What is the current understanding of triple nucleoside reverse transcriptase inhibitor (NRTI) regimens?
Triple NRTI therapy is not generally recommended. Regimens of ZDV/3TC/ABC and d4T/3TC/ABC have been shown to be less efficacious than standard non-nucleoside reverse transcriptase inhibitor (NNRTI)- or PI-based therapy, whereas unacceptably high rates of virological failure have been observed with the combinations ddI/d4T/3TC, ddI/d4T/ABC, ABC/TDF/3TC and TDF/ddI/3TC. The high rate of virological failure observed with ABC/TDF/3TC and TDF/ddI/3TC has been related to the strong selective pressure on the K65R mutation, which confers significant resistance to all drugs in these regimens. Evidence suggests that inclusion of ZDV may improve the performance of triple NRTI regimens, reflecting favourable antagonistic interactions between the mutational pathways induced by ZDV (TAMs) and those induced by ABC (L74V and K65R) or TDF (K65R). The hypersusceptibility to ZDV conferred by both K65R and M184V may play a role in improving responses [5]. Reciprocal interactions between mutations include: