Expanded assessment from a set of phase 3 trials show non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine has high efficacy among treatment-naïve patients with HIV-1 and common resistance-associated mutations (RAMs).
The findings, presented during the International AIDS Society (IAS) AIDS 2020 Virtual Sessions
this week, established new understanding of the novel, marketed therapy for patients with HIV-1 originally treated in the phase 3 DRIVE-FORWARD and DRIVE-AHEAD trials.
Investigators, led by Ernest Asante-Appiah, PhD, of Merck & Co., sought an evaluation of doravirine activity among a large panel of clinical samples submitted for routine drug-resistance testing.
Asante-Appiah and colleagues conducted their retrospective analysis on the impact of baseline RAMs in treatment-naïve patients from the pair of clinical trials.
Doravirine susceptibility was evaluated through genotype and phenotype data from 4070 treatment-naïve and -experienced samples between August 2018-August 2019. Investigators compared RAM prevalence and susceptibility to all NNRTIs approved by the US Food and Drug Administration (FDA).
Among observed marketed NNRTIs were doravirine, nevirapine, efavirenz, rilpivirine, and etravirine. Clinical significance was retrospectively evaluated through the prevalence of baseline RAMs and the proportion of patients achieve HIV-1 RNA <50 copies/mL at weeks 48 and 96.
Using established biological and clinical cut-offs for NNRTIs and a doravirine biological cut-off of three fold, the rate of samples susceptible to doravirine, nevirapine, efavirenz, rilpivirine, and etravirine was 92.5%, 77.5%, 81.5%, 89.5%, and 91.5%, respectively.
At a five-fold doravirine cut-off, susceptible samples increased to 94.5%. Individual doravirine RAMs among patients ranged from 0.02% to 2.29%.
Among 228 (5%) samples resistant to non-doravirine NNRTIs, 28.5% remained susceptible to the novel therapy. The prevalence and median fold-change for doravirine in samples bearing common NNRTI RAMs—as per >50 isolates— included K103N (14.3%, 1.25), V106I (5.4%, 1.28), Y181C (5.3%, 2.23), among others.
Astante-Appiah and colleagues observed approximate two-fold increased doravirine susceptibility due to common NNRTI RAMs in the absence of NNRTI RAMs. They also noted instances of doravirine hyper-susceptibility.
The most prevalent RAM at baseline of the phase 3 clinical trials was V106I, which was detected in just 5 treatment-naïve patients (0.7%). All 5 achieved HIV-1 RNA <50 copies/mL at weeks 48 and 96.
Investigators concluded HIV-1 patients with common NNRTI RAMs show benefit from doravirine, based on this retrospective analysis.
“Clinical samples with common NNRTI RAMs show high susceptibility to doravirine,” they wrote. “In phase 3 clinical trials, doravirine demonstrated high efficacy in a small group of treatment-naïve participants with common NNRTI RAM.”
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