Issues in the design and analysis of therapeutic trials in human immunodeficiency virus infection

The first randomized trial of antiviral therapy in human immunodeficiency virus (HIV) disease included 282 patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex and was stopped in 1986 after an average follow-up of 4 months because of a substantial reduction in mortality in the group who received zidovudine (AZT). The era of anti-HIV treatment had begun. This paper discusses some of the difficulties which have emerged over the subsequent 10 years as new anti-HIV drugs have been developed requiring evaluation in clinical trials. The trials in which the British Medical Research Council has played a major role (the Concorde, Alpha and Delta trials) and some of the key trials conducted by the AIDS Clinical Trials Group (ACTG) (the ACTG 019 and ACTG 175 trials) and the Community Programs for Clinical Research on AIDS (CPCRA) (the CPCRA 007 trial) in the US will be used to illustrate some of the issues faced by clinical trialists and governmental regulatory agencies in the evaluation of therapies for a disease which, in spite of advances in therapy, still has a high mortality.