Clinical Resistance to Lenacapavir During Treatment of HIV Infection: A Review

Lenacapavir (LEN) is the first-in-class capsid inhibitor that inhibits HIV capsid function in vitro with picomolar activity. LEN has been approved for the treatment of HIV in combination with other antiretroviral agents (ARVs), as well as for the prevention of acquisition of HIV-1 in people who may benefit from pre-exposure prophylaxis (PrEP). In vitro investigations of the resistance profile of LEN have identified resistance-associated mutations (RAMs) at six residues in the HIV-1 capsid protein (CA), all found in the CA structural pocket where LEN binds and conferring LEN-resistance with various degrees of loss of susceptibility. LEN was initially evaluated in a clinical study (CAPELLA) of heavily treatment-experienced (HTE) people with HIV (PWH), in which 14 of 72 participants had emergence of in vitro-predicted LEN RAMs. Despite the presence of LEN RAMs in these participants with viral rebound, treatment with LEN led to viral suppression in a large majority of HTE PWH in CAPELLA. In treatment-naïve participants receiving subcutaneous LEN + asynchronous oral ARVs (CALIBRATE) 4 of 157 participants had emergence of LEN RAM after >2 years of study. In contrast, no cases of viral rebound with resistance to LEN have been observed in virologically suppressed PWH switching to the once-daily single-tablet regimen (STR) combining LEN with the integrase strand-transfer inhibitor (INSTI) bictegravir after up to 48 weeks in two Phase 3 studies, and for >3 years in Phase 2. Similarly, no resistance to LEN has been observed after up to 96 weeks in the Phase 2 study of once-weekly regimen of the deoxyadenosine analog RT inhibitor islatravir + LEN. Finally, in the Phase 2 study of the 6-monthly injectable LEN + 2 broadly neutralizing antibodies (bNAbs) combination, only one instance of resistance to LEN was observed in conjunction with loss of susceptibility to one of the bNAbs through 1 year of treatment. Overall, resistance to LEN in regimens using synchronous dosing (daily or weekly oral, or 6-monthly injectable) has been rare in clinical studies. As the use of LEN is predicted to increase in the near future with these potential new combinations, capabilities to test for capsid resistance are being developed through global commercial options as well as through regional health institutions.