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Infectious Disease Reports 2013; volume 5:s1e2

Recent developments in HIV ing world needs access to new HIV treatments, an AIDS-free generation depends upon it. Correspondence: Osman Ebrahim, Department of treatment and their Medical Microbiology, Faculty of Health Sciences, dissemination in poor countries University of Pretoria, PO Box 1073, Houghton 2041, Johannesburg, South Africa. Osman Ebrahim,1 Introduction Tel. +27.11.6479142 - Fax: +27.11.6428921 E-mail: [email protected] Ahmad Haeri Mazanderani2 1Department of Medical Microbiology, In June 2011, as the world entered the Key words: HIV/AIDS, antiretroviral therapy, Faculty of Health Sciences, University fourth decade of the HIV/AIDS epidemic, UN developing countries. Member States unanimously endorsed a new of Pretoria; 2Department of Medical Conflict of interest: the authors declare no con- set of Global AIDS Response targets to be Virology, Faculty of Health Sciences, flict of interests. achieved by 2015. These included eliminating University of Pretoria and National new amongst children, substantially Received for publication: 19 February 2013. Health Laboratory Service, Tshwane reducing the number of AIDS-related maternal Accepted for publication: 19 February 2013. Academic Division, South Africa deaths, and halving the sexual transmission of This work is licensed under a Creative Commons 1 HIV. Despite the absence of an effective vac- Attribution NonCommercial 3.0 License (CC BY- cine and an incidence of 2.5 million new infec- NC 3.0). tions last year, 70% of whom reside in sub- Abstract Saharan Africa, there has been renewed hope ©Copyright O. Ebrahim and A.H. Mazanderani, that the epidemic can be controlled.2 The opti- 2013 As the world enters the fourth decade of the mism is partly on account of evidence which Licensee PAGEPress, Italy Infectious Disease Reports 2013; 5:s1e2 HIV/AIDS epidemic a number of new drugs suggests antiretroviral therapy (ART) can doi:10.4081/idr.2013.s1.e2 have been developed that address current chal- effectively prevent the transmission of HIV,3 lenges with antiretroviral therapy (ART), such and data demonstrating a decline in incidence as pill burden, and drug-resistance. and death rates in some of the most afflicted The WHO currently recommends one of two These new agents have not only been devel- countries of the world.² HIV treatment is esti- only treatment regimens - a first-line regimen (an oped from established drug-classes, namely mated to have saved 14 million life years since NNRTI plus two NRTIs, one of which should be nucleoside inhibitors 1995 in low- and middle-income countries and AZT or TDF) for initiating treatment in all (NRTIs), non-nucleoside reverse transcriptase genuine efforts are underway to scale up roll- those who are HIV positive with CD4+ inhibitors (NNRTIs) and protease inhibitors out programmes with a target of having 15use mil- counts of less than 350 cells l (and/or have (PIs), but also include innovative ways of sup- lion HIV-infected people on treatment by stage III-IV disease), and a second-line regi- pressing viral replication. Intergrase inhibitors 2015.1,2 Amid this renewed emphasis on treat- and receptor blockers have been ment, we look at recent developments in the men (a boosted PI plus two NRTIs, developed which, combined with NRTIs, field of antiretroviral therapy, and in particular one of which should be AZT or TDF depending NNRTIs and PIs, comprise highly active anti- their role and dissemination in the developing on first-line choice. ATV/r or LPV/r are the pre- retroviral therapy regimens able to tackle all world. ferred PIs) in the event of first-line treatment 5 aspects of the HIV life cycle with minimal toxi- Currently 8 million people access ART glob- failure. Both regimens contain a cocktail of city. Furthermore, the ability of pharmaceuti- ally, with 54% of people who are eligible for three drugs which were developed over a cal companies to formulate these powerful treatment in the developing world receiving decade ago. Subsequently, new HIV treatments drugs into fixed-dose combinations provides ART.2 The majority of this treatment is made have emerged within the global ART landscape exciting new strategies for reducing pill bur- available through donor-sponsored roll-out which promise to facilitate scaling up distribu- den, thus ensuring adherence and limiting the programmes which have adopted a public- tion of ART by lowering costs and assisting emergence of drug-resistance. The enthusi- health approach as advocated by the World supply management; improving adherence on asm with which these new drugs have been Health Organisation (WHO). In contrast to account of better side-effect profiles, easier to received has, however, been tempered by the individualized specialist physician manage- administer formulations and reduced pill-bur- reality of limited access in the developing ment, these programmes have been designed den; and enhancing efficacy by providing the world, further highlighting the Non-commercial disparity for low- and middle-income countries as a possibility of a third-line regimen in the event between rich and poor countries in the fight means of providing greater access to ART of drug-resistance. These new medicines against HIV/ AIDS. Access to these treatments whilst taking into consideration the limited include fixed-dose combinations (FDCs), bet- in low- and middle-income countries will resources and expertise available.4 By employ- ter drug formulations, new drugs belonging to require the necessary political will, regulatory ing standardized and simplified treatment pro- established classes, such as second-generation approval, affordability of drugs, as well as effi- tocols real progress has been made in scaling- NNRTIs and PIs, and agents from whole new cient procurement and supply management up HIV/AIDS services in the developing world.2 drug-classes, which include the strategies. The priority of developing countries However, a successful ART programme not inhibitors and fusion inhibitors. Appreciating remains increased scale up of ART, but there is only depends on the accessibility of drugs, but the need to improve the efficiency and effec- also a need to acquire new drugs in order to also continued adherence to medicines that tiveness of HIV treatment programmes, the tackle toxicity and drug-resistance, both of remain effective. Apart from societal factors, WHO and the Joint United Nations Programme which threaten the sustainability of such pro- and in particular community leadership, which on HIV/AIDS (UNAIDS) launched Treatment grammes. Thankfully, the vast majority of is increasingly being appreciated as having a 2.0 in July 2010, a strategy to further simplify patients receiving ART in the developing world central role in the sustainability of HIV treat- treatment regimens to support the scale up of are still on first-line regimens, thus allowing ment programmes,2 the antiretrovirals (ARVs) ART by promoting the use of new drugs.6 The time for newer agents to be made available as themselves critically influence the distribu- interconnectivity between distribution, adher- part of third-line treatment option. However, tion, adherence and effectiveness of HIV treat- ence and efficacy of antiretroviral therapy, and there is no room for complacency - the develop- ment. the potential impact of new developments in

[page 2] [Infectious Disease Reports 2013; 5:s1e2] Review

HIV treatments on ART roll-out programmes in facing roll-out programmes in the developing advantage is its efficacy against B the developing world is the focus of this world. which, along with , make it an addi- review. We will first discuss new drug innova- FDCs are, of course, not without complica- tionally attractive first-line option in areas tions, including FDCs, new agents with tions. No single regimen can safely be used for with a high prevalence of , such as reduced side-effects, better formulations, and all patients and standardising treatment is in sub-Saharan Africa, China and South- drugs that can be used to address the increas- approaches to accommodate drug toxicity is East Asia. Tenofovir is of course not a new ing threat of drug-resistance. Thereafter we challenging.4 The WHO has in the past used an drug, having been approved by the FDA in briefly discuss the distribution of new HIV FDC containing d4T+lamivudine+ 2001. However, it was very slow to be approved treatments in the developing world, and the as first-line therapy which caused consider- by regulatory agencies in the developing world, shortcoming thereof, with a focus on South able morbidity, the toxicity of d4T and nevirap- an important bottle-neck that we shall consid- Africa. ine being well documented.9 er later in more detail, and it has only recently Exciting new FDCs include Eviplera and replaced d4T, AZT and ddI as a first-line agent Complera, which contains a cocktail of teno- in WHO guidelines.5 fovir, , and rilpivarine (an FDA Tenfovir is, however, not without side- New drug developments approved second generation NNRTI), and effects, which include and bone Quad, a formulation of tenofovir, emtric- demineralization. The of tenofovir, There are currently 27 FDA approved ARVs, itabine, and . Quad is GS-7340, which requires a much reduced and more than 15 drugs and combinations in unique on account of it including a second- dosage may alleviate some of these problems. the development pipeline.6 Each agent targets generation (elvitegravir) Newer NNRTIs and PIs also boast reduced a specific point in the HIV life-cycle, with a and the pharmacoenhancer cobicistat – side-effects, such as and . suppressive ARV regimen having the net effect designed specifically as a pharmacokinetic A new heat-stable formulation of of preventing viral replication. Drug classes booster. Eviplera has been found to be as effec- atazanavir/ritonavir is now available, and has include the older more established nucleoside tive as atripla with the added advantage of not the additional benefit of only requiring one pill and reverse transcriptase inhibitors containing thus avoiding neuropsy- taken daily – a much more favourable option (NRTIs and NtRTIs), non-nucleoside reverse chiatric side effects,10 whereas Quad promises comparedonly with the twice daily dosing of two transcriptase inhibitors (NNRTIs) and the pro- to be an attractive FDC which could potentially pills of heat-stable -ritonavir. tease inhibitors (PIs). Two new classes have be used as a second- or third-line regimen that Furthermore, integrase inhibitors are unlikely recently been added to the armamentarium, would avoid the neuropsychiatric symptoms of to produce severe side effects as the enzyme these being the integrase inhibitors and entry efavirenz and skin-rashes associated with integrase is not normally present in human inhibitors (including CCR5 coreceptor antago- other NNRTIs, and the metabolic side-effectsuse cells. nists and fusion inhibitors). For a list of new commonly experienced with protease developments, both approved and in the inhibitors.11 7 New formulations pipeline, please refer to Table 1. A number of additional FDCs are in develop- ment including those based on cobicistat boosted darunavir, and the third integrase Recent developments include FDA approved inhibitor, , both combined with two oral suspension of darunavir for children older Fixed dose combinations NtRTIs.7 than 3 years of age; chewable tablets for children 2-18 years old; oral powder The WHO suggests regimens that are easy and tablets of tenofovir for children 2-18 years to administer, such as those that involve fewer old; and tablets for children 6-18 pills with simple dosing schedules, as a way to New drugs with good safety years old.11 However, genuine advancement in ensure or improve patient adherence.6 FDCs new-drugs designed for treating children with have been endorsed as a solution to the profile HIV is lacking and further research on appro- numerous pills and dosing schedules involved priate drug regimens in paediatric and adoles- in taking Highly Active Antiretroviral HIV co- with , viral cent populations is critically needed.14 Treatment (HAART), with some combinations hepatitis and other opportunistic infections is containing a fully-suppressive HAARTNon-commercial regimen common, especially in the developing world. that requires a single daily dose and doesn’t Simultaneous treatment of co-infections and need refrigeration. A number of such FDCs HIV is problematic not only because of the high New drugs and resistance have been developed for first-line therapy but pill-burden but also due to drug-drug interac- have been slow to penetrate treatment pro- tions, overlapping , and paradoxical Invariably, increased access to treatment grammes in the developing world. HAART reg- reactions. This can potentially affect drug brings new challenges, including the looming imens in a single (TDF+FTC+EFV, mar- adherence and lead to treatment failure. spectre of drug-resistance. A recent systematic keted as atripla) have been available in the US (d4T), (AZT) and review of the literature suggests that 60% of since 2006 and promise to be cost effective (ddI) are still widely used in devel- people failing NNRTI-based first line therapy treatment options. South Africa, which has the oping countries as an NRTI backbone in the in low- and middle-income countries have drug largest antiretroviral programme in the world, first-line regimen.12 Toxicities from these med- resistance.15 has been detect- will finally have such a combination starting in icines in the form of lipoatrophy, increased ed in 80% of South African patients who expe- 2013 with the South African department of skin pigmentation, peripheral neuropathy and rienced failure of a first-line HAART regimen, health reporting to have saved R2.2 billion on are well documented. Tenofovir with dual-class drug-resistant virus present in its latest tender.8 Apart from improving treat- (TDF), an NtRTI, is in comparison well tolerat- 64.3% of participants.16 Drug resistance can ment adherence FDCs are also considered to ed on account of having a low affinity for mito- also be transmitted, with data from WHO sur- assist prescribing and aid procurement and chondrial polymerase and can actually improve veys suggesting that greater coverage of anti- supply management – important challenges lipoatrophy and dyslipidaemia.13 Another retroviral therapy is associated with a higher

[Infectious Disease Reports 2013; 5:s1e2] [page 3] Review

Table 1. HIV treatment pipeline 2003-2012. Class Drug name Generic name Brand name Sponsor Status NRTI FTC Emtricitabine Emtriva Triangle/Gilead Approved (2003) NRTI AG1549 Agouron/Pfizer Discontinued (2005) NRTI DAPD Gilead/Emory/RFS Pharma Discontinued (2010) NRTI MIV-310, FLT Boehringer Ingelheim/Medivir/Beijing Mefuvir To Mefuvir (2008) NRTI ACH-126443 Achillion Phase II (2007) NRTI D-d4T, DPC-817 Reverset Pharmasset/Incyte Discontinued (2006) NRTI SPD-754, AVX-754, ATC Shire BioChem/Avexa Discontinued (2010) NRTI Pharmasset Discontinued (2008) NRTI 4’-Ed4T, OBP-601 (ex festinavir) BMS-986001 Bristol-Myers Squibb Phase II (2012) NRTI CMX-157 Chimerix Phase I (2012) NtRTI GS-7340, PMPA Gilead Phase II (2012) NNRTI TMC-125 Etravirine Intelence Janssen (ex Tibotec) Approved (2008) NNRTI Advanced Life Sciences/ Sarawak MediChem Phase II (2005) NNRTI DPC-083, AI-183 Bristol-Myers Squibb Discontinued (2004) NNRTI TMC-278 Edurant Janssen (ex Tibotec) Approved (2011) NNRTI BILR-355/r BS Boehringer Ingelheim Discontinued (2008) NNRTI UK-453061 Lersivirine Pfizer Phase II (2012) NNRTI Viramune XR Boehringer Ingelheim Approved (2011) NNRTI Rilpivirine-LA Janssen (ex Tibotec) Phase I (2012) injectable PI Atazanavir Reyataz Bristol-Myers Squibbonly Approved (2003) PI VX-175, GW-433908 Lexiva Vertex/GlaxoSmithKline Approved (2003) PI Aptivus Boehringer Ingelheim Approved (2005) PI TMC-114 Darunavir Prezista Janssen (ex Tibotec) Approved (2006) PI GSK-640385 GlaxoSmithKlineuse Discontinued (2007) PI PPL-100 Ambrillia/Merck Discontinued (2008) FI T-20 Fuzeon Trimeris/Hoffmann-La Roche Approved (2003) CCR5RI SCH-C, SCH-351125 Schering-Plough Discontinued (2004) CCR5RI UK-427857 Selzentry Pfizer Approved (2007) CCR5RI SCD-D, SCH-417 Schering-Plough Discontinued (2010) CCR5RI/2RI TAK-652, TBR-652 Takeda/Tobira Phase II (2012) InI MK-0518 Raltegravir Isentress Merck Approved (2007) InI GS-9137, JTK-303 Elvitegravir Gilead Submitted (2012) InI S/GSK-1349572 Dolutegravir GlaxoSmithKline/Shionogi/ViiV Phase III (2012) InI GSK-1265744 GlaxoSmithKline/ Shionogi Phase II (2012) InI GSK-1265744 (LA) Long-acting GSK-1265744 GlaxoSmithKline/Shionogi Phase I (2012) Anti-CD4 Mab TNX-355, Hu5A8 Tanox/Biogen Idec/TaiMed Phase II (2011) AI PRO-542 Progenics Discontinued (2004) AI PA-457, MPC-4326 Panacos/Vitex/Myriad Discontinued (2011) AI PRO-140 Progenics Discontinued (2011) AI (gp120) BMS-663068 Non-commercialBristol-Myers Squibb Phase II (2012) PK booster GS-9350 Cobicistat Gilead Submitted (2012) PK booster SPI-251 Sequoia Discontinued (2011) PK booster CTP-518 GlaxoSmithKline On hold (2012) FDC ABC/3TC Zidovudine/lamivudine Epzicom GlaxoSmithKline Approved (2003) FDC FTC/TDF Emtricitabine/tenofovir Truvada Gilead Approved (2004) FDC EFV/FTC/TDF Efavirenz/emtricitabine/ Atripla Bristol-Myers Approved (2006) tenofovir Squibb/Gilead FDC RLV/FTC/TDF Rilpivirine/emtricabine/ Complera/Eviplera Janssen (ex Tibotec)/Gilead Approved (2011) tenofovir FDC EVG/COBI/ FTC/TDF Elvitegravir/cobicistat/ Quad Gilead Submitted (2012) emtricitabine/tenofovir FDC Elvitegravir/cobicistat/ Gilead Phase II (2012) emtricitabine/GS-7340 FDC Darunavir/cobicistat/emtricitabine/GS-7340 Janssen (ex Tibotec)/Gilead Phase II (2012) FDC Dolutegravir//lamivudine 72-Trii ViIV Phase III (2012) Adapted from Clayden et al., 2012 with permission.7 NRTI, nucleoside reverse transcriptase inhibitor; NtRTI, nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverese transcriptase inhibitor; PI, protease inhibitor; FI, fusion inhibitor; CCR5RI, CCR5 receptor inhibitor; CCR2RI, CCR2 receptor inhibitor; InI, integrase inhibitor; AI, attachment inhibitor; MI, ; PK booster, pharmacokinetic booster; FDC, fixed dose combination.

[page 4] [Infectious Disease Reports 2013; 5:s1e2] Review prevalence of transmitted drug resistance, par- which requires advanced laboratory support, ing sustained access to HIV treatment. ticularly to NNRTIs.15 8.6% of newly HIV-1 diag- prior to its use. Enfuvirtide is the prototype of UNAIDS recommends countries to take steps nosed young adults in Uganda have been found the fusion inhibitors and was specifically towards building local pharmaceutical capacity to have transmitted drug-resistance, compared designed for the treatment of HIV-1 infection in order to take full advantage of the flexibili- with 0% in a study conducted four years earli- in ART-experienced adults and children over 6 ties permitted under the Trade-Related Aspects er.17 years of age. It needs to be administered by of Intellectual Property Rights (TRIPS) agree- The proportion of patients on a second-line subcutaneous injection and binds to HIV ment.2 regimen in resource-limited settings is cur- protein, thereby inhibiting fusion of HIV with rently estimated to be between 1-5%.18 As scale the target cell. For salvage therapy the drug up of ART continues and access to seems to be very valuable in individual cases, monitoring improves, demand for second-line although it probably has only a minor role to Lowering costs treatment will increase. Similarly, patients will play in the future of HIV treatment in the increasingly need third-line regimens, as the developing world.26 Generic drugs have been found to be on inevitable eventuality of virological failure on average a third of the price when compared second-line treatment arises. A number of new with medicines of brand companies. The dis- drugs have been approved to address these tribution of these agents in the developing needs, including second generation NNRTIs, Dissemination of antiretrovi- world has been contingent on the lack of prod- PIs, as well as new classes of drugs such as rals in developing countries uct patents in India over older drugs, the issu- integrase inhibitors, CCR5 (chemokine recep- ing of voluntary licenses by brand companies tor) antagonists and fusion inhibitors. The provision of ART across the developing to generic manufacturers, and the non- Darunavir, a new non-peptidic protease world does not represent a single uniform enforcement of patents.28 India is the world’s inhibitor, has demonstrated impressive poten- practice. A number of parallel programmes largest producer of generic medicines, cy in the presence of PI resistant mutants, including those sponsored by national govern- accounting for more than 80% of global ARV hence its importance in treating therapy-expe- ments, NGOs, as well as private practice all purchasing, supplying the majority of ARVs to 19 rienced patients. Etravirine, a second-gener- operate in low- and middle-income countries. developingonly countries.29 However, the produc- ation NNRTI, was approved in 2008 for ART- As the majority of those living with HIV reside tion and exportation of generic pharmaceuti- experienced adult patients and has been found in sub-Saharan Africa, and as South Africa has cal agents is being challenged by ongoing to be effective in the presence of NNRTI resist- the largest ARV programme in the world, we negotiations for an EU-India Free Trade ant mutants, including the signature mutation have chosen to limit our focus to this part of Agreement that could potentially overrule K103N.20 Rilpivirine, like Etravirine, is also a the world. Furthermore, as countriesuse continue India’s national patent laws. As newer ARVs second generation NNRTI and is effective to increase their domestic expenditure in are more widely-patented than older drugs this against most NNRTI resistant viruses. The funding the HIV/ AIDS response, with South threatens the supply of life-saving medicines advantage of Rilpivirine is that it comes in a 25 Africa having increased its spending five-fold to where they are needed most.30 Drugs that mg dose and has a longer half half-life (40 from 2006-2009 and currently funding more are currently under patent include agents that hours), making it a useful drug for FDCs.11 than 75% of its national roll-out programme,2 could be used in third-line regimens which are The integrase inhibitors, which include the authors of this review consider the dissem- not currently available to the majority of Raltegravir, the first of its class, and newer ination of new ARVs in South Africa to be par- patients failing second-line treatment in the agents dolutegravir and elvitegravir, are attrac- adigmatic for the rest of the developing world. developing world. These agents include the tive options for third-line treatment in the The provision of ARVs in the developing second generation NNRTI etravarine and PI developing world as they belong to an entirely world is dependent on multiple factors includ- darunavir (both under patent until 2019), and new class of drug with no risk of cross-resist- ing political will, regulatory approval, afford- the first generation integrase-inhibitor ralte- ance from prior ART exposure in first- and sec- ability of drugs, as well as procurement and gravir (under patent until 2022), hence the ond-line therapy.21 They also have a wide range supply management. The global economic cri- appeal by activist groups for earlier availability of efficacy for R5 and X4 tropic viruses as well sis that began in 2008 has seen a decrease in of generic versions of these new medicines. as suppressing the replication of HIV-2. donor spending for the HIV/AIDS epidemic in However, as HIV treatment patents have not Raltegravir has been found to beNon-commercial able to sup- low- and middle-income countries. As two- been universally enforced in the past it is hard press viral loads to below 50 copies/mL in thirds of all AIDS expenditure in Africa comes to determine whether patent protection will in patients with extensive treatment history.22 from external sources, this dependency threat- itself prevent the timely dissemination of cost- However, it has a low genetic barrier to resist- ens to destabilize efforts to increase availabil- effective ARVs to the developing world. ance which can compromise its efficacy as ity of ARVs to where they are needed most, and Concerns over the quality of generic drugs mutants are able to develop rapidly on a failing in particular delay the dissemination of new is being addressed by bioequivalence studies regimen.23 HIV treatments. The United Nations estimates conducted by the FDA, approval of which ren- Additional drugs that can be used to treat there is a US $9 billion deficit in the HIV fund- ders the products eligible for purchase under HIV resistant strains include CCR5 antago- ing needed to meet its 2015 goals, and has sub- the PEPFAR programme. Such quality assur- nists and fusion inhibitors, both of which pre- sequently proposed a number of strategies that ance checks are necessary to ensure quality vent entry of the virus into target cells. can be adopted to bridge the resource gap. medicines are distributed to developing coun- Maraviroc, a CCR5 antagonist and the first Innovative taxation models such as financial tries. However, regulatory bodies in the devel- drug of its class, is currently used in treat- transaction tax, also known as the Robin Hood oping world appear to be slowing the distribu- ment-experienced CCR5-tropic HIV-1 infected Tax, is being advocated by UNAIDS and was tion of drugs already approved by the FDA. For patients in high-resource countries.24 Recently recently adopted in France where a portion will example, the South Africa Medicines Control it has also been shown to have activity against be put towards the fight against HIV/AIDS.27 Council (MCC) only approved Tenofovir in CCR5-tropic HIV-2 infections.25 However, its Furthermore, investing in local manufacturing 2007, whereas it had been approved by the FDA use is severely limited in the developing world and simplifying market access to drugs are in 2001. Approval of fixed-dose combinations on account of the need for HIV tropism testing, understood as being central to efforts in ensur- has also proven to be slow. UNAIDS has cited

[Infectious Disease Reports 2013; 5:s1e2] [page 5] Review weak drug regulatory capacity and inefficient 2012;15:s18351. processes as contributing to the lengthy regu- References 11. Cohen C, Elion R, Ruane P, et al. latory approval cycle in Africa. The current sit- Randomized, phase 2 evaluation of two uation is seen as providing an opportunity for 1. United Nations General Assembly. Political single-tablet regimens elvitegravir/cobici- joint ventures and new avenues for collabora- Declaration on HIV/AIDS: intensifying our stat/emtricitabine/ tion, innovation and technology transfer, with efforts to eliminate HIV and AIDS. fumarate versus efavirenz/emtricitabine/ an African Medicines Regulatory Agency being Resolution adopted by the General tenofovir disoproxil fumarate for the ini- recommended as a possible solution for faster, Assembly on 10 June 2011. Geneva: tial treatment of HIV infection. AIDS cheaper and fairer distribution of much need- UNAIDS; 2011. 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