Oral PrEP


  1. 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. Data from the iPrEx, Partners PrEP, and TDF2 studies have shown that daily oral tenofovir/emtricitabine (TDF/FTC) (marketed as Truvada) use is safe and effective for reducing risk of infection in heterosexual men and women, men who have sex with men, and transgender women. Data from these studies formed the basis of Gilead’s application to the US Food and Drug Administration for approval of TDF/FTC as PrEP (Gilead is the manufacturer and patent holder for TDF/FTC). Trial data show that TDF/FTC reduces HIV transmission risk for people who take it correctly and consistently.

  2. Epidemiological Justification for the Prevention Area

    A safe, effective, and acceptable oral prevention regimen would be another tool for HIV-prevention programs. Three placebo-controlled clinical trials have shown significant reduction in HIV acquisition among HIV-negative persons who received and took an ARV pill daily, as shown in the following:

    Trial Study Drug Population Results
    iPrEX TDF/FTC Men who have sex with men, transgender women; Brazil, Ecuador, Peru, South Africa, Thailand, United States Risk reduced by 44%; higher protection (73%) among most consistent users
    Partners PrEP TDF and TDF/FTC Serodiscordant heterosexual couples; Uganda, Kenya Risk reduced by 67% (TDF)
    75% (TDF/FTC)
    TDF2 TDF/FTC Men and women; Botswana Risk reduced by 62%

    One placebo-controlled trial that included prophylaxis with TDF–FTC (FemPrEP) and the oral TDF arm of the VOICE trial did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low.

    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 work to understand the interaction between the behavioral and biomedical aspects of these results, and the implications for PrEP.

  3. Core Programmatic Components

    Roll-out of ARV PrEP has not started, but programs will 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 sensitive risk factors.
    • Providing individual education, counseling, and adherence support.
    • HIV testing before PrEP provision.
    • Regimen selection.
    • Regular follow-up to assess safety, toxicity, HIV status, and potential resistance.
    • Identifying and costing service delivery approaches.

    Successful implementation will depend on involvement of national ministries of health, normative agencies, donors, provider organizations, and community groups.

  4. Current Status of Implementation Experience

    Guidelines for prescribing and using PrEP are available from a range of groups, including state health departments in the US, the US Centers for Disease Control (CDC) and national-level clinician groups as well as guidelines on international demonstration projects from the World Health Organization. In the US the Food and Drug Administration (FDA) has approved daily Truvada for HIV prevention, and some communities in the US are exploring how it might best be delivered.

    Outside the US, Truvada as PrEP is not approved by local regulators and in most cases remains inaccessible outside research studies. The optimal approach to PrEP is being studied in the United States. Attention is increasingly focused on questions such as: 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 balance using ARVs for PrEP with providing ARVs for treatment?

UPDATED 05/2015

What We Know

Antiretrovirals for Primary HIV Prevention: the Current Status of Pre- and Post-Exposure Prophylaxis

Krakower, D. S., Jain, S., Mayer, K. H. Current HIV/AIDS Reports, (March 2015), 12(1): 127–138, doi: 10.1007/s11904-014-0253-5.

This review provided the most recent findings on pre-and post-exposure prophylaxis (PEP and PrEP, respectively). PEP is most effective when started immediately after high-risk exposure and should be administered in diverse clinical settings. While well-tolerated PEP treatment regimens are available, adherence to PEP medications and attendance at clinical visits is challenging to certain groups of individuals, especially vulnerable populations like men who have sex with men (MSM). The authors noted that efficacy of PrEP ranged from 44 to 75 percent among several studies that demonstrated reductions in HIV incidence. However, in two studies of African women that did not demonstrate PrEP efficacy, medication nonadherence was suggested as the primary explanation for why the two studies did not demonstrate protection with the same regimen. Data from a 72-week open-label study of daily PrEP among MSM and transgender women (iPrEx OLE) suggested that less-than-perfect adherence to daily PrEP still provides high levels of protection. Further, a modeling study of the South African HIV epidemic concluded that providing PrEP to the general population was costly, whereas focused provision of PrEP to those at greatest risk of HIV acquisition was cost-effective. The authors concluded that expansion of PEP and PrEP provision could help decrease the number of new HIV infections globally, but additional research is needed.

The Promise of Pre-Exposure Prophylaxis with Antiretroviral Drugs to Prevent HIV Transmission: A Review

Hankins, C.A. and Dybul, M.R. Current Opinions in HIV/AIDS (January 2013), 8(1): 50–58. doi: 10.1097/COH.0b013e32835b809d.

In this review, the authors summarize clinical trial findings on oral and topical pre-exposure prophylaxis (PrEP), and how it might be applied with combination HIV-prevention strategies. Findings from the trials indicated mixed results regarding effectiveness. Oral PrEP taken daily was found effective in the Pre-Exposure Prophylaxis Initiative (iPrEx), Partners' PrEP, and TDF2 trials, but not in the Fem-PrEP or the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial tenofovir arm. Tenofovir vaginal gel was found effective for topical protection in the South African Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial when used pericoitally, but not applied daily (in the VOICE trial). These findings show that adherence is critical to ensure adequate drug levels for protection, and as important as efficacy in determining program success. In the clinical trials, no cases of drug resistance were identified, reported risky sexual behaviors declined, and adverse events among participants were limited. Although overall results varied, PrEP is estimated to be generally cost-effective, particularly when persons at highest HIV risk are targeted. The future of PrEP is expanding with local prophylaxis, systematic prophylaxis, and multiuse technologies such as vaginal rings that can be used for both contraception and STI prevention. The authors conclude that antiretroviral-based prevention strategies should include quality counseling to support adherence.

Antiretroviral Prophylaxis for HIV Infection in Injecting Drug Users in Bangkok, Thailand (the Bangkok Tenofovir Study): A Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial

Choopanya, K., Martin, M., Suntharasamai, P., et al. The Lancet (June 2013), E-publication ahead of print. doi: 10.1016/S0140-6736(13)61127-7.

The authors reported findings from the Bangkok Tenofovir Study, which assessed whether pre-exposure prophylaxis (PrEP) with daily oral tenofovir would reduce the risk of HIV transmission among people who inject drugs (PWID) in Bangkok, Thailand. Findings showed that PrEP with daily oral tenofovir, combined with HIV-prevention interventions, decreased HIV risk by nearly 49 percent among PWID. High adherence was associated with treatment efficacy. A total of 2,143 HIV-negative participants ages 20 to 60 (average age 31) from 17 drug treatment facilities were randomly assigned to receive daily oral tenofovir (n = 1,204) or a placebo (n = 1,209), and consented to directly observed therapy or monthly follow-up visits. Fifty-two participants became infected with HIV (33 percent in the tenofovir arm [incidence rate of 0.35 per 100 person-years (PY)]; 67 percent in the placebo arm [incidence rate of 0.68 per 100 PY]). Adherence was similar between the groups. The estimated efficacy of tenofovir increased from 46 to 56 percent among adherent participants; efficacy was among two adherent groupswomen and participants age 40 or older. Reported use of injection drugs, needle-sharing, and sex with multiple partners decreased during the three-month follow-up. Tenofovir resistance in HIV-positive participants was not detected. The authors concluded that HIV prevention package for PWID should include PrEP with tenofovir.

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

Baeten, J. M., Donnell, D., et al. The New England Journal of Medicine (August 2012), doi: 10.1056/NEJMoa1108524.

The authors of this randomized trial of oral antiretroviral therapy for use as pre-exposure prophylaxis (PrEP) conducted among 4,747 HIV-1 serodiscordant heterosexual couples from Kenya and Uganda assigned the HIV-1–seronegative partner in each couple to one of three study regimens—once-daily tenofovir (TDF), combination tenofovir–emtricitabine (TDF–FTC), or matching placebo—and followed monthly for up to 36 months. At enrollment, the HIV-1–seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. The study found that 82 HIV-1 infections occurred during the study: 17 in the TDF group; 13 in the TDF-FTC group; and 52 in the placebo group, indicating a relative reduction of 67 percent in the incidence with TDF and 75 percent with TDF-FTC. The authors reported that both medications significantly reduced the HIV-1 incidence among both men and women. Moreover, the study showed that all HIV-1 transmission occurred between serodiscordant partners. The authors concluded that PrEP could reduce HIV-1 acquisition in heterosexual populations and called for the implementation of pre-exposure prophylaxis as a public health measure.

Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women

Marrazzo, J. M., Ramjee, G., Richardson, B. A., et al. The New England Journal of Medicine (February 2015), 372(6). doi: 10.1056/NEJMoa1402269.

This randomized, placebo-controlled trial of daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir–emtricitabine (TDF-FTC), or 1 percent tenofovir (TFV) vaginal gel as pre-exposure prophylaxis against HIV-1 infection enrolled 5,029 women in South Africa, Uganda, and Zimbabwe. Participants were assigned to one of five regimens: oral TDF (300 mg) and TDF-FTC placebo; oral TDF-FTC (300 mg of TDF and 200 mg of FTC) and TDF placebo; oral TDF placebo and oral TDF-FTC placebo; vaginal 1 percent TFV gel; or vaginal placebo gel. The primary analysis included as end points only HIV-1 infections that were acquired after enrollment. The authors reported -49 percent effectiveness with TDF; −4.4 percent with TDF-FTC; and 14.5 percent with TFV gel. TFV was detected in 30 percent, 29 percent, and 25 percent of randomly selected plasma samples from participants receiving TDF, TDF-FTC, and TFV gel, respectively. The authors concluded that none of the drug regimens evaluated during this study reduced rates of HIV-1 acquisition in an intent to treat analysis and that daily adherence to study products, both oral and vaginal TFV-based formulations, was low. They called for effective and acceptable prevention interventions for women at high risk for sexual acquisition of HIV-1, and stated that more accurate measures were required to estimate product use during biomedical HIV-1–prevention trials.

Tailored Combination Prevention Packages and PrEP for Young Key Populations

Pettifor, A., Nguyen, N. L., Celum, C., et al. Journal of the International AIDS Society (February 2015), 18(2), S1, doi: 10.7448/IAS.18.2.19434.

The authors conducted a comprehensive review of the evidence to date on prevention strategies, challenges to prevention, and combination prevention packages for young key populations, defined as men who have sex with men (MSM), transgender persons, people who sell sex, and people who inject drugs (PWID). The study focused specifically on the role of pre-exposure prophylaxis (PrEP) in prevention packages for those under the age of 24, and particularly those under 18 years of age. The authors noted that PrEP could offer highly effective, time-limited primary prevention for adolescents and young key populations, provided that they could access health services and were motivated to use PrEP. However, young key populations face unique challenges to accessing PrEP. For PWID, these challenges included adherence to medications (due to low social support), incarceration, and detoxification. Challenges for young MSM and transgender women included unstable housing, discrimination, and violence; challenges for young sex workers included increased risk of sexual and physical violence from clients and law enforcement, along with social and economic marginalization. The authors concluded that conducting effective PrEP interventions will require addressing structural barriers, such as access to HIV testing, prevention, and care, health services, and PrEP, along with other prevention strategies, including decriminalizing the practices of key populations, reducing stigma and discrimination, and empowering communities.

Uptake of Pre-exposure Prophylaxis, Sexual Practices, and HIV Incidence in Men and Transgender Women who have Sex with Men: A Cohort Study

Grant, R. M., Anderson, P. L., and McMahan, V. The Lancet Infectious Diseases (July 2014), 14(9): 820–829. doi: 10.1016/S1473-3099(14)70847-3.

This cohort study assessed the effect of pre-exposure prophylaxis (PrEP) on the uptake, adherence, and sexual practices of HIV-negative men and transgender women who have sex with men, all of whom were previously enrolled in PrEP trials. During the 72-week open-label extension study, the authors measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. Of 1,603 eligible participants, 1,230 (77 percent) wanted to receive PrEP. The study found high uptake of PrEP across a range of demographic subgroups among study participants who had access to PrEP at no charge through an experienced health care provider. Participants who engaged in risky sexual behavior and those with sexually transmitted infections were more likely to accept PrEP. Reasons for not wanting PrEP included concerns about side effects (50 percent), not wanting to take a pill every day (16 percent), and preference for other prevention methods (14 percent). In terms of adherence, the study found overall retention to be lower with younger participants. Main reasons for interrupting the treatment include side effects (3–7 percent), effects of an unrelated comorbidity (1 percent), relocation, or travel (2–4 percent). The study also found that PrEP users reported safer sexual behaviors.

Adherence and Acceptability in MTN 001: A Randomized Cross-Over Trial of Daily Oral and Topical Tenofovir for HIV Prevention in Women

Hendrix, C., Minnis, A., Guddera, V., et al; AIDS and Behavior (February 2013), 17 (2): 737–747. doi: 10.1007/s10461-012-0333-8.

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. US 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)

Abbas, U. L., Hood, G., Wetzel, A. W., et al. PLOS ONE (2011), 6(4), p. e18165. doi: 10.1371/journal.pone.0018165.

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 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.

The New Role of Antiretrovirals in Combination HIV Prevention: A Mathematical Modelling Analysis

Cremin, I., Alsallaq, R., Dybul, M., et al. AIDS (January 2013), 27: 447–458. doi: 10.1097/QAD.0b013e32835ca2dd.

The authors developed and analyzed a mathematical model to examine the optimal application, impact, and cost-effectiveness of three HIV prevention interventions: 1) pre-exposure prophylaxis (PrEP); 2) earlier antiretroviral therapy (ART) initiation for HIV-positive persons; and 3) PrEP and earlier ART combined with medical male circumcision in a high HIV-prevalence context (KwaZulu-Natal, South Africa). Potential impact was estimated with PrEP alone, in combination with earlier ART, and both interventions combined with medical male circumcision. The results indicated that using only PrEP in this context would have limited impact, unless the cost could be considerably reduced. Providing earlier ART would be more cost-effective in terms of infections averted and quality-adjusted life years gained. However, PrEP, in addition to earlier ART, would have a greater impact on reducing HIV incidence. A concentrated approach to ensure high adherence rates in a PrEP intervention could be more effective, according to the authors. Earlier ART and PrEP combined with medical male circumcision at high coverage levels could greatly reduce HIV incidence. The authors conclude that an evidence-based combination prevention approach provides the greatest potential for HIV prevention.

Pre-Exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

Grant, R. M., Lerma, J. R., Anderson, P. L., et al. The New England Journal of Medicine (2010), 363 (27): 2587–2599. doi: 10.1056/NEJMoa1011205.

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

Paltiel, A. D., Freedberg, K. A., Scott, C. A., et al. Clinical Infectious Diseases (2009), 48: 806–815. doi: 10.1086/597095.

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 US 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 (US$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.

Antiretroviral Resource Allocation for HIV Prevention

Singh, J.A. AIDS (March 2013), 27 (6): 863–865. doi: 10.1097/QAD.0b013e32835f2b30.

In this article, J.A. Singh discusses the ongoing debate surrounding the designation of antiretroviral (ARV) resources for HIV treatment versus HIV prevention. According to Singh, HIV treatment and prevention, utilizing pre-exposure prophylaxis (PrEP), should be implemented simultaneously, and also concurrently with an expanded HIV testing and counseling (HTC) program. Treatment and prevention should not be viewed as incompatible. It is unethical to deny ARV treatment for prevention because many people are at high risk of HIV but are unable to protect themselves. The treatment as prevention model is flawed in settings where HIV prevalence is high, multiple concurrent partnerships are common, and the implementation of HTC for couples challenging. ARV allocation for HIV prevention is a human rights responsibility. Many countries have accepted the International Covenant on Economic, Social and Cultural Rights to provide “minimum core obligations.” Importantly, this covenant includes vulnerable populations who have limited or no access to HIV services. Multisectoral stakeholders must identify groups that are in urgent need of prioritized access. Policies will need to be adopted to ensure sustainable programmatic implementation of HIV treatment and PrEP. The author concludes that implementing the strategies concurrently with scaled-up HTC access may help achieve the "AIDS-free generation" goal of the Joint United Nations Program on HIV and AIDS.

Putting it Into Practice

Interim Guidance: Pre-Exposure Prophylaxis for the Prevention of HIV Infection in Men Who Have Sex with Men

Smith, D. K., Grant, R. M., Weidle, P. J., et al. Morbidity and Mortality Weekly Report (2011), 60 (3): 65–68.

United States 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.

Where to Deploy Pre-Exposure Prophylaxis (PrEP) in Sub-Saharan Africa?

Verguet, S., Stalcup, M., and Walsh, J.A. Sexually Transmitted Infections (August 2013), E-publication ahead of print. doi:10.1136/sextrans-2012-050891.

The authors used a deterministic epidemiologic model to assess the impact and cost-effectiveness of implementing a pre-exposure prophylaxis (PrEP) intervention from 2013 to 2017 for the general adult population in 42 countries in sub-Saharan Africa. The findings suggest a large impact on HIV, with maximum impact and cost-effectiveness in general adult populations with low levels of male circumcision and high HIV-prevalence. Southern African countries would benefit most from PrEP; West and Central African countries would benefit least. PrEP would be most cost-effective in generalized epidemics; but in other contexts, PrEP should be prioritized for key populations. If implemented at 10 percent coverage in the region for five years, PrEP could prevent 390,000 HIV infections, 53,000 deaths, and 5,400,000 disability-adjusted life years (DALYs). The greatest impact would be in South Africa; the smallest in Djibouti (940,000 and 200 infections averted, respectively). Overall, the cost-effectiveness of PrEP was US$5,800/DALY. PrEP was more cost-effective in South Africa ($1,100/DALY) than in the Democratic Republic of the Congo ($18,500/DALY). In high-risk populations, PrEP would substantially increase protection (557,000 infections averted at $3,800/DALY). The authors provided a model that can be adapted to help make health policy decisions about PrEP interventions. PrEP would likely be most cost-effective as a targeted intervention within a combination of HIV-prevention strategies.

High Acceptability of HIV Pre-Exposure Prophylaxis but Challenges in Adherence and Use: Qualitative Insights from a Phase I Trial of Intermittent and Daily PrEP in At-Risk Populations in Kenya

Van der Elst, E.M., Mbogua, J., Operario, D., et al. AIDS and Behavior (July 2013), 17 (6): 2162–2172. doi: 10.1007/s10461-012-0317-8.

To understand factors influencing pre-exposure prophylaxis (PrEP) adherence, the authors conducted 10 focus group discussions and seven in-depth interviews with men who have sex with men (MSM) and female sex workers (FSWs) who participated in a clinical trial testing the safety of and adherence to oral PrEP in Kenya. Twenty-three MSM from Nairobi and 23 MSM and five FSWs from Mtwapa participated. The findings emphasized that behavioral interventions to promote adherence are important for success of PrEP, and showed that both individual and social factors influence PrEP adherence and acceptability. Three key themes emerged. First, acceptance of PrEP was high among at-risk users, though participants suggested physical changes to the pills to improve acceptability. Second, participants discussed the social challenges (stigma, relationship conflict) of taking PrEP. Third, participants said that lifestyle and behavior risks, such as transactional sex and alcohol abuse, were barriers to adherence. Future PrEP users should be counseled on the limitations of the method and the importance of behavioral risk-reduction strategies to support efficacy of the method. The authors concluded that future research and interventions using PrEP should consider drug, behavior, social contexts, and adherence limits of target populations in real-world settings.

Using Geospatial Modelling to Optimize the Rollout of Antiretroviral-Based Pre-Exposure HIV Interventions in Sub-Saharan Africa

Gerberry, D.J., Wagner, B.G., Garcia-Lerma, J.G., et al. Nature Communications (December 2014), doi: 10.1038/ncomms6454.

The authors of this study used geospatial modelling to compare two plans (based on egalitarian or utilitarian principles) for rolling out antiretroviral (ARV)-based microbicides and other ARV-based pre-exposure interventions in sub-Saharan African countries. The egalitarian plan seeks to maximize equal access to ARV resources across a geographic region; the utilitarian plan uses geographic targeting to maximize the number of HIV infections prevented. Both plans assume the same resource use and adhere to international ethical standards for resource allocation. The authors compared the two rollout plans under resource constraints in terms of: 1) the geographic strategy needed for implementation; 2) the optimal location for launching the rollout; and 3) the number of HIV infections prevented. They found overall that a utilitarian strategy that uses geographic targeting at the provincial level could prevent approximately 40 percent more HIV infections in the first year of the rollout than the egalitarian plan. This finding reflected geographic variations in incidence in sub-Saharan Africa, the authors said. They concluded that different rollout plans can affect the success of interventions to prevent HIV, even assuming similar availability of ARVs. Specifically, in low-resource provinces, geographic targeting should be used to maximize the impact of limited supplies. Further geographic targeting in provinces where incidence rates are very high could result in even greater resource utilization efficiency.

Estimating the Cost-Effectiveness of Pre-Exposure Prophylaxis to Reduce HIV-1 and HSV-2 Incidence in HIV-Serodiscordant Couples in South Africa

Jewell, B.L., Cremin, I., Pickles, M., et al. PLOS ONE (January 2015), doi: 10.1371/journal.pone.0115511. eCollection 2015.

The authors revised an existing simulation model to include herpes simplex virus-2 (HSV-2) acquisition, transmission, and interaction with HIV-1 among serodiscordant couples in South Africa, before and for one year after antiretroviral therapy (ART), to estimate the cost-effectiveness of daily oral tenofovir-based pre-exposure prophylaxis (PrEP). The model used data from the Partners in Prevention HIV/HSV Transmission trial testing the use of pre-exposure prophylaxis (PrEP) for HIV-1 uninfected partners. The simulation began when the HIV-1 serodiscordant couple was identified; the HIV-infected partner in each couple initiated ART when his/her CD4 cell count fell below 350 cells/μl; and the HIV-1-uninfected partner took daily oral PrEP until his/her partner initiated ART and was assumed to achieve HIV-1 viral suppression. The authors estimated the cost per disability-adjusted life-year (DALY) averted for Scenario 1, in which PrEP had no effect on HSV-2 acquisition, and Scenario 2, in which there was a 33 percent reduction. The simulation showed that after a 20-year intervention, the cost per DALY averted was US$10,383 for Scenario 1 and US$9,757 for Scenario 2—modestly lower than a scenario with no effect. The authors concluded that the protective effect against HSV-2 has public health advantages, particularly given the absence of effective prevention strategies for HSV-2, but doesn’t significantly affect cost-effectiveness of PrEP in HIV-1-serodiscordant couples.

Effects of Partnership Change on Microbicide Gel Adherence in a Clinical Trial (HPTN 035)

Gorbach, P.M., Kelly, C.W., Borgerding, J.A., et al. AIDS and Behavior (October 2013), E-publication ahead of print. doi: 10.1007/s10461-013-0651-5.

The authors examined the effect of sexual partnership changes on women’s adherence to microbicide gel use in the HIV Prevention Trial Network (HPTN) 035 trial. Self-reported adherence among women with ongoing partners (n=1,571) and among women with new partners (n=123) was compared. The findings showed that having a new partner affected self-reported adherence to a microbicide gel—those who indicated having a new partner reported using a microbicide gel less frequently than women reporting having an ongoing partner. Reported gel use at last vaginal sex was 100 percent among women with ongoing partners compared to 75 percent for women with new partners. Factors associated with self-reported high adherence included having an ongoing partner, older age, and higher rates of reported sex in the past week. Further, more women with new partners acquired HIV compared to those with an ongoing partner (9.8 versus 4.5 percent). The findings emphasize the importance of evaluating partnership status among women in similar trials. However, the authors suggested that future studies refine methods for measuring partner status to further understand its effects. They advocated for male-focused outreach to promote awareness of new HIV-prevention methods, along with high-quality counseling for women to encourage them to introduce these methods to new partners.

Antiretroviral Agents Used by HIV-Uninfected Persons for Prevention: Pre- and Postexposure Prophylaxis

Grant, R. M. Clinical Infectious Diseases (2010), 50 (S3): S96–101. doi: 10.1086/651479.

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.

Planning for Pre-exposure Prophylaxis to Prevent HIV Transmission: Challenges and Opportunities

Kim, S. C., Becker, S., Dieffenbach, C., et al. Journal of the International AIDS Society (2010), 13 (24). doi: 10.1186/1758-2652-13-24.

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.

Adherence Challenges with Drugs for Pre-Exposure Prophylaxis to Prevent HIV Infection

Gengiah, T.N., Moosa, A., Naidoo, A., et al. International Journal of Clinical Pharmacy (October 2013), E-publication ahead of print. doi: 10.1007/s11096-013-9861-1.

The authors reviewed Phase II and III clinical trials of antiretroviral (ARV) and non-ARV drugs for oral pre-exposure prophylaxis (PrEP) and topical microbicides for HIV prevention conducted over the past 20 years, focusing on the role of adherence. Most trials reported adherence as a major challenge, and several demonstrated links between moderate to high adherence and PrEP effectiveness, and between suboptimal adherence and product failure. Dosage form, strategy, and interval may also affect adherence. Between 2007 and 2012, seven trials of oral PrEP were conducted, with self-reports and pill counts used as standard adherence measures (although some studies also monitored drug levels in blood). Daily use was effective for oral PrEP, but users’ motivation and risk perception were crucial. Barriers to PrEP adherence included age (under 25), marital status (unmarried women), intermittent dosing, and low risk perception. Thirteen trials of topical microbicides were completed (1992-2012). Before 2010, all microbicide trials failed to show effectiveness; the first to show effectiveness (CAPRISA 004) used an ARV drug with adherence support for dosing instructions. For microbicides, intermittent dosing strategies (applying the gel around sexual intercourse) are more effective than daily application. Promising candidate agents in pre-clinical and Phase I trials for HIV-prevention include combination and multipurpose technologies, which may improve adherence by focusing on formulation, ease of dosing, and multi-use.

Male Partner Influence on Women's HIV Prevention Trial Participation and Use of Pre-exposure Prophylaxis: the Importance of "Understanding"

Montgomery, E.T., van der Straten, A., Stadler, J., et al. AIDS and Behavior (November 2014), E-publication ahead of print.

Male partners are believed to have significant influence over their female partner’s ability to negotiate about and use female-controlled HIV prevention methods. The authors of this study investigated how men influenced their female partner’s ability to participate in the ongoing Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, specifically the VOICE C arm, which examined social and structural influences on women’s use of antiretroviral tablets or a vaginal gel. The authors recruited 102 randomly selected trial participants in Johannesburg, South Africa. They conducted in-depth and ethnographic interviews and focus group discussions with the female participants, and in-depth interviews and focus group discussions with 22 male partners. Data analysis showed that many male partners did not fully understand or trust the research; and as a result discouraged their female partner's use of the product or participation in the study. The study also found that because of the men's reluctance to agree with their participation in the study, women were less likely to disclose their use of the product. The authors concluded that research is needed to identify and test strategies to proactively involve male partners in order to enhance women’s involvement and commitment to these trials.

Packaging PrEP to Prevent HIV: An Integrated Framework to Plan for Pre-Exposure Prophylaxis in Clinical Practice

Underhill, K., Operario, D., Skeer, M. R., et al. Journal of Acquired Immune Deficiency Syndromes (2010), 55 (1): 8–13. doi: 10.1097/QAI.0b013e3181e8efe4.

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.

Pre-exposure Prophylaxis State of the Science: Empirical Analogies for Research and Implementation

Golub, S. A., Operario, D., & Gorbach, P. M. Current HIV/AIDS Reports (2010), 7 (4): 201–209.

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.

Acceptability of Pre-Exposure Prophylaxis among Men Who Have Sex with Men and Transgender Women in Northern Thailand

Yang, D., Chariyalertsak, C., Wongthanee, A., et al. PLOS ONE (October 2013), 8 (10): e76650.

Given the limited research on transgender (TG) populations, particularly regarding their attitudes towards pre-exposure prophylaxis (PrEP), the authors conducted a survey in 2012 with Thai TGs (n=107) and men who have sex with men (MSM) (n=131) to explore PrEP awareness and acceptability, and patterns of medication use among TG and MSM. Awareness was high—two-thirds of participants had knowledge of PrEP—and acceptability was 41 and 37 percent for MSM and TGs, respectively. The findings showed that these populations differ in terms of HIV risk behaviors, medication use, and factors associated with PrEP acceptability. More TG participants primarily engaged in receptive anal sex than MSM (74 versus 24 percent). Nearly half of TGs reported regularly taking oral medication (compared to 21 percent of MSM); further, 45 percent of TGs reported taking female hormones (versus 6 percent of MSM). Having private insurance and knowledge of PrEP were independently associated with PrEP acceptability among TG, while factors for MSM were previous HIV testing, history of sexually transmitted infections, infrequent sex, and regularly planned sex. Of those taking medications, 68 and 73 percent of MSM and TG respectively feared drug interactions. Since most TGs take regular medication, this behavior should be leveraged to improve PrEP adherence. The authors called for continued research and PrEP educational campaigns that discuss treatment interactions.

Acceptability of PrEP for HIV Prevention among Women at High Risk for HIV

Guest, G., Shattuck, D., Johnson, L., et al. Journal of Women’s Health (2010), Vol. 19 No. 4, pp. 791–798.

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 to make pill-taking part of their routine. This suggests that future programs will need to give users 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 might translate into more routine service settings, this study suggests that a daily oral pill may be a feasible HIV-prevention option.

Implementation Science of Pre-Exposure Prophylaxis: Preparing for Public Use

Underhill, K., Operario, D., Mimiaga, M. K., et al. Current HIV/AIDS Reports (2010), 7: 210–219.

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 five-theme framework can serve as a starting point for thinking systematically about PrEP implementation and the broader field of implementation science.

Evaluating the Cost-Effectiveness of Pre-Exposure Prophylaxis (PrEP) and its Impact on HIV-1 Transmission in South Africa

Pretorius, C., Stover, J., Bollinger, L., et al. PLOS ONE (2010), 5 (11): e13646.

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 ages 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 that 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.

Pre-Exposure Antiretroviral Prophylaxis Attitudes in High-Risk Boston Area MSM: Limited Knowledge and Experience but Potential for Increased Utilization after Education

Mimiaga, M. J., Case, P., Johnson, C. V., et al. Journal of AIDS (2009), 50: 77–83.

This paper reports findings from a study of 227 HIV-negative 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.

Tools and Curricula

UNAIDS/WHO Pre-Exposure Prophylaxis Modelling Meeting: Meeting Report

Joint United Nations Programme on HIV/AIDS & World Health Organization. (2011).

This report summarizes discussions among 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 address 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 illuminates some of the thinking and decisions 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 recommendations for how these different groups can coordinate and link their work with demonstration projects and service providers. It also describes how modeling contributes to decision making.

PrEP Resources

AIDS Vaccine Advocacy Coalition: Global Advocacy for HIV Prevention. (n.d.).

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 these HIV-prevention options. Information and links for AVAC and external resources are updated regularly. Information on PrEP is presented under three categories: Playbook 2014, 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. It is a helpful source of timely information on PrEP as well as other HIV-prevention approaches.

Pre-Exposure Prophylaxis for HIV Prevention: Promoting Safe and Effective Use in the United States

Centers for Disease Control and Prevention. (2011).

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 CDC’s approach to developing those formal U.S. public health service guidelines in collaboration with other key agencies.

Additional Resources

Conference on Retroviruses and Opportunistic Infections (CROI)

CROI Foundation and International Antiviral Society, Seattle, Washington (February 23–26, 2015).

The annual Conference on Retroviruses and Opportunistic Infections (CROI) brought together top basic, translational, and clinical researchers from around the world to share the latest studies, important developments, and best research methods in the ongoing battle against HIV/AIDS and related infectious diseases. CROI is a global model of collaborative science and the premier international venue for translating basic and clinical investigation into clinical practice in the field of HIV and related viruses. Researchers presented new globally important data on three oral pre-exposure prophylaxis (PrEP) trials and findings from the Follow-on African Consortium for Tenofovir Studies (FACTS 001) on tenofovir microbicide gel. All three PrEP trials showed high rates of consistent use and very high rates of protection against HIV infection, while the FACTS 001 trial of 1 percent tenofovir gel found low adherence and no protection. The conference included presentations on evolving knowledge and practice in the areas of medical male circumcision, and on prevention, treatment, and diagnosis of pediatric HIV infection. In addition, several conference sessions presented programmatic experience on how to scale up existing interventions and demonstrate impact.
Webcasts, abstracts, electronic posters, and other electronic resources from CROI 2015 are now available online here: http://www.croiconference.org/

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, 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 among the key groups for whom more data are needed.

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, findings, and implications for pre-exposure prophylaxis in these and other populations.

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.