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Every-6-Month Lenacapavir With
F/TAF Controls HIV Through 28 Weeks
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IAS 2021, 11th IAS Conference on HIV Science, July 18-21, 2021
Mark Mascolini
Lenacapavir, the every-6-month subcutaneous agent that targets several steps in HIV’s life cycle, lowered viral load below 50 copies through 28 weeks when combined with daily emtricitabine/tenofovir alafenamide (F/TAF) in 94% of previously untreated people [1]. This open-label phase 2 study, CALIBRATE, also evaluated daily oral lenacapavir plus F/TAF. Two of 103 people taking subcutaneous lenacapavir stopped treatment because of a drug-related adverse event, both a grade 1 injection site reaction.
This novel antiretroviral thwarts HIV replication by disrupting the capsid shell around the viral genome. Lenacapavir interferes with transport of HIV into the target cell nucleus, with viral assembly and release from the target cell, and with capsid assembly. Pharmacokinetic study of lenacapavir supports twice-yearly subcutaneous dosing [2]. Researchers are developing lenacapavir for antiretroviral-naive people with HIV, for people with heavy antiretroviral experience, and for HIV prevention.
CALIBRATE enrolled 182 people with no antiretroviral experience who had a viral load above 200 copies and a CD4 count above 200 cells/uL. In an open-label format, researchers randomized participants in a 2:2:2:1 ratio to 1 of 4 groups: (1) subcutaneous lenacapavir every 6 months (927 mg on day 15 after oral lead-in) plus daily oral F/TAF through week 28 followed by subcutaneous lenacapavir plus daily oral TAF (without F), (2) same doses for 28 weeks followed by subcutaneous lenacapavir plus the oral integrase inhibitor bictegravir daily, (3) daily oral lenacapavir for 28 weeks (600 mg on days 1 and 2, then 50 mg daily thereafter) plus oral F/TAF, with same drugs and doses thereafter, and (4) oral bictegravir plus F/TAF for 28 weeks and thereafter.
The 182 study participants had a median age of 29, 7% were female at birth, 52% were black, and 45% were Hispanic. Median pretreatment viral load stood at 4.37 log10 copies/mL (about 23,400 copies) and median CD4 count at 437.
In the combined lenacapavir arms (groups 1 to 3), 147 of 157 people (94%) had a viral load below 50 copies at week 28 by FDA snapshot analysis. All 25 people randomized to bictegravir plus F/TAF had a sub-50 copy load at week 28.
Two of 53 people (3.8%) in lenacapavir group 2 had a viral load at or above 50 copies at week 28. One of these 2 people had emergent resistance mutations at week 10 (Q67H and K70R in capsid; M184M/I in reverse transcriptase), even though lenacapavir concentrations remained in the target range.
No serious adverse events or grade 4 adverse events related to study drugs emerged in 28 weeks. Nausea was marginally more frequent with subcutaneous lenacapavir than with the oral formulation (12% vs 8%), but diarrhea rates were similar with injected and oral lenacapavir (6% and 8%). Two people stopped treatment because of adverse events—both with grade 1 injection site reactions. Sixty-three of 103 people (61%) getting subcutaneous lenacapavir reported no injection site reactions, and 33 of 40 reactions (83%) were grade 1 and resolved quickly.
No grade 3 or 4 lab abnormalities were judged clinically relevant, and no one dropped out of the study because of grade 3 or 4 lab abnormalities.
The ongoing CAPELLA trial is evaluating lenacapavir in people with heavy antiretroviral experience, but recruiting is closed [3].
References
1. Gupta SK, Berhe M, Crofoot G, et al. Long-acting subcutaneous lenacapavir dosed every 6 months as part of a combination regimen in treatment-naïve people with HIV: interim 16-week results of a randomized, open-label, phase 2 induction-maintenance study (CALIBRATE). IAS 2021, 11th IAS Conference on HIV Science, July 18-21, 2021. Abstract OALB0302.
2. Begley R, Lutz J, Rhee M, et al. Lenacapavir (GS-6207) sustained delivery formulation supports 6-month dosing interval. International AIDS Conference 2020 Virtual. July 6-10, 2020. https://www.natap.org/2020/IAC/IAC_36.htm
3. ClinicalTrials.gov. Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (CAPELLA). ClinicalTrials.gov identifier NCT04150068. https://clinicaltrials.gov/ct2/show/NCT04150068
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