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Original Research |

Combination Therapy With Telaprevir for Chronic Hepatitis C Virus Genotype 1 Infection in Patients With HIV: A Randomized Trial

Mark S. Sulkowski, MD; Kenneth E. Sherman, MD, PhD; Douglas T. Dieterich, MD; Mohammad Bsharat, PhD; Lisa Mahnke, MD, PhD; Jürgen K. Rockstroh, MD; Shahin Gharakhanian, MD, DPH; Scott McCallister, MD; Joshua Henshaw, PhD; Pierre-Marie Girard, MD, PhD; Bambang Adiwijaya, PhD; Varun Garg, PhD; Raymond A. Rubin, MD; Nathalie Adda, MD; and Vincent Soriano, MD, PhD
[+] Article and Author Information

This article was published at www.annals.org on 17 May 2013.


From Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Cincinnati College of Medicine, Cincinnati, Ohio; Mount Sinai School of Medicine, New York, New York; University of Bonn, Bonn, Germany; Vertex Pharmaceuticals, Cambridge, Massachusetts; Hôpital St. Antoine, Paris, France; and Hospital Carlos III, Madrid, Spain.

Acknowledgment: The authors thank the coordinators, nurses, and patients involved in the study; Theorem Clinical Research, Oracle Health Sciences Global Business Unit, i3 Research and i3 Global, Covance Laboratories, Quest Pharmaceuticals, and ICON Central Laboratories for coordinating and implementing various aspects of the study; Christina (Tina) Karunaratne for clinical project management; Eileen Zhang, PhD, for virology analyses; Min Chen, MS, for statistical programming; Yang Dai, PhD, for pharmacokinetic data analysis; Jonathan Kirk for graphic design support; Leslie Lescale-Matys, PhD, for study conduct and data analysis; and Kristin Stephan, PhD, Frances Smith, PhD, Karen Eisenhauer, PhD, and Mrudula Donepudi, PhD, for medical writing and editorial assistance (all from Vertex Pharmaceuticals). The authors also thank the site investigators (see Appendix 1).

Grant Support: By the National Institute on Drug Abuse (K24DA034621 and R01DA16065), National Institute of Allergy and Infectious Diseases (P30AI094189), National Center for Research Resources and the National Institutes of Health Roadmap for Medical Research (UL1RR025005), National Institute of Diabetes and Digestive Kidney Diseases (K24 DK070528), Hickey Foundation–HONE Project (GCO 09-0395), and the National Institute of Mental Health (R34 MH099930-01A1). Funding was also provided by the Fundación Investigación y Educación en SIDA, European AIDS Treatment Network (LSHM-CT-2006-037570), European Community's Seventh Framework Program FP7/2007-2013 Collaborative HIV and Anti-HIV Drug Resistance Network (Project 223131), and Red de Investigación en SIDA (ISCIII-RETIC-RD12/0017/0031).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0291.

Reproducible Research Statement: Study protocol: Available from Dr. Rubin (e-mail, raymond_rubin@vrtx.com). Statistical code and data set: Not available.

Requests for Single Reprints: Mark S. Sulkowski, MD, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 1830 Building, Room 445, Baltimore, MD 21287; e-mail, msulkowski@jhmi.edu.

Current Author Addresses: Dr. Sulkowski: Johns Hopkins University School of Medicine, 600 North Wolfe Street, 1830 Building, Room 445, Baltimore, MD 21287.

Dr. Sherman: University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267.

Dr. Dieterich: Mount Sinai School of Medicine, 1468 Madison Avenue, Annenberg 21-42, New York, NY, 10029.

Drs. Bsharat, Mahnke, Garg, and Rubin: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA, 02139.

Dr. Rockstroh: Department of Medicine I, Universitätsklinikum Bonn, Siegmund-Freudstr. 25, 53105 Bonn, Germany.

Dr. Gharakhanian: Cambridge Innovation Center, One Broadway, 14th Floor, Cambridge, MA 02142.

Dr. McCallister: Gilead Sciences, 333 Lakeside Drive (300-132084), Foster City, CA 94404.

Dr. Henshaw: 616 Vernon Way, Burlingame, CA 94010.

Dr. Girard: Service des Maladies Infectieuses, Hôpital St. Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France.

Dr. Adiwijaya: 16 Brighton Street, Belmont, MA 02478.

Dr. Adda: Transgene, 5 Cambridge Center, Cambridge, MA 02142.

Dr. Soriano: Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain.

Author Contributions: Conception and design: M.S. Sulkowski, D.T. Dieterich, S. Gharakhanian, S. McCallister, P.M. Girard, V. Garg, N. Adda.

Analysis and interpretation of data: M.S. Sulkowski, K.E. Sherman, D.T. Dieterich, M. Bsharat, L. Mahnke, S. Gharakhanian, S. McCallister, J. Henshaw, B. Adiwijaya, V. Garg, R.A. Rubin, N. Adda, V. Soriano.

Drafting of the article: M.S. Sulkowski, K.E. Sherman, D.T. Dieterich, L. Mahnke, S. McCallister, P.M. Girard, V. Soriano.

Critical revision of the article for important intellectual content: M.S. Sulkowski, D.T. Dieterich, J.K. Rockstroh, S. Gharakhanian, S. McCallister, J. Henshaw, P.M. Girard, R.A. Rubin, N. Adda, V. Soriano.

Final approval of the article: M.S. Sulkowski, K.E. Sherman, D.T. Dieterich, L. Mahnke, J.K. Rockstroh, S. Gharakhanian, S. McCallister, J. Henshaw, P.M. Girard, V. Garg, R.A. Rubin, N. Adda, V. Soriano.

Provision of study materials or patients: M.S. Sulkowski, K.E. Sherman, D.T. Dieterich, J.K. Rockstroh, P.M. Girard.

Statistical expertise: M. Bsharat, B. Adiwijaya.

Administrative, technical, or logistic support: B. Adiwijaya.

Collection and assembly of data: M.S. Sulkowski, D.T. Dieterich, L. Mahnke, S. McCallister, P.M. Girard, R.A. Rubin, N. Adda, V. Soriano.


Ann Intern Med. 2013;159(2):86-96. doi:10.7326/0003-4819-159-2-201307160-00654
Text Size: A A A

Chinese translation

Background: Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a–ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown.

Objective: To assess the safety and efficacy of TVR plus PEG-IFN-α2a–ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration.

Design: Phase 2a, randomized, double-blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853)

Setting: 16 international multicenter sites.

Patients: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment–naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a–ribavirin or placebo plus PEG-IFN-α2a–ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a–ribavirin.

Measurements: HCV RNA concentrations.

Results: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a–ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a–ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a–ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a–ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a–ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a–ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR.

Limitation: Small sample size and appreciable dropout rate.

Conclusion: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a–ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a–ribavirin.

Primary Funding Source: Vertex Pharmaceuticals and Janssen Pharmaceuticals.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

Part A patients did not receive concomitant antiretroviral therapy. Part B patients were assigned 1 of 2 HIV treatment regimens: efavirenz, tenofovir, and emtricitabine, or ritonavir-boosted atazanavir with tenofovir and either emtricitabine or lamivudine. Patients were assigned to receive either TVR/P–R or P–R. Patients in part A were randomly assigned in a 1:1 ratio and the 2 groups of patients in part B were randomly assigned in a 2:1 ratio to receive TVR/P–R or P–R. HCV = hepatitis C virus; P–R = peginterferon-α2a–ribavirin alone for 48 wk; TVR/P–R = telaprevir combined with peginterferon-α2a–ribavirin for 12 wk, followed by peginterferon-α2a–ribavirin for an additional 36 wk.

* The most common reasons for exclusion were low CD4 cell count, low creatinine clearance, low or undetectable HCV viral load, low absolute neutrophil count, high HIV viral load, high α-fetoprotein level, positive hepatitis B test result, or out of treatment window.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Mean (95% CI) log10 HCV RNA levels from baseline through 12 wk, by treatment group.

HCV RNA levels were assessed at 0, 1, 2, 4, and 7 d and at 2, 3, 4, 8, and 12 wk. The numbers of patients with HCV RNA measures at each time point are shown. HCV = hepatitis C virus; P–R = peginterferon-α2a–ribavirin alone for 48 wk; TVR/P–R = telaprevir combined with peginterferon-α2a–ribavirin for 12 wk, followed by peginterferon-α2a–ribavirin for an additional 36 wk.

Grahic Jump Location

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