Strategies to improve treatment outcome 10

Interest in therapeutic drug monitoring (TDM) as an adjunct in the management of HIV infection has increased in recent years. The protease inhibitors (PIs) have stimulated the most interest in TDM as they have considerable interand intra-individual variability in plasma levels and marked potential for drug interactions that may lead to reduced or elevated PI plasma concentrations. There may also be a role for TDM with non-nucleoside reverse transcriptase inhibitors (NNRTIs), although this practice is not well established. TDM is currently not appropriate for nucleoside analogue reverse transcriptase inhibitors (NRTIs) as NRTIs require intracellular phosphorylation to achieve their active form, and there is only a weak correlation between plasma concentrations of parent NRTIs and intracellular concentrations of NRTI triphosphates. By measuring drug concentrations in plasma and guiding the clinician in dosage adjustments, TDM may be used to maintain adequate drug exposure and to prevent or overcome virological breakthrough (if drug exposure is too low) or toxicity (if drug exposure is too high). There are a variety of reasons TDM should be useful in clinical practice. These include: • a correlation between drug concentrations and antiviral effect; • variability in plasma drug concentration (due to effects of metabolism via cytochrome P-450, in particular P-450 CYP3A4, p-glycoprotein, the effects of food on absorption, drug interactions, and hepatic dysfunction); • possible correlation between drug concentrations and toxicity; • possible correlation between drug clearance and hepatic dysfunction; • a potential, limited role in assessing adherence to therapy. Despite these theoretical reasons for using TDM, there is a lack of evidence to support its use and introduction into routine clinical practice. The only group in which clinical data support the use of TDM is treatment-naïve patients with ‘wild type’ viral isolates, where the target plasma drug levels for effective inhibition are defined. The first study to investigate the utility of TDM (the PharmAdapt study) was performed in treatment-experienced patients for whom first-line antiretroviral therapies failed. In this study 180 patients received genotypic testing to inform the choice of their new regimen, and were then randomly assigned to a TDM group or a control group that did not receive the results of drug-level monitoring. PI levels were assessed following four weeks of the new antiretroviral regimen. The clinician was advised of the results four weeks later, with dosage adjustment permitted at that time. The plasma HIV viral load at week 12 was used as the primary outcome measure. Neither the reduction in plasma HIV viral load from baseline nor the percentage of patients reaching a plasma HIV viral load of less than 200 copies/mL was different between the TDM and control groups. Several questions have been raised about the design of this study and the design of TDM studies in general; for example, which plasma concentrations should be targeted. Other concerns have been raised about the delay between measuring drug level and subsequent dose adjustment, as well as differences in patient adherence between the two groups, which may have accounted for the negative results of this study. On the other hand, results from the ATHENA study have been impressive. One hundred and forty-seven treatment-naïve patients commencing nelfinaviror indinavir-containing regimens (a subgroup of a total of 600 participants enrolled) were followed for 12 months. Discontinuations were 17.4% in the TDM group and 39.7% in the control group (p=0.003). This difference was driven by a lower rate of virological failure in the nelfinavirtreated TDM recipients (2.4% versus 17.6%, p=0.02) and fewer toxicity-related discontinuations in the indinavir-treated TDM patients (9.5% versus 40.0%, p=0.03). Efficacy, defined as viral load <500 copies/mL using an intent-to-treat analysis, was 94.2% and 79.5% at six months in the TDM and control groups, respectively (p=0.009). At 12 months the results continued to favour the TDM group; a viral load <500 copies/mL was achieved by 78.2% of the TDM group versus 55.0% of those who did not have TDM. These results were largely due to dosage reductions in the indinavir patients and dosage increases in the nelfinavir group. Not accounted for in