Although not yet recommended, regimens combining both a non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitors (PI) can be used as first-line therapy, or as second-line or salvage therapy in patients who need to change antiretroviral treatment because of nucleoside reverse transcriptase inhibitors (NRTI) intolerance or virological failure with resistance to NRTI. Such combinations should not be used in patients infected with HIV-1 group O and HIV-2, due to the natural resistance to NNRTI of these subtypes. Dual NNRTI and PI combinations used as first-line therapy allow to spare NRTI, leaving a fully active class of drugs for later use, and delaying the risk of toxicity related to NRTI exposure, particularly mitochondrial toxicity. Several studies have shown that adding a NNRTI improves the efficacy of a second-line or salvage therapy based on a new combination of PI(s) and new or recycled NRTI(s). A possible explanation for the efficacy of NNRTI-containing regimens in NRTI-pretreated patients is that mutations conferring resistance to NRTI can increase the susceptibility of the viruses to the NNRTI. However, the decision to use a NNRTI in a salvage regimen needs to be weighed against the concern that subsequent failure will exhaust therapeutic options with any compound of this class, due the large degree of cross-resistance between the three available NNRTI. NNRTI and PIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions. The decrease in PIs plasma concentrations observed when they are combined with nevirapine or efavirenz is reduced when low doses of ritonavir, which strongly inhibits cytochrome P450, are associated with the combination of PI and NNRTI.