If antiretroviral therapy is not working in an individual who is 100-percent adherent to the regimen, drug monitoring of antiretroviral drugs may determine if the lack of treatment response is due to inadequate drug concentrations. Recent studies have suggested that the failure to achieve adequate plasma (one of the components of blood) levels of antiretroviral drugs may contribute to lack of treatment success.
Poor adherence, poor absorption, metabolism, elimination, drug interactions and other reasons may explain why adequate drug concentrations are not reaching the virus. Individual differences in body chemistry limit the effectiveness of treatments for some. Therapeutic drug monitoring (TDM) for antiretrovirals is one way to address this issue, but there is much debate regarding its usefulness in routine clinical care.
Establishing the relationship between plasma concentrations and antiviral effects for both nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is difficult since their anti-HIV effects are not accurately measured by analyzing plasma concentrations. Certain target concentrations, however, are associated with improved antiviral effect for protease inhibitors (PIs).
The levels a drug achieves in plasma varies between individuals as well as within the same individual.
For example, your drug levels may be different in the morning than in the afternoon, and your drug levels may also be different than those of another person who is on the same regimen. Reasons for these fluctuations include drug-to-drug interactions, drug-to-food interactions and problems of adherence.
The significance of TDM for PIs in the treatment of HIV infection has yet to be completely understood and no routine standardized test for TDM exists. The potential benefits and limitations of using TDM for monitoring the antiviral effects of PIs, however, can be summarized as follows:
Drug levels are linked to antiviral effect for all five currently approved PIs, and plasma concentrations significantly contribute to a drug's therapeutic response.
TDM can enhance antiretroviral activity and prevent individuals from failing therapy by individualizing and optimizing drug therapy.
TDM tests generally have good sensitivity and specificity.
TDM over time may address variability within one individual.
Therapeutic concentration (the amount of a drug needed to suppress the virus to a desired level) and maximum toxic levels for each drug (and possibly each drug combination) have yet to be defined. Without this information, using TDM to adjust doses is meaningless.
PIs exhibit significant pharmacokinetic variability from person to person and between different individuals. Pharmacokinetic (PK) is the process of absorption, distribution, metabolism, and excretion of a drug.
Absorption of antiretroviral drugs, for example, is affected by factors such as meals, stomach acidity and antacids. Unless an individual generally eats the same meal each day, concentrations would be expected to fluctuate from day to day. Moreover, since the target concentration required may be substantially higher in a treatment-experienced individual than in an individual who is treatment-naive, the target concentration will vary between individuals.
Confounding factors (factors which distort the true effects of the drugs) may limit the effectiveness of TDM. These factors include synergy between classes of drugs, cross-resistance among classes of drugs, and relationships between adherence, drug exposure, and outcome.
No studies verify that monitoring PIs to achieve a desired plasma concentration provides clinical benefit and decreases the probability of unwarranted toxicities.
Achievement of adequate concentrations of antiretroviral drugs is clearly one factor involved in successful therapy. An increasing body of evidence demonstrates that target concentrations associated with response exist.
Despite these facts, some people feel that TDM of antiretrovirals is probably of minimal value for treating individuals and that less attention should be placed on drug levels. These individuals believe more effort should be focused on developing new drugs and strategies which achieve plasma levels well above the maximum concentration to suppress HIV.
Although monitoring of PI concentrations is not standard in routine clinical care, it may still play an important role in other aspects of HIV management, such as evaluating drug-to-drug interactions and perhaps periodically assessing adherence.
Although TDM tests are commercially available, their widespread use will be limited until a standardized, accurate and inexpensive method to measure drug actions in the body is available.
In general, these tests are expensive ($150 to $200), limited to selected sites, and may not be available for all approved and investigational drugs for which an individual may be receiving. Before insurance companies pay for the service, they must be convinced that TDM is useful.
In order to carefully interpret any results, clinicians must have a thorough understanding of the pharmacokinetics and pharmacodynamics (the physiological effects of drugs and the mechanisms of their actions) of PIs. Studies now under way will address the clinical utility of TDM.
Nancy Wongvipat, M.P.H., is a health education specialist in AIDS Project Los Angeles' Education Division. She can be reached by calling (323) 993-1511 or by e-mail at nwongvipat@APLA.org.