Back HIV Prevention Pre-exposure (PrEP) Tenofovir Alafenamide Subdermal Implant Shows Promise for HIV PrEP in Beagle Study

Tenofovir Alafenamide Subdermal Implant Shows Promise for HIV PrEP in Beagle Study

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A sustained-release subdermal implant was able to maintain consistently high levels of tenofovir in cells with no adverse events in an animal study, offering proof-of-concept that an implant may be a good candidate for HIV pre-exposure prophylaxis, or PrEP, according to a study described in the April 20 edition of Antimicrobial Agents and Chemotherapy.

Studies including iPrEx and PROUD have shown that once-daily tenofovir/emtricitabine (Truvada) reduces the risk of HIV infection by around 90%, with higher levels of protection among people with blood drug levels indicating optimal adherence. The Ipergay study found that "event driven " PrEP taken before and after sex may also be effective. But in prevention studies to date, substantial numbers of participants did not take Truvada consistently, and poor adherence remains PrEP's Achilles' heel. A product that can deliver drugs at a stable level over time -- perhaps for a month or longer -- could help overcome this barrier.

Manjula Gunawardana from Oak Crest Institute of Science and colleagues tested a novel subdermal (under the skin) implant that delivers tenofovir alafenamide (TAF), a pro-drug that is metabolized in the body to the active agent tenofovir diphosphate.

Prior studies have shown that orally administered TAF suppresses HIV as well as the current tenofovir disoproxil fumarate (TDF) formulation found in Truvada, but it produces adequate intracellular drug levels with lower doses and has less detrimental effects on the kidneys and bones 

Gunawardana's team evaluated a matchstick-sized device that delivers TAF at 0.92 mg/day in beagle dogs over 40 days, looking at pharmacokinetics and preliminary safety outcomes.

Results

  • The implant maintained low-level systemic exposure to TAF (median 0.85 ng/mL) over the study period.
  • The device also maintained high concentrations of the active metabolite tenofovir diphosphate in peripheral blood mononuclear cells over the first 35 days.
  • The observed levels were more than 30 times higher than those associated with PrEP efficacy in humans, the researchers stated.
  • No adverse events related to treatment with the test device were noted during the course of the study.

"Our report on the first sustained release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates successful proof-of-principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations," the study authors concluded.

Other researchers are also testing long-acting injectable drugs for PrEP, and have found that monthly injections of the investigational integrase inhibitor cabotegravir (GSK1265744) protected monkeys against infection with an HIV-like virus and appear to reach adequate protective levels in humans.

5/31/15

Reference

M Gunawardana, M Remedios-Chan, CS Miller, et al. Pharmacokinetics of Long-acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis. Antimicrobial Agents and Chemotherapy. April 20, 2015 (Epub ahead of print).