The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients.
OBJECTIVE
The relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-naïve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied.


METHODS
Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported.


RESULTS
No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of <25 micromol/l.


CONCLUSIONS
The great majority of treatment-naïve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-naïve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy.
Josephson
Filip
F
Department of Clinical Pharmacology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. filip.josephson@karolinska.se
Andersson
Maria C H
MC
Flamholc
Leo
L
Gisslén
Magnus
M
Hagberg
Lars
L
Ormaasen
Vidar
V
Sönnerborg
Anders
A
Vesterbacka
Jan
J
Böttiger
Ylva
Y
D000480:Alkynes; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D001663:Bilirubin / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D002986:Clinical Trials as Topic; D003521:Cyclopropanes; D004347:Drug Interactions; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D016896:Treatment Outcome; D019562:Viral Load
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D000069446:Atazanavir Sulfate; C098320:efavirenz; D019438:Ritonavir; D001663:Bilirubin