Efficacy Of Pre-exposure Prophylaxis Research Articles

Estimating efficacy in a randomized trial with product nonadherence: application of multiple methods to a trial of preexposure prophylaxis for HIV prevention.

Antiretroviral preexposure prophylaxis (PrEP) for persons at high risk of human immunodeficiency virus infection is a promising new prevention strategy. Six randomized trials of oral PrEP were recently conducted and demonstrated efficacy estimates ranging from 75% to no effect, with nonadherence likely resulting in attenuated estimates of the protective effect of PrEP. In 1 of these trials, the Partners PrEP Study (Kenya and Uganda, 2008-2011), participants (4,747 serodiscordant heterosexual couples) were randomized to receipt of tenofovir (TDF), coformulated TDF/emtricitabine (FTC), or placebo. Intention-to-treat analyses found efficacy estimates of 67% for TDF and 75% for TDF/FTC. We applied multiple methods to data from that trial to estimate the efficacy of PrEP with high adherence, including principal stratification and inverse-probability-of-censoring (IPC) weights. Results were further from the null when correcting for nonadherence: 1) among the strata with an estimated 100% probability of high adherence (TDF hazard ratio (HR) = 0.19, 95% confidence interval (CI): 0.07, 0.56; TDF/FTC HR = 0.12, 95% CI: 0.03, 0.52); 2) with IPC weights used to approximate a continuously adherent population (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.15, 95% CI: 0.04, 0.52); and 3) in per-protocol analysis (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.16, 95% CI: 0.05, 0.53). Our results suggest that the efficacy of PrEP with high adherence is over 80%.

Invited commentary: every good randomization deserves observation.

Preexposure prophylaxis (PrEP) is a promising approach to prevention of human immunodeficiency virus (HIV) transmission, in which an HIV-negative individual takes a single daily dose of an antiretroviral drug so that, if exposed to HIV, an active antiretroviral drug is already present in his or her system. In this issue of the Journal, Murnane et al. (Am J Epidemiol. 2015;182(10):848-856) use data from the Partners PrEP Study (Kenya and Uganda, 2008-2011) to estimate the efficacy of PrEP under perfect adherence. We discuss Murnane et al.'s work and then examine the larger issues of generalizability or transportability of findings from a randomized trial to a new setting when adherence to an intervention determines its effectiveness. We discuss sufficient conditions for generalizability and use causal directed acyclic graphs to show how these assumptions might play out when trials are used to make inferences about the effect of PrEP in current and future real-world target populations.

HIV pre-exposure prophylaxis (PrEP): a review of current knowledge of oral systemic HIV PrEP in humans.

Despite established HIV prevention strategies and broadly available diagnostic strategies in developed western countries, rates of HIV new infections remain high. Alternative strategies for HIV prevention, particularly among men who have sex with men (MSM), are crucial. HIV pre-exposure prophylaxis (PrEP) has been discussed as one additional option that this review seeks to explore. An online search identifying PrEP-relevant literature from 1st January 2010 to 1st August, 2015 was performed. The iPrEx study, first published in 2010, demonstrated a reduction in relative risk (RRR) of HIV seroconversion of 44 % for continuous PrEP with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in MSM. The efficacy of PrEP has been confirmed for continuous PrEP in the PROUD study and for intermittent PrEP in the IPERGAY study (RRR = 86 % in both studies). The PrEP was well tolerated in all studies, and the evolution of HIV resistance has been low. Compensatory increased sexual risk behavior was not observed in recent studies. In contrast to the high efficacy of risk reduction for HIV transmission in MSM, the results of TDF PrEP and TDF/FTC PrEP studies using microbicidal agents or pills among heterosexual women were different (RRR 6-75 %). Continuous and intermittent PrEP demonstrated high efficacy in preventing HIV seroconversion, notably among MSM. PrEP was well tolerated. Adherence was critical for high efficacy in all studies. Further studies to evaluate implementation strategies and cost-effectiveness in different risk populations are needed as well as drug approval in Europe.

Time to Be PROUD of the Effectiveness of PrEP

The efficacy of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) was demonstrated in the IPrEX trial, but implementation has been

Motivations for Reducing Other HIV Risk-Reduction Practices if Taking Pre-Exposure Prophylaxis: Findings from a Qualitative Study Among Women in Kenya and South Africa.

Findings from a survey conducted among women at high risk for HIV in Bondo, Kenya, and Pretoria, South Africa, demonstrated that a substantial proportion would be inclined to reduce their use of other HIV risk-reduction practices if they were taking pre-exposure prophylaxis (PrEP). To explore the motivations for their anticipated behavior change, we conducted qualitative interviews with 60 women whose survey responses suggested they would be more likely to reduce condom use or have sex with a new partner if they were taking PrEP compared to if they were not taking PrEP. Three interrelated themes were identified: (1) "PrEP protects"--PrEP was perceived as an effective HIV prevention method that replaced the need for condoms; (2) condoms were a source of conflict in relationships, and PrEP would provide an opportunity to resolve or avoid this conflict; and (3) having sex without a condom or having sex with a new partner was necessary for receiving material goods and financial assistance--PrEP would provide reassurance in these situations. Many believed that PrEP alone would be a sufficient HIV risk-reduction strategy. These findings suggest that participants' HIV risk-reduction intentions, if they were to use PrEP, were based predominately on their understanding of the high efficacy of PrEP and their experiences with the limitations of condoms. Enhanced counseling is needed to promote informed decision making and to ensure overall sexual health for women using PrEP for HIV prevention, particularly with respect to the prevention of pregnancy and other sexually transmitted infections when PrEP is used alone.

Defining success with HIV pre-exposure prophylaxis: a prevention-effective adherence paradigm.

Clinical trial data have shown that oral pre-exposure prophylaxis (PrEP) is efficacious when taken as prescribed; however, PrEP adherence is complex and must be understood within the context of variable risk for HIV infection and use of other HIV prevention methods. Different levels of adherence may be needed in different populations to achieve HIV prevention, and the optimal methods for achieving the necessary adherence for both individual and public health benefits are unknown. Guidance for PrEP use must consider these questions to determine the success of PrEP-based HIV prevention programs. In this article, we propose a new paradigm for understanding and measuring PrEP adherence, termed prevention-effective adherence, which incorporates dynamic HIV acquisition risk behaviors and the use of HIV alternative prevention strategies. We discuss the need for daily PrEP use only during periods of risk for HIV exposure, describe key issues for measuring and understanding relevant behaviors, review lessons from another health prevention field (i.e., family planning), and provide guidance for prevention-effective PrEP use. Moreover, we challenge emerging calls for sustained, near perfect PrEP adherence regardless of risk exposure and offer a more practical and public health-focused vision for this prevention intervention.

The promises and challenges of pre‐exposure prophylaxis as part of the emerging paradigm of combination HIV prevention

IntroductionTowards the end of the twentieth century, significant success was achieved in reducing incidence in several global HIV epidemics through ongoing prevention strategies. However, further progress in risk reduction was uncertain. For one thing, it was clear that social vulnerability had to be addressed, through research on interventions addressing health systems and other structural barriers. As soon as antiretroviral treatment became available, researchers started to conceive that antiretrovirals might play a role in decreasing either susceptibility in uninfected people or infectiousness among people living with HIV. In this paper we focus on the origin, present status, and potential contribution of pre-exposure prophylaxis (PrEP) within the combination HIV prevention framework.DiscussionAfter a phase of controversy, PrEP efficacy trials took off. By 2015, daily oral PrEP, using tenofovir alone or in combination with emtricitabine, has been proven efficacious, though efficacy seems heavily contingent upon adherence to pill uptake. Initial demonstration projects after release of efficacy results have shown that PrEP can be implemented in real settings and adherence can be high, leading to high effectiveness. Despite its substantial potential, beliefs persist about unfeasibility in real-life settings due to stigma, cost, adherence, and potential risk compensation barriers.ConclusionsThe strategic synergy of behavioural change communication, biomedical strategies (including PrEP), and structural programmes is providing the basis for the combination HIV prevention framework. If PrEP is to ever become a key component of that framework, several negative beliefs must be confronted based on emerging evidence; moreover, research gaps regarding PrEP implementation must be filled, and appropriate prioritization strategies must be set up. Those challenges are significant, proportional to the impact that PrEP implementation may have in the global response to HIV.

Cabotegravir long-acting for HIV-1 prevention

Preexposure prophylaxis (PrEP) with daily Truvada has demonstrated clinical efficacy against HIV-1 acquisition that correlates with high adherence. Long-acting antiretroviral drugs offer an alternative to daily regimens and may improve PrEP adherence. This review summarizes the preclinical nonhuman primate studies for evaluating the efficacy of cabotegravir long-acting as PrEP and the ongoing phase 2a studies assessing safety, tolerability, and acceptability of cabotegravir long-acting. Cabotegravir is an HIV-1 integrase strand transfer inhibitor with intrinsic properties that permit its formulation as a long-acting injectable suspension. In clinical evaluation, cabotegravir long-acting has a half-life that permits infrequent dosing, possibly once every 3 months. In validated macaque models, cabotegravir long-acting demonstrated high protection against both rectal and vaginal transmission at clinically achievable drug concentrations. PrEP, after approval of Truvada, continues to evolve to address adherence limitations of daily dosing. As a long-acting injectable antiretroviral drug, cabotegravir long-acting permits quarterly dosing and demonstrated high efficacy in macaque models supporting dose selection and clinical development. Clinical studies have confirmed dose selection in phase 2a trials with cabotegravir long-acting to ultimately lead to phase 2b/3 PrEP efficacy trials.

Preparing for the Rollout of Pre-Exposure Prophylaxis (PrEP): A Vignette Survey to Identify Intended Sexual Behaviors among Women in Kenya and South Africa if Using PrEP.

IntroductionSeveral clinical trials have demonstrated the efficacy of pre-exposure prophylaxis (PrEP) in reducing HIV risk. One concern with introducing PrEP is whether users will engage in riskier sexual behaviors.MethodsWe assessed the effect that PrEP may have on sexual risk behaviors by administering a survey to 799 women in Bondo, Kenya, and Pretoria, South Africa. Participants were asked about their sexual behavior intentions twice — once as if they were taking PrEP and once as if they were not taking PrEP — within four risk situations (vignettes). They responded using a 5-point ordinal scale. We used a series of linear mixed effects models with an unstructured residual covariance matrix to estimate the between- and within-subject differences in the mean likelihood of engaging in risky sexual behavior across the PrEP and non-PrEP contexts. We also calculated the total percentage of participants who reported a greater likelihood of engaging in risky sexual behavior if taking PrEP than if not taking PrEP, by vignette.ResultsWe found statistically significant differences in the mean likelihood of engaging in risky sexual behavior with the between-subject comparison (-0.17, p < 0.01) and with the within-subject comparison (-0.31, p < 0.001). Depending on the vignette, 27% to 40% of participants reported a greater likelihood of engaging in risky sexual behavior if taking PrEP than if not taking PrEP.ConclusionsOur findings indicate that modest increases in risky sexual behavior could occur with PrEP. Although responses from the majority of participants suggest they would not be more likely to engage in risky sexual behavior if they took PrEP, a substantial proportion might. Programs rolling out PrEP should be prepared to assist similar women in making informed choices about reducing their risk of HIV and about their sexual health beyond HIV prevention.

Knowledge, Indications and Willingness to Take Pre-Exposure Prophylaxis among Transwomen in San Francisco, 2013.

Safe and effective HIV prevention strategies are needed for transwomen. Transwomen in the US have a 34 times greater odds of being infected with HIV than all adults age 15-49, and in San Francisco, California 42.4% of transwomen are estimated to be infected with HIV. Pre-exposure prophylaxis (PrEP) is the first biomedical intervention with promise for reducing HIV acquisition in transwomen. However, little is known about whether transwomen know about PrEP, are taking PrEP and would be good candidates for PrEP based on their risk profile and behaviors. A population-based dataset was analyzed to determine how many transwomen in San Francisco knew about PrEP by the end of 2013 – more than a year after iPrex results demonstrated efficacy of PrEP in preventing HIV. We found that of 233 transwomen, only 13.7% had heard of PrEP. Transwomen who were living with HIV compared to those who were HIV-negative, and those who recently injected drugs compared to non-injection drug users were more likely to have heard of PrEP. Based on CDC guidelines for PrEP among MSM and IDU, 45 (30.2%) transwomen of the 149 HIV-negative transwomen in the sample were candidates for PrEP. This estimate based on CDC criteria is arguably low. Given that almost half of transwomen in San Francisco are living with HIV, this findings points to a need for further consideration of PrEP criteria that are specific and tailored to the risks for HIV faced by transwomen that are different from MSM and injection drug users. Research to scale up access and test the effectiveness of PrEP for transwomen is also urgently needed.

Explaining the Efficacy of Pre-exposure Prophylaxis (PrEP) for HIV Prevention: A Qualitative Study of Message Framing and Messaging Preferences Among US Men Who have Sex with Men.

We investigated message comprehension and message framing preferences for communicating about PrEP efficacy with US MSM. We conducted eight focus groups (n=38) and n=56 individual interviews with MSM in Providence, RI. Facilitators probed comprehension, credibility, and acceptability of efficacy messages, including percentages, non-numerical paraphrases, efficacy ranges versus point estimates, and success- versus failure-framed messages. Our findings indicated a range of comprehension and operational understandings of efficacy messages. Participants tended to prefer percentage-based and success-framed messages, although preferences varied for communicating about efficacy using a single percentage versus a range. Participants reported uncertainty about how to interpret numerical estimates, and many questioned whether trial results would predict personal effectiveness. These results suggest that providers and researchers implementing PrEP may face challenges in communicating with users about efficacy. Efforts to educate MSM about PrEP should incorporate percentage-based information, and message framing decisions may influence message credibility and overall PrEP acceptability.

Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis.

Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day(-1) in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml(-1); interquartile range [IQR], 0.60 to 1.50 ng ml(-1)) and tenofovir (TFV; median, 15.0 ng ml(-1); IQR, 8.8 to 23.3 ng ml(-1)), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/10(6) cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.

HIV Drug Therapy in the Americas 16-18 April 2015, Mexico City, Mexico.

HIV Drug Therapy in the Americas 16-18 April 2015, Mexico City, Mexico.

Pharmacologic prevention of human immunodeficiency virus in women: practical approaches for the obstetrician and gynecologist.

Obstetricians and gynecologists (Ob-Gyns) play a crucial role in efforts to detect and prevent human immunodeficiency virus (HIV) infection in women. Multiple strategies can be implemented into general practice as part of a comprehensive primary women's health care agenda. Educational and behavioral strategies to reduce HIV acquisition in women can now be supplemented with pharmacologic measures. This article aimed to review the literature regarding preexposure prophylaxis (PrEP) for HIV prevention in women. After reading this article, readers should be able to describe available methods to prevent HIV acquisition in women, select appropriate candidates for PrEP, and outline the steps necessary for initiation of PrEP. A review of the available literature was obtained by a PubMed search of HIV prevention, women, preexposure prophylaxis, and PrEP. Additional information was obtained from the Centers for Disease Control and Prevention; the American Congress of Obstetricians and Gynecologists; and expert opinion in the fields of obstetrics and gynecology, infectious diseases, and reproductive infectious diseases. This review of the literature summarizes the efficacy of PrEP in HIV prevention and identifies limitations and barriers of PrEP. Women who are at risk for HIV acquisition and candidates for PrEP are clearly defined. Certain populations face unique challenges in HIV prevention and the administration of PrEP, and clinical guidelines and references are provided. This article provides a practical guide for the initiation, maintenance, and discontinuation of PrEP for the general Ob-Gyn. Preexposure prophylaxis is an effective measure to prevent HIV in women. The Ob-Gyn plays a key role in the identification of at-risk women and the initiation of HIV prevention. This information is relevant to general Ob-Gyns and other women's health providers.

Clinical Treatment Options Infectious Diseases: Update on PrEP Implementation, Adherence, and Advances in Delivery.

Pre-exposure prophylaxis (PrEP) is an effective and evidence-based HIV-prevention option and is recommended for individuals with substantial risk for HIV infection [1]. Randomized controlled trials have demonstrated that daily oral PrEP dramatically reduces the risk of HIV infection when it is taken as directed. Concerns regarding widespread emergence of antiretroviral resistance attributable to PrEP and behavioral disinhibition have to date not been observed in clinical trials and open-label demonstration projects. PrEP has great potential as part of an HIV risk reduction strategy and barriers to wider implementation including community education, prescriber availability, and elimination of financial barriers should be aggressively pursued. Adherence is critical to PrEP efficacy and has varied across study populations; developing and refining ways of measuring and supporting adherence is essential to the success of PrEP. Evaluation of long-acting medications and alternative formulations for PrEP is underway and may lead to the wider implementation and impact of PrEP.

Pre-exposure prophylaxis to prevent HIV infection: current status, future opportunities and challenges.

As the global incidence of HIV exceeds 2 million new infections annually, effective interventions to decrease HIV transmission are needed. Randomized, placebo-controlled studies have demonstrated that daily oral antiretroviral pre-exposure prophylaxis (PrEP) with a fixed-dose combination tablet containing tenofovir disoproxil fumarate and emtricitabine can significantly reduce HIV incidence among diverse at-risk populations. In these studies, the efficacy of PrEP was correlated with levels of adherence. Official guidelines recommend provision of PrEP to people at greatest risk of HIV acquisition, and demonstration projects suggest that high levels of uptake and adherence are possible outside of controlled studies. However, several potential barriers to implementing PrEP remain. These challenges include low awareness and utilization of PrEP by at-risk individuals, uncertainty about adherence in 'real-world' settings, the majority of healthcare providers being untrained in PrEP provision, limited data about potential adverse effects from long-term use of tenofovir-emtricitabine, high costs of PrEP medications, and stigma associated with PrEP use and the behaviors that would warrant PrEP. Innovative pharmacologic chemoprophylactic approaches could provide solutions to some of these challenges. Less-than-daily oral dosing regimens and long-acting injectable medications could reduce pill burdens and facilitate adherence, and local delivery of PrEP medications to genital compartments via gels, rings and films may limit systemic drug exposure and potential toxicities. As the portfolio of chemoprophylactic agents and delivery systems expands to meet the diverse sexual health needs and product preferences of individuals who may benefit from PrEP, it is hoped that antiretroviral chemoprophylaxis could become an acceptable, feasible, and highly effective addition to existing HIV prevention strategies.

Antiretrovirals for primary HIV prevention: the current status of pre- and post-exposure prophylaxis.

In light of the 2 million HIV infections that occur globally each year, there is a need to optimize strategies that integrate biomedical and behavioral approaches to HIV prevention. Post-exposure prophylaxis (PEP) immediately after acute high-risk exposures and pre-exposure prophylaxis (PrEP) for those who engage in recurrent high-risk behaviors are promising bio-behavioral approaches to decreasing HIV transmission. Guidelines have recommended PEP for occupational and non-occupational exposures for over 15years, but uptake of PEP has been limited, partly as a result of insufficient awareness of this intervention among persons at highest risk for acquiring HIV. However, since the publication of large randomized clinical trials demonstrating the efficacy of PrEP, and the dissemination of guidelines endorsing its use, there is a renewed focus on bio-behavioral prevention. Numerous studies have recently assessed the acceptability of bio-behavioral prevention programs among diverse populations or described experiences implementing these programs in "real-world" settings. As research and clinical data informing optimal utilization of PEP and PrEP are rapidly accumulating, this review provides a timely summary of recent progress in bio-behavioral prevention. By contextualizing the most noteworthy recent findings regarding PEP and PrEP, this review seeks to inform the successful implementation of these promising prevention approaches.

Human Immunodeficiency Virus Pre-Exposure Prophylaxis: Is it the Answer?

Human Immunodeficiency Virus Pre-Exposure Prophylaxis: Is it the Answer?

Patterns and correlates of PrEP drug detection among MSM and transgender women in the Global iPrEx Study.

Adherence to pre-exposure prophylaxis (PrEP) is critical for efficacy. Antiretroviral concentrations are an objective measure of PrEP use and correlate with efficacy. Understanding patterns and correlates of drug detection can identify populations at risk for nonadherence and inform design of PrEP adherence interventions. Blood antiretroviral concentrations were assessed among active arm participants in iPrEx, a randomized placebo-controlled trial of emtricitabine/tenofovir in men who have sex with men and transgender women in 6 countries. We evaluated rates and correlates of drug detection among a random sample of 470 participants at week 8 and a longitudinal cohort of 303 participants through 72 weeks of follow-up. Overall, 55% of participants (95% confidence interval: 49 to 60) tested at week 8 had drug detected. Drug detection was associated with older age and varied by study site. In longitudinal analysis, 31% never had drug detected, 30% always had drug detected, and 39% had an inconsistent pattern. Overall detection rates declined over time. Drug detection at some or all visits was associated with older age, indices of sexual risk, including condomless receptive anal sex, and responding "don't know" to a question about belief of PrEP efficacy (0-10 scale). Distinct patterns of study product use were identified, with a significant proportion demonstrating no drug detection at any visit. Research literacy may explain greater drug detection among populations having greater research experience, such as older men who have sex with men in the United States. Greater drug detection among those reporting highest risk sexual practices is expected to increase the impact and cost-effectiveness of PrEP.

Depot-medroxyprogesterone acetate does not reduce the prophylactic efficacy of emtricitabine and tenofovir disoproxil fumarate in macaques.

Concerns that the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) may increase the risk of HIV acquisition in women led to questions on whether DMPA could reduce efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model to investigate the impact of prolonged DMPA exposure on PrEP with emtricitabine/tenofovir disoproxil fumarate. Twelve pigtail macaques treated with DMPA were exposed vaginally to simian HIV once a week for up to 5 months and received either placebo (n = 6) or emtricitabine/tenofovir disoproxil fumarate (n = 6). All control macaques were infected, whereas the PrEP-treated animals remained protected (P = 0.0007). This model suggests that women using DMPA will fully benefit from PrEP.