CONSIDERATIONS IN CHOICE OF A CLINICAL END-POINT FOR AIDS CLINICAL-TRIALS

In most clinical trials of antiretroviral therapy for patients infecte d with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS defining event. We review featur es of combined endpoints and use data from the Terry Beirn Community P rograms for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty and sensitivity. We conclude that this endpoint is not relevant because: (i) the 19 dif ferent events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of dea th; and (ii) events after the first are ignored, thus the event profil e of patients is not taken into account in making treatment comparison s. We also conclude that power may be low with use of this endpoint if treatments under study do not have an immediate impact on disease pro gression, if some events which occur soon after randomization represen t a disease process that has already begun to incubate, or if treatmen t differences for the various events constituting the combined endpoin t are differentially effected by treatment. Since the ease and certain ty of diagnosis of each of the 19 events also vary, we recommend that survival be the primary endpoint of antiretroviral trials, and that al l opportunistic events experienced by patients, not just the first, be collected and summarized. Trial reports should include comparisons of incidence of each event by treatment group so that readers can rank e vents as they please. A single summary measure which considers severit y and the entire event profile, as described here, would also be usefu l for assessing the impact of treatments on quality of life. Further r esearch on approaches for weighting and combining multiple outcome mea sures is needed.