by Carolyn Chu, MD, MSc, AAHIVS, AAHIVM Chief Medical Officer
August 1, 2023
Ogbuagu O, Segal-Maurer S, Ratanasuwan W, et. al. Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial. Lancet HIV. 2023 Jul 11; S2353-3018(23)00113-3. doi: 10.1016/S2352-3018(23)00113-3. PMID: 37451297
This analysis describes week 52 virologic outcomes of lenacapavir use in 72 highly treatment experienced participants with multi-drug resistance who were enrolled in a phase 2/3 multi-national trial. 36 individuals were enrolled into cohort 1 and randomized to oral lenacapavir or placebo. At day 15, individuals were switched to optimized background therapy (OBT) plus lenacapavir. Cohort 2 included 36 participants who received OBT plus lenacapavir beginning at enrollment. Overall, 33/72 (46%) had investigator-reported resistance to at least two drugs in all four major ART classes and 12/72 (17%) had no fully active ARVs in the OBR. 34/36 in cohort 1 and 32/36 from cohort 2 completed the main phase of 52 weeks. At week 52, 30/36 (83%) in cohort 1 and 26/36 (72%) in cohort 2 had VL < 50 copies/mL (combined rate: 78%). Efficacy was generally similar regardless of number of fully active ARVs in the OBR as well as use of dolutegravir, boosted darunavir, ibalizumab, or fostemsavir. 11 participants in cohort 1 and 11 in cohort 2 met criteria for resistance analysis: 9 participants had capsid RAMs (8 with resistance up to week 26 and 1 with emergent resistance at week 52). All 9 were at high risk of emergent lenacapavir resistance, with 4 having no fully active drugs in their OBR and 5 with inadequate OBR adherence. Despite emergent capsid RAMs, 4/9 resuppressed while maintaining lenacapavir use (2 with and 2 without OBR change). No emergent INSTI or PI mutations were observed. 47/72 (65%) had at least one study drug-related injection site reaction. Median duration of injection site reactions after 1st injection was 6 days; median duration of nodules was 227 days and of indurations was 113 days. Lab abnormalities of grade 3 or higher occurred in 23/72 (32%) participants.
Week 52 results for lenacapavir efficacy and safety are consistent with those previously reported for week 26, with one participant developing capsid resistance associated mutations after week 26. Injection site reactions were relatively common, and the duration of these reactions is notable. Given the trial’s small sample size and potential challenges of both identifying and supporting ongoing adherence to an optimized background regimen, additional data and experience will be invaluable. Further, additional guidance on when to consider capsid resistance testing is needed.
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