JAIDS Journal of Acquired Immune Deficiency Syndromes:
Preexposure Prophylaxis for HIV Prevention: Where Have We Been and Where Are We Going?
Baeten, Jared M. MD, PhD*,†,‡; Haberer, Jessica E. MD, MS§,‖; Liu, Albert Y. MD, MPH¶,#; Sista, Nirupama PhD**
Departments of *Global Health;
‡Epidemiology, University of Washington, Seattle, WA;
§Center for Global Health, Massachusetts General Hospital and
‖Department of Medicine, Harvard Medical School, Boston, MA;
¶Bridge HIV, San Francisco Department of Public Health and
#Department of Medicine, University of California San Francisco, San Francisco, CA; and
**Global Health, Population and Nutrition, FHI360, Durham, NC.
Correspondence to: Jared M. Baeten, MD, PhD, Department of Global Health, University of Washington, Box 359927, 325 Ninth Avenue, Seattle, WA 98104 (e-mail: firstname.lastname@example.org).
Supported by the US National Institutes of Health (grants R01 MH095507, R01 MH098744, R01 MH095628, and for the HIV Prevention Trials Network: UM1 AI068619).
N.S.: owns personal stock as investment in Gilead Sciences, Pfizer, and other pharma. J.E.H.: received funding for research from IAVI on preexposure prophylaxis against HIV infection. This work informed some of my contributions to the submitted article but did not support the manuscript directly. Received salary support from Mass General for clinical care, which is unrelated to the submitted manuscript. Receives funding from Gates Foundation for research on preexposure prophylaxis against HIV infection. This work informed some of my contributions to the submitted article but did not support the article directly. Received a small honorarium for speaking at an IAPAC conference, which was unrelated to the submitted article. Received a small honorarium and travel expenses for speaking at a UW course, which was unrelated to the submitted article. Received Natera stock options as a consultant. This work was unrelated to the submitted article. Received a small honorarium from Harvard CFAR for participating in a CFAR grant review, which was unrelated to the submitted article. Received a small honorarium and travel expenses for participating in an NICHD grant review, which was unrelated to the submitted article. Received a small honorarium and travel expenses for participating in an AHRQ technical expert panel, which was unrelated to the submitted article. Received a small honorarium and travel expenses from FHI 360 for providing consultation on a preexposure prophylaxis study. This work informed some of my contributions to the submitted article but did not support the article directly.
Abstract: Preexposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral medications to reduce their risk of acquiring HIV infection, is an efficacious and promising new HIV prevention strategy. The past 2 years have seen significant new advances in knowledge regarding PrEP, including definitive demonstration that PrEP reduces the risk of HIV acquisition, regulatory approval of combination oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as the first PrEP agent with a label indication for sexual HIV prevention, and the development of normative guidance for clinical prescribing of PrEP. In PrEP clinical trials, HIV protection was strongly correlated with PrEP adherence; therefore, understanding and supporting adherence to PrEP are key to maximizing its public health impact. As would be expected for any new HIV prevention approach, questions remain, including how to motivate uptake of and sustain adherence to PrEP for HIV prevention in high-risk populations, how much use is sufficient to achieve HIV protection, and the potential of “next-generation” PrEP agents to improve this effective prevention strategy. At this important transition point—from demonstration of efficacy in clinical trials to thinking about implementation and effectiveness—this review addresses where we have been and where we are going with PrEP for HIV prevention.
In July 2012, the US Food and Drug Administration approved the first label indication for an antiretroviral agent—the oral combination emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), sold as branded Truvada—to be used as pre-exposure prophylaxis (PrEP) to reduce the risk of sexual acquisition of HIV infection by persons at high risk.1 More than 2.5 million persons are newly infected with HIV each year worldwide, resulting in a growing treatment and care burden,2 and thus, novel strategies to prevent HIV acquisition, such as PrEP, remain urgently needed. This review will address where we have been and where we are going with PrEP for HIV prevention.
WHERE HAVE WE BEEN?
Rationale and Demonstration of PrEP Efficacy for HIV Prevention
The idea of prophylaxis to reduce the risk of an infectious disease is well established—one example is malaria chemoprophylaxis in travelers. Evidence to suggest that PrEP could reduce HIV risk grew out of successful HIV prevention of mother-to-child HIV transmission with antiretroviral prophylaxis3–6 and from non-human primate studies showing that PrEP before mucosal simian HIV challenge provided partial or full protection against infection.7–11 TDF and FTC had biologic properties that made these reverse transcriptase inhibitors attractive as first-generation PrEP agents: potent antiretroviral activity against all HIV subtypes, activity early in HIV's lifecycle, long-intracellular half-life, able to achieve high concentrations in the genital tract, convenient daily dosing with few drug interactions, and established safety profiles from their use as part of combination antiretroviral therapy (ART) regimens. When used for HIV treatment, TDF is a once-daily 300 mg dose, and FTC/TDF includes 200 mg of FTC; these standard doses were chosen for clinical trials of PrEP. In non-human primate studies, there was some evidence of greater HIV protection using FTC/TDF compared with TDF alone, suggesting that combination PrEP could provide greater benefit than from a single agent.8
Five efficacy trials of TDF and/or FTC/TDF as PrEP for HIV prevention have been completed and 2 are ongoing (Table 1). Trial protocols included monthly study visits with HIV serologic testing, clinical safety evaluation, and individualized adherence counseling, as well as a package of HIV prevention services provided to all participants (including HIV and risk-reduction counseling, screening and treatment for sexually transmitted infections, and free provision of condoms).
Three of these trials12,14,18—involving men who have sex with men (iPrEx) and heterosexual men and women (Partners PrEP and TDF2) from a diversity of geographic settings—demonstrated that PrEP reduced the risk of HIV acquisition, with intention-to-treat comparisons against placebo showing HIV protection efficacies between 44% and 75%. Importantly, although pharmacokinetic studies suggested lesser accumulation of tenofovir in vaginal compared with rectal tissue after TDF dosing,19,20 subgroup analyses in the 2 trials that included both sexes (Partners PrEP and TDF2) found comparable HIV protection for both women and men. Thus, these randomized placebo-controlled trial results provide definitive evidence that PrEP “works” for HIV prevention.
PrEP Adherence and HIV Protection
A strong dose–response relationship between adherence to PrEP pill taking and HIV protection was demonstrated across PrEP efficacy trials (Table 1). Higher HIV protection was seen in trials with higher adherence, and no HIV protection was found in 2 trials (FEM-PrEP and VOICE13,15) in which adherence to PrEP, as measured by detection of PrEP medications in blood samples from a random subset of subjects, seems to have been very low. In iPrEx and Partners PrEP, analyses of detection of PrEP medications in blood samples suggests that those using PrEP may have achieved an ∼90% reduction in HIV risk, which likely hints at the true biologic efficacy of PrEP for HIV protection. Thus, just as consistent use of ART is needed to achieve HIV treatment benefits,21 adherence is critical to the efficacy of PrEP.
One important factor for achieving high adherence in PrEP trials seems to have been external support. In qualitative work, support from the HIV-infected member of a serodiscordant couple seems to be related to better PrEP pill taking in the Partners PrEP Study, and participants in iPrEx noted the importance of support from research staff, family, and friends.22,23 Conversely, low perception of HIV risk may explain low PrEP adherence—in FEM-PrEP, 70% of women reported they felt themselves at little risk for acquiring HIV, despite a nearly 5% annualized HIV incidence in that trial.13 In iPrEx, PrEP efficacy was higher in men reporting (versus not reporting) unprotected receptive anal sex at baseline, suggesting that self-perception of risk might increase PrEP use.12 Additional factors associated with lower adherence in Partners PrEP included younger age, male gender, higher socioeconomic status, and heavy alcohol use24; in iPrEx, younger age and region (non-US sites compared with US sites) were also associated with lower adherence.25 In VOICE, adherence was lower in younger unmarried women, who also had the highest HIV incidence in this trial.15
Additional Outcomes From PrEP Trials: Safety, Resistance, and Sexual Behavior
Trials have found that TDF and FTC/TDF PrEP seem to be well tolerated, with the rate of both serious and mild adverse events generally balanced between those receiving PrEP and those receiving placebo. The most prominent side effects were gastrointestinal (eg, nausea), and these symptoms were present only in a minority of subjects (∼10% or less), were mild in severity, and were generally limited to the first month after initiation of the medication. PrEP has been associated with an average ∼1% reduction in bone mineral density but not with increased fracture risk over the study period.14,26,27 Although TDF has been associated with renal complications in HIV-infected persons, PrEP clinical trials did not find increased risk of renal complications in healthy HIV-uninfected persons. Finally, data from Partners PrEP28 and from the Antiretroviral Pregnancy Registry29 suggest that the use of TDF and FTC/TDF in early pregnancy is not associated with increased rates of birth defects, although more data are needed to fully assess the safety of these medications through pregnancy.
Antiretroviral resistance was rare and limited to those with seronegative acute infection at the time of PrEP initiation. The absence of PrEP-selected drug resistance among persons acquiring HIV during the trials is potentially a manifestation of the strong correlation between PrEP use and protection: low use of PrEP provides little HIV protection but little risk of resistance if infection is acquired, whereas high adherence blocks most transmissions. Taking a public health perspective, the number of cases of antiretroviral resistance in PrEP trials is presented against the number of HIV infections prevented by PrEP in Table 2.
Finally, the question of increased sexual risk taking accompanying PrEP use was explored in iPrEx and Partners PrEP, where self-reported condom use increased and sexually transmitted infection diagnoses decreased during follow-up. Although the self-reported data are potentially limited by recall and social desirability biases, these data potentially suggest that PrEP could work synergistically with other components of the HIV prevention package provided to trial participants.30
WHERE ARE WE GOING?
Unanswered Questions From PrEP Trials and Progress With PrEP Demonstration Projects
First-generation PrEP trials have demonstrated proof-of-concept that antiretroviral PrEP provides protection against HIV acquisition, but, as expected for this new prevention strategy, a number of important scientific and implementation questions remain (Table 3); many of these same questions are also relevant for implementation of ART to reduce the infectiousness of persons with HIV infection as a prevention intervention.31 For PrEP, the overarching unknown is whether HIV protection efficacy, as proven in clinical trials, will translate into substantive effectiveness in real-world practice. A number of considerations influence the priority questions for PrEP implementation. First, levels and patterns of adherence to PrEP in the setting of known efficacy are unknown. Although medication adherence is often lower when moving from clinical trials to practice settings,32 individuals with ongoing HIV risk who seek out prescription PrEP that is known to “work” may be highly motivated to adhere. Second, sexual risk taking in the context of known PrEP efficacy is unexplored, including whether risk compensation might result in reduced PrEP benefits and the level and types of behavioral intervention(s) needed to maximize prevention synergy.33 Third, further study is required to identify optimal HIV testing approaches to reliably detect HIV infections among individuals initiating and continuing PrEP and to minimize selection of resistance. Fourth, the longer-term health effects of oral FTC/TDF in HIV-negative PrEP users, including renal safety and bone mineral density, require further evaluation, particularly for those with underlying comorbidities (eg, hypertension, diabetes) and for women who may use PrEP during pregnancy and breastfeeding. No PrEP clinical trials included pregnant women; however, PrEP has the potential to reduce the risk of seroconversion during conception and pregnancy, particularly for HIV serodiscordant couples desiring pregnancy. Pregnancy is a high-risk period for HIV acquisition, and acute infection during pregnancy is associated with higher risk of transmission to the fetus,34 and thus, studies of PrEP safety and use in pregnancy should be a priority. Finally, additional research is needed to determine how best to prioritize populations who will benefit most from PrEP, the best time period for use of PrEP as an intervention (eg, in women when they cannot negotiate safer sex or in women wanting to get pregnant), level of interest in taking PrEP in these communities, and optimal delivery settings for PrEP to maximize public health impact.
To address unanswered questions for PrEP implementation, PrEP demonstration projects are being planned or underway (Table 4). Target populations include men who have sex with men (MSM) and transgender women, heterosexual serodiscordant couples, young sexually active heterosexual men and women, and female sex workers, across 5 continents and in a diversity of delivery settings. Common objectives across demonstration projects include assessing (1) feasibility, acceptability, and uptake of PrEP; (2) levels and patterns of PrEP adherence; (3) changes in sexual risk behavior; (4) safety and tolerability; and (5) HIV incidence and resistance among seroconverters. Three projects are open-label extensions of PrEP clinical trials and will provide opportunities to determine the impact of providing information about efficacy and safety of PrEP in well-characterized cohorts.
Although the current portfolio of PrEP demonstration projects is scientifically, programmatically, and geographically diverse, PrEP is not being evaluated in all populations, with important gaps including young African women; projects still in planning or proposal stages may address some of these gaps. In addition, coordination across projects will be important, so that core data are collected and can be compared across time, minimizing duplication and maximizing synergy across projects.35 The World Health Organization is currently compiling a framework for country-level protocol development of PrEP demonstration projects. Key messages include involvement of high-risk populations and measurement of adherence as a primary outcome. A key consideration for PrEP demonstration work is that projects should not simply track retention on PrEP alone but particularly when PrEP is needed (ie, during period of high risk) and as PrEP use relates to other HIV prevention services (eg, condoms, male circumcision).
What Adherence Means for PrEP Outside of Clinical Trials
Understanding adherence to PrEP in implementation settings must consider whether PrEP is needed and desired. In contrast to ART, which is lifelong, PrEP is likely best used for periods (months to a few years) of highest behavioral risk—for example, when attempting to conceive,36 around the time of sexual debut or coming out, and when previously safe sexual behavior patterns are modified. Perfect adherence during times of no risk (eg, no sex) is not likely cost-effective or appropriate, but good adherence during periods of higher risk is essential. In iPrEx and in Partners PrEP, participants reporting no sex (and therefore no risk of HIV acquisition) were more likely to have low adherence,24 suggesting that self-assessment of risk may be possible to some degree—analogous to other prevention strategies that are not lifelong (eg, oral contraceptives). PrEP implementation should assess when individuals want to take PrEP (ie, the “season of PrEP”) and how long they take it (ie, persistence of adherence). Guidance for when and how to start and stop PrEP and still achieve effective protection is needed. In one study (the Partners Demonstration Project), PrEP will be provided to HIV serodiscordant couples as a “bridge” to stable ART initiation by the HIV-infected partner.37
PrEP studies have used several adherence measures, each with important strengths and weaknesses (Table 5). Objective measurements likely provide the most reliable data, and electronic monitoring is the only way to capture patterns of adherence, which are particularly important for assessing adherence behavior as related to periods of risk. A number of demonstration projects are incorporating drug-level testing to monitor PrEP adherence. If resources in demonstration projects and implementation settings are limited, use of objective adherence measures may still be considered for a subset of the study population.
The level of adherence needed to achieve HIV protection is not clear; however, PrEP use may potentially permit behavioral imperfection. In the iPrEx study, statistical modeling combining pharmacokinetics and drug data estimated that 2 PrEP doses per week might achieve a 76% reduction in HIV, rising to >95% for ≥4 doses per week.38 However, PrEP concentrations necessary for HIV protection are potentially related to the intensity and route of viral exposure (eg, penile, vaginal, parenteral, rectal) and the drug (TDF, FTC/TDF, or other agents). There are currently no data to guide less-than-daily dosing of oral FTC/TDF as PrEP. In addition, it is not clear if less-than-daily dosing would necessarily achieve higher adherence: in one small study among MSM in Kenya and serodiscordant couples in Uganda, adherence to intermittent (twice weekly and postcoital) PrEP was lower compared with daily PrEP.14,18 Adherence may change over time depending on variable risk, preferences, and other factors in an individual's life (eg, alcohol use, income). Although tailoring PrEP to those most likely to adhere may be an attractive strategy for increasing cost-effectiveness, those individuals may be difficult to identify and may be a moving target.
An important question will be how best to motivate and support ongoing PrEP use, highlighting the need to develop and rigorously evaluate effective, scalable PrEP adherence interventions for diverse populations. PrEP demonstration projects will research a range of interventions to support adherence, risk reduction, and other psychosocial needs. Client-centered brief counseling sessions, directed approaches based on cognitive behavioral therapy and problem-solving therapy for those with low adherence, and use of electronic reminders or text messages are being evaluated in demonstration projects. Good adherence support will be critical to ensure the behavioral success of this biological agent for HIV prevention. That said, counseling should not be so onerous as to present logistical or financial barriers to access the medication. Demonstration projects should explore standardized approaches for providing appropriate counseling within the real-world context.
PrEP Use Outside of Demonstration Projects
Normative guidance for prescribers regarding PrEP for MSM and high-risk heterosexuals has been released in the United States.39,40 The guidance stresses the importance of delivering PrEP as part of a package of prevention services, including HIV testing, risk-reduction counseling, and prevention and treatment of sexually transmitted infections, as well as adherence messaging. HIV testing and PrEP refills are recommended no less frequently than every 3 months, and attention to acute HIV infection, particularly at PrEP initiation (or reinitiation), is important. To maximize the potential benefits of PrEP, it will need to be accessible to at-risk populations, who are most often not engaged in care. PrEP is a primary prevention intervention, and prescribing by primary and community care providers, who are more likely to encounter the populations most at risk, is needed. For individuals not regularly engaged in care, collaboration with community-based organizations will be needed to identify at-risk HIV-negative individuals, provide education about PrEP, and link them into primary care.41 Providers in a variety of settings—public clinics, antenatal care, and sexually transmitted infection clinics—might be PrEP prescribers or initiate linkages to primary care. Counseling support might be delivered through community-based nonclinical settings with strong linkages to PrEP clinical providers.42
Next-Generation PrEP Studies
Demonstration of efficacy and regulatory approval of daily oral FTC/TDF PrEP was a milestone for HIV prevention,43 but potentially only the first step in developing a suite of PrEP options. Both TDF and FTC have long half-lives (∼150 hours and ∼48 hours, respectively), which provides substantial drug concentrations to be present for several days after each dose,44 and non-human primate models indicate that dosing even as infrequently as once a week may be sufficient for protection if postexposure dosing is also used.8,45 The HIV Prevention Trials Network is evaluating different intermittent dosing strategies, and theory-based determinants of sexual and pill taking behavior in heterosexual women in Africa and in MSM in the United States and Thailand (HIV Prevention Trials Network 067). Nonetheless, careful attention to adherence will be critical in studies of less-frequent PrEP dosing. Alternative PrEP agents to FTC/TDF, including oral and topical vaginal maraviroc, dapivirine and other agents formulated into long-acting vaginal rings, and injectable agents (eg, rilpivirine), are being evaluated; importantly, formulations to address adherence challenges (eg, sustained release injections, long-acting vaginal rings) are under study.
During the past 2 years, PrEP has moved from hypothesis to proof of principle: for persons at ongoing risk of HIV infection, PrEP provides a time-limited highly efficacious HIV prevention strategy. As with all prevention strategies, PrEP is only effective if used, and maximum PrEP benefits, at both individual and population levels, will likely be achieved by combining PrEP with other effective HIV prevention interventions. Implementation of PrEP, in research demonstration projects and implementation settings, is the next step. As we move from where we have been to where we are going with PrEP, there is a tremendous opportunity to maximize the benefits of this promising HIV prevention strategy.
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HIV prevention; preexposure prophylaxis; sexual HIV transmission
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