Key research on testing for PI levels

Key research on testing for NNRTI levels

Barrett (2002) developed a pharmacokinetic model of efavirenz clearance. This model was subsequently used by Fiske (2001) to analyse data from 524 patients who received efavirenz and for whom pharmacokinetic data were available. 56% reported CMS symptoms, but no relationship between EFV AUC or C_max was found; C_max was 10.9 in those with CNS symptoms, 11.1 in those with mild symptoms (n=184), 10.8 in those with moderate symptoms (n=97) and 10.7 in those with severe symptoms (n=14). Data were also analysed for association between HIV RNA response at week 8 and EFV AUC and C_min. No significant relationship was found.

Nunez (2001) reported a case control study in which 15 patients with severe efavirenz CNS toxicity were compared with 36 control patients also receiving EFV. Efavirenz plasma levels above 3.5ug/ml were associated with CNS toxicity (p=0.002; OR 6.3).

See also Efavirenz - key research in Drugs used by people with HIV for further information on pharmacokinetic studies of efavirenz.

Pharmacogenetic studies of drug levels

Fellay (2002) of the Swiss HIV Cohort Study found that median drug concentrations in 123 patients receiving nelfinavir or efavirenz were strongly associated with particular gene patterns in the multidrug-resistance transporter gene. This gene governs the production of p-glycoprotein, which in turn controls how much of a foreign substance is allowed to cross barriers in the body such as the wall of the intestine and the barrier between the blood and the brain. High levels of p-glycoprotein are associated with low levels of protease inhibitors. Individuals with the MDR-1 TT genotype had significantly lower median drug concentrations than individuals with the CT or CC genotypes. Paradoxically, those with the TT genotype (and the lowest average plasma drug concentrations) had the largest CD4 cell increases 6 months after starting treatment (257 cells vs 165 cells in the CT group and 121 cells in the CC group).

The association between MDR-1 genotype and immunological response to treatment was also analysed in a separate study by the same research group of 80 patients with high baseline CD4 cell counts (>500 cells/mm³) who received amprenavir, saquinavir or nelfinavir in clinical trials together with abacavir. MDR-1 3435 TT genotype was associated with a significantly greater CD4 cell increase after six months of treatment than the other genotypes (196 cells vs 161 and 142 cells for the CT and CC genotypes respectively).

Expression of the MDR1 gene, which controls p-glycoprotein, was found to be significantly lower in individuals with the TT genotype, when compared with the CT or CC genotypes, and this relationship was echoed in an analysis of p-glycoprotein levels in PBMCs.

In Caucasians, the MDR-1 genotypes are distributed in the following proportions: CC (25%), CT (50%), TT (25%). In non-Caucasians distribution differs, with the TT genotype seen in lower proportions among Black Africans and people of African descent.

Inhibitory quotient

Castagna (2002) reported on response to lopinavir in 55 PI-experienced individuals. Normalised inhibitory quotient was calculated individually as the ratio of the trough concentration to virtual phenotype divided by the ratio of the population mean trough concentration to the cut-off IC₅₀ for the virtual phenotype. NIQ when lopinavir levels reached steady state was related to virologic outcome at weeks 12, 24 and 48. At week 48 only lopinavir NIQ and baseline viral load were predictive of a reduction in viral load. NIQ < 0.6 was associated with the lowest viral load reduction (-0.7 log), and NIQ >14.5 with the greatest reduction (-2.8 log).

Fletcher (2002) reported on the relationship between IQ and virologic outcome at week 16 in 34 PI-experienced individuals who received saquinavir in ACTG 359, a study which recruited people with experience of virologic failure on at least one protease inhibitor. Saquinavir trough IQ was associated with HIV RNA reduction at week 4 but not at week 16, while AUC IQ was associated with virologic outcome at weeks 4 and 8.

Baldini (2002) reported on the relationship between virologic outcome, phenotypic resistance and IQ in 22 PI-experienced patients commencing an amprenavir and lopinavir-containing regimen. Drug levels were assessed at the beginning of week 2. 6 patients discontinued due to adverse events. Lopinavir levels 3 hours post-dose were predictive of the extent of HIV RNA reduction between weeks 2 and 16, while higher amprenavir and lopinavir IQ were both predictive of viral load reduction > 1 log between weeks 2 and 16.

See also Resistance testing to select treatment in Anti-HIV therapy: Resistance for further information on studies which have combined resistance testing and therapeutic drug monitoring to select or adjust treatment.

Therapeutic drug monitoring and resistance testing

See also Resistance testing to select treatment in Anti-HIV therapy: Resistance for details of studies which combined the use of resistance testing and therapeutic drug monitoring to optimise treatment.

References

Aarnoutse RE et al. International interlaboratory quality control program for measurement of antiretroviral drugs in plasma. Antimicrobial Agents and Chemotherapy 46(3): 884-886, 2002.

Back DJ et al. Potential clinical relevance of drug transporters in antiretroviral pharmacology. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract S3, 2001.

Baldini F et al. A prospective study of deep salvage therapy with lopinavir/r, amprenavir and NRTIs: Final 24 week data, pharmacokinetics and association of drug levels/drug susceptibility with virologic response. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 423, 2002.

Barrett JS et al. Population pharmacokinetic meta-analysis with efavirenz. International Journal of Clinical Pharmacology Therapy 40(11): 507-519, 2002.

Baxter JD et al. Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy. AIDS 16(8): 1131-1138, 2002.

Bossi P et al. GENOPHAR: a randomized study of plasma drug measurements in association with genotypic resistance testing and expert advice to optimize therapy in patients failing antiretroviral therapy. HIV Medicine 5: 352-359, 2004.

Brundage RC et al. Quantitation of sex differences and drug interactions: pharmacologic studies of saquinavir (SQV) in ACTG 359. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 779, 2002.

Burger DM et al. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antiviral Therapy 3(4): 215-220, 1998.

Burger D et al. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naﶥ HIV-1-infected individuals. AIDS 17: 1157-1165, 2003.

Burger D et al. Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations. Therapeutic Drug Monitoring 25(1): 73-80, 2003b.

Casado JL et al. A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response. HIV Clinical Trials 1(1): 13-19, 2000.

Castagna A et al. The normalised inhibitory quotient (NIQ) of lopinavir is predictive of viral load response over 48 weeks in a cohort of highly experienced HIV-1 infected individuals. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 128, 2002.

Chan S et al. Potential early predictors of long-term virologic response to nelfinavir mesylate (Viracept): plasma drug concentration, baseline viral load, and initial 4-week change in viral load. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract A-11, 1998.

Dalmau D et al. Indinavir pharmacokinetics and their correlation with virologic and immunologic parameters. Twelfth World AIDS Conference, Geneva, abstract 42276, 1998.

Descamps D et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Journal of the American Medical Association 283(2): 205-211, 2000.

Durant J et al. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study. AIDS 14(10): 1333-1339, 2000.

Fellay J et al. Response to antiretroviral treatment in HIV-1 infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359(9300): 30-36, 2002.

Fiske WD et al. An assessment of population pharmacoinetic parameters of efavirenz on nervous system symptoms and suppression of HIV-RNA. 41st Interscience Conference on Antimocrobial and Antiviral Chemotherapy, Chicago, abstract 1727, 2001.

Flexner C et al. Role of multidrug transporters in HIV pathogenesis. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract S4, 2001.

Fletcher CV et al. The inhibitory quotient (IQ) for saquinavir (SQV) predicts virologic response to salvage therapy. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 129, 2002.

Gatti G et al. High variability of indinavir parameters of systemic exposure in HIV+ patients observed prospectively in everyday clinical practice. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract A-66, 1998.

Hennessy M et al. Intracellular indinavir pharmacokinetics in HIV positive patients. Fifth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P282, 2000.

Hoetelmans RMW et al. Plasma concentrations of saquinavir (SQV) determine HIV-1 RNA response over a 48-week period. Twelfth World AIDS Conference, Geneva, abstract 42261, 1998.

Hoetelmans RMW et al. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. AIDS 12:F111-F115, 1998b.

Huisman MT et al. P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Molecular Pharmacology 59(4): 806-813, 2001.

Huisman MT et al. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS 16(17): 2295-2301, 2002.

Kakuda T et al. Inhibitory quotient (IQ) of protease inhibitors (PIs) using a standardized determination of IC50 does not predict clinical outcome. Forty Third Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract A-1799, 2003.

Kim R. Role of P-glycoprotein in CNS and genital tract penetration. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract S1, 2001.

Kewn S et al. Development of enzymatic assays for quantification of intracellular lamivudine and carbovir triphosphate levels in peripheral blood mononuclear cells from human immunodeficiency virus-infected patients. Antimicrobial Agents and Chemotherapy 46(1): 135-143, 2002.

Khaliq Y et al. Effect of nelfinavir (NFV) on short and long-term plasma exposure of saquinavir in hard-gel capsule (SQV-HGC) during tid and bid dosing regimens. Fourth International Conference on Drug Therapy in HIV Infection, Glasgow, abstract P43, 1998.

Le Moing V et al. Plasma levels of indinavir and nelfinavir at time of viral response may have a different impact on the risk of further viral failure in HIV-infected patients. 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy, Chicago, abstract I-1733, 2001.

Marzolini C et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 15(1): 71-75, 2000.

Meaden ER et al. P-glycoprotein and MRP1 expression and reduced ritonavir and saquinavir accumulation in HIV-infected individuals. Journal of Antimicrobial Chemotherapy 50(4): 583-588, 2002.

Mouroux M et al. Early virological failure in naive human immunodeficiency virus patients receiving saquinavir (soft gel capsule)-stavudine-zalcitabine (MIKADO trial) is not associated with mutations conferring viral resistance. Journal of Clinical Microbiology 38(7): 2726-2730, 2000.

Nunez M et al. An assessment of population pharmacokinetic parameters of efavirenz on nervous system symptoms and suppression of HIV-RNA. 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy, Chicago, abstract 1724, 2001.

Perello L et al. Therapeutic drug monitoring in HIV-infected patients receiving indinavir. Twelfth World AIDS Conference, Geneva, abstract 42272, 1998.

Sadler BM et al. In vivo effect of alpha(1)-acid glycoprotein on pharmacokinetics of amprenavir, a human immunodeficiency virus protease inhibitor. Antimicrobial Agents an Chemotherapy 45(3): 852-856, 2001.

Shulman N et al. Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia. Antimicrobial Agents and Chemotherapy 46(12): 3907-3916, 2002.

Starr SE et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. New England Journal of Medicine 341(25): 1874-1881, 1999.

Urban A et al. Combined use of prospective antiretroviral pharmacokinetic profiling and HIV-1 genotype resistance testing in managing antiretroviral therapy. Seventh European Conference on Clinical Aspects and Treatment of HIV-Infection, Lisbon, abstract 1222, 1999.

Walsh J et al. Virologic rebound on HAART in the context of low treatment adherence is associated with a low prevalence of antiretroviral drug resistance. Journal of Acquired Immune Deficiency Syndromes 30(3): 278-287, 2002.

Wegner S et al. The potential role of resistance testing and therapeutic drug monitoring in the optimization of antiretroviral drug therapy. Antiviral Therapy 4 (supp 1): 77, 1999.