engleski

A376S in the Connection Subdomain of HIV-1 Reverse Transcriptase Confers Increased Risk of Virological Failure to Nevirapine Therapy

The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4 ; 95% confidence interval [CI], 2.0- 54.7), but it did not affect efavirenz outcome the same way (RH = 0.5 ; 95% CI, 0.1-2.2) (P value for interaction = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

Benzoxazines/pharmacology/therapeutic use; Drug Resistance; Viral/ genetics; Female; Genotype; HIV Infections/ drug therapy/virology; HIV Reverse Transcriptase/ genetics; HIV-1/drug effects/enzymology/ genetics; Humans; Male; Middle Aged; Models; Molecular; Mutation; Nevirapine/pharmacology/ therapeutic use; Protein Structure; Tertiary; Reverse Transcriptase Inhibitors/pharmacology/ therapeutic use; Risk Factors; Treatment Failure; Viral Load

Group Authors: EuroSIDA.