STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC

Lennox JL. Lancet. 2009 Sep 5;374(9692):796-806 ; Rockstroh JK. J Acquir Immune Defic Syndr. 2013 May 1;63(1):77-85.

Type of ARV Trial
Head-to-head comparative trials for first line ART since 2006


  • At 48 weeks of treatment, RAL was non-inferior to EFV, in combination with TDF/FTC. Virologic non-inferiority of RAL was confirmed through W24. RAL was superior to EFV for virologic outcome at week 240
  • RAL + TDF/FTC led to more rapid viral load decline (significantly more patients with HIV RNA < 50 c/mL for weeks 2 to 16)
  • Greater increase in CD4 was observed in the RAL group. It was significant from W156
  • Upon virologic failure, resistance mutations to RAL was found in few cases
  • RAL was associated with significantly fewer overall and drug-related clinical adverse events, and CNS-related adverse events than was EFV
  • Mean changes in lipid parameters were smaller for RAL than for EFV
  • RAL + TDF/FTC is an alternative to EFV + TDF/FTC as a first-line combination regimen in treatment-naïve HIV-infected patients

Design :

*Randomisation was stratified by baseline HIV RNA (< or > 50,000 c/mL) and viral hepatitis co-infection status

Objective :

  • Non inferiority of RAL vs EFV: % HIV RNA < 50 c/mL by per protocol, non-completer = failure analysis (lower margin of the 2-sided 95% CI for the difference = - 12%, 90% power)

Baseline characteristics and patient disposition :

RAL was administered with or without food, EFV on an empty stomach at bedtime, TDF/FTC in the morning with food

Response to treatment at week 48 :

* Exclusion of discontinuations due to intolerability or reasons unrelated to treatment

Safety at W48 :

Safety: neuropsychiatric symptoms :

  • At Week 8
    • CNS-related adverse events had occurred in 10% of RAL patients vs 18% of EFV patients (P = 0.0149)
    • Retrospective sensitivity analysis (additional symptoms): > 1 CNS-related adverse event: 20% vs 52% (P < 0.0001)
    • Most symptoms were self-limited
  • At Week 48
    • Cumulative incidence of CNS-related adverse event was significantly lower in patients on RAL: 14% vs 23% in the main analysis (P = 0.0044); 26% vs 59% in the sensitivity analysis (P < 0.0001)
    • These events were generally mild: 62% of RAL vs 79% of EFV
    • Only 1 patient, on EFV, discontinued the trial because of CNS-related adverse event

Cumulative treatment outcome for the entire 5 years study :

Cumulative Discontinuation Rate due to AE (%) :

Response to treatment at week 240 (5 years)

Increases in fasting serum triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol from baseline were significantly lower at W240 (P < 0.005) in RAL than EFV

* Exclusion of discontinuations due to intolerability or reasons unrelated to treatment

Cumulative summary of genotypicresistance data for patients with RNA > 400 c/mL at the time of virologic failure out to week 240

* Integrase gene could not be amplified in 5 cases

  • Emergence of RAL resistance in 4 patients (1.4%)
    Sequencing data of the 4 patients with emergence of RAL-associated mutations
    • Q148H + G140S,
    • Q148R + G140S,
    • Y143Y/H + L74L/M + E92Q +T97A,
    • Y143R

Drug-related adverse events in > 5% in either group over 5 years :