Background
Non-adherence to HIV treatment increases the risk of viral rebound and the development of drug resistance. Long-acting formulations have shown improved compliance compared with conventional regimens requiring frequent dosing, leading to better outcomes and treatment continuation. Here, an in situ forming implant system (ISFI) was used to develop a long-acting (LA) formulation that can co-deliver two drugs post-administration of a single formulation. These ISFI formulations are injectable and solidified to implants after subcutaneous injection. If there is a risk of adverse effects from the implant, the implant can be safely removed to stop drug delivery.
Methods
First, an injectable LA formulation of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR-ISFI) was developed. The second drug, an integrase strand transfer inhibitor dolutegravir (DTG), was incorporated into the same formulation using co-solvent optimization. The pharmacokinetics of developed formulations were evaluated in BALB/c mice, and the pre-clinical efficacy of HIV suppression was assessed in humanized mice.
Results
The DOR-ISFI delivered DOR plasma concentrations >10×IC95 for 140 days and efficiently protected against multiple vaginal HIV challenges in humanized mice. The two-drug formulation DTGDOR-ISFI co-delivered DTG and DOR in serum for 9 months above the IC90. Drugs penetrated tissues relevant for HIV infection including lymph nodes, brain, spleen, gut, and genital tracts of male and female humanized mice. During preclinical evaluation of HIV maintenance therapy, this DTGDOR-ISFI effectively suppressed HIV for at least 4 weeks after discontinuation of antiretroviral therapy (ART). Removal of the implant successfully stopped the delivery of both drugs.
Conclusions
DTGDOR-ISFI is an important advance in managing HIV suppression by reducing the number of injections and simplifying LA drug delivery.
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