Potential Role of Doravirine for the Treatment of Patients with Transmitted Drug Resistance

Research Square (Research Square)(2022)

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Abstract Background: Doravirine has a unique resistance profile but how this profile might increase its usefulness beyond first-line therapy in persons with susceptible viruses has not been well studied. We sought to determine scenarios in which doravirine would retain activity against isolates from ART-naïve persons with transmitted drug resistance (TDR) and to identify gaps in available doravirine susceptibility data.Methods: We analyzed published in vitro doravirine susceptibility data and applied the results to 42,535 RT sequences from ART-naïve persons published between 2017 and 2021. NNRTI-resistance mutations (DRMs) were defined as those with a Stanford HIV Drug Resistance Database doravirine penalty score either alone or in combination with other mutations.Results: V106A, Y188L, F227C/L, M230L, and Y318F were associated with the greatest reductions in doravirine susceptibility. However, several DRMs and DRM combinations lacking these canonical resistance mutations had >10-fold reduced susceptibility including G190E, one isolate with G190S, three isolates with L100I+K103N, one isolate with K103N+P225H, and isolates with L100I+K103N+V108I and K101E+Y181C+G190A. Of the 42,535 ART-naïve sequences, 3,374 (7.9%) contained a DRM of which 2,788 (82.6%) contained 1 DRM (n=33 distinct mutations), 426 (12.6%) contained 2 DRMs (79 distinct pairs of mutations), and 143 (4.2%) contained ³3 DRMs (86 distinct mutation patterns). Among the 2,788 sequences with one DRM, 112 (4.0%) were associated with ³3.0-fold reduced doravirine susceptibility while 2,625 (94.2%) were associated with <3.0-fold reduced susceptibility. Data were not available for individual DRMs in 51 sequences (1.8%). Among the 426 sequences with two DRMs, 180 (42.3%) were associated with ³3.0 fold reduced doravirine susceptibility while just 32 (7.5%) had <3.0 fold reduced susceptibility. Data were not available for 214 (50.2%) sequences containing 2 DRMs. Conclusions: First-line therapy containing doravirine plus two NRTIs is expected to be effective in treating most persons with TDR as more than 80% of TDR sequences had a single DRM and as more than 90% with a single DRM were expected to be susceptible to doravirine. However, caution is required for the use of doravirine in persons with more than one DRM even if none of the DRMs are canonical doravirine-resistance mutations.
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doravirine,drug resistance,treatment
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