Recent advances and new challenges in cisgender women’s gynaecological and obstetric health in the context of HIV

Abstract

Although rates of HIV have declined globally over the past ten years, UNAIDS estimates 1.7 million new infections occurred in 2019, with cisgender women and girls accounting for 48%.¹ AIDS-related illnesses are the leading global cause of mortality in cisgender women aged 15-49, and in many sub-Saharan Africa countries, young women face substantially higher HIV risk than their male counterparts. Drivers of this increased risk include sexual and reproductive health characteristics unique to cisgender women. This review discusses the role of sexually transmitted infections, contraception and pregnancy in HIV risk, and biomedical HIV prevention technologies available and in development.

INTRODUCTION

Worldwide the number of new HIV infections has decreased in recent years, with a 23% decline in the number of annual HIV infections between 2010 and 2019; however, progress towards prevention has been significantly under target with over three times the number of HIV infections occurring in 2019 than the 2020 UNAIDS goal of 500,000.² While HIV among women and girls has been decreasing at a faster rate globally than among men and boys, the epidemic varies dramatically by region. In Africa, most HIV infections occur in women and adolescent girls, and in eastern and southern Africa, the epidemic is disproportionately concentrated in adolescent girls and young women (aged 15-24) with 30% of new HIV infections occurring in this group which comprises only 10% of the total population. The reasons for increased HIV risk in women in these regions are multi-factorial and include behavioural, structural, and biological risk factors. In this review we aim to summarize recent advances in our understanding of ways that sexually transmitted infections (STIs), vaginal microbiota, contraception, and pregnancy render cisgender women (cis women) susceptible to HIV and progress toward effective biomedical prevention.

SEXUALLY TRANSMITTED INFECTIONS AND NON-OPTIMAL VAGINAL MICROBIOTA

Overview

STIs³, non-optimal vaginal microbiota (otherwise known as bacterial vaginosis, BV)⁴, and vulvovaginal candidiasis have likely played a major role in the HIV pandemic⁵. These infections and conditions are highly prevalent among women residing in regions most affected by HIV^6,7, and cause increased susceptibility to other STIs including HIV, as well as increased risk of secondary and vertical HIV transmission.^5,8–12

Global burden of STIs, BV and candidiasis

The global prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae , Trichomonas vaginalis, and Treponema pallidum (syphilis) among women is estimated to be 3.8%, 0.9%, 5.3% and 0.5%, respectively.⁷ Prevalence is highest in Africa, particularly in South Africa, the epicenter of the HIV pandemic, chlamydia prevalence is estimated at 11.2-17.8%, gonorrhea prevalence at 1.9-10.1% and trichomoniasis prevalence at 4.6-19.7% among 15-49 year old women.⁷ The global prevalence of herpes simplex virus type 2 (HSV-2) among women was estimated to be 11% overall and 14.8% among women in 2012, with the highest prevalence again observed in Africa (32%).¹³ While being common worldwide, BV prevalence is also high in Africa, ranging between 18.5-65.9% among women residing in East and Southern Africa.⁶ Although not sexually transmitted, recurrent vulvovaginal candidiasis affects approximately 7% of women globally.¹⁴

Risk of HIV associated with STIs, BV and candidiasis

Modelling studies in African women suggest that the overall population HIV risk attributable to STIs, BV, and candidiasis is over 50%, with HSV-2 being the most influential followed by BV.^5,10 A systematic review and meta-analysis found that prevalent and incident HSV-2 were associated with 2.7-fold and 4.7-fold increased risk of HIV acquisition, respectively.¹⁵ BV, as diagnosed by Nugent score, increases HIV risk by 70%¹⁶, however certain non-optimal vaginal microbial communities identified using molecular sequencing have been associated with >4.4-fold increased risk of HIV acquisition.¹¹ A systematic review including 30 longitudinal studies found that chlamydia, gonorrhea and trichomoniasis infections were associated with increased risk of HIV acquisition in women, with 2.8-, 2.6- and 1.5-fold increased risk, respectively.^17,18

Potential mechanisms of increased HIV risk

The possible mechanisms underlying this heightened risk of HIV associated with STIs, BV and candidiasis include an increase in inflammatory cytokines, influx of HIV target cells, and reduced epithelial barrier integrity in the female genital tract (FGT).^19–22 Many studies have shown that STIs, BV and candidiasis are associated with increases in concentrations of HIV-associated genital cytokines.^20,23–25 Inflammatory cytokines and chemokines create an environment conducive to the establishment of productive HIV infection by recruiting and activating HIV target cells¹⁹ and disrupting the epithelial barrier, allowing HIV to access target cells present in the submucosa.²¹ Another mechanism for the increased risk of HIV associated with BV is likely the loss of Lactobacillus spp., leading to reductions in lactic acid, hydrogen peroxide and other antimicrobial proteins that potently inhibit HIV and other STIs, as well as concomitant inflammation associated with non-Lactobacillus dominated communities.^11,26,27

However, data on the effects of STIs, BV and candidiasis on host mechanistic factors (e.g., inflammatory profiles, antimicrobial peptides, immune cell populations etc.) that may impact HIV acquisition are inconsistent.^17,24,28 It is likely that multiple, complex factors work together to influence HIV acquisition risk, in variable ways. For example, recent work suggests that host genetic factors may modify the effect of BV on HIV susceptibility²⁹ and that the risk of HIV associated with BV (and possibly STIs and candidiasis) is not equivalent in all women and warrants further investigation. Similarly, BV has been associated with marked increases in genital inflammatory cytokines, with concurrent chemokine downregulation .^24,28 As both inflammatory cytokines and chemokines have been associated with increased HIV risk^20,23,25, the impact of inflammatory cytokine upregulation, with concomitant chemokine downregulation, on HIV infection is unknown. This response may be a tolerance mechanism developed by a host that has co-evolved with specific microbial communities, however further studies are needed to fully understand the mechanisms and implications.

Approaches to reduce risk

Despite clear evidence that STIs, BV, and candidiasis increase risk of HIV acquisition, previous trials aimed at improving STI management as a mechanism to reduce HIV incidence yielded conflicting findings. While enhanced STI syndromic management (treatment according to clinical signs or symptoms) reduced HIV incidence by ~42% in a trial conducted in Tanzania³⁰, this was not recapitulated in a subsequent trial in Uganda.³¹ Other studies evaluating the impact of population-wide STI treatment and HSV-2 suppressive therapy also found no significant change in HIV acquisition.^32–35 However, each of these interventions had limitations that likely impacted the outcomes, and these trials have highlighted gaps in our current diagnostic, preventative and therapeutic strategies for these infections and conditions. For example, syndromic management as an STI control strategy is largely ineffective because the majority of STIs are asymptomatic; however, asymptomatic infections are associated with equivalent levels of FGT inflammation as symptomatic infections.²³ Currently, syndromic management is the strategy for STI, BV and candidiasis management in resource-limited settings, due to the high cost and lack of equipment for diagnostic testing, including in regions of high HIV prevalence.

On the horizon

A major gap in this area is the lack of accurate, inexpensive, and equipment free point-of-care (POC) diagnostics for most of these conditions. Although near POC nucleic acid amplification tests (NAATs) exist that are highly accurate, these tests are expensive and the cost effectiveness and feasibility of implementation in resource-limited settings have yet to be evaluated. On the horizon are less expensive NAATs with battery-operated equipment and shorter processing times, as well as novel strategies to improve the sensitivity of antigen-detecting rapid POC diagnostics.^36–38 Another strategy to optimize case identification and reduce the number of women requiring expensive etiological testing is to develop risk-scoring tools. Recently, it was shown that prescreening of women to determine those at risk of STIs prior to NAAT testing using risk-scoring (based on whether women were pregnant, had transactional sex, new sexual partners, or relevant clinical signs observed by a physician) was a feasible and sensitive approach.³⁹ Another more objective approach that we and others are developing is the measurement of inflammatory markers using an inexpensive rapid POC test for prescreening.⁴⁰

Novel BV treatment options are also an exciting area of ongoing work. Current BV treatment recommendations are limited as most women with symptomatic BV experience BV recurrence within 6 months of treatment. Treatment of asymptomatic BV, which is rarely diagnosed, is not recommended, even though women experiencing asymptomatic BV often have high levels of FGT inflammation, which has been linked to HIV risk.^11,41 The development of biotherapeutics and bioactives for adjunctive BV treatment is a promising and active field of research at present.⁴² However, there are still major gaps in our understanding of the FGT microbiome, particularly in populations at high risk of HIV infection, and continued work in this area is critical to inform the development of novel therapeutics and preventatives. Although suppressive therapy for HSV-2 may reduce genital ulceration, HSV-2 may induce a persistent state of susceptibility to HIV infection due to chronic but subclinical inflammation.⁴³ For bacterial STIs, antibiotic therapy is effective, however increases in antibiotic resistance, highlights the need for continued drug discovery. Multidrug-resistant N. gonorrhoeae has emerged in recent years, as well as some reports of drug resistant T. pallidum and Mycoplasma genitalium.⁴⁴

A major gap is the lack of effective vaccines against common STIs that would mitigate many of these concerns. There are however candidates for N. gonorrhoeae and C. trachomatis vaccines in preclinical development and a C. trachomatis vaccine is in phase I clinical trial.⁴⁵ Prophylactic and therapeutic HSV-2 vaccine candidates are currently in phase I and/or II trials.⁴⁶

CONTRACEPTION

Overview

In many countries with high prevalence of STIs, BV, and HIV, there are also high rates of unintended pregnancy, low levels of contraceptive use, and high unmet need for contraception.^47,48 Except for condoms, no contraceptive methods protect against HIV and STIs.⁴⁹ The question of whether there is an association between the use of hormonal contraception, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM) and increased risk of HIV acquisition in women has been debated for more than 30 years ^50,51,52

Potential mechanisms of increased HIV risk

Endogenous and exogenous steroid hormones (estrogens and progestogens) affect FGT biology in ways that may protect against or increase susceptibility to HIV acquisition, respectively. Briefly, progestin-dominant states are associated with epithelial barrier thinning, increased recruitment of HIV target cells, increased cervical mucus thickness and increased Simian Immunodeficiency Virus (SIV) acquisition in non-human primates.^53,54 On the contrary, estrogens are associated with epithelial cell proliferation, decreased cervical mucus thickness and Lactobacillus-dominated microbial communities which have beneficial antimicrobial effects as described previously and protection against SIV.^55,27 The copper IUD, while non-hormonal, has also been shown to affect FGT biology and is associated with increased inflammation, vaginal microbiota diversity and HIV target cells.^56–59

Findings from the ECHO Trial

The uncertainty surrounding the possible association between DMPA-IM and HIV led to the execution of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. ECHO was a randomised, multinational, open-label trial comparing HIV incidence among 7829 African women randomised to DMPA-IM, a copper IUD and a levonorgestrel implant. Women aged 16-35 years were enrolled from 12 sites in four African countries and followed for 12-18 months from 2015 to 2018.⁵² The trial was statistically powered to detect ≥50% difference in HIV acquisition between the randomized arms, and no statistically significant differences were found when comparing DMPA-IM versus copper IUD, DMPA-IM versus LNG implant, and copper IUD versus LNG implant.⁵² Following a review of these and other related data, the World Health Organization (WHO) concluded that all three methods are safe to use by women with substantial risk for HIV.⁶⁰ HIV incidence among women in this study was high (3.81 per 100-women years [95% CI 3.45-4.21], as was STI prevalence at baseline and study exit (chlamydia 18% and 15% respectively; gonorrhea 5% and 5%, respectively; HSV-2 baseline prevalence 38%).^52,61,60 Although there has been some controversy in the field surrounding this decision, the most recent systematic review on hormonal contraception and HIV acquisition among women supports this conclusion.⁶² Nonetheless, as described previously, mechanistic studies suggest that certain contraceptives impact FGT biology in ways that are likely relevant to sexual and reproductive health, although possibly of insufficient magnitude and/or duration to impact HIV acquisition.^56,63,64 Continued research to understand these biologic effects are important for the development of novel contraceptives and multipurpose prevention products (MPTs) that concurrently protect from pregnancy, STIs and HIV.

Approaches for providing contraception to women at risk of HIV and STIs

While WHO guidelines recommend that women at high risk of HIV can use all contraceptive methods without restriction, it also recommends a renewed emphasis on integrating HIV and STI services within family planning services, including HIV testing (and self-testing) for women and their partners, diagnostic STI management, and pre-exposure prophylaxis (PrEP).⁶⁰ In settings of high HIV/STI risk, women should be encouraged to use condoms independent of their contraceptive choice until a wider range of MPTs are available. Moreover, guidance on contraception and HIV acquisition should be incorporated into country guidelines.

On the horizon

The need for novel MPTs is becoming widely recognized.⁶⁵ While male and female condoms are the only dual protection methods currently available⁶⁶, over 20 MPTs are in development designed to protect women’s reproductive health within indications for pregnancy, BV, chlamydia, gonorrhoeae, human papillomavirus, HSV-2, Zika virus, hepatitis C, and other pathogens .^67,68At the same time innovative service delivery models that successfully integrate HIV and STI services within family planning settings should be brought to scale and evaluated.

PREGNANCY

Overview

HIV risk is elevated during pregnancy and postpartum^69–71 and women living in settings with concurrent high HIV and fertility rates spend 15-20% of their lives pregnant and postpartum,⁷² a substantial period of time. HIV incidence is likely increased due to biological and behavioral changes that result from pregnancy but may be prevented with the use of PrEP and other modalities. Here, we discuss the epidemiology of HIV during pregnancy, potential mechanisms that increase HIV susceptibility during pregnancy, and interventions to prevent HIV acquisition during pregnancy.

Risk of HIV associated with pregnancy

Studies of the risk of HIV acquisition during pregnancy and postpartum have revealed conflicting results⁷⁰ and are challenging to conduct because they are inherently observational, therefore cannot account for HIV-associated factors that differ between women who become pregnant and those who do not (e.g., condom use, sexual frequency). A 2014 meta-analysis of 19 cohort studies estimated an HIV incidence of 4.7 per 100 person-years during pregnancy and 2.9 per 100 person-years postpartum⁷⁰, but concluded that HIV incidence was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6). However, using sophisticated statistical techniques to account for behavioral differences between pregnant and non-pregnant women, a 2018 per coital act analysis estimated HIV transmission probabilities associated with each condomless sex act in early (2.2/1000 sex acts), late (3.0/1000 sex acts), and postpartum periods (4.2/1000 sex acts) and concluded that HIV risk is 3-4-fold higher in late pregnancy and postpartum relative to non-pregnant times, a statistically significant finding.⁷¹

Potential mechanisms of increased HIV risk

Elevations in HIV risk during pregnancy and postpartum are likely due to biologic and behavioral changes. Behavioral changes that often result in increased exposure to HIV include decreases in condom use, the introduction of new sexual partners for men, and the re-introduction of sex between the index couple following delivery.^71,73 While these behavioral changes are well recognized and their association with increased HIV risk is well established, biologic mechanisms by which pregnancy increases HIV susceptibility are only hypothesized and require further research.

Biologic changes induced by pregnancy and carried into the postpartum period that may increase susceptibility include fluctuations in immune function, reproductive hormones, and vaginal microbiota. During pregnancy, there is a steady increase in progesterone and estradiol levels to support implantation and maintenance of the fetus.⁷⁴ Following delivery, progesterone falls to pre-pregnancy levels within 3-5 days after delivery.^75,76 As described previously, both hormones have been implicated in alterations in immunity and mediating increased and decreased risk for HIV infection. In late pregnancy, inflammatory cytokine levels increase and are thought to be important for induction of labor. This inflammation is not only detectable in maternal plasma and amniotic fluid, but elevations in vaginal IL 1α/β and IL-6 increase as pregnancy ensues.⁷⁷ High levels of these cytokines are associated with increased risk for HIV infection in non-pregnant women²⁰ and could potentially be related to increased risk for HIV in late pregnancy.

Vaginal microbiota are generally characterized as being dominated by stable Lactobacillus-dominated communities during pregnancy, however, few studies have included women at high risk for HIV acquisition.⁷⁸. Shifts in vaginal microbiota in late pregnancy and postpartum could theoretically render a woman more susceptible to HIV infection. However, the biological mechanisms underlying increased susceptibility to HIV during pregnancy or postpartum are largely unknown.

Approaches to reduce risk

WHO guidelines and numerous countries recommend daily oral PrEP (see Biomedical Prevention below) during pregnancy in conjunction with other prevention interventions (e.g. condom use, frequent HIV testing) when women have substantial risk for HIV.⁷⁹ In Kenya, PrEP is available through maternal and child health programs and a recent implementation science evaluation demonstrated 22% uptake and 38% continuation rates in the general population of women accessing prenatal care.⁸⁰ Although most epidemiologic data used to estimate HIV incidence during pregnancy were collected in women not using PrEP, it has been shown that the use of tenofovir disoproxil fumarate (TDF)-based drugs during pregnancy is relatively safe and effective against HIV infections.^81,82 In a systematic review of TDF-based regimens in pregnancy in 2017, either as HIV treatment or prevention, there were no significant differences in stillbirth/pregnancy loss, preterm delivery less than 37 weeks, low birth weight, infant or maternal mortality.⁸¹ Since then, additional studies have continued to show that use of TDF PrEP is safe during pregnancy and breastfeeding. Additional studies on safety, as well as the impact of reduced circulating concentration of antiretrovirals during pregnancy, are ongoing to complement this body of evidence.⁸²

In addition to the use of PrEP in pregnancy and postpartum, a multitude of other interventions could potentially decrease HIV risk during this period. STI rates are high during pregnancy,⁸³ and, as previously described, are associated with increased HIV transmission.¹⁰ Therefore, integration of sexual and reproductive health services, as well as targeted STI and BV testing and treatment, instead of syndromic management, could be successful interventions to alleviate the risk of transmissions during pregnancy.

In HIV serodiscordant heterosexual couples attempting pregnancy, safer conception packages which are effective in reducing risk of sexual HIV transmission between partners must be discussed in the preconception period. While lifelong antiretroviral therapy (ART) is a priority and dramatically prevents HIV transmission when viral loads are undetectable, other prevention options include PrEP use by the partner who is not living with HIV, tracking fertility indicators and limiting condomless sex to days with peak fertility, vaginal self-insemination if the woman is the partner living with HIV, male circumcision, sperm washing if the man is the partner living with HIV, and fertility care for couples who experience sub- or infertility.

BIOMEDICAL PREVENTION

Important advances have been made over the past decade which expand biomedical HIV prevention options for women, and a robust pipeline of products in development suggest more options are on the horizon.

Treatment as prevention

Landmark findings from two clinical trials, and subsequent observational studies, found no confirmed cases of HIV transmission among heterosexual couples when the partner living with HIV was virally suppressed, suggesting an HIV transmission risk estimate of 0.00 (0.00 – 0.07) per 100 years.^84–86 While this is the most effective biomedical intervention available, achieving widespread and sustained viral suppression among people living with HIV presents significant challenges. Since 2016, the WHO has recommended lifelong ART for all people living with HIV with initiation as soon as possible after diagnosis. However, at the end of 2019, among an estimated 38 million people living with HIV, 68% of adults were receiving ART and 59% had achieved viral suppression.⁸⁷ To improve these metrics, a continued comprehensive HIV response, which successfully identifies and treats HIV infected individuals and prevents transmission to their partners across the lifespan, is required. Data suggest that most HIV transmission occurs when the transmitting partner is unaware of their HIV status, highlighting the necessity of widespread access to HIV testing programs, normalizing HIV testing, and immediate linkage to care.⁸⁷ Once in care, maintenance of viral suppression and prevention of transmission to infected partners requires a comprehensive approach, including viral load and drug resistance monitoring, disclosure and adherence support, and safer conception options for reproductive-aged couples. While the UNAIDS 2020 90-90-90 targets were not fully achieved in all countries, significant progress has been made at all steps in the HIV testing and treatment cascade, and continued efforts to meet these targets will assure that HIV treatment for infected individuals contributes substantially to HIV prevention efforts.⁸⁸

Pre-exposure prophylaxis

Use of antiretrovirals as PrEP by people with substantial risk of HIV is a highly effective prevention tool for women and men. Oral tenofovir/emtricitabine (TDF/FTC) is approved by numerous regulatory authorities for HIV prevention and dapivirine (DPV) delivered via an intravaginal ring (IVR) recently received a positive opinion by the European Medicines Agency (EMA).^89–91 Notably, the WHO 2017 essential medicines list also includes TDF/lamivudine (3TC) as a TDF/FTC alternative, based on data from the HIV treatment literature demonstrating interchangeability of FTC and 3TC. Additionally, TDF monotherapy was found to be safe and effective for HIV prevention among women,^89,92 though in practice is used infrequently⁹³ Most recently, the cabotegravir long-acting (CAB-LA) injectable was found to be superior to oral TDF/FTC for HIV prevention.⁹⁴ Vaginal 1% TFV gel was found to be effective in a single trial, however two subsequent trials did not demonstrate sufficient effectiveness to move the product forward to regulatory approval.⁹⁵

Oral Pre-exposure Prophylaxis

In this review we focus on TDF/FTC PrEP as the only regulatory authority-approved oral regimen, first approved by the US FDA in 2012. Since 2015, the WHO has recommended that all individuals at substantial risk of HIV infection be offered PrEP⁷⁹, inclusive of pregnant and breastfeeding women, and in 2017 both the U.S. Food and Drug Administration and the European Medicines Agency approved extension of the TDF/FTC for PrEP label to include adolescents.^96,97 A 2016 meta-analysis, which included both placebo-controlled trials and trials with no control (PrEP vs. no PrEP) suggested a 51% reduction in HIV risk associated with TDF/FTC use, with adherence significantly modifying effectiveness.⁹² When limiting to individuals with high adherence, TDF/FTC reduced HIV risk by 90%.⁹² In regard to safety, no significant increases in clinical adverse events were observed in the primary TDF/FTC effectiveness trials, though some data suggest small reductions in creatinine clearance⁹² and bone mineral density⁹⁸, the latter of which has not been associated with increased risk of fracture. As previously described, data suggest no significant differences in adverse pregnancy outcomes associated with TDF- vs. non-TDF containing antiretroviral regimens⁸¹, however, the use of PrEP in pregnant and breastfeeding women should continue to be balanced against HIV risk while additional safety data in these populations are accrued. Importantly, data suggest that at least 7 daily doses are necessary upon PrEP initiation to achieve sufficient vaginal tissue levels necessary for protection and once PrEP is discontinued, protection wanes immediately.⁹⁹

Despite demonstrated effectiveness in all populations, oral PrEP access and uptake remains well below the 2020 UNAIDS target of 3 million people receiving PrEP.¹⁰⁰ The majority of global PrEP initiations occur among cis-gendered men who have sex with men in high income countries.⁹³, However, national programs are now available in 76 countries¹⁰¹ and multi-country initiatives are increasing PrEP access to women and men globally, particularly among adolescent girls and young women and female sex workers.^93,102

Dapivirine intravaginal ring

The DPV IVR, used monthly, was found to be effective for HIV prevention in two large, parallel trials.^90,91 As with oral TDF/FTC PrEP, effectiveness varied with adherence. Overall, the trials found 27% and 31% reductions in HIV risk among women in the DPV IVR vs. placebo arms, and a 65% reduction among those who were adherent per protocol.¹⁰³ Subsequent open-label extension (OLE) studies suggested that women may be more likely to use the ring in the context of known effectiveness, with 90-95% of worn returned rings having evidence of use.^104,105 Corresponding to higher adherence observed in the OLE studies, modelling data also suggested higher reductions in HIV acquisition as compared to placebo (39% and 63% in the two OLE studies, respectively) as compared to the earlier clinical trials. The DPV IVR received a positive opinion from the EMA for HIV prevention among cisgender women aged 18 years and older in combination with safer sex practices when oral PrEP is not available or cannot be used, WHO prequalification status in 2020 and is recommended by WHO as an additional prevention choice for women at substantial risk of HIV infection as part of combination prevention approaches.^106,107 Following the positive EMA opinion, the International Partnership for Microbicides is preparing applications for regulatory approval in eastern and southern African countries of high HIV incidence among women as well as in the U.S.. Ongoing studies are evaluating the safety of the DPV ring, as well as oral TDF/FTC, in adolescent girls and young women, pregnant and breastfeeding women.¹⁰⁸

Cabotegrivir long-acting injectable

CAB LA is an investigational integrase inhibitor in development for both HIV prevention and treatment, administered as an intra-muscular injection every 8 weeks. Two clinical trials of CAB LA for HIV prevention were recently stopped early following interim analyses which demonstrated superior efficacy versus daily oral TDF/FTC. An 89% lower HIV incidence was observed among cisgender women. The trials will continue until the planned study end, with all participants in the TDF/FTC arm offered CAB LA. Data from both trials are expected to be submitted for regulatory approvals in 2021. Research is ongoing to understand whether there are any drug resistance concerns among individuals who may become HIV infected after CAB LA discontinuation due to the product’s long half-life.¹¹⁰

On the horizon

While multiple biomedical prevention methods – including oral, an intravaginal and most recently, a long-acting injectable – have been found to effectively prevent HIV in women, novel methods with varying delivery mechanisms and dosing schedules are in late-stage development to address the unique needs and preferences of individuals and thus expand global PrEP uptake. Two new oral regimens are soon to be evaluated in late-stage trials among cisgender women. Evaluation of the safety and efficacy of once-monthly oral islatravir - a investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) - in a randomized controlled trial among cisgender women and adolescent girls at high risk of HIV in sub-Saharan Africa and the U.S is ongoing.¹¹¹ In addition, evaluation of daily oral emtricitabine and tenofovir alafenamide (F/TAF) among cisgender women at the direction by the U.S. FDA following approval by the agency - based on DISCOVER, a non-inferiority trial - for men and transgender women who have sex with men, is expected.^111,112 While the results of DISCOVER and other studies demonstrate different side effect profiles of TDF/FTC and F/TAF, there is no evidence of superior effectiveness for F/TAF vs. TDF/FTC.

Novel mechanisms under evaluation in late-stage studies include monoclonal antibodies and vaccines. Twin phase 2b clinical trials to evaluate the safety, tolerability and efficacy of the VRC01 antibody, administered every 8 weeks over three years, found that a broadly neutralizing antibody (bnAb) called VRC01 was effective at preventing the acquisition of HIV strains that were sensitive to the bnAb, but not sufficient to demonstrate effectiveness in the trial overall. Future research around bnAbs for prevention is expected to include more potent, and possibly multiple, bnAbs.¹¹⁴ One vaccine effectiveness trial among cisgender women is currently ongoing, following numerous trials that failed to show sufficient efficacy over the preceding decades.¹¹⁷ The Imbokodo Study¹¹⁸, also phase 2b, is evaluating the effectiveness of a heterologous prime/boost vaccine regimen of Ad26.Mos4.HIV and Aluminum Phosphate-adjuvanted Clade C gp140 among women at high risk of HIV in Sub-Saharan Africa. The trial aims to enroll over 2600 women and complete follow-up in 2022.

While PrEP offers prevention of HIV, women have other reproductive and sexual health prevention needs not addressed by currently available methods. Moreover, robust data are lacking on the impact of PrEP on pregnancy and other STIs in women. Looking forward a robust pipeline of MPTs for the combined prevention of pregnancy, HIV, BV and other STIs are in varying stages of development designed to meet the multiple and complex sexual and reproductive health needs of women.⁶⁸

The past ten years have witnessed approval of oral PrEP and a positive EMA opinion for the DPV IVR, discovery of an effective bi-monthly injectable, and hope for bnAbs for HIV prevention among women. The research pipeline for the next ten years includes, but is not limited to, long-acting oral and injectable regimens, monoclonal antibodies, implants, vaccines – and the hope in that pipeline is for an expansive portfolio of biomedical prevention modalities to meet the diverse preferences and needs of women at risk of HIV throughout the world.

CONCLUSIONS

Women and girls have unique risks for HIV that must be considered in the context of their sexual and reproductive healthcare. STIs and BV increase the risk of HIV; however, are often asymptomatic and thus leave women at silent increased risk. Contraception, which is often used by women during the period of life when HIV risk is highest, can alter FGT microbiota and inflammation, but widely used methods evaluated in the ECHO Trial (DMPA-IM, LNG implant, copper-IUD) did not differentially increase risk of HIV. Data on HIV risk in pregnancy and the postpartum period are inconclusive but suggest the potential for increased risk during those periods of a woman’s reproductive life. Fortunately, several biomedical technologies have been shown to reduce HIV risk in women, though our understanding of ways to improve adherence requires additional research. Novel MPTs in development recognize the interconnectedness of women’s varying needs for simultaneous protection from pregnancy, STIs, BV and other pathogens throughout the life course and offer promise for improved sexual and reproductive health outcomes for women over the next ten years.