Minority Variants Associated with Transmitted and Acquired HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor Resistance: Implications for the Use of Second-Generation Nonnucleoside Reverse Transcriptase Inhibitors JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Varghese, V., Shahriar, R., Rhee, S., Liu, T., Simen, B. B., Egholm, M., Hanczaruk, B., Blake, L. A., Gharizadeh, B., Babrzadeh, F., Bachmann, M. H., Fessel, W. J., Shafer, R. W. 2009; 52 (3): 309-315


K103N, the most common nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutation in patients with transmitted resistance and in patients receiving a failing NNRTI-containing regimen, is fully susceptible to the new NNRTI, etravirine. Therefore, we sought to determine how often NNRTI-resistant mutations other than K103N occur as minority variants in plasma samples for which standard genotypic resistance testing detects K103N alone.We performed ultradeep pyrosequencing (UDPS; 454 Life Sciences a Roche Company, Branford, CT) of plasma virus samples from 13 treatment-naive and 20 NNRTI-experienced patients in whom standard genotypic resistance testing revealed K103N but no other major NNRTI-resistance mutations.Samples from 0 of 13 treatment-naive patients vs. 7 of 20 patients failing an NNRTI-containing regimen had minority variants with major etravirine-associated NNRTI-resistant mutations (P = 0.03, Fisher exact test): Y181C (7.0%), Y181C (3.6%) + G190A (3.2%), L100I (14%), L100I (32%) + 190A (5.4%), K101E (3.8%) + G190A (4.9%), K101E (4.0%) + G190S (4.8%), and G190S (3.1%).In treatment-naive patients, UDPS did not detect additional major NNRTI-resistant mutations suggesting that etravirine may be effective in patients with transmitted K103N. In NNRTI-experienced patients, UDPS often detected additional major NNRTI-resistant mutations suggesting that etravirine may not be fully active in patients with acquired K103N.

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