BACKGROUND: Azodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity. OBJECTIVE: A first phase I/II clinical study of ADA. METHODS: ADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage. RESULTS: Fifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 x 10(6) cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10 copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P < 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10 copies/ml compared with baseline and 5/ 11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47-243%), and viral load decrease of 1.04 log10 copies/ml (range 0.52-1.23). CONCLUSIONS: The maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.