Simplification of antiretroviral treatment--how to sustain success, reduce toxicity and ensure adherence avoiding PI use.

Shortly after protease inhibitors (PI) began to be widely prescribed for the treatment of HIV infection in 1996, we learned that the virological efficacy of highly active antiretroviral therapy (HAART) was frequently associated with severe quality of life impairment. In fact, failure of PI-based regimens is often due to poor adherence resulting from high pill burden, complex dosing schedules, adverse events, or long-term toxicity. The metabolic and morphologic abnormalities associated with prolonged PI use are of particular concern: fat accumulation and abnormalities of lipid and glucose metabolism may increase the risk of cardiovascular disease, and body-shape changes (lipodystrophy) may also have a psychological impact or decrease patients' willingness to adhere to therapy. The efficacy of PI-sparing regimens in drug-naïve subjects, which typically consist of nucleoside reverse transcriptase inhibitors (NRTIs) with or without non-nucleoside reverse transcriptase inhibitors (NNRTIs), gives support to simplification strategies. In patients who have maintained durable virologic suppression on a PI-based regimen, the replacement of a PI by an NRTI, usually abacavir (ABC), or an NNRTI, has been shown to be associated with maintenance of virologic suppression, while leading to improvements in adherence and in some PI-related toxicities. The replacement of a PI by an NNRTI or ABC is usually followed by reductions in total cholesterol and triglycerides, though this is less true with efavirenz (EFV) than with nevirapine (NVP) or ABC. While there may be some improvement in fat accumulation after switching from a PI-based regimen, no improvement in lipoatrophy has been demonstrated after PI switches, possibly because this toxicity is due to NRTIs rather than PIs. However, NVP should be used with caution in patients co-infected patients with hepatitis B or C, and EFV may be poorly tolerated in individuals with psychiatric morbidity. Patients taking methadone may require dosage increases with switches to either NVP or EFV.