The evolution of antiretroviral therapy is now addressed to develop regimens consisting of two instead of three drugs and it is also increasingly oriented to develop long-acting parenteral formulations in order to increase treatment adherence and to reduce the multifaceted individual burden associated to daily intake of drugs. This new way was first paved by the dual association consisting of the INSTI Cabotegravir and the NNRTI Rilpivirine, whose formulations allow for a single administration every two months. In 2022 a new drug with a novel mechanism of action and a longer persistence of effective drug concentrations was made available in many countries for the treatment of drug-resistant HIV infection in association to other antiretrovirals. Lenacapavir is a first in class capsid inhibitor that exerts its inhibitory effect on HIV replication by binding to a structural protein of the capsid. This unprecedented mechanism of action actually differs from those of all prior antiretrovirals as Lenacapavir interferes with multiple stages rather than with a single enzyme. Such binding determines a series of inhibitory effects on sequential steps of the HIV life cycle and the net result is that of an impressive intrinsic antiretroviral potency, as testified both by in vitro studies and the 10-day monotherapy clinical study with single injections. The antiretroviral activity of Lenacapavir is unaffected by any mutation conferring resistance to older antiretrovirals. Lenacapavir is slowly released from the site of injection and this requires an initial coverage by its oral formulation (half-life: 10-12 days) in order to provide adequate pharmacokinetic exposure in the first days of treatment. The subcutaneous administration of Lenacapavir (half-life: 8-12 weeks) is then scheduled every 6 months. Lenacapavir is metabolized by CYP3A and UGT1A1, it is a substrate of Pgp and a moderate inhibitor of CYP3A. While co-administration with strong inducers of these enzymatic entities is contraindicated or it is not recommended in case of weaker inducers, few are the potential interactions of Lenacapavir as perpetrator (by its moderate inhibitory effect on CYP and weak inhibition of Pgp). In most such cases no preventive dosage adjustments are recommended and clinical monitoring only is advised. Lenacapavir overall characteristics thus meet the major clinical-pharmacologic expectations of this new era of antiretroviral development. A safe and truly potent antiviral drug, with a low metabolic interactive potential and a frequency of administration with the potential to be successfully employed beyond the current therapeutic indications.
Keywords: HIV; Lenacapavir; Pharmacology; capsid inhibitors.