A randomized trial comparing the introduction of ritonavir or indinavir in1251 nucleoside-experienced patients with advanced HIV infection

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to com pare the introduction of ritonavir or indinavir in patients with previous n ucleoside experience and CD4(+) cell counts below 50/mm(3). Concomitant ant iretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, ana lyzed through the whole period of observation by the intention-to-treat app roach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment appr oach. Evaluation of efficacy also included CD4(+) cell and RNA response. Th e trial enrolled 1251 patients in 5 months. At baseline, mean CD4(+) cell c ount was about 20 cells/mm(3) and mean HIV RNA copy number was 4.9 log(10)/ ml in both groups. Overall, 402 patients in the ritonavir group and 250 pat ients in the indinavir group permanently discontinued the assigned treatmen t (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this d ifference dependent on a higher number of discontinuation for adverse event s in the ritonavir group. After a mean followup of 307 days (ritonavir, 304 ; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (riton avir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60 ) were observed. CD4(+) cell counts increased in both groups in patients st ill receiving treatment, with about 100 cells gained by week 24 and 150 cel ls gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log(10) or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 pat ients in the indinavir group developed at least one grade 3/serious new adv erse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0. 0001). Favorable CD4(+) cell and RNA responses at 24 and 48 weeks were obse rved in both groups of patients remaining on treatment. Indinavir showed sl ightly better effects in sustaining RNA, CD4(+) cell, and body weight respo nses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).