Advancing HIV prevention using tenofovir-based pre-exposure prophylaxis

Abstract

Tenofovir-based pre-exposure prophylaxis (PrEP) revolutionized the global HIV prevention landscape. Prior to the proof-of concept trial in 2010, which demonstrated that tenofovir (TFV) could prevent sexual transmission of HIV, prevention options were largely limited to behavior change, condoms, and circumcision. Several subsequent studies evaluating oral tenofovir disoproxil fumarate (TDF) or the TDF/emtricitabine (FTC) combination as PrEP for HIV prevention provided evidence for regulatory approval and inclusion in national and international guidelines. By 2021, 1.5 million people had initiated oral tenofovir-based PrEP, contributing to declines in HIV incidence in some regions. Here we reflect on how oral tenofovir-based PrEP became an important component of combination HIV prevention programs across the globe.

Introduction

The scale of the HIV problem and the need for HIV prevention

Forty years after the discovery of the human immunodeficiency virus (HIV), the pandemic continues to be a global public health concern. In 2020, there were an estimated 37.6 million people living with HIV and about 690,000 people died from AIDS-related causes [1,2]. Encouragingly, global HIV trends show a 55% decline in AIDS-related deaths since 2001, translating to an estimated 16.2 million AIDS-related deaths averted [3]. These declines are attributed to the increased access to antiretroviral drugs for both prevention and treatment. With regards to treatment, substantial progress has been made in scaling up access for people living with HIV. The number of individuals on antiretroviral therapy (ART) has increased from 7.5 million in 2010 to 27.4 million by 2021. This dramatic scale up is a result of the implementation of the UNAIDS “Fast-Track strategy” [4] that set global targets for 2020 to establish a trajectory towards achieving the 2016 UN General Assembly Political Declaration on ending AIDS as a public health threat by 2030 [5]. The UNAIDS Fast-Track Strategy monitors progress towards epidemic control, including the ambitious HIV treatment targets of 90–90–90, that is, 90% of those who are infected know their status; 90% of those who are infected are initiated on ART and 90% of those on ART are virally suppressed, and a target of 500 000 new HIV infections. In 2020, 84% of people living with HIV globally were aware of their HIV status, of which 73% were on treatment and 66% were virally suppressed [6].

Although global trends in HIV prevention are also encouraging, with 44% fewer new HIV infections in 2020 compared with 2001 and a 70% reduction in mother-to-child transmission of HIV, the progress in preventing new HIV infections, particularly the prevention of sexually acquired HIV, has been lagging [3]. The 1.5 million new HIV infections that have been estimated for 2020 is three times higher than the 2020 targets for HIV prevention set by UNAIDS in 2016 [5].

Most of the new HIV infections in 2020 occurred among key and marginalized populations such as sex workers, men who have sex with men (MSM), people who inject drugs (PWID), transgender people, and young women. In 2020, 65% of HIV infections globally were among key populations and their sexual partners and almost half of all new HIV infections occurred in eastern and southern Africa. Preventing new HIV infections among key populations and vulnerable groups is therefore a global priority.

In sub-Saharan Africa, adolescent girls and young women despite representing just 10% of the population, account for 25% of HIV infected persons and 86% of new HIV infections. Young women aged 15–24 years are up to three times more likely to be living with HIV than their male counterparts [7]. One of the main drivers of high HIV incidence rates in young women is age-disparate sexual partnering that creates an ongoing “Cycle of HIV Transmission” [8] despite the high HIV prevalence that characterizes the generalized epidemics in this region. Age-disparate sex is common throughout southern and eastern Africa and has undermined the impact of universal test and treat strategies on HIV prevention because male sexual partners in their 20s and 30s often have poor ART coverage and newly infected men unknowingly continue to transmit the virus to their sexual partner(s) as the HIV antibody tests used for HIV testing do not detect recent infection [9]. Further, some young women find it challenging to insist on mutual monogamy or condom use, particularly with older male partners who they may be economically dependent on and who may be engaged in multiple concurrent sexual partnerships. The ongoing high rates of HIV transmission in young women in sub-Saharan Africa present a challenge to achieving the UNAIDS goal of “ending AIDS as a public health threat” by 2030. Reducing HIV in young women could change the course of the epidemic in sub-Saharan Africa and accelerate global progress in HIV prevention.

In this commemorative issue of the journal, we reflect on the progress made in the field of preventing sexual transmission of HIV with a particular focus on the role of oral tenofovir-based pre-exposure prophylaxis (PrEP) for HIV prevention, which for the first time also offers a women-initiated discrete technology that has the potential to reduce population level HIV incidence in sub-Saharan Africa.

Multiple approaches to prevention

In generalized HIV epidemics where heterosexual transmission of HIV is dominant, there is a concomitant epidemic of vertical transmission of HIV from infected mothers to their infants in utero, during labor and delivery and post-partum through breastfeeding. The prevention of vertical HIV transmission from mother-to-child has been one of the greatest successes in HIV prevention. Antiretroviral drugs, both as prophylaxis for the infant and prophylaxis and treatment for the mother, have been successfully used to reduce transmission of HIV from mother-to-child to the point where elimination of this mode of transmission has become a possibility, with several countries already achieving this goal [10–12]. However, progress in preventing sexually transmitted HIV has proven far more challenging with limited prevention options for the first 29 years of the epidemic. Effective prevention options included (1) behavioral interventions such as abstinence, mutual monogamy [13], and condom use [14]; (2) behavior change interventions such as delaying sexual debut [15] and HIV counseling and testing [16]; and (3) biomedical interventions such as treatment of sexually transmitted infections [17] and medical male circumcision [18].

These sexual prevention options have had limited impact, especially for young women in sub-Saharan Africa because some find it challenging to negotiate the adoption of these prevention options particularly with older male sexual partners. Notably, most of these prevention options place power for HIV prevention in the hands of male sexual partner. To address this social challenge, substantial efforts continue to be made in finding new biomedical tools to prevent HIV, including women-initiated risk-reducing technologies such as microbicides—topical agents applied to the female genital tract to prevent HIV infection [19]. The quest for microbicides was subsequently expanded to include evaluation for rectal use in MSM populations and now includes the evaluation of systemic products.

Transition to antiretroviral-based prevention technologies

Clinical trials of several non-HIV specific microbicide candidates (nonoxynol-9, C31 G—SAVVY, BufferGel^TM, Carraguard®, PRO2000, and cellulose sulfate - UsherCell^TM) evaluated in the late 1980s and throughout the 1990s were mostly safe but were not effective in preventing HIV [20–29]. Early studies on daily oral TDF for HIV prevention in women conducted between 2004 and 2006 in Ghana, Cameroon, and Nigeria were unable to demonstrate effectiveness due to the small number of HIV infections observed during the study in these countries [30].

In 2004, researchers from the Centre for the AIDS Programme of Research in South Africa decided to assess a topical formulation of tenofovir based on data from animal models, and clinical data on the safety of tenofovir gel from the HPTN 050 and HPTN 059 trials [31,32] and their experience in its use for ART provision for AIDS patients through the recently established PEPFAR program. The lead CAPRISA investigators approached Gilead Sciences in California for a donation of adequate quantities of the active pharmaceutical ingredient (API) of tenofovir and technology transfer to manufacture the gel formulation to conduct a large phase IIb trial.

At the time, John Martin was Chairman and CEO of Gilead Sciences. He had already been spearheading innovative programs to make AIDS treatment available to the poor in low- and middle-income countries and his treatment access programs revolutionized our ability to access highly effective first-line drugs like tenofovir and provide antiretroviral therapy at low cost to millions who required it. Dr Martin was supportive of the proposal to assess tenofovir for prevention and Gilead Sciences provided the tenofovir needed for the phase IIb trial for formulation into a topical gel.

Proof-of-concept that tenofovir-based pre-exposure prophylaxis prevents sexually transmitted HIV

Working in partnership with the scientific research organizations, CONRAD (Contraception Research and Development) and FHI360 (formerly Family Health International), with funding from USAID and the South African Ministry of Science and Technology, the investigators based at CAPRISA spent two and a half years developing the protocol and preparing for study implementation of the CAPRISA 004 tenofovir gel trial in 2007. The CAPRISA 004 trial, was a phase IIb trial that assessed a coitally dependent dosing strategy in 889 rural and urban South African women. This trial showed that tenofovir gel used before and after sex reduced acquisition of HIV infection in women by 39% (95% Confidence Interval (CI): 6; 60) overall and by 54% among women who used the product consistently [33]. This study also showed that tenofovir gel prevented genital herpes (HSV-2) [34], an incurable lifelong condition, which potentiates the spread of HIV infection.

This trial was proof of concept that antiretroviral drugs could prevent sexual transmission of HIV and HSV-2 infection and provided the first evidence for what is today known as pre-exposure prophylaxis or PrEP for HIV prevention.

While important, these results alone were insufficient to license tenofovir gel for HIV prevention. The Microbicide Trials Network’s VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial [35] that included daily use of tenofovir gel, did not confirm the findings from the CAPRISA 004 trial. An analysis of detectable drug levels in blood from the VOICE trial participants showed low levels of adherence to the daily dosing regimen, with adherence being 23% in the tenofovir gel arm [35]. The Follow-on African Consortium for Tenofovir Studies 001 (FACTS 001), which was designed as a confirmatory study for the CAPRISA 004 trial, showed that tenofovir gel had no impact on HIV and notably only about half of the women trial had detectable drug levels [36].

The VOICE and FACTS 001 trials highlighted the importance of achieving high adherence for PrEP to be effective and data from the CAPRISA 004 trial confirmed that high tenofovir levels were essential to achieve high levels of protection [37]. Subsequent case-control analyses from the VOICE, FACTS 001 and CAPRISA 004 trials [35,36,38], focusing on women with detectable drug levels, revealed that tenofovir gel was 52%–57% effective when used consistently. Although behavioral factors such as adherence partially explain the modest efficacy observed in this case cohort analysis of the data from these topical PrEP trials, recent data point to other biological factors, such as vaginal dysbiosis [39] and genital inflammation [40], that potentially undermine the effectiveness of tenofovir gel in women. Further, topical delivery of tenofovir leads to substantially lower systemic tenofovir concentrations (∼1–10 ng/ml) than oral administration (25 and 50 ng/ml) that may also explain its reduced effectiveness in women [37].

Given these challenges, topical tenofovir is no longer being pursued as a PrEP strategy.

Oral tenofovir-based pre-exposure prophylaxis trials provide evidence for licensure for HIV prevention

Between 2010 and 2015, results from several oral tenofovir-based PrEP trial became available.

The first was the innovative iPREX trial that included 2,499 men or transgender women who have sex with men and showed that daily oral TDF/FTC reduced HIV incidence by 44% (95% CI 15; 63) [41]. Importantly, among those who took PrEP as prescribed (daily), the risk of infection was reduced by 99% [42]. Further evidence for the effectiveness of daily oral PrEP came from the PartnersPrEP trial [43], which included 4,758 HIV discordant couples from Kenya and Uganda and showed that daily oral TDF and TDF/FTC reduced HIV incidence by 67% (95% CI 44; 81) and 75% (95% CI 55; 87), respectively. Interestingly, the effectiveness was higher in HIV uninfected heterosexual men than cisgender women in these discordant couples but it was the first time that oral PrEP was shown to be effective in cisgender women [43]. These trials provided the necessary evidence for licensure of oral tenofovir-based PrEP for HIV prevention in 2012 in the United States [44].

Oral PrEP was also shown to be effective in other populations and locations including in the Botswana TDF-2 trial [45], which was conducted among 1,200 heterosexual men and women from the general population and showed that daily oral TDF-FTC reduced HIV incidence by 62% (95% CI 22; 83) and the Bangkok Tenofovir Study, which showed that daily oral PrEP was 49% effective in a population of PWID in Thailand [46].

However, two trials that only included cis-women (VOICE and FEM-PrEP) showed no protective effect of oral PrEP [35,47]. An analysis of drug concentrations revealed that <30% of the women in these trials were able to adhere to the prescribed daily use of the intervention highlighting the strong correlation between high rates of adherence and effectiveness. Following these disappointing results there was a perception that oral PrEP may not be a good option for HIV prophylaxis for cisgender women.

Given that daily adherence can be challenging, even in a clinical trial setting, the IPERGAY trial [48] assessed an “on demand” oral PrEP dosing strategy that provided the first evidence that intermittent oral PrEP was highly effective in preventing HIV infection in MSM. The IPERGAY trial included 400 HIV uninfected MSM wherein participants took a double dose of TDF/FTC within 24 h before each act of perceived high HIV risk sexual encounter, and an additional two pills 24 h and 48 h after sex. An 86% reduction in the incidence of HIV with on demand oral PrEP (95% CI: 39–99%, p = 0.002) [49] was achieved compared to placebo. The Pragmatic Open-Label Randomized Trial of Pre-exposure Prophylaxis (PROUD) study [50] in MSM utilizing 13 sexual health clinics in England also showed an 86% reduction in HIV incidence and showed no evidence of increased risky sexual behavior among MSM taking daily oral PrEP. In this trial, participants were randomly assigned (1:1) to receive daily oral TDF/TFC either immediately or after a deferral period of 1 year.

These two trials provided convincing evidence that it is possible to implement oral PrEP in real-world settings with high adherence.

The World Health Organization released guidelines in 2015 recommending the use of oral tenofovir-containing PrEP for populations at high risk of HIV, including cisgender women [51]. These recommendations, combined with the regulatory approval of tenofovir-containing oral PrEP (TDF/FTC and F/TAF) for HIV prevention by several countries, made the prophylactic use of antiretroviral drugs, as part of a comprehensive HIV prevention package, a reality. In October 2019, the US FDA approved the antiretroviral combination FTC and tenofovir alafenamide (TAF) (Descovy) for PrEP use in MSM, PWID, and transgendered women but not for cisgender women. TAF is a prodrug that is absorbed more rapidly than TDF and produces higher intracellular levels of tenofovir diphosphate. In clinical studies, TAF has an improved safety profile compared to TDF, high potency, and prolonged intracellular activity [52,53]. In the DISCOVER study, the oral FTC/TAF combination was shown to be non-inferior, but not superior, to oral TDF/FTC in preventing HIV infection in MSM. In this trial, the oral FTC/TAF had more favorable effects on bone mineral density and biomarkers of renal safety than oral FTC/TDF in this population [54]. Data on efficacy of oral FTC/TAF for use in cisgendered women are still pending.

Oral tenofovir-based PrEP is now an integral component of combination HIV prevention programs in many countries and is being scaled up throughout the world. As of October 2021, 53 countries had regulatory approval for oral TDF/FTC as PrEP. Of these, 41 had included PrEP within their HIV policies and guidelines. Data from 86 countries shows that since 2014, about 1.5 million people have initiated PrEP through demonstration projects, clinical trials, implementation initiatives, and end user studies [55]. The United States, South Africa, Zambia, Uganda, Kenya, Nigeria, and Australia have the highest number of PrEP users.

While oral PrEP has only been recently introduced into HIV prevention programs, its impact is already becoming apparent as emerging data reveal that PrEP has started to reduce new HIV infections, particularly among MSM populations, in cities where PrEP use is high. For example, oral PrEP implementation in Australia was followed by a 35% decline in the number of new HIV diagnoses in MSM [56]. Similarly, in London, there was a 40% reduction in new HIV infections among in MSM between 2015 and 2016 [57]. In San Francisco, oral PrEP use has been steadily increasing since 2014 and about 70% of all MSM were on oral PrEP in 2020 [58]. HIV incidence among MSM in San Francisco is estimated to have declined by 47% following oral PrEP introduction and programmatic scale up [59]. While encouraging, it is important to note that these incidence reductions among MSM populations may also be due to the simultaneous scale up of ART in these settings and the progress made is possibly because of these combined ARV-based treatment as prevention and primary prevention efforts.

In addition to MSM, oral PrEP is an important prevention option for heterosexual individuals and those in HIV sero-discordant partnerships. Notably for cisgender women, oral PrEP is a particularly important HIV prevention option as it is one of the few strategies that can be directly controlled by them, making oral PrEP more than an HIV prevention technology but also empowering women by giving them a technology to protect themselves, or without concurrence of their male sexual partner. Initiatives targeted at young women that include oral PrEP provision, for example the PEPFAR-funded DREAMS (Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe) program are also measuring declines in HIV incidence. For example, in Zimbabwe, HIV incidence among young women in DREAMS communities was lower than in non-DREAMS communities (3.1/100 person-years vs 5.3/100 person-years) and women in DREAMS communities were more likely to report ever and ongoing oral PrEP and consistent condom use [60].

Although oral PrEP appears to be suitable and highly effective for MSM, even when used intermittently, women seem to require near-perfect adherence to oral tenofovir-containing HIV prevention therapy and may need to take 5 or 6 out of 7 doses in a week, in order to be protected against HIV [61,62].

Novel, longer acting antiretroviral products and formulations are thus being developed for women. The monthly Dapivirine intravaginal ring [63,64] and the two monthly long-acting injectable, cabotegravir [65], are two of the most advanced candidates that are currently being reviewed by regulators and may soon become available. Recent results from the HPTN 084 trial have shown that cabotegravir was superior to TDF/FTC in preventing HIV infection in cisgender women [66]. These new long-acting PrEP products offer the distinct advantage of not only requiring less frequent end-use behavior, but can also be used more discretely compared to oral PrEP. New PrEP candidates in the pipeline that include tenofovir are as follows: a long-acting TAF implant, an intravaginal ring delivering both tenofovir and levonorgestrel (TFV/LNG), a combination vaginal insert containing TAF and elvitegravir (EVG), and fast dissolve vaginal tablets containing TFV/FTC and TFV only. Other longer-acting PrEP candidates currently being evaluated include combinations of broadly neutralizing antibodies as well as new classes of antiviral drugs such as islatravir (monthly tablets and annual implants) and lenacapavir (a 6 monthly subcutaneous injection).

Being at the helm of Gilead Sciences, John Martin played a pivotal role in development of tenofovir-based PrEP. He took a personal interest in several of the studies and provided support for several investigator-initiated studies on PrEP. As the field of HIV prevention moves on to newer long-acting PrEP technologies, it is a salient reminder that tenofovir-containing PrEP laid the foundation of this novel HIV prevention approach.

As of 2021, the world is not on track to meet the UNAIDS 2030 targets for HIV prevention and much more needs to be done to improve equitable access and availability to proven prevention options including PrEP. While oral tenofovir-based PrEP is making a contribution in some populations and regions, the next chapter in PrEP that goes beyond tenofovir-containing formulations including the expansion of long-acting products is just beginning. Until there is a protective vaccine, access and affordability to the increasing array of efficacious PrEP formulations that meet the needs of all populations at risk of acquiring HIV are going to be critical in enhancing progress toward achieving the UN 2030 goal of ending AIDS as a public health threat.