The Lancet

Copyright 1993 by The Lancet Ltd.
Volume 341(8849)             Apr 3, 1993             pp 889-890
Preliminary analysis of the Concorde trial.
[Letters to the Editor]

Aboulker, Jean-Pierrre; Swart, AnnMarie.

INSERM SC10, 16 Av Paul Vaillant Couturier, 194807 Villejuif, France (Jean - Pierre Aboulker); MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology, Royal Brompton National Heart and Lung Hospital, London SW3 6NP, UK (Ann Marie Swart, on behalf of the Concorde Coordinating Committee)

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Sir,- We report preliminary findings from the Concorde trial, a multicentre, randomised, double-blind, placebo-controlled study. Concorde was designed in 1988 to determine whether symptom-free HIV-infected individuals would benefit from starting zidovudine at randomisation (Imm) rather than deferring treatment until the onset of symptomatic disease (the Def group, who initially received placebo). The endpoints were progression to CDC group IV disease (AIDS or "minor" AIDS-related complex [ARC] based on one or more minor opportunistic infections or one constitutional symptom), death, and severe drug toxicity. In October, 1989, after early termination of a similar trial (ACTG 019) in the USA (1), the protocol was modified to allow participants to begin zidovudine on the basis of at least two CD4 counts of less than 500/mu L at least 1 month apart. The trial was analysed on an intention-to-treat basis.

Between October, 1988, and October, 1991, 1762 individuals were randomised from centres in the UK, Ireland, and France; 13 were randomised in error. Our analysis is based on the remaining 1749, of whom 877 Imm were allocated to 250 mg zidovudine four times daily and 872 Def to matching placebo. Two interim analyses were reviewed by an independent data and safety monitoring committee. Preliminary findings of a planned definitive analysis of events taking place up to December 31, 1992, based on 5328 person-years of follow-up (mean follow-up 3 years) are reported here. The characteristics of the two groups at baseline were similar for age, sex (15% were women), CD4 cell counts (table I), p24 antigen, Beta 2 microglobulin, risk group, and time since first positive HIV test.


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*Table I. Clinical outcome in a preliminary analysis of the concorde trial *.

Only 7% of participants (8% Def, 6% Imm) were lost from follow-up for more than 6 months. Although, following the protocol modification, 231 Imm and 282 Def subjects started open-label zidovudine before developing symptomatic disease, there was a striking difference in the amount of zidovudine taken by the two groups: those in the Imm group spent 85% of total time on study before progression to ARC or AIDS on zidovudine in the first 18 months compared with only 7% for the Def group (the figures for the first 3 years were 82% and 14%, respectively).

There was a clear difference in the changes in CD4 cell count over time between the two groups. Median changes from baseline at 3 months were +20 cells Imm and -10 cells Def, a difference of 30 cells (95% CI 16-44; p<0.0001). Differences between the groups at 6 and 12 months were 35 and 32 cells, respectively (p<0.0001 for both). This difference was observed up to 3 years, although based on smaller numbers.

By contrast with the differences in CD4 count, there was no significant difference in clinical outcome between the two therapeutic strategies. The 3-year survival rates were 92% (90-94%) in the Imm group and 93% (92-95%) in the Def group (p=0.15, two-tailed), with no significant differences overall or in subgroup analyses by CD4 count at baseline (table I). This conclusion was unchanged when analyses were restricted to deaths classified as probably HIV related. Similarly, there was no significant difference in rates of progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to "minor" ARC, AIDS, or death these rates were 29% (Imm) and 32% (Def).

3 patients had life-threatening adverse events that may have been drug-related, 2 while taking zidovudine and 1 on placebo. The frequency of severe haematological and other expected adverse events associated with a dose of 1 g zidovudine daily for up to 4 years was very low but significantly different between the two groups: 16 Imm and 3 Def participants stopped trial capsules for anaemia, neutropenia, or both, and the estimated proportion of participants with haemoglobin dropping below 10 g/dL was 5% and 1%, respectively, at 1 year and 9% and 2%, respectively, at 3 years. A further 82 (9%) Imm and 37 (4%) Def subjects stopped for other adverse events, most of which were gastrointestinal.

To date, the results of four placebo-controlled studies of zidovudine in early HIV infection have been published from the USA, two like Concorde in symptomless infection and two in early symptomatic infection (1-4) . The total number of progressions to AIDS or death in these trials combined was 186 compared with 346 in Concorde. Three of the four studies were terminated early with average follow-up of about 1 year or less (1-3) . The fourth had an average follow-up of just over two years and did not show a survival difference (4). The main finding from these four trials was a delay in the clinical progression to AIDS or severe ARC. The findings from Concorde at a comparable short follow-up time were not inconsistent with this. However, such a delay was not seen over the longer follow-up period.

In conclusion, Concorde has not shown any significant benefit from the immediate use of zidovudine compared with deferred therapy in symptom-free individuals in terms of survival or disease progression, irrespective of their initial CD4 count. The discrepancy between this result and the significant effect of immediate zidovudine on CD4 cell counts casts doubt on the value of using changes over time in CD4 count as a predictive measure for effects of antiviral therapy on disease progression and survival. Concorde provides a valid comparison of the strategies of immediate versus deferred treatment with zidovudine since there was a striking difference between the two groups in the amount of zidovudine taken on study before progression to ARC or AIDS. A more detailed analysis is being prepared and follow-up continues in all patients.

REFERENCES

1. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990; 332: 941-49. [Medline Link] [Context Link]

2. Merigan TC, Amato DA, Balsley J. Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. Blood 1991; 78: 900-06. [Medline Link] [Context Link]

3. Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. Ann Intern Med 1990; 112: 727-37. [Medline Link] [Context Link]

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