Issues in the design of trials comparing management strategies for heavily pretreated patients

Abstract

Strategies for the optimal management of heavily pretreated patients with multiple drug resistance mutations in whom viral suppression is not possible are not well defined. Trials of strategic management approaches (as opposed to testing the effect of one specific drug) in this area have been mainly limited to evaluating treatment interruptions, testing the benefits of multidrug ('mega-highly active antiretroviral therapy') regimens, and evaluating the use of resistance test data for choosing new regimens. Treatment interruption before the start of a new regimen has been found to be detrimental, in terms of the risk of clinical disease, compared with no interruption. Mega-highly active antiretroviral therapy has not yet convincingly been shown to improve overall outcomes. The use of genotypic resistance testing has been shown to be useful when constructing a new regimen. Several challenges exist in designing future strategic trials in this area. These include the formulation of suitable new strategies which are generalizable across specific drugs and drug classes, the choice of suitable and feasible endpoints, and the incorporation of sufficient flexibility (so that patients are not too constrained to commit to entry) without compromising the ability to answer the question.