title: Analysis of virological efficacy in trials of antiretroviral regimens: drawbacks of not including viral load measurements after premature discontinuation of therapy.
abstract: OBJECTIVE
  To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle.
  
  
  METHODS
  Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (EuroSIDA) starting their first HAART regimen.
  
  
  METHODS
  Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified as responders (ITT/s=f); and 2) patients with a pVL below a given cut-off at week 48 whether they remained on initial assigned therapy or switched therapy were responders (ITT/s incl). In both analyses, patients with missing data at week 48 were classified as failures (i.e., non-responders).
  
  
  RESULTS
  According to ITT/s=f, 22-70% of the patients starting a HAART regimen in a RCT experienced a virological response at week 48. Only two RCTs had complete follow-up data (n=424): between 29 and 62% achieved a virological response at week 48 in the six treatment arms evaluated in the studies according to ITT/s=f, and 41-72% according to ITT/s incl. Among those who discontinued the therapy to be evaluated in these two trials, 13-45% (cohort: 39-74%) subsequently experienced a virological response at week 48. The subsequent response rates were associated with the reason for discontinuation (toxicity versus confirmed virological failure: 63 vs 33%), varied largely across regimens and were not associated with the discontinuation rate.
  
  
  CONCLUSIONS
  Discontinuation of follow-up at switch from the therapy to be evaluated remains common in antiretroviral treatment trials, but leads to an imprecise and incomplete assessment of the intrinsic effect of a given regimen. Complete follow-up of all patients should be encouraged strongly as this will allow for several complementary analytic approaches and a focus on optimal treatment strategies rather than specific regimens.
authors.affiliation: Copenhagen HIV Programme-044, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Kirk
authors.forename: Court
authors.initials: C
authors.lastname: Pedersen
authors.forename: Matthew
authors.initials: M
authors.lastname: Law
authors.forename: Roy M
authors.initials: RM
authors.lastname: Gulick
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.forename: Julio
authors.initials: J
authors.lastname: Montaner
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Phillips
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D019562:Viral Load