Reverse transcriptase-mediated retrotranscription is a unique and essential characteristic of retroviruses such as the human immunodeficiency virus (HIV), and the enzyme is targeted by both nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs have the advantage that they bind directly to the reverse transcriptase enzyme, do not require cellular activation and are not incorporated into nascent viral DNA. Unfortunately, highly specific NNRTIs are associated with the rapid emergence of resistance mutations and extensive cross-resistance. Therefore, there is a continued need for new antiretroviral agents with increased potency, improved convenience of administration and reduced toxicity. Rilpivirine (TMC-278, R-278474) is a novel diarylpyrimidine that is easily synthesized and formulated and exhibits potent preclinical antiviral activity, high oral bioavailability and a favorable safety profile. The agent also showed antiviral efficacy as once-daily monotherapy and in combination with other antiretrovirals in clinical trials in HIV-1-infected individuals. Rilpivirine did not induce any viral genotype or phenotype changes during the study periods. Phase III clinical trials are planned to evaluate rilpivirine as a once-daily component of combination therapies for the treatment of HIV-1 infection.
