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 controversial. 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 virologic outcomes over 10 years in a hypothetical population of 10 000 HIV-infected patients in which therapy (with the possibility of three sequential regimens before the development of multidrug-resistant virus) is started immediately versus starting progressively at rates of 5, 10, 15, 20 or 30% of the original population each year. The model used inputs from available clinical trial data: virologic success rate and durability of the response of the first and subsequent regimens. We performed one-way and two-way sensitivity 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 virus. In contrast, the population as a whole would have had better virologic 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 justify immediate initiation of therapy over a wide range of success rates of the delayed start.


CONCLUSIONS
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 antiretroviral therapy.
Tebas
P
P
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63108, USA. tebas@im.wustl.edu
Henry
K
K
Nease
R
R
Murphy
R
R
Phair
J
J
Powderly
W G
WG
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003663:Decision Trees; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008390:Markov Chains; D015233:Models, Statistical; D013997:Time Factors; D016896:Treatment Outcome
D019380:Anti-HIV Agents