Therapeutic Drug Monitoring: A Tool to Individualize Highly Active Antiretroviral Therapy in HIV Infected Patients

Peter      Langmann; Michael      Zilly; Ralf      Winzer; Hartwig      Klinker

doi:10.2174/157341206777934635

Abstract

In HIV-infection, therapeutic drug monitoring (TDM) has been proposed to optimize highly active antiretroviral therapy (HAART) response. Pharmacokinetics of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz and nevirapine have been proved suitable for monitoring their plasma drug levels. In contrast, nucleoside reverse transcriptase inhibitors (NRTI) contain lack of a certain correlation between plasma levels and drug efficacy. Currently, TDM under HAART is limited by some uncertainty which pharmacokinetic predictor to prefer and on which drug concentration or range to rely on. In a therapy naive patient trial (ATHENA) on indinavir or nelfinavir based drug regimens, the study arm with use of TDM resulted in prevention of virological failure or treatment discontinuation due to drug toxicity. Current data ascribed increasing importance to TDM in ritonavir boosted PI combinations especially for lopinavir, atazanavir and fosamprenavir. Besides, further applications are proposed in selected patients groups (i.e. children, pregnancy, renal or hepatic dysfunction, weight loss) to confirm adequate drug concentrations and manage drug-drug- interactions. PI double-boosting in salvage regimens in patients with multiple NRTI associated mutations should also require TDM for handling dose adjustments, moreover, treatment experienced patients might benefit from TDM in combination with viral resistance testing. Limitations to the application of TDM are considered as non standardized procedures or techniques permitted to correlate pharmacological and virological data therefore, an approach towards standardization is needed. So far the inhibitory quotient (IQ) (necessitating phenotypical resistance testing) or the genotypic inhibitory quotient (GIQ) (referring to the number of viral mutations using a genotypic resistance test), could become increasingly important in this context. In assessing adherence, TDM allows to confirm the correct medication intake, but only the last few doses taken by a patient will be reflected. Without TDM, numerous interactions by co-administered drugs (antibiotics, antacid drugs, hypnotics, herbals, life-style drugs) turn out to possibly lead to obscure interpretations and individual medical care remains elusive. Currently, the interpretation of PI and NNRTI drug levels is based on increasing experience using TDM. Even though TDM in HAART is not the gold standard of care, yet, it provides security in guiding patients on an individual therapy and might be linked with pharmacogenomics in resource-rich countries.

Keywords: Therapeutic Drug Monitoring, HAART, PI, NNRTI, HIV