Predictors of Virologic Response to Ritonavir-Boosted Protease Inhibitors

The primary mechanism of resistance to protease inhibitors involves the stepwise accumulation ofmutations that alter and block the substrate binding site of HIV protease. The large degree of crossresistanceamong the different protease inhibitors is a source of considerable concern for the managementof patients after treatment failure. Although the output of HIV-resistance tests has beenbased on therapeutically arbitrary criteria, there is now an ongoing move towards correlating testinterpretation with virologic outcomes on treatment. This approach is undeniably superior, in principle,for tests intended to guide drug choices. However, the predictive accuracy of a given stratagemthat links genotype or phenotype to drug response is strongly influenced by the study design, datacapture and the analytical methodology used to derive it. There is no definitively superior methodologyfor generating a genotype-response association for use in interpreting a resistance test, and thevarious approaches used to date all have their strengths and weaknesses. Combining the informationof therapeutic drug monitoring and resistance tests is likely to be of greatest clinical utility in antiretroviral-experienced patients harboring HIV strains with reduced susceptibility. The combination ofpharmacologic and virologic parameters as a predictor of the virologic response has been mergedinto the parameter known as “inhibitory quotientâ€?. This article discusses the potential interest of theuse of inhibitory quotients as an approach for enhancing the potency and durability of boostedprotease inhibitors against protease inhibitor-resistant viruses.