Timing of antiretroviral therapy. Use of Markov modeling and decision analysis to evaluate the long-term implications of therapy

Background: The timing of initiation of antiretroviral therapy is controver sial. Current guidelines are heavily based on the principle of 'hit early, hit hard', although the long-term implications of this approach are unknown . Methods: Using Markov modeling and decision analysis we modeled the virolog ic outcomes over 10 years in a hypothetical population of 10 000 HIV-iniect ed patients in which therapy (with the possibility of three sequential regi mens before the develop ment of multidrug-resistant virus) is started immed iately versus starting progressively at rates of 5, 10, 15, 20 or 30% of th e original population each year. The model used inputs from available clini cal trial data: virologic success rate and durability of the response of th e first and subsequent regimens. We performed one-way and two-way sensitivi ty analysis to evaluate changes in the input variables. Results: If therapy is started immediately in all patients, by 10 years 57% would be undetectable, but 38% would have detectable multidrug-resistant v irus. In contrast, the population as a whole would have had better virologi c outcomes if one waited before starting treatment at any progression rate: for example, initiating therapy in 10% of the subjects per year results in 64% of patients being undetectable and 24% with multidrug-resistant virus. Two-way sensitivity analysis demonstrates that immediate initiation should be at least 15 to 20% better than delayed antiretroviral therapy to justif y immediate initiation of therapy over a wide range of success rates of the delayed start. Conclusion: Our analysis, utilizing optimistic outcomes based on short-term clinical trials, provides a theoretical basis for questioning the current aggressive early use of therapy and should help prompt studies that look at when and how to start antirelroviral therapy. (C) 2001 Lippincott Williams Wilkins.