Should non-nucleoside reverse transcriptase inhibitors be combined?

In the treatment of HIV-infected patients, an urgent need exists for more conveniently dosed and better tolerated regimens with improved virological and immunological efficacy. Based on preclinical studies, the combination of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) was considered to fulfill this. Several clinical studies, however, have shown different results with regard to mechanism of action, pharmacokinetics, efficacy and toxicity of dual NNRTI regimens. Combinations of two NNRTIs have shown additive or synergistic inhibitory effects on the HIV-1 reverse transcriptase activity and the viral replication of HIV-1 in vitro, although antagonistic effects have also been described. When nevirapine and efavirenz were administered in combination, the exposure to efavirenz was decreased due to induction of metabolism by nevirapine. When compared with single NNRTI regimens, dual NNRTI regimens showed similar but not superior results with regard to virological and immunological success in treatment-naive and pretreated HIV-1-infected patients. However, NNRTI-associated adverse events, such as clinical hepatitis, elevated liver enzymes, rash, central nervous system toxicity and psychiatric disorders, occurred more frequently when two NNRTIs were administered concomitantly. In conclusion, regimens with both nevirapine and efavirenz seem to result in similar antiviral and immunological efficacy with an increased incidence of adverse events compared with single NNRTI regimens. The combination of two NNRTIs is therefore less desirable than other available and effective treatment options.