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Factors affecting patient adherence to therapy, such as frequent daily dosing and complex dosing schedules, are widely understood to be key obstacles to the durability of effective anti-HIV therapy. Didanosine, a nucleoside analogue reverse transcriptase inhibitor (NRTI) that is a core component of combination antiretroviral regimens, is currently indicated for twice-daily dosing. However, the active metabolite of didanosine (2′,3′-dideoxyadenosine-5′-triphosphate) has a long intracellular half-life that supports the use of didanosine in a more patient-friendly, once-daily dosing schedule. Clinical studies in which didanosine was administered either once or twice daily, as monotherapy or in combination with another NRTI, have demonstrated the equivalence of both dosing schedules, with respect to safety and tolerability, virologic and immunologic endpoints, and short-term clinical effects (e.g., weight gain). Preliminary results from recent studies support the clinical efficacy and utility of once-daily didanosine in combination antiretroviral regimens that provide maximal drug exposure, while allowing for once- or twice-daily dosing of all component drugs.