title: The effect of HIV-1 resistance mutations after first-line virological failure on the possibility to sequence antiretroviral drugs in second-line regimens.
abstract: BACKGROUND
  One of the more vigorous debates in the field of highly active antiretroviral therapy (HAART) is how to start it and what the optimal drug sequence is.
  
  
  METHODS
  A retrospective cohort analysis was performed. The aim was to evaluate which variables could influence the virological response to second-line genotypic-based HAART in patients with virological documented first-line HAART failure. A positive response was defined as a confirmed HIV RNA level < 50 copies/ml.
  
  
  RESULTS
  Two hundred and eight patients were included. Demographic characteristics, risk factors for HIV acquisition, and drugs included in the initial treatment did not significantly influence the considered outcome. According to a multiple logistic model, the presence of thymidine analogue mutations (TAMs) had a negative association with the virological outcome (P = 0.006), whereas the use of a boosted protease inhibitor (PI) in second-line HAART was positively associated with the endpoint (P = 0.001). Patients receiving a genotypic-based second-line HAART containing a boosted PI achieved a viral load < 50 copies/ml in a 74.2% of cases compared with 52.2% of those whose therapy did not contain a boosted PI. This difference was statistically significant (P = 0.002) with an odds ratio (OR) of 2.63 and a 95% confidence interval (CI) ranging from 1.46 to 4.76. This last variable positively influenced the outcome even when the analysis was restricted to patients harbouring a virus presenting TAMs. In this case, second-line HAART was successful in 66.7% of cases with an OR of 3.25 and a 95% CI ranging from 1.28 to 8.25 (P = 0.014).
  
  
  CONCLUSIONS
  the wider range of available therapeutic options has made resistance and drug-sequencing considerations a crucial point in selecting first-line HAART. Our data indicate that, by limiting the risk of selecting or accumulating TAMs, it could be possible to save further therapeutic options. In second-line regimens, the higher antiviral effect and genetic barrier of boosted PIs may overcome the limits of the use of NRTI backbones, which retain only a partial effectiveness.
authors.affiliation: Divisione di Malattie Infettive, Ospedali Riuniti, Bergamo, Italy. franco31556@hotmail.com
authors.forename: Franco
authors.initials: F
authors.lastname: Maggiolo
authors.forename: Diego
authors.initials: D
authors.lastname: Ripamonti
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
authors.forename: Claudio
authors.initials: C
authors.lastname: Arici
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Eugenia
authors.initials: E
authors.lastname: Quiros-Roldan
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Minoli
authors.forename: Laura
authors.initials: L
authors.lastname: Sighinolfi
authors.forename: Paola
authors.initials: P
authors.lastname: Nasta
authors.forename: Fredy
authors.initials: F
authors.lastname: Suter
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D004351:Drug Resistance; D023381:Endpoint Determination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D013936:Thymidine / Q000031:analogs & derivatives / Q000235:genetics; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D013936:Thymidine