgow in November. Igor Karpov, Saulius Caplinskas, and Andrzej Hor- ban, each reporting on the situation in their respec- The 1st course took place in Minsk, Belarus, Sep- tive countries, presented a session dedicated to HIV tember 12-13th, 2008, and was attended by over 50 in Eastern Europe. participants from 15 Eastern European countries. The course was organized by CHIP together with our The second course took place in Glasgow preceding colleagues in Minsk, Igor Karpov and Anna Vassi- the 9th International Congress on Drug therapy in lenko. HIV Infection. Thirty-nine delegates from 12 Euro- pean countries participated. The teaching was a This course was significant in that it catered to the mixture of lecture sessions and case presentations. needs of Eastern European physicians by conduc- The topics covered included treatment in pregnancy, ting all sessions with simultaneous Russian-English management of HIV in infants, interpretation of drug translation. Financial scholarships were provided resistance mutations, and the treatment of patients by NEAT for 50 participants to attend the day-and-a- co-infected with hepatitis B, C, and TB. There was half course. Additionally, each participant received very positive feedback from the attendees who an USB-stick containing course material, courtesy of found the discussion of case studies in breakout the WHO. sessions particularly useful.

The ACTIVATE training in Minsk focused on Eastern European physicians. Leading physicians in the

NEAT EUROPEAN AIDS TREATMENT NETWORK

The activities of the NEAT network increased in 2008 tion in clinical trials, and regulatory and ethical and CHIP played an active role as a partner and requirements in trans-national research. member of the working group related to launching the clinical trials and implementing the training CHIP looks forward to implementing the clinical and education workpackage. The three training and trials through the NEAT network and will continue education grants awarded to CHIP in 2008 were for to find new ways to contribute to this exciting Training in Eastern Europe, HICDEP implementa- collaboration.

49 DISSERTATIONS IN 2008

Analyses of observational studies and randomised trials to increase understanding of the occurrence and role of drug resistance in HIV infection

Summary of Ph.D thesis defended successfully in 2008

Dr. Zoe Fox, Ph.D, HIV Research Statistician

This thesis explores the relationship between the use of antiretroviral therapy (ARVs) and drug resistance emergence in HIV-1 infected individuals. It also describes the combined impact of treatment use and resistance mutations on virological and immunological response in individuals who are under follow-up in one of four trials: MaxCmin1, MaxCmin2, COLATE or SMART; and three observational studies: Euro- SIDA, the UK CHIC study and the UK drug resistance database.

The emergence of resistance to an ARV that an individual is receiving may influence viral replication rates, which could increase the risk of CD4+ T cell count deterioration, clinical progression and death, un- less changes are made to the treatment regimen. Individuals may exhaust all treatment options if large amounts of resistance mutations are detected in their viral sub-populations. In the current era, new ARVs are still arriving on the market, but resistance to these ARVs is only partially understood. Understanding what mutations emerge in individuals who are failing treatment and the impact of specific mutations and combinations of mutations on the likelihood of responding to future regimens is still essential for being able to administer long-term therapy successfully.

Research for this thesis started just after the introduction of ritonavir boosted protease inhibitors (PI/ rs). Drug resistance emergence among individuals who experienced virological failure on a PI/r containing regimen is described in detail, and the relationship between resistance at baseline and virological response is also quantified. Other aspects of drug resistance are investigated, including: the potential benefit of harbouring the M184I/V mutation, the impact of resistance on immunological response and the relationship between resistance and viral re-suppression rates amongst patients who interrupt an NNRTI containing regimen.

This thesis outlines the benefits of resistance testing and highlights some of the key issues with inter- preting resistance data. Resistance tests are generally performed on a selective group of individuals so caution needs to be used when extending the results to all HIV-1 infected individuals. Further, consensus sequences are useful for indicating resistance that is present in the predominant virus; however, more minor, archived, species are not usually identified through this method and these may also be an important determinant of therapy response.

50 Risk of AIDS, Death or Pancreatitis according to Anti-Retroviral Therapy among HIV-infected patients

Summary of Ph.D thesis successfully defended in 2008 Christian Holkmann-Olsen, MD, Ph.D.

This Ph.D thesis includes three published manuscripts based on work conducted within EuroSIDA, an observational study on European HIV-1 infected patients, in the period 2004-2007 at the Copenhagen HIV Programme. The overall aim in this Ph.D. thesis was to assess the risk of AIDS, death and pancreatitis according to CD4 count, HIV-RNA and use of different antiretroviral treatment with and without interruption.

Since regulatory authorities in 1997 allowed drugs to be approved without data from clinical endpoint trials, it was unknown whether the relationship between the HIV-RNA or CD4 cell count and risk of AIDS or death continued to hold true for newer antiretroviral drugs used also in combination antiretroviral therapy (cART) regimens. To investigate this, 6,814 patients taking different cART regimens were included in the analysis. Person-years at risk, numbers of AIDS and death events and incidence rates (IRs) of these events were calculated for specific categories of the latest CD4 count and HIV-RNA, according to which drugs were currently used in the regimen. Poisson regression models were used to assess the incidence rate ratios (IRRs) comparing specific drugs and combinations of drugs after adjusting for confounding factors, including latest CD4 cell count and HIV-RNA. The results showed that for a given, latest CD4 cell count and HIV-RNA persons were at similar risk for AIDS and death regardless of which cART regimen taken, and that there was no detrimental or additional beneficial effect of the newer cART regimens. This implies that the markers currently used for gauging patients´ risk of clinical progression to AIDS or death can be interpreted similarly, regardless of which regimen the patient is receiving.

There were few published data on treatment interruption (TI) and the association with disease progression to AIDS or death in clinical practice, and results were not entirely consistent. Hence, there was a need to investigate this relation and assess the risk factors for developing new AIDS or death among HIV-infected people interrupting their cART regimens for 3 months or more. To look at this, 3,811 patients starting cART with a CD4 cell count and a HIV-RNA available within six months of starting cART were included in the study. The IR and risk factors for TI were determined, and the IRRs for TI and AIDS events or death were assessed using Poisson regression models. In EuroSIDA, one out of five patients followed in a five-year period interrupted the entire cART regimen for three months or more corresponding to IRs published by other cohort studies. Compared to patients staying on cART continuously, these patients have a more than doubled risk of AIDS or death. The increased risk were explained by lower latest CD4 counts and higher HIV-RNAs following cART interruption. Use of antiretroviral drugs was reported to be associated with long-term toxicities, including cases of pancreatitis. Studies have published widely vary- ing incidence rates of pancreatitis, and although some studies suggested that NRTI drugs in general and ddI/d4T in particular may lead to increased risk of pancreatitis, other did not find evidence for such an association. To study this, 9,678 patients on ART since prospective collection of pancreatitis events were contributing to follow-up time in the analysis until a diagnosis of pancreatitis or the last study visit. Fac- tors associated with pancreatitis were investigated using Poisson regression model. Cumulative lengths or exposure to ddI and/or d4T and other ART were included as time-updated variables. In EuroSIDA, the IR of pancreatitis was higher than in the background population, but lower than published by studies on HIV-infected people in earlier years. There was no evidence that the IR differed according to cumulative ddI/d4T use. Pancreatitis was associated with lower CD4 counts, indicating that immunodeficiency may increase the risk of developing pancreatitis. However, caution must be taken when assessing the association of risk factors with pancreatitis due to a small number of events.

To conclude, also newer cART drugs reduce the risk of AIDS or death, and latest CD4/HIV-RNA can be used as surrogate markers. Interruption of cART (TI) is associated with an increased risk of clinical progression, explained by post-TI changes in CD4/HIV-RNA. The increased risk of pancreatitis in HIV-infected seems to be associated with immunodeficiency and not with specific ART use.

51 Factors associated with different responses to combination antiretroviral therapy in an observational cohort study of HIV-1 infected patients

Summary of Ph.D thesis defended successfully in 2008

Dr. Wendy Bannister, Ph.D., HIV Research Statistician

The introduction of combination antiretroviral therapy (cART) into clinical practice for the treatment of HIV in 1995-1996 has led to dramatic reductions in mortality and morbidity. Factors linked to a positive response to therapy include a potent and tolerable regimen, good adherence and low levels of HIV drug resistance. The aims of this thesis were to investigate factors potentially associated with different responses to cART measured using virological and immunological predictive markers, and also to look at the development of toxicities to a specific regimen. The analyses were based on data from the EuroSIDA study, which is an observational cohort of 14,310 HIV-1 infected patients from Europe, Israel and Argen- tina. Data collected includes demographic history, CD4 cell counts, viral loads and details of all drugs taken. EuroSIDA also collects viral sequence data for its resistance database.

Investigation into virological response to first-line cART across geographical regions found evidence of variation, which was most apparent in early-cART years. Virological response improved over calendar time in all regions, especially in East Europe. Neither HIV-1 subtype nor transmitted drug resistance (TDR) were found to be associated with virological response to cART, however statistical power was limited. A significantly decreased risk of virological failure was found in patients starting efavirenz compared with nevirapine, which did not appear to be explained by baseline drug resistance. Finally, incidence of abacavir discontinuation due to a hypersensitivity reaction side effect of the drug appeared to be higher in patients starting abacavir as part of first-line therapy but decreased in recent years.

In conclusion, this thesis has compared a variety of different responses to antiretroviral therapy across subsets of a large heterogeneous population. It is hoped that these findings will contribute to research in monitoring trends in response to therapy and provide insight into association with the genetic variabi- lity of the virus.

52 FUNDING

CHIP is entirely dependent on external project-spe- Pharmaceutical Industry cific funding: The EuroSIDA grant does not cover all proposed activities and therefore industry funding for the analy- EU tical work related to resistance mutations, toxicities CHIP as coordinator is completing the third year of and co-infections is a valuable contribution to the funding for EuroSIDA in February 2009. Currently activities. Sponsorship agreements are only entered we are deeply involved in establishing the research if the scientific question to be investigated under agenda for EuroSIDA to be integrated in the combi- the agreement is found scientifically sound and va- ned next application from five prior funded projects luable for patient safety and treatment as evaluated under the umbrella of EuroCOORD. CHIP is involved by the Scientific Steering Committee. The resulting as a partner in two additional EU projects ACTIVATE reports are often used for regulatory submission as and NEAT – and currently contributing to two 7th response to requests from the regulatory authori- Framework Program applications. ties. Also D:A:D was funded by the HAART Oversight Com- NIH mittee for an additional period including merger CHIP receives limited funding as International 13 in 2012. The prolonged funding also includes a Coordinating Centre in the INSIGHT Network. The major increase in the type of events collected by START study was preliminary granted 10 million USD adding chronic liver disease, end-stage kidney di- in early summer 2007 to be used for an initial study sease and non-AIDS defining cancers. Likewise, an phase over two years. Further funding will depend additional cohort of 5,000 patients will be included. on interim analysis and recalculation of sample size. The Oversight Committee originally was formed Additional funding has now been obtained from a based on a requests from EMEA that follow closely long list of providers: Agence Nationale de Recher- the D:A:D results and continued funding. ches sur le SIDA et les Hépatites Virales (ANRS), Together with the University of Bordeaux, CHIP is France; Australian National Health and Medical administering the activities of the legal entity estab- Research Council (NHMRC); Bundesministerium fur lished to take care of the International Workshop on Bildung und Forschung (BMBF), Germany; Division HIV Observational Databases (IWHOD). of Clinical Research, NIAID, NIH; National Institute It is important to notice that CHIP is not involved in for Mental Health (NIMH), NIH; National Institute clinical trials with pharma companies as sponsor, of Neurological Disorders and Stroke (NINDS), NIH; being regulatory registration studies or phase IV National Cancer Institute (NCI), NIH; European AIDS post marketing studies. The only exception being Treatment Network (NEAT); Department of Bioethics, the phase II study undertaken by the non-profit NHI, Clinical Center. company International Partnership for Microbioci- des (IPM) based in South Africa, developing a micro- The funding of the already initiated studies will bicide application in an intravaginal ring device. continue as planned until completion of the trials: It is important for us that the activities of CHIP are ESPRIT and SILCAAT in February 2009 and STALWART driven by an academic research agenda supported in June 2009. by public funding and that CHIP is a strictly non-pro-

53 fit research organisation working solely for the be- is encouraged by and in line with the policies of our nefit of patients by conducting high quality science. public sponsors. We emphasize that the private co-funding we raise

Financial contributors

Study Public Private Boehringer-Ingelheim Bristol-Myers Squibb Gilead Sciences EuroSIDA EU Commision GlaxoSmithKline Merck & Co Inc Pfizer Inc Tibotec Abbott Laboratorie Boehringer-Ingelheim The Oversight Committee for The Bristol-Myers Squibb Evaluation of Metabolic Complications of Gilead Sciences D:A:D HAART GlaxoSmithKline EMEA Merck & Co Inc FDA Pfizer Inc Roche Pharmaceuticals ESPRIT NIH SILCAAT NIH STALWART NIH SMART NIH INSIGHT network NIH Lundbeck Foundation A.P. Møller og hustru Chastine Mærks PASS Danish Research Council Mc-Kinney Møllers Foundation Toyota Foundation B.R.A.H.M.S.-Diagnostica GmbH ANRS, Agence nationale de recherches sur le SIDA COHERE Augustinus Foundation Dutch HIV Monitoring Foundation NEAT EU Commission ACTIVATE EU Commission EuroCOORD-CHAIN EU Gilead Sciences Tibotec Boehringer-Ingelheim NIH/Office of AIDS Research Roche Pharmaceuticals IWHOD NEAT Gilead Sciences ANRS, Agence nationale de recherches sur le SIDA GlaxoSmithKline Pfizer Inc.

54 ACKNOWLEDGEMENTS

In the monitor group Liselotte Borup left CHIP after We also thank Leif Høj, Bioinformatic Scientist for five years of dedicated contribution, for a job at his contribution to kicking-off the computer based Astra Zeneca just next door to her home and Mie neural network model predicting resistance pat- Kofoed Djursner went for a job at the CRO aCROnor- terns; Leif found new challenges at Microsoft. dic. We thank both for their valuable contribution.

Bjørn Lyngsøe 23 February 1951 - 01 October 2008 CHIP lost a dear friend and colleague on October 1 this year when Bjørn passed away due to prostate cancer. Bjørn approached life with curiosity and enthusiasm. He was inspirational to all of us in the time he spent at CHIP. We have many fond memories of him and he will live on in our minds and hearts forever.

AWARDS

Many of our PhD students were awarded grants in Lars Peters Young Investigator Award for the CROI the passed year: 2008 conference, Boston, USA. Daria Podlekareva, Young Investigator Award for the Justyna Kowalska, Junior scholarship award for the CROI 2008 conference in Boston, USA and Junior HIV9 Glasgow Conference 2008, Glasgow, UK. Scholarship for HIV9 Glasgow Conference 2008, Glasgow, UK. Travel Grant Mexico.

55 Summer party 2008 This year’s summer party included various team activities during the day; “penguin” soccer, rope pulling, creation of facemasks, and many other games. In the evening we learned how to dance disco and a nice dinner was served.

CHIP TRIVIA Did you know that in 2008… • the CHIP staff ate 1,500 kilos of fresh fruit • and we drank 2,100 litres of coffee • the CHIP monitors carried out 130 monitoring visits • 16 posters were created • 3 Ph.Ds were successfully defended • 146,292 pages for EuroSIDA forms were printed 2 of ink and 20,186 staples • we used 274 m for the EuroSIDA forms Other CHIP Activities

56 Trip to the Helipad at Rigshospitalet (Copenhagen University Hospital) On the 9 March a group of CHIP´ers had the unique chance of going for a tour to the helipad at Rigshospitalet. The technical manager at RH showed us around and told about the construction of the helipad and procedures when helicopters are flying in and out. It was a very interesting and very stormy experience 80 metre up out in the open!

Average Impact Factor CHIP articles based on single publications CHIP publishes approximately 12,00 20 articles in the field of HIV annually, primarily in interna- 10,00 tional peer-reviewed journals. 8,00 The impact factors from these publications have been 9.16 6,00

and 9.92 per article in 2006 and 4,00 2007. Please see figure for an overview of CHIP’s publications 2,00

and impact factor from 2000-08. 0,00 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year Other CHIP Activities

57 PUBLICATIONS 2008

1. In vivo study of experimental pneumococcal meningitis 9. EACS Executive Committee. European AIDS Clinical Society using magnetic resonance imaging. CT Brandt, H Simonsen, (EACS) guidelines on the prevention and management of M Liptrot, LV Sogaard, JD Lundgren, C Ostergaard, N Frimodt- metabolic diseases in HIV. JD Lundgren, M Battegay, G Beh- Moller, IJ Rowland BMC Med Imaging. 2008 Jan 14;8(1):1 rens, S De Wit, G Guaraldi, C Katlama, E Martinez, D Nair, WG [Epub ahead of print] Powderly, P Reiss, J Sutinen, A Vigano; 2. Comparison of genotypic resistance profiles and virological HIV Med. 2008 Feb;9(2):72-81 response between patients starting nevirapine and efavirenz 10. Use of nucleoside reverse transcriptase inhibitors and risk in EuroSIDA. WP Bannister, L Ruiz, A Cozzi-Lepri, A Mocroft, of myocardial infarction in HIV-infected patients enrolled in O Kirk, S Staszewski, C Loveday, A Karlsson, A Monforte, B the D:A:D study: a multi-cohort collaboration. Writing group: Clotet, JD Lundgren; EuroSIDA Study Group CA Sabin, SW Worm, R Weber, P Reiss, W El-Sadr, F Dabis, S AIDS. 2008 Jan 30;22(3):367 De Wit, M Law, A D´Arminio Monforte, N Friis-Møller, O Kirk, C 3. The role of antiretroviral therapy on the incidence of pan- Pradier, I Weller, AN Phillips, JD Lundgren. creatitis in HIV-positive individuals in the EuroSIDA study. CJ Lancet. 2008 Apr 26;371(9622):1417-26. E pub 2008 Apr 2 Smith, CH Olsen, A Mocroft, JP Viard, S Staszewski, G Panos, 11. Outcomes from monitoring of patients on antiretroviral T Staub, A Balxhult, N Vetter, JD Lundgren for the EuroSIDA therapy in resource-limited settings with viral load, CD4 cell study group. AIDS. 2008 Jan 2;22(1):47-56 count, or clinical observation alone: a computer simulation 4. Impact of bacteremia on the pathogenesis of experimental model. AN Phillips, D Pillay, AH Miners, DE Bennett, CF Gilks, pneumococcal meningitis. CT Brandt, D Holm, M Liptrot, C JD Lundgren. Lancet. 2008 Apr 26;371(9622):1443-51 Østergaard, JD Lundgren, N Frimodt-Møller, IC Skovsted and 12. Incidence of pancreatitis in HIV-infected patients, and the IJ Rowland. J Infect Dis. 2008 Jan 15;197(2):235-244 association with antiretroviral therapy. CJ Smith, A Mocroft, 5. Procalcetonin in liver transplant patients - yet another stone JD Lundgren; EuroSIDA Study Group. turned. JU Jensen and JD Lundgren. Crit Care Med. 2008, Jan AIDS. 2008 May 11;22(8):997-8. 22;12:108 13. Changes over time in risk factors for cardiovascular disease 6. Incidence and risk factors for new onset diabetes mel- and use of lipid-lowering drugs in HIV-infected individuals litus in HIV infected patients: the D:A:D study. S de Wit, CA and impact on myocardial infarction. Data Collection on Sabin, R Weber, SW Worm, P Reiss, C Cazanave, W El-Sadr, Adverse Events of Anti-HIV Drugs Study Group. CA Sabin, A A d´Arminio Monforte, E Fontas, MG Law, N Friis-Møller, JD d’Arminio Monforte, N Friis-Moller, R Weber, WM El-Sadr, P Lundgren. Diabetes Care. 2008 Feb 11 Reiss, O Kirk, P Mercie, MG Law, S De Wit, C Pradier, AN Phil- 7. Regional differences in the risk of triple class failure in lips, JD Lundgren. Clin Infect Dis. 2008 Apr 1;46(7):1101-10 European patients starting cART after 1 January 1999. A Mo- 14. Inferior clinical outcome of the CD4+ cell count-guided croft, A Horban, B Clotet, A d’Arminio Monforte, JR Bogner, antiretroviral treatment interruption strategy in the SMART P Aldins, T Staub, F Antunes, C Katlama, JD Lundgren for the study: role of CD4+ Cell counts and HIV RNA levels during EuroSIDA study group. HIV Med. 2008 Jan;9(1):41-6 follow-up. Strategies for Management of Antiretroviral 8. Loss to follow-up in an international, multicentre observatio- Therapy (SMART) Study Group. JD Lundgren, A Babiker, W nal study. A Mocroft, O Kirk, P Aldins, A Chies, A Blaxhult, N El-Sadr, S Emery, B Grund, JD Neaton, J Neuhaus, AN Phillips. Chentsova, N Vetter, F Dabis, J Gatell and JD Lundgren, for the J Infect Dis. 2008 Apr 15;197(8):1145-55 EuroSIDA study group. HIV Med. 2008 9(1):261-269

58 15. Determination of the underlying cause of death in three 22. Prevention Strategies for Cardiovascular Disease in HIV-In- multicenter international HIV clinical trials. AR Lifson, WH fected Patients. JH Stein, CM Hadigan, TT Brown, E Chadwick, Belloso, C Carey, RT Davey, D Duprez, WM El-Sadr, JM Gatell, J Feinberg, N Friis-Møller, A Ganesan, MJ Glesby, D Hardy, DC Gey, JF Hoy, EA Krum, R Nelson, DE Nixon, N Paton, C Pe- RC Kaplan, P Kim, J Lo, E Martinez, JM Sosman; for Working dersen, G Perez, RW Price, RJ Prineas, FS Rhame, J Sampson, Group 6. Circulation. 2008 Jun 19. [Epub ahead of print] J Worley. HIV Clin Trials. 2008; 9:177-185 23. Indicator disease-guided testing for HIV--the next step for 16. Interruption of antiretroviral therapy and risk of cardiova- Europe? B Gazzard, N Clumeck, A d’Arminio Monforte, JD scular disease in persons with HIV-1 infection: explora- Lundgren. HIV Med. 2008 Jul;9 Suppl 2:34-40 tory analyses from the SMART trial. AN Phillips, A Carr, J 24. Fungal infection as a risk factor for HIV disease progression Neuhaus, F Visnegarwala, R Prineas, WJ Burman, I Williams, among patients with a CD4 count above 200/microl in the F Drummond, D Duprez, WH Belloso, FD Goebel, B Grund, A era of cART. D Podlekareva, A Mocroft, O Kirk, P Reiss, P Hatzakis, J Vera, JD Lundgren. Antivir Ther. 2008;13(2):177-87 Aldins, C Katlama, H Kovari, HJ Stellbrink, A D’Arminio Mon- 17. Transmitted drug resistance and association with virological forte, JD Lundgren. Scand J Infect Dis. 2008 Jun 18:1-6. [Epub and CD4 cell count response to combination antiretroviral ahead of print] therapy in EuroSIDA. WP Bannister, A Cozzi-Lepri, B Clotet, A 25. Pneumonia in HIV-Infected Persons: Increased Risk with Mocroft, J Kjær, P Reiss, V von Wyl, A Lazzarin, C Katlama, AN Cigarette Smoking and Treatment Interruption. FM Gordin, Phillips, L Ruiz, JD Lundgren and the EuroSIDA study group. MP Roediger, PM Girard, JD Lundgren, JM Miro, A Palfreeman, J Acquir Immune Defic Syndr. 2008 Jun 9. [Epub ahead of MC Rodriguez-Barradas, MJ Wolff, PJ Easterbrook, K Clezy, LN print] Slater. Am J Respir Crit Care Med. 2008 Jul 10. [Epub ahead of 18. Modelled in vivo HIV fitness under drug selective pressure print] and estimated genetic barrier towards resistance are pre- 26. The Procalcitonin And Survival Study (PASS) - a randomised dictive for virological response. K Deforche, A Cozzi-Lepri, K multi-center investigator-initiated trial to investigate Theys, B Clotet, RJ Camacho, J Kjær, K Van Laethem, AN Phil- whether daily measurements biomarker Procalcitonin and lips, Y Moreau, JD Lundgren, and A-M Vandamme on behalf of pro-active diagnostic and therapeutic responses to abnor- the EuroSID Study Group. Antivir Ther. 13:399-407 mal Procalcitonin levels, can improve survival in intensive 19. State of the Science Conference. Initiative to Decrease care unit patients. Calculated sample size (target populati- Cardiovascular Risk and Increase Quality of Care for Patients on): 1000 patients. JU Jensen, B Lundgren, L Hein, T Mohr, PL Living With HIV/AIDS Executive Summary. SK Grinspoon, Petersen, LH Andersen, AO Lauritsen, S Hougaard, T Mantoni, C Grunfeld, DP Kotler, JS Currier, JD Lundgren, MP Dubé, SE B Bømler, KJ Thornberg, K Thormar, J Løken, M Steensen, P Lipshultz, PY Hsue, K Squires, M Schambelan, PW Wilson, KE Carl, JA Petersen, H Tousi, P Søe-Jensen, M Bestle, S Hestad, Yarasheski, CM Hadigan, JH Stein, RH Eckel. MH Andersen, P Fjeldborg, KM Larsen, C Rossau, CB Thom- Circulation. 2008 Jun 19. [Epub ahead of print] sen, C Ostergaard, J Kjaer, J Grarup, JD Lundgren. 20. Epidemiological Evidence for Cardiovascular Disease in BMC Infect Dis. 2008 Jul 13;8:91 HIV-Infected Patients and Relationship to Highly Active Anti- 27. Prediction of phenotypic susceptibility to antiretroviral retroviral Therapy. JS Currier, JD Lundgren, A Carr, D Klein, CA drugs using physiochemical properties of the primary en- Sabin, PE Sax, JT Schouten, M Smieja; for Working Group 2. zymatic structure combined with artificial neural networks. Circulation. 2008 Jun 19. [Epub ahead of print] J Kjær, L Høj, Z Fox, JD Lundgren. HIV Med. 2008 Jul 2. [Epub 21. Development of Appropriate Coronary Heart Disease Risk ahead of print] Prediction Models in HIV-Infected Patients. M Schambelan, 28. Optimal HIV testing and earlier care:the way forward in PW Wilson, KE Yarasheski, WT Cade, VG Dávila-Román, RB Europe. T Coenen, J Lundgren, J Lazarus, S Matic. Sr D’Agostino, TA Helmy, M Law, KE Mondy, S Nachman, LR HIV Med. 2008 JUl;9 Suppl 2:1-5 Peterson, SW Worm; for Working Group 5. Circulation. 2008 Jun 19. [Epub ahead of print]

59 29. Incidence of abacavir hypersensitivity reactions in Euro- 37. Detection of HIV drug resistance during antiretrovrial treat- SIDA. WP Bannister, N Friis-Møller, A Mocroft, J-P Viard, J ment and clinical progression in a large European cohort van Lunzen, O Kirk, P Gargalianos, D Bánhegyi, A Chiesi, JD study. A Cozzi-Lepri, AN Phillips, B Clotet, A Mocroft, L Ruiz, Lundgren, and the EuroSIDA study group. O Kirk, A Lazzarin, A Wiercinska-Drapalo, A Karlsson, JD Antivir Ther. 2008;13(5):687-96 Lundgren for the EuroSIDA Study Group. 30. The clinical application of the EuroSIDA risk score. J Reekie, AIDS. 2008 Oct 18;22(16):2187-98. A Mocroft, O Kirk and J D Lundgren. 38. Cardiovascular risk in HIV Disease. Edited by JS Currier and AIDS & Hepatitis digest. 2008; 126:1-5 JD Lundgren. Curr. Opin in HIV & AIDS. 3(3):205-251, May 31. Use of nucleoside reverse transcriptase inhibitors and risk of 2008 myocardial infarction in HIV-infected patients. The SMART/ 39. Guidelines for managing cardiovascular risk: an evolving INSIGHT and the D:A:D study groups. Writing committee: area. JS Currier, JD Lundgren Curr. Opin in HIV & AIDS. JD Lundgren, J Neuhaus, A Babiker, D Cooper, D Duprez, W 3(3):205-206, May 2008 El-Sadr, S Emery, F Gordin, J Kowalska, A Phillips, RJ Prineas, 40. Conventional cardiovascular risk factors in HIV Infection: P Reiss, C Sabin, R Tracy, R Weber, B Grund and JD Neaton. how conventional are they? C Sabin, SW Worm Curr. Opin in AIDS.2008, 22:F17-F24 HIV & AIDS. 3(3):214-219, May 2008 32. Risk for opportunistic disease and death after reinitiating 41. Antiretroviral therapy as a cardiovascular disease risk factor: continous antiretroviral therapy in patients with HIV pre- fact or fiction? A review of clinical and surrogate outcome viously receiving episodic therapy. A randomized trial. The studies. N Friis-Møller, M Smieja, D Klein Curr. Opin in HIV & SMART study group. Writing group: WM El-Sadr, B Grund, AIDS. 3(3):220-225, May 2008 J Neuhaus, A Babiker, CJ Cohen, J Darbyshire, S Emery, JD 42. EuroSIDA: a prospective observational study of chronic HIV Lundgren, A Phillips and JD Neaton. Infection across the European Continent. JD Lundgren, O Ann Intern Med. 2008;149:289-299 Kirk, A Mocroft [Bookchapter from “A Decade og HAART”, 33. HIV-induced immunodeficiency and mortality from AIDS- published by Oxford University Press. p.195-212] defining and non-AIDS-defining malignancies. A Monforte, D 43. Presence of the metabolic syndrome (MS) is not a better Abrams, C Pradier, R Weber, P Reiss, F Bonnet, O Kirk, M Law, predictor of cardiovascular disease (CVD) than the sum of S De Wit, N Friis-Møller, AN Phillips, CA Sabin, JD Lundgren; its components in HIV-infected individuals. Data Collection Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) on Adverse Events of Anti-HIV Drugs (The D:A:D study). SW Study Group. AIDS. 2008 Oct 18;22(16):2143-53 Worm, CA Sabin, P Reiss, W El-Sadr, AD Monforte, C Pradier, 34. The elusive search for an HIV vaccine-And what to do mean- R Thiebaut, M Law, M Rickenback, S De Wit, JD Lundgren, NF while. JV Lazarus, A Häggblom, L Kirkegaard, JD Lundgren, S Møller NF. Diabetes Care. 2008 Dec 3. [Epub ahead of print] Matic. Vaccine. 2008 Sep 24. abstract 35. Inflammatory and Coagulation Biomarkers and Mortality in 44. Response to combination antiretroviral therapy: variation by Patients with HIV Infection. LH Kuller, R Tracy, W Belloso, SD age. The Collaboration of Observational HIV Epidemiological Wit, F Drummond, HC Lane, B Ledergerber, J Lundgren, J Neu- Research Europe (COHERE) Study group. haus, D Nixon, NI Paton, JD Neaton for the INSIGHT SMART AIDS. 22(12):1463-1473, July 31, 2008 Study Group. PLoS Med. 2008 Oct 21;5(10):e203. 36. The EuroSIDA study: regional differences in HIV-1 epidemic and treatment response to antiretroviral therapy among HIV-infected patients across Europe - a review of published results. D Podlekareva, W Bannister, A Mocroft, L Abrosi- mova, I Karpov, JD Lundgren, O Kirk for the EuroSIDA study group Cent Eur J Public Health. 2008 Sep;16(3):99-105.

60 Presentations 2008

15th Conference on Retroviruses and Opportunistic Infections, 8. Hepatitis Virus Co-infections and Risk of Diabetes Mellitus Boston, February 2008 (DM) and Myocardial Infarction (MI) in HIV-infected Persons: Poster presentations The D:A:D Study. R Weber, C Sabin, P Reiss, S De Wit, S 1. The use and response to second combination antiretrovi- Worm, M Law, F Dabis, A d’Arminio Monforte, E Fontas, J ral therapy (cART) regimens in EuroSIDA. A Cozzi-Lepri, M Lundgren Cunnington, A Lazzarin, B Clotet, B Knysz, P Gargalianos, C Oral presentations Katlama, A Karlsson, AN Phillips, J D Lundgren 1. Re-initiation of antiretroviral therapy (ART) in the CD4-gui- 2. What frequency of monitoring is needed for health-care in ded ART interruption group in the SMART study lowers risk a HIV-infected person? J Reekie, B Gazzard, H Sambatakou, of opportunistic disease or death. W El-Sadr and the SMART A Chiesi, J van Lunzen, N Clumeck, O Kirk, A Mocroft, L Ma- study group chala, J Lundgren 2. Elevated levels of interleukin-6 and D-dimer are associated 3. Indicators of the use of health care interventions across with an increased risk of death in patients with HIV. L Kuller Europe. D Podlekareva, J Reekie, A Rakhmanova, A Horban, A and the SMART study group Mocroft, I Karpov, P Domingo, F Antunes, O Kirk, JD Lundgren 3. Age/sex-specific death rates in ART naïve patients with and the EuroSIDA study group CD4 count above 350 cells/mm3 compared with the general 4. Do Thymidine Analogues, Abacavir, Didanosine and Lamivu- population. R Lodwick, K Porter, C Sabin, B Ledergerber, A dine Contribute to the Risk of Myocardial Infarction (MI)? Cozzi-Lepri, P Khaykin, A Mocroft, L Jacobson, S de Wit, A Recent Use of Abacavir and Didanosine, but not of Thymidine Phillips on behalf of the Study Group on Death Rates at High Analogues, Is Associated with Risk of Myocardial Infarction. CD4 Count in Antiretroviral Naive Patients The 9th Internatio- Writing group: CA Sabin, SW Worm, R Weber, P Reiss, W El- nal Congress on Drug Therapy in HIV Infection, Sadr, R Thiebaut, S De Wit, M Law, A D’Arminio Monforte, N Friis-Møller, O Kirk, C Pradier, S Collins, I Weller, AN Phillips, Polish National Conference on HIV, Warsaw, June 2008 JD Lundgren on behalf of the D:A:D study group Poster presentation 5. Deterioration of renal function (DRF) associated with current 1. Risk of myocardial infarction attributable to abacavir: Analy- level of immunodeficiency. O Kirk, A Mocroft, A d’Armino sis to assess the number needed to treat to harm. Justyna D. Monforte, A-BE Hansen, JM Gatell, S Caplinskas, G Fätken- Kowalska, Ole Kirk, Amanda Mocroft, Jens D. Lundgren heuer, P Reiss, E Vinogradova, JD Lundgren for the EuroSIDA study group. XVII International HIV Drug Resistance Workshop, Sitges, 6. Characteristics and clinical outcome of patients with HIV- June 2008 associated tuberculosis (HIV/TB) in Europe and Argentina. Poster presentations D Podlekareva, A Mocroft, A Panteleev, J Toibaro, A Rakhma- 1. In silico identification of physiochemical properties at nova, V Riekstina, H-J Furrer, O Suetnov, F Post, O Kirk and mutating positions relevant to reduced susceptibility to the HIV/TB Study Group amprenavir. L Høj, J Kjær, O Winther, A Cozzi-Lepri and JD 7. Hepatitis C virus (HCV) coinfection does not influence the Lundgren. CD4 cell recovery in HIV infected patients with maximum 2. The rate of accumulation of NNRTI-resistance in patients virologic suppression within the EuroSIDA cohort. L Peters, A kept on a virologically failing regimen containing NNRTI: a Mocroft, V Soriano, J Rockstroh, P Aldins, M Losso, L Valerio, EuroSIDA Study. A Cozzi-Lepri, B Clotet, R Paredes, J Kjær, AN P Reiss, B Ledergerber, JD Lundgren for the EuroSIDA study Phillips, and JD Lundgren for the EuroSIDA study group. group.

61 3. Treatment-ermergent gag cleavage site mutations during 4. Predicting the short term risk of diabetes in HIV infected virological failure of ritonavir-boosted protease-inhibitors. patients in the D:A:D cohort: The D:A:D study group. K Petou- A Garcia- Diaz, Z Fox, UB Dragsted, J Kjær, N Clumeck, A Phil- menos, E Fontas, SW Worm, R Weber, S De Wit, M Bruyand, lips, JD Lundgren and AM Geretti. CA Sabin, P Reiss, W El-Sadr, A D´Arminio-Monforte, N Friis-Møller, JD Lundgren, M Law on behalf of the D:A:D study XVII International AIDS Conference, Mexico City, August 2008 group. Oral presentations 5. The relationship between an adverse effect of antiretroviral 1. Use of nucleos(t)ide reverse transcriptase inhibitors (NRTIs) treatment and underlying risk in number needed to treat and risk of myocardial infarction in HIV-infected patients to harm - risk of myocardial infarction and abacavir use. J enrolled in the SMART study. JD Lundgren and the SMART/ Kowalska, O Kirk, A Mocroft, L Høj, N Friis-Møller, P Reiss, JD INSIGHT and D:A:D Study Groups. Lundgren 2. TB and injecting drug use in Eastern Europe Clinical and 6. Poor clinical oputcome in HIV-infected patients coinfected Epidemiological Aspects and Implications for Public Health. with mycobacterium tuberculosis (TB) in Eastern Europe. The D Podlekareva HIV/TB collaborative study. D Podlekareva, A Mocroft, F Post, V Riekstina, J Miro, H Furrer, M Bruyand, E Malashenkov, Glasgow, November 2008 E Girardi, JJ Toibaro, J Cayla, R Miller, N Obel, A Skrahin, N Oral presentations Chentsova, JD Lundgren, O Kirk and the HIV/TB study group. 1. Patterns of prior viral suppression on cART as predictors of Poster presentation future risk of viral rebound. J Reekie, A Mocroft, B Lederger- 1. Are non-B subtypes less susceptible to antiretroviral drugs? ber, M Beniowski, B Clotet, J van Lunzen, A Chiesi, C Pradier, - a bioinformatical approach to prediction on non-B subtype L Machala, JD Lundgren susceptibility. J Kjær, L Høj, N Friis-Møller, P Reiss, JD Lundgren 2. Opportunistic infections in immunocompromised but virologically suppressed HIV-1 infected patients. W Bannister, A Mocroft, O Kirk, P Reiss, A d´Arminio-Monforte, J Gatell, M Fischer, H Trocha, A Rakhmanova, and JD Lundgren. 3. The rate of change of CD4 count (CD4 slopes) in patients with stable HIV viremia currently taking combination antiretroviral therapy or off all antiretrovirals. A Mocroft, AN Phillips, B Ledergerber, J Bogner, K Lacombe, A Wiercinska- Drapalo, P Reiss, O Kirk, JD Lundgren for the EuroSIDA study group.

62 Edited by: Karen Skov Hansen and Maria Paulsen CHIP (Copenhagen HIV Programme)

Layout: Zofia Kruszona, Photo: Susanne Østergaard AV-group, Hvidovre Hospital, Print: Kailow Graphic A/S 02/2009 Also private photos from CHIP staff members are included in the report. University of Copenhagen, Faculty of Health Sciences The Panum Institute/Building 21.1 Blegdamsvej 3B 2200 Copenhagen N Denmark Tel: +45 35 45 57 57 Fax: +45 35 45 57 58 www.cphiv.dk [email protected]