Doravirine Resistance Patterns Identified Through Week 192 in the DRIVE-FORWARD and DRIVE-AHEAD Phase 3 Clinical...

Area of Science:

• Virology
• Infectious Diseases
• Pharmacology

Background:

• Doravirine is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) developed to overcome resistance issues common with older NNRTIs.
• Specific resistance mutations like K103N, Y181C, and G190A often limit the efficacy of previous NNRTIs.
• Understanding doravirine's resistance profile is crucial for its effective use in HIV-1 treatment regimens.

Purpose of the Study:

• To evaluate the development of genotypic and phenotypic resistance to doravirine.
• To assess resistance through 192 weeks in the phase 3 DRIVE-FORWARD and DRIVE-AHEAD studies.
• To compare doravirine's resistance patterns with those of other NNRTIs.

Main Methods:

• Phase 3, randomized, double-blind studies (DRIVE-FORWARD and DRIVE-AHEAD) in treatment-naive adults with HIV-1.
• Participants received doravirine or a comparator (darunavir/ritonavir or efavirenz) for 96 weeks, followed by an open-label doravirine extension.
• Resistance testing was performed on participants with virologic failure or treatment discontinuation and detectable HIV-1 RNA.

Main Results:

• Development of doravirine resistance was uncommon: genotypic resistance was detected in 1.3% and phenotypic resistance in 1.0% of participants.
• Resistance primarily emerged within the first 48 weeks of treatment.
• Observed doravirine resistance-associated mutations (e.g., V106A/I/M, F227C) were distinct from common NNRTI mutations (K103N, Y181C, G190A).

Conclusions:

• Doravirine demonstrated a low rate of resistance development in treatment-naive HIV-1 patients over 192 weeks.
• The resistance profile of doravirine differs significantly from older NNRTIs, suggesting a preserved activity against common NNRTI resistance mutations.
• These findings support doravirine's role as an effective option in HIV-1 management, particularly concerning resistance.