Pre-exposure Prophylaxis Agents Research Articles

HIV Pre-Exposure Prophylaxis: New and Upcoming Drugs to Address the HIV Epidemic.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) provides a critical intervention toward ending the HIV epidemic and protecting people with reasons to utilize PrEP. PrEP options continue to expand as new administration modalities offer the potential to tailor PrEP use for individual success. We have provided the evidence for new and emerging antiretroviral agents for PrEP (cabotegravir, lenacapavir, dapivirine, and broadly neutralizing antibodies), divided into pharmacology, animal model, and human data, accompanied by a summary and suggested place in therapy. Cabotegravir is a US Food and Drug Administration (FDA)-approved intramuscular injection given every 2 months with a strong body of evidence demonstrating efficacy for HIV PrEP, lenacapavir administered subcutaneously every 6 months is currently under investigation for HIV PrEP, dapivirine vaginal ring is an available PrEP option for women in certain areas of Africa, and broadly neutralizing monoclonal antibodies have been challenged in demonstrating efficacy in phase 1-2 study for HIV PrEP to date. Clinical literature for individual agents is discussed with data from major studies summarized in tables. This review provides a detailed overview of recently available and premier candidate PrEP drugs.

Safety surveillance for PrEP in pregnant and breastfeeding women.

The risk of HIV acquisition is higher during pregnancy and postpartum than other times. Newly acquired maternal HIV infection associated with high primary viraemia, substantially increases the risk of vertical HIV transmission. Pre-exposure prophylaxis (PrEP) reduces the risk of HIV acquisition. Currently available products include oral tenofovir/emtricitabine (TDF/FTC) and tenofovir alafenamide (TAF)/FTC), long-acting cabotegravir (CAB-LA) and the dapivirine ring (DVR). All except oral TDF/FTC have limited safety data available for use in pregnant and breastfeeding women. The safety of new PrEP agents for pregnant women and the fetus, infant and child, either exposed in utero or during breastfeeding is an ongoing concern for health care workers and pregnant and breastfeeding women, particularly as the safety risk appetite for antiretroviral (ARV) agents used as PrEP is lower in pregnant and breastfeeding women who are HIV-uninfected, compared to women living with HIV taking ARVs as treatment. With the widespread rollout of TDF/FTC among pregnant women in South Africa and other low-middle income countries (LMIC) and the potential introduction of new PrEP agents for pregnant women, there is a need for safety surveillance systems to identify potential signals of risk to either the mother or fetus, measure the burden of such a risk, and where appropriate, provide specific reassurance to PrEP users. Safety data needs to be collected across the continuum of the product life cycle from pre-licensure into the post-marketing period, building a safety profile through both passive and active surveillance systems, recognising the strengths and limitations of each, and the potential for bias and confounding. Pharmacovigilance systems that aim to assess the risk of adverse birth outcomes in pregnant women exposed to PrEP and other agents need to consider the special requirements of pregnancy epidemiology to ensure that the data derived from surveillance are sufficiently robust to inform treatment policies. Here we review the known safety profiles of currently available PrEP candidates in women of child-bearing potential, pregnancy and breastfeeding and discuss pragmatic approaches for such surveillance in HIV-endemic LMICs.

Preferences and acceptability for long-acting PrEP agents among pregnant and postpartum women with experience using daily oral PrEP in South Africa and Kenya.

Long-acting pre-exposure prophylaxis (PrEP) options could overcome barriers to oral PrEP persistence during pregnancy and postpartum. We evaluated long-acting PrEP preferences among oral PrEP-experienced pregnant and postpartum women in South Africa and Kenya, countries with high PrEP coverage with pending regulatory approvals for long-acting injectable cabotegravir and the dapivirine vaginal ring (approved in South Africa, under review in Kenya). From September 2021 to February 2022, we surveyed pregnant and postpartum women enrolled in oral PrEP studies in South Africa and Kenya. We evaluated oral PrEP attitudes and preferences for long-acting PrEP methods in multivariable logistic regression models adjusting for maternal age and country. We surveyed 190 women in South Africa (67% postpartum; median age 27 years [IQR = 22-32]) and 204 women in Kenya (79% postpartum; median age 29 years [IQR = 25-33]). Seventy-five percent of participants reported oral PrEP use within the last 30 days. Overall, forty-nine percent of participants reported negative oral PrEP attributes, including side effects (21% South Africa, 30% Kenya) and pill burden (20% South Africa, 25% Kenya). Preferred PrEP attributes included long-acting method, effectiveness, safety while pregnant and breastfeeding, and free medication. Most participants (75%, South Africa and Kenya) preferred a potential long-acting injectable over oral PrEP, most frequently for a longer duration of effectiveness in South Africa (87% South Africa, 42% Kenya) versus discretion in Kenya (5% South Africa, 49% Kenya). Eighty-seven percent of participants preferred oral PrEP over a potential long-acting vaginal ring, mostly due to concern about possible discomfort with vaginal insertion (82% South Africa, 48% Kenya). Significant predictors of long-acting PrEP preference included past use of injectable contraceptive (aOR = 2.48, 95% CI: 1.34, 4.57), disliking at least one oral PrEP attribute (aOR = 1.72, 95% CI: 1.05, 2.80) and preferring infrequent PrEP use (aOR = 1.58, 95% CI: 0.94, 2.65). Oral PrEP-experienced pregnant and postpartum women expressed a theoretical preference for long-acting injectable PrEP over other modalities, demonstrating potential acceptability among a key population who must be at the forefront of injectable PrEP rollout. Reasons for PrEP preferences differed by country, emphasizing the importance of increasing context-specific options and choice of PrEP modalities for pregnant and postpartum women.

Overcoming structural barriers to diffusion of HIV pre-exposure prophylaxis

HIV prevention with antiretroviral medication in the form of pre-exposure prophylaxis (PrEP) offers a critical tool to halt the HIV pandemic. Barriers to PrEP access across drug types, formulations, and delivery systems share remarkable commonalities and are likely to be generalizable to future novel PrEP strategies. Appreciation of these barriers allows for planning earlier in the drug-development pathway rather than waiting for the demonstration of efficacy. The purpose of this article is to propose a core set of considerations that should be included in the drug-development process for future PrEP interventions. A literature synthesis of key barriers to PrEP uptake in the United States was conducted to elucidate commonalities across PrEP agents and delivery methods. Based on the published literature, we divided challenges into three main categories of structural barriers: (1) provider and clinic characteristics; (2) cost considerations; and (3) disparities and social constructs, with potential solutions provided for each. Pragmatic strategies for examining and overcoming these barriers before future PrEP regulatory approval are recommended. If these strategies are considered well before the time of commercial availability, the potential for PrEP to interrupt the HIV pandemic will be greatly enhanced.

What's Trending on Twitter Regarding the Most Recently Approved Oral Agent for HIV Pre-Exposure Prophylaxis (PrEP)?

Introduction: Pre-exposure prophylaxis (PrEP) is a key therapeutic strategy for HIV prevention. Descovy® is the most recently approved oral agent for PrEP. Despite availability, there continues to be suboptimal PrEP use among at-risk individuals. Social media platforms have a role in disseminating health information, to include education on PrEP. Material and methods: A content analysis was conducted of "tweets" posted on Twitter® during the initial year of Descovy's FDA approval for PrEP. The coding schema captured content related to the indication, appropriate use, costs, and safety profile of Descovy. Results: Most tweets provided information on target population, dosing strategy, and side effects of Descovy. Information on costs and appropriate use was frequently missing. Conclusion: Health educators and providers should be aware of gaps in social media messaging concerning PrEP and should educate patients to ensure they are well informed when considering PrEP.

Acceptability of Event-Driven and Long-Acting HIV Pre-Exposure Prophylaxis Formulations Among Transgender Women Engaged in Street-Based Sex Work in Baltimore, Maryland.

We assessed acceptability of nonoral HIV pre-exposure prophylaxis (PrEP) formulations among transgender women (TW) engaged in street-based sex work in Baltimore, Maryland. In a K-means cluster analysis, TW (N=36) were partitioned into groups characterized by high interest in long-acting injectable PrEP only (Injectable Enthusiasts, 36%), high interest in injectables and subdermal implants (Long-Acting Acceptors, 36%), and low interest across PrEP formulations (Non-Acceptors, 28%). TW's interest in novel PrEP agents varied widely across formulations (range: 22-66%) and clustered around numerous relational, occupational, and structural factors, highlighting the importance of availing multiple PrEP formulations for this impacted population.

Clinical Considerations in the Selection of Preexposure Prophylaxis for HIV Prevention in Canada.

According to the Public Health Agency of Canada, approximately 62,050 people were living with HIV in Canada in 2018, and of those, 13% were undiagnosed. Currently, no single strategy provides complete protection or is universally effective across all demographic groups at risk for HIV. However, HIV preexposure prophylaxis (PrEP) is the newest HIV prevention strategy that shows promise. To date, two products have received an indication for PrEP by Health Canada: emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF) and emtricitabine/tenofovir alafenamide (Descovy®; FTC/TAF). Despite the high efficacy of these PrEP intervention methods, access to PrEP in Canada remains low. Identifying and addressing barriers to PrEP access, especially in high-risk groups, are necessary to reduce HIV transmission in Canada. While guidelines published by the Center for Disease Control and Prevention (CDC) include FTC/TAF information, the efficacy of FTC/TAF for PrEP has not yet been considered in Canada's clinical practice guidelines. Thus, the current paper reviews data regarding the use of FTC/TDF and FTC/TAF for PrEP, which may be useful for Canadian healthcare providers when counseling and implementing HIV prevention methods. The authors highlight these data in relation to various at-risk populations and review ongoing clinical trials investigating novel PrEP agents. Overall, FTC/TDF PrEP is effective for many populations, including men who have sex with men, transgender women, heterosexuals with partners living with HIV, and people who use drugs. While there is fewer data reported on the efficacy of FTC/TAF to date, recent clinical trials have demonstrated noninferiority of FTC/TAF in comparison to FTC/TDF. Notably, as studies have shown that FTC/TAF maintains renal function and bone mineral density to a greater extent than FTC/TDF, FTC/TAF may be a safer option for patients experiencing renal and/or bone dysfunction, for those at risk of renal and bone complications, and for those who develop FTC/TDF-related adverse events.

HIV Prevention Tools Across the Pregnancy Continuum: What Works, What Does Not, and What Can We Do Differently?

Multiple tools exist to support the primary prevention of HIV in pregnant and postpartum women; however, there are opportunities to enhance their use and impact. This review summarizes the current status of HIV prevention tools and existing gaps and opportunities to improve their use along the pregnancy care continuum. HIV screening efforts have steadily improved with close to universal screening of pregnant women in several East and Southern African countries. Strategies to implement partner testing through the distribution of HIV self-test kits are promising though linkage to care remains challenging. Syphilis screening rates are increasing though detection of other sexually transmitted infections could benefit from improved diagnostic capacity. Male and female condoms are rarely used and are often not the optimal tool of choice during pregnancy. Oral pre-exposure prophylaxis (PrEP) is a promising tool, although barriers such as the need for daily adherence, side effects, and stigma may limit its use. There is a growing pipeline of PrEP agents with alternative delivery platforms that might suit women's preferences better and supports the notion that choice is vital to improving HIV prevention coverage during the pregnancy-postpartum continuum. Clear guidance on which tools to use and how to use them, safety data supporting their use, and surveillance data documenting the scale and effectiveness of the tools will be imperative in establishing a path to more impactful prevention efforts among pregnant and postpartum women.

Female Genital Fibroblasts Diminish the In Vitro Efficacy of PrEP against HIV.

The efficacy of HIV pre-exposure prophylaxis (PrEP) is high in men who have sex with men, but much more variable in women, in a manner largely attributed to low adherence. This reduced efficacy, however, could also reflect biological factors. Transmission to women is typically via the female reproductive tract (FRT), and vaginal dysbiosis, genital inflammation, and other factors specific to the FRT mucosa can all increase transmission risk. We have demonstrated that mucosal fibroblasts from the lower and upper FRT can markedly enhance HIV infection of CD4+ T cells. Given the current testing of tenofovir disoproxil fumarate, cabotegravir, and dapivirine regimens as candidate PrEP agents for women, we set out to determine using in vitro assays whether endometrial stromal fibroblasts (eSF) isolated from the FRT can affect the anti-HIV activity of these PrEP drugs. We found that PrEP drugs exhibit significantly reduced antiviral efficacy in the presence of eSFs, not because of decreased PrEP drug availability, but rather of eSF-mediated enhancement of HIV infection. These findings suggest that drug combinations that target both the virus and infection-promoting factors in the FRT—such as mucosal fibroblasts—may be more effective than PrEP alone at preventing sexual transmission of HIV to women.

Cabotegravir: The First Long-Acting Injectable for HIV Preexposure Prophylaxis.

Review the pharmacology, pharmacokinetics, efficacy, safety, and role of long-acting injectable cabotegravir (CAB-LA) in HIV preexposure prophylaxis (PrEP). A literature search was performed using PubMed and Google Scholar (2012 to April 2022) with the search terms cabotegravir, preexposure prophylaxis, and PrEP. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, prescribing information, and review articles. All English-language articles of studies assessing the efficacy and safety of CAB-LA for PrEP were included. CAB-LA is the first long-acting injectable therapy approved for HIV-1 PrEP in both men and women. It is a suspension given intramuscularly every other month. CAB-LA has been shown to be more effective than daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in preventing HIV-1 infection among high-risk individuals. Two phase 3 trials were stopped early on the basis of superior efficacy of CAB-LA. The most common adverse effects were injection site reactions (ISRs), although they tended to decrease over time, and few participants in clinical trials discontinued use due to ISRs. CAB-LA may be particularly useful for individuals with known adherence problems to oral therapy, those with renal impairment, and those with decreased bone mineral density. However, CAB-LA is more expensive than generic TDF/FTC and may be associated with weight gain. CAB-LA is the first long-acting injectable agent for HIV PrEP. It is more effective than oral TDF/FTC, is well-tolerated aside from ISRs, and has few clinically significant drug-drug interactions.

The future of long-acting agents for preexposure prophylaxis.

The main reason for the failure of oral preexposure prophylaxis (PrEP) regimens for HIV is poor adherence. Intramuscular cabotegravir was recently approved for PrEP, and a number of other long-acting antiretroviral formulations and products are currently in clinical development. This includes subcutaneous and intravenous injections, implants, and microarray (microneedle) patches, as well as extended duration oral drugs. The success and future uptake of these products will depend on a variety of factors. Long-acting delivery of antiretroviral agents for PrEP confers significant advantages over short-acting oral delivery. This is exemplified by the superior efficacy of intramuscular cabotegravir given every eight weeks as compared to daily oral co-formulated tenofovir disoproxil fumarate and emtricitabine. There is also evidence for PrEP efficacy for a broadly neutralizing monoclonal antibody given intravenously every eight weeks. One of the leading candidates for long-acting PrEP, islatravir, was being studied as a monthly oral drug or a nonerodable subcutaneous implant inserted for up to 12 months. However, clinical studies of this agent were put on hold in late 2021 because of unanticipated lymphopenia. Long-acting antiretroviral products have substantial promise for PrEP and have particular advantages over daily oral drugs based mainly on improved adherence. However, there are barriers to further uptake that include the need for more intensive interaction with systems of healthcare delivery, greater expense and complexity of implementation, and unexpected long-term toxicities.

The predictive value of macaque models of preexposure prophylaxis for HIV prevention.

We review macaque models for preexposure prophylaxis (PrEP) for HIV prevention and highlight their role in advancing currently approved and novel PrEP agents. The development of the repeat low dose simian HIV (SHIV) challenge models represented a significant advancement in preclinical PrEP modeling that has allowed the investigation of PrEP under conditions that better mimic HIV exposures in humans. These models incorporate relevant drug pharmacology to inform drug correlates of PrEP protection. Models of rectal, vaginal, and penile infection are now available and have been found to predict clinical efficacy of all the currently approved PrEP strategies including daily oral PrEP with the combination of emtricitabine and tenofovir disoproxil fumarate or tenofovir alafenamide, and a long-acting formulation of the integrase inhibitor cabotegravir. These models are being used to test new PrEP modalities including the nucleoside reverse transcriptase-translocation inhibitor islatravir and long-acting capsid inhibitors. The SHIV models have also been supplemented by sexually transmitted infection co-infections with Chlamydia trachomatis, Treponema pallidum or Trichomonas vaginalis to assess the impact of inflammation on PrEP efficacy. Clinical efficacy validated current PrEP macaque models supporting their continued use to advance novel PrEP agents to improve global PrEP coverage.

Population-Level Correlation Between Incidence of Curable Sexually Transmitted Infections and Human Immunodeficiency Virus (HIV)-1 Among African Women Participating in HIV-1 Pre-Exposure Prophylaxis Trials.

Highly efficacious oral pre-exposure prophylaxis (PrEP) is the global standard for human immunodeficiency virus (HIV)-1 prevention, including in clinical trials of novel PrEP agents using active-comparator designs. The analysis assessed whether incident sexually transmitted infections (STIs) can serve as a surrogate indicator of HIV-1 incidence that might occur in the absence of PrEP. We analyzed data from 3256 women randomized to placebo groups of oral and vaginal PrEP trials (MTN-003/VOICE and MTN-020/ASPIRE). Regression modeling assessed the correlation between incident individual STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, each considered separately) and incident HIV-1. Across 18 sites in 4 countries (Malawi, South Africa, Uganda, Zimbabwe), STI and HIV-1 incidences were high: HIV-1 4.9, N gonorrhoeae 5.3, C trachomatis 14.5, and T vaginalis 7.1 per 100 person-years. There was limited correlation between HIV-1 incidence and incidence of individual STIs: N gonorrhoeae (r = 0.02, P = .871), C trachomatis (r = 0.49, P = <.001), and T vaginalis (r = 0.10, P = .481). The modest association with C trachomatis was driven by country-level differences in both C trachomatis and HIV-1, with no statistically significant association within countries. Sexually transmitted infection incidence did not reliably predict HIV-1 incidence at the population level among at-risk African women participating in 2 large PrEP trials.

Mapping Interests in Event-Driven and Long-Acting Pre-exposure Prophylaxis Formulations onto the HIV Risk Environment of Street-Based Female Sex Workers: A Latent Class Analysis.

Despite growing availability, HIV pre-exposure prophylaxis (PrEP) uptake and adherence remains suboptimal among female sex workers (FSW) in the United States. Using cross-sectional data from a survey of 236 street-based cisgender FSW in Baltimore, Maryland, we examined interest in event-driven and long-acting PrEP formulations. Latent class analysis identified discrete patterns of interest in five novel PrEP agents. Multinomial latent class regression then examined factors associated with probabilistic class membership. A three-class solution emerged as the best-fit latent class model: Injectable Acceptors (~ 24% of sample), Universal Acceptors (~ 18%), and Non-Acceptors (~ 58%). Compared to Non-Acceptors, Universal Acceptors had significantly (p < 0.05) higher odds of reporting condomless vaginal sex with clients, client condom coercion, and client-perpetrated physical violence. Relative to Non-Acceptors, Injectable Acceptors were distinguished by significantly higher rates of condomless vaginal sex with clients and injection drug use. Expanding PrEP options for FSW could help overcome barriers to PrEP initiation and persistence.

Where are the pregnant and breastfeeding women in new pre-exposure prophylaxis trials? The imperative to overcome the evidence gap

Pregnant and breastfeeding populations are at substantial risk of acquiring HIV in some settings, yet are underrepresented in clinical trials of new pre-exposure prophylaxis (PrEP) agents. Several PrEP formulations are in development (eg, vaginal rings, long-acting injectables, and other modalities). Pregnant and breastfeeding populations are typically excluded from initial clinical trials. We identified 14 PrEP trials of novel agents in non-pregnant or non-breastfeeding populations, and six phase 1-3 trials and open label extensions among pregnant and breastfeeding populations, that are currently ongoing or complete. A framework shift is needed to consider the ethical costs of excluding pregnant and breastfeeding populations at risk for HIV in PrEP clinical trials and promote inclusion to maximise the benefits from PrEP tools in the pipeline. Research on new PrEP agents should include pregnant and breastfeeding populations to avoid delays in reaching those who could benefit from PrEP after efficacy is established.

HIV Prevention Utilizing Long-acting Injectables

Pre-exposure prophylaxis (PrEP) is an essential component in ending the HIV pandemic. Unfortunately, PrEP uptake has not been optimal to date. This is due to various reasons, one of which is adherence. Long-acting injectables may help to overcome this barrier. This brief review discusses the long-acting injectables currently in use for PrEP (cabotegravir) and HIV treatment (cabotegravir and lenacapavir), as well as those currently undergoing clinical trials. Other promising agents are being studied, including islatravir and broadly neutralizing monoclonal antibodies. Furthermore, agents currently used for HIV treatment will likely be evaluated in preclinical and clinical studies for their use as PrEP agents.

HIV prevention: better choice for better coverage.

IntroductionAntiretroviral‐based pre‐exposure prophylaxis (PrEP) is today an established, effective and safe method of HIV prevention used in multiple countries worldwide by a broad range of populations at risk of HIV infection. Biomedical innovations are critical in supporting the primary prevention of HIV; however, their potential can only be maximized if end‐user challenges are recognized, described and used to develop next‐generation models.DiscussionFirst‐generation PrEP, a daily oral pill, is highly efficacious, discreet and affords users the ability to commence and conclude treatment rapidly. However, consistent daily adherence and persistence is challenging, especially among younger populations, due in part to side effects, the risk of stock‐outs and a lack of pill storage options. Second‐generation PrEP, longer acting agents that require less frequent dosing, could overcome such challenges. Agents that have shown efficacy in clinical trials include a monthly vaginal ring and PrEP injectables to be administered every 8 weeks, while products in development include 6 monthly injectables, oral therapy that uses monthly rather than daily pills, implants and the potential for long‐acting passive immunization.ConclusionsSecond‐generation PrEP agents will have the potential to offer improved adherence and less frequent reminders once they have undergone further development and the delivery systems that will best support them have been established. In order to pursue global UNAIDS targets of reducing new HIV infections to fewer than 500,000 annually by 2025, and to ensure that all people have access to prevention options that meet their specific prevention needs, both early and next‐generation PrEP options are needed.

Fitting a vaccine into the HIV prevention landscape.

The development of highly effective treatment and prevention strategies for HIV has been a significant scientific achievement over the past 25 years. Although progress has been made in the global access of antiretroviral treatment (ART), the UNAIDS 2020 global targets were not achieved because of structural and individual barriers. Therefore, the global targets are being revised for the 2025–2030 timeframe [1]. In this article, we will discuss the current state of HIV treatment and prevention and describe the research agenda that will help advance the next generation of strategies. In the context of this rapidly evolving prevention and treatment landscape, the levels of efficacy expected from an HIV vaccine increase. While using some of the lessons learned from SARS-CoV-2 vaccines, we will also point out that a safe, efficacious and durable HIV vaccine is achievable and remains a worthy goal. As of June 2020, global ART coverage was estimated at 26 million people living with HIV (PLWH), two-thirds of the universal treatment target. Current estimates of adherence suggest that 59% of PLWH are virus-free worldwide and thus can expect relatively normal life spans [2]. Furthermore, global endorsement of “undetectable equals untransmissible”, also known as U = U, makes ART the most potent and widely used preventive approach today [3]. The first long-acting injectable ART regimen delivered via monthly injection has been approved by regulatory authorities. Additional long-acting formulations are in development, including several containing broadly neutralizing antibodies (bNAbs) that could potentially extend the injection time from once every 6 months to once a year. Simplified delivery of long-acting combinations will result in both greater population coverage and durable virologic suppression. Furthermore, greater population coverage with these potent, durable regimens will boost the role of treatment as prevention in helping to control the global HIV pandemic. With these significant periods of time between doses, long-acting ART may well soon become a preferred option for treatment of PLWH. Except for barrier methods and adult medical male circumcision, all successful HIV prevention methods rely on antiretroviral drugs [4, 5]. The hypothesis has been that if there is a sufficient concentration of drug blocking HIV replication in the exposed tissues, then virus cannot establish infection, allowing the individual to remain HIV-free. Studies of different drug regimens of oral pre-exposure prophylaxis (PrEP) have shown that with adherence, protection from acquisition of HIV is remarkably high, greater than 95% and consistent across populations [6]. However, with only approximately a million PrEP users in 70 countries, the full impact of this powerful preventive tool is far from being fully achieved [6]. A major challenge facing PrEP-based HIV prevention has been the lack of sustained use by individuals who would gain the most benefit from the intervention. In studies comparing methods to improve PrEP rollout, high PrEP uptake and initiation was achieved at onset, but was then followed by significant levels of PrEP discontinuation [7]. One strategy to address adherence challenges has been the development of long-acting PrEP. In 2020, PrEP trials of an injectable drug, administered every 8 weeks, demonstrated superior efficacy compared to the standard daily oral PrEP among at-risk women and men. This significant achievement will soon lead to drug approval and implementation [8, 9]. As with therapy, new agents for PrEP are moving forward in the evaluation process that could increase the amount of time between doses to once or twice a year. This could lead to increased adherence, with significant improvements in effectiveness and less burden on the health system, compared to daily pills. In addition to antivirals, bNAbs are being explored as prevention modalities. The recently completed Antibody Mediated Prevention (AMP) trials demonstrated that the protection from infection is governed by the sensitivity of the virus to the bNAbs [10]. In addition to advancing important options for treatment and prevention of HIV infection, bNAbs also serve as a window into the levels of activity a future HIV vaccine will need to be able to trigger [11]. New medications for HIV treatment are also being evaluated for HIV prevention. Based upon the properties of each new drug, a variety of dosing options are under consideration – from weekly to once or twice a year, delivered by pill or injection. Currently, biomedical HIV prevention modalities include daily pills, monthly vaginal rings and injections every 8 weeks. The next generation of bNAbs have also been engineered to have optimized neutralization breadth and longer half lives in vivo [12]. Optimized cocktails of two and three antibodies are in development and, based upon the AMP results, have a high probability of success. Using bNAbs as a guide, it is reasonable to set an aspirational goal for vaccine efficacy that is significantly higher than previously proposed. Progress is being made in defining the requirements for induction of bNAbs via immunization and using new tools and technologies to deliver specifically engineered vaccines it should be possible to reproducibly and durably trigger production of antibodies from at least three bNAb families. Based upon the activity of bNAbs, it may be possible to achieve a level of efficacy in the 75–85% range. Importantly, there are two HIV vaccine efficacy trials ongoing, HVTN 705, Imbokodo, and HVTN 706, Mosaico [13, 14]. As an approach to facilitate and improve HIV vaccine discovery, there are lessons we can learn from SARS-CoV-2 vaccines [15]. As research focused on HIV vaccine discovery moves forward, there are many new tools and platforms we can adapt from the SARS-CoV-2 vaccines, including the utilization of various platform technologies and the development of optimally conformed immunogens. Acknowledging that the natural immunity that is induced by current HIV vaccines or HIV infection does not provide protection, the new tools that SARS CoV-2 can provide help to iterate vaccine strategies faster [15, 16]. Addressing the fundamental challenges of HIV vaccine development, combined with operationalizing new concepts, and fostering significant industry engagement will be the research focus for the next decade. The research described throughout this Journal Supplement will play a critical role to achieve our 2030 targets of durable control of the HIV pandemic. The authors have no competing interests or holdings. First draft was assembled by CD. AF and FD edited the drafts and CD assembled the final submission. None. None.

Pharmacokinetic/pharmacodynamic investigation of raltegravir with or without lamivudine in the context of HIV-1 pre-exposure prophylaxis (PrEP).

BackgroundTo characterize their potential use in pre-exposure prophylaxis (PrEP) we compared the pharmacokinetics of raltegravir and lamivudine in genital tissue against ex vivo tissue infection with HIV-1.MethodsOpen-label trial of 36 HIV-negative females and males randomized to 7 days raltegravir 400 mg twice daily and 7 days raltegravir 400 mg+lamivudine 150 mg twice daily (after washout), or vice versa. Blood, saliva, rectal fluid, rectal tissue, vaginal fluid and vaginal tissue were sampled at baseline and on and off PrEP during a total of 12 days, for pharmacokinetics and antiviral activity via ex vivo HIV-1BaL challenge. Ex vivo infectivity was compared with baseline. The trial has been registered in https://clinicaltrials.gov/ with the identifier NCT03205566.ResultsSteady state for both drugs was reached by day 4. Dosing with raltegravir alone provided modest ex vivo HIV protection with higher drug levels in rectal tissue and vaginal tissue than in plasma on and off PrEP. Off PrEP, plasma and vaginal concentrations declined rapidly, while persisting in the rectum. On PrEP, the highest lamivudine concentrations were in the rectum, followed by vaginal tissue then plasma. Lamivudine washout was rapid in plasma, while persisting in the rectum and vagina. Raltegravir/lamivudine increased ex vivo protection on and off PrEP compared with raltegravir alone, reaching maximum protection at day 2 in rectal tissue and at day 8 in vaginal tissue.ConclusionsRaltegravir 400 mg+lamivudine 150 mg showed high levels of ex vivo HIV protection, associated with high drug concentrations persisting after discontinuation in vaginal and rectal compartments, supporting further investigation of these agents for PrEP.

Using the adherence-efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized, controlled trial.

IntroductionRandomized trials of new agents for HIV pre‐exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well‐characterized adherence‐efficacy relationship for F/TDF to back‐calculate the (non‐PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).MethodsThe DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non‐inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV‐DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV.ResultsThere were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person‐years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV‐negative controls, 5% of the person‐time years had low, 9% had medium and 86% had high TFV‐DP levels. A non‐informative prior distribution for counterfactual bHIV, combined with the prior for TFV‐DP level‐efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV.ConclusionsBased on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non‐PrEP control group in randomized, active‐controlled PrEP trials that include a F/TDF‐comparator group.