The Vaginal Microbiome and its Potential to Impact Efficacy of HIV Pre-exposure Prophylaxis for Women
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Purpose of Review
This review describes existing evidence addressing the potential modulation of pre-exposure prophylaxis (PrEP) products, specifically 1% tenofovir (TFV) gel and oral tenofovir-based PrEP, by vaginal dysbiosis and discusses future considerations for delivering novel, long-acting PrEP products to women at high risk for vaginal dysbiosis and HIV.
We describe results from analyses investigating the modification of PrEP efficacy by vaginal dysbiosis and studies of biological mechanisms that could render PrEP ineffective in the presence of specific microbiota. A secondary analysis from the CAPRISA-004 cohort demonstrated that there is no effect of the 1% TFV gel in the presence of non-Lactobacillus dominant microbiota. Another recent analysis comparing oral tenofovir-based PrEP efficacy among women with and without bacterial vaginosis in the Partners PrEP Study found that oral PrEP efficacy is not modified by bacterial vaginosis. Gardnerella vaginalis, commonly present in women with vaginal dysbiosis, can rapidly metabolize TFV particularly when it is locally applied and thereby prevent TFV integration into cells. Given that vaginal dysbiosis appears to modulate efficacy for 1% TFV gel but not for oral tenofovir-based PrEP, vaginal dysbiosis is potentially less consequential to HIV protection from TFV in the context of systemic drug delivery and high product adherence.
Vaginal dysbiosis may undermine the efficacy of 1% TFV gel to protect women from HIV but not the efficacy of oral PrEP. Ongoing development of novel ring, injectable, and film-based PrEP products should investigate whether vaginal dysbiosis can reduce efficacy of these products, even in the presence of high adherence.
KeywordsPre-exposure prophylaxis Efficacy HIV prevention Vaginal dysbiosis Bacterial vaginosis Women
HIV is a leading cause of morbidity and mortality among women globally, and biomedical HIV prevention products such as pre-exposure prophylaxis (PrEP) are being developed and scaled up to prevent HIV among women [1, 2, 3, 4, 5, 6]. Daily tenofovir-based oral PrEP is highly efficacious in reducing HIV incidence when adherence levels are high and it is currently being rolled out to populations with substantial HIV risk [7, 8]. Other PrEP products (e.g., dapivirine, tenofovir alafenamide (TAF), and maraviroc rings, biodegradable tenofovir (TFV) films, cabotegravir injections, TAF or maraviroc pills, TFV implants), are at various stages of the research and development process and are promising, longer-acting HIV prevention options [9•, 10•, 11•, 12]. However, it has recently been hypothesized that the efficacy of topically applied PrEP products may be moderated by vaginosis dysbiosis, a general term indicating that vaginal microbiota are sub-optimal [13••]. This is a significant public health concern given that bacterial vaginosis (a condition diagnosed using microscopy and/or clinical criteria) is common in settings where HIV is highly prevalent and has been shown to significantly influence risk of HIV acquisition through inflammatory pathways [14, 15, 16•, 17, 18•, 19••]. Specifically, vaginal dysbiosis can result in higher vaginal pH (due to lower concentrations of Lactobacillus species) and increased activated CCR5+ CD4+ T cells in vaginal mucosa and pro-inflammatory cytokines in cervical secretions [15, 16•, 18•, 19••, 20, 21•]. Specific bacteria (e.g., Gardnerella vaginalis, Prevotella, Atopobium) and/or microbial diversity may play a significant role in increased HIV risk, with four-fold increases in HIV risk observed among women with non-Lactobacillus dominant genital bacterial communities compared with those with less diverse microbiota [18•, 21•]. These women need PrEP products that will work effectively in an environment of vaginal dysbiosis [18•, 21•].
Results from oral PrEP trials have demonstrated that product adherence is an important moderator of PrEP efficacy [22•, 23•, 24, 25, 26]. To maximize the impact of PrEP in preventing HIV acquisition among women, PrEP research and delivery programs are developing strategies to improve product adherence. An additional parallel objective is to thoroughly understand whether vaginal microbial communities can impact PrEP efficacy even when product adherence is high. Unanswered questions remain about the biological mechanisms of the potential interaction between vaginal dysbiosis and PrEP efficacy in preventing HIV acquisition and whether this relationship varies by PrEP delivery mechanisms (i.e., oral, topical) and product formulations (i.e., TFV-, dapivirine-, or cabotegravir-based). This article summarizes the existing data from two analyses on the interaction between the vaginal microbiome and estimated PrEP efficacy, provides commentary about hypothesized relationships, and suggests directions for future PrEP development and implementation research in conjunction with vaginal microbiome investigations.
Text of Review
Potential for Vaginal Dysbiosis to Modulate Efficacy of HIV Prevention Products
The CAPRISA-004 randomized controlled trial demonstrated proof-of-concept that topically applied 1% TFV gel was efficacious in preventing HIV among a sample of 889 HIV-uninfected women in South Africa . The overall gel efficacy was 39% (95% CI: 6–60%) in the sample and 54% (95% CI: 4–80%) among participants with high adherence to the gel BAT24 dosing regimen (defined as one dose within 12 h before sex, one dose as soon as possible within 12 h after sex, and no more than two doses in 24 h) . These findings were not replicated in the FACTS 001 or MTN-003/VOICE randomized trials, which also included samples of HIV-uninfected women in sub-Saharan Africa but were undermined by very low product use of 1% TFV gel [23•, 28•]. Trials of oral tenofovir-based PrEP have found that it is highly efficacious in preventing HIV infection, but oral PrEP efficacy estimates also vary widely by overall adherence to the study product [7, 23•, 24]. The Partners PrEP Study found that oral tenofovir-based PrEP (either as co-formulated emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or single agent TDF) had 66% efficacy for FTC/TDF and 71% efficacy for TDF among women . Adherence to the daily pills was high in the Partners PrEP Study (approximately 82% of plasma samples from randomly selected participants had detectable TFV levels), which correlated with the high efficacy of oral PrEP seen in this trial . Two other studies of oral PrEP (VOICE, FEM-PrEP) conducted among women with lower adherence levels did not find a significant protective PrEP effect [7, 23•, 24].
Summary of analyses examining the effect of vaginal microbiota on PrEP efficacy in HIV-uninfected women
Measurement of vaginal dysbiosis
Overall PrEP efficacy
Efficacy among women with vaginal dysbiosis
1% TFV gel
60% of the sample had > 50% gel adherence, measured by monthly empty gel applicator returns
Mass spectrometry to identify bacterial proteins at baseline
Classified women as Lactobacillus-abundant or non-Lactobacillus-abundant
18% (95% CI: −77 to 63%) among women with non-Lactobacillus-abundant microbiota
61% (95% CI: 11–84%) among women with Lactobacillus-abundant microbiota
Partners PrEP study 
Oral FTC/TDF or TDF alone
82% adherence, measured by detection of tenofovir in plasma in a random sample of participants
Gram stain microscopy to characterize women with BV (Nugent score 7–10), intermediate microbiota (score 4–6), and normal microbiota (score 0–3) at baseline and annual follow-up visits
(95% CI: 45.5–84.0%)
73% (95% CI: 6–92%) efficacy for women with BV
63% (95% CI: −67 to 92%) efficacy for women with intermediate microbiota
77% (95% CI: 43–90%) efficacy for women with normal microbiota
A secondary analysis with 688 women from the CAPRISA-004 study used mass spectrometry-based proteomics to classify women as having either Lactobacillus dominant or non-Lactobacillus dominant vaginal microbiota at baseline [13••]. In women with non-Lactobacillus dominant microbiota at baseline, of which Gardnerella vaginalis was the most common, the 1% TFV gel-based PrEP was not efficacious (efficacy 18%; 95% CI – 77 to 63%) [13••]. This is in contrast to women with Lactobacillus dominant microbiota at baseline, where efficacy was 61% (95% CI 11–84%). Approximately 60% of study participants had > 50% gel adherence, as was determined by empty applicator returns, and there were no differences in adherence seen by dominant vaginal microbiota group [13••]. When restricting the sample to women with > 50% adherence (n = 416), again the gel was efficacious in preventing HIV for women with Lactobacillus dominant microbiota (efficacy 78%; 95% CI 29–95%) but did not significantly reduce HIV incidence in the presence of non-Lactobacillus dominated microbiota (efficacy 26%; 95% CI −98 to 73%) [13••].
A secondary analysis from the Partners PrEP Study, a randomized placebo-controlled PrEP efficacy trial, determined whether vaginal microbiota modified the efficacy of oral tenofovir-based PrEP (either FTC/TDF or single agent TDF) [31••]. For this analysis, women’s follow-up time was classified into subgroups by bacterial vaginosis status using Nugent scoring from microscopy at baseline and annual study visits [31••]. There were no differences in oral PrEP efficacy between periods when women had normal microbiota (Nugent score 0–3), intermediate microbiota (score 4–6), and bacterial vaginosis (score 7–10). Similarly, oral PrEP efficacy was not reduced during periods when women had Gardnerella vaginalis/Bacteroides morphotypes relative to those with Lactobacillus morphotypes (interaction p = 0.9) [31••]. These results suggest that vaginal microbiota are unlikely to moderate the efficacy of oral PrEP, which is systemically distributed and has greater TFV detection in plasma than topically applied TFV gel [31••, 32].
Hypothesized Mechanisms for Association between Vaginal Dysbiosis and PrEP Efficacy
Pharmacokinetic data have identified key differences between the active study drugs delivered by oral versus topical products which could also help explain associations between vaginal dysbiosis and PrEP efficacy. TFV, contained in 1% TFV gel, is a nucleoside reverse transcriptase that can be measured in plasma and cervicovaginal fluid. When administered as a gel, TFV concentrations in plasma are low and concentrations in fluid reflect levels of drug use . Among women in the CAPRISA-004 trial, few HIV seroconverters (14.7%) had TFV concentrations > 100 ng/mL in cervicovaginal fluid, a significantly lower number than a comparable subgroup of non-seroconverters (32.8%, p = 0.037 for the comparison with seroconverters) [36•]. Thus, event-driven TFV gel dosing achieved only limited systemic TFV exposure, but levels of TFV near the application site are correlated with HIV protection [36•, 37]. With topical gel, the presence of Gardnerella vaginalis could render the gel ineffective, particularly because there are low levels of TFV in plasma to enact systemic protection after locally applied TFV has been depleted.
The molecular structure of TFV, a purine analogue, also renders it particularly vulnerable to rapid metabolism by Gardnerella vaginalis and other vaginal microbiota because it requires intracellular phosphorylation to become activated TFV-DP [13••, 35]. Cell cultures that combined TFV, Jurkat cells (HIV T lymphocyte target cells), and Gardnerella vaginalis (along with Lactobacillus spp.) showed that Gardnerella vaginalis is able to metabolize TFV faster than it can be converted to its TFV-DP active form by target cells [13••]. While Prevotella and Mobiluncus species have also been shown to metabolize TFV, they likely cleave it into an inactive adenine metabolite at a slower rate than Gardnerella vaginalis [13••].
With current formulations of oral PrEP, TFV is delivered as a prodrug (TDF) to improve its bioavailability in the gastrointestinal tract . TFV can be detected in plasma for about one week after oral dosing, indicating longer-term systemic availability of TFV than has been seen for gel-based PrEP but lower concentrations in vaginal tissue than gel-based dosing [32, 38]. Pharmacokinetic studies of oral PrEP have shown that TFV-DP has more difficulty reaching protective concentrations in the female genital tract than in colorectal tissue, and higher levels of adherence (about 6–7 doses/week) are thought to be required to provide effective HIV prevention for people having vaginal exposure to HIV [38, 39•]. Results from the Partners PrEP Study, VOICE, and FEM-PrEP have shown that oral FTC/TDF and TDF are efficacious with high adherence levels, but oral PrEP is not protective for women with lower adherence to the dosing regimen [7, 23•, 24]. Therefore, daily pill dosing may be unforgiving to missed doses but vaginal microbiota are unlikely to modulate oral PrEP efficacy by metabolizing TFV in the female genital tissue.
Implications for Future PrEP Research and Implementation Programs
Additional research is currently underway to develop, test, and deliver new PrEP products at scale, including vaginal rings, long-acting films and injectables, biodegradable implants, and new oral pill formulations. Studies of these products are well positioned to consider whether vaginal dysbiosis could impact PrEP efficacy even in the context of high product adherence, as these different active drugs and delivery methods will likely have differential vulnerability to modulation by vaginal dysbiosis. For example, the dapivirine intravaginal ring contains 25 mg of dapivirine (released over four weeks) that could have different susceptibility to rapid Gardnerella vaginalis metabolism than TFV [9•, 10•]. However, dapivirine concentrations decrease rapidly in vaginal tissue and cervicovaginal fluid after ring removal, and the drug may have a shorter half-life in tissue than is seen with gel-based TFV [35, 40•]. If dapivirine is metabolized by Gardnerella vaginalis, this may impact its protective benefits against HIV acquisition. Cabotegravir injections represent another promising PrEP approach and can deliver sustained drug concentrations over a 4–8-week period . This PrEP product also provides systemic drug delivery and its efficacy may be less affected by local Gardnerella vaginalis metabolism, as was seen with oral PrEP. Further investigation is warranted.
In addition, unanswered questions remain about whether extended-release TFV-based film products in development (to be topically applied) will be susceptible to reduced efficacy by Gardnerella vaginalis metabolism. Studies of the TFV film will need to assess whether the film delivery mechanism is capable of altering innate HIV immunity through changes to the mucin expression and the quantity of high mannose glycoproteins in the vaginal environment, as has also been suggested for the 1% TFV gel . Additionally, the TFV gel was shown to alter local microbial communities in the vagina, making women using these products more susceptible to bacterial dysbiosis and HIV acquisition through inflammatory pathways, and it will be important to explore similar associations for other topically applied HIV prevention products [15, 18•, 42].
Future studies exploring the relationship between vaginal dysbiosis and PrEP efficacy among women will need to consider several factors that are likely to influence findings, including characteristics of the PrEP drug, adherence to PrEP, and measurement of confounding variables. As has been discussed, PrEP drug type (i.e., TFV, FTC, dapivirine, cabotegravir), drug delivery mechanism (i.e., oral, topical, injectable), active drug concentrations achieved in plasma and cervicovaginal tissue, half-life of drug in target cells, and adherence to the drug product all have the potential to impact PrEP availability in target tissue and drug metabolism by specific vaginal bacteria. In addition, co-infections such as herpes simplex virus-2 (HSV-2) and chlamydia can increase risk of both vaginal dysbiosis and HIV infection and obscure the true relationship between vaginal dysbiosis and PrEP efficacy [16•]. Additional strong confounders in the association between vaginal dysbiosis and PrEP efficacy include condomless sex, STI treatment, and use of products for vaginal washing. Observational studies must continue to collect data on these variables in order to accurately interpret results on the association between vaginal dysbiosis and PrEP efficacy.
This review has several limitations which help to highlight directions for future research on the links between vaginal microbiota and PrEP efficacy. Given that this is an emerging research field, only two studies have been conducted to date examining the impact of vaginal dysbiosis on 1% TFV gel and oral PrEP efficacy, and it is difficult to generalize their findings to other study populations and PrEP products. These two studies collected microbiome data infrequently, and only at the baseline visit for the CAPRISA-004 study [13••, 31••]. Studies with more frequent vaginal swab collection could prospectively measure associations between PrEP efficacy and frequently fluctuating microbial communities, while also eliminating concerns about temporality of the relationship between microbiota and HIV incidence. Also, studies that incorporate sensitive measurement techniques such as broad range 16-s rRNA gene PCR with pyrosequencing and taxon-directed quantitative PCR probes could quantify the abundance of bacterial species and help to distinguish whether specific bacteria or the overall diversity of bacterial communities are associated with reduced PrEP efficacy. Finally, biomarker data collected from future topical PrEP trials would be able to add to this body of research about the potential mechanism of the association between vaginal dysbiosis and PrEP efficacy.
For PrEP to attain its greatest population impact, it is paramount to optimize adherence. An important priority for the research community is to continue work to develop and implement long-term PrEP methods (i.e., ring, film, and injectable products) that ease the burden of daily adherence and can effectively deliver PrEP drugs to target tissue in any vaginal microbiome environment [43, 44]. An additional priority is to continue developing innovative implementation strategies to improve daily oral PrEP adherence among women and frame PrEP as a tool to support women’s lives [4, 45]. Oral PrEP remains a critical biomedical HIV prevention strategy for women with symptomatic or asymptomatic bacterial vaginosis, who are protected from HIV acquisition when adherence to the daily pills is high, and there remains a need to improve oral PrEP access for women regardless of their bacterial vaginosis status [31••].
Recent evidence suggests that vaginal dysbiosis can reduce the efficacy of TFV-based gel PrEP formulations, through altered drug metabolism. However, oral FTC/TDF-based PrEP is not impacted by bacterial vaginosis, with its systemic drug delivery and high drug concentrations in plasma that are not susceptible to metabolism by vaginal microbiota. A priority for research on novel topical biomedical HIV prevention strategies is to explore how vaginal microbiota interact with PrEP products to potentially alter the availability of active drug and product efficacy. For the scale-up of oral PrEP, optimizing delivery approaches that maximize adherence remains critical to achieve population level reductions in HIV incidence.
We are grateful for the dedication of the thousands of women who have participated in PrEP clinical trials and open-label demonstration projects around the world.
Compliance with Ethical Standards
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
Conflict of Interest
The authors declare that they have no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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