HIV therapeutics in 2026

(A. M. N. Tsibris and M. S. Hirsch, J Virol 84:5458-5464, 2010, https://doi.org/10.1128/jvi.02524-09). First-generation antiretroviral medications, many now discontinued, have been replaced by integrase strand transfer inhibitor-based regimens that offer superior efficacy, higher genetic barriers to resistance, and the convenience of a single-tablet fixed-dose combination. Dolutegravir and bictegravir are now the anchors of most first-line therapies worldwide, and two-drug and nucleoside reverse transcriptase inhibitor (NRTI)-sparing strategies have emerged, allowing for simplification of treatment of patients who had been previously on complex regimens. The most consequential recent advance, though, has been the introduction of long-acting injectable medications, including cabotegravir-rilpivirine for treatment, standalone cabotegravir for pre-exposure prophylaxis (PrEP), and lenacapavir, a first-in-class capsid inhibitor for both treatment and PrEP. For people with multidrug-resistant HIV, new agents including fostemsavir, ibalizumab, and lenacapavir have made virologic suppression achievable in virtually all heavily treatment-experienced patients. An investigational and emerging pipeline that includes third-generation integrase inhibitors, nucleoside reverse transcriptase translocation inhibitors, maturation inhibitors, and broadly neutralizing antibodies promises further expansion of HIV therapeutic options. These advances, however, come with potential challenges, including emergent resistance to long-acting agents, metabolic consequences of lifelong therapy in an aging population, persistent inequities in global access to newer agents, and often insufficient safety data in pregnancy and breastfeeding. This review provides a clinical assessment of the current antiretroviral options, from legacy agents to investigational therapies, with attention to the resistance, implementation, and special population considerations that will shape HIV practice in the future.