The Partners PrEP trial enrolled 4,758 HIV serodiscordant, heterosexual couples in Kenya and Uganda in a randomized three-arm trial evaluating daily tenofovir (TDF) or emtricitabine (FTC)/TDF against placebo to prevent HIV infection. Participating couples received a standard HIV treatment and prevention package, including risk-reduction counseling and condoms. Both regimens reduced the risk of HIV-1 infection among the HIV-negative male or female partner; TDF was 67 percent efficacious and FTC/TDF was 75 percent efficacious. (Of 82 HIV infections, 17 occurred in the TDF arm, 13 in the FTC/TDF arm, and 52 in the placebo arm). Both regimens were safe, HIV-1 resistance was rare, and adherence was high. In July 2011, the trial’s independent Data and Safety Monitoring Board recommended the study results be reported and the placebo arm discontinued early due to strong evidence of effectiveness. The trial showed that among heterosexual men and women with a known HIV-1–infected partner, daily oral TDF and FTC/TDF safely and substantially reduced the risk of HIV-1 infection. Data in this abstract will later be reported in a peer-reviewed journal article.

The TDF2 study demonstrated that daily oral antiretroviral therapy can reduce HIV acquisition among uninfected men and women exposed through heterosexual sex. In this trial, 1,219 HIV-seronegative male and female participants aged 18 to 39 were randomized to receive either oral tenofovir (TDF)/emtricitabine (FTC) or matching placebo once daily. Monthly study visits included HIV testing and risk reduction counseling, sexually transmitted infection management, and adverse event monitoring. The overall protective efficacy was 62.6 percent, with greater efficacy (77.9 percent) when the analysis included only those who were actually on study medication when infected. There were no reported differences in serious adverse events, and adherence (measured by pill count) was similar across the active and placebo groups. This study shows that daily TDF/FTC was effective and safe for preventing HIV infection among heterosexual men and women. Data from other pre-exposure prophylaxis (PrEP) studies underway, and further analysis of TDF2 results including drug level testing, will provide additional information to help determine how to position PrEP for use in heterosexual populations.

With increased access to antiretroviral therapy (ART) in South Africa, and tenofovir-based drugs included in first-line treatment, introducing these same agents as pre-exposure prophylaxis (PrEP) may increase resistance and limit their effectiveness for treatment. This model worked to predict the effect of increased ART and PrEP implementation on spread of HIV and drug resistance in South Africa. The models included sexual behavior, HIV transmission, HIV disease progression, and the emergence of drug resistance in the context of the heterosexual HIV epidemic in South Africa. It looked at cumulative new infections prevented and the prevalence of transmitted and acquired resistance from ART and from PrEP. The model suggests that while ART and PrEP together will have a bigger impact on HIV prevention than either ART or PrEP alone, using the same drugs for both treatment and prevention will increase the prevalence of drug resistance. PrEP roll-out would be expected to contribute far less to drug resistance than ART. However, consistent with several other models, this work suggests that PrEP use by people already infected with HIV could increase resistance from PrEP.

This study used mathematical modeling to examine factors that may influence the prevalence of HIV drug resistance after pre-exposure prophylaxis (PrEP) implementation. PrEP regimens being tested use some of the same antiretroviral drugs that are used to treat AIDS. The possibility that PrEP could contribute to drug resistance, limiting the effectiveness of these drugs for treatment, is a concern. In the model, PrEP was introduced when HIV prevalence among sexually active 15- to 49-year-olds reached 20 percent, mirroring a “sub-Saharan” epidemic. The model included many different factors (age, gender, sexual activity, HIV status, stage of disease, coverage and discontinuation of PrEP, and HIV drug susceptibility) and simulated three scenarios to look at the impact of PrEP on HIV prevention and drug resistance. The model indicates that the rate and length of PrEP use by people already infected with HIV is the most important driver in HIV drug resistance in this population. These outcomes underscore the important role that HIV testing and monitoring will need to play in PrEP programs in order to mitigate the spread of resistance.

This study forecasts clinical, epidemiologic, and economic impact of pre-exposure prophylaxis (PrEP) using emtricitabine (FTC)/tenofovir (TDF) delivered to men who have sex with men (MSM) in the United States who are at high risk of HIV infection. It predicts reduced lifetime HIV risk in U.S. MSM but also predicts a high discounted mean lifetime treatment cost. The study used a common computer simulation of HIV acquisition, detection, and care, and also sought to account for a number of uncertainties, including the level of effectiveness, risks of resistance and toxicity, behavioral disinhibition, and drug costs. It calculated outcomes including lifetime risk of infection, life expectancy, quality-adjusted life expectancy, and cost. It concludes that PrEP could have a substantial impact on the incidence of HIV transmission among the study population. Using this model’s assumptions about efficacy (50 percent) and cost (U.S.$753/month), FTC/TDF PrEP is not currently seen as cost-effective based on quality-adjusted life-year gained. However, lower prices and/or higher efficacy could make it cost-effective, especially in younger or high-risk populations. Despite concerns about cost-effectiveness, and in light of the limits of other HIV prevention interventions and research, the authors conclude that additional study of PrEP is warranted.

This mathematical modeling (simulation) study estimated the potential long-term impact of pre-exposure prophylaxis (PrEP) in different epidemics in India, Botswana, and Kenya among sex workers and their clients. Although this model used a similar scenario as did Abbas et al. in their model, Vissers et al. predicted a smaller impact of PrEP in sub-Saharan Africa (0.14 averted HIV infections per person per year of PrEP compared to 0.33 averted HIV infections per person per year). The predicted impact of PrEP in southern India was much lower than that in sub-Saharan Africa. In southern India, levels of condom use during commercial sex acts are relatively high, so lower rates of condom use could substantially decrease or even negate the impact of PrEP in that setting. This model suggests that the public health impact of PrEP can be substantial, but may be diminished, or even reversed, by changes in risk behavior. PrEP implementation needs to not be seen as a substitute for condoms.

This was the first completed clinical trial to date on the use of tenofovir pre-exposure prophylaxis (PrEP) in humans. The trial was designed to assess safety and preliminary efficacy of PrEP with daily tenofovir in HIV-negative women at high risk for HIV infection. However, efficacy could not be assessed due to premature closures of the study sites in Cameroon and Nigeria. A total of 936 HIV-negative women were randomized to tenofovir or placebo. Tenofovir was not associated with increased adverse events compared to the placebo. Two women on tenofovir and eight women on placebo were diagnosed with new HIV infections during the trial, but the difference was not statistically significant. All women received standard of care prevention counseling. The average number of sexual partners in the past month decreased from 21 at baseline to 14 during follow-up. Reported condom use increased from 52 percent at baseline to 95 percent at the 12-month follow-up. This study demonstrated that tenofovir is safe for HIV-negative women, but it was not able to assess efficacy.

This article reviews evidence, status, and challenges related to use of antiretroviral therapy in HIV prevention, including preclinical and clinical research, and implementation. Lack of animal models and surrogate markers for HIV prevention mean efficacy must be assessed in large trials that enroll healthy people. Prevention trials work with communities to provide a range of information and services, experience that will be valuable to inform roll-out of new prevention approaches in these communities. Pre-exposure prophylaxis (PrEP) is a “biomedical” prevention product that also depends on access and use, so has crucial behavioral, social, and economic dimensions. Concerns about PrEP include adherence, resistance, and risk compensation. These may or may not prove to be problems. Adherence, uneven in trials, may improve once the drugs are proven safe and effective. Implementation will need to incorporate HIV testing, key to identifying HIV infection and limiting resistance. More sensitive HIV tests appropriate for service settings are a priority. Increased sexual risk taking has generally not been seen in trials; new prevention tools may increase people’s interest and ability to use protection without increasing risk taking. Cost-effectiveness of PrEP and programs to deliver it will be related to efficacy, dosing, targeting at-risk populations, and other factors.

Recognizing the challenges of transitioning from clinical trials to program implementation, this commentary proposes a five-part structure for optimizing pre-exposure prophylaxis (PrEP) implementation in clinical practice: prescription, safety screening, behavioral intervention, integration of PrEP with other health care services, and population-level monitoring. Providing drugs will require eligibility guidelines and clinical algorithms for different populations and settings. Feasibility and costs related to monitoring safety (HIV testing, resistance, side effects, sexually transmitted infections) will be key to individual- and population-level impact. Behavioral interventions and support to optimize dosing, promote adherence, and minimize risk behaviors will be critical through both counseling and community education. Behavioral interventions may be difficult to standardize in guidelines and across user groups. Services will need to be established in diverse clinical settings to reach different users and may need to combine clinical and non-clinical service providers to deliver all program components. PrEP users will be in regular contact with care, likely over a long period of time, and as such will need integrated care and referral systems. Finally, national monitoring and evaluation systems will be critical to generate information for adjusting guidelines and determining whether PrEP has an overall benefit.

This paper reports on acceptability in an early pre-exposure prophylaxis trial assessing the effectiveness of daily oral tenofovir among 400 women in Ghana to prevent HIV infection. (The trial was stopped early.) The study used structured questionnaires and qualitative interviews, and the analysis includes participants’ perspectives and social and contextual factors as well as adherence measures. Overall, acceptability was good, and reported adherence to the daily pill was > 82 percent. Problems generally declined as physical side effects decreased, and participants devised strategies for making pill-taking part of their routine. This suggests that future programs will likely need to provide users with enough time to become accustomed to the product and its use. The authors recommend that efforts continue to develop better acceptability measures and to examine the complex interplay among adherence, safety, and effectiveness. While it is unclear how findings from a clinical trial may translate into more routine service settings, this study suggests that a daily oral pill may be a feasible HIV prevention option.

The article presents results of a modeling exercise that aimed to estimate the cost-effectiveness as well as the potential impact of pre-exposure prophylaxis (PrEP) on HIV transmission in the context of expanding antiretroviral therapy (ART) programs. Using a model developed to study the ART program in South Africa, it examines the coverage and potential impact on HIV incidence of ART and PrEP programs compared to a scenario where ART coverage expands at its current rate. Its assumptions about cost for PrEP and ART include services like counseling and testing as well as the drugs. The model varies levels of condom substitution, targeting high-risk groups, and coverage, and finds that the most cost-effective approach would involve targeting women aged 25 to 35 in an optimistic efficacy scenario (90 percent). The model finds that assuming growing availability of ART, PrEP has a “window” within which it would be cost-effective as treatment rolls out, relative to universal test and treat, which is both a treatment and prevention approach. It notes the role of other prevention interventions; while PrEP and universal test and treat are effective relative to other interventions, they are also relatively expensive. It recommends additional work in other settings with generalized epidemics and ART programs.

This publication, part of the AIDS Vaccine Advocacy Coalition’s Anticipating and Understanding Results series, outlines scientific and policy issues related to pre-exposure prophylaxis (PrEP). While the summary of research results is now dated, it highlights several topics that are not examined in most other resources on PrEP implementation: procurement, resource mobilization, financing, national and international policies, and normative guidance. Given complex and diverse funding structures for AIDS prevention globally, it is important to identify and mobilize potential sources of funding through the Global Fund to Fight AIDS, Tuberculosis and Malaria, the U.S. President’s Emergency Plan for AIDS Relief, national budgets, national health plans, and insurance coverage. Building awareness and support for PrEP among national health leaders will lay the groundwork for incorporating PrEP into national AIDS plans, with delivery strategies tailored to specific epidemic profiles. Working with other global health agencies, the World Health Organization should prepare to issue normative guidance for PrEP to ensure it is available as soon as possible after effectiveness is demonstrated. It underscores the importance of adequate and sustained funding for PrEP research and implementation.

This article, written as pre-exposure prophylaxis (PrEP) trials were beginning, presages a number of issues about PrEP research and implementation. Some issues anticipated here—including immediate widespread demand and side effects specific to HIV-negative people—have not proven problematic so far. Resource allocation, risk compensation, and public health policy are addressed within an ethical framework. The authors consider and reject the notion that providing PrEP could tacitly condone risky behavior, arguing that, as public health policy, new prevention should be offered to people regardless of their behavior. Delivering PrEP will require guidelines for use, community education, and infrastructure. Unlike vaccines or microbicides, drugs for oral PrEP are available and can be manufactured at scale. Appropriate HIV counseling and testing may be challenging with fewer resources available than in trials. PrEP will need to be provided in the context of other prevention approaches; prevention is already underfunded, so new resources will be needed. The authors identify marshaling resources from donors, planning for guidelines, and coordinating governments and regulatory agencies as priorities while clinical testing is ongoing. They underscore that despite its complexity, PrEP is a promising potential intervention and should be supported.

The AIDS Vaccine Advocacy Coalition (AVAC), a nonprofit organization, works to accelerate the ethical development and global delivery of new and emerging HIV prevention options, including male circumcision, pre-exposure prophylaxis (PrEP), microbicides and AIDS vaccines. Its website includes accessible and substantive summaries, policy analysis, research findings, links, and a range of other resources on all of these HIV prevention options. Information and links for AVAC and external resources are updated regularly. Information on PrEP is presented under three categories: Playbook 2012, summarizing AVAC’s analysis, perspectives, and recommendations; What’s New, covering recent developments; and Background, with a range of information on PrEP research and implementation. The page contains information and links to a range of resources on PrEP: introductory information, ongoing trials and recent results, and in-depth PrEP resources. It is a helpful source of timely information on PrEP as well as other HIV prevention approaches.

This summary table lists all ongoing and planned PrEP trials: open label; safety and effectiveness; and safety, adherence, acceptability, and feasibility. It contains brief descriptions of each trial’s phase, start date, sponsor/funder, location, population, intervention arm(s), and the status and/or when results are expected. Information in the table is updated periodically.