title: Drug-class-wide resistance to antiretrovirals in HIV-infected patients failing therapy: prevalence, risk factors and virological outcome.
abstract: BACKGROUND
  Drug-class-wide resistance (DCWR) to antiretrovirals substantially reduces treatment options.
  
  
  METHODS
  A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens.
  
  
  RESULTS
  NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (< 1 year) to 35.3% (> 4 years) and from 1.2% (< 1 year) to 34.8% (> 4 years), respectively (P < 0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%-51.3%) and by 53% (20.5%-94.3%) for each year of treatment, and by 17% (95% CI: 5.6%-29.3%) and by 32% (17.7%-50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (< 1 year) to 32.6% (> 4 years; P < 0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load < 500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574-0.979), NNRTI (OR: 0.746; 95% CI: 0.572-0.975), PI (OR: 0.655; 95% CI: 0.456-0.941), three-class (OR: 0.220; 95% CI: 0.082-0.593) resistance.
  
  
  CONCLUSIONS
  The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.
authors.affiliation: National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy. tozzi@inmi.it
authors.forename: Valerio
authors.initials: V
authors.lastname: Tozzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Zaccarelli
authors.forename: Sandro
authors.initials: S
authors.lastname: Bonfigli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lorenzini
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Liuzzi
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Trotta
authors.forename: Federica
authors.initials: F
authors.lastname: Forbici
authors.forename: Caterina
authors.initials: C
authors.lastname: Gori
authors.forename: Ada
authors.initials: A
authors.lastname: Bertoli
authors.forename: Rita
authors.initials: R
authors.lastname: Bellagamba
authors.forename: Pasquale
authors.initials: P
authors.lastname: Narciso
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D006678:HIV / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D016879:Salvage Therapy; D013997:Time Factors; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors