HIV Prevention Knowledge Base
Biomedical Interventions: Oral Pre-exposure Prophylaxis (PrEP) for HIV Prevention
HIV Preexposure Prophylaxis: New Data and Potential Use
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.
ARV PrEP for HIV-1 Prevention among Heterosexual Men and Women
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 FEM-PrEP Trial of Emtricitabine/Tenofovir Disoproxil Fumarate (Truvada) among African Women
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.
Daily Oral Antiretroviral Use for the Prevention of HIV Infection in Heterosexually Active Young Adults in Botswana: Results from the TDF2 Study
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.
Pre-exposure Chemoprophylaxis for Prevention of HIV Among Trans-women and MSM: iPrEx Study
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.
Predicting the Impact of ART and PrEP with Overlapping Regimens on HIV Transmission and Drug Resistance in South Africa
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.
MTN-001: A Phase 2 Cross-over Study of Daily Oral and Vaginal TFV in Healthy, Sexually Active Women Results in Significantly Different Product Acceptability and Vaginal Tissue Drug Concentrations
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.
Factors Influencing the Emergence and Spread of HIV Drug Resistance Arising from Rollout of Antiretroviral Pre-exposure Prophylaxis (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.
Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men
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.
HIV Preexposure Prophylaxis in the United States: Impact on Lifetime Infection Risk, Clinical Outcomes, and Cost-Effectiveness
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.
Circulating HIV Type 1 Drug Resistance will Have Limited Impact on the Effectiveness of Preexposure Prophylaxis among Young Women in Zimbabwe
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.
The Impact of Pre-exposure Prophylaxis (PrEP) on HIV Epidemics in Africa and India: A Simulation Study
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.
Changes in Sexual Risk Behavior among Participants in a PrEP HIV Prevention Trial
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.
Tenofovir Disoproxil Fumarate for Prevention of HIV Infection in Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial
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.
Potential Impact of Antiretroviral Chemoprophylaxis on HIV-1 Transmission in Resource-limited Settings
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.