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A long-acting capsid inhibitor, lenacapavir, has been approved for treatment of HIV infection in those with limited options. Lenacapavir (Sunlenca), the first agent in a new antiretroviral class known as capsid inhibitors, was approved by the FDA on December 22, 2022 for patients with multidrug-resistant HIV infection or intolerance to or safety concerns with other drug classes. Lenacapavir binds two subunits of the viral capsid, disrupting the viral life cycle at several points and ultimately preventing production of replication-competent virus. Lenacapavir is administered initially as an oral regimen (600 mg days 1 and 2; 300 mg day 8), followed on day 15 by subcutaneous injection (927 mg as two 1.5-mL injections); alternatively, oral and subcutaneous therapy can be initiated simultaneously (600 mg orally days 1 and 2; 927 mg subcutaneously day 1). Subsequently, maintenance dosing with subcutaneous lenacapavir is given approximately every 26 weeks.
In the phase 3 CAPELLA trial. opens in new tab, 36 patients (cohort 1) with drug-resistant virus failing their current regimen were randomized to lenacapavir or placebo. At day 14, all patients in cohort 1 were switched to optimized background therapy (OBT) plus lenacapavir. An additional 36 patients (cohort 2) received OBT plus lenacapavir beginning at enrollment. The primary endpoint (0.5-log reduction in viral load at day 14 in cohort 1) was achieved by 88% (lenacapavir arm) versus 17% (placebo arm). At week 26, patients in cohorts 1 and 2 had similar rates of viral suppression (<50 copies/mL in 81% and 83%, respectively) that was maintained at week 52. Mutations associated with decreased susceptibility to lenacapavir (primarily M66I) developed in eight patients, four of whom re-suppressed virus without a change in therapy. The drug was well tolerated; the most common adverse events were injection-site reactions (ISR) in 62%, and only one patient discontinued therapy because of an ISR. Significant drug-drug interactions occur between lenacapavir and strong UGT1A1 inhibitors, and with potent CYP, P-gp, or UGT inducers including atazanavir-based regimens, etravirine, and rifamycins. No dosage adjustment is necessary in those with creatinine clearance >15 mL/min. Estimated cost. opens in new tab is $42,250 for the first year and $39,000 annually thereafter.
