Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV
Himmel Sci Med Com, L.L.C., Bala Cynwyd, PA 19004, USA
Center for Advanced Biotechnology and Medicine (CABM), Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA
Author to whom correspondence should be addressed.
Formerly at the Albert Einstein College of Medicine, Department of Biochemistry, Bronx, NY 10461, USA.
Pharmaceuticals 2020, 13(6), 122; https://doi.org/10.3390/ph13060122
Received: 15 May 2020 / Revised: 5 June 2020 / Accepted: 5 June 2020 / Published: 11 June 2020
(This article belongs to the Section Medicinal Chemistry)
In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, better safety profiles, and lower doses or pill burdens than other NNRTIs in the clinic, combination therapies including either of these two drugs have led to higher adherence than other NNRTI-containing treatments. In a separate development, HIV integrase strand transfer inhibitors (INSTIs) have shown efficacy in treating AIDS, including raltegravir (RAL), elvitegravir (EVG), cabotegravir (CAB), bictegravir (BIC), and dolutegravir (DTG). Of these, DTG and BIC perform better against a wide range of resistance mutations than other INSTIs. Nevertheless, drug-resistant combinations of mutations have begun to emerge against all DAPYs and INSTIs, attributable in part to non-adherence. New dual therapies that may promote better adherence combine ETR or RPV with an INSTI and have been safer and non-inferior to more traditional triple-drug treatments. Long-acting dual- and triple-therapies combining ETR or RPV with INSTIs are under study and may further improve adherence. Here, highly resistant emergent mutations and efficacy data on these novel treatments are reviewed. Overall, ETR or RPV, in combination with INSTIs, may be treatments of choice as long-term maintenance therapies that optimize efficacy, adherence, and safety.