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Antimicrobial Agents and Chemotherapy, October 2005, p. 3997-4008, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.3997-4008.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Effect of Ribavirin on Intracellular and Plasma Pharmacokinetics of Nucleoside Reverse Transcriptase Inhibitors in Patients with Human Immunodeficiency Virus-Hepatitis C Virus Coinfection: Results of a Randomized Clinical Study

M. Rodriguez-Torres,1* F. J. Torriani,2 V. Soriano,3 M. J. Borucki,4 E. Lissen,5 M. Sulkowski,6 D. Dieterich,7 K. Wang,8 J.-M. Gries,8 P. G. Hoggard,9 D. Back,9 for the APRICOT Study Group

Fundacion de Investigacion de Diego, Santurce, Puerto Rico,1 University of California, San Diego, California,2 Hospital Carlos III, Madrid, Spain,3 University of Texas Health Center, Tyler, Texas,4 Virgen del Rocío University Hospital, Seville, Spain,5 Johns Hopkins University School of Medicine, Baltimore, Maryland,6 Mt. Sinai School of Medicine, New York, New York,7 Roche, Nutley, New Jersey,8 University of Liverpool, Liverpool, United Kingdom9

Received 28 February 2005/ Returned for modification 28 April 2005/ Accepted 14 July 2005

The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 µg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC0-12 h) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma Cmax were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC0-12 h at steady state were 0.274 (95% confidence interval, –0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, –0.06 to 0.08) for d4T-TP:dTTP, and –0.081 (95% confidence interval, –0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.

* Corresponding author. Mailing address: Fundacion de Investigación de Diego, Ave. De Diego #359, Suite 302, Santurce, Puerto Rico 00909. Phone: (787) 722-1248. Fax: (787) 725-6130. E-mail: fdciondeinvest{at}aol.com.

Antimicrobial Agents and Chemotherapy, October 2005, p. 3997-4008, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.3997-4008.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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