Preexposure Prophylaxis—a New Addition to the Armamentarium Against Human Immunodeficiency Virus

Abstract

At the end of 2015, 36.7 million people worldwide were living with human immunodeficiency virus (HIV)/AIDS with 2.1 million newly diagnosed. The development of antiretroviral therapy was a remarkable milestone that vastly transformed the manner in which HIV/AIDS patients were managed. The introduction of preexposure prophylaxis (PrEP) ushers in a new era that could again redefine the course of this global epidemic. Daily administration of oral combination tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) and TDF alone as PrEP has demonstrated efficacy in preventing new HIV cases in a number of trials. The results of these studies represent major advances in preventing HIV acquisition and provide convincing evidence that widespread use of daily oral TDF-FTC by heterosexuals, men, women, and intravenous drug users and use of vaginal TDF is safe and effective. Low adherence has been cited as reason for failures in a few studies and poses a significant challenge when implementing PrEP in the real world in highly diverse communities. Several studies investigating a variety of strategies for PrEP delivery are underway to mitigate treatment challenges. Emerging strategies include the use of alternative antiretrovirals, novel formulations, and routes of administration, as well as dosing regimens. This article reviews literature on prior studies, current concerns and challenges, and future strategies for implementing effective PrEP.

Introduction

At the end of 2015, 36.7 million people worldwide were living with human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS) with 2.1 million newly diagnosed. ¹ A multifaceted approach to decrease the number of newly diagnosed individuals focuses on prevention. Several novel prevention strategies have been investigated including an investigational HIV vaccine aimed at inducing neutralizing antibodies, treatment as prevention, and the use of antiretroviral (ARV) therapy for postexposure and preexposure prophylaxis (PrEP). Although the search for the elusive HIV vaccine evades researchers, PrEP has emerged as a viable option to curb the spread of HIV. Preexposure prophylaxis is a prevention strategy where ARVs are administered to high-risk populations who have not yet been infected with HIV but have continued exposure to HIV. The concept of PrEP is not new and has been successfully used in pregnant women to prevent mother-to-child transmission. Mathematical models estimate that over the next 10 years, administering PrEP could potentially prevent 2.7 to 3.2 million new HIV-1 infections in sub-Saharan Africa, the area most affected by the HIV epidemic. ² Breakthrough clinical studies of oral combination tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) and TDF alone administered once daily as PrEP demonstrated efficacy ranging from 44% to 75% in reducing HIV acquisition in a number of trials.^3–5 Contrarily, a few studies have demonstrated lack of efficacy and have cited low adherence or nonadherence as reasons for failure. This article reviews literature on past successes with PrEP, current barriers and challenges to overcome issues related to adherence for successful implementation, and future novel concepts and regimens on the horizon for PrEP.

Efficacy Studies

In 1995, Tsai et al ⁶ conducted one of the first studies using tenofovir injection for PrEP in nonhuman primates. The study demonstrated that 4 weeks of daily TDF completely prevented acquisition of simian immunodeficiency virus (SIV) in macaques. Despite this initial success with injectable TDF, subsequent studies involving oral or rectal TDF alone provided no or partial protection against SIV acquisition; however, a number of years later, studies using FTC in combination with TDF showed significant protection.^7,8 These primate studies set the stage for the future exploration and creation of PrEP in humans as we know it today. Five groundbreaking studies provided data on the efficacy and safety of TDF and TDF-FTC in reducing HIV transmission in a variety of high-risk populations. These studies include the Center for AIDS Program of Research in South Africa (CAPRISA) 004, Pre-exposure Prophylaxis Initiative (iPrEx) trial, TDF2 study, Partners PrEP, and the Bangkok Tenofovir Study (BTS).

The CAPRISA 004 trial assessed the efficacy and safety of 1% TDF gel administered vaginally in heterosexual women from South Africa. A total of 889 women aged 18 to 40 years were instructed to apply 1% vaginal TDF gel or placebo 12 hours prior to coitus and a second dose within 12 hours after coitus. ⁹ Patient follow-up continued for a total of 30 months. At the conclusion of the study, study authors determined that the application of vaginal TDF gel decreased overall HIV infection by 39% when compared with placebo (95% confidence interval [CI]: 6%-60%]. Further analysis determined that increased adherence provided greater protective effect against HIV acquisition. For high adherers (adherence > 80%), efficacy increased to 54% (P = .025); efficacy in intermediate adheres was 38% (adherence: 50%-80%); and 28% in low adherers (adherence < 50%). The study provided evidence for the safe and effective use of vaginal gel in PrEP by women.

The iPrEX study was groundbreaking in that it was one of the first to investigate the use of daily oral TDF-FTC versus placebo in men who have sex with men (MSM) and transgender women who have sex with men. ⁴ About 2500 participants from 6 different countries were included with follow-up at an average of 21 months. Overall, the iPrEx trial demonstrated a 44% reduction in HIV acquisition. Further analysis indicated that efficacy increased to 73% in participants who reported 90% adherence or more at 49% of their visits (95% CI: 41-88; P < .001). The authors concluded that although a significant reduction in HIV acquisition was achieved, the reduction was not as great as initially envisioned. Furthermore, although reported adherence was high, drug levels did not correlate and were noticeably lower.

The TDF2 study was conducted in 1200 HIV-negative heterosexual adults in Botswana who administered TDF-FTC or placebo for a median of 1.1 years and maximum of 3.7 years. ³ The overall efficacy in the modified intention-to-treat analysis was 62.2% compared with placebo (95% CI: 21.5-83.4; P = .03). ³ Adherence was similar between both groups and was considered high at 84.1% and 83.7% in the TDF-FTC and placebo groups, respectively. Efficacy was again much higher in the group where adherence was higher at 77.9% (95% CI: 41.2-93.6; P = .0053). There was a lower than expected retention due to logistical challenges; therefore, study investigators closed study enrollment early. The low rate of retention was attributed to patient relocation or scheduling conflicts; a reflection of real-world challenges in implementing PrEP. Despite the early closure, the study duration allowed investigators to ascertain potential long-term effects of TDF-FTC administration. These included decreases in bone mineral density at the forearm, hip, and lumbar spine in participants taking TDF.

The Partners PrEP study evaluated the protective effects of PrEP in HIV serodiscordant heterosexual couples in Kenya and Uganda. ⁵ A total of 4747 couples were randomly assigned to receive once-daily TDF (n = 1584), TDF-FTC (n = 1579), or placebo (n = 1584). Preexposure prophylaxis reduced the rate of HIV acquisition by 67% with TDF (95% CI: 44-81; P < .001) and 75% with TDF-FTC (95% CI: 55-87; P < .001) compared with placebo. In this study, tenofovir was detectable in 82% of samples obtained from a selected number of participants. Detectable tenofovir levels were associated with a greater relative risk reduction of more than 85% (86% with TDF; 90% with TDF-FTC) compared with undetectable levels. During study evaluation, 8 participants in the active treatment arm were identified as having HIV infection at baseline, and 2 of these participants were found to have developed antiviral resistance to the active medication. One participant in the TDF group displayed K65R mutation and the other in the TDF-FTC group exhibited an M184V mutation indicating resistance to FTC.

The BTS studied the use of a once-daily TDF for preventing HIV acquisition among adult injection drug users in Bangkok, Thailand. ¹⁰ Participants were offered the choice between daily directly observed therapy or self administration at home and recorded on diary cards. A total of 2413 participants were enrolled. In total, 17 participants in the TDF group and 33 in the placebo group became infected with HIV which translated to a 48·9% reduction in HIV incidence.

Encouraging results from the CAPRISA trial guided the study design of the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial in African women. ¹¹ The goal was to determine the efficacy of daily vaginal TDF compared with oral TDF and oral TDF-FTC each compared with respective placebo interventions. Participants were randomly assigned to 5 study arms: vaginal gel with TDF, vaginal gel placebo, daily oral TDF, daily TDF-FTC, and daily oral placebo. Although self-reported adherence was 90%, results indicated that there was no difference between any active comparator group and placebo in reducing the rate of HIV acquisition −49.0% with TDF (hazard ratio for infection: 1.49; 95% CI: 0.97-2.29), −4.4% with TDF-FTC (hazard ratio: 1.04; 95% CI: 0.73-1.49), and 14.5% with TFV gel (hazard ratio: 0.85; 95% CI: 0.61-1.21). Further analysis indicated that although self-reported adherence was high, TFV levels pointed to low adherence. A recent publication determined that VOICE trial participants named several reasons for misrepresenting their level of adherence. ¹² The reasons included human fallibility, staff impressions of participants, anxiety over removal from study, an environment where overstating adherence seemed acceptable, circumventing additional counseling associated with perceived nonadherence, and distrust of the staff and study agents. Study authors concluded that more sophisticated methods of assessing adherence that do not rely on self-reporting as the singular means for detecting adherence are required. ¹²

Similarly, results from the FEM-PrEP study involving heterosexual women from Kenya, South Africa, and Tanzania did not demonstrate a statistically significant difference between the TDF-FTC and placebo group. ¹³ The authors hypothesized that once-daily oral TDF-FTC could provide more than 30% protection against HIV acquisition; however, study results proved otherwise. In total, 34 patients in the TDF-FTC group and 39 patients in the placebo group had newly acquired HIV infection (hazard ratio: 0.87; 95% CI: 0.55-1.38; P = .56).The study was closed early due to futility with the primary cause attributed to a less than 40% adherence rate which was corroborated with serum drug levels despite patient self-adherence reporting 95%. The authors speculate that the low adherence was due to the participants’ perception that they were at a low risk of HIV infection.

The results of these studies represent major advances in preventing HIV acquisition and provide convincing evidence that widespread use of daily oral TDF-FTC by heterosexuals, men, transgender individuals, women, and intravenous drug users, and use of vaginal TDF is safe and effective. However, significant challenges to implementation in the real world with highly diverse communities continue to threaten progress in the global fight against HIV. Adherence to dosing regimen has surfaced as an essential aspect in defining efficacy outcomes of clinical trials. The prior studies reviewed thus far have shown that there is a direct relationship between adherence and efficacy. Therefore, efforts to improve outcomes should be geared toward developing regimens that are tailored to individual patients to encourage adherence. These new formulations would protect against societal stigma associated with daily ARV administration, obviate the need for daily medication administration, and maintain patient privacy.

Current Research in PrEP

Several studies investigating different strategies for the delivery PrEP are underway to mitigate treatment challenges. Emerging strategies include the use of alternative antiretrovirals, novel formulations, and routes of administration, as well as dosing regimens. Novel formulations include intramuscular injections, topical administration, and vaginal rings administered immediately prior to sexual activity. Alternate antiretroviral agents are also (eg, maraviroc [MVC]-containing and tenofovir alafenamide [TAF] regimens) being investigated as alternatives to TDF-FTC to limit side effects and concerns for resistance. ¹⁴ Long-acting (LA) agents such as cabotegravir and rilpivirine are in various stages of research. Below is a review of these investigational agents and strategies.

Tenofovir alafenamide (TAF)

The ultimate success of PrEP hinges on the attainment of adequate tissue concentrations at anatomical sites that are likely to be points of infection. The varying degrees of tissue concentrations and differences in half-lives shed light on the importance of adherence and tissue penetration. Patterson et al ¹⁵ determined that active intracellular phosphorylated metabolites of TDF (tenofovir diphosphate [TDF-DP]) and emtricitabine (FTC triphosphate) were detectable in blood plasma, rectal, vaginal, and cervical tissues 14 days after a single dose of TDF-FTC. The AUC for FTC in genital secretions was 27 times greater than blood plasma and the AUC for TDF was 2.5-fold greater in genital secretions than in blood plasma. ¹⁵ Tenofovir diphosphate is the active moiety of its parent compound and possesses a longer half-life of 48 hours in plasma in healthy patients. ¹⁶ Although TDF is largely well tolerated and reaches adequate tissue concentrations, it is associated with elevated serum creatinine, and loss of bone density in some patients. Tenofovir alafenamide (TAF), a new prodrug formulation of tenofovir, is expected to have lower toxicity although the same metabolite TDF-DP is produced after phosporylattion. ¹⁷ The potency of tenofovir alafenamide is 1,000 times more than fumerate salt and also 10 times more potent than the oral prodrug TDF. ¹⁸ As a prodrug, TAF produces high drug levels in T cells with smaller doses; therefore, lower doses are needed to reach similar blood levels as TDF. ¹⁷ This reduces exposure to drug which may result in lower side effects within bones, kidneys, and other organ tissues. Tenofovir alafenamide has not yet been approved for use in PrEP and has not been extensively evaluated in humans. Although combination TAF-FTC for HIV prevention was successful in eliminating simian-human immunodeficiency virus (SHIV) infection in macaques through rectal exposure, TAF pharmacokinetic studies in humans show lower than expected levels within the genital mucosa. ¹⁹ In a recent pharmacokinetic study, women were treated with a single 25-mg dose of TAF and TDF to determine TDF-DP concentrations in cervical tissue, vaginal tissue, cervicovaginal fluid, and colorectal tissue more than 14 days. ²⁰ Tenofovir alafenamide concentrations in genital and rectal tissues levels were 2-fold lower than anticipated, although plasma blood levels were 9 times higher than TDF. Even though preliminary pharmacokinetic data indicated lower drug levels in the genital area, use of TAF to replace TDF in PrEP may offer an opportunity for use in those who would otherwise not be candidates for the current PrEP regimen. Researchers are taking it a step further and investigating the delivery of TAF through a sustained-release subdermal implant. This novel drug delivery system is a polyvinyl alcohol–coated silicone cylinder implant with orthogonal delivery designed to gradually release TAF. ²¹ This product is currently in the planning stages, but to make this a viable option, researchers must address the drug’s lower potency and concentrations in tissues.

Maraviroc (MVC)—alternative ARV

Trepidations about long-term side effects and resistance associated with TDF-FTC have led researchers to search for alternative ARVs for PrEP. Maraviroc, an entry inhibitor currently used for HIV treatment in patients who predominantly express the R5 variant of the virus, is being evaluated as a potential alternative. Maraviroc generates high drug concentrates in the genital tract and rectum and exhibits limited development for resistance, making it an ideal agent for PrEP. ¹⁴ In 2016, results of 2 separate trials to determine the safety and tolerability of MVC regimens compared with TDF-FTC were made available.^14,22 These 2 studies were phase 2, multisite, randomized, double-blinded trials to prevent HIV transmission but in different populations. The HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 (HPTN/ACTG A5305) study evaluated at-risk MSM, including transgender women. ¹⁴ The second study enrolled at-risk women (female born). ²² The study design and inclusion criteria were similar for both groups. Participants were HIV-uninfected men and women who reported having unprotected vaginal or anal intercourse with ≥1 man who had an unknown HIV status or known to be HIV infected within 90 days of study enrollment. Patients received MVC, MVC + FTC, MVC + TDF, or TDF-FTC for more than 48 weeks. A total of 406 men and 188 women completed their respective studies. Overall, male patients randomized to MVC-based regimens had similar safety and tolerability profile compared with TDF-FTC. Five patients seroconverted and 4 of the 5 had low (3 patients) or undetectable (2 patients) MVC levels, but there was no evidence of genotypic resistance in those that seroconverted. In the female study, there was no statistical difference in adverse events between the treatment arms containing MVC compared with TDF-FTC. Gastrointestinal and renal toxicities were similar in both groups. Adherence was determined by plasma drug concentrations of active study drugs and was 65% at week 24 and 60% at week 48. There was no difference in plasma drug concentrations between study arms. Both studies provided vital safety and tolerability information that could potentially influence future research of MVC-containing regimens for PrEP. Although seroconversion occurred in 5 and 0 participants in the MSM and women’s study, respectively, both studies were not powered to detect efficacy; therefore, no conclusion could be made regarding the efficacy of MVC in reducing the risk of HIV acquisition. Results of bone mineral density, adherence, behavioral, and quality of life studies with MVC are forthcoming. ²²

Dapivirine—monthly vaginal ring

Dapivirine is a non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI) whose delivery through a vaginal ring is currently being investigated. A monthly vaginal ring containing dapivirine is considered an inconspicuous, easy-to-use self-administered LA option for women. The ring is self-inserted into the vagina and replaced every month. The flexible silicone matrix polymer ring slowly releases dapivirine over 1 month locally without extensive systemic absorption. The 1-month ring has undergone phase 1 and phase 2 trials and is being studied in an open-label extension study. A 3-month option is in development. The phase 3 Microbicide Trials Network 020—A Study to Prevent Infection with a Ring for Extended Use (MTN-020-ASPIRE) Study evaluated the effectiveness of a monthly dapivirine vaginal ring to eliminate the low rate of adherence observed in prior studies. ²³ The study was a phase 3, randomized, double-blind, placebo-controlled trial where women inserted monthly vaginal rings containing dapivirine or placebo and followed for a minimum of 12 months. A total of 2629 HIV-seronegative women from Malawi, South Africa, Uganda, and Zimbabwe were enrolled (n = 1313 dapivirine group; n = 1316 placebo). In total, 168 women acquired HIV infection, 71 in the dapivirine group, and 97 in the placebo group, which translated to a 27% (P = .046) lower rate of HIV acquisition in the dapivirine group. Adherence, measured by dapivirine plasma levels, was 82%. Efficacy varied according to age with women ≥25 years having a higher rate of efficacy at 61% (CI: 32-77; P < .001) versus 10% in women <25 years (CI: −41 to 43; P = .64). Further analysis indicated that participants 18 to 21 years of age had both lower adherence and protection against HIV acquisition (−21%; CI: −133 to 31; P = .45). There was no significant difference between both groups regarding safety. The rate of NNRTI mutations was also similar (8 of 68 participants [12%] in the dapivirine group and 10 of 96 [10%] in the placebo group; P = .80). Although this study provided evidence for additional PrEP options for women, its applicability is limited to women who engage exclusively in vaginal sex. Based on the drug’s route of administration, it is doubtful that dapivirine concentrations will provide systemic protection against anal intercourse. It is important to note that the study’s baseline characteristics indicated that 25 (2%) participants in the dapivirine group and 29 (2%) in the placebo group participated in anal sex in the previous 3 months prior to study enrollment. Therefore, although efficacy was achieved, one cannot confidently conclude that the observed seroconversions occurred as a result of low adherence or due to the practice of anal intercourse.

Cabotegravir and rilpivirine—extended or LA drug formulations

Extended or LA drug formulations have been used in a number of disease states to increase adherence particularly in areas such as psychiatry and contraception. Treatment failures in the VOICE and FEM-PrEP studies attributed to nonadherence, lend weight to suggestions that LA agents, and drug delivery systems could potentially eliminate this barrier to successful treatment. Sustained release or LA ARV formulations could potentially be the key to increasing the overall effectiveness of PrEP. These new formulations are designed to steadily release drug over a period of days or weeks without repeated administration. A potential drawback to using a LA formulation may include the prolonged exposure to medications that may require titration. However, the advantages include the obvious increased adherence, convenience, potential for avoidance of gastrointestinal toxicity, and certain drug-drug inter-actions. ²⁴ Rilpivirine, an NNRTI, and cabotegravir, a strand-transfer integrase inhibitor, are currently being studied as potential LA antiretroviral agents for PrEP. The pharmacokinetics of both agents supports infrequent dosing. Cabotegravir is available as a tablet and a LA nanosuspension injection with half-life of 40 hours and 21 to 50 days, respectively. ²⁴ Rilpivirine also has extended half-life of ~50 hours and ~30 to 90 days for the tablets and LA nanosuspension injection, respectively. Each agent has been studied as monotherapy for prevention and in combination for HIV treatment. Two phase 2b treatment studies, Long-Acting Antiretroviral Treatment Enabling (LATTE) and LATTE-2 provided significant antiviral activity and were well tolerated during both the induction and maintenance phases at the 32-week interim analysis.^25,26 Study results at week 48 will provide dose selection for further phase 3 efficacy studies. The cabotegravir and rilpivirine studies presented here will focus on HIV prevention and will be described here.

Cabotegravir LA HIV PrEP studies

Phase 2 studies evaluating cabotegravir LA as monotherapy for prevention have either been completed or are still underway. The phase 2a studies include a Phase IIa Study to Evaluate the Safety, Tolerability and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ECLAIR) study (results presented at the February 2016 Conference on Retroviruses and Opportunistic Infections [CROI] conference), and the study HPTN 077 (NCT02178800) is still underway. The phase 2b/3 study, HPTN 083 (NCT02720094), is currently recruiting participants to evaluate the efficacy and safety injectable cabotegravir against daily oral TDF-FTC as PrEP in men and transgender women who have sex with men. The primary end points are the number of HIV infections and clinical or laboratory adverse events of grade 2 or higher. The ECLAIR study was presented at the CROI in Boston in February 2016. This study evaluated LA cabotegravir (cabotegravir LA) as monotherapy for the prevention of HIV in HIV-uninfected adult men who are at low risk of HIV infection.^27,28 The purpose of the study was to evaluate the safety, tolerability, and acceptability of oral cabotegravir and injectable cabotegravir compared with placebo. In this 41-week study, 126 participants underwent an initial safety assessment and received cabotegravir 30-mg tablets (n = 105) or placebo (n = 21) for 4 weeks and then transitioned to intramuscular injections of cabotegravir LA 800 mg or placebo administered once every 12 weeks for 3 cycles. The doses chosen were based on prior phase 1 animal studies of SHIV transmission of cabotegravir LA which demonstrated target through concentrations of 4× protein-adjusted 90% inhibitory concentration (PA-IC₉₀) of 0.664 mg/mL were required for prevention. ²⁷ Overall, cabotegravir LA was well tolerated with 74% (67/91) of patients preferring cabotegravir injections over oral delivery. However, the mean drug concentration was below the minimum target of 4× PA-IC90; therefore, a dosing strategy of 600 mg Q8 weeks is under evaluation before efficacy studies in phase 3.

Rilpivirine LA HIV PrEP studies

The safety and pharmacokinetic/pharmacodynamic profile of rilpivirine LA for potential PrEP have been assessed in 2 phase 1 studies (NCT01275443 and NCT01656018).^29,30 Pharmacokinetic data from those phase I studies indicated that a 1200-mg dose of rilpivirine LA given every 8 weeks was capable of producing plasma and tissue concentrations that would be necessary for preventing HIV infection.^30,31 Lower doses of rilpivirine LA have resulted in breakthrough HIV infections and resistance in phase 1 studies. The 1200-mg dose regimen was evaluated in the HPTN-076 study (NCT02165202) a phase 2 expanded safety and acceptability study that enrolled women in South Africa, Zimbabwe, and the United States who are at low risk of acquiring HIV. The HPTN-076 study required a 4-week run in with oral rilpivirine (25-mg capsules) before receiving 1200 mg of rilpivirine (2 injections are required for 1 dose) at 8-week intervals for a total of 6 doses with a follow-up visit 32 weeks after the last injection compared with placebo. Results presented at the CROI conference in February 2017 showed that a total of 136 women were enrolled and >80% found the injections easier to use and >73% felt as, though, it could provide long-term protection; however, ~30 felt that injections were painful. ³² Unlike cabotegravir, rilpivirine concentrations were consistently above the PA-IC₉₀ of 12.5 ng/mL through 8 weeks postinjection. ³² Adverse events were similar between both groups. The HPTN-076 study results represent promising support for future efficacy studies rilpivirine.

Drug Resistance

The development of resistance during therapy is of great concern especially in patients who display suboptimal adherence. In most of the studies that reported on resistance, resistance developed in patients that had acute HIV infections at the time of study initiation.^4,5 Importantly, the overall development of resistance while on PrEP has been relatively low at 6% (305 total seroconversions). ³³

M184V/I mutation was reported by all studies. According to Montgomery et al ³³ mutations associated with TDF-FTC during PrEP decay rapidly and do not persist longer than 6 months after stopping PrEP.

The TeNoRes Study provides compelling data on resistance patterns against the recommended first-line tenofovir-based regimens for treatment of HIV in the World Health Organization’s updated 2016 guidelines.^34,35 Tenofovir resistance to HIV is a result of one mutation at position 65 (lysine to arginine; K65R) in the reverse transcriptase gene. According to the TeNoRes study, drug resistance occurred in a high percentage of patients who experienced virologic failure on a tenofovir-containing first-line regimen overall in low-income and middle-income counties. ³⁵ The same level of resistance was not identified in high-income areas, and prevalence was considered to be low. ³⁵ Viral failure in those with tenofovir resistance occurred in 20% of those from Europe to greater than 50% in sub-Saharan Africa. Because PrEP depends primarily on the administration of tenofovir, there is great concern over the transmission of tenofovir-resistant strains. Surveillance and monitoring of those on PrEP are recommended to maintain the benefits.

Conclusions

The studies presented provide insight into the areas where greater efforts are needed to attain the goal of eradicating HIV. With promising results from the various studies conducted in high-risk populations, the greatest barrier to optimal efficacy remains adherence. To address this barrier, the development of an array of prevention alternatives is underway. The US Centers for Disease Control and Prevention (CDC) announced that HIV infections fell by 18% between 2008 and 2014. ³⁶ The CDC attributes this decline to the aggressive push for prevention. The Food and Drug Administration approved PrEP for HIV prevention in 2012 and adopted the “High Impact Prevention” strategy that focuses on the National HIV/AIDS Strategy of reducing the current annual HIV incidence of about 50 000 infections by 25% in 5 years. ³⁷ There has been progress, but there is much more to do. Capitalizing on the new formulations and delivery modes reviewed here coupled with testing and education can help in reaching the ultimate goal of eradicating HIV infections.