Antiretroviral combinations implicated in emergence of the L74I and L74V resistance mutations in HIV-1-infected patients

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Abstract
Background: Very little is known about the alternative L74I mutation. This lack of knowledge has led to contradictory and confusing attitudes to L74I; although this mutation is not listed by the International AIDS Society – USA, it is increasingly included in several resistance algorithms. Objective: To compare and clarify the role of each antiretroviral compound and the resistance background in the emergence of the L74I and L74V mutations. Methods: We focused on the treatment used at the exact time of any L74V or L74I emergences in 74 patients, and we compared the use of each nucleoside reverse transcriptase inhibitor (NRTI) separately and in combination between the 74I and the 74V groups. The distribution of other NRTI and non-NRTI mutations between the two groups was also analysed. Results: A majority of L74I mutations is selected under the zidovudine plus abacavir combination or under tenofovir with thymidine analogue mutations in the resistance background. The K103N substitution also plays an important role in the L74I emergence when not associated with the other non-NRTI mutations seen in this study: L100I, G190A and Y181C. Didanosine plays the principal role in the L74V emergence. Conclusions: This study shows that the L74I and the L74V correspond to two different mutation pathways, conferring probably different resistance and replication advantages on HIV depending on the context. Taking into account more systematically the L74I mutation, whose impact is certainly currently underestimated, would increase our understanding of this substitution and its effects on the drug activity in vivo.

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