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

J Acquir Immune Defic Syndr. 2009 Nov 1;52(3):309-15. doi: 10.1097/QAI.0b013e3181bca669.

Abstract

Objectives: 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.

Methods: 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.

Results: 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%).

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use
  • Drug Resistance, Multiple, Viral*
  • Drug Therapy, Combination
  • Genetic Variation
  • Genotype
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • Humans
  • Mutation
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use

Substances

  • Anti-HIV Agents
  • Pyridazines
  • etravirine
  • HIV Reverse Transcriptase