Antiretroviral therapeutic drug monitoring (TDM) is an additional monitoring tool to assist in the management of HIV-infected patients. Antiretroviral TDM is frequently undertaken in Europe, but less often in the USA. This overview will assess the principles, current evidence for, and limitations of TDM. Lastly, the potential role of TDM in southern Africa will be discussed. Southern African Journal of HIV Medicine Vol. 7 (2) 2006: pp. 10-1

Maartens, G

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JUNE 2006                                               THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE10GENERAL PRINCIPLES OF TDMThe vast majority of drugs used in clinical practice do not require TDM. It is far easier for clinicians to adopt a ‘one sizefits all’ approach to dosing. Alternatively doses may bemodified according to response. However, with some drugsthis will result in high rates of toxicity, or suboptimal efficacy. The characteristics that make drugs suitable for TDM include:■ A narrow therapeutic window■ Good correlation between drug concentration and effector toxicity■ Variable pharmacokinetics in different individuals■ The availability of a reliable assay.Digoxin and the first-line anticonvulsants are examples ofdrugs where TDM plays an important role. However, even whenall of these characteristics are present, TDM is seldom done asa routine part of management for every patient. Clinicianstypically use TDM if there are clinical concerns such as toxicity,poor efficacy, drug interactions, or special groups at risk ofaltered levels. This use of TDM is rational and appropriate, asthere are very few randomised controlled trials to support theroutine use of TDM.WHICH ANTIRETROVIRALS ARE SUITABLE FOR TDM?The nucleoside reverse transcriptase inhibitors (NRTIs) are pro-drugs, which require activation by intracellular phos-phorylation. There is a poor correlation between plasma NRTIlevels and effect. Only a few laboratories are capable ofmeasuring intracellular levels. NRTIs are therefore not suitablefor TDM.Non-nucleoside reverse transcriptase inhibitors (NNRTIs)display highly variable pharmacokinetics. The key cytochromeP450 isoenzyme responsible for metabolising efavirenz,CYP2B6, has a polymorphism that results in slowermetabolism. This polymorphism occurs much more frequentlyin African Americans than Caucasians1 – it is unclear whetherthis polymorphism will occur commonly in southern Africa.There is a correlation between higher plasma levels andneuropsychiatric adverse effects of efavirenz, and betweenlower levels and virological failure.2 A populationpharmacokinetic study has shown that Thai and South Africanpatients have lower clearance of nevirapine, resulting ingreater exposure, than patients in ‘Western countries’.3 Thismay account in part for high rates of nevirapine-inducedhepatotoxicity, particularly among women with a lower bodymass index, reported in a South African study.4 Highernevirapine levels are associated with a greater chance ofvirological success.5The protease inhibitors (PIs) also have highly variablepharmacokinetics. Plasma concentrations of PIs have beenshown to correlate with virological success.6 High levels ofcertain PIs correlate with adverse drug reactions, notablynephrolithiasis with indinavir7 and dyslipidaemia withlopinavir/ritonavir.8Therefore both NNRTIs and PIs have many characteristics thatmake them potentially suitable candidates for TDM.ARE RELIABLE ANTIRETROVIRAL ASSAYSAVAILABLE?Currently there are no commercial kits to measure drug levelsof antiretrovirals, though a few are in development, soantiretroviral TDM is conducted by laboratories that havedeveloped their own in-house assays. It is therefore essentialthat laboratories participate in regular quality control toensure that their assays are reliable. In a recent survey oflaboratories conducting TDM, only 12 out of 31 had assaysthat were in the acceptable range for more than 90% ofmeasurements.9LIMITATIONS OF TDMA number of randomised controlled trials have been conducted to assess the value of routine TDM. In these studies patientsL A B O R A T O R YANTIRETROVIRAL therapeuticdrug monitoringGary Maartens, MB ChB, FCP (SA), MMed, DTM&HDivision of Clinical Pharmacology, University of Cape TownAntiretroviral therapeutic drug monitoring (TDM) is an additional monitoring tool to assist in the management of HIV-infectedpatients. Antiretroviral TDM is frequently undertaken in Europe, but less often in the USA. This overview will assess theprinciples, current evidence for, and limitations of TDM. Lastly, the potential role of TDM in southern Africa will be discussed.11were randomised to control or TDM arms, where the treatingclinician was advised about the antiretroviral level and, ifnecessary, to adjust the dose. Two of these studies10,11 showedhigher rates of virological suppression in the TDM arms.However, a number of other studies have failed to show abenefit for routine TDM.12,13 One problem encountered in theserandomised trials is that clinicians often did not make therecommended dose adjustments. In some trials the follow-upwas very short. Lastly, the trials were under-powered. Until alarge trial is conducted to address the weaknesses of theexisting studies, there does not appear to be a role for routineTDM for all patients treated with antiretrovirals.A recent study14 found that drug levels, particularly for PIs,were very variable in individual patients sampled at differenttimes. This could partly be explained by the variability in theeffect of dosing with food, which is important for the PIsstudied. In addition, adherence can clearly affect drug levels;indeed, TDM is one tool to detect poor adherence. Controllingfor adherence is difficult in clinical practice. This study14highlights the importance of not making major clinicaldecisions on the basis of a single TDM result.PATIENTS AT HIGHER RISK OF DRUG LEVELS OUTSIDE REFERENCE RANGESGiven that current evidence does not support routine TDM, it makes sense to utilise TDM in patients at particular risk foreither suboptimal or toxic levels. CHILDRENSeveral important physiological changes in childhood,particularly early childhood, affect the pharmacokinetics ofdrugs.15 Firstly, the volume of distribution is affected as totalbody water is high in neonates and remains high in youngchildren. Neonates have impaired drug absorption, metabolismand excretion, while in young children these parameters areenhanced compared with adults. Many authorities thereforerecommend TDM in young children, especially as there are verylimited data available for most antiretrovirals in children.PREGNANCYMany physiological changes in pregnancy affect pharma-cokinetics:16■ Increased GIT motility■ Decreased protein binding■ Increased volume of distribution (fat and water)■ Mild hepatic enzyme induction■ Increased renal excretion.Up to a third of pregnant epileptics experience an increasedfrequency of seizures owing to sub-therapeutic anticonvulsantlevels, illustrating that these physiological changes ofpregnancy are clinically relevant. A recent study showed lowerlopinavir levels in pregnant women.17 Despite this, the womenstill had good virological suppression. This change in PI levelsinduced by pregnancy is likely to be relevant when a degree ofPI resistance is present – TDM should be considered in thissetting.DRUG INTERACTIONSMany PIs are substrates of the important drug transporter,P glycoprotein. Their levels can be affected by drugs thatinhibit or induce P glycoprotein. PIs and NNRTIs aremetabolised by the cytochrome P450 system, and their levelscan be affected by drugs that inhibit or induce this system. Ifa drug known to have such interactions has to be co-administered, TDM should be considered.LIVER DISEASEPIs and NNRTIs are metabolised by the cytochrome P450system, which occurs primarily in the liver. Unlike renaldisease, there is no accurate biochemical marker to indicatehow much hepatic impairment is present. TDM shouldtherefore be considered for patients with evidence of liverfailure, as they may experience toxicity due to high levels.INTEGRATING TDM AND PI RESISTANCE DATA –WHAT’S THE IQ?PI resistance can to a certain extent be overcome byincreasing the levels. It therefore makes sense to integrate theresistance data and the drug level. This is done using theinhibitory quotient (IQ), which is calculated by dividing thetrough level by a factor, depending on the resistance testconducted. This is typically a genotypic test, and the troughlevel is divided by the number of major PI mutations. Thisgenotypic IQ has been shown to correlate with virologicalsuccess in PI-experienced patients.18Note that this strategy cannot be used with the NNRTIs, as asingle mutation generally confers very high-level resistance,which cannot be overcome by increasing the dose.A ROLE FOR TDM IN SOUTHERN AFRICA?Antiretroviral TDM could play an important adjunctive role inour area. Clearly this will be a limited resource, confined tohigh-risk patients or to those with some degree of PIresistance. There is a danger that laboratories will offer TDMwithout the necessary quality assurance. Until commercial kitsbecome available, TDM should only be conducted by specialistpharmacology laboratories that participate in regular qualityassurance.REFERENCES1. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and centralnervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS2004; 18: 2391-2400.2. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenzplasma levels can predict treatment failure and central nervous system sideeffects in HIV-1 infected patients. AIDS 2001; 15: 71-75. 3. Kappelhoff BS, van Leth F, MacGregor TR, Lange JM, Beijnen JH, Huitema AD.Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NNstudy. Antivir Ther 2005; 10: 145-155.4. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associatedwith nevirapine use in HIV-infected patients. J Infect Dis 2005; 191: 825-829. 5. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevirapine inplasma is associated with an improved virological response in HIV-1 infectedindividuals. AIDS 2001; 15: 1089-1095. THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                              JUNE 2006JUNE 2006                                               THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE126. Durant J, Clevenbergh P, Garraffo R, et al. Importance of protease inhibitorplasma levels in HIV-infected patients treated with genotypic-guided therapy:pharmacological data from the Viradapt Study. AIDS 2000; 14: 1333-1339. 7. Dieleman JP, Gyssens IC, van der Ende ME, de Marie S, Burger DM. Urologicalcomplaints in relation to indinavir plasma concentrations in HIV-infectedpatients. AIDS 1999; 13: 473-478.8. Gonzalez de Requena D, Blanco F, Garcia-Benayas T, Jimenez-Nacher I,Gonzalez-Lahoz J, Soriano V. Correlation between lopinavir plasma levels andlipid abnormalities in patients taking lopinavir/ritonavir. AIDS Patient Care STDS2003; 17: 443-445.9. Droste JA, Aarnoutse RE, Koopmans PP, Hekster YA, Burger DM. Evaluation ofantiretroviral drug measurements by an interlaboratory quality controlprogram. J Acquir Immune Defic Syndr 2003; 32: 287-291.10. Burger D, Hugen P, Reiss P, et al. Therapeutic drug monitoring of nelfinavir andindinavir in treatment-naive HIV-1-infected individuals. AIDS 2003; 17: 1157-1165.11. Fletcher CV, Anderson PL, Kakuda TN, et al. Concentration-controlled comparedwith conventional antiretroviral therapy for HIV infection. AIDS 2002; 16: 551-560.12. Haas DW. Can responses to antiretroviral therapy be improved by therapeuticdrug monitoring? Clin Infect Dis 2006; 42: 1197-1199. 13. Khoo SH, Lloyd J, Dalton M, et al. Pharmacologic optimization of proteaseinhibitors and nonnucleoside reverse transcriptase inhibitors (POPIN) – arandomized controlled trial of therapeutic drug monitoring and adherencesupport. J Acquir Immune Defic Syndr 2006; 41: 461-467.14. Nettles RE, Kieffer TL, Parsons T, et al. Marked intraindividual variability inantiretroviral concentrations may limit the utility of therapeutic drugmonitoring. Clin Infect Dis 2006; 42: 1189-1196.15. Fraaij PL, Rakhmanina N, Burger DM, de Groot R. Therapeutic drug monitoringin children with HIV/AIDS. Ther Drug Monit 2004; 26: 122-136.16. Mirochnick M, Capparelli E. Pharmacokinetics of antiretrovirals in pregnantwomen. Clin Pharmacokinet 2004; 43: 1071-1087.17. Stek AM, Capparelli E, Best B, et al. Reduced lopinavir exposure duringpregnancy: preliminary pharmacokinetic results from PACTG 1026. XVInternational AIDS Conference, 11-16 July 2004, Bangkok, Thailand. 18. Marcelin AG, Cohen-Codar I, King MS, et al. Virological and pharmacologicalparameters predicting the response to lopinavir-ritonavir in heavily proteaseinhibitor-experienced patients. Antimicrob Agents Chemother 2005; 49: 1720-1726.

Antiretroviral therapeutic drug monitoring

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Antiretroviral therapeutic drug monitoring

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