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HIV/AIDS JOURNAL

Volume 15, Supplement 4

Eleventh International Congress on Drug Therapy in HIV Infection 11–15 November 2012, Glasgow, UK

Scan this QR code with Joint Academic Sponsors

University College London Medical School

(UCLMS), UK

Karolinska Institutet Stockholm

Sweden

Weill Cornell Medical College of Cornell University

New York, USA

International AIDS Society Academic Medical Centre

University of Amsterdam The Netherlands

PRE‑ AND POST‑EXPOSURE PROPHYLAXIS

LATE

PRESENTERS

ADHERENCE

AE s

CLINICAL

PHARMACOLOGY

COMMUNITY

INITIATIVES ^COST

EFFECTIVENESS

ARV DELIVERY

HIV‑RELATED INFECTIONS

LABORATORY MONITORING

AGEING

M TC T

TREATMENTS AND TARGETS

NON‑AIDS MORBIDITIES AND MORTALITY

TREATMENT AS PREVENTION

RESISTANCE

TR EA TM EN T OF C HIL DR EN

TREATMENT STRATEGIES

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Volume 15, Supplement 4 November 2012

About the journal

The Journal of the International AIDS Society, an official journal of the Society, provides a peer‑reviewed, open access forum for essential and innovative HIV research, across all disciplines.

All articles published by the Journal of the International AIDS Society are freely accessible online. The editorial decisions are made independently by the journal’s editors‑in‑chief.

Email: editorial@jiasociety.org Website: http://www.jiasociety.org eISSN: 1758‑2652

Editorial board

Editors-in-Chief: Susan Kippax (Australia), Papa Salif Sow (Senegal), Mark Wainberg (Canada) Executive Editor: Shirin Heidari (Switzerland) Managing Editor: Mirjam Curno (Switzerland) Editorial Board:

Quarraisha Abdool Karim (South Africa) Dennis Altman (Australia)

Joe Amon (United States) Judith Auerbach (United States) Francoise Barré‑Sinoussi (France) Chris Beyrer (United States) Nomita Chandhiok (India) Mark Cotton (South Africa) Mary Crewe (South Africa) John N. Erni (China) Alex Ezeh (Kenya) Nathan Ford (South Africa) Diane Havlir (United States) Kuan‑Teh Jeang (United States) Fatima Juarez (Mexico) Elly Katabira (Uganda) Sukhontha Kongsin (Thailand)

Ivette Lorenzana de Rivera (Honduras) Kathleen MacQueen (United States) Julio Montaner (Canada)

Hector Perez (Argentina) Deborah Posel (South Africa) Subhasree Raghavan (India) Naomi Rutenberg (United States) Seema Sahay (India)

Gabrielle Scarlatti (Italy) Amalio Telenti (Switzerland) Marco Vittória (Switzerland) Ian Weller (United Kingdom) Alan Whiteside (South Africa) Yazdan Yazdanpanah (France)

Publisher

International AIDS Society Avenue de France 23 1202 Geneva, Switzerland Tel: +41 (0) 22 710 0800 Email: info@iasociety.org

Website: http://www.iasociety.org Indexing/abstracting

The Journal of the International AIDS Society is indexed in a variety of databases including PubMed, PubMed Central, MEDLINE, Science Citation Index Expanded and Google Scholar.

Advertising, sponsorship and donations Please contact the editorial office if you are interested in advertising on our journal’s website. We also gladly receive inquiries on sponsorship and donations to support open access publications from authors in low‑ and middle‑income countries.

Supplements

The Journal of the International AIDS Society publishes supplements, special issues and thematic series on own initiative or based on proposals by external organizations or authors. Inquiries can be sent to the editorial office at editorial@jiasociety.org. All articles submitted for publication in supplements are subject to peer review. Published supplements are fully searchable and freely accessible online and can also be produced in print.

Disclaimer

The authors of the articles in this supplement carry the responsibility for the content and opinions expressed therein.

The editors have made every effort to ensure that no inaccurate or misleading content or statements appear in this supplement. However, in all cases, the publisher, the editors and editorial board, and employees involved accept no liability for the consequences of any inaccurate or misleading content or statement.

Copyright

The content in this supplement is published under the Creative Commons Attribution‑NonCommercial 3.0 Unported (http://

creativecommons.org/licenses/by‑nc/3.0/) license. The license allows third parties to share the published work (copy, distribute, transmit) and to adapt it, under the condition that the authors are given credit, that the work is not used for commercial purposes, and that in the event of reuse or distribution, the terms of this license are made clear. Authors retain the copyright of their articles, with first publication rights granted to the Journal of the International AIDS Society.

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Volume 15, Supplement 4 November 2012

Abstract supplement

Eleventh International Congress on Drug Therapy in HIV Infection 11 – 15 November 2012

Infectiousness is dictated by the concentration of HIV-1 in relevant fluids (regardless of route of transmission) and the viral genotype and phenotype. People newly infected with HIV-1 (i.e. acute infection) and those with STI co-infections excrete such a large concentration of virus as to be ‘‘hyperinfectious.’’ The actual transmission of HIV likely occurs in the first few hours after exposure.

The probability of transmission may be as low as 1/10,000 episodes of intercourse or 1/10 sexual exposures when anal intercourse is practiced. The transmission of HIV is generally limited to one or a small number of founder variants which themselves may be

‘‘hyperinfectious.’’ Synergistic behavioural and biologic HIV prevention strategies have been developed and implemented. Safer sex includes limiting the number of sexual partners, use of male latex condoms, and structural interventions to reduce exposure. These strategies appear to have contributed to reduced HIV incidence in many countries. Biological interventions have proved catalytic: these include treatment of inflammatory cofactors, voluntary male cir- cumcision and use of antiviral agents either for infected people (who can be rendered remarkably less contagious) or as pre- and post- exposure prophylaxis (PrEP and PEP). Ecologic evidence suggests that broader, earlier antiviral treatment of HIV may be reducing incidence in some (but not all) populations. However, maximal benefit of HIV

‘‘treatment for prevention’’ and application of PrEP will likely require a program of universal ‘‘test and treat,’’ where many more infected patients are identified, linked to care, and treated very early in disease and for life. Community randomized trials designed to support this approach are under way in Africa. The ‘‘test and treat’’

prevention strategy is resource-intensive and serves to emphasize research that searches for a cure for HIV infection so that people living with HIV can eventually reduce or stop treatment. Likewise, success in HIV prevention emphasizes the importance zof development of an HIV vaccine, which remains focused on agents that may evoke CTL responses, antibody dependent cytotoxicity, and (perhaps most important) broad neutralizing antibodies. A human clinical trial (RV144) and animal experiments have provided hope, excitement and a roadmap for development of an HIV vaccine.

http://dx.doi.org/10.7448/IAS.15.6.18066

KL2

HIV eradication: virological chances and clinical perspectives Perno, C

University of Rome ‘Tor Vergata’, Rome, Italy.

Once a retrovirus infects a eukaryotic cell and integrates within chromosomal DNA, it becomes part of its genome and can be activated/transcribed/translated to produce viral proteins and/or new viral particles. Over the years, some of these retroviruses may lose their pathogenicity and become adapted to the new host. Under these conditions, retroviruses can paradoxically ameliorate the functional portfolio of the infected cell, thus potentially increasing its functionality and/or chances of survival in a difficult environment.

Individuals whose cells are infected by retroviruses have acquired, in the last millions of years, innovative functions that, once transmitted to the new generation through germinal cells, have become essential for their homeostasis, or even for their survival. This is the case of some endogenous retroviruses, whose products are mandatory for the proper vascularization of human placenta. To our knowledge, there are no natural means able to selectively eliminate retroviral genes from an infected cell or an individual. Therefore, the chances of getting naturally cured by retroviruses, once infection is set and viral genomes are spread into the body, are minimal or absent. HIV is a retrovirus that behaves as all other retroviruses that interacted with humans in the past millennia. Its fate is to remain forever within the infected body. For these reasons, the chances of getting rid of HIV infection and being biologically cured (that is, eliminating all viral genomes from the body) are very limited if we consider current knowledge, biotechnology and available medical tools (yet it cannot be fully excluded in very peculiar cases). The option offered by the so-called ‘‘functional cure’’ is different. In this case, medical manipulation may create conditions whereby viral genomes, decreased in number and function by proper therapies/vaccines, are no longer able to harm the host for an indefinite period of time. Patients do remain infected, but viral replicative cycles are absent, and progression of the disease is interrupted. This latter clinical approach may be suitable, and this is where clinical research is directing its efforts. If achievable, infected persons should cope with the virus and keep it under control for decades, without support of chronic antiviral therapy. In conclusion, the proper knowledge of the biological characteristics of HIV helps in selecting the best strategies aimed at obtaining the maximum achievable clinical result.

KL3

From HIV to global health: opportunities and challenges El-Sadr, W

Columbia University and International Center for AIDS Care and Treatment Programs (ICAP), New York, USA.

Remarkable advances have been achieved over the past decade in confronting the global HIV epidemic. By the end of 2010, 6.5 million persons living with HIV had initiated antiretroviral therapy in low and middle-income countries, the majority in sub Saharan Africa. Of the total of 2.5 new HIV infections that occurred in 2010, 1.9 million occurred in sub Saharan Africa. Nonetheless, 22 countries in sub Saharan Africa have experienced a decrease in HIV incidence.

These remarkable achievements have involved a transformation of fragile health system. Examples include new models of care, task shifting, infrastructure enhancement, establishment of new data systems and mobilization of communities.

However, many of the same countries where HIV is prevalent also confront other health threats including high maternal and child mortality, high rates of tuberculosis and malaria as well as a burgeoning non-communicable chronic disease threat. Addressing these health threats requires taking the lessons learned from the HIV response and adapting them to confront these threats. Through building on the foundation established, similar progress may be achieved in addressing these health threats while maintaining the momentum of the HIV response.

KEYNOTE LECTURES

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O11 - ART FOR PREVENTION AND TREATMENT

O111

Pre-exposure prophylaxis: where are we in Europe?

Molina, JM

Saint-Louis Hospital and University of Paris, Paris, France.

Despite major advances in HIV therapy, the number of new HIV infections remains very high, even in high-income countries where resurgence among men who have sex with men (MSM) has been witnessed. New prevention strategies have therefore to be assessed in order to curb the incidence of HIV infection. Recent studies have explored the effectiveness of antiretroviral therapy (ART) for HIV prevention and have generally yielded encouraging results. ART has been used successfully to prevent mother-to-child transmission of HIV, HIV acquisition following occupational or sexual exposure to HIV (post-exposure prophylaxis), and more recently, to reduce the risk of HIV transmission within a serodiscordant couple by treating the HIV- positive partner (HPTN 052 study). Another possible use of ART in prevention is pre-exposure prophylaxis, where ART is taken by an HIV- seronegative individual before HIV exposure. This PrEP strategy has been validated in animal models and more recently assessed in clinical trials in humans. The results of six large efficacy trials of PrEP are now available, but results have been inconsistent. The use of tenofovir gel in women at higher risk in Sub-Saharan Africa has shown efficacy when given before and after sex in the Caprisa 004 study (reduction of 39% of the incidence of HIV), whereas no efficacy was shown with daily use in the VOICE trial. Similarly, daily oral PrEP with tenofovir or tenofovir and emtricitabine has proved effective in the Iprex trial in MSM (reduction of 42% of HIV incidence), in the Partners PrEP study (reduction of 67 to 75% in HIV incidence) and in the TDF-2 trial (reduction of 63% in HIV incidence), but not in the Fem-PrEP or the VOICE trials in women. There are many potential explanations for these apparently conflicting results, such as the populations in which these strategies have been assessed, the differential pharmacokinetics of ART in the male and female genital tracts and most likely the high level of adherence which is required to confer protection against HIV acquisition. These results have also generated a lot of controversy about the implementation of PrEP. Some think that the data are good enough to rollout PrEP in key populations at higher risk. Others think more research is needed before PrEP is implemented because of concerns around safety, emerging resistance, cost and change in sexual behaviour that might offset the benefit of PrEP. Safety is indeed a major concern in healthy individuals. New studies are underway to address these issues and are assessing PrEP regimens in open-label studies (Iprex-OLE in MSM), intermittent PrEP regimens to try to improve adherence, new ART classes and new modalities of drug delivery. PrEP is therefore a promising biomedical intervention that might be used in the near future in addition to current prevention methods to prevent HIV infection and help control the spread of this infection.

O112

When to start: as soon as possible Saag, M

University of Alabama, Birmingham, USA.

Debate regarding ‘‘When to start’’ antiretroviral (ARV) therapy has raged since the introduction of zidovudine in 1987. Based on the entry criteria for the original Burroughs Wellcome (002) study, the field has been anchored to ‘‘CD4 counts’’ as the prime metric to indicate ARV treatment initiation for asymptomatic HIV-positive individuals. The pendulum has swung back and forth, based mostly on the efficacy and toxicity of available regimens. In today’s world, several factors have converged that compel us to initiate therapy as soon as possible: (i) The biology of viral replication (1 to 10 billion viruses/day) screams that we should be starting early. (ii) Resultant inflammation from unchecked replication is associated with earlier onset of multiple co-morbid conditions. (iii) The medications available today are more efficacious and less toxic than in years past.

(iv) Clinical trials have demonstrated benefit for all but the highest CD4 strata ( 450 to 500 cells/mL). (v) Some cohort studies have demonstrated clear benefit of ARV therapy at any CD4 count, and almost all cohort studies have demonstrated no detrimental effects of early treatment. (vi) In addition to the demonstrated and inferred benefits to the individual patient, we now have a public health benefit of earlier intervention: treatment is prevention. Finally, from a practical/common sense perspective, we are talking about life-long therapy. Whether we start at a CD4 count of 732 or 493/mL, the patient will be on therapy for over 40 to 50 years! There does not seem to be much benefit in waiting, and there is likely to be significant long-term harm. Treat early!

O113

When to start: not so fast Lundgren, J

Copenhagen University Hospital and University of Copenhagen, Copenhagen, Denmark.

It remains controversial whether and, if so, the extent to which antiretroviral therapy (ART) results in net benefit if used by HIV- positive persons with a high CD4 count, particularly those with early HIV infection. This controversy is primarily reflecting lack of solid evidence from randomized controlled trials. Currently published trials have compared early ART with initiation of ART below currently globally accepted thresholds for initiation (i.e. CD4 count at 350 cells/

mL) and, hence, are unable to inform this discussion. Analyses on large observational studies that have attempted to address this question have shown inconsistent results; therefore, those results are considered low-quality evidence, as per the GRADE criteria used by, for example, WHO when formulating guidelines. In resource-constrained regions, not even observational data are available to inform this question. The START study is underway to answer this question. Data remain blinded, but START may show net harm from early use of ART;

such a result would severely undermine use of ART as prevention in early HIV infection. Prescription of any type of medicine is guided by the principle of ‘‘do no harm’’ that is, ‘‘the doctor should not prescribe medications unless s/he knows that the treatment is un- likely to be harmful.’’ Hence, the balance of risk/benefit to individuals versus prevention benefit is important to accurately determine, and current guidelines of generally initiating ART once the patient de- velops HIV-related symptoms or the CD4 count drops to levels around 350 cells/mL should be adhered to until further evidence has emerged.

ORAL ABSTRACTS

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O114

Late presenters: what can we do?

Mussini, C

University of Modena, Modena, Italy.

Late presentation represents a major problem for patients with HIV infection. Actually, it should be made a distinction between late testers and late presenters since the strategies to reduce the percentage of these two groups of subjects could be different.

Indeed, the first population is represented by individuals unaware of their serological status, while in the second case the problem is related to engagement and retention in care. Concerning the first population, it has been shown that most of the patients had been seen by their family doctor or admitted to hospital during the year before HIV diagnosis. Indeed, this is a relevant problem, and new strategies to increase the level of suspicion of HIV infection among doctors who are non-HIV specialists are needed, as testing in presence of indicator diseases, should be applied. Concerning the population of late presenters, American data showed a percentage of engagement in care ranging between 50 and 59%. These low percentages could be due to the American Health System, while in a public health system setting, the percentage of patients not engaged in care or lost to follow-up could be lower, even if still relevant. Another important factor that should be considered in both populations is stigma. Indeed, many patients that present late, either late testers or late presenters, are immigrants and have important cultural barriers to disclose their HIV serostatus to family members and friends. Obviously, all subjects unaware or refusing their HIV infection could potentially infect their partners. In conclusion, all efforts should be made to reduce the phenomenon of late presentation since these two populations represent an epidemiological problem not only for the prognosis of the single patient but also for the treatment as prevention strategy.

O12 - CLINICAL CHALLENGES

O121

HIV, co-morbidity and ageing Reiss, P

Academic Medical Center, University of Amsterdam, Division of Infectious Diseases and Department of Global Health, Amsterdam, The Netherlands.

As treatment for HIV infection needs to be used continuously and lifelong, issues concerning long-term outcomes, including those involving tolerability and safety of treatment, are gaining increasing importance. Although current combination antiretroviral therapy (cART) regimens are generally better tolerated than those in the early days of cART, treatment toxicity remains an important cause for discontinuation of (components) of treatment. Moreover, several of the potential toxicities of cART (including cardiovascular, metabolic, renal and bone toxicity) overlap with known ageing-associated co- morbidities. Given that our patient population with HIV is increasingly getting older as a result of the success of cART in reducing traditional HIV-associated morbidity and mortality, these co-morbidities are increasingly being seen and importantly influence patient management. Moreover, persons with HIV, in spite of having suppressed viraemia on cART seem to be at increased risk of the premature development of age-associated non-communicable co-morbidities, including cardiovascular, chronic kidney, liver and pulmonary disease, diabetes mellitus, osteoporosis, non-AIDS associated malignancies,

and neurocognitive impairment. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated ageing. The underlying pathogenesis is likely to be multifactorial and, apart from include sustained immune activa- tion, both systemically and within the central nervous system.

The presentation will review the current state of knowledge and investigation in this area.

O122

TB and HIV: how can we reduce mortality?

Lawn, S

University of Cape Town, Cape Town, South Africa.

Despite ART scale-up, tuberculosis (TB) remains a leading cause of HIV-related deaths worldwide and much of this disease may remain unascertained. In patients receiving ART, TB incidence is highest during the first few months of treatment (many cases of which were prevalent disease missed by baseline screening) and long-term rates remain several-fold higher than background. We identify three groups of patients starting ART for which different interventions are required to reduce TB-related deaths. First, diagnostic screening is needed in patients who have undiagnosed active TB so that timely anti-tuberculosis treatment can be started. This may be greatly facilitated by new diagnostic assays such as the Xpert MTB/RIF assay and a novel point-of-care urine test for lipoarabinomannan (LAM).

Second, patients with a diagnosis of active TB need optimised case management, which includes early initiation of ART (with early timing now defined by randomised controlled trials), trimethoprim- sulphamethoxazole prophylaxis and treatment of co-morbidity. Third, in high TB burden settings, all remaining patients who are TB-free at enrolment have high ongoing risk of developing TB and require optimised immune recovery (with ART ideally started early in the course of HIV infection), isoniazid preventive therapy and infection control to reduce infection risk. Further specific measures are needed to address multi-drug resistant TB (MDR-TB) and there are now new promising developments in antimycobacterial agents.

Finally, in high burden settings, scale-up of all these interventions requires nationally and locally tailored models of care that are patient-centred and provide integrated health care delivery for TB, HIV and other co-morbidities.

O123

HIV in women Mulcahy, F

St James’s Hospital, Dublin, Ireland.

Globally over 50% of HIV-infected individuals are women. With the widespread use of HAART, we can expect women to have mortality rates approaching normal. Indeed, studies have shown that women may expect a slower disease progression than men following seroconversion; furthermore, it appears that female who injects drugs can live longer than their male counterparts. However, other studies from cohort analysis have reported worse outcomes in women. In essence, many studies are consistently underpowered to adequately address these questions. The proportion of women in clinical trials remains at 20 to 30%, with pregnancy potential being a major exclusion factor. Hence, many questions remain unanswered.

Recent data suggest women are more likely to present late with a new AIDS diagnosis. Why this should be the case is not well understood.

In addition, HIV-positive women should have the same access to reproduction health as their negative counterparts, but unfortunately

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many inequalities remain. Advise on contraception and fertility services are very variable across both the developed and developing world. Data are limited on the most appropriate use of contraceptives in the presence of HAART, the possible drug interactions and possible increased risk of HIV transmission. There remain significant differences in guidelines regarding prevention of mother-to-child transmission (MTCT) across Europe, and implications of stopping and starting HAART for MTCT have not been adequately addressed. The mode of timing of delivery, and the effect of length of time of ruptured membranes on this decision is also contentious. Further issues relate to the desire for HIV-positive women to breastfeed in the setting of HIV viral suppression, where some guidelines now support women in this situation and others categorically would inform child protection authorities. Finally as women age it is more difficult to separate the effect of the menopause and its symptoms from the increased HIV- related cardiovascular and bone fracture risk. This presentation aims to discuss key issues which conflicting or inadequate data fail to resolve.

O13 - LIVING LONGER WITH ART

O131

Review of life expectancy in people with HIV in settings with optimal ART access: what we know and what we don’t Sabin, C

University College London, London, UK.

Life expectancy (LE) is an important indicator of health used widely by government and healthcare agencies to monitor trends over time and to determine resource allocation, as well as by insurance companies and pension providers. LE of the HIV-positive population has increased dramatically since the introduction of combination antiretroviral therapy (cART); indeed, it is now believed that LE may be similar to that of the general population in some subgroups. There are, however, specific subgroups in which LE remains substantially im- paired. The impact of HIV and of cART on mortality may be expressed in several ways. LE itself provides an estimate of the average additional number of years that an individual would be expected to live beyond a particular age. However, the detrimental impact of HIV may also be described in terms of the number of years of life lost or the gains in LE if HIV were to be eliminated as a cause of morbidity in the population. My presentation will start with a description of the different methods that researchers have used to describe the mortality outcomes of those with HIV, and the impact of cART on these. I will then consider how LE in the HIV-positive population has changed over time and will describe the impact of demographic factors (e.g. gender, age, ethnic group) on LE. To investigate the circumstances under which LE may return to normal levels, I will also consider the potential impact of timely diagnosis and linkage into care, continued engagement with care, optimal initiation of cART and maintenance of viral suppression on LE. Finally, I will discuss some of the limitations of the approaches used to estimate LE, with particular emphasis on the confounding effects of lifestyle and behavioural factors when making any comparison with LE in the general population.

O132

Currently available medications may not be sufficient for lifelong treatment of HIV

Jansson, J¹; Wilson, D¹; Carr, A²; Petoumenos, K¹and Boyd, M¹

1University of New South Wales, Kirby Institute, Sydney, Australia.²St Vincent’s Hospital, Sydney, Australia.

Purpose of the study: Combination antiretroviral therapy (cART) has greatly improved the life expectancy of people living with HIV (PLHIV).

A series of cohort studies have predicted near-to-normal life expectancies for PLHIV receiving cART but have not considered the impact of multi-class resistance on long-term survival. Our study aims to project the future life expectancy of PLHIV in a resource-rich setting in the context of the currently available antiretroviral treatments.

Methods: Patient antiretroviral treatment data, including time on each regimen until treatment failure, were sourced from an observational cohort of 3434 predominantly male (94.2%) PLHIV in Australia over the period 1997 to 2010. These data were analyzed in an individual-based mathematical model to calculate the time until exhaustion of all treatment options and the expected impact on HIV-associated mortality. Standardized mortality ratios were used to simulate expected survival before and after treatment exhaustion.

Summary of results: The model estimated that the median time until exhaustion of currently available treatment options is 43.4 years (interquartile range 31.4 to 58.6 years). However, the model predicts that 10% of PLHIV will use up all currently available cART options after just 22.6 years. The figure shows the survival proportions of males from age 20 years in four mortality scenarios:

(1) the general population mortality rate; (2) the mortality rate in PLHIV as currently measured (without considering exhaustion of currently available treatments); (3) mortality rate in PLHIV considering additional mortality due to limited cART options; and (4) mortality rate if no cART is available. PLHIV who start currently available cART regimens at age 20 years are expected to live to a median of 64.7 (95% uncertainty bound (UB)61.8 to 69.3) years of age, when adjusting for treatment option exhaustion.

This is a substantial improvement on no cART (median survival to 27.6 [95% UB27.2 to 28.1] years of age) but is lower than the expected life expectancy (82.2 years of age) of an HIV-negative male in the general population. The gap between life expectancy among PLHIV and the general population is greater for those infected at younger ages.

Conclusions: As treatment options are exhausted in the coming years, a substantial difference in life expectancy between PLHIV and the general population is expected, particularly for people who acquire HIV at a younger age or who are currently highly treatment- experienced.

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O133

Life expectancy of HIV-1-positive individuals approaches normal conditional on response to antiretroviral therapy:

UK Collaborative HIV Cohort Study May, M¹; Gompels, M²and Sabin, C³

1University of Bristol, Bristol, UK.²North Bristol NHS Trust Bristol, UK.³University College London, Medical School, London, UK.

Life expectancies (LEs) of patients in UK Collaborative HIV Cohort (UK CHIC) stratified by CD4 count at start of antiretroviral therapy (ART) have been estimated [1] but not gains in years of life in response to ART. We estimated LE associated with attained CD4 count and viral suppression at different durations of ART. Patients in UK CHIC aged 20 years who started ART in 2000 to 2008 (excluding person who injects drugs) were followed to end of 2010. All-cause mortality was ascertained from clinic notes and by linkage to national records. We used the nearest CD4 count before ART and the last in each of years 1 to 5 of ART and determined whether patients were virally suppressed (HIV-1 RNA B400 copies/mL) in the past year for those remaining under follow-up. Poisson models were used to estimate mortality rates by sex, age, latest CD4 count ( B200, 200 to 349, ]350) and viral suppression for each duration of ART. Abridged life tables were constructed from age-specific mortality rates to estimate LE for ages 20 to 85 years. Results are presented as the average number of years that will be lived after exact age 35 years. A total of 17,021 patients started ART from 2000 to 2008 of whom 708 (4.2%) died; 3956 (23%) were lost to study follow-up. There was no difference in mortality between those with attained CD4 350 to 499 and ]500. On starting ART, male LE at exact age 35 was 36, 44 and 42 (female LE 38, 46 and 44) years for attained CD4 B200, 200 to 349, ]350, respectively; after 5 years on ART, it was 22, 42 and 46 (female LE 27, 46 and 51) years, respectively. Only 17% of patients had CD4 ]350 at ART start, compared with 78%

of patients on ART for 5 years. The difference in LE between suppressed versus unsuppressed patients was around 11 years. The figure shows that both CD4 count and viral suppression contribute to changes in LE. Male patients that increased their CD4 in the 1st year of ART from B200 to 200349 or ]350 gained 6 and 11 years of LE to 42 and 48 years, respectively, with similar rises for women.

Overall, LE was 4 years greater for those on ART for 5 years compared with those starting ART. Individuals that attain viral suppression and a CD4 count 350 within 1 year of ART start have a normal LE with 35-year olds estimated to live to over 80 years on average. LE in patients with CD4 count B200 beyond 5 years on ART drops by 15 years. Estimated LE may be biased by under-ascertain- ment of deaths, missing CD4 measurements and extrapolation beyond available data.

Reference

1. May M, Gompels M, Delpech V, Porter K, Post F, Johnson M, et al.

Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ.

2011;343:d6016.

O14 - THE HIV RESEARCH TRUST

O141

Clinical pharmacokinetics of antiretroviral drugs in Ugandan patients

Lamorde, M

Makerere University, Kampala, Uganda; Glasgow Resource Limited Scholar 2008 and HIV Research Trust Scholar.

Clinical pharmacokinetic data on antiretroviral drugs are scarce in African HIV-1-positive patients. Most available pharmacokinetic data are derived from ethnically distinct Caucasian research volunteers.

This presentation will focus on the clinical pharmacokinetics training and research outputs of an HIV Research Trust scholarship recipient in Uganda. The work highlights the need for post-marketing pharmacokinetic studies in the target populations in order to optimize therapy for patients in resource-limited settings.

O21 - ROYAL COLLEGE OF PHYSICIANS AND SURGEONS OF GLASGOW LOCK LECTURE

O211

Treatment optimization in low- and middle-income countries

Cooper, D

University of New South Wales, Sydney, Australia.

The unprecedented, successful collaborative international effort to provide universal access to HIV care, including effective antiretroviral therapy (ART), has reached a critical time point. The global economic downturn, changing donor priorities and competing priorities in the health sector threaten the capacity of various agencies to maintain support for the continued scale-up of access toward the UN General Assembly-agreed target of 15 million people with HIV/AIDS receiving ART by 2015. This aspiration has recently received added impetus as we have come to understand that treatment acts as prevention by reducing the infectiousness of treated individuals. It is now necessary to review the elements of the success to date, in order to be able to do more with less. These elements include efforts to optimize delivery of HIV care, including ART, in low- and middle-income countries (LMIC); the emergence of new agents and drug classes which have simplified HIV treatment and made broader successful management more achievable; and changes to commencement protocols. Recent studies have indicated that earlier commencement of HIV therapy is beneficial, leading to changes in the recommended ART initiation threshold in LMIC to B350 CD4 T cells/mL. Studies currently underway are investigating approaches to second-line ART in LMIC. The results from these studies will better inform the rollout of effective second-line therapy. In addition, the financial cost of ART makes

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optimization of dosing an important consideration in LMIC, in order to maximize effectiveness while limiting costs. ART monitoring is also an important priority in LMIC. Efforts to develop simple and reliable technologies that can provide rapid results in the field are underway.

The final priority is operational optimization, to ensure service delivery through initiatives such as exploiting economies of scale and the training and retention of health professionals. Although the challenges in LMIC are substantial and evolving, considerable inroads have been and are being made into optimizing HIV treatment in this area, which is crucial in reducing the global impact of the disease.

O22 - ART DILEMMAS IN RESOURCE- LIMITED SETTINGS

O221

HAART rollout in the new fiscal and economic environment Moatti, J

Aix-Marseille University, Marseille, France.

The trend towards universal access for HIV prevention and treatment that was initiated at the beginning of the 21st century (international donor funding has been multiplied by 3 to reach 27 billion US$ in 2010) has been threatened by the 20089 economic crisis which currently translates in a fiscal crisis for most developed countries (including the US, France and the UK the main donors for HIV/

AIDS). Other advances such as the drastic drop in ARV drug prices are also threatened (generic first line drugs close to marginal cost, insufficient drop in second line drug prices, etc.). The presentation will discuss the negative consequences of slowing down and delaying universal access on macro-economic growth in the most affected countries and suggest alternative sources of funding such as the financial transaction tax recently introduced by the French Parliament.

O222

Eliminating paediatric infections and keeping mothers alive Gray, G

University of the Witwatersrand, Johannesburg, South Africa The global plan of reducing the number of new child HIV infections and a reduction in the number of HIV-related maternal deaths by 2015 will require inordinate political commitment and strengthening of health systems in Sub-Saharan Africa where the burden of HIV infections in pregnant women is the highest. Preventing HIV infection in women of child-bearing age and unwanted pregnancies in HIV-positive women forms the cornerstone of long-term control of paediatric HIV infections. To achieve the goal of eliminating paediatric HIV infection by 2015, health systems strengthening to address prevention of mother-to-child HIV transmission cascade attrition and focusing on the elimination of breastmilk transmission is critical. Understanding the pathogenesis of breastmilk transmission and the mechanisms by which antiretroviral therapy impacts on transmission through this compartment will drive future interventions. Identifying and retaining HIV-positive pregnant women in care and committed to long-term antiretroviral therapy will improve maternal outcomes and concomitant reductions in maternal mortality. Research assessing the natural history of HIV infection and long- term outcomes in women who interrupt antiretroviral therapy post-weaning is urgently required. Data on the outcome of women

who opt to continue the long-term use of antiretroviral therapy after initiating therapy during pregnancy will determine future policy in countries considering option B. The prevalence of antiretroviral resistance and impact on survival in infants who sero-convert whilst receiving neonatal prophylaxis, or are exposed to maternal HAART through breastmilk at a population level, are currently unknown. In addition to the provision of biomedical interventions, healthcare workers and policy makers must address the structural, cultural and community issues that impact on treatment uptake, adherence to medication and retention in care.

O223

HIV drug resistance surveillance in low- and middle-income countries: 2004 to 2010

Bertagnolio, S¹; Parkin, N²and Jordan, M³

1HIV Department, World Health Organization, Geneva, Switzerland.

2Data First Consulting, Belmont, USA.³Division of Geographic Medicine and Infectious Disease, Department of Public Health and Community Medicine Tufts University School of Medicine, Boston, USA.

Background: At the end of 2011, over 8 million people were receiving antiretroviral therapy (ART) in low- and middle-income countries (LMIC), a 26-fold increase from 2003. Some degree of HIV drug resistance (HIVDR) will emerge among populations on combination ART even when high levels of adherence are achieved. In 2004, the World Health Organization (WHO) initiated global HIVDR surveillance to monitor emergence and transmission of HIVDR in countries scaling-up ART.

Methods: WHO HIVDR surveillance strategy was designed to inform public health decision-making regarding choice of ART and to identify ART programme factors which could be adjusted to minimize HIVDR emergence. The strategy includes (1) surveillance of transmitted HIVDR (TDR) in recently infected populations, (2) surveillance of acquired HIVDR (ADR) in populations on ART and (3) monitoring of early warning indicators (EWI) of HIVDR which are ART programme factors favouring HIVDR emergence. Surveys used standardized protocols. Epidemiological and sequence data were quality assured.

Results: TDR: Eighty-two surveys were conducted in 30 countries in 2004 to 2010, assessing 3588 recently infected individuals. Pooled analysis indicates an overall prevalence of 3.1% TDR to at least one drug class, 1.6% to non-nucleoside reverse transcriptase inhibitor (NNRTI), 1.3% to nucleoside reverse transcriptase inhibitor (NRTI) and 0.7% to protease inhibitor (PI). Levels of NNRTI resistance, particularly in the areas surveyed in Africa, increased over time, reaching 3.4% (95% CI1.8 to 5.2%) in 2009. Greater ART coverage was associated, though modestly, with increased prevalence of TDR to NNRTI (P-value adjusted for region0.039). ADR: Thirty-six ADR surveys assessing 6370 people in 12 LMIC were conducted in 2007 to 2010. HIVDR prevalence to any drug among those initiating ART ranged from 4.8% (95% CI3.8 to 6.0%) in 2007 to 6.8% (95%

CI4.8 to 9.0%) in 2010. Ninety per cent of patients alive and on therapy at 12 months achieved viral load B1000 c/mL. Among people with virological failure, 72% had HIVDR to at least one drug.

EWI: EWIs were monitored at 2017 clinics in 50 countries assessing 131,686 people since 2004. Overall, 75% of clinics met the target of 100% of patients receiving appropriate ART; 69% of clinics met the B20% target for lost to follow-up at 12 months; and only 65% of clinics provided a continuous supply of ART during a 12-month period.

Conclusion: Expansion of ART in LMIC has resulted in an overall increase in HIVDR, particularly to NNRTI in Africa. EWIs reveal important gaps in service delivery and programme performance.

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While these data call for continued and improved scale up of surveillance, they also suggest that resistance is under control in the areas surveyed, and the majority of patients initiating or switching therapy are likely to respond to currently available first- and second- line therapy.

O224

Does early initiation of ART in infants affect virological and resistance outcomes? Data from the CHER trial after 6 years of follow-up

Violari, A¹; Cotton, M²; Otwombe, K¹; Hunt, G³; Kalimashe, M³; Panchia, R¹; Morris, L³; Pillay, D⁴; Babiker, A⁵and Gibb, D⁵

1University of the Witwatersrand, Perinatal HIV Research Unit, Johannesburg, South Africa.²Stellenbosch University, Children’s Infectious Diseases Clinical Research Unit, Tygerberg, South Africa.

3National Institute for Communicable Diseases (NICD), AIDS Virus Research Unit, Johannesburg, South Africa.⁴University College London, London, UK.⁵MRC Clinical Trials Unit, London, UK.

Purpose of the study: Virological outcomes and resistance patterns in children initiating protease inhibitor (PI)-based antiretroviral therapy (ART) immediately following HIV-1 diagnosis are not well described. Challenges include maintaining adherence in asymptomatic patients with very high pre-ART viral loads. The CHER trial compared deferred but continuous ART (arm 1) with early limited ART (arms 2 and 3).

Methods: LPV/rZDV3TC was commenced either immediately (in 250 of 252 children randomized in arms 2 and 3) or at clinical/

immunological progression (103 of 125 children in arm 1). Interrup- tion of ART occurred after 40 (arm 2) or 96 weeks (arm 3) and re- initiation with LPV/rZDV3TC was based on immunologic/clinical criteria. Viral load was measured on all children with a stored specimen at their last visit, having been on initial or restarted ART following interruption (arms 2 and 3) for at least 24 weeks. Children in arms 1, 2 and 3 not initiating ART due to death (16, 0, 0), LTFU (2, 2, 0) or other reason (4, 0, 0) are excluded. Resistance testing was performed on samples with a viral load (VL) ]1000 c/mL together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and PI inhibitor mutations were analyzed using a validated in-house population-based sequencing assay and the IAS 2011 mutation list.

Summary of results: A total of 377 infants were enrolled; median was age 7.4 (interquartile range (IQR) 6.7 to 8.9) weeks and median baseline viral load was log105.7. By end of study (June 2011), 353/

377 children had started LPV/rZDV3TC. Median (IQR) age at ART initiation in arms 1, 2 and 3 was 26.1 (19.9 to 40), 7.4 (6.6 to 8.7) and 7.5 (6.6 to 9.0) weeks. Median (IQR) duration on ART was 240 (216 to 252), 243 (200 to 260) and 240 (194 to 257) weeks in arms 1, 2 and 3, respectively. HIV-1 RNA was B400 c/mL in 88/101 (87%), 95/113 (84%) and 97/117 (83%) (P0.96). Twenty-two of thirty-two children with VL 1000 c/mL (2/5, 8/14, 12/13 in arms 1, 2 and 3) have had resistance tests to date; nine (41%) had mutations. There were seven with M184V mutations (1, 4, 2 in arms 1, 2 and 3); two with major PI mutations (V82A/L76V) (one in each of arms 1 and 2);

and two with major NNRTI mutations (K103N/M230L) (one in each of arms 2 and 3). Two of ten children tested to date had NNRTI mutations prior to starting PI-based triple therapy.

Conclusions: Virological response on ART was excellent in this large cohort of infants initiating LPV/rZDV3TC at a very young age, with no differences between randomized strategies, suggesting that planned interruption after early limited ART does not adversely affect virological outcomes. Overall, approximately 40% of those on ART with VL 1000 c/mL had a resistance mutation; PI mutations were

infrequent, despite around 5 years on therapy. Ongoing work will investigate impact of length of time with detectable viral load on risk of developing resistance.

O225

Evolution of resistance in paediatric patients with failure on antiretroviral therapy

Orrell, C¹; Levison, J²; Ciaranello, A²; Bekker, L¹; Kuritzkes, D³; Freedberg, K²and Wood, R¹

1University of Cape Town, Desmond Tutu HIV Centre, Cape Town, South Africa.²Massachusetts General Hospital, Division of Infectious Diseases, Boston, USA.³Harvard Medical School, Boston, USA.

Introduction: HIV-1 resistance data to inform treatment sequencing are limited for children with virological failure on first- and second- line antiretroviral therapy (ART) in Sub-Saharan Africa.

Methods: HIV-1-infected children aged 515 years were retro- spectively identified from an ART cohort in Cape Town, South Africa (2003 to 2010). First-line ART was either non-nucleoside reverse transcriptase inhibitor (NNRTI) or lopinavir/ritonavir-based (with the exception of children B6 months old who received full-dose ritonavir as the sole protease inhibitor (PI) from 2004 to 2007).

Second-line ART was the alternative regimen. Treatment outcomes, including virological failure, loss to care, death or remaining in care, were determined. Genotypic resistance testing was conducted on stored serum from children at first- or second-line virological failure (two consecutive HIV-1 RNA levels 1000 copies/ml). International AIDS Society criteria defined resistance mutations.

Results: Of 472 children starting first-line ART, 352 (75%) remained in care, 45 (9%) were lost and 4 (1%) died on first-line treatment.

Seventy-one (15%) had observed virological failure, and 37 of these children had specimens available for genotype testing. Eight children (22%) had wild-type virus, seven (19%) had thymidine analog mutations (TAMs), 24 (65%) had NNRTI resistance and two (5.4%) had multiple protease resistance (PR). Of the 78 children who received second-line ART, 54 (71%) remained in care, 6 (8%) were lost and 1 (1%) died during second-line treatment. Fifteen (20%) had observed virological failure; 13 had samples available for genotype.

Three (23%) had wild-type virus, eight (62%) had TAMs, nine (69%) had NNRTI resistance, and five (38%) had multiple PI resistance all of whom had received full-dose ritonavir.

Conclusion: Although virological failure was infrequent in children on first- and second-line ART, rates of observed resistance including multiple PR resistance after failure were high. Reasons for high rates of resistance include use of full-dose ritonavir and continued viremia.

Wild-type virus was common, suggesting poor adherence or challenges in correct dosing. Genotype resistance testing in children with virological failure may optimize selection of subsequent regimens and inform recommendations for sequencing of existing ART.

O23 - DRUG RESISTANCE

O231

Importance of minor variants and their detection (ultra- deep sequencing) in the management of HIV infection Paredes, R

University Hospital Germans Trias i Pujol, Barcelona, Spain.

Sanger genotypic drug resistance assays currently used for routine HIV management often miss low-frequency drug-resistant HIV

Abstract supplement - Eleventh International Congress on Drug Therapy in HIV Infection

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