Switching from etravirine to doravirine in people with HIV harbouring NNRTI resistance-associated mutations: the DorSwitch pilot study

Vollständiger Abstract

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Abstract Objectives The objective of this study is to evaluate the efficacy, resistance profile, pharmacokinetics (PK) and safety of switching from etravirine to doravirine in virologically suppressed, treatment-experienced individuals with prior non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations (NNRTI-RAMs). Methods DorSwitch is a prospective pilot study including 13 adults with sustained virological suppression and documented historical NNRTI-RAMs. Etravirine was replaced by doravirine while maintaining the remaining antiretroviral backbone. Drug-specific resistance penalty scores were generated using the Stanford HIV Drug Resistance Database (HIVdb) algorithm. PK analyses were performed in participants receiving darunavir/cobicistat plus doravirine. Virological, immunological, metabolic and safety outcomes were assessed over 48 weeks. Results Twelve participants completed 48 weeks of follow-up; one discontinued at Week 4 for personal reasons while virologically suppressed. All participants evaluable at Weeks 24 and 48 maintained HIV-1 RNA < 50 copies/mL, and no virological failures occurred. The median number of NNRTI-RAMs per individual was 2 (IQR 1–3). Doravirine showed lower or equal Stanford HIVdb penalty score (HIVdb-PS) than etravirine in 11/13 participants. In two cases, higher doravirine PS were driven by Y318F and G190E mutations detected in peripheral blood mononuclear cell HIV-1 DNA; both individuals remained virologically suppressed through Week 48. In seven participants receiving darunavir/cobicistat plus doravirine, trough concentrations (Cmin) were consistent with expected exposure concentrations. Total cholesterol and LDL cholesterol decreased significantly over follow-up, while body weight showed a modest, non-significant reduction. No doravirine-related serious adverse events were observed. Conclusions In this small, highly selected pilot cohort, switching from etravirine to doravirine as part of an otherwise suppressive regimen was associated with maintenance of virological suppression through Week 48 and a more favourable predicted NNRTI resistance profile in most participants. The favourable resistance profile, safety, metabolic effects and PK findings consistent with expected exposure—particularly in combination with darunavir/cobicistat— support further evaluation of doravirine as a switch option in carefully selected individuals with prior NNRTI failure.