Among the devils in the details are protease sequence, susceptibility, and structure in CRF02_AG viruses.

Diverse and distinct subtypes of HIV-1, including complex circulating recombi-nant forms (CRFs), have been outstrip-ping the prototypic subtype B isolates in much of Africa, Latin America, and Asia. However, in the course of drug development , preclinical in vitro studies, pivotal clinical trials, and analyasis of long-term treatment have largely focused on subtype B virus infection. With " scale-up " in global treatment, the pathogenesis and drug susceptibility of non–subtype B HIV-1 infection outside of the United States is a critical question for regional and national treatment guidelines and for clini-cians in the United States and Europe who are confronting an increasingly cosmopolitan epidemic. The work of Kinomoto, Appiah-Opong, and colleagues [1] on the protease inhibitor–susceptibility of Ghanaian viruses of subtype CRF02_AG raises important questions about HIV treatment regimens in West Africa and, more generally , about the susceptibility of non–sub-type B viruses. Are the currently approved antiretrovirals, licensed largely on the basis of clinical trials conducted in the United States and Europe, as active against non– subtype B viruses (specifically CRF02_AG, the dominant CRF in West Africa) as they are against subtype B viruses? Do common , subtype-related polymorphisms in gag-pol in subtype CRF02_AG viruses— some of which are associated with drug resistance—significantly impact the effectiveness or the outcome of protease in-hibitor–based therapies? Do the modest changes in drug susceptibility, carefully sought through sensitive recombinant phenotypic assays and in structural binding studies, identify an important mechanism for drug failure and selection of resistance in non–subtype B infection? Despite nearly 10 years of HAART, only a handful of clinical studies compare patients who have subtype B infection with patients who have non-subtype B infection in terms of their response to commonly prescribed regimens. Comparisons of patients infected with different viral subtypes are limited by the diversity of HIV, both within and between subtypes, as well as by differences in site and host factors, including pharmacogenomics, nutritional status, adherence, access, and educational and socioeconomic status. With respect to randomized clinical trials, there is an encouraging trend in the conduct of pivotal clinical trials of HAART. Increasingly , phase III clinical trials are becoming truly global, including sites in Europe, Latin America, Africa, and Asia where non–subtype B viruses predominate. Analysis of these clinical trials may provide insight into the effects of variation in viral subtype and host genomics. However, among the widely divergent and evolving subtypes and CRFs, even large international …