Research Initiative Treatment Action (RITA!); Vol 5, No. 4 October 1999
 

Beyond CD4 T cell counts, plasma viral load testing and drug resistance monitoring, there lies yet another assay competing for the attention of HIV-infected people and their healthcare providers: therapeutic drug monitoring (TDM).

Scientists have shown that the blood level of protease inhibitors (PI) is correlated with antiviral effect. For some patients, inadequate PI blood levels could therefore explain clinical drug failure. Other reasons for drug failure include non-adherence and partially suppressive treatment regimens.

With the link established between drug concentration—at least for the protease inhibitors—and drug effect, clinical drug monitoring has drawn supporters. Edward Acosta, PharmD, in an article for Medscape, writes, "TDM seeks to increase the probability of an optimum [treatment] response for all patients."

TDM's principal use is the identification of patients who fail to absorb adequate levels of drug. So how many patients are poor absorbers? Charles Flexner, MD, an expert in HIV pharmacology with Johns Hopkins University, has suggested that non-adherence to treatment accounts for the great majority of sub-therapeutic drug levels, with perhaps only 5 to 10% of patients who actually take their medications failing to absorb enough drug.

For those who do fail to absorb adequate drug, TDM may serve to establish that fact. But what these patients really need, Flexner argues, is a test capable of predicting—before treatment starts—who absorbs well and who does not.

Moreover, Stephen Piscitelli, PharmD, has identified several limitations of TDM:

• Blood levels vary not only between patients, but within the same patient. "This means," Piscitelli writes, " that a blood level collected on Monday and used to make therapeutic decisions may be markedly different from one drawn on Friday."
• The plasma level of a particular protein affects protease inhibitors. When that protein level rises—as it does during stress, injury or infection—the drugs are less active against HIV. Therefore, simply measuring drug level, without also measuring protein level, may overstate "the true 'active' concentration" of drug.
• What constitutes adequate drug level? The answer for treatment naïve patients is likely to differ from the answer for treatment-experienced patients.
• The logistics and scheduling for TDM blood draws would pose a challenge for many patients and clinics. Two weeks or more may pass from time of blood draw to receipt of results. In the meantime, antiviral resistance may have already developed.
• Interpreting the results of a TDM blood draw can be challenging. For example, the plasma half-life of didanosine (Videx) is 1 to 2 to hours. But it is the intracellular concentration of this drug, and not the plasma concentration, that matters. The intracellular half-life of didanosine is over eleven hours. A clinician with a report of undetectable plasma levels of didanosine might mistakenly conclude that the patient was either nonadherent or a poor absorber, when in fact the patient was taking the medication as prescribed.
• TDM is expensive.

TDM has a certain understandable appeal. But the assay has significant limitations and is unlikely to become part of the routine care of patients anytime soon.

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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org

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