The antiretroviral treatment (ART) approach is the best-prescribed approach to date for pre-exposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination ARVs (cARVs) regimen has become cumbersome for healthy individuals leading to non-adherence. Recent surveys showed high acceptance of parenteral sustained-release ART enhancing PrEP adherence. Our approach is to design a parenteral nanoparticle (NP)-based cARV sustained-release (cARV-SR) system as long-acting HIV PrEP. In this work, we reported a new combination of two potent ARV, (tenofovir alafenamide fumarate (TAF) and bictegravir (BIC)) loaded nanoformulation intended as cARV-SR for PrEP. The BIC+TAF NPs were fabricated by standardized in-house methodology. In-vitro intracellular kinetics, cytotoxicity, and HIV-1 protection studies demonstrated BIC+TAF encapsulation prolonged drug retention, reduced drug-associated cytotoxicity, and enhanced HIV protection. In human PBMCs, nanoformulated BIC+TAF demonstrated significant (p < 0.05) improvement in the drug’s selectivity index by 472 times compared to the BIC+TAF in solution. In-vivo pharmacokinetic (PK) study of BIC, TAF and respective drug metabolite in female BALB/c mice after single subcutaneous BIC+TAF NPs demonstrated plasma drug concentrations of BIC and tenofovir (TFV) above intracellular IC50 level during the entire 30-day study period, and prolonged persistence of both active drugs in the HIV target organs including vagina, colon, spleen, and lymph nodes. This report demonstrated encapsulation of BIC+TAF in a nanoformulation improved its therapeutic selectivity and in-vivo pharmacokinetics of free drugs. Based on these preliminary studies, we hypothesize cARV-SR has potential as an innovative once monthly delivery for PrEP.
A new combination bictegravir+tenofovir alafenamide nanoformulation with prolonged sustained-drug-release potency for HIV-1 PrEP: A concept evaluation study.