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Lenacapavir resistance analysis in a phase Ib clinical proof of-concept study: Resistance to HIV Capsid Inhibitor Rare and Linked to Single Mutation
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HIV Drug Therapy/Glasgow 2020, October 5-8, 2020
Mark Mascolini
Emergence of HIV resistant to the capsid maturation inhibitor lenacapavir proved rare in a phase 1b trial and linked to a single mutation, Q67H [1]. Resistance developed at low concentrations of subcutaneous lenacapavir, much lower levels that will be attained with doses being used phase 2 and 3 clinical trials.
Lenacapavir inhibits HIV replication by disrupting the HIV capsid at several stages in the viral lifecycle. The capsid, a shell around the viral genome, is essential for "virtually every step of infection through a series of interactions with multiple host cell factors"[2]. Lenacapavir has activity against all HIV-1 subtypes and HIV-2, synergizes with major antiretroviral classes, and appears to have no cross-resistance to other antiretroviral classes, including maturation inhibitors. A single subcutaneous shot may remain active up to 6 months [3].
Standard in vitro resistance selection experiments identified 7 mutations in HIV-1 capsid protein linked to reduced susceptibility to lenacapavir. None of those mutations could be detected in 500 clinical isolates from antiretroviral-naive people, 500 isolates from antiretroviral-experienced people who had not taken a protease inhibitor (PI), or 500 isolates from antiretroviral-experienced people with a PI failure history. Further worked showed no phenotypic resistance (loss of susceptibility) to lenacapavir in 15 antiretroviral-naive people or 36 antiretroviral-experienced people.
Gilead Science researchers conducted a phase 1 dose-ranging study to pick an appropriate dose of lenacapavir [3]. They used data from that study to see which mutations might emerge in people taking lenacapavir and to characterize the dynamics of any such mutations.
The phase 1 double-blind, placebo-controlled trial randomized HIV-positive capsid inhibitor-naive people to a single subcutaneous injection of 20, 50, 150, 450, or 750 mg of lenacapavir, with 6 people in each dose group getting the capsid inhibitor and 2 getting placebo [4]. No one was taking other antiretrovirals. Researchers previously reported from 1.3 log10 copies (about 20-fold) to 2.3 log10 (about 200-fold) drops in viral load after 10 days of lenacapavir, compared with no viral load decline in people getting placebo [4]. Half of the participants had injection site reactions, which were usually mild and transient.
All study participants had genotypic and phenotypic resistance assays plus next-generation sequencing before entering the trial and at the end of monotherapy. Over the course of the trial, researchers recorded emergence of capsid mutations or change in phenotypic susceptibility to lenacapavir.
Of the 39 people enrolled in the trial, 29 got lenacapavir and 10 got placebo. Before treatment began, no one had previously identified lenacapavir resistance mutation, and everyone had full susceptibility to the drug. Follow-up resistance analyses identified the Q67H capsid mutation after 10 days in 2 people (6.9%) who got the lenacapavir injection. One person who got the lowest lenacapavir dose, 20 mg, had Q67H detected in a mixed viral population by both standard population sequencing and next-generation sequencing. The second person received the second-lowest lenacapavir dose, 50 mg, and had Q67H detected by next-generation sequencing alone.
Gilead investigators noted that the doses taken by people with emergent Q67H, 20 and 50 mg, yield lenacapavir levels below those expected in phase 2 and 3 trials of the capsid inhibitor. The study supporting every-6-month dosing used up to 900 mg of lenacapavir [3]. In the initial resistance selection study, among all the mutations detected Q67N had the least impact on viral fitness and susceptibility to lenacapavir. The researchers suggested that may explain emergence of Q67N at low doses in the phase 1b trial.
References
1. Margot N; Ram R, Parvangada P, et al. Lenacapavir resistance analysis in a phase Ib clinical proof of-concept study. HIV Drug Therapy/Glasgow 2020, October 5-8, 2020. Abstract O324.
2. Campbell EM, Hope TJ. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol. 2015;13:471-483. doi: 10.1038/nrmicro3503
3. 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
4. Daar E, McDonald C, Gordon Crofoot G, et al. Dose-response relationship of subcutaneous long-acting HIV capsid inhibitor GS-6207. Conference on Retroviruses and Opportunistic Infections. March 2020. Abstract 469. https://www.croiconference.org/abstract/dose-response-relationship-of-subcutaneous-long-acting-hiv-capsid-inhibitor-gs-6207/
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