Abstract
We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.
Highlights
Clinical availability of antiretroviral (ARV) delivery systems that provide durable protection fromHIV transmission could revolutionize the way we fight the global HIV/AIDS pandemic. (1) Once daily oralTruvadaTM (emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg) prevents the sexual transmission of HIV when used before sexual exposure to HIV (2-6)
The iPrEX randomized control trial demonstrated that moderate adherence to pre-exposure prophylaxis (PrEP) was associated with 92% protection from seroconversion in men who have sex with men; a post-hoc analysis of peripheral blood mononuclear cells (PBMCs) TFV-DP concentrations estimated that PBMC-TFV-DP concentrations higher than 16 fmol/106 cells are associated with protection with 90% sensitivity (28)
We describe a reservoir implant capable of delivering tenofovir alafenamide hemifumarate (TAF) in the subcutaneous space for a period of several months, and we tested this implant system in New Zealand White (NZW) rabbits and rhesus macaques for up to 12 weeks
Summary
Clinical availability of antiretroviral (ARV) delivery systems that provide durable protection from. TruvadaTM (emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg) prevents the sexual transmission of HIV when used before sexual exposure to HIV (2-6). A recent clinical study demonstrated the effective drug levels of a subdermal drug-eluting implant releasing islatravir (MK-8591) for prevention of sexual transmission of HIV(9). Long-acting drug-delivery systems are fundamentally easier for individuals to use than once-daily oral pills. Studies on adherence to methods of contraception generally show that increased duration and subsequent reduced need for daily-repeated action by the user is correlated with increased contraceptive efficacy (10-13). Long-acting delivery systems of ARVs have the potential to increase adherence, providing the durable drug concentrations required to prevent HIV infection, while users are sexually exposed to the virus
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