Extending Combination Therapy With Peginterferon Alfa–2B Plus Ribavirin for Genotype 1 Chronic Hepatitis C Late Responders: A Report of 9 Cases

Abstract

The large number of chronic hepatitis C patients infected by genotype 1 constitutes an important therapeutic challenge because they are the most resistant to combination therapy with interferon alfa and ribavirin. [1][2][3] In these patients, the sustained virologic response to peginterferon and ribavirin for 48 weeks is around 42%. 3,4 It has been shown that one important factor of sustained virologic response (SVR) is rapid hepatitis C virus (HCV)-RNA clearance, ranging from 75% for those patients who cleared the virus at week 12 to only 32% for those who lost HCV RNA at week 24. 3 It has been suggested that extending therapy in patients who cleared HCV RNA between weeks 12 and 24 (i.e., late responders) could increase SVR.We selected 9 patients with chronic hepatitis C who were infected with genotype 1 in treatment with pegylated interferon alfa-2b plus ribavirin who cleared HCV RNA between weeks 12 and 24 for therapy prolonged to 72 weeks. Three were men and 6 were women, with a median age of 41 Ϯ 14.57 years. All patients had elevated alanine aminotransferase levels, positive HCV RNA, and a liver examination showing chronic hepatitis. Patients were treated with a mean dose of 1.0 g/kg of peginterferon alfa-2b once weekly (PEG-INTRON, Schering-Plough, Kenilworth, NJ), plus 800 mg/d of ribavirin (Rebetol, Schering-Plough). HCV RNA was analyzed by using a quantitative, real-time, reverse-transcriptase polymerase chain reaction technique with a lower limit of detection of 100 IU/L. 4 Eight patients completed therapy and 6 months of follow-up. One patient stopped therapy at week 48 because of thyroid alterations. Table 1 shows patient characteristics and changes in HCV-RNA levels from baseline to week 12. In all patients, HCV RNA was positive at week 12 of therapy but undetectable at week 24 and throughout the 72 weeks of therapy. At week 24 of follow-up, 7 patients maintained an SVR and one relapsed (case 3).This study, with a small number of patients, showed that prolonged combination therapy with peginterferon and ribavirin is very useful in late virologic responders because it increases SVR. HCV-RNA determination has an important role not only in the decision to stop therapy but also in better adjusting therapy. 3,[5][6][7] Currently, nonresponders can be detected by a quantitative HCV-RNA test at week 12, showing a decline of less than 2 logs in HCV-RNA concentrations. 3,5 In these patients, combination therapy should be stopped because the probabilities of a sustained response are almost nil. In patients who achieve an early virologic response, the probabilities of achieving an SVR were 80% for those who cleared HCV RNA at week 12 and sooner, and 40% for those who achieved a 2-log reduction in HCV-RNA concentrations but still remained HCV-RNA positive as a recent review of multicenter studies has shown. 5 All of our patients had a 2-log decline but remained HCV-RNA positive at week 12 and, taking into account the previous results, their probabilities of achieving an SVR are lower than those patients who we...

Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1–infected slow responders

“…Seventy-two weeks of peginterferon-␣2b (1.0 g/kg/week) and ribavirin (800 mg/day) achieved impressive response rates (when compared with those of a historical control) in a small group of slow responders to therapy. 5 In a subgroup analysis from a German multicenter trial, 8 slow responders to peginterferon-␣2a (180 g/week) and ribavirin (800 mg/day) showed statistically superior rates of SVR when treated for 72 weeks compared with 48 weeks. Similarly, in a multicenter trial from Spain using peginterferon-␣2a (180 g/week) and ribavirin (800 mg/day), slow responders benefited from 72 weeks of treatment relative to 48 weeks.…”

“…[1][2][3][4] Although treatment for genotype 1-infected patients is typically given for 48 weeks, there has been interest in extending therapy duration, particularly in slow-responders. 5 Patients treated with peginterferon and ribavirin who do not achieve a 12-week early virologic response (defined by an undetectable serum HCV RNA level or Ͼ2-log decrease relative to a pretreatment RNA level) have only a 3% or lower chance of achieving an SVR. 6,7 However, there is an important dichotomy in response rate between patients who, after 12 weeks of therapy, attain undetectable serum viral RNA versus patients who achieve at least a 2-log decrement in baseline HCV RNA yet still have detectable viremia.…”

Randomized Trial of Peginterferon alfa-2b and Ribavirin for 48 or 72 Weeks in Patients with Hepatitis C Virus Genotype 1 and Slow Virologic Response

“…HCV RNA analyses were performed at a central laboratory using quantitative reverse transcriptase polymerase chain reaction (COBAS Taqman, Roche) assay with a lower limit of quantitation of 30 IU/mL. HCV RNA levels were evaluated at screening, baseline, and treatment weeks 4,8,12,24,48, and 72 (group B) and at week 24 followup. Trugene HCV Genotyping (Bayer HealthCare LLC, Tarrytown, NY) was used to determine HCV genotype.…”

“…4,5 Several studies adopting this approach have shown that extending therapy to 72 weeks may increase SVR rates in selected G1 patients. [6][7][8][9][10][11] However, the on-treatment virologic criteria used to select patients for extended therapy vary across studies. Accurately defining which G1 patients will benefit from extended treatment is important, because prolonged treatment is associated with increased adverse events and higher costs.…”

Extended-therapy duration for chronic hepatitis C, genotype 1: The long and the short of it

“…Investigators from Spain and Israel were the first to report successful treatment extension to 72 wk for slow responders to peginterferon and ribavirin [27] . Slow responders were defined as those patients with at least a 2 log 10 decline in HCV RNA from baseline, yet detectable viremia at 12 wk after receipt of 1.0 mcg of peginterferon alpha-2b weekly and 800 mg ribavirin daily.…”