Pharmaceutical, clinical, and resistance information on doravirine, a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection

Abstract

As part of a combined antiretroviral regimen, doravirine is safe and effective at suppressing viral replication in both treatment-naive and treatment-experienced adults living with human immunodeficiency virus (HIV)-1 who have no history of drug resistance against doravirine. In virologically suppressed individuals switching to a combination of doravirine, lamivudine, and tenofovir disoproxil fumarate, no resistance was found after 48 weeks. In treatment-naive individuals, rare cases (<2%) of emergent drug resistance have been reported, often involving the development of substitutions at position V106. From these few clinical cases, it is inferred that cross-resistance with other non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be limited. In contrast, the use of doravirine as a second NNRTI should be evaluated on a case-by-case basis in the presence of pre-existing resistance. Importantly, doravirine remains active against K103N viruses in vitro, and limited clinical evidence suggests this to be the case in patients as well. Since K103N is by far the most prevalent (<70%) NNRTI substitution found in clinical practice, resistance against doravirine-based antiretroviral therapies is expected to be rare, even for treatment-experienced individuals. This review summarizes chemical, pharmacological, and clinical information about doravirine with an emphasis on drug resistance. The efficacy results from an early phase clinical trial evaluating doravirine in combination with islatravir are also provided.

Keywords: HIV; antiretroviral therapy; doravirine; drug resistance; highly active; reverse transcriptase inhibitors.

Figure 1

Chemical structure of doravirine. 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3- yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile