180 Emerging Issues in HIV Drug Resistance Francois Clavel Hosp Bichat-Claude Bernard, Paris, France

HIV resistance is the near inevitable consequence of failure of antiretroviral drugs to fully suppress viral replication in treated patients.  Once resistance has emerged, it is usually irreversible, and extensive cross-resistance within each class of antiretroviral agents can severely compromise the further efficacy of HAART regimens.  Therefore, any attempt to control virus replication in patients harboring resistant HIV variants should combine drugs that can be proved to retain maximal antiviral activity.

Predicting treatment responsiveness of drug-resistant HIV currently relies in part on tests that detect the presence of characteristic mutations in the viral genome or directly measure viral susceptibility to the drugs in tissue culture.  These predictions, however, are often imprecise, a general phenomenon that could have several explanations.  Four aspects of HIV resistance that could contribute in the difficulty to predict viral behavior in vivo will be emphasized in this talk.

·        The selection of resistant variants occurs within a complex population of constantly evolving viral quasi-species, among which only majority species can be evaluated by current resistance tests.  Examples of the importance of minority virus populations in the evolution of resistance are particularly demonstrative with NNRTIs, PIs and entry inhibitors.

·        Cross-resistance is often non-linear. Viruses displaying multiple protease mutations but low cross-resistance can rapidly evolve to high cross-resistance at the expense of minimal genotypic changes.  Preventing the emergence of such key resistance mutations though a maximized early response should be an important goal of salvage antiretroviral therapy.

·        HIV responsiveness to nucleoside analogues such as d4T, ddI and TDF is difficult to delineate.  The susceptibility values measured for these drugs in tissue culture are often remarkably low in spite of RT mutations that testify of their evolution toward resistance.  While these values are therefore often considered as underestimates of the real capacity of HIV to escape these drugs in vivo, there is increasing evidence that nucleoside analogues can retain significant residual activity in vivo in spite of prolonged escape and accumulation of numerous mutations in RT.

·        Viral fitness or replicative capacity could play an important part in the pattern of viral escape after HAART failure and in the pathogenesis of the disease in patients failing therapy.  Although there is convincing evidence that most resistant HIV strains are less fit than their wild-type parental counterparts, the mechanisms involved in balancing maximal resistance at a minimal cost for HIV need to be better understood.