Oral Pre-exposure Prophylaxis (PrEP) for HIV Prevention
I. Definition of the Prevention Area
Pre-exposure prophylaxis (PrEP) aims to prevent acquisition of HIV through use of antiretroviral (ARV) agents before potential exposure to HIV. Several trials of daily oral PrEP have been completed, and other trials of daily and intermittent use of oral PrEP and injectable agents are underway. The primary strategy being tested involves daily use of one (tenofovir [TDF]) or two (TDF/emtricitabine [FTC]) oral ARV drugs.
II. Epidemiological Justification for the Prevention Area
A safe, effective, and acceptable oral prevention regimen could provide another tool for HIV prevention programs. Three placebo-controlled clinical trials have shown significant reduction in HIV acquisition among HIV-negative persons who received an ARV pill to take daily, as shown in the following:
Men who have sex with men, transgendered women;
Risk reduced by 44%; higher protection (73%) among most consistent users
TDF and TDF/FTC
Serodiscordant heterosexual couples;
Risk reduced by: 67% (TDF)
Men and women; Botswana
Risk reduced by 62%
One placebo-controlled trial (FemPrEP) and the oral TDF arm of the VOICE trial were stopped early when data reviews determined that they would be unlikely to answer the study question. (VOICE continues to evaluate daily oral TDF/FTC.). Both trials studied the impact of PrEP in African women.
Data from all these trials suggest that effectiveness is strongly correlated with adherence and that thus far the incidence of acquiring drug-resistant HIV is low. The FemPrEP trial data strongly suggest that the lack of effectiveness was due mainly to women in the trial not taking the tablets consistently. Researchers are continuing to work to understand the interaction between the behavioral and biomedical aspects of these results, and the implications for PrEP.
III. Core Programmatic Components
Roll-out of ARV PrEP has not started, but programs would involve the following components:
- Educating health workers and at-risk populations
- Producing, distributing, and providing ARVs for PrEP
- Recruiting risk candidates who may not wish to disclose risk factors with sensitivity
- Providing individual education and counseling and adherence support
- Testing for HIV before PrEP is provided
- Selecting the regimen
- Following up regularly to assess safety, toxicity, HIV status, and potential resistance
- Identifying and costing service delivery approaches.
Successful implementation would depend on active involvement of national ministries of health, normative agencies, donors, provider organizations, and community groups.
IV. Current Status of Implementation Experience
PrEP is not yet being rolled out in programs largely due to the cost of the approach in large populations and concerns about adverse effects in HIV-negative individuals, yet the optimal approach is being explored through implementation science studies. For example, iPrEX-OLE is exploring implementation questions with iPrEX trial participants; implementation studies are also beginning in the United States. Attention is increasingly focused on implementation questions. Will PrEP need to be taken every day? Will intermittent dosing be effective, less costly, and easier to use? What is the best way to provide PrEP (e.g., service setting, packaging, pricing)? Which groups or individuals should be prioritized? Will side effects prove tolerable to healthy people? Will PrEP promote emergence of resistant HIV? Will people taking PrEP engage in riskier behaviors, offsetting PrEP's benefits? Will PrEP be safe and effective for women who are pregnant or wish to conceive? How can the global health community best balance using ARVs for PrEP with providing ARVs for treatment?
The Centers for Disease Control and Prevention has issued interim guidance for PrEP among men who have sex with men in the United States while formal guidance is developed. Gilead Sciences, the pharmaceutical company that sponsors TDF and TDF/FTC, submitted data to the U.S. Food and Drug Administration requesting a labeling change that approves TDF/FTC as PrEP to reduce the risk of HIV acquisition among adults. The request is being considered under priority review. Efforts to build on completed and ongoing trials are important to understand how best to utilize this potentially important new tool for HIV prevention.
This commentary reviews the history of pre-exposure prophylaxis (PrEP) for HIV prevention and evidence to date. Most of the drugs studied are based on tenofovir (tablets or gel) or tenofovir combined with emtricitabine. Four studies have demonstrated PrEP's safety and effectiveness (CAPRISA 004, Partners PrEP, iPrEX, and TDF2) in reducing HIV transmission while two (FemPREP and VOICE) have not shown effectiveness. Drug adherence is critical and complex to ensure and to measure. Further analyses and ongoing trials will provide insights on key issues and PrEP's potential in new populations. It outlines key issues related to implementation, reviewing evidence and outstanding questions: defining "high risk," identifying individuals who may benefit, identifying those health facilities best positioned to provide PrEP, counseling, risk assessment and safety monitoring, and cost. PrEP roll-out will be complex, and implementation studies are key to informing sound program design. The author concludes that implementing new prevention strategies is a welcome challenge.
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.
This abstract reports on FEM-PREP, an oral pre-exposure prophylaxis (PrEP) trial in women in Africa that stopped early for futility after a planned interim analysis determined that the trial was unlikely to be able to demonstrate effectiveness. This randomized, double-blind, placebo-controlled trial enrolled 2,120 women in South Africa, Kenya, and Tanzania to study whether once-daily oral emtricitabine (FTC)/tenofovir (TDF) reduces the risk of HIV infection. Thirty-three infections occurred in the FTC/TDF group and thirty-five in the placebo group (estimated hazard ratio 0.94). The study found no resistance to TDF, and the four cases of resistance to FTC waned over time. Drug-level analysis showed lower adherence than self-report or pill count data. Despite substantial efforts to support participants to take the tablets, it appears that low adherence to the study drug may have undermined the trial's ability to determine whether FTC/TDF is effective in reducing the risk of HIV. This underscores the critical role of adherence in PrEP and the importance of future PrEP trials and programs focusing on adherence. 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.
This abstract discusses additional data from the iPrEX trial on effectiveness, durability of the effect, and adverse events. Data in the presentation slides indicate that the protective effect of emtricitabine (FTC)/tenofovir (TDF) to reduce HIV infection continued for the additional 12 weeks of the trial. These data also confirmed the dose response of effectiveness: FTC/TDF's efficacy in preventing HIV acquisition increased to 68 percent among those who used the drugs most consistently (> 90 percent of doses). There was no evidence of resistance among participants who became infected after starting pre-exposure prophylaxis or of increased risk behaviors. No difference was observed in serious adverse events; adverse events in the FTC/TDF arm (headache, nausea, weight loss) were resolved. Creatinine was somewhat elevated, which may warrant further follow-up. Issues will continue to be studied in iPrEX-OLE, the trial open label extension that should offer more insights into drug use when participants know the drug is effective.
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 is the first study to compare tenofovir oral tablets and vaginal gel in the same women. It studied acceptability of the two formulations and how the different drug regimens were absorbed by and distributed in the body. Women in the United States and Africa used the vaginal gel, the oral tablet, or both daily for six weeks and then switched. All three regimens were safe and well tolerated, and self-reported adherence was very high (94 percent). Most participants reported they would be "likely" to use the products: oral (93 percent), vaginal (83 percent), and both (82 percent). All (100 percent) of women in the African sites said they would use either tablets or gel. U.S. women preferred tablets (72 percent), while women at the African sites preferred each equally and liked that the gel increased sexual pleasure. Gel use resulted in much higher drug concentrations in the vaginal tissue, whereas the tablet was associated with a higher concentration in blood. This study confirms that different women prefer different regimens, that overall acceptability for both is high, and that the regimens may work differently because of drug availability.
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 article reports results of the iPrEX study, which demonstrated that oral pre-exposure prophylaxis (PrEP) reduced the risk of HIV acquisition by 44 percent among men and transgendered women who have sex with men. The 2,499 HIV-negative participants enrolled in iPrEX were randomized to receive emtricitabine (FTC)/tenofovir (TDF) or placebo once daily; all participants received a comprehensive HIV risk reduction package. The trial took place in Brazil, Ecuador, Peru, South Africa, Thailand, and the United States. Of the 100 incident HIV infections, 36 occurred in the FTC/TDF group and 64 in the placebo group. The authors report that while self-reported adherence to the study regimen was high, adherence based on drug blood levels was substantially lower. The study concludes that PrEP is effective for slowing the spread of HIV in this population. However, it cautions that the optimal PrEP regimen has not been established and that data from iPrEX cannot be applied to other populations, which are being studied in other PrEP trials.
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.
Potential for drug resistance is a concern with pre-exposure prophylaxis (PrEP) roll-out, and this study uses risk equations to predict whether PrEP, in the presence of circulating drug resistance, will reduce the risk of infection with HIV. The model calculated the monthly risk of infection with HIV before and after the introduction of PrEP. Analyses were performed for different ranges of PrEP's effectiveness and assumptions about the degree to which circulating drug resistance would reduce PrEP's effectiveness and the transmissibility of HIV. The model used actual data on women aged 17 to 29 in Zimbabwe. Unlike previous models, it incorporated condom use as well as the potential impact of drug resistance. Based on their analysis, the authors conclude that circulating drug resistance will not have a substantial impact on the effectiveness of PrEP or its public health impact. Instead, these will depend mainly on various other factors: the drug's efficacy and risk behaviors including overall condom use, frequency of sex, the degree to which PrEP is substituted for condoms, and the degree to which people not currently using condoms do use PrEP. The authors underscore the importance of behavioral interventions as integral to PrEP introduction.
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.
Potential for increasing risk behaviors is a common concern related to pre-exposure prophylaxis or other new HIV prevention approaches. This study was conducted among women in Ghana who participated in safety and effectiveness trial of daily oral tenofovir to prevent HIV. All participants received condoms and risk reduction counseling. (The trial was stopped early so did not determine whether oral tenofovir was effective for HIV prevention.) Analysis of self-reported sexual behavior and qualitative data was used to map changes in sexual risk behavior. In contrast to concerns about risk compensation, the study found that risk behavior, on average, decreased across the 12-month trial. This is consistent with findings from other HIV prevention trials. In this study, both the number of sexual partners and rate of unprotected sex acts declined. Subanalysis indicated that "risky" women with more partners were also more likely to use condoms and less likely to have other high-risk behaviors like anal sex. Participants attributed their behavior change to the counseling they received. While the trial's HIV prevention counseling was effective overall, subgroups may need different approaches and messages. These findings may also be relevant to sample size calculations for future HIV prevention trials.
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.
Clinical trials are evaluating the efficacy of pre-exposure prophylaxis (PrEP), but will not specifically assess its public health impact. A mathematical model was used to simulate the effects of PrEP on an HIV-1 epidemic in sub-Saharan Africa with optimistic, neutral, and pessimistic scenarios. The optimistic scenario assumed 90 percent efficacy of PrEP, 75 percent coverage of the general HIV-uninfected population, and no change in sexual behavior among persons taking the medication. With these assumptions, the model predicted a 74 percent decline in cumulative new HIV infections after 10 years. If PrEP were targeted to the highest risk groups (16 percent of the population), the model estimated a 28.8 percent decline in new infections. This approach could avert 2.7 to 3.2 million new HIV-1 infections in southern sub-Saharan Africa over 10 years. The neutral scenario predicted a 6.8 percent decrease in new HIV infections with a risk-targeted strategy; the pessimistic scenario predicted a 0.8 percent decrease. The projected decreases would be partially offset, however, if people using PrEP increased risky sexual behavior or discontinued the drugs. These results suggested that PrEP could be cost-effective if efficacy and adherence were high, long-term use were sustained, and sexual disinhibition were prevented.
U.S. public health agencies are developing guidelines for pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM), but they will take time to complete and publish. These interim recommendations are intended to guide clinical practice so that MSM and providers avoid possibly unsafe and less-effective PrEP regimens. The article notes that in iPrEX, emtricitabine (FTC)/tenofovir (TDF) PrEP showed a significant added benefit within a comprehensive HIV prevention package, and cites a safety study of TDF for PrEP among MSM in the United States. It concludes that daily FTC/TDF as PrEP can contribute to HIV prevention for MSM if it is targeted to MSM at high risk for HIV, it is delivered as part of a comprehensive prevention package, and it includes regular monitoring of HIV status, side effects, adherence, and risk behaviors. The guidance includes specific recommendations for determining eligibility, beginning the regimen, follow-up, and discontinuation. It notes that PrEP should only be considered for MSM until trials in other populations are completed.
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.
This paper outlines key action points from a 2009 international meeting "Planning for PrEP" that launched a collaborative program of work on the major policy, regulatory, delivery, program implementation, and user-perspective issues related to pre-exposure prophylaxis (PrEP). Participants identified research and action steps needed to complement clinical trial data to maximize the public health impact of PrEP. They recommended developing a "proof of deliverability" pathway, analogous to the "proof of concept" studies in clinical research, to demonstrate PrEP's feasibility in different cultural, ethical, legal, and political settings. The group identified priority activities: model costs and benefits for different epidemics and populations, factoring in testing and resistance, conduct targeted market research, establish regulatory pathways that will influence funders and policymakers, and develop an implementation framework. The article highlights the importance of ensuring coordination, collaboration, and effective communication; country ownership; and working with normative bodies. Recognizing that clinical trial results are just one step in PrEP becoming a public health intervention, the article underscores that this work must be done concurrent with clinical research.
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.
Underscoring that the potential of pre-exposure prophylaxis (PrEP) as a new biomedical intervention for HIV prevention will depend on behavioral and social factors, this article reviews knowledge across a number of behavioral and social science disciplines to draw out lessons for PrEP. It focuses on three individual-level behaviors: adoption of PrEP, adherence to PrEP regimens, and sustained risk reduction practices. A table summarizes the most relevant analogies. Key issues regarding adoption of PrEP include communicating and processing risk and probability to address partial effectiveness, comprehension and application of information on risk in decision making, framing effects as positive or negative, and stigma and its impact on behavior. Lessons from antimalarial prophylaxis, treating latent tuberculosis, oral contraceptive pills, and HIV treatment can inform adherence strategies. Information relevant to sustained risk reduction can be drawn from research on risk perception and how it informs decisions and behaviors in HIV prevention and highly active antiretroviral therapy programs. In presenting empirical analogies directly relevant to PrEP implementation, this article emphasizes that interdisciplinary learning will be critical to the success of PrEP.
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.
This article reviews published and unpublished literature on pre-exposure prophylaxis (PrEP) implementation and organizes the issues and challenges raised around five themes: scientific groundwork, regulatory and policy groundwork, stakeholder and infrastructure groundwork, delivery, and long-term monitoring. It identifies more detailed topics under each of these themes. It argues that PrEP, comprised of biomedical, behavioral, and structural elements, exemplifies the increasing emphasis on multifaceted HIV prevention strategies. As such, PrEP provides an impetus to shape and expand the field of implementation and delivery science for HIV prevention. Lessons from PrEP planning can benefit other combination interventions to prevent HIV. The authors propose that the framework of five themes can serve as a starting point for thinking systematically about PrEP implementation and the broader field of implementation science.
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 paper reports findings from a study of 227 HIV-uninfected men who have sex with men (MSM) in the Boston, MA, area. Recognizing that intentions to use pre-exposure prophylaxis (PrEP), acceptability, and adherence will be critical to PrEP's use-effectiveness, the study explored behavioral and demographic characteristics likely to be associated with intention to use PrEP among MSM. After being given information about PrEP, participants were interviewed about their knowledge of and intention to use PrEP as well as a range of demographic and behavioral information. Few (19 percent) in this diverse high-risk MSM population were aware of the potential of antiretroviral therapy for HIV prevention. After hearing about PrEP, most (74 percent) reported an interest in using it, especially if it had no side effects and was available free of charge. Interest in future PrEP use was not associated with higher risk behaviors, but it was associated with relatively lower education and modest income. This study identifies the potential for rapid uptake of PrEP among this population, as well as the importance of careful community and individual educational messages.
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 study examined awareness and use of post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) among 1,819 HIV-uninfected gay/bisexual men in California. PEP is currently indicated after a high-risk exposure to HIV. At the time of the study, PrEP effectiveness had not been established, but media reports suggested that gay men had started using PrEP and that some physicians were prescribing it. Overall, knowledge of both PEP and PrEP was low, with only 16 percent of the study population aware of PrEP and less than half (47 percent) aware of PEP. Approximately two-thirds (67 percent) of the study participants indicated that they would take PrEP if it were safe and effective. Older, wealthier men with higher risk profiles were more likely to have heard of PEP. Participants who reported risky behaviors were more likely to know about PrEP and to indicate they would be willing to use it. Friends and media were the main sources of information on PrEP, suggesting that accurate reporting and community education campaigns are and will remain critical.
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.
In the i-PrEX trial, detectable levels pre-exposure prophylaxis (PrEP) drugs were found in the plasma or peripheral blood mononuclear cells (PBMCs) of 22 of 43 seronegative men who have sex with men (MSM), compared with only 3 of the 34 HIV-infected MSM participating in the intervention arm of the study. The predicted efficacy of the iPrEx trial increased from 44% to more than 90% when detectable drug in the plasma or PBMCs were taken into consideration. The study documented in this article, which was a substudy of iPrEx, seeks to understand the relationship between adherence and drug concentrations in the body. Data from iPrEx and from another study, STRAND, were used to measure the active form of tenofovir (intracellular TFV-DP) in PBMCs, in order to better understand the relationship between TFV-DP concentrations and PrEP efficacy. Data from the iPrEx trial were used to estimate drug concentrations associated with decreased HIV acquisition. Data from the STRAND trial were utilized to establish a link between expected TFV-DP concentrations when two, four, or seven doses of tenofovir disoproxil fumarate (TDF) were directly observed every week. Among STRAND trial participants assigned to receive oral PrEP, the relationship between drug concentration and HIV infection risk was found to be significant. The risk of HIV acquisition was similar in participants in the STRAND trial control arm compared with those in the intervention arm with undetectable concentrations. PrEP efficacy improved when participants were directly observed taking increased doses per week--76 percent when two doses were taken, 96 percent for four doses, and 99 percent for seven. In conclusion, PrEP can be an effective HIV prevention strategy for men who have sex with men with good adherence to a regimen of multiple doses each week.
Okwundu and colleagues conducted a systematic analysis of six randomized controlled trials of oral pre-exposure prophylaxis (PrEP) to prevent HIV transmission for high-risk individuals--such as people in serodiscordant sexual relationships and men who have sex with men. The review, which includes data from more than 9,849 participants, evaluated daily oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo, TDF versus placebo, and daily TDF-FTC versus intermittent TDF-FTC. The authors found a 49 percent reduction in risk of acquiring HIV in the four trials comparing TDF-FTC to the placebo. In two of the trials that compared TDF to the placebo, the authors found a 62 percent reduction in risk of acquiring HIV infection. Although participants reported a high rate of adherence in both trials, some participants' drug levels suggested that the level of adherence may be lower than reported.
The article reports on the primary findings of the Preexposure Prophylaxis Trial for HIV Prevention among African Women (FEM-PrEP) in Kenya, South Africa, and Tanzania, which was stopped early because the protocol being evaluated did not meaningfully reduce the HIV infection rate. The study was randomized, double blinded, and placebo controlled to test the efficacy of the once-daily oral dose of tenofovir-emtricitabine (TDF-FTC) among women at high risk for HIV infection in an effort to reduce their HIV acquisition. HIV-negative women were recruited between June 2009 and April 2011, and 2,120 women were randomized to the placebo and intervention arms. Of the 68 HIV seroconversions, 33 occurred in the PrEP intervention arm and 35 in the control arm. The estimated hazard ratio in acquiring HIV in the TDF-FTC group, 0.94, was not significant between study groups. Although 95 percent of the women reported "usually" or "always" taking their assigned drug, testing showed drug levels to be quite low among seroconverting TDF-FTC group women, who showed only 26 percent of the target drug levels at the beginning of the infection window and 21 percent at the end of the window. Drug levels in uninfected women in the control group were slightly higher, with 35 percent at the beginning of the infection window and 37 percent at the end of the window. Most women viewed themselves at no or low risk for HIV infection. Because the trial demonstrated no reduction of HIV infection as a result of PrEP, it was therefore stopped. The authors surmise that perception of low risk levels could have triggered poor adherence to the assigned drug regimen, which in turn could have affected its effectiveness.
This randomized, double-blinded, and placebo-controlled study examined the effects of PrEP in an HIV-negative heterosexual population in Botswana as a means to measure its effectiveness in reducing HIV acquisition. The trial closed early because of low retention. All participants exited the study by May 2010, after five years, with the exception of those who acquired HIV, who were pregnant, or who had ongoing serious adverse events; these participants were followed for an additional year. For the original trial, 1,219 participants underwent randomization, and 89.3 percent completed exit procedures. Between the intervention and control arms, there was no significant difference with regards to early withdrawal and loss to follow-up, and adherence rates were similar, based on pill counts and self-reported data. Adverse effects were more numerous, and more statistically significant, in the TDF-FTC group than in the placebo group, with 18.5 percent experiencing nausea, 11.3 percent vomiting, and 15.1 percent dizziness. Bone density declined significantly in the TDF-FTC group compared with the placebo group. Thirty-six participants became infected with HIV during the trial--10 in the intervention group and 26 in the placebo group, equaling a 62.2 percent efficacy level in the TDF-FTC group. Drug levels in those who seroconverted were significantly lower than for those who did not seroconvert. The findings in this trial are consistent with those of other studies, where drug levels are high in the intervention group and that group shows reduced HIV transmission rates.
The qualitative study reported here, conducted between October 2009 and April 2010, sought to understand the acceptability of pre-exposure prophylaxis (PrEP) and PrEP adherence in two populations in Kenya at high risk for acquiring HIV infection--men who have sex with men and female sex workers. The qualitative sample was selected from a larger randomized, placebo-controlled blind trial where daily and intermittent PrEP was prescribed. The intermittent dose of Truvada was prescribed for Mondays and Fridays, and within two hours after sexual intercourse but no more than one dose per day. The 72 participants enrolled in the trial were assigned either to the intervention arm or the placebo arm; 51 participated in the qualitative portion of the study. Focus group discussions and semi-structured, in-depth interviews were conducted with participants who completed the trial, and in-depth interviews were conducted with individuals who discontinued the study or who during their monthly clinical visits revealed low adherence. It was found that acceptability was high and that counseling and commitment increased adherence. Participants suggested that the pill's shape and color could be improved to increase their comfort in taking it and to cause less discoloration in their mouths and thus be less noticeable to others. Side effects subsided over time. Participants preferred the intermittent dosing, but those on intermittent dosing expressed greater difficulties with adherence, especially after sexual intercourse. Barriers to adherence included alcohol use, work schedules, and stigma and discrimination. Risk reduction caused by participation in the study was noted. In conclusion, the authors recommended that behavioral activities such as counseling and social support could enhance PrEP adherence in these high-risk populations.
This report summarizes discussions among many of the leading mathematical modelers and public health professionals working on pre-exposure prophylaxis (PrEP). Convened by the World Health Organization and the Joint United Nations Programme on HIV/AIDS, participants reviewed PrEP modeling processes, outcomes, and priority next steps. Models discussed addressed the potential impact and cost for delivering oral PrEP and microbicides in different epidemiological contexts and populations. Some also examine potential concerns such as drug resistance and behavioral disinhibition. The report sheds light on some of the thinking and decision making behind assumptions reflected in the models, many of which are in the literature, including what data are used and what additional data would be useful to inform modeling. It includes reflections and recommendations about how these different groups can best coordinate and link their work with demonstration projects and service providers. It also describes the contribution modeling can make to decision making.
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 fact sheet from the U.S. Centers for Disease Control and Prevention (CDC) summarizes a number of key issues related to pre-exposure prophylaxis (PrEP) use in the United States. It emphasizes implications for men who have sex with men, noting that effectiveness had only been demonstrated among that population, and includes cautions about what is and is not known, partial effectiveness and the need to use PrEP in conjunction with other risk reduction measures, and the importance of adherence and close collaboration with a health provider. It outlines practical interim guidance for physicians as formal guidelines are being developed, and maps out CDC's approach to developing those formal U.S. public health service guidelines in collaboration with other key agencies.
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.
Published just prior to the International AIDS conference in Vienna and in anticipation of the CAPRISA 004 tenofovir gel trial results, this publication contextualizes pre-exposure prophylaxis (PrEP) research within the broader arena of antiretroviral-based prevention trials (which included tenofovir in a vaginal gel as well as oral PrEP). It describes how HIV prevention trials are conducted and maps out several scenarios and the implications for further research, ongoing trials, implementation programs, and advocacy.
Epidemiologists at the U.S. Centers for Disease Control and Prevention have issued interim guidance on pre-exposure prophylaxis (PrEP) for heterosexual adults in the wake of the U.S. Food and Drug Administration's approval of Truvada, a combination antiretroviral drug, for use as PrEP. This new guidance is based on data from four different clinical trials that randomized participants to receive combination oral PrEP of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)--the two active components of Truvada--or a placebo. In two of the studies, daily oral TDF/FTC was found to be safe for reducing the risk of sexual HIV transmission when used consistently. The four primary guidelines include: 1) contraindication for PrEP for those with positive or unknown HIV status; 2) daily PrEP for men and women at high risk of acquiring HIV from penile-vaginal intercourse; 3) use by serodiscordant couples attempting to conceive; and 4) pregnancy testing for women before starting PrEP and periodically during PrEP, so that, if they become pregnant, health care providers can advise them of the possible risks and benefits of continuing PrEP during the pregnancy. The guidance also advises health care providers to tell patients that PrEP efficacy depends on adherence to daily doses and that the long-term safety for HIV-negative adults or fetuses has not yet been determined.
Clinical trials of regimens for pre-exposure prophylaxis (PrEP) have been successful in two populations--men and transgender women who have sex with men (MSM-TG) and serodiscordant heterosexual couples. However, how these results translate to real world settings is less known. The World Health Organization (WHO) recommends that countries implement demonstration projects that will offer advice on key safety, effectiveness, adherence, and sustainability questions surrounding PrEP interventions. The guidance provides an overview of the research conducted to date and recommendations on PrEP for serodiscordant couples, MSM-TG, and other groups. The guidance lists nine key points to guide demonstration projects, among them ensuring the HIV-negative status of participants, monitoring participants' safety, supporting high adherence levels, and developing transition mechanisms for those who want or need to discontinue treatment. Plans are for the WHO to review and revise this guidance in 2015.
The website offers the latest news on the past, present, or ongoing status of biomedical HIV prevention research studies. Readers can review summary tables from various HIV prevention clinical trials, search information on prevention trials, see what is new on the site this month, and review the user's guide for help in using the site. The site offers information about the following biomedical prevention trials: microbicides, pre-exposure prophylaxis, treatment as prevention, and vaccines.
PrEP Using Daily Oral TDF/FTC or TDF in Women (and Men): What the Science Tells Us in March 2012
AIDS Vaccine Advocacy Coalition. (2012).
This one-page brief, aimed at advocates, summarizes the implications of concluded and ongoing clinical trials and other research on pre-exposure prophylaxis (PrEP), including new information presented at the 2012 Conference on Retroviruses and Opportunistic Infections. It states that PrEP using a daily oral tenofovir (TDF) or TDF/emtricitabine (FTC) tablet reduces the risk of HIV in women and men, and summarizes the information to support this statement. It provides brief descriptions of information to support additional conclusions from PrEP research to date, underscoring that adherence is critical to effectiveness, that risk perception appears to contribute to an individual's willingness and ability to adhere to the daily regimen, and that regular HIV testing is and will remain critical to addressing resistance. Finally, the brief identifies pregnant women and adolescents as among the key groups where more data are needed.
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Partners PrEP Study Demonstrates that PrEP Significantly Reduces HIV Risk: Key Messages
University of Washington, International Clinical Research Center. (2011).
This document lists "key messages" prepared by the study team in anticipation of the release of results from the Partners PrEP study. Randomization was stopped early at the recommendation of the trial's independent Data Safety and Monitoring Board due to overwhelming evidence of effectiveness, and results were announced at the International AIDS Conference in July 2011, just a week later. This document provides an overview of the trial, its conduct, the trial findings, and their implications for pre-exposure prophylaxis in these and other populations.
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PrEP Implementation Policy Forum: Developing Country-level Preparation and Capacity for PrEP Implementation
International AIDS Society. (2007).
This report contains proceedings of a policy forum focused on country-level preparedness for pre-exposure prophylaxis (PrEP). It outlines approaches for translating research into policy and deriving lessons from implementation planning for male circumcision for HIV prevention. Ministry of Health representatives from several key countries emphasized that country-level preparedness will be predicated on the evidence, defining target populations, cost and financing, and addressing stigma and integration into existing health systems. The report also addresses designing global and national PrEP guidelines and affordability and availability of PrEP drugs. It concludes with 10 "Key Take Home Messages" to consider in preparing for PrEP implementation.
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Criteria for Drugs Used in Pre-exposure Prophylaxis Trials against HIV Infection
Derdelinckx, I., Wainberg, M. A., Lange, J. M., et al. PLoS Medicine (2006), Vol. 3, p. e454.
This paper proposes criteria for deciding which medications should be used for pre-exposure prophylaxis (PrEP). Drug safety is a critical consideration because PrEP is given to healthy individuals for long-term prevention. Drugs used for PrEP must be potent against HIV, easy to use, cost-effective, and have a high barrier to resistance. Theoretically, drugs that interfere with HIV replication before the virus enters the host cell are preferable. An ideal PrEP drug would also have a unique resistance profile and not be used in treatment of established HIV infection, but such a medication does not yet exist.
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