Tenofovir-based Oral PrEP Prevents HIV Infection among Women

Abstract

Purpose of review

Despite tremendous promise as a female-controlled HIV prevention strategy, implementation of pre-exposure prophylaxis (PrEP) among women has been limited, in part because of disparate efficacy results from randomized trials in this population. This review synthesizes existing evidence regarding PrEP efficacy for preventing HIV infection in women and considerations for delivering PrEP to women.

Recent findings

In three efficacy trials, conducted among men and women, tenofovir-based oral PrEP reduced HIV acquisition in subgroups of women by 49–79% in intent-to-treat analyses, and by >85% when accounting for PrEP adherence. Two trials did not demonstrate an HIV prevention benefit from PrEP in women, but substantial evidence indicates those results were compromised by very low adherence to the study medication. Qualitative research has identified risk perception, stigma, and aspects of clinical trial participation as influencing adherence to study medication. Pharmacokinetic studies provide supporting evidence that PrEP offers HIV protection in women who are adherent to the medication.

Summary

Tenofovir-based daily oral PrEP prevents HIV acquisition in women. Offering PrEP as an HIV prevention option for women at high risk of HIV acquisition is a public health imperative and opportunities to evaluate implementation strategies for PrEP for women are needed.

Introduction

HIV/AIDS is the leading cause of death among women of reproductive age, and a combination of biological, behavioral, and sociocultural factors result in women bearing a disproportionate burden of the global HIV epidemic [1, 2]. HIV prevention strategies available to women at risk of sexual transmission include abstinence from sexual activity, female and male condoms, and antiretroviral therapy (ART) use or voluntary male medical circumcision by their partners; however, all of these strategies depend on male partner cooperation. Tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis (PrEP) is a novel prevention strategy in which HIV uninfected individuals use an oral antiretroviral medication as chemoprophlaxis to reduce HIV acquisition [3]. PrEP holds tremendous promise as a female-controlled prevention approach, and international normative bodies recommend PrEP for persons at substantial HIV risk, including women [4–8]. However, the delivery of PrEP to women at high risk of HIV is underdeveloped due to complicated results from clinical trials that assessed PrEP efficacy among women. In addition, cost, policies, infrastructure, and limited availability of antiretroviral medications are logistical factors limiting the scale-up of PrEP in areas of high HIV burden. In order to maximize the impact of PrEP, it is important to understand the different PrEP efficacy results across trials, draw a definitive conclusion about the HIV prevention benefit of PrEP for women, and identify elements from clinical trials and open-label studies that are important to address within programs delivering PrEP to women.

Text of Review

Randomized Clinical Trials of PrEP among Women

Five double-blind, placebo-controlled randomized clinical trials of daily oral TDF-based PrEP that included heterosexual women were conducted [9–15] (Table 1). All trials were carried out in settings with high HIV burden and study subjects received a comprehensive package of HIV prevention services including frequent HIV testing, risk reduction and adherence counselling, condoms, and treatment for sexually transmitted infections (STI). Participants received intensive adherence counselling to take study drug once per day, and multiple methods were used to measure adherence, including self-report, daily diaries, clinic-based counts of returned pills and bottles, and testing archived blood samples for tenofovir. Despite similarities in study design and analytic approach, the primary intent-to-treat efficacy results varied substantially across trial populations.

Table 1.

Double-Blind Placebo-Controlled Randomized Trials that Included HIV Uninfected Heterosexual Women to Assess the Efficacy of Daily Oral Tenofovir Disoproxil Fumarate (TDF)-Based Pre-Exposure Prophylaxis (PrEP) for HIV Prevention

Study Characteristics				Benefit of PrEP (95% CI)
Name	Study Population	Sample Size	Oral PrEP Agent	Plasma TDF in a Random Sample of Participants	Overall Efficacy	Female Subgroup Efficacy	Additional Analyses among Women
Partners PrEP Study Baeten et al. (9, 14, 15)	Heterosexual HIV-1 uninfected persons in HIV-1 serodiscordant relationships: Kenya, Uganda	4,747 serodiscordant couples (including 1,785 in which the HIV uninfected partner was female)	TDF-FTC	81%	75% (55, 87%)	66% (28, 84%)	Tenofovir > 40 ng/mL: 94% (−17, 100%) Age < 30 years: 72% (25, 90%) Partner viral load > 50,000 copies/mL: 72% (13, 91%)
			TDF	83%	67% (44, 81%)	71% (37, 87%)	Tenofovir > 40 ng/mL: 85% (−90, 99%) Age < 30 years: 77% (29, 92%) Partner viral load > 50,000 copies/mL: 84% (29, 96%)
TDF2 Thigpen et al. (11)	Heterosexual men and women: Botswana	1,219 (557 women)	TDF-FTC	79%	62% (22, 83%)	49% (−22, 81%)	With censoring after self-reported discontinuation of study medication: 75% (24, 94%)
Bangkok Tenofovir Study Choopanya et al. (13)	Male and female injection drug users: Thailand	2,413 (489 women)	TDF	67%	49% (10, 72%)	79% (17, 97%)
FEM-PrEP Van Damme et al. (12)	Heterosexual women: Kenya, Tanzania, and South Africa	2,120 women	TDF-FTC	24%	6% (−52, 41%)	NA
VOICE Marrazzo et al. (10)	Heterosexual women: South Africa, Uganda, Zimbabwe	3,019 women (an additional 2,010 women were assigned to tenofovir gel)	TDF-FTC	29%	−4% (−49, 27%)	NA
			TDF	30%	−49% (−129, 3%)	NA

Three of the five studies found that daily oral PrEP reduced the risk of HIV acquisition overall and in subgroup analyses of women. In the Partners PrEP Study, which included 1,785 Kenyan and Ugandan women with a mutually disclosed HIV-infected partner, PrEP efficacy among women was 66% and 71% for the two PrEP medications tested, and PrEP efficacy did not differ substantially between men and women [9]. In further analyses, the protective effect of PrEP was consistent in subgroups of women at high risk for HIV acquisition [10]. PrEP efficacy among women in the TDF2 study in Botswana was 49%, although the small sample size limited statistical precision [12]. Although women comprised only 20% of participants in the Bangkok Tenofovir Study (BTS), PrEP efficacy among this subgroup was 79% [13]. In contrast, two trials among African women, (FEM-PrEP, conducted among 2,120 women from Kenya, Tanzania, and South Africa and VOICE, conducted among 3,019 women from South Africa, Zimbabwe and Uganda), demonstrated no effect of daily oral PrEP on HIV acquisition [14, 15].

Data from all five trials consistently demonstrated that HIV acquisition occurred during periods of low or no adherence to PrEP. Having tenofovir detected in blood samples was associated with ≥85% protection from PrEP [11] and the frequency of tenofovir detection in each overall trial population strongly paralleled the HIV protection observed in each study. In the three trials that demonstrated a protective effect from PrEP, tenofovir was detected in 67–83% of samples from a random subset of participants [9, 12, 13], compared to 24–30% in the two trials with null results [14–16], leading to the conclusion that PrEP protects women from HIV infection when it is used.

Biological Factors Influencing PrEP Efficacy among Women

A number of biological factors have been hypothesized to influence the protective effect of PrEP in women. Foremost among these is the presence of adequate PrEP medication at the time of HIV exposure. Preventing HIV acquisition through sexual contact likely depends on sufficient adherence to achieve tenofovir levels in genital (or rectal) tissues that can prevent viral replication and dissemination. Men who have sex with men (MSM) and transgender women, for whom rectal exposure carries the greatest HIV risk, appear to benefit from near-complete HIV protection with blood levels reflecting as few as four doses of TDF-based PrEP per week [17]. MSM who used an event-driven, coitally-dependent PrEP regimen achieved high rectal concentrations of tenofovir and reduced HIV acquisition by 86% [18]. The body of evidence to define the level of tenofovir and number of doses required to confer this level to women is limited, particularly studies linking pharmacokinetics to in vivo pharmacodynamics. Available data suggest that more consistent dosing is required to achieve sufficient levels of tenofovir in vaginal tissue than rectal tissues [14, 19–21]; however, as demonstrated in the efficacy clinical trials of PrEP, women who were generally adherent to a daily PrEP regimen were strongly protected against HIV.

Additional hypotheses have questioned whether the benefits of PrEP may be compromised in younger women who are more susceptible to HIV because of immature genital mucosa, in women with sexually transmitted infections (STIs), in women who encounter a high viral inoculum (i.e., due to high viral concentrations or acute HIV infection in partners), and due to interactions with hormonal contraceptives [14, 22–24]. Physiological features, including a higher proportion of exposed cervico-vaginal epithelium tissues, and increased levels of pro-inflammatory cytokines in genital secretions and inflammatory immune cells in cervicovaginal fluid, may put younger women at higher risk of HIV acquisition [25]. On average, HIV-uninfected participants in the Partners PrEP Study, TDF2, and BTS were older than women in FEM-PrEP and VOICE [9, 14, 15]; however, the protective effect of tenofovir-based PrEP was 72–77% in a subgroup analysis of women <30 years old in the Partners PrEP Study [10]. The baseline prevalence of bacterial STIs was lower in the Partners PrEP Study, as compared to VOICE and FEM-PrEP [14, 15, 26], and differences in recurrent and undiagnosed STIs or vaginal washing and drying, may have heightened women’s susceptibility to HIV [27]. However, in the Partners PrEP Study the protective effect of PrEP was 67–71% in a subgroup analysis of couples diagnosed with an STI in the past three months, and 83% of all HIV-uninfected women in the study reported daily vaginal washing [10, 26].

HIV incidence among women in the Partners PrEP placebo arm was 2.8 per 100 person years, substantially lower than incidence rates seen in FEM-PrEP (5.0 per 100 person years) and VOICE (4.2–4.6 per 100 person years) [9, 14, 15]. One proposed explanation for this difference is that women in the Partners PrEP Study were primarily exposed to HIV by chronically infected men, who were potentially less infectious than acutely infected men [27]. While infectivity is a strong predictor of HIV transmission, the majority of infections in generalized HIV epidemics are transmitted from persons with chronic HIV [28, 29], and thus it is likely that the majority of transmissions in FEM-PrEP and VOICE were as well. The overall protective effect of PrEP was 76–78% among all HIV uninfected participants and 72–84% among women whose partner had a viral load ≥50,000 copies/mL in the Partners PrEP Study, providing evidence that the prevention benefit of PrEP was not attenuated with exposure to high HIV viral load [10]. Animal models have demonstrated that the protective effect of TDF-based PrEP does not diminish over time, regardless of the number of challenges, suggesting that there may not be a threshold effect of PrEP when taken with sufficient adherence [30, 31].

The high pregnancy incidence rate among women initiating oral contraceptives during FEM-PrEP initially suggested a potential interaction between oral contraceptives and PrEP [32, 33]. However, low adherence to oral contraceptives, especially among new users, is thought to be the driving factor behind this pregnancy incidence and women who adopted oral contraceptives at study enrollment were also less likely to adhere to study drug [16, 34]. TDF-based PrEP does not interact with oral, injectable or implantable contraception to reduce either the effectiveness of contraceptives to prevent unintended pregnancy nor the HIV prevention benefit of PrEP [33, 35]. Indeed, PrEP is one strategy that could mitigate concern regarding the potential increased risk for HIV acquisition among women using progestin-based injectable contraception [36].

Behavioral Factors Influencing PrEP Effectiveness among Women

Although challenging to accurately measure, motivation to prevent HIV acquisition is likely tied to self-perceived risk, which in turn influences adherence to HIV prevention strategies [37]. Despite inclusion criteria based on objective measures of HIV risk and the high observed HIV incidence among placebo arm participants [38], 50% of women enrolled in FEM-PrEP thought they had “no chance” of acquiring HIV in the next 12 weeks and seroconverters described underestimating their risk and rationalizing their risk behavior(s) [14, 37, 39]. Adherence was highest among older participants in BTS, VOICE, and the Partners PrEP Study [15, 40, 41]; younger participants in VOICE and FEM-PrEP were likely less experienced navigating personal risk and this may have influenced their HIV prevention decision-making [24]. In qualitative interviews, VOICE participants acknowledged that their trial participation was motivated by increased HIV risk from male partners with additional sexual partners, however women often had to compromise study drug adherence and keep their trial participation covert to maintain these relationships [42].

Across trials, personal assessment of high HIV risk, coupled with social and clinic-based support, facilitated greater self-efficacy to adhere to daily oral PrEP. HIV uninfected participants in the Partners PrEP Study had known exposure to HIV from their mutually-disclosed HIV infected study partner and both partners received adherence counselling during the trial [39]. PrEP provided a solution to the “discordance dilemma” by simultaneously preventing HIV acquisition and maintaining the partnership, especially prior to ART initiation by the HIV infected partner [43]. Low or no adherence to PrEP in the Partners PrEP Study was associated with no or infrequent sex with a study partner, suggesting that participants modified their PrEP use based on fluctuations in their sexual activity and perceived HIV risk [11, 41]. Participants in the BTS were self-identified injection drug users attending drug treatment centers who had potential for parenteral and sexual exposure and 93% of participants elected to attend daily study visits [40]. Although participants did receive compensation for each study visit, these characteristics also suggest a high motivation for risk reduction.

Despite PrEP being a discrete female-controlled prevention method, community-level stigma related to HIV infection impacted women’s adherence to study drug [44, 45]. Women in VOICE described the importance of taking their study drugs secretly in order to preserve their healthy, HIV uninfected image [45]. Women perceived stigma associated with HIV and encountered suspicion from community members about why an HIV uninfected person would take antiretrovirals [45]. Men expressed concerns about possible undisclosed HIV positive status and additional sexual partners when their female partners used PrEP. Some male partners felt threatened by women’s participation in research and exercising autonomy to access health care [42, 44, 46]. It was taxing for women to manage social relationships while participating in the VOICE study; these challenges contributed to women concealing study participation and missing PrEP doses [45, 47].

Features of clinical trials also influenced the behaviors of trial participants. Overall study retention in FEM-PrEP and VOICE was 82–91%, and quality clinical care, education, and modest financial reimbursement in settings with limited opportunity for income generation, motivated women to maintain their participation [9, 12–15, 42, 47–49]. However, retrospectively, participants in FEM-PrEP and VOICE expressed ambivalence about research and the importance of adhering to study medication, including reluctance to use investigational drugs with the potential for side effects and unknown levels of HIV protection [15, 42, 49]. Inaccurate self-reported adherence was common in the trials. Participants in FEM-PrEP cited perceived consequences, such as trial termination, negative reactions from study staff, and additional time needed to explain their non-adherence during study visits, as reasons for over-reporting adherence [42, 49]. Some VOICE participants believed that tenofovir testing would rectify inaccurate self-reported adherence, and poor adherence by some women could be overcome by high adherence from others [42].

The HIV Prevention Benefit of PrEP Requires Adherence

The conflicting results across trials regarding the benefit of PrEP for women have challenged the HIV prevention community. However, when analyzed collectively, there is a clear conclusion that daily oral TDF-based PrEP is protective for women, established through subgroup analyses, consistency across studies when adherence is evaluated, and bolstered by analogous data from men. Like any medication, adherence is required for PrEP to be efficacious. Pharmacokinetic studies suggest that consistent adherence is required to achieve sufficient concentrations of tenofovir in vaginal tissues and a substantial proportion of women across studies attained this level of high adherence. The lack of a protective effect observed in FEM-PrEP and VOICE can be attributed to overall low adherence to study medication and is not due to biological features unique to women [50, 51]. While adherence challenges observed across all trials have important implications for PrEP delivery to women, they should not detract from the overall conclusion that PrEP protects women from HIV acquisition when taken with sufficient adherence (Figure 1).

Figure 1.

Schematic depicting the totality of evidence for tenofovir-based oral pre-exposure prophylaxis (PrEP) to prevent HIV among women

Delivering PrEP to Women

The next steps for PrEP delivery to women include implementation within routine healthcare, in the context of a now-proven protective benefit from PrEP and without the incentives of clinical trials. Clinical trial data suggest that PrEP is tolerant of some missed doses, and additional research is needed to understand how many doses can be missed and still provide HIV protection for women, as well as whether that differs in the presence of cofactors influencing HIV susceptibility.

Integrating Time-Limited PrEP into Existing Reproductive Health Services

Integrating HIV risk assessment and PrEP dispensation into established sexual and reproductive health services that women access routinely, including HIV/STI testing and counselling, antenatal care, and contraceptive counselling is a natural strategy to maximize the impact of PrEP [24]. Delivery strategies for time-limited PrEP use during periods when a woman’s HIV risk is greatest – including new partnerships with men of unknown HIV status, with HIV infected male partners prior to ART initiation, during pregnancy and pregnancy attempts when condom use is reduced - are feasible, safe, and cost-effective [52–59]. Providers can use risk scoring tools to identify women with the highest risk for HIV acquisition using routinely collected clinical and demographic data [60, 61].

Facilitating Adherence in Public Health Settings

Individuals’ adherence patterns changed relatively little during the clinical trials: in general, those who initiated PrEP maintained their adherence, especially if they adhered through the end of the first month [11, 15]. Greater public health impact may come from prioritizing PrEP for those who will achieve this sustained high adherence, directing adherence support to the subset with adherence challenges, and assisting women to assess their risk and match PrEP use with their most vulnerable periods [58]. PrEP delivery to women must be coupled with realistic expectations of and mechanisms to facilitate adequate adherence, including personal risk assessment and social support [24, 62–64]. Community sensitization regarding antiretroviral medications for prevention, not just treatment, of HIV may create a context that is more receptive to PrEP use. When it is safe for a woman to share her desire for HIV prevention, her invitation to a male partner to participate in decision-making about PrEP may facilitate her high adherence.

Initial data suggest that adherence to and HIV protection from PrEP is higher in open label-studies when the HIV prevention benefit is well understood by users. Among MSM enrolled in the PROUD study, high self-reported adherence to daily oral TDF-based PrEP was substantiated by blood tenofovir levels and provided 86% protection from HIV [65]. Among HIV serodiscordant couples enrolled in the Partners Demonstration Project using PrEP as a “bridge” until the HIV infected partner sustains ART use, tenofovir was detected in 86% of samples tested and contributed to an estimated 96% reduction in HIV [66, 67].

Open-label studies also suggest that adherence to daily dosing may be preferred over intermittent or event-driven dosing, perhaps because it fits into daily routines and does not require anticipating sex [68, 69]. In ADAPT (HPTN 067), an open-label study of oral PrEP dosing frequency among young South African women, adherence was assessed through Wisepill monitoring. Women randomized to a daily dosing schedule had higher adherence overall and 75% of sexual acts covered by PrEP, as compared to 52–56% of sex acts among women randomized to less than daily or intermittent dosing to align with sexual activity [68]. Long-acting formulations of PrEP delivered as injectables or vaginal rings, including multi-purpose technologies that provide dual protection against HIV and unintended pregnancy, are currently being evaluated and may provide alternative strategies to daily oral PrEP in the future [70–73]. Analogous to contraception, for which multiple methods permit choices to accommodate individual women’s needs, multiple delivery mechanisms for PrEP may allow more women to achieve HIV protection [74].

Conclusion

Tenofovir-based oral PrEP is an effective HIV prevention strategy for heterosexual women. Significant public health impact from PrEP will require delivery strategies that integrate PrEP into existing health services and address the individual, community, and structural level factors that influence adherence. More than thirty years into the HIV epidemic, oral PrEP is the first intervention that women can control themselves and it offers highly efficacious prevention against HIV.

Key Points.

• Clinical trial data demonstrate that daily tenofovir-based oral pre-exposure prophylaxis (PrEP) prevents HIV acquisition among women when taken with sufficient adherence.

• Pharmacokinetic studies provide evidence that daily dosing of tenofovir-based oral PrEP reaches concentrations in vaginal tissues that are consistent with levels needed for HIV prevention.

• Evidence from clinical trials and emerging data from open-label studies demonstrate that women who are at risk of HIV and motivated to use PrEP can adhere sufficiently to the daily regimen and be protected against HIV.

• Innovative strategies to motivate women at risk to use daily PrEP and scalable adherence support strategies need to be identified and integrated into delivery models.