Unmet therapeutic needs in the new era of combination antiretroviral therapy for HIV-1.

Significant advances in outcomes have been achieved with combination antiretroviral therapy (cART) in patients living with HIV. However, several ongoing needs remain with respect to the development of new treatments. The need for new or enhanced cART may become increasingly apparent as patients live longer with HIV and a greater proportion die from non-AIDS-related illnesses. Immunological response to cART is variable and immune failure occurs, despite virological control. Moreover, viral suppression can be incomplete due to insufficient antiviral efficacy, acquired or transmitted drug resistance, suboptimal pharmacokinetics/pharmacodynamics and lack of adherence. Chronic immune activation may continue even when viral replication is relatively restrained. Patients continue to experience cardiovascular and metabolic complications, due to disease, treatment and ageing. In addition, neurocognitive impairment and malignancy are important sources of ongoing morbidity despite cART. HIV also affects immune system senescence and bone turnover. This review discusses potential unmet needs with respect to these issues.