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DDI in Treatment Experienced HIV-infected Patients
  Reported by Jules Levin
Molina and colleagues from France reported preliminary results from the Jaguar Study (H-447) in the first HIV slide session at ICAAC on Sunday afternoon.
This study was a randomized multicenter, double-blind, placebo-controlled phase 4 study (29 sites). Patients were under stable ART with virologic failure: plasma HIV RNA 1,000 to 100,000 copies/ml; CD4 count >100; and they had no tenofovir or ddI in the regimen they were taking just prior to this study. Of note, about 70% of patients in the study had prior ddI experience.
DDI (400 mg or 250 mg once daily according to weight) or placebo was added to baseline antiretroviral regimen for 4 weeks (randomization was 2:1, ddI to placebo). The primary endpoint of the study is HIV RNA from baseline to week 4. The study will also look at: relationships between changes in plasma HIV RNA and baseline genotypic and phenotypic resistance test results; safety and tolerability; relationships between changes in plasma HIV RNA and plasma and intracellular concentrations of ddI/ddA-TP.
The study is enrolling 168 patients, calculated to demonstrate superiority of the ddI over the placebo with 90% power to detect 0.5 log difference.
The baseline characteristics of the patients in the ddI & placebo study arms were similar: median age (43 & 42 yrs); 85% & 78% male; CDC stage C, more advanced HIV (17% & 19%); median CD4 count (382 vs 361); median plasma HIV RNA (3.8 vs 3.8 log); median number of NAMS, nucleoside analogue mutations, (4 & 4); previous ddI experience (65% & 74%).
The distribution regarding the percent of patients with certain mutations between the two study arms was similar. M184V was present in 90% of patients. T215, M41L, D67N, K70R, K219E/Q are AZT associated resistance mutations and can be associated also with d4T drug resistance that were present in 30-60% of patients. The 74 mutation is a drug mutation associated with ddI and was present in about 15% of patients.
After 4 weeks 1 patient was lost to follow-up in the ddI arm & 0 in the placebo arm. 1 had withdrawn from the ddI arm & 3 from the placebo arm (2 patient choice, 1 serious AE. 98% (n=108) in ddI arm & 95% (n=55) in placebo arm completed study.
  --Patients with <400 copies/ml at week 4: 31% in ddI arm vs 5% in placebo --patients with <50 copies/ml at wk 4: 11% in ddI vs 0% in placebo (p<0.01) --median change in CD4 count at wk 4: +3 vs –11 (p=0.4)
--Patients receiving ddI with up to 2 NAMS (n=36) had –0.8 to 1 log reductions in viral load --patients with 4 NAMS (n=12) & receiving ddI had –0.6 log reduction in viral load (p=0.002) --patients with 5 NAMS (n=17) had –0.6 log reduction in viral load but was not statistically significant (p=0.059) --patients with 6 or more NAMS did not show viral load reductions of significance
--Patients with 3 or less TAMs (thymidine analogue mutation) who received ddI had a significant viral load response --patients with 0 TAMs (n=23) had –0.7 log reduction --patients with 1 TAM (n=17) had –1 log reduction --patients with 2 TAMs (n=10) had –0.7 log reduction --patients with 3 TAMs (n=25) had –0.5 log reduction --patients with 4 or more TAMs did not have significant viral load reduction
In the question and answer session following the presentation the speaker was asked if patients who had the ddI mutation 74 had a response, but the answer was not clear on whether these patients responded with a viral load reduction. Some observers felt the speaker said no and others felt the response was not clear. Also in the Q & A session Dan Kuritzkes, a noted resistance researcher, expressed concern that 4 weeks may be too short a time period to evaluate the responses.
Adverse Events
38% in the ddI arm and 36% in placebo reported adverse events. Diarrhea was 4% (grade 1) in ddI and 4% (grades 1-2) in the 2 groups. Drug related adverse events was reported as 12% in ddI arm & 13% in placebo. Serious adverse events was 3% in ddI arm and 4% in placebo (admission for liver biopsy, acute delirium, septic shock, malaise, pneumonia).
The results of this study should help identify treatment-experienced patients who will benefit from ddI therapy.
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