The relevance of pharmacologic monitoring in HIV disease

Determining the reasons for failure of highly active antiretroviral therapy (HAART) has long been a frustrating question for researchers and clinicians alike. Very often, the underlying causes of therapeutic failure in individual HIV-positive patients are established after the fact – when viral load has rebounded and a switch to a second-line regimen is inevitable. But times are changing and, with new laboratory markers, intervention before virologic failure occurs has become a possibility.

The emergence of drug-resistant virus is often described as the root cause of virologic failure in patients receiving HAART. Yet, when reviewing what is currently known about the various pathways that can lead to virologic rebounds in patients receiving HAART, the development of drug resistance is much more of a consequence of failure than a factor contributing to it.

As explained by Dr. Hoetelmans and a number of his peers, virologic failure – along with the emergence of drug-resistant virus – often begins with insufficient drug exposure in patients receiving HAART. And while it is true that poor adherence and other behavioural factors are frequently linked to substandard plasma concentrations, the actual pharmacokinetics of individual drugs can also be blamed.

It is important to note that plasma concentrations may also be associated with excessive toxicity. A number of studies have shown that high doses of protease inhibitors are associated with reversible liver damage, kidney stones (indinavir; Crixivan), and circumoral parasthesia (ritonavir; Norvir).

Enter therapeutic drug monitoring (TDM), a somewhat complicated laboratory test that allows researchers and clinicians to measure blood levels of antiretroviral drugs and, as a result, tinker with dosing in an individualized manner. TDM is currently recommended by the British HIV Association and the French Department of Health in its HIV treatment guidelines released last year (see the special report on these guidelines in the December 1999 issue of The PRN Notebook) and is being offered by a number of laboratories in the Netherlands, France, and England. While TDM is not typically employed in the United States, most clinicians are familiar with its usefulness, particularly for patients being treated with narrow therapeutic index drugs (e.g., phenytoin (Dilantin), digoxin (Lanoxin), lithium bicarbonate, and theophylline).

Whether or not TDM will enter the clinical care vernacular for HIV-infected patients is still not known. Answers to this central question will eventually come from the studies – both retrospective and prospective – currently under way and planned for the future.