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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e32835b809d
15 MILLION ON ART BY 2015: A REALISTIC TARGET OR JUST A DREAM?: Edited by Joep M.A. Lange

The promise of pre-exposure prophylaxis with antiretroviral drugs to prevent HIV transmission: a review

Hankins, Catherine A.a,b; Dybul, Mark R.c,d

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Author Information

aDepartment of Global Health, Academic Medical Centre, University of Amsterdam and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands

bDepartment of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

cThe O’Neill Institute for National and Global Health Law, Georgetown University, Washington, District of Columbia

dThe George W. Bush Institute, Dallas, Texas, USA

Correspondence to Catherine Hankins, BA, MD, MSc, CCFP, FRCPC, Amsterdam Institute for Global Health and Development, Pietersbergweg 17, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Tel: +31 20 566 1961; e-mail: c.hankins@aighd.org

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Abstract

Purpose of review: Public health experts are wrestling with how to translate recent scientific findings from pre-exposure prophylaxis (PrEP) effectiveness trials into real-world programmes. This review summarizes clinical trial findings on oral and topical PrEP, discusses how decision-makers can evaluate the place of PrEP within combination prevention and highlights anticipated developments that could be important in future HIV-prevention strategies.

Recent findings: PrEP taken daily as oral tablets to create systemic protection has been found to be effective in the Pre-Exposure Prophylaxis Initiative (iPrEx), Partners’ PrEP and TDF2 trials, but not in Fem-PrEP or the Vaginal and Oral Interventions to Control the Epidemic (VOICE) tenofovir arm. Tenofovir gel for topical protection was effective in CAPRISA 004 when used peri-coitally but not in VOICE with daily use. These findings underscore the importance of adherence to achieve adequate drug levels and the potential additive role of PrEP within combination prevention. Pivotal phase III trials are underway of the dapivirine ring, whereas phase I trials of injectable formulations show promise.

Summary: Antiretroviral-based HIV-prevention programmes should be tailored to those most likely to be adherent, providing them with state-of-the-art counselling and support to achieve high adherence during the time period of use. Long-acting products, if found well tolerated and effective, could be ideal for overcoming adherence challenges.

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INTRODUCTION

An estimated 2.2 million individuals acquired HIV infection in 2011 [1], making it paramount to expand HIV-prevention choices for people worldwide. Pre-exposure prophylaxis (PrEP) for HIV is the use of antiretroviral drugs to prevent HIV acquisition [2]. The concept of chemoprophylaxis using the same product for prevention as for treatment is not novel. Travellers to malaria-endemic areas use drugs to prevent malaria and antiretroviral prophylaxis is proven to prevent mother-to-child HIV transmission [3–5]. There is now a growing body of evidence that PrEP, as oral tablets and injections to create systemic protection or gels and rings applied vaginally or rectally for local topical protection, in combination with safer sex measures, is effective in preventing sexual transmission of HIV.

Although early trials of vaginal microbicides [6–8] were not successful, they provided a foundation for subsequent efforts, culminating in proof-of-concept results for a vaginal gel containing the nucleotide reverse transcriptase inhibitor, tenofovir [9]. After systemic tenofovir, administered by intravenous, subcutaneous or oral routes, prevented acquisition of simian and simian-HIVs in nonhuman primates [10▪▪], clinical trials of oral PrEP in diverse populations and settings began in 2005. They focused on either 300 mg tenofovir disoproxil fumarate (TDF) or 300 mg TDF/200 mg emtricitabine (FTC) taken once daily.

Tenofovir and FTC are phosphorylated intracellularly to form active agents that inhibit HIV replication. Tenofovir diphosphate concentrations are about 100-fold higher in rectal tissue than in cervicovaginal tissue with oral TDF/FTC [11] and about 1000-fold higher in vaginal tissues with tenofovir gel than with oral TDF/FTC [10▪▪].

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Recently, the US Food and Drug Administration (US FDA) approved daily TDF/FTC (Truvada) for oral PrEP, to be used in combination with safer sex practices to reduce risk of sexually acquired HIV infection in adults at high risk of HIV exposure [12]. TDF/FTC for PrEP must only be used by individuals confirmed to be HIV-negative who continue to be HIV-negative during use, when tested at least every 3 months. PrEP is contraindicated in individuals with unknown or positive HIV status. The WHO has released recommendations for PrEP use in demonstration projects for serodiscordant couples and for men and transgender women who have sex with men [13]. These projects studying service delivery models, acceptability, cost–effectiveness, adherence, safety, drug resistance and other aspects in real-world settings will inform guidance to be released within 5 years for PrEP implementation and scale-up.

Biomedical HIV prevention options have expanded recently. Voluntary medical male circumcision (VMMC) reduces HIV transmission from females to males by about 60% [14–16], with scale-up underway in countries with predominantly heterosexual epidemics [17]. Treatment of HIV-positive persons decreases circulating HIV levels, thereby reducing onward transmission [18]. Building on the backbone of behaviour change, male and female condoms, and structural interventions, combination prevention strategies incorporating novel biomedical modalities could bring about an HIV-free generation.

Public health experts are wrestling with how to translate scientific findings from PrEP effectiveness trials into real-world programmes. This review summarizes clinical trial findings on oral and topical PrEP, discusses how decision-makers can evaluate the place of PrEP within combination prevention and highlights anticipated developments that could be important in future prevention strategies.

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TOPICAL AND ORAL PRE-EXPOSURE PROPHYLAXIS: WHAT DO CLINICAL TRIALS REVEAL ABOUT EFFECTIVENESS?

The South African Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial among 889 women reported the first positive PrEP findings in July 2010. Overall effectiveness of 1% tenofovir vaginal gel used before and after sex was 39% [hazard ratio 0.61; 95% confidence interval (CI) 0.40–0.94; P = 0.017], increasing to 54% for women who reported using the product as instructed for more than 80% of their sex acts (P = 0.025) [9]. Threshold tenofovir diphosphate concentrations for protection are unknown, but a case–control analysis revealed that women with cervicovaginal fluid concentrations above 1000 ng/ml had a 74% lower risk of HIV acquisition than women in the placebo arm [19].

In November 2011, the 5000-women Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial's Data Safety Monitoring Board (DSMB), however, recommended stopping the tenofovir gel arm early for lack of efficacy [20]. Conducted in South Africa, Zambia and Zimbabwe, VOICE tested 1% tenofovir gel used daily, whether or not sex was anticipated or had occurred. Only after study completion will data analysis indicate whether women used the gel and it provided no protection or they simply did not use it.

The South African Follow-on AIDS Consortium of Tenofovir Studies (FACTS) 001 trial enrolling 2900 women uses the same peri-coital dosing as CAPRISA 004 [21]. The US FDA considers FACTS 001 the second pivotal trial needed for licensure of coital-use 1% tenofovir gel and has agreed to fast track approval should it confirm a reduction in women's risk of HIV acquisition [22]. Meanwhile, CAPRISA 008 is exploring the acceptability and feasibility of offering tenofovir gel in family planning clinics to CAPRISA 004 participants.

Trials of oral PrEP for HIV have also had mixed results. The Pre-Exposure Prophylaxis Initiative (iPrEx) trial in Brazil, Ecuador, Peru, South Africa, Thailand and the US evaluated daily oral TDF/FTC in 2499 HIV-negative men or transgender women who have sex with men. Recruited participants were considered at higher risk for HIV exposure because they used condoms inconsistently or not at all during sex with a partner of positive or unknown HIV status, had high numbers of sex partners or exchanged sex for commodities. They were randomized to once-daily TDF/FTC versus placebo. Whereas the overall reduction in risk was 44% (95% CI 15–63), plasma and intracellular drug levels among those in the active arm differed: 8% of seroconverters versus 54% of nonseroconverters had detectable drug [23]. Those who took the pills were almost 13 times less likely to seroconvert than those with no drug detected (OR 12.9; 95% CI 1.7–99.3): a 92% reduction in HIV acquisition risk (CI 40–99%). On the basis of the iPrEx findings, the US Centers for Disease Control released interim clinical guidelines for similar patients [24]. A post-trial implementation study, iPrEx-open label extension (OLE), is gathering ‘real-world’ information on ways to improve adherence while reducing HIV testing frequency to quarterly, rather than monthly, as in the trial. It will determine whether knowledge of PrEP effectiveness stimulates improved adherence, thereby reducing the risk of HIV acquisition, or leads to behavioural risk compensation, that is an altered perception of risk associated with more risky sexual behaviours [25].

In July 2011, the DSMBs of two trials, the Partners’ PrEP trial in Kenya and Uganda among 4758 serodiscordant heterosexual couples (one partner was HIV-positive and one was HIV-negative) and the Botswana TDF2 HIV Prevention Study (TDF2) trial in Botswana among 1219 heterosexual men and women, recommended revealing their results publicly. TDF/FTC taken daily reduced HIV risk by 62% (95% CI 23–83; P = 0.03) in TDF2 [26▪▪] and by 75% (95% CI 55–87; P < 0.001) in Partners’ PrEP [27▪▪]. The TDF-only arm of Partners’ PrEP found a 67% (95% CI 44–81; P < 0.001) reduction in risk. Whereas TDF2 is offering TDF/FTC to all participants after the trial, Partners’ PrEP, having found no significant difference between TDF alone and TDF/FTC, has randomized placebo recipients to the two active arms. Of note, the TDF2 trial was underpowered to show differences in PrEP effectiveness between men and women, whereas the Partners’ PrEP trial found no significant difference by sex.

In contrast, the VOICE trial closed its oral TDF arm for futility in September 2011 [28] and the completed Fem-PrEP trial, conducted among 2120 HIV-negative women in Kenya, South Africa and Tanzania, found that TDF/FTC taken daily did not protect women. Although 95% of women in both arms of Fem-PrEP reported that they usually or always took their pills and pill counts suggested that study drug was taken on 88% of days, only 15% of seroconverting women had target plasma drug levels at either end of the infection window. The investigators concluded that the study could not evaluate PrEP effectiveness due to poor adherence [29▪▪].

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KEY ISSUES IDENTIFIED IN THE CLINICAL TRIALS

Among the key issues that clinical trials conducted to date have identified are adherence, drug resistance, behavioural risk compensation and safety.

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Adherence

Although differences in the populations studied, sexual behaviours, genital mucosa integrity and other co-factors for HIV acquisition plausibly contributed to the divergent trial results; low levels of actual use leading to inadequate drug concentrations in the genital tract was clearly a key factor [30▪▪,31▪,32▪]. Whereas self-reported medication use and pill counts were generally unreliable across the trials, there was a clear relationship between detectable drug levels as a marker of adherence and outcome. In Partners’ PrEP, a medication event monitoring system (MEMS) and unannounced household visits, along with partner support, achieved the highest adherence levels. Drug was detected in 82% of 902 samples from a random sub-group of 198 active-arm participants who did not acquire HIV. Relative risk reductions were 86% with detectable TDF and 90% with detectable TDF/FTC in Partners’ PrEP [27▪▪] and 92% with detectable TDF/FTC in iPrEX [23].

It remains to be seen which of the adherence support measures used in the clinical trials can be effective in PrEP roll-out, but iPrEX found both next-step counselling and neutral assessment to be feasible, acceptable low-intensity approaches [33▪]. In next-step counselling, patients are experts, with providers assisting patients to identify adherence-related needs and solutions for incorporating PrEP within the context of their lives. Evaluation is underway in iPrEx-OLE to determine whether this brief adherence-support discussion approach correlates with drug detection levels [34].

The frequency of dosing could impact adherence. However, a study using MEMS in African men who have sex with men and sex workers found lower adherence to intermittent (twice a week) and post-coital dosing than to daily PrEP [35▪].

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Drug resistance

No case of drug resistance was seen in trial participants who became infected after being placed on tenofovir-containing PrEP [23,26▪▪,27▪▪]. All five cases of resistance found in the iPrEx, Partners’ PrEP and TDF2 started PrEP with unrecognized acute infection, highlighting the critical importance of ensuring that people starting PrEP are not in the HIV-negative window period before HIV antibodies appear. These five cases occurred against a backdrop of a total of 118 infections averted in these trials. It is predicted that drug resistance from treatment scale-up will far exceed that from PrEP [36].

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Behavioural risk compensation

As seen in other biomedical HIV prevention trials, reported risky sexual behaviours declined in all arms of the PrEP trials and remained lower through the trials than at baseline. However, participants received monthly counselling, HIV testing and access to condoms. Interestingly, in iPrEX, efficacy was highest in those least likely to report condom use for receptive anal sex at baseline [23], suggesting individual selection preferences for different prevention methods. Whether expectation of known benefit will lead to risk compensation remains to be seen in follow-up studies.

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Safety

Adverse events among thousands of healthy, HIV-negative trial participants were not severe and generally declined after the first month [23,26▪▪,27▪▪]. Decreases in bone mineral density scores were seen in TDF2 [26▪▪] and iPrEx [37], but were not measured in Partners’ PrEP or Fem-PrEP, and periods of observation were short (1–2 years). Further monitoring of the effects of TDF and TDF/FTC on bone mineral density over longer periods of use is warranted. Likewise, monitoring liver and kidney (proximal tubular) function, after establishing initial normal hepatic and renal function, will be important in longer-term demonstration projects. Although safety studies of tenofovir use in pregnancy have been generally reassuring [38–40], ongoing assessment of exposed infants to rule out longer-term effects remains important.

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Next steps

As conditions of US FDA approval, Truvada's manufacturer, Gilead Sciences, Inc., will develop an adherence questionnaire to assist prescribers in identifying individuals at risk for low adherence, evaluate viral isolates from individuals who acquire HIV while taking TDF/FTC for drug resistance and collect data on pregnancy outcomes for women who become pregnant while taking TDF/FTC for PrEP.

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PRE-EXPOSURE PROPHYLAXIS AS A COMPONENT OF COMBINATION PREVENTION

The challenge for policy makers is to decide what role PrEP should play in strengthening country combination prevention programmes to meet Universal Access Targets [41] and Millennium Development Goals [42]. Combination prevention combines behavioural, biomedical and structural interventions to address both the immediate risks and underlying causes of vulnerability to HIV infection and the pathways that link them [43]. It is evidence-informed, human rights-based and context-specific. Effective prevention programmes are tailored to local epidemics, with relevant components delivered at an intensity, quality and scale necessary to achieve intended effects. The added value of systemic or topical PrEP within combination prevention will depend on its efficacy, cost–effectiveness, acceptability and the availability of resources.

In terms of population-level impact, mathematical modelling predicts that tenofovir gel used by South African women in 80% or more of sexual encounters would avert up to 2 million new infections and 1 million AIDS deaths over 20 years, with gel use as low as 25% being cost effective [44]. Studies of oral PrEP cost–effectiveness have estimated cost per HIV infection averted [45,46▪,47], cost per quality-adjusted life year (QALY) gained [46▪,48–52], cost per disability-adjusted life year (DALY) averted [53▪], cost per year life saved [54] and PrEP years per infection averted [55]. Some models address PrEP in general, whereas others prioritize key populations in epidemic settings as diverse as southern Africa, the USA, Botswana, Kenya, southern India, South Africa, Ukraine and Peru. Although the overall results are heterogeneous, PrEP is generally estimated to be a potentially cost-effective addition to HIV-prevention programmes, particularly when those at highest risk of HIV exposure are prioritized [56].

A mathematical model that translates adherence data from the trials into population-level predictions, based on the population proportions in each adherence category, estimates that adherence is as important as efficacy in determining programme success [57]. Modellers could usefully examine key questions concerning implementation, as was done for VMMC [58] prior to the refinement of a decision-maker's programme planning tool [59]. This tool is actively used by countries planning national VMMC programmes and tracking implementation costs [60]. Unlike the VMMC vertical programme approach, a PrEP-inspired practical, user-friendly interactive modelling tool informed by modelling consensus would need to address the cost and impact of introducing PrEP programming against a backdrop of scale-up of other prevention programmes and antiretroviral treatment.

Pre-exposure prophylaxis prevents acute HIV infection and its high viraemia fuelling HIV transmission [61], constituting primary prevention and providing partial protection, as do VMMC and correct and consistent male and female condom use. PrEP can be complementary to early treatment for prevention (T4P), another novel antiretroviral-based strategy that also requires knowledge of HIV status. In the HIV Prevention Trials Network (HPTN 052) trial, T4P reduced genotypically linked HIV transmission by 96% among serodiscordant couples when the HIV-positive partner began HIV treatment at CD4 cell counts between 350 and 550 cells/μl [62▪▪]. Some couples may prefer PrEP for the seronegative person to early treatment for the seropositive person. Regardless of whether treatment is initiated early or according to local treatment eligibility criteria, PrEP may be useful for the seronegative partner for the 6 months until the partner achieves undetectable viral loads on treatment. PrEP may reduce the risk of HIV acquisition peri-conceptually when serodiscordant couples desire pregnancy [63,64].

The acceptability of PrEP has been assessed in populations as diverse as men who have sex with men in China [65,66], Thailand [67,68], Peru [69], France [70], Canada [71], the USA [72,73] and Australia [74,75]; serodiscordant couples in Kenya [76▪]; female sex workers in China [77] and truck drivers in India [78]. A study among 1790 sex workers, men who have sex with men, people who inject drugs, serodiscordant couples and young women in Peru, Ukraine, India, Kenya, Botswana, Uganda and South Africa found that respondents generally perceived that PrEP would give them further HIV prevention choices and 61% reported they definitely would use PrEP [79]. Policy makers, healthcare workers and representatives of nongovernment organizations involved in HIV prevention in the same countries expressed appreciation of the potential benefits of PrEP in prioritizing and empowering key populations. Perceived challenges and programmatic considerations resulted in about half indicating that they would wait to see PrEP implemented in other countries before introducing it in their own [80▪]. Healthcare providers interviewed in California during the year after the iPrEx results acknowledged implementation challenges, but most expressed optimism that they could prescribe and monitor PrEP in their practice [81].

A key consideration will be provider capacity to assist confirmed HIV-negative people in deciding whether they could adhere and when and for how long PrEP might be a good choice for them to complement condom use and other safer sex measures. As with contraceptive choices, rather than being a continuous prevention strategy, PrEP might be selected by people as circumstances in their lives change or in the context of certain sexual partnerships.

Equity and justice are key ethical issues for decision-makers wishing to avoid exacerbating existing healthcare inequalities [82]. Universal access to antiretroviral treatment has not been achieved in many countries under existing national guidelines [83]. Difficult decisions are required to make PrEP available for those at highest risk of HIV exposure, particularly those who are marginalized and stigmatized. At the population level, prioritization of PrEP for those at highest risk of HIV exposure will require addressing structural barriers such as stigma and discrimination, criminalization and lack of tailored healthcare delivery into which PrEP programming can be integrated. Although PrEP is not approved by national authorities [84] other than the FDA, debate is underway on whether it should be part of the prevention package offered to all HIV-prevention trial participants or as a comparator arm in trials of novel strategies.

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FUTURE DEVELOPMENTS

The PrEP research pipeline is diversifying, in terms of candidate drugs, dosing strategies and delivery mechanisms.

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Local prophylaxis

Over 70 microbicide candidates are in the preclinical development pipeline, including 35 attachment, fusion and entry inhibitors [85▪▪,86]. The hyperosmolar properties of vaginal tenofovir gel have been modified for rectal use, with a safety and adherence phase II trial planned for USA, Peru, South Africa and Thailand [87].

Long-term controlled release dosage forms for intravaginal delivery of antiretroviral prophylaxis are the subject of intense interest among engineers and pharmaceutical scientists [88▪▪]. Both the Microbicide Trial Network's ASPIRE trial [89] and the International Partnership for Microbicides Ring Study [90] are pivotal phase III trials evaluating a vaginal ring that slowly releases the non-nuclease reverse transcriptase inhibitor (NNRTI) dapivirine to bind to and disable HIV's reverse transcriptase enzyme. These vaginal rings, inserted and removed by the women themselves, are flexible products that fit comfortably high up inside the vagina, are seldom felt by either partner during sex and are already widely used to deliver hormonal contraception.

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Systemic prophylaxis

Findings are awaited from the phase III Bangkok Tenofovir Study, following 2413 people who inject drugs [91]. Phase II trials of intermittent PrEP with TDF/FTC are enrolling in France [92] and the USA [93] to determine whether intermittent pre- and post-exposure dosing provides comparable effectiveness with decreased pill requirements and decreased symptoms. HPTN 069 is testing the entry inhibitor maraviroc against TDF/FTC, alone or in combination [94].

Animal studies of integrase strand inhibitors [95,96] show promise and phase I trials of long-acting injectables, such as the NNRTI rilpivirine (TMC 278) [97] and the HIV integrase inhibitor S/GSK1265744 [98], have reported safety and tolerability.

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Multiuse technologies

Work is proceeding to develop multipurpose technologies such as vaginal rings that avert unintended pregnancies and prevent sexually transmitted infections, including HIV [99]. In addition, considerable thought is being given to designing innovative trials to assess potentially beneficial combinations of prevention tools, such as oral PrEP provided concomitantly with an HIV vaccine. Such a combination might prevent HIV acquisition during the course of immunizations before full development of vaccine-induced immunity or might influence immune responses sufficiently during HIV exposure to increase the likelihood of vaccine protection [100▪].

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CONCLUSION

The incorporation of PrEP into combination HIV-prevention programming is in its formative stage [101]. Thirty years into the HIV epidemic, the current HIV-prevention armamentarium is failing to stop HIV transmission. Clearly, people need HIV prevention options for different periods in their lives as their own circumstances change. PrEP-based discreet, user-controlled protection against HIV transmitted through sex will potentially range from pills and coital gel to rings and long-lasting injectable formulations.

Tailored communication strategies accompanying PrEP introduction need to emphasize the importance of correct and consistent usage, along with the partial protection it affords, and that PrEP is additional to other safer sex strategies, including the correct and consistent use of male and female condoms. As HIV testing and counselling is scaled up, people will increasingly be able to adopt HIV-prevention strategies based on knowledge of serostatus, including the use of antiretroviral-based strategies such as PrEP and T4P. Programme planners and healthcare personnel prescribing any antiretroviral-based prevention strategy should tailor such programmes to those most likely to be adherent, providing them with state-of-the-art counselling and ensuring effective support to achieve high adherence during the period of time they use it. Long-acting products formulated as rings or injectables, if found well tolerated and effective, could be ideal for overcoming PrEP adherence challenges.

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Acknowledgements

The authors thank Gabriela Gomez and Marja Nieuwpoort, Amsterdam Institute of Global Health and Development, for their assistance.

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Conflicts of interest

Catherine Hankins: no conflicts of interest.

Mark Dybul: the O’Neill Institute for National and Global Health Law, Georgetown University has received funding support on Pre-Exposure Prophylaxis from the Bill and Melinda Gates Foundation.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 80).

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This review presents pharmacological and ecological data supporting the use of antiretroviral drugs for HIV prevention, discusses possible causes of divergent PrEP trial results and considers the best strategies for antiretroviral drug use to reduce HIV spread at the individual and the population level.

32▪. Kashuba AD, Patterson KB, Dumond JB, Cohen MS. Preexposure prophylaxis for HIV prevention: how to predict success. Lancet 2012; 379:2409–2411.

This commentary reviews trial results, highlighting the need for strong and durable tissue concentrations of active PrEP agents, with respect to their tissue penetration, intracellular metabolism and tissue half life, and the importance of rigorous, prospective measurement of adherence accompanied by effective counselling in future trials.

33▪. Amico KR. Adherence to preexposure chemoprophylaxis: the behavioral bridge from efficacy to effectiveness. Curr Opin HIV AIDS 2012; 7:542–548.

Neutral assessment and next-step counselling became hallmarks of the late phase of the successful study of tenofovir/emtricitabine pre-exposure prophylaxis among men and transwomen who have sex with men in the iPrEx trial. This article presents the feasibility and acceptability of this adherence support approach that is now being employed in the open label trial iPrEx OLE.


35▪. Mutua G, Sanders E, Mugo P, et al. Safety and adherence to intermittent preexposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PLoS One 2012; 7:e33103.

This trial randomized 67 men who have sex with men and 5 female sex workers in Kenya to daily oral PrEP or intermittent PrEP (Friday, Monday and within 2 h of sex) with tenofovir/emtricitabine versus daily or intermittent placebo, finding that safety was similar across all groups and acceptability was high, regardless of dosing regimen.

36. Parikh UM, Mellors JW. HIV-1 drug resistance resulting from antiretroviral therapy far exceeds that from preexposure prophylaxis. Clin Infect Dis 2012; 55:303–304.author reply 304.

37. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir preexposure prophylaxis randomized clinical trial in San Francisco. PLoS One 2011; 6:e23688.

38. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012; 26:1151–1159.

39. Kuhn L, Bulterys M. Does maternal use of tenofovir during pregnancy affect growth of HIV-exposed uninfected infants? AIDS 2012; 26:1167–1169.

40. Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Med 2012; 9:e1001217.

41. WHO/UNAIDS/UNICEF. Global HIV/AIDS response: epidemic update and health sector progress towards Universal Access, Progress report 2011 (http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20111130_UA_Report_en.pdf), 2012.


43. Hankins CA, de Zalduondo BO. Combination prevention: a deeper understanding of effective HIV prevention. AIDS 2010; 24 (Suppl 4):S70–S80.

44. Williams BG, Abdool Karim SS, Karim QA, Gouws E. Epidemiological impact of tenofovir gel on the HIV epidemic in South Africa. J Acquir Immune Defic Syndr 2011; 58:207–210.

45. Abbas UL, Anderson RM, Mellors JW. Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings. PLoS One 2007; 2:e875.

46▪. Hallett TB, Baeten JM, Heffron R, et al. Optimal uses of antiretrovirals for prevention in HIV-1 serodiscordant heterosexual couples in South Africa: a modelling study. PLoS Med 2011; 8:e1001123.

This model of the impact of PrEP and early treatment for prevention in HIV-serodiscordant couples in South Africa estimates that PrEP provided to the seronegative partner is at least as cost effective as early antiretroviral treatment in keeping couples alive and without a new HIV infection, if the annual cost of PrEP is less than 40% the cost of ART and PrEP is more than 70% effective.

47. Pretorius C, Stover J, Bollinger L, et al. Evaluating the cost-effectiveness of preexposure prophylaxis (PrEP) and its impact on HIV-1 transmission in South Africa. PLoS One 2010; 5:e13646.

48. Paltiel AD, Freedberg KA, Scott CA, et al. HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis 2009; 48:806–815.

49. Desai K, Sansom SL, Ackers ML, et al. Modeling the impact of HIV chemoprophylaxis strategies among men who have sex with men in the United States: HIV infections prevented and cost-effectiveness. AIDS 2008; 22:1829–1839.

50. Alistar SS. Effectiveness and cost-effectiveness of oral preexposure prophylaxis for injection drug users in mixed HIV epidemics. 33rd Annual Meeting of the Society for Medical Decision Making Hillsborough, USA; 2011.

51. Koppenhaver RT, Sorensen SW, Farnham PG, Sansom SL. The cost-effectiveness of preexposure prophylaxis in men who have sex with men in the United States: an epidemic model. J Acquir Immune Defic Syndr 2011; 58:e51–e52.

52. Juusola JL, Brandeau ML, Owens DK, Bendavid E. The cost-effectiveness of preexposure prophylaxis for HIV prevention in the United States in men who have sex with men. Ann Intern Med 2012; 156:541–550.

53▪. Gomez GB, Borquez A, Caceres CF, et al. The potential impact of preexposure prophylaxis for HIV prevention among men who have sex with men in Lima, Peru. PLoS Med 2012; 9:e1001323. doi: 10.1371/journal.pmed.1001323. [Epub ahead of print].

This model investigating the population-level impact, cost, and cost–effectiveness of a PrEP programme offered to men and transwomen who have sex with men in Lima, Peru, as part of combination prevention, estimates that only extreme behaviour change among those not adhering to PrEP would counteract the cost-effective impact of a programme tailored to those most vulnerable to HIV exposure.

54. Walensky RP, Park JE, Wood R, et al. The cost-effectiveness of pre-exposure prophylaxis for HIV infection in South African women. Clin Infect Dis 2012; 54:1504–1513.

55. Vissers DC, Voeten HA, Nagelkerke NJ, et al. The impact of preexposure prophylaxis (PrEP) on HIV epidemics in Africa and India: a simulation study. PLoS One 2008; 3:e2077.

56. Gomez GB, Borquez A, Case KK, et al. The cost and impact of scaling up pre-exposure prophylaxis for HIV prevention: a systematic review of cost–effectiveness modelling studies [submitted for publication]

57. Supervie V, Blower S. Predicting effect of preexposure prophylaxis on HIV epidemics. Lancet 2012; 379:2423.

58. UNAIDS/WHO/SACEMA. Male circumcision for HIV prevention in high HIV prevalence settings: what can mathematical modelling contribute to informed decision making? PLoS Med 2009; 6:e1000109.


60. Hankins C, Forsythe S, Njeuhmeli E. Voluntary medical male circumcision: an introduction to the cost, impact, and challenges of accelerated scaling up. PLoS Med 2011; 8:e1001127.

61. Hollingsworth TD, Anderson RM, Fraser C. HIV-1 transmission, by stage of infection. J Infect Dis 2008; 198:687–693.

62▪▪. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493–505.

This 9-country trial that enrolled 1763 serodiscordant couples, randomized to have the HIV-positive partner receive early antiretroviral therapy at CD4 cell counts between 350 and 550 cells/μl, demonstrated a 96% reduction in the risk of genotypically linked HIV transmission to the HIV-negative partner, interpreted widely as ‘treatment for prevention’.

63. Curran K, Baeten JM, Coates TJ, et al. HIV-1 prevention for HIV-1 serodiscordant couples. Curr HIV/AIDS Rep 2012; 9:160–170.

64. Matthews LT, Baeten JM, Celum C, Bangsberg DR. Periconception preexposure prophylaxis to prevent HIV transmission: benefits, risks, and challenges to implementation. AIDS 2010; 24:1975–1982.

65. Jackson T, Huang A, Chen H, et al. Cognitive, psychosocial, and sociodemographic predictors of willingness to use HIV pre-exposure prophylaxis among Chinese men who have sex with men. AIDS Behav 2012; 16:1853–1861.

66. Zhou F, Gao L, Li S, et al. Willingness to accept HIV preexposure prophylaxis among Chinese men who have sex with men. PLoS One 2012; 7:e32329.

67. van Griensven F, Thienkrua W, Sukwicha W, et al. Sex frequency and sex planning among men who have sex with men in Bangkok, Thailand: implications for pre and postexposure prophylaxis against HIV infection. J Int AIDS Soc 2010; 13:13.

68. Chariyalertsak S, Kosachunhanan N, Saokhieo P, et al. HIV incidence, risk factors, and motivation for biomedical intervention among gay, bisexual men, and transgender persons in Northern Thailand. PLoS One 2011; 6:e24295.

69. Galea JT, Kinsler JJ, Salazar X, et al. Acceptability of preexposure prophylaxis as an HIV prevention strategy: barriers and facilitators to preexposure prophylaxis uptake among at-risk Peruvian populations. Int J STD AIDS 2011; 22:256–262.

70. Lorente N, Fugon L, Carrieri MP, et al. Acceptability of an ‘on-demand’ preexposure HIV prophylaxis trial among men who have sex with men living in France. AIDS Care 2012; 24:468–477.

71. Leonardi M, Lee E, Tan DH. Awareness of, usage of and willingness to use HIV preexposure prophylaxis among men in downtown Toronto, Canada. Int J STD AIDS 2011; 22:738–741.

72. Brooks RA, Landovitz RJ, Kaplan RL, et al. Sexual risk behaviors and acceptability of HIV preexposure prophylaxis among HIV-negative gay and bisexual men in serodiscordant relationships: a mixed methods study. AIDS Patient Care STDS 2012; 26:87–94.

73. Nodin N, Carballo-Dieguez A, Ventuneac AM, et al. Knowledge and acceptability of alternative HIV prevention bio-medical products among MSM who bareback. AIDS Care 2008; 20:106–115.

74. Holt M, Murphy DA, Callander D, et al. Willingness to use HIV preexposure prophylaxis and the likelihood of decreased condom use are both associated with unprotected anal intercourse and the perceived likelihood of becoming HIV positive among Australian gay and bisexual men. Sex Transm Infect 2012; 88:258–263.

75. Poynten IM, Jin F, Prestage GP, et al. Attitudes towards new HIV biomedical prevention technologies among a cohort of HIV-negative gay men in Sydney, Australia. HIV Med 2010; 11:282–288.

76▪. Heffron R, Ngure K, Mugo N, et al. Willingness of Kenyan HIV-1 Serodiscordant Couples to Use Antiretroviral-Based HIV-1 Prevention Strategies. J Acquir Immune Defic Syndr 2012; 61:116–119.

When 181 serodiscordant Kenyan couples in which the HIV-positive partner had a CD4 cell count above 350 were given a hypothetical choice of early treatment or PrEP for HIV prevention, only 52.5% of HIV-positive partners preferred initiating ART early, whereas 56.9% of HIV-negative partners preferred using PrEP.

77. Zhao Z, Sun Y, Xue Q, et al. Acceptability of preexposure prophylaxis among female sex workers in Xinjiang. Zhejiang Da Xue Xue Bao Yi Xue Ban 2011; 40:281–285.

78. Schneider JA, Dandona R, Pasupneti S, et al. Initial commitment to preexposure prophylaxis and circumcision for HIV prevention amongst Indian truck drivers. PLoS One 2010; 5:e11922.

79. Eisingerich AB, Wheelock A, Gomez GB, et al. Attitudes and acceptance of oral and parenteral HIV preexposure prophylaxis among potential user groups: a multinational study. PLoS One 2011; 7:e28238.

80▪. Wheelock A, Eisingerich AB, Gomez GB, et al. Views of policymakers, healthcare workers and NGOs on HIV preexposure prophylaxis (PrEP): a multinational qualitative study. Br Med J Open 2012; 2.

This international study of preferences, concerns and views on PrEP of policy makers, healthcare workers and nongovernmental organization representatives reveals levels of awareness of PrEP, perceived benefits and challenges, stigma as a significant barrier and programmatic concerns, against the backdrop of current combination prevention programming.

81. Arnold EA, Hazelton P, Lane T, et al. A qualitative study of provider thoughts on implementing pre-exposure prophylaxis (PrEP) in clinical settings to prevent HIV infection. PLoS One 2012; 7:e40603.

82. Jay JS, Gostin LO. Ethical challenges of preexposure prophylaxis for HIV. J Am Med Assoc 2012; 308:867–868.

83. Macklin R, Cowan E. Given financial constraints, it would be unethical to divert antiretroviral drugs from treatment to prevention. Health Aff (Millwood) 2012; 31:1537–1544.

84. UNAIDS/WHO. Ethical considerations in biomedical HIV prevention trials. http://dataunaidsorg/pub/manual/2007/jc1349_ethics_2_11_07_en.pdf, 2007.

85▪▪. Abdool Karim SS, Baxter C. Overview of microbicides for the prevention of human immunodeficiency virus. Best Pract Res Clin Obstet Gynaecol 2012; 26:427–439.

This review describes the classes of microbicides tested to date, mechanisms of action, formulations, trial results and preclinical candidates in the pipeline before describing the obstacles to microbicide development.

86. Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med 2012; 2:a007385.

87. MTN 017. Phase II safety and acceptability study of tenofovir gel reformulated for rectal use. http://wwwmtnstopshivorg/news/studies/mtn017/backgrounder.

88▪▪. Kiser PF, Johnson TJ, Clark JT. State of the art in intravaginal ring technology for topical prophylaxis of HIV infection. AIDS Rev 2012; 14:62–77.

This review presents new long-term, slow-release drug-delivery device designs for the prevention of sexually transmitted infections. It reviews progress in preclinical programmes, including for antiretroviral drugs supported by investigational new drug filings, from engineering and pharmaceutical perspectives.

89. MTN 020. Phase III sister studies of a microbicide ring to prevent HIV: ASPIRE and The Ring Study. http://wwwmtnstopshivorg/news/studies/mtn020/factsheet.

90. IPM International Partnership for Microbicides Ring Study http://wwwipmglobalorg/the-ring-study.

91. Martin M, Vanichseni S, Suntharasamai P, et al. Enrollment characteristics and risk behaviors of injection drug users participating in the Bangkok Tenofovir Study, Thailand. PLoS One 2011; 6:e25127.

92. ANRS Intervention Preventive de l’Exposition aux Risques avec et pour les GAYS. http://wwwipergayfr/.

93. HPTN 067. ADAPT study: a phase II, randomized, open-label, pharmacokinetic and behavioral study of the use of intermittent oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis, (PrEP). http://wwwhptnorg/research_studies/hptn067.asp.

94. HPTN 069. Phase II randomized, double-blind, study of safety and tolerability of maraviroc, maraviroc + emtricitabine, maraviroc + tenofovir or tenofovir + emtricitabine for preexposure prophylaxis to prevent HIV transmission in at-risk men who have sex with men. http://wwwhptnorg/research_studies/hptn069.asp.

95. Neff CP, Ndolo T, Tandon A, et al. Oral preexposure prophylaxis by antiretrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model. PLoS One 2010; 5:e15257.

96. Dobard C, Sharma S, Parikh UM, et al. Paper # 30: High Protection against Vaginal Infection in Macaques by PEP with Gel Containing RAL. 18th Conference on Retroviruses and Opportunistic Infections. Boston; 2011.

97. Jackson A, Else L, Tjia J, et al. Oral abstract 35: phase 1 trial: rilpivirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV- females and rectum in males. 19th Conference on Retroviruses and Opportunistic Infections. Seattle; 2012.

98. Spreen W, Ford S, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. XIX International AIDS Conference. Washington DC; 2012.

99. CAMI. Coalition Advancing Multipurpose Innovations. http://wwwcami-healthorg/.

100▪. Shattock RJ, Warren M, McCormack S, Hankins CA. AIDS. Turning the tide against HIV. Science 2011; 333:42–43.

This policy forum presents the rationale for conducting trials that combine HIV vaccine candidates with novel biomedical prevention technologies, including PrEP, and introduces concepts of combination implementation to create additive or synergistic effects, stimulating incremental reductions in HIV incidence.

101. Abdool Karim SS, Gray GE, Martinson N. Clinical decisions. Preexposure prophylaxis for HIV prevention. N Engl J Med 2012; 367:462–465.

Keywords:

combination HIV prevention; pre-exposure prophylaxis; programme implementation; tenofovir

© 2013 Lippincott Williams & Wilkins, Inc.

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