Therapeutic Drug Monitoring: The Next Best Thing in HIV Treatment?
Therapeutic drug monitoring (TDM) uses blood levels of a drug to adjust its dose to achieve the maximal benefit and/or to achieve the minimal toxicity. This approach to customizing drug dosing has great appeal for the treatment of HIV. The promise of TDM is that it could increase HIV suppression and possibly lower drug side effects. The problem with TDM is that the studies are difficult to conduct, and there have not been adequate TDM trials to support its routine use in the clinic. Several studies have shown better HIV suppression with the use of TDM. However, it is difficult to separate the effect of TDM in increasing adherence compared to its effect in increasing the blood levels of drugs. Several studies are now under way by the AIDS Clinical Trials Group (ACTG) and others, evaluating TDM.
TDM is not routinely used in most areas of medicine, so this approach needs to be tested. However, the rationale for TDM is supported by retrospective data showing that there are great variations from person to person in bloods levels of some anti-HIV drugs, particularly the protease inhibitors (PIs). It has been shown that the people with the higher blood levels have greater HIV suppression.
Many factors are responsible for the different blood levels in different people. These include known and unknown genetic variations, different absorption rates, different rates of removal of the drug once it reaches the blood, and different rates of protein binding, which can make a drug unavailable. Also, since people vary greatly by body fat and lean muscle composition, it may be beneficial to customize the dose. Some drugs are stored in body fat and may last longer in the body of people with greater body fat.
What needs to be shown in large trials is that by adjusting the dose in individual people, the outcome of treatment will be enhanced. Data similar to that obtained for PIs is harder to come by for the nucleoside reverse transcriptase inhibitors (NRTIs) because they are activated inside the cell and the blood level does not necessarily correlate with the level of the activated nucleoside inside the cell.
The basic approach of TDM is to measure the level of the drug in the blood when it is near its lowest, just prior to the next scheduled dose. This is called the trough level. The trough level should be high enough to suppress HIV replication. In the past, another obstacle to TDM trials has been that the ideal trough level for the individual person was not known. However, the phenotype resistance test allows determination of what the minimally effective blood level of a drug should be, at least for the PIs.
The general design of the current, long-awaited, TDM trials is a comparison, by randomization, between a group of people on standard dosing and a group receiving active monitoring and adjustments in the blood level of the PI. TDM trials can be challenging because a person needs to come to the clinic at precise times related to their dosing schedule to obtain accurate trough levels, and then return after an adjustment to determine if the adjustment has had the desired effect. Also, there is a concern about additional side effects when people are given drugs at higher doses than those usually prescribed. It may be that some side effects are not directly related to the blood level of the drug.
Most TDM trials are focusing on people with evidence of some degree of HIV drug resistance because this is where the greatest effect of customizing drug dosing may be observed. If the HIV virus is very sensitive, the difference in drug levels from person to person may not make much difference. But when only higher drug levels suppress HIV, TDM may make the difference between total versus partial HIV suppression.
Another potential benefit of TDM could be lowering the dose in people with higher than necessary levels, to reduce side effects. Studies are currently being conducted to examine the blood level of drugs to see if they correlate with side effects, such as the altered thought processes that some people experience from Sustiva. Do those people have higher blood levels than people not experiencing those side effects?
Hopefully the results of the current TDM studies will determine if this approach should be used in all people receiving HIV treatment.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.