ARV PrEP for HIV infection can be delivered orally or topically as a gel, film, suppository, or sustained-release intravaginal ring.³³ In 2016, the WHO released updated guidance on PrEP with a recommendation that oral tenofovir DF–containing PrEP be offered to individuals at substantial risk of acquiring HIV as an additional prevention option in combination with other preventive strategies.⁷² The recommendations provisionally defined substantial HIV infection risk as an HIV incidence higher than 3/100 person-years without use of PrEP. Populations identified as having such risk include certain subgroups of MSM, transgender women in multiple settings, and heterosexual women and men who have sex with partners who have HIV and are not receiving treatment or who have not been diagnosed. The guidelines also note that these new recommendations allow for offering PrEP to patients based on local epidemiology and individual assessment, as opposed to risk group, so that implementation may be informed by local information on the settings and circumstances of HIV transmission. This aims to enable a broader range of populations to benefit from PrEP.

The CDC provide detailed guidelines on the use of PrEP, including in MSM (Table 3).⁷³

Table 3. CDC Guidance on HIV PrEP for MSM⁷³

The CDC clinical guidelines on the use of PrEP includes recommendations for PrEP in at-risk heterosexually active adults (Table 4).⁷³ Note that these recommendations are for individuals who are at an ongoing, very high risk for sexual acquisition of HIV infection, such as those whose partners are known to have HIV infection.

Table 4. CDC Guidance on HIV PrEP for Heterosexually Active Adults at Ongoing, Very High Risk of Sexually Acquired HIV Infection⁷³

The CDC clinical guidelines on the use of PrEP includes recommendations for PrEP in at-risk people who inject drugs (Table 5).⁷³

Table 5. CDC Guidance on HIV PrEP for People Who Inject Drugs⁷³

Current guidelines from the International Antiviral Society (IAS)-USA panel also recommend daily oral PrEP with emtricitabine/tenofovir DF for adult patients at risk for sexual exposure as well as all individuals who inject drugs.⁷⁴ To ensure adequate tissue levels, the IAS-USA panel recommends a 7-day lead-in period with daily oral PrEP before sexual exposure.

Oral PrEP
Based on the positive protective benefit of emtricitabine/tenofovir DF for prevention of HIV in the studies discussed below, in 2012, the FDA approved emtricitabine/tenofovir DF to reduce the risk of sexually acquired HIV infection in adults at high risk, and in 2018, the FDA expanded the indication to include at-risk adolescents. In September 2019, the FDA approved a second 2-drug combination, emtricitabine/tenofovir AF, for PrEP in adults and adolescents weighing at least 35 kg to reduce the risk of HIV infection from sexual acquisition, excluding individuals at risk from receptive vaginal sex.⁷⁵ Individuals at risk of HIV acquisition from receptive vaginal sex were excluded from the indication because prevention efficacy data are not yet available in this population. The approval of emtricitabine/tenofovir AF for PrEP is based on comparable prevention efficacy vs emtricitabine/tenofovir DF in men and transgender women who have sex with men demonstrated in the DISCOVER trial.¹¹ The CDC PrEP guidelines have not yet been updated to reflect the availability of this new option.⁷³

Tenofovir DF. The first study of oral tenofovir DF, conducted among 936 women in Ghana, Nigeria, and Cameroon, was designed to evaluate whether oral tenofovir DF taken once daily could reduce the incidence of HIV infection in women.⁷⁶ Although the study was never completed at the Nigeria and Cameroon sites (due to community and political opposition), it nevertheless provided important data supporting the safety of oral tenofovir DF in HIV-uninfected women. There were no differences in clinical or laboratory adverse events between the tenofovir DF and placebo arms. In addition, there was no evidence of increased risk taking (risk disinhibition) associated with the use of oral PrEP. There were 6 HIV infections among women randomized to placebo and 2 among women receiving tenofovir DF (P = NS).

A placebo-controlled safety study of once-daily oral tenofovir DF was completed by the CDC in nearly 400 MSM recruited from Atlanta, San Francisco, and Boston.⁷⁷ Participants were randomly assigned to 1 of 4 study arms. Participants in 2 of the arms received either tenofovir DF or placebo immediately on enrollment, whereas participants in the other 2 arms received either tenofovir DF or placebo 9 months after enrollment. Risk disinhibition was evaluated by recording sexual behavior prior to drug randomization and comparing these data with sexual behaviors after randomization. This study was not powered for efficacy in preventing HIV but did provide new information on the safety and acceptability of daily PrEP among US MSM. The prospective data on sexual disinhibition for this population when taking daily oral PrEP suggested that there was no increase in sexual risk-taking while men were using ARVs for HIV prevention.⁷⁸

Bangkok Tenofovir
The Bangkok Tenofovir Study found that daily oral tenofovir DF PrEP reduced the risk of HIV infection in people who inject drugs.¹⁷ The study enrolled 2413 HIV-negative individuals who reported injecting drugs in the previous year. Participants were randomized to tenofovir DF or placebo and could choose between monthly visits or daily directly observed therapy. Fifty HIV infections occurred during follow-up: 17 in the tenofovir DF group and 33 in the placebo arm, equating to a 48.9% reduction in HIV incidence (95% CI: 9.6% to 72.2%; P = .01). Nausea was more common in the tenofovir DF arm, but the frequency of serious adverse events did not differ significantly between arms.

Emtricitabine/Tenofovir DF. The iPrEx study randomized 2499 HIV-negative men or transgender women who have sex with men to receive a combination of once-daily emtricitabine/tenofovir DF or placebo. Results showed that 64 patients in the placebo arm became infected vs only 36 patients in the emtricitabine/tenofovir DF arm, which reflects a 44% reduction in the incidence of HIV (95% CI: 15% to 63%; P < .001).⁸ Furthermore, for patients who took the drug as directed throughout the trial, emtricitabine/tenofovir DF was nearly 100% effective at preventing HIV acquisition. However, a subanalysis revealed that emtricitabine/tenofovir DF was not effective in the small number of transgendered women in the trial (15% of participants), with 11 infections occurring in each arm.⁷⁹ There was no evidence of an increase in sexual risk behavior during the study according to an analysis that included assessments at baseline, after drug initiation, and through follow-up.⁸⁰ Whereas similar serious adverse event rates were recorded in the 2 study arms, nausea was reported more frequently during the first 4 weeks in the emtricitabine/tenofovir DF arm vs the placebo arm.⁸

Partners PrEP
The Partners PrEP study enrolled 4747 HIV-serodiscordant heterosexual couples from Kenya and Uganda.⁹ The HIV-negative partner in each couple was randomly assigned to tenofovir DF, emtricitabine/tenofovir DF, or placebo for 36 months. However, the placebo arm was terminated early by the data and safety monitoring board due to the finding that both PrEP strategies significantly reduced HIV acquisition vs placebo. Indeed, tenofovir DF decreased HIV acquisition risk by 67% vs placebo (P < .001) and emtricitabine/tenofovir DF decreased the risk by 75% (P < .001). In addition, the risk was decreased in both men and women: The efficacy of tenofovir DF was 71% in women (P = .002) and 63% in men (P = .01), and the efficacy of emtricitabine/tenofovir DF was 66% in women (P = .005) and 84% in men (P < .001). The rates of death, serious adverse events, and laboratory events reported were low and not significantly different between arms, and there were no efficacy differences between the 2 active regimens. The adherence rate as assessed by a return pill count was 97%. As assessed by measurement of tenofovir in the plasma samples collected during study visits, adherence to study tablets exceeded 80%.

TDF2
The TDF2 study randomized 1219 HIV-uninfected, heterosexually active adults in Botswana to emtricitabine/tenofovir DF or placebo for ≥ 12 months of follow-up and found that the overall protective efficacy of emtricitabine/tenofovir DF was 62.2% (95% CI: 21.5% to 83.4%; P = .03).¹⁰ The reduction in HIV acquisition was observed in both men and women, and medication adherence was similar between the study arms. Some adverse events occurred more frequently with emtricitabine/tenofovir DF vs placebo, including nausea (18.5% vs 7.1%; P < .001), vomiting (11.3% vs 7.1%; P = .008), and dizziness (15.1% vs 11.0%; P = .03), but rates of serious adverse events were similar between arms.

IPERGAY and PROUD
In early 2015, data from 2 additional clinical trials, IPERGAY, conducted in France, and PROUD, conducted in the United Kingdom, likewise demonstrated that emtricitabine/tenofovir DF given as PrEP is highly effective in reducing HIV transmission in HIV-negative MSM; a finding that prompted the data and safety monitoring boards from both trials to recommend allowing all study participants to receive emtricitabine/tenofovir DF.⁸¹ In the PROUD trial, which was initially only intended to be a pilot study to determine the feasibility of a larger study, 544 HIV-uninfected participants were randomized 1:1 to receive oral emtricitabine/tenofovir DF either immediately or deferred until after 12 months.⁸² At the time of analysis, 465 patient-years had been accrued. The incidence of HIV infection was 1.2/100 patient-years in the immediate PrEP arm compared with 9.0/100 patient-years in the deferred arm, demonstrating an 86% reduction in HIV transmission (90% CI: 64-96; P = .0001). Based on these results, it was found that 13 men in a similar population would need to receive this PrEP for 1 year to avert 1 HIV infection. Overall, 28 patients interrupted PrEP, 13 for drug-related events, and 20 of 21 were able to restart PrEP.

In the IPERGAY trial, 414 HIV-uninfected participants were given oral emtricitabine/tenofovir DF or placebo “on demand” at the time of sexual exposure with a schedule of 2 tablets 2-24 hours before sex, 1 tablet 24 hours later, and another tablet 24 hours after the second dose, or the option of daily usage for frequent exposures.⁸³ After showing early efficacy, the trial was subsequently amended to offer PrEP to all participants. All participants had a median of 9 months follow up. A median of 15 tablets were taken per month per patient. The incidence of HIV transmission was 6.6/100 patient-years in patients taking placebo compared with 0.91/100 patient-years in patients taking PrEP, demonstrating a relative reduction of 86% (95% CI: 40% to 98%; P = .002). Correct use of PrEP was reported for 43% of sexual acts in the PrEP arm and for 40% of sexual acts in the placebo arm. The rate of serious adverse events was similar in both arms. This trial demonstrates that PrEP given “on demand” can be highly effective and could provide a good alternative to a daily regimen of emtricitabine/tenofovir DF to improve adherence and reduce HIV transmission rates in high risk populations such as MSM with high risk profiles. It should be noted however, that the study population in the IPERGAY trial took emtricitabine/tenofovir DF a median of 16 days (12-24 days) each month, a frequency of tenofovir DF usage that was associated with decreased risk of HIV infection (Table 6).⁸⁴

The current IAS-USA guidelines include pericoital, or on-demand, oral emtricitabine/tenofovir DF as an alternative PrEP option for MSM with infrequent sexual exposure.⁷⁴ Dosing should follow the “2-1-1” strategy used in the IPERGAY trial: 2 emtricitabine/tenofovir DF tablets taken with food 2-24 hours before sex, followed by 1 tablet taken 24 hours after the first (doubled) dose, and then 1 more tablet 24 hours later. The guidelines panel recommends that the first (doubled) emtricitabine/tenofovir DF dose should be taken closer to the 24-hour precoital time point than the 2-hour time point. Note that on-demand PrEP is not recommended for other groups at risk for HIV infection or in those with active HBV infection.

Table 6. Effect of Tenofovir Levels in Dried Blood Spots on HIV Infection Incidence⁸⁴

Partners Demonstration Project
Similar efficacy results with PrEP were also seen in another ongoing prospective trial, The Partners Demonstration Project, in which serodiscordant heterosexual couples in Africa were offered ART to the partner with HIV regardless of CD4+ cell count and PrEP with emtricitabine/tenofovir DF to the uninfected partner until the partner with HIV reached 6 months of ART therapy.³³ At the time of analysis (858 person-years accrued), 2 cases of HIV transmission had occurred demonstrating a 96% (95% CI: 81-99; P < .001) reduction in risk of HIV transmission. In both cases of HIV transmission, the HIV-uninfected partner reported interruptions in PrEP use and tenofovir was undetectable in plasma samples at the time of seroconversion.

HPTN 067/ADAPT
The randomized HPTN 067/ADAPT trial has also evaluated nondaily, time-driven or event-driven oral emtricitabine/tenofovir DF PrEP in several different cohorts, including MSM and transgender women in Bangkok, Thailand, and in Harlem, New York, and women in Cape Town, South Africa. In this trial, participants began with a lead-in 6-week period of directly observed therapy, after which they were randomized to one of 3 arms for 24 weeks of self-administered dosing: continuous once-daily PrEP, time-driven PrEP (1 dose twice weekly plus 1 dose after sex), or event-driven PrEP (1 dose before sex and 1 dose after sex). Coverage of sex acts (vaginal and anal), defined as taking ≥ 1 PrEP pill within 4 days before having sex and ≥ 1 PrEP pill within 24 hours following sex, was a primary endpoint of the trial. The results differed based on the cohort. In the United States (Capsule Summary) and South African cohorts, continuous daily dosing provided better coverage of sex acts and higher adherence vs time-driven or event-driven PrEP.^85,86 However, in the Bangkok cohort, time-driven PrEP provided coverage of sex acts comparable to daily dosing whereas event-driven PrEP was associated with lower coverage of sex acts (Capsule Summary).⁸⁷ Adherence was higher with daily vs time-driven PrEP, but the difference was not statistically significant; adherence to event-driven PrEP was significantly lower than each of the other 2 arms. It is important to note that coverage of sex acts as defined in HPTN 067/ADAPT has not been demonstrated to be an effective PrEP strategy (ie, 1 pill up to 4 days before and 1 pill up to 24 hours after sex). Investigators concluded that the results of this trial generally support current recommendations for continuous daily oral PrEP dosing.

Prevenir
Further data supporting the efficacy of both daily and on-demand PrEP with oral emtricitabine/tenofovir DF come from an interim analysis of the open-label prospective ANRS Prevenir trial. In this study, a cohort of predominantly MSM in the Paris region at high risk of HIV acquisition and with inconsistent condom use were given the option of daily vs on-demand (≥ 1 pill < 24 hours before and 1 pill < 24 hours after sex) oral emtricitabine/tenofovir DF PrEP.⁸⁸ No incident HIV infections were observed during a mean follow-up of 7 months at the time of the interim analysis, which included 724 participants receiving daily PrEP and 870 receiving on-demand PrEP (Capsule Summary).

FEM-PrEP
Studies evaluating tenofovir DF–based PrEP have not been consistently positive. In the FEM-PrEP study, which evaluated the protective effect of emtricitabine/tenofovir DF vs placebo in 2120 HIV-negative women in Kenya, South Africa, and Tanzania, emtricitabine/tenofovir DF did not significantly reduce the rate of infection compared with placebo, and it was associated with significantly increased rates of nausea (P = .04), vomiting (P < .001), and alanine aminotransferase elevations (P = .03).¹⁵ However, adherence rates in this study were low, with recent pill use evident in < 27% of women who acquired HIV infection and < 38% in matched uninfected controls.⁷³ The authors suggested that the low adherence rates may partially account for the lower efficacy of emtricitabine/tenofovir DF in heterosexual women in the FEM-PrEP trial compared with the Partners PrEP and TDF2 trials.⁷³ Of note, a high proportion of women in this study did not perceive themselves to be at risk for infection, which might have negatively affected their adherence to prophylactic therapy.

One hypothesis that has been proposed as an explanation for the discordance between the efficacy of PrEP in the FEM-PrEP¹⁵ and VOICE trials compared with the iPreX and Partners PrEP trials is that efficacy may be lower in populations who have a higher incidence of HIV infection. Investigators reported data from an analysis aimed at addressing this possibility by evaluating the efficacy of PrEP within higher-risk subgroups in the Partners PrEP trial, including high-risk female subgroups.⁸⁹ The results showed that within high-risk subgroups of women who experienced an HIV infection rate > 5 per 100 person-years in the placebo arm (compared with 2 per 100 person-years for overall placebo arm), the efficacy of tenofovir DF or emtricitabine/tenofovir DF for protecting against HIV infection was estimated to range from 64% to 84% (all P < .05). All subgroups demonstrated > 94% attendance rates for monthly visits and tenofovir DF detection rates > 70% for random plasma samples. These findings indicate that when adherence rates are high, PrEP is highly effective even in high-risk heterosexual subgroups. Additional research is under way to explain the discordant results in the PrEP trials. However, it is clear that the low level of adherence to daily prevention regimens, both oral and topical, among younger and unmarried women in the FEM-PrEP and VOICE trials who had the highest risk of HIV likely accounts for the difference in the results. Although daily medication use for people in HIV-serodiscordant partnerships was highly acceptable to the couples participating in Partners PrEP, many young unmarried women who are unaware of the HIV status of their sex partners likely need different options for prevention of HIV.

ATN113
Between August 2013 and September 2014, 78 HIV-uninfected adolescent MSM (aged 15-17 years) who self-reported high-risk sexual behavior were enrolled in the ATN113 trial conducted in 6 cities across the United States. The open-label study evaluated the safety of emtricitabine/tenofovir DF as PrEP for 48 weeks in combination with counseling on safer sex practices. Self-reported high-risk behaviors included anal intercourse without the use of a condom with a partner with HIV or of unknown status, ≥ 3 male sex partners, exchange of goods or services for sex, and intercourse with a male with a known sexually transmitted infection. The study found that emtricitabine/tenofovir DF was well tolerated with unintended grade 3 weight loss being the most severe adverse event (n = 2).^90,91 A decrease in bone mineral density occurred in 4 participants (modest decrease in 3 participants and > 4% decline in 1 participant).⁹¹ Three participants acquired HIV during the course of the study. The annualized HIV incidence was 6.4 per 100 person-years (95% CI: 1.3-18.7).⁹⁰ Tenofovir diphosphate blood levels in each of the participants who acquired HIV during the study were consistent with suboptimal adherence (fewer than a mean of 2 doses per week).⁹¹ No genotypic mutations associated with resistance to tenofovir DF or emtricitabine were detected. Dried blood assays of tenofovir diphosphate (TFV-DP) levels also demonstrated a marked decline in overall adherence levels after Week 12 of the study when participant clinic visits switched from monthly to quarterly. This finding suggests that additional adherence support may be needed for adolescents receiving PrEP. The results of ATN113 in combination with the well-established safety and efficacy of this combination for PrEP in adults led the FDA to expand the indication for daily oral emtricitabine/tenofovir DF PrEP in combination with safer sex practices to include use in at-risk adolescents weighing ≥ 35 kg.⁹¹

Pharmacokinetics of Emtricitabine/Tenofovir DF PrEP. Several pharmacokinetic analyses have contributed to a better understanding of both the onset and duration of oral PrEP activity. Results from the CellPrEP study demonstrated that 89% of participants (21 HIV-uninfected volunteers) reached a 90% effective concentration of TFV-DP in peripheral blood mononuclear cells after 7 days of daily oral emtricitabine/tenofovir DF.⁹² In addition, the inferred HIV risk reduction based on TFV-DP concentrations remained > 90% for 7 days after stopping PrEP. Of note, the inferred risk reduction estimations in CellPrEP were based on data obtained from drug concentrations and efficacy in MSM enrolled in the iPrEx study; therefore, the findings cannot be extrapolated to heterosexual men, women, or HIV transmission via other routes. In a pharmacokinetic substudy of IPERGAY, samples were taken during a 24-hour period from 12 participants who received a single double-dose of oral emtricitabine/tenofovir DF. Emtricitabine was detected at high concentrations (comparable to levels in patients receiving emtricitabine-containing ART) in rectal tissue samples as early as 30 minutes after dosing, whereas tenofovir was not detected at comparable concentrations until 24 hours post dosing.⁹³ When investigators assessed ex vivo HIV infectivity of rectal biopsies from 10 substudy participants, the results showed that the double-dose of emtricitabine/tenofovir DF reduced the proportion of patients with rectal tissue samples susceptible to HIV infection (vs samples taken before dosing) but did not eliminate susceptibility, suggesting that postexposure doses are required in addition to the pre-exposure double dose to achieve full protection.

Tenofovir AF. Tenofovir AF is an alanine ester prodrug of tenofovir that is characterized by reduced systemic levels of tenofovir. Tenofovir AF is largely delivered as tenofovir AF to lymphocytes and macrophages and then metabolized intracellularly to tenofovir and phosphorylated to the active TFV-DP. This pathway contrasts with that of tenofovir DF, which is converted to tenofovir in the blood, then taken up by cells. Compared with tenofovir DF, plasma tenofovir levels after oral administration of tenofovir AF are 90% lower, whereas intracellular concentrations of tenofovir are up to 20-fold higher, allowing for lower dosing compared with tenofovir DF and reduced toxicity.⁹⁴

DISCOVER
In the phase III DISCOVER trial, emtricitabine/tenofovir AF was compared with emtricitabine/tenofovir DF for daily oral PrEP in cis-MSM and transgender women at high risk of HIV infection. The primary endpoint of HIV incidence per 100 patient-years was 0.16 for emtricitabine/tenofovir AF vs 0.34 for emtricitabine/tenofovir DF, establishing the noninferiority of emtricitabine/tenofovir AF, with an HIV incidence rate ratio of 0.47 (95% CI: 0.19-1.15). While both PrEP regimens were well tolerated with low rates of discontinuation for AEs (1% to 2%), emtricitabine/tenofovir AF was linked with significantly improved renal and bone safety outcomes at Week 48 vs emtricitabine/tenofovir DF.¹¹

Further analyses of data from the DISCOVER trial to identify factors contributing to the apparent numerically decreased HIV infection rate observed with emtricitabine/tenofovir AF vs emtricitabine/tenofovir DF as PrEP found that the intracellular TFV-DP concentrations in peripheral blood mononuclear cells were 6.3-fold higher with emtricitabine/tenofovir AF vs emtricitabine/tenofovir DF (Capsule Summary).⁹⁵ At Week 4, peripheral blood mononuclear cell TFV-DP EC₉₀ was reached by 98% of patients receiving emtricitabine/tenofovir AF vs 68% of patients receiving emtricitabine/tenofovir DF. EC₉₀ was reached within 1-2 hours of the first emtricitabine/tenofovir AF dose vs after 3 daily doses of emtricitabine/tenofovir DF. A simulation indicated that concentrations greater than the EC₉₀ would last for 16 days after the final dose of emtricitabine/tenofovir AF vs only 10 days after discontinuation of emtricitabine/tenofovir DF.

Oral PrEP Implementation. Despite data demonstrating high efficacy of oral PrEP within the context of a clinical trial, additional data have accrued on practical aspects of PrEP implementation in a community setting, particularly regarding real-world adherence and behavioral risk compensation. The US PrEP Demonstration Project was a prospective, open-label, cohort study designed to evaluate PrEP uptake, adherence, efficacy, and safety as well as sexual risk behavior and HIV resistance among HIV-negative MSM and transgender women (N = 557) receiving care at STD clinics and community-based health clinics in 3 US cities: San Francisco, Miami, and Washington, DC. After 481 person-years of follow-up, the results demonstrated relatively high rates of adherence, particularly among participants at higher risk (those with ≥ 2 condomless anal sex partners in the previous 3 months) (Capsule Summary).⁹⁶ Overall, 63% of participants had protective levels of TFV-DP in dried blood spot at all study visits. Black participants and participants at the Miami site had significantly lower adherence levels, as measured by the proportion of participants with protective TFV-DP levels in dried blood spots at the end of the study, compared with white participants and the San Francisco site. The rate of HIV infection was low at 0.43/100 person-years during the follow-up period despite a high STD incidence rate (90/100 person-years).

Another open-label feasibility study, ATN 110, evaluated PrEP uptake, safety, adherence, and effects on sexual risk taking in 200 HIV-uninfected US MSM aged 18-22 years who were receiving an additional informational or behavioral intervention to prevent HIV infection in community-based settings. In this trial, daily oral PrEP was generally safe and well tolerated, with only 3 adverse events (all grade 3) considered to be related to study treatment.⁹⁷ Adherence based on TFV-DP levels decreased over time, particularly when the frequency of study visits decreased from every 4 weeks to every 12 weeks (between Week 12 and 24). Adherence levels were lowest in black men throughout the study. In this trial, participants reporting condomless anal intercourse during the study showed higher adherence levels (P = .01), suggesting that individuals who are at the greatest risk of infection may also be most likely to adhere to PrEP. The HIV incidence rate was 3.29/100 person-years; all 4 participants who acquired HIV infection during the study had undetectable TFV-DP levels at the time of HIV diagnosis.

Maraviroc. Another ARV agent evaluated for the prevention of HIV is maraviroc. The randomized, double-blind NEXT-PrEP study evaluated the safety and efficacy of maraviroc alone or with emtricitabine or tenofovir DF, compared with emtricitabine/tenofovir DF, in MSM and at-risk women in the United States and Puerto Rico (<a rel="noopener noreferrer" rel="noopener noreferrer" href="https