The antiretroviral drug pipeline: prospects and implications for future treatment research.

PURPOSE OF REVIEW: A number of investigational antiretroviral drugs in clinical development could alter the future treatment landscape for resource-limited settings and contribute to optimized therapy for HIV infection.

RECENT FINDINGS: Several nucleoside reverse transcriptase inhibitors (NRTIs) are in development, including festinavir (BMS-986001), a thymidine analogue similar to stavudine but with reduced potential for toxicity, CMX-157, a hexadecyloxypropyl conjugate of tenofovir and tenofovir alafenamide (GS-7340), a prodrug of tenofovir achieving much higher intracellular triphosphate concentrations with a lower dose than tenofovir disoproxil fumarate. MK-1439 is a well tolerated once-daily non-NRTI (NNRTI) with activity against most NNRTI-associated resistance mutations. Albuvirtide is a long-acting parenteral fusion inhibitor related to enfuvirtide, and BMS-663068 is an oral HIV attachment/entry inhibitor. Ibalizumab (formerly TNX-355) is an mAb that binds to CD4 and lowers HIV plasma viral RNA in infected patients. Cenicriviroc is a CCR5-antagonist that also has activity against the inflammatory chemokine CCR2. The integrase strand transfer inhibitor (InSTI) dolutegravir was recently approved in the U.S. and is an attractive component of future regimens because of efficacy, tolerability, apparent safety and once-daily dosing; it also maintains some activity against raltegravir and elvitegravir-resistant mutants. The dolutegravir analogue GSK-1265744 appears to be equipotent and is being developed as a long-lasting injectable parenteral agent. The selective cytochrome P450 3A4 inhibitor cobicistat is a better tolerated alternative to ritonavir for pharmacokinetic 'boosting', but may also result in clinically undesirable drug interactions.

SUMMARY: There are several investigational antiretroviral drugs with significant promise for inclusion in future primary and secondary combination regimens.