TAF may be effective as once-weekly PrEP

Tenofovir alafenamide (TAF) could be used as once-weekly oral PrEP, an animal study conducted by the US Centers for Disease Control suggests.

Options for non-daily PrEP are limited, due to the lack of agents that persist in the body long enough to permit weekly or monthly dosing. Pharmaceutical company Merck attempted to develop its nucleoside reverse transcriptase translocation inhibitor islatravir as monthly oral PrEP but had to discontinue that research programme after the high doses of islatravir needed for monthly dosing caused white blood cell suppression. Merck is now focused on a different drug from the same class, MK-8527.

Injectable cabotegravir PrEP, dosed once every two months, is approved for use in the United States and European Union but implementation of injectable PrEP has been slow. Gilead Sciences is investigating its HIV capsid inhibitor lenacapavir (Sunlenca) as a twice-yearly injectable form of PrEP.

Once-weekly oral PrEP would be convenient for many people and potentially easier to deliver than injectable PrEP or implants, which would require a healthcare worker to carry out injections or insertion of the implant. Healthcare worker and facility capacity are important constraints on expanding access to PrEP options, so pursuing a variety of dosing schedules and delivery methods will be beneficial not only for users but for enabling wider access.

Tenofovir alafenamide is a newer formulation of tenofovir disoproxil (TDF), the mainstay of oral PrEP. TAF stays in the body longer than TDF and is less likely to harm kidney function when dosed at levels used for treatment. At the moment, it is only used as PrEP in combination with emtricitabine (Descovy).

Researchers at the US Centers for Disease Control carried out a study in macaques to test the pharmacokinetics and preventive efficacy of weekly doses of TAF.

First, they gave single doses of 13.7mg/kg (n=5) or 27.4mg/kg (n=2) to pigtailed macaques to evaluate plasma and cellular drug concentrations over a seven-day follow-up period. The lower dose achieved tenofovir diphosphate concentrations above 600fmols/10⁶ cells in peripheral blood mononuclear cells at day 7, while the higher dose achieved a median concentration of 4390 fmols/10⁶ cells at day 6. Plasma concentrations peaked five hours after dosing and were undetectable by 72 hours after dosing.

Following the pharmacokinetic evaluation, the researchers tested the efficacy of weekly doses against twice-weekly vaginal or rectal challenges with SHIV, the simian equivalent of HIV.

A weekly TAF dose of 27.4mg/kg protected five out of six macaques against infection through intravaginal challenge over six weeks of challenges, whereas six untreated macaques were infected after a median of four challenges (a protective efficacy of 94%). Whereas protected macaques had median intracellular drug concentrations of 3290 fmols/10⁶ cells six days after dosing, the macaque that was infected had low median concentrations (405 fmols/10⁶ cells) in the two weeks prior to SHIV detection.

A weekly dose of 13.7mg/kg also had a protective efficacy of 94% and produced a median concentration of 1137 fmols/10⁶ cellsat day 6 in protected animals, whereas the median day 6 drug concentration in the infected animal was 1088 fmols/10⁶ cells.

A weekly TAF dose of 27.4mg/kg protected three out of six macaques against 12 rectal challenges, while three macaques receiving TAF were infected at challenges 7, 9 and 12. The protective efficacy against rectal infection was 80%. Curiously, the median intracellular drug concentrations were more than twice as high at days 3 (9133 vs 4417 fmols/10⁶ cells) and 6 (5150 vs 2203 fmols/10⁶ cells) in those animals that became infected than in those protected.

In macaques that experienced breakthrough infections despite TAF dosing, viral load was significantly lower than in animals infected in the control group in those subject to intravaginal challenge, but not rectal challenge.

The study investigators say that further research is needed to optimise the dosing for rectal protection. They say it is possible that tenofovir diphosphate is less active against HIV in the rectal mucosa than in the vaginal mucosa, requiring a higher TAF dose, but the study did not measure tenofovir diphosphate levels in the rectal or vaginal mucosa. For vaginal protection, the protective dose of 27.7mg/kg would equate to a weekly human dose of 450mg (compared to a treatment dose of 25mg a day). A previous dose-ranging human study during the development of TAF showed that daily doses of up to 600mg were well tolerated.