Future PrEP Drugs, Delivery Methods, Technologies Target Adherence Issue

The efficacy of tenofovir disoproxil fumarate-based oral therapy, taken once a day for pre-exposure prophylaxis (PrEP) for HIV, is undisputed, but as with almost any other kind of medications taken at home, it has one flaw.

It relies on patient adherence.

A new review published in The Lancet describes the future landscape of therapeutics in development for what the authors call the next generation of HIV prevention, or PrEP 2.0.

Drawing from similarities from contraception research, the pipeline for future PrEP therapies includes long-acting injectables, immunotherapies, vaginal rings, multipurpose prevention technologies, implantable drug delivery strategies, and transdermal patches.

The combination of tenofovir disoproxil fumarate and emtricitabine was adopted by the World Health Organization as a strategy to reduce HIV incidence. In the United States, the pill is sold as Truvada. But remembering to take a pill once a day can be a challenge for many that the drug targets; the most at-risk populations include women, teenagers and young adults age 15 to 24, racial and ethnic minority men who have sex with men, and transgender women.

The pipeline aims to expand the range of available PrEP regimens and “offer preventive technologies that will appeal to a wide variety of individuals with different needs over the course of their sexually active lifespan,” the authors wrote.

Globally, nearly 37 million people were estimated to be living with HIV in 2017, and a quarter of those were unaware of their infection status. There is an urgent need for prevention strategies, as nearly 2 million people acquired new infection in 2017, and 20% of those on treatment were not virally suppressed. Yet antiretroviral therapy has benefits both for treatment and prevention.

In multiple studies, the effectiveness of tenofovir disoproxil fumarate and emtricitabine is positively associated with adherence as measured by biomarker correlates of dosing, in particular plasma and intracellular drug concentrations, with a 96% risk reduction in men who have sex with men (MSM) estimated from drug concentrations consistent with taking an average of 4 or more doses per week.

However, for women, it is critical that daily doses are not skipped in order to achieve optimal protection. Pharmacokinetic studies have shown substantially lower concentrations of tenofovir diphosphate in vaginal tissue than in rectal tissues; rectal tenofovir diphosphate concentration was 100-times higher than that observed in vaginal and cervical tissues after a single dose. Six to 7 doses per week are needed to reach vaginal and cervical tissue in order to reach a level considered protective.

While tenofovir disoproxil fumarate and emtricitabine was shown in 1 trial to be 66% effective in protecting women from HIV infection, 2 other trials showed that low adherence weakened efficacy. Other populations also have lower adherence in diverse settings.

Alternative PrEP agents include:

Islatravir

Islatravir or 4ʹ-ethynyl-2-fluoro-deoxyadenosine (also known as MK-8591) is a novel nucleoside reverse transcriptase translocation inhibitor; it will be studied in an upcoming phase 2b study in combination with doravirine, an already approved non-nucleoside reverse transcriptase inhibitor (NNRTI) and lamivudine. It appears to be suitable for weekly, or even less frequent dosing, as it has a long half-life (50 to 60 hours in the blood and 120 hours inside cells). It blocks 2 different stages of the HIV replication lifecycle by preventing HIV from making a DNA copy of its genes and stops integrated HIV DNA inside of host cells being used to replicate new viral particles. It can be taken orally on a daily basis or over extended intervals, or via subdermal implant.

Maraviroc

Maraviroc, a CCR5 receptor antagonist, was evaluated for safety in a phase 2, 48-week safety and tolerability study aiming to compare 4 treatment regimens: maraviroc alone, maraviroc plus emtricitabine, maraviroc plus tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate and emtricitabine in MSM, trans women, and cis women. The regimens were generally safe and well tolerated. The study was not powered for efficacy, but the authors said all 5 seroconversions in MSM occurred in groups receiving maraviroc. Moreover, in those acquiring HIV infection, drug concentrations were absent, low, or variable.

Long-acting injectable drugs

Long-acting injectable drugs include cabotegravir, which could also come as a daily oral tablet. Cabotegravir (also known as GSK1265744) is chemically similar to dolutegravir.

Phase 3 trials for long-acting cabotegravir in combination with long-acting rilpivirine for HIV treatment showed safety and antiviral efficacy. One potential drawback of an injectible, however, is the prolonged subtherapeutic pharmacokinetic effect. It is still unclear whether this effect represents a prolonged period of antiviral activity or a period of vulnerability to HIV infection.

Rilpivirinehas had phase 1 and phase 2 trials. It is a nanoparticle formulation at a concentration of 300 mg/mL.39 A major concern is the potential risk of selection of NNRTI-resistant HIV-1 in newly infected people because of the prolonged subtherapeutic concentrations of long-acting rilpivirine after dosing is delayed or stopped.

Biologics

Another prevention approach is to use broadly neutralising HIV-1 monoclonal antibodies (bNAbs) There are current efforts to isolate bNAbs from chronically infected patients, long-term non-progressors, or others with extremely low levels of viral load in the absence of conventional oral ART. A group of patients called elite controllers, who make up around 1% of individuals living with HIV-1, are thought to develop bNAbs that neutralize more than 80% of circulating HIV-1 strains. bNAbs, which would require intravenous administration, are currently in pre-clinical trials or early phase 1 studies. They include VRC01 and 3BNC117 (targeting the CD4 binding site); PGT121, and PGDM1400 (targeting the V3 loop of the HIV-1 envelope protein); and 3BNC117-LS, VRC01LS, 10—1074LS, and VRC07–523LS (long-acting versions of the parent bNAbs). Previous clinical trials showed that VRC01, 3BNC117, and 10–1074 are safe and well tolerated.

Vaginal rings

Dapivirine is an NNRTI that has activity against a broad range of HIV-1 subtypes and was developed for topical administration. It has been studied in 2 phase 3 studies and showed HIV risk reduction of 27% and 31%. Follow-on extensions showed even better results and improved adherence.