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When to Switch Antiretroviral Therapy
S G Deeks
Univ of California, San Francisco
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Background: Many patients (pts) treated with combination antiretroviral therapy fail to achieve complete viral suppression. Ongoing viral replication in the presence of therapy leads to the accumulation of drug-resistance mutations, resulting in increased levels of viremia and a greater risk of disease progression.
Methods: The recommended approach for most pts experiencing incomplete viral suppression with their first or second regimen is to modify treatment as soon as possible, with the goal of preventing the accumulation of drug-resistant mutations. The question of “when to switch” antiretroviral therapy for the heavily pre-treated pt with limited therapeutic options is not clear. Such pts have one of three broadly defined options: switch to an aggressive regimen with a goal of maximal viral suppression, interrupt all therapy, or continue a partially effective regimen despite the presence of drug-resistant HIV. Optimizing individual treatment strategies requires an understanding of the complex relationship between replication of drug-resistant virus and subsequent immunologic and clinical outcomes.
Results: To address this issue we have performed a series of studies focusing on the determinants of partial viral suppression in pts with drug-resistant viremia, and have observed the following: 1) drug resistance increases over time, although the rate of resistance mutation accumulation is not constant; 2) antiviral drug therapy often has persistent anti-HIV activity against resistant strains (e.g., drug-resistance is rarely complete); 3) HIV is often constrained in its ability to develop high-level drug resistance while maintaining replicative capacity; and 4) CD4+ T cell counts and HIV-specific T-cell activity are often preserved during incomplete viral suppression, perhaps due to altered virulence of the drug-resistant variant.
Conclusions: An understanding of these factors may allow for development of optimal therapeutic strategies in pts with drug-resistant viremia.
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