Methodological issues in the use of composite endpoints in clinical trials: examples from the HIV field

Background In many fields, the choice of a primary endpoint for a trial is not always the ultimate clinical endpoint of interest, but rather some surrogate endpoint believed to be relevant for predicting the effect of the intervention on the clinical endpoint. The classic example of such a field is clinical HIV treatment research, where a variety of primary endpoints are used to evaluate the efficacy of new antiretroviral drugs or new combinations of existing drugs. The choice of endpoint reflects either the goal of therapy as recommended by treatment guidelines (e.g. rapid virological suppression) or the licensing requirements of official drug approval organizations (e.g. time to loss of virological response [TLOVR]). Purpose To review the diversity of endpoints used in recent clinical trials in HIV infection and highlight the methodological issues. Methods We identified articles relating to antiretroviral therapy by searching PubMed and through hand searches of relevant conference abstracts. We restricted the search to randomized controlled trials conducted in HIV-infected adults published/presented from January 2005 until March 2008. Results We identified 28 trials in antiretroviral-naive patients (i.e. patients who were starting antiretroviral therapy for the first time at the time of randomization) and 23 trials in antiretroviral-experienced patients. Most trials were performed for purposes of drug licensing, but others were focused on strategies of using approved drugs. Most trials (40 of 51) used a composite primary endpoint (TLOVR in 13). Of note, 22 of these 40 studies reported that they had used a purely virological efficacy endpoint, but the primary endpoint was actually a composite one due to the way in which missing data and treatment switches were considered as failures. Limitations Examples are restricted to HIV clinical trials. Conclusions Whilst most current HIV clinical trials use composite primary endpoints, there are substantial differences in the components that make up these endpoints. In HIV and other fields where precise definitions are variable, guidelines for standardization of definition and reporting would greatly improve the ability to compare trial results. Clinical Trials 2010; 7: 19-35. http:// ctj.sagepub.com.