Low frequency nonnucleoside reverse-transcriptase inhibitor-resistant variants contribute to failure of efavirenz-containing regimens in treatment- experienced patients

J Infect Dis. 2010 Mar;201(5):672-80. doi: 10.1086/650542.

Abstract

Background: The contribution of low frequency drug-resistant human immunodeficiency virus type 1 (HIV-1) variants to failure of antiretroviral therapy is not well defined in treatment-experienced patients. We sought to detect minor nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants at the initiation of multidrug efavirenz-containing therapy in both NNRTI-naive and NNRTI-experienced patients and to determine their association with virologic response.

Methods: Plasma samples at entry and at time of virologic failure from patients enrolled in the AIDS Clinical Trials Group study 398 were analyzed by standard genotype, single-genome sequencing and allele-specific polymerase chain reaction (K103N and Y181C) to detect and quantify minor NNRTI-resistant variants.

Results: Minor populations of NNRTI-resistant variants that were missed by standard genotype were detected more often at study entry in NNRTI-experienced patients than NNRTI-naive patients by both single-genome sequencing (8 of 12 vs 3 of 15; P = .022) and allele-specific polymerase chain reaction (11% Y181C, 5 of 22 vs 3 of 72, respectively; P = .016). K103N variants at frequencies 11% were associated with inferior HIV-1 RNA response to efavirenz-containing therapy between entry and week 24 (change in HIV-1 RNA level, +0.5 vs -1.1 log(10) copies/mL; P < .001).

Conclusions: Minor NNRTI-resistant variants were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens.

Publication types

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

MeSH terms

  • Anti-HIV Agents / therapeutic use*
  • Antiretroviral Therapy, Highly Active / methods*
  • Benzoxazines / therapeutic use*
  • Drug Resistance, Viral*
  • Genetic Variation
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Reverse Transcriptase / genetics*
  • HIV-1 / classification
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Mutation, Missense
  • Plasma / virology
  • Polymerase Chain Reaction / methods
  • Selection, Genetic
  • Sequence Analysis, DNA
  • Treatment Failure

Substances

  • Anti-HIV Agents
  • Benzoxazines
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • efavirenz