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Adherence to antiretroviral therapy is key for successful treatment of HIV-infected persons. To enhance adherence, multilevel interventions are necessary. This is often a challenge, as this case of an HIV-infected man with a history of poor adherence and multiple virological failures shows. With a multidisciplinary approach, comprehensive intervention strategies were used to facilitate the patient's adherence to an enfuvirtide-based regimen. The interventions are described in detail and include adherence support with modified daily observed therapy, support regarding symptom management, and social relationships. The patient's clinical progress was monitored using indicators such as clinical surrogate markers, adherence to antiretroviral therapy, and HIV-related symptom and depression scores. The case illustrates how interventions that were individualized, culturally sensitive, and provided by a team of health care providers enabled a patient to optimize his adherence, which led to significant improvement in his clinical surrogate markers and subjective quality of life.