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Still Hard to Prove Therapeutic Benefit With Therapeutic Drug Monitoring
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
Although therapeutic drug monitoring (TDM)--adjusting an antiretroviral dose based on low or high plasma concentrations--remains an intuitively attractive proposition, proof that it improves response or avoids toxicity has largely eluded researchers. This string of failures, or semi-successes, continued with ACTG A5146, a randomized trial assessing the value of changing protease inhibitor (PI) levels after TDM in people with at least one PI failure.
Lisa Demeter (University of Rochester) and ACTG coworkers figured a normalized inhibitory quotient (NIQ) by calculating each patient's IQ as PI trough 2 weeks after beginning a salvage PI divided by fold-change in 50% inhibitory concentration to that PI at screening. NIQ equaled patient IQ divided by IQ of a reference population that responded virologically to that PI. Demeter theorized that people with an NIQ at or below 1 would benefit from a higher PI dose. Thus at study week 4 the ACTG team randomized 91 people with a low week 2 NIQ to standard of care and 92 to TDM. Only physicians of people in the TDM arm got the NIQs and could raise the PI dose for a persistently low NIQ.
Nine in 10 patients were men, half were white, and median age stood at 45 years. Entry viral load measured 4.36 log (about 20,000 copies), median CD4 count 194, and median number of active PIs (figured by vircoTYPE) 0.7. No one took darunavir, and all PIs used except nelfinavir got a ritonavir boost. Study participants could take double PIs.
Twenty week after randomization, people in the TDM group had significantly higher PI troughs than people in the control arm, except for the 32% taking fosamprenavir. Median NIQ rose significantly more with TDM than without TDM (69% versus 25%, P = 0.01). When Demeter eliminated people taking fosamprenavir, the TDM group did even better in bolstering their median NIQ (87% versus 25%, P = 0.006).
But when Demeter looked at the primary endpoint--difference in log viral load change 20 weeks after randomization--she saw no significant difference between TDM (+0.09 log) and no TDM (+0.02 log, P = 0.17). Neither did the two groups differ in time to virologic failure or toxicity.
In analyses not planned before ACTG A5146 began, statisticians did coax forward some hints of TDM benefit. People who started the trial with 0.7 or more active PIs benefited virologically from TDM (P = 0.002 versus no TDM), whereas people with fewer than 0.7 active PIs did not (P = 0.35). The investigators believe that analysis suggests high levels of PI resistance in the study group could have obscured any TDM benefit. Unavailability of darunavir during the trial surely did not help.
In another unplanned analysis, Hispanics and blacks (49% of study participants) benefited from TDM (P = 0.035 for Hispanics, P = 0.05 for blacks), but whites did not (P = 0.40). Blacks and Hispanics did not differ from whites in body mass index, starting viral load or CD4 count, level of PI resistance or adherence, or fosamprenavir use.
Demeter and colleagues volunteered no hypotheses for why amprenavir levels did not rise with dose adjustment of fosamprenavir. (Amprenavir is the active metabolite of fosamprenavir.) But they suggested that frequent use of fosamprenavir by study participants may have blunted any TDM benefit. The researchers also declined to speculate on why blacks and Hispanics seemed to benefit from TDM when whites did not.
Reference
1. Demeter L, Jiang H, Mukherjee L, et al. A prospective, randomized, controlled, open-label trial evaluating the effect of therapeutic drug monitoring and protease inhibitor dose escalation on viral load responses in antiretroviral-experienced, HIV-infected patients with a normalized inhibitory quotient. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 35.
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