CONCORDE - MRC ANRS RANDOMIZED DOUBLE-BLIND CONTROLLED TRIAL OF IMMEDIATE AND DEFERRED ZIDOVUDINE IN SYMPTOM-FREE HIV-INFECTION/

Concorde is a double-blind randomised comparison of two policies of zi dovudine treatment in symptom-free individuals infected with human imm unodeficiency virus (HIV): (a) immediate zidovudine from the time of r andomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the de velopment of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991 , 1749 HIV-infected individuals from centres in the UK, Ireland, and F rance were randomly allocated to zidovudine 250 mg four times daily (8 77 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 3 1, 1992 (total 5419 person-years; median 3.3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of th ose allocated to the Def group, 418 started zidovudine at some time du ring the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subseque ntly) and most of the remainder on the basis of low CD4 cell counts. T hose in the Imm group spent 81% of the time before ARC or AIDS on zido vudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups an d the fact that the number of clinical endpoints (AIDS and death) in C oncorde (347) outnumbers the total of those in all other published tri als in symptom-free and early symptomatic infection, there was no stat istically significant difference in clinical outcome between the two t herapeutic policies. The 3-year estimated survival probabilities were 92% (95% CI 90-94%) in Imm and 94% (92-95%) in Def (log-rank p = 0.13) , with no significant differences overall or in subgroup analyses by C D4 cell count at baseline. Similarly, there was no significant differe nce in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (I mm) and 32% (Def) (p = 0.18), although there was an indication of an e arly but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups. Median changes from ba seline at 3 months were +20 cells/mu L (Imm) and -9 cells/mu L (Def), a difference of 29 cells/mu L (95% CI 16-42; p < 0.0001) which persist ed for up to 3 years. Thus such persistent differences in CD4 cell cou nt do not necessarily imply long-term differences in clinical outcome. 6 participants had life-threatening adverse events that were judged t o be possibly drug related: 4 occurred on trial capsules before unblin ding (3 on zidovudine, 1 on placebo) and 2 occurred on open zidovudine . Despite a daily dose of 1 g of zidovudine, the frequency of severe h aematological and other adverse events on trial therapy was low but si gnificantly higher in the Imm group: 16 Imm and 2 Def participants sto pped trial drug for haematological events and the estimated proportion s with haemoglobin dropping below 10 g/dL were 5% and 1%, respectively , at 1 year and 8% and 2%, respectively, at 3 years. Another 83 (9%) I mm and 36 (4%) Def participants stopped for other adverse events, pred ominantly gastrointestinal or neurological symptoms (headaches) or mal aise.