Therapeutic drug monitoring is used today in several other diseases. For example, treatments for asthma, epilepsy and certain bacterial infections sometimes employ therapeutic drug monitoring to determine the correct dosage. Several recent studies in HIV infection too have shown that variable blood levels of HIV drugs can have a major impact on the success or failure of antiretroviral therapy. These variations can be caused by how much drug reaches the blood, how rapidly the drug is cleared from the blood, or by metabolic interactions with other drugs. Some studies are now taking place to assess prospectively whether or not measuring antiviral drug blood levels -- then individually tailoring doses to ensure continuous therapeutic levels -- can reduce the incidence of treatment failure.
Since suboptimal drug concentrations are likely to lead to viral rebound, therapeutic drug monitoring might offer a way to achieve optimal concentrations and thus prevent the emergence of resistance and cross-resistance -- or it might not. Therapeutic drug monitoring has already been included in French treatment guidelines (particularly in the setting of suboptimal response to protease inhibitor-containing regimens) and is available to some HIV-infected individuals in several European countries (including France, the Netherlands, and the U.K.) at a cost of $50-75 per person per drug. The clinical benefits of therapeutic drug monitoring, however, remain to be proven.
Plasma concentrations of antiretroviral drugs, particularly the protease inhibitors, vary significantly among individuals. Both the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized through the liver by the cytochrome p450 system, creating complex two- and three-way interactions when these drugs are used together or with other drugs metabolized by the p450 system. In addition, all three classes of drugs may be affected by cellular influx and efflux systems mediated by p-glycoprotein (P-gp), which has been implicated in multi-drug resistance to cancer chemotherapy (see the accompanying article by Yvette Delph). The effects of P-gp on the distribution, metabolism and excretion of drugs, including protease inhibitors, in the body are great. Much is already known about the link between HIV drug pharmacokinetics and treatment outcomes. Let's examine what is already known about the link between HIV drug pharmacokinetics and treatment outcomes.
Later, as the drug lost market share to its more potent classmates indinavir and ritonavir, Roche belatedly conducted studies of higher Invirase doses and of a new soft gel capsule saquinavir formulation, which was dosed at a concentration able to achieve more potent and durable viral suppression. Eventually the new formulation, dubbed Fortovase, was licensed by the FDA and substantially replaced Invirase (dwindling supplies of which are being dumped by Roche in developing countries). Nevertheless, because the pill count for Fortovase, when used as a single protease inhibitor, remains daunting, it is most often used today in combination with ritonavir.
Two recent studies, ACTG 359 and VIRADAPT, showed that pharmacology can help explain treatment failure. This is different, however, from demonstrating that pharmacology -- used in the clinic -- can help maximize treatment success. At least one ongoing study, ATHENA, is attempting to validate the use of therapeutic drug monitoring in a prospective manner.
The ACTG 359 executive summary explained that "the explanation for the inferior virologic effect in the adefovir arms may be that subjects had extensive nucleoside experience or discontinued lamivudine [3TC] upon study entry. . . . The lack of additivity or synergy in the delavirdine plus adefovir combination arms may well be due to an adverse pharmacokinetic interaction between delavirdine and adefovir first demonstrated in the intensive pharmacokinetic substudy (ACTG 884) of the current study . . . [which] showed that delavirdine levels were halved when co-administered with adefovir . . . In addition, saquinavir levels were reduced by about half in the delavirdine plus adefovir combination arms, possibly as a direct result of the decreased delavirdine levels."
So the unexpected adefovir-delavirdine effect caused a chain reaction which, in turn, caused a delavirdine-saquinavir effect, reducing levels of both delavirdine and saquinavir. Clearly, it would have been preferable if the pharmacokinetic substudy had been carried out before ACTG 359.
One hundred and eight individuals with viral load over 10,000 copies/mL who had been treated with protease inhibitors for at least three months and with NRTIs for at least six months were randomized to a control group (N=43) or a group which received genotypic testing results (N=65) before switching therapies. The genotyping technology used was the Visible Genetics TrueGene assay. For six months study participants were treated according to their study group, after which all study participants underwent any necessary treatment changes according to genotypic results received every three months. (A drug resistance table was provided to guide treatment switch decisions.)
The 6-12 month analysis assessed RNA changes from baseline at months 9 and 12, the proportion of individuals with RNA <200 copies/mL. Treatment groups were well-matched by baseline viral load (4.0 log10), CD4 count (210/mm3), prior antiretroviral treatment, and baseline mutation frequency.
The study results showed that protease inhibitor drug exposure was inversely correlated with plasma HIV RNA changes for all four protease inhibitors. What's more, genotypic guided therapy, protease inhibitor concentrations and primary protease mutations independently affected responses to therapy. Thus, both resistance assays and pharmacologic drug testing may be useful to improve treatment responses in experienced patients.
The time to HIV RNA below the limit of quantification were 100 days for the concentration-controlled group compared to 176 days for the standard therapy group (p=0.056). The proportion of individuals reaching a plasma viral load below the limit of quantification were 91% (10 of 11) in the concentration-controlled group and 69% (9 of 13) in the standard therapy group. The investigators concluded that, "preliminary observations support the hypothesis that interpatient differences in antiretroviral drug concentrations contribute to heterogeneity in viral suppression."
What to measure? Trough levels aren't ideal; areas under the curve (AUCs) are impractical; fixed time points are arbitrary; so they are using random sampling with population pharmacokinetic curves. Six hundred individuals will be enrolled, of whom 50% will be treatment naive. Pharmacokinetic results are available to primary doctors within four weeks of sampling. Although everyone's plasma is tested, only half the study participants will be randomized to receive therapeutic drug monitoring test results and expert advice, while control group results are not reported to the primary care physician. The study is about two-thirds enrolled.
In Noordwijk, preliminary results indicated that between 26-41% of people were receiving less than 75% of the target protease inhibitor concentration, and between 5-11.5% were receiving more than 200%, depending on the protease inhibitor. Eighty-six percent of people on nevirapine were receiving adequate concentrations. Of course, no one knows whether the target concentration ratios are correct. It's too early to know whether physicians are using the information from the therapeutic drug monitoring assay to guide therapy. There are no correlations yet with viral load or resistance. The study is ongoing.
Baltimore pharmacologist Charles Flexner gave an overview of this issue in the on-line Hopkins HIV Report (January 2000). He points out that therapeutic drug monitoring can be useful in certain therapeutic settings, such as with the anticoagulant drug warfarin, the anti-convulsant phenytoin, and the immunosuppressive, cyclosporin. However, continues Flexner, "Therapeutic drug monitoring is rarely useful for antibiotics . . . The therapeutic index for most antibiotics is high. . . . Few studies . . . demonstrate a clear-cut relationship between antibiotic concentration and outcome. . . . The most important exception is the aminoglycoside class, where therapeutic drug monitoring is used mainly to prevent toxicity." At the 12th World AIDS Conference in Geneva, two abstracts found a relationship between protease concentrations and virologic outcomes, while three found no such relationship. Flexner goes on to state that "it is essential to show, prospectively, that adjusting dose to achieve some pre-determined target concentration actually improves outcome." The Fletcher study cited above offers some preliminary evidence that this may be the case with AZT+3TC+indinavir, but its small size (N=24), and the increasing use of indinavir at the twice daily 800 milligram dose (in combination with ritonavir 100 or 200 mg BID) may reduce its clinical relevance.
Flexner notes that "some drugs (like AZT and 3TC) exert significant anti-HIV effects yet routinely have trough concentrations of zero." This is (at least in part) because these drugs are active in their intracellular, triphosphate forms, which are not measured by plasma tests. However, this point indicates that therapeutic drug monitoring may be more useful in certain drug classes, and for certain drugs, than in other classes and for other drugs.
In another timely discussion of therapeutic drug monitoring, the Medscape website (hiv.medscape.com) featured a debate between NIH pharmacokineticist Stephen Piscitelli (author of the useful and stimulating study which demonstrated that the popular herbal antidepressant St. John's wort causes dangerous reductions in indinavir concentrations, Piscitelli 2000) and Edward Acosta on the "limited value" (Piscitelli) vs. the "promise" (Acosta) of therapeutic drug monitoring in HIV infection. Piscitelli cites "at least seven substantial obstacles that suggest that therapeutic drug monitoring will have little significance in clinical practice" (see "Some Unanswered Questions About Therapeutic Drug Monitoring," in this issue).
Piscitelli concludes that therapeutic drug monitoring may have a useful role in clinical trials, but "for treating individual patients, less attention should be placed on drug levels and more effort . . . focused on developing new drugs and strategies (ABT-378, indinavir+ritonavir, etc.) which achieve plasma concentrations well in excess of the IC95 to HIV."
Acosta responds by citing the previously mentioned saquinavir data and other protease inhibitor monotherapy studies. He concludes that "the significance of therapeutic drug monitoring for protease inhibitors in the treatment of HIV . . . has yet to be completely understood." He suggests that it may be useful for "random adherence checks," although most pharmacologists at the Noordwijk meeting disagreed with the concept that adherence could be measured pharmacokinetically.
This raises another issue, which is that if an individual is experiencing difficulty adhering to an antiretroviral regimen, measuring and adjusting the regimen dosage may not make much difference. Some therapeutic drug monitoring studies have been distorted by the so-called "white coat effect," in which patients not normally adherent dutifully take all of the pills they're supposed to in the knowledge that they're about to be monitored for drug levels. This would tend to overstate drug exposure over the long term.
The question of whether to measure adherence or drug levels, or both, to optimize therapeutic responses, or to prevent, or identify early and mitigate, antiretroviral treatment failure, remains unanswered at this time. Nor is it clear whether the best use of limited resources is to provide routine therapeutic drug monitoring in the clinic, or simply to develop therapeutic regimens which are more forgiving and have better pharmacokinetic profiles.
One thing that is clear, however, is that pharmaceutical manufacturers need to be more pro-active in providing access to their compounds for drug-drug interaction studies both before and after FDA approval.