Studies

A randomized, open label, study to compare the safety and biological effects of combinations od Didanosine (ddI) and Stavudine (d4T) to Didanosine monotherapy in antiretroviral naïve HIV infected subjects with CD4 cell counts of 150-350 /uL

December 31, 1998

Project no.: HIV-NAT 002

Introduction:

  • Previous studies have shown that d4T and ddI given to antiretroviral naïve subjects with CD4 counts of 200-500 cells/mm3 are safe and confer significant surrogate marker benefits, with CD4+ cell count increase of 60-80 cells/mm3 and reduction of HIV RNA of approx. 1.5log10 from baselin.
  • Benefit is sustained up to 52 weeks. (Pollard et al 1996)
  • Average body weight of Thais have HIV-1 subtype E. At commencement of this study, Thai national ARV guildlines recommeneded initiation of therapy if CD4+ cell count < 350 cells/ul and monotherapy ddI was standard of care

Objective:

  • To evaluate the safety of concurrent administration of d4T and ddI in a range of doses.
  • To evalute the effect of different dosing schedules on CD4+ lymphocyte counts and plasma HIV-RNA.
  • To access safety and optimal dosing schedule for use in a Thai population whose body weight is generally lower than populations previously studies with d4T and ddI

Primary Study Endpoints:

  • Efficacy: as assessed by changes in plasma HIV-RNA and CD4 cell count and the emergence of d4T and/or ddI resistance mutations
  • Safety: as assessed by occurrence of adverse events. Discontinuation/withdrawal from study.

Study design:

  • Patients were randomized to one of four arms.
  • Within each arm, medication dose was adjusted according to weight, above or below 60 kg.
  • Follow up every 4 weeks to 48 weeks.
  • Arms:
    • ddI 400/250 mg/day Monotherapy
    • d4T 40/30 mg/day + ddI 200/150 mg/day Low-Low
    • d4T 80/60 mg/day + ddI 200/150 mg/day High-Low
    • d4T 40/30 mg/day + ddI 400/250 mg/day Low-High
    • d4T 80/30 mg/day + ddI 400/250 mg/day High-High

Study Result:

  • 78 patients were randomized into the study.
  • All of the regimens were considered safe and were well tolerated.
  • At 24 weeks, reduction of HIV-RNA was significantly greater in the four d4T + ddI combination arms compared to the ddI monotherapy arm. (p = 0.001, adjusted for gender and body weight)
  • At week 24, 78% of patients had undetectable HIV-RNA in the pooled combination arms, vs. 21% in the ddI monotherapy arm.
  • Adding d4T at 24 weeks to ddI monotherapy abolished this difference at 48 weeks.
  • Treatment with ddI at the “high” dose was related to a better HIV-RNA outcome at week 48 in those arms. There was no stastically significant difference in outcome in the othre four arms