CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC

Molina JM. Lancet. 2008 Aug 23;372(9639):646-55; J Acquir Immune Defic Syndr. 2010 Mar;53(3):323-32

Type of ARV Trial
Head-to-head comparative trials for first line ART since 2006
» PI vs PI
» ATV/r + FTC/TDF vs LPV/r + FTC/TDF


  • ATV/r QD demonstrated similar antiviral efficacy to LPV/r BID, when coadministered with TDF/FTC (1)
    • With less gastrointestinal toxicity
    • But with a higher rate of hyperbilirubinemia
  • At W96 (2), HIV RNA < 50 c/mL was obtained in 74% of ATV/r patients vs 68% of LPV/r patients (p < 0.05 in the intent-to-treat analysis) confirming non-inferiority of ATV/r to LPV/r
  • Safety analysis at W96 confirmed W48 results
    • Treatment-related gastrointestinal adverse events were more frequent with LPV/r
    • Hyperbilirubinemia and/or jaundice was the most frequent ATV/r-related adverse event
    • Lipid elevations were significantly higher with LPV/r
  • These results support current recommendation of ATV/r + TDF + FTC QD as a preferred first-line regimen for the treatment of HIV-infected patients

Design :

Objective :

  • Non inferiority of ATV/r vs LPV/r at W48: % HIV RNA < 50 c/mL by intention to treat, confirmed virologic response, non completer equals failure (CVR, NC = F) (lower margin of the 2-sided 95% CI for
    the difference = - 10%, 90% power)

Baseline characteristics and patient disposition :

Response to treatment at week 48 :

Virologic failure :

  • Definition: failure to achieve confirmed HIV RNA < 400 c/mL by W48, or rebound of HIV RNA > 400 c/mL after achieving confirmed HIV RNA < 400 c/mL without re-suppression, or discontinuation due to insufficient HIV RNA response before W48

Safety at W48: ATV/r vs LPV/r :

  • Serious adverse events occurred in similar proportions: 12% vs 10%
  • Grade 2 to 4 treatment-related nausea and diarrhoea were less frequent with ATV/r: 4% vs 8% and 2% vs 11%, respectively
    • Initiation of anti-diarrhoeal medication: 9% vs 22%
  • Grade 2 to 4 jaundice: 4% of ATV/r patients vs none of LPV/r patients
  • Grade 3/4 hyperbilirubinaemia: 34% vs < 1%
  • Grade 3/4 elevations in triglycerides and total cholesterol were significantly less frequent with ATV/r: < 1% vs 4% and 7% vs 18%, respectively
  • Median change in calculated creatinine clearance (Cockroft) was similar in both groups = - 1%
  • Mean increases in total cholesterol, non-HDL cholesterol and triglycerides were significantly lower on ATV/r (p < 0.0001 for the 3)
  • Use of lipid-lowering agents through W48: 2% vs 8%

Summary :

  • ATV/r QD was non inferior to LPV/r BID, when co-administered with TDF/FTC
  • Similar virologic reponse of the 2 PI/r in patients with high HIV RNA at enrolment
  • Results suggest reduced virologic response to LPV/r in patients with baseline CD4 < 50/mm3 mainly because of intolerance to LPV/r in this highly immunosuppressed subgroup
  • Development of major PI-associated resistance mutations occurred in 2 ATV/r patients and no LPV/r patients
  • Incidence of diarrhoea and nausea was lower with ATV/r than with LPV/r
  • Incidence of hyper bilirubinemia with ATV/r was high, but less than 1% of patients discontinued due to jaundice
  • Lipid elevations were less pronounced with ATV/r