When treating infection, whether bacterial or viral, there is always a risk of the infectious agent to develop drug resistance. The treatment of HIV infection is especially susceptible to drug resistance which is a serious clinical concern in the chemotherapeutic treatment of the infection. Drug resistant HIV-strains emerge if the virus is able to replicate in the presence of the antiretroviral drugs.
NNRTI-resistant HIV-strains have the occurring mutations mainly in and around the NNIBP affecting the NNRTI binding directly by altering the size, shape and polarity on different areas of the pocket or by affecting, indirectly, the access to the pocket. Those mutations are primarily noted in domains which span amino acids 98-108, 178-190 or 225-238 of the p66 subunit. The most frequent mutations observed in viruses isolated from patients who have been on a failing NNRTI containing chemotherapy are Lys-103N and Tyr-181C. NNRTI resistance has been linked to over 40 amino acid substitutions in vitro and in vivo.
Antiretroviral drugs are never used in monotherapy due to rapid resistance development. The highly active antiretroviral therapy (HAART) was introduced in 1996. The treatment regimen combines three drugs from at least two different classes of antiretroviral drugs.
The advance of etravirine over other NNRTIs is that multiple mutations are required for the development of drug resistance. The drug has also shown activity against viruses with common NNRTI resistance associated mutations and cross-resistance mutations.