In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.
Methods We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 µg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.
Results
We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).
Conclusions Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164 [ClinicalTrials.gov]
Source Information
From Saint Louis University School of Medicine, St. Louis (A.M.D.); the Virginia Commonwealth University Medical Center, Richmond (M.L.S.); the University of Colorado School of Medicine, Denver (G.T.E.); the Keck School of Medicine, University of Southern California, Los Angeles (K.L.L.); the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (J.E.E., E.C.W., M.G.G.); the University of Texas Southwestern Medical Center, Dallas (W.M.L.); the University of Michigan Medical Center, Ann Arbor (A.S.L.); the University of Connecticut Health Center, Farmington (H.L.B.); the University of California, Irvine, and the Veterans Affairs Long Beach Healthcare System, Long Beach, CA (T.R.M.); the University of Washington, Seattle (C.M.); the New England Research Institutes, Watertown, MA (K.K.S.); and Massachusetts General Hospital and Harvard Medical School, Boston (J.L.D.).
Address reprint requests to Dr. Di Bisceglie at the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, 3635 Vista Ave., St. Louis, MO 63110, or at dibiscam@slu.edu.
Adrian M. Di Bisceglie, M.D., Mitchell L. Shiffman, M.D., Gregory T. Everson, M.D., Karen L. Lindsay, M.D., James E. Everhart, M.D., M.P.H., Elizabeth C. Wright, Ph.D., M.P.H., William M. Lee, M.D., Anna S. Lok, M.D., Herbert L. Bonkovsky, M.D., Timothy R. Morgan, M.D., Marc G. Ghany, M.D., Chihiro Morishima, M.D., Kristin K. Snow, Sc.D., Jules L. Dienstag, M.D., for the HALT-C Trial Investigators
[Added protocol of Roche’s all-oral INFORM-1 study.]
The following paragraphs are in descending order of likelihood of success. (Paragraphs 6 and 7 are “catchall” groupings that do not explicitly mention all of the applicable drug candidates within the grouping.)
1. The two leading protease inhibitors: Telaprevir (VRTX/JNJ; phase-3) and Boceprevir (SGP; phase-3). These two drugs have shown comparable efficacy in 24-28 week regimens of phase-2 trials in the genotype-1, treatment-naïve setting: #msg-31190433, #msg-33793333, #msg-33282976. Background posts: VRTX PROVE-1/2 trials made simple: #msg-29019931; PROVE-1/2 detailed results: #msg-28746843; overview of Telaprevir phase-3 program: #msg-26228377; Boceprevir starts phase-3: #msg-29474929.
Telaprevir and Boceprevir are also being tested in the second-line setting, Telaprevir in 24- and 48-week regimens and Boceprevir in 36- and 48-week regimens. Background posts: Telaprevir phase-3 REALIZE study: #msg-32901932; Telaprevir phase-2b PROVE-3 study: #msg-29896176; Telaprevir ‘107’ open-label phase-2 extension for PROVE-1/2 failures: #msg-33282976; Boceprevir phase-3 RESPOND-2 study: #msg-29474929.
2. ITMN-191 a.k.a. R7227 (ITMN/Roche; phase 1b), a protease inhibitor that may be even better than Telaprevir and Boceprevir but is still early in development: #msg-28126092.
3. Locteron (Biolex; phase-2), a long-acting interferon made in transgenic plants that is all but indistinguishable from the SoC peg-ifn products marketed by Roche and SGP: #msg-28786162. (Biolex recently bought out its partner, OctoPlus, and raised $60M to fund the Locteron program: #msg-32662307, #msg-32662762.)
4. Various oral agents in phase-1 or phase-2 that use an established MoA. These include TMC435 (Medivir/JNJ; phase-2), a protease inhibitor: #msg-33283588; BI201335 (B-I; phase-2), a protease inhibitor: #msg-33564560; R7128 (VRUS/Roche; phase-1b), a nucleoside polymerase inhibitor: #msg-33300630 (kidney tox in monkeys), #msg-32238916, #msg-32651030; GS-9190 (GILD; phase-2 starting by year-end), a non-nucleoside polymerase inhibitor: #msg-32919311; and ANA598 (ACHN, phase-1b), a non-nucleoside polymerase inhibitor: #msg-33172848.
5. The “other” interferons: Albuferon (HGSI/NVS; phase-3): #msg-26199740; IFN-alpha-XL (FLML; phase-1): #msg-28837983; and IFN-Lambda (ZGEN; phase-1b): #msg-33311734.
6. Miscellaneous very-early-stage compounds that use an established MoA — e.g. IDX184 (IDIX; phase-1), a nucleotide polymerase inhibitor: #msg-31043481, #msg-26915921; and ACH-1625 (ACHN; preclinical), a protease inhibitor: #msg-31459921.
7. Miscellaneous early- and very-early-stage compounds that use a novel MoA — e.g. NS5A inhibitors from various companies: #msg-33270620, #msg-33270670; ANA773 (ANDS, phase-1), an oral TLR7 modulator: #msg-33244419; IL-7 (Cytheris, phase-1/2) an injectable immunomodulator: #msg-33152073; GI-5005 (GlobeImmune, phase-2), an injectable immunomodulator: #msg-33322543; Sirna-034 (MRK; status unknown), a dual siRNA: #msg-12665661; ACH-1095 (ACHN/GILD; preclinical), an NS4A inhibitor: #msg-31459921; and clemizole (Stanford University; preclinical), an NS4B inhibitor: #msg-31857987.
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