title: Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.
abstract: BACKGROUND
  Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.
  
  
  METHODS
  Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.
  
  
  RESULTS
  Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).
  
  
  CONCLUSIONS
  Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.
authors.affiliation: Institute of Infection & Global Health, University of Liverpool, Liverpool, United Kingdom. geretti@liverpool.ac.uk
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Geretti
authors.forename: Zoe
authors.initials: Z
authors.lastname: Fox
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Clare
authors.initials: C
authors.lastname: Booth
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lipscomb
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: Gilda
authors.initials: G
authors.lastname: Tachedjian
authors.forename: John
authors.initials: J
authors.lastname: Baxter
authors.forename: Giota
authors.initials: G
authors.lastname: Touloumi
authors.forename: Clara
authors.initials: C
authors.lastname: Lehmann
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Andrew
authors.initials: A
authors.lastname: Phillips
mesh_terms: D000328:Adult; D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000097:blood; D016017:Odds Ratio; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz