July 9, 2001
David Burger is a clinical pharmacologist from the Netherlands, perhaps best known for leading the Athena Trial. His talk was predicated around the question of whether therapeutic drug monitoring (TDM) should be considered the standard of care at this point. The problems are well known: many HIV drugs have narrow margins between efficacy and toxicity, person-to-person variation is large, and response is related to having adequate drug exposure.
Dr. Burger suggested that five ingredients are needed for the elixir of TDM to be effective.
Accurate assays must be available. Quality control between laboratories is lacking. In a recent abstract at the pharmacology meetings, 17 labs were sent identical samples. Thirteen produced accurate results similar to each other; four had potentially dangerous errors.
We must understand the relationship between drug exposure and virologic response for that drug. This also means we must be able to establish therapeutic target levels, which depends not only on the pharmacodynamics but also on the IC50 of the patients' virus.
We must have an effective intervention. This may be increasing the dose or adding ritonavir for pharmacologic enhancement. Sometimes, however, there is not a favorable interaction or the patient cannot tolerate an increased dose.
Ultimately, we should have randomized, controlled trials showing TDM improves outcomes for that drug. In the Athena trial, patients on indinavir or nelfinavir had lower rates of discontinuation if randomized to the TDM arm. For nelfinavir, the benefit was realized as increased efficacy. For indinavir, it was decreased toxicity. It is important to realize that neither Athena, nor the Pharmadapt trial -- which failed to show a benefit from TDM -- were optimally designed. More trials are needed.
Lastly, physicians have to be willing to act based on the TDM results. In a survey done by Burger's group, 50% of physicians felt unwilling to change dose based on TDM.
Burger's final conclusions were that TDM for indinavir and nelfinavir use in naive patients was indeed appropriate. In other situations, he felt it remained experimental, but it should be strongly considered in some circumstances, including children, those with organ failure, and those who might have unexpected or poorly understood drug interactions. I find his argument reasonably compelling, but for physicians in the U.S., problems one and two remain -- that is finding a reliable lab and having appropriate target levels.
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