Seventy-two weeks of peginterferon and ribavirin for patients with partial early virologic response?

Current American Association for the Study of Liver Diseases and AmericanGastroenterological Association guidelines recommend 48 weeks of treatment with peginterferon and ribavirin (1000-1200 mg/day) for patients infected with hepatitis C genotype 1.1,2 The goal of treatment is a sustained virologic response (SVR) defined as a negative hepatitis C virus (HCV) RNA 6 months after therapy is stopped. In registration trials, approximately 45%ofHCV genotype 1–infected subjects achieved an SVR; lower SVR was reported in nonregistration studies.3,4 SVR is associated with a greater than 99% chance of being free of HCV infection 5 years later5 and, in retrospective studies, a reduced rate of liver disease complications.6 Both pretreatment and on-treatment variables predict the likelihood of achieving an SVR. Hepatitis C genotype is the strongest pretreatment variable predicting response, with SVR lowest for genotype 1 followed by genotypes 4, 3, and 2. Other pretreatment variables associated with reduced SVR include higher weight/body mass index, higher viral load, older age, advanced liver fibrosis, and being male.7 For unclear reasons, African Americans, in comparison with Caucasians, with genotype 1 HCV infection have a significantly reduced SVR.8 Virologic response at treatment week 4 and at treatment week 12 predicts the likelihood of achieving, or not achieving, an SVR. The earlier in treatment HCV RNA becomes undetectable in the blood, the greater the likelihood of achieving SVR is.9 Ninety percent of patients with a rapid virologic response (RVR; defined as undetectable HCV in serum at treatment week 4) will have an SVR, and some patients may require only 24 weeks of treatment.10 Patients with an early virologic response (EVR; defined as undetectable or greater than 100-fold decline in HCV RNA level at week 12 of treatment) have a 70% probability of achieving an SVR, whereas those without such a response are unlikely to achieve SVR ( 3%), andmost guidelines recommend discontinuation of treatment. Patients with an EVR consist of two subgroups with differing probabilities of achieving SVR. The majority of subjects with EVR have undetectable HCV RNA.11 Absence of HCV RNA in the serum at treatment week 12 has been termed a complete early virologic response (cEVR). Less commonly, subjects have a 100-fold decline in the HCV RNA level but continue to have detectable HCV RNA. This response has been called a partial early virologic response (pEVR), and such patients are less likely to achieve an SVR than are subjects with cEVR.9 The definition of EVR and those of pEVR and cEVR are based largely, but not entirely, on the measurement of HCV RNA by quantitative polymerase chain reaction (PCR) assays with an upper limit of 800,000 IU/mL (in undiluted serum) and a lower limit of detection (LLOD) of 600 IU/mL (that is, Roche Amplicor HCV Monitor) and by qualitative HCVRNA PCR assays with an LLOD of approximately 50-100 IU/mL (that is, Roche Amplicor HCV). TaqMan real-time polymerase chain reaction (RT-PCR) is a PCR-based quantitative HCV assay with an LLOD of 10 IU/mL and a greater dynamic range than prior quantitative PCR assays. Importantly, among subjects with a viral load of more than 1,000,000 IU/mL, the viral load as measured by TaqMan RT-PCR assays is approximately 0.45 log greater than the viral load as measured by the Roche Amplicor HCVMonitor assay.12 This difference in measurement of the HCV viral load would result in a greater number of subjects with a high viral load achieving an EVR when assessed by TaqMan RT-PCR than when measured by PCR. Also, it might alter the usefulness of EVR (as defined with PCR assays) to predict nonresponse to 48 weeks of combination treatment. In an effort to improve SVR among patients with genotype 1 hepatitis C, investigators have increased the dose of interferon/ribavirin (for example, induction dosing, daily interferon, and higher doses of ribavirin) and extended treatment from 48 to 72 weeks. Although several clinical trials are in progress, the existing data are not convincing that higher doses of interferon or ribavirin or Abbreviations: cEVR, complete early virologic response; ETR, end-of-treatment response; EVR, early virologic response; HCV, hepatitis C virus; LLOD, lower limit of detection; PCR, polymerase chain reaction; pEVR, partial early virologic response; RR, relapse rate; RT-PCR, real-time polymerase chain reaction; SVR, sustained virologic response. Address reprint requests to: Timothy R. Morgan, M.D., Chief of Hepatology–11, 5901 East Seventh Street, Long Beach, CA 90822. E-mail: timothy.morgan@ va.gov; fax: 562-826-8023. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.22030 Potential conflict of interest: Dr. Hoefs is on the speaker’s bureau of Gilead and Roche. Dr. Morgan is on the speakers’ bureau of and received grants from ScheringPlough. He is a consultant for, is on the speakers’ bureau of, and received grants from Hoffmann-La Roche.