Initiation of Long-Acting Antiretroviral Combinations Achieve Sustained Virologic Remission in Early-Life SIV Infection

Long-acting (LA) antiretroviral agents offer a promising strategy to overcome adherence challenges in HIV prevention and treatment. However, their efficacy in early life has not been evaluated. Using a highly translational newborn macaque model of simian immunodeficiency virus (SIV) infection, we assessed the preventive and therapeutic potential of LA lenacapavir (LEN), alone or in combination with cabotegravir (CAB). Despite its efficacy in adult pre-exposure prophylaxis setting, early LEN monotherapy failed to prevent viral acquisition following intravenous SIV exposure at birth and resulted in virologic failure in infected infants. In contrast, combined administration of LA LEN and LA CAB rapidly suppressed viremia within 2 weeks and maintained undetectable viral loads for up to 1 month. Initiation of combination therapy at 2 days post infection led to rapid virus control and sustained virologic remission in majority of infants following analytical treatment interruption. By comparison, CAB-based regimens incorporating subtherapeutic doses of either LEN or rilpivirine (RPV) were ineffective in preventing infection. Together, these findings demonstrate that LA LEN monotherapy is insufficient for prevention or treatment following early-life HIV exposure and highlight the importance of early initiation of potent LA combination regimens to overcome adherence barriers and achieve potential pediatric HIV remission.