Background:  The nucleoside reverse transcriptase inhibitor (NRTI) resistance mutation L74V is well documented, but little is known about the L74I which also associated with HIV treatment failure and is encountered in virologic practice. The aim of this study was to evaluate the factors that influence the 74I/74V ratio and those linked to the emergence of L74I vs L74V.

Methods:  Among 3274 reverse transcriptase gene sequences, we analyzed the influence of each NRTI and non-NRTI (NNRTI) resistance mutation on the 74I/74V ratio. Use of each NRTI and NNRTI compound was also studied in 240 patients with available treatment history. Odds ratios (OR) were analyzed with a regression logistic test in uni- and multivariate analyses.

Results:  The proportions of L74I and V were 7% and 14%, respectively. In the sequences harboring T215F, the L74I represented 63% of the L74 mutations vs 29% in the sequences with T215Y (p <0.0001). In multivariate analyses, the mutations V75M/S/T/A, T215F, and K70R were strongly associated with the 74I/74V ratio increase with an OR of 6.8 (range, 3.8 to 12.1), 7.2 (3.1 to 16.4), and 3.9 (1.7 to 6.47), respectively (p <0.0001). The K219N increased also this ratio with an OR of 2.0 (1.1 to 3.5, p <0.05). According to the HIV-resistance history of 67 patients, the presence of the T215Y, T215F, and K70R preceded the L74I/V emergence in 98%, 88%, and 100% of cases, respectively. For 97% of patients, the L74I selection was not followed by the L74V emergence in their virologic follow-up. Among 240 patients with ART history, the multivariate analyses showed that the selection of L74V was linked to the didanosine or abacavir use with an OR of 5.7 (1.54 to 21.1) and 2.0 (1.1 to 3.7), respectively (p <0.05). The L74I selection was associated with the abacavir or efavirenz use with an OR of 2.4 (1.2 to 4.98) and 2.2 (1.08 to 4.4), respectively (p <0.05).

Conclusions:  The mutation L74I represents a third of the L74 mutations and so concerns a number of patients not inconsiderable. It seems to be a stable and full resistance mutation and not a way leading to the L74V. The preexistence of T215F or K70R mutations, which belong to profile #2 of thymidine analog mutations, select for the L74I preferentially. Presence of abacavir or efavirenz in the therapeutic history is linked to the L74I selection.