Sensitive testing of plasma HIV-1 RNA and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resistance prior to starting first-line antiretroviral therapy with etravirine or efavirenz

J Antimicrob Chemother. 2014 Apr;69(4):1090-7. doi: 10.1093/jac/dkt474. Epub 2013 Nov 27.

Abstract

Objectives: This study investigated strategies that may increase the yield of drug resistance testing prior to starting antiretroviral therapy (ART), and whether transmitted and polymorphic resistance-associated mutations (RAMs) correlated with virological outcomes.

Methods: We carried out retrospective testing of baseline samples from patients entering the SENSE trial of first-line ART in Europe, Russia and Israel. Prior to randomization to etravirine or efavirenz plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), plasma samples underwent routine Sanger sequencing of HIV-1 RT and protease ((plasma)SS) in order to exclude patients with transmitted RAMs. Retrospectively, Sanger sequencing was repeated with HIV-1 DNA from baseline peripheral blood mononuclear cells (PBMCSS); baseline plasma samples were retested by allele-specific PCR targeting seven RT RAMs (AS-PCR) and ultra-deep RT sequencing (UDS).

Results: By (plasma)SS, 16/193 (8.3%) patients showed ≥ 1 transmitted RAM affecting the NRTIs (10/193, 5.2%), non-nucleoside reverse transcriptase inhibitors (4/193, 2.1%) or protease inhibitors (2/193, 1.0%). No additional RAMs were detected by AS-PCR (n = 152) and UDS (n = 24); PBMCSS (n = 91) yielded two additional samples with one RAM each. Over 48 weeks, 4/79 (5.1%) patients on etravirine and 7/78 (9.0%) on efavirenz experienced virological failure; none had baseline RAMs. Conversely, 11/79 (13.9%) patients randomized to etravirine had one polymorphic RAM from the etravirine score in baseline plasma (V90I, V106I or E138A), without any impact on virological outcomes.

Conclusions: The detection of resistance increased marginally with PBMC testing but did not increase with sensitive plasma testing. A careful consideration is required of the cost-effectiveness of different strategies for baseline HIV drug resistance testing.

Keywords: ART; HIV; genotyping.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anti-HIV Agents / therapeutic use*
  • Benzoxazines / therapeutic use
  • DNA, Viral / genetics*
  • DNA, Viral / isolation & purification
  • Drug Resistance*
  • Europe
  • Female
  • Genotyping Techniques / methods*
  • HIV Infections / drug therapy
  • HIV Infections / virology*
  • HIV-1 / genetics*
  • HIV-1 / isolation & purification
  • Humans
  • Israel
  • Male
  • Microbial Sensitivity Tests / methods
  • Middle Aged
  • Pyridazines / therapeutic use
  • RNA, Viral / genetics*
  • RNA, Viral / isolation & purification
  • Russia
  • Treatment Outcome
  • Young Adult

Substances

  • Anti-HIV Agents
  • Benzoxazines
  • DNA, Viral
  • Pyridazines
  • RNA, Viral
  • etravirine
  • efavirenz