Effect of widely used combinations of antiretroviral therapy on liver CYP3A4 activity in HIV-infected patients.
OBJECTIVE
To evaluate the effects of combined antiretroviral drugs (HAART) on liver CYP3A4 activity using the [(14)C-N-methyl]-erythromycin breath test (ERMBT).


METHODS
HIV-infected patients (31 women, 30 men) with mean (+/- SD) age of 38 +/- 9 years were enrolled and underwent complete clinical and laboratory evaluation. Patients were divided into five groups and were treated with two nucleoside analogues (NAs) and one of the following: nelfinavir alone (n = 13), any ritonavir-boosted protease inhibitor with (n = 8) or without (n = 13) nevirapine, nevirapine alone (n = 15), or a third NA (n = 12). Three or four ERMBTs were performed 7 days prior to (D-7) and at the beginning of treatment (D0), D14 (only for patients taking nevirapine) and on D28.


RESULTS
Mean baseline liver CYP3A4 activity displayed high interindividual variability (47%) but low intraindividual variability (15%). Women had 30% higher ERMBT values than men [2.7 +/- 1.3 vs. 1.9 +/- 0.7; 95% confidence interval (CI) 20.5, 49.5; P = 0.003]. The ERMBT data correlated with body weight, alpha- and beta-globulins and alanin aminotransferases (0.10 < r(s) < 0.20; P < 0.01). Whereas nevirapine had no effect on liver CYP3A4 activity, nelfinavir-based and ritonavir-boosted drug regimens inhibited it by 69% (95% CI 64.7, 72.9; P = 0.005) and by 95% (95% CI 93.3, 96.7; P = 0.001), respectively.


CONCLUSIONS
Evaluation of the effect of HAART on liver CYP3A4 activity may aid in preventing inappropriate treatment regimens in HIV-infected patients.
Mouly
Stéphane
S
Unit of Therapeutic Research, Department of Internal Medicine, Lariboisiere Hospital, Paris, France.
Rizzo-Padoin
Nathalie
N
Simoneau
Guy
G
Verstuyft
Céline
C
Aymard
Guy
G
Salvat
Cécile
C
Mahé
Isabelle
I
Bergmann
Jean-François
JF
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D001944:Breath Tests / Q000379:methods; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin / Q000032:analysis; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D008099:Liver / Q000201:enzymology*; D008297:Male; D019888:Nelfinavir / Q000627:therapeutic use; D019829:Nevirapine / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D012737:Sex Factors
D019380:Anti-HIV Agents; D019469:Indinavir; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D019829:Nevirapine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019888:Nelfinavir; D019438:Ritonavir