When combined with pegylated interferon alpha-2b (Peg-IFN α-2b) for the treatment of genotype 1 chronic hepatitis C (CHC) in Korea, the current guideline for the initial ribavirin (RBV) dose is based on body weight. However, since the mean body weight is lower for Korean patients than for patients in Western countries, current guidelines might result in Korean patients being overdosed with RBV.
We retrospectively reviewed the medical records of patients with genotype 1 CHC who were treated with Peg-IFN α-2b and RBV combination therapy. We divided the patients into groups A (≥15 mg/kg/day,
The early response rates (92.0% vs. 83.3%,
RBV dose reduction is performed frequently when patients are treated according to the current Korean guidelines. Given that lowering the RBV dose did not appear to decrease the virologic response during therapy, reducing RBV doses below the current Korean guideline may be effective for treatment, especially in low-weight patients.
The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease. An estimated 180 million people are infected worldwide.
We retrospectively reviewed the medical records of patients with genotype 1 CHC, who were treated with the combination therapy of Peg-IFN α-2b (subcutaneous injection of 1.5 µg per kg body weight per week) and RBV based on body weight (1,000 mg for patients weighing <75 kg or 1,200 mg for patients weighing ≥75 kg), from October 2004 to February 2010, at Soon Chun Hyang University, Bucheon Hospital and Cheonan Hospital. The inclusion criteria for this study included men and women aged over 18 years, with serologically proven and treatment-naive CHC. In addition, the patients were required to have had detectable HCV RNA and compensated liver disease. Patients with liver cirrhosis and other forms of liver disease or other severe underlying diseases, i.e. cardiovascular disease and neoplasm, such as hepatocellular carcinoma, were excluded from our study. The initial RBV dose was defined as the cumulative RBV dose taken during the first 4 weeks converted to dosage per body weight per day. Based on their initial RBV dose, all patients were divided into two groups: Group A (≥15 mg/kg/day) and Group B (<15 mg/kg/day). Medical records of the study patients were reviewed to obtain baseline demographic features and clinical course after treatment with combination therapy. The primary objective of our study was to compare SVR, early virologic response (EVR) and dose reduction rates between the two groups following Peg-IFN α-2b plus RBV administered over 48 weeks.
HCV-RNA was determined in each participating center using commercially available polymerase chain reaction assays (Amplicor HCV or Amplicor HCV Monitor, Roche Diagnostics, Basel, Switzerland). Only patients with baseline and 12- or 24-week HCV-RNA determinations were included in the statistical analyses. The EVR was defined as ≥2 log reduction or complete absence of serum HCV RNA at week 12 of therapy compared with the baseline level. The SVR was defined as undetectable HCV-RNA (<50 IU per mL) 24 weeks after discontinuation of therapy.
Per protocol, the RBV dose had to be reduced by 200 mg daily in patients who experienced a decrease in hemoglobin level of more than 2 g/dL during treatment, and by 400 mg daily if hemoglobin levels decreased to less than 10 g/dL. RBV was discontinued if a patient without significant cardiovascular disease experienced a decrease in hemoglobin to a level below 8.5 g/dL or if a patient with stable cardiovascular disease maintained a hemoglobin value <12 g/dL, despite of being on a reduced dose of 600 mg for 4 weeks. Hematopoietic growth factors, such as erythropoietin, have been shown to improve the quality of life, but not SVR rates. In this study, we reduced the RBV dose instead of treatment with erythropoietin for patients with anemia. Further dose reduction for other adverse events was based on the severity of the side-effects, including myalgia and flu-like symptoms. However, the use of erythropoietin was not allowed. We decreased Peg-IFN α-2b dose for patients who developed neutropenia. Given that the dose of Peg-IFN α-2b is more vital in achieving SVR than the RBV dose, we only included in this study patients who had been treated for 48 weeks or more, to reduce the impact of the Peg-IFN α-2b dose.
Data were analyzed with SPSS software for Windows version 16.0 (Chicago, IL). Continuous variables are expressed as mean±standard deviation and categorical variables as absolute and relative frequencies. Mean differences were tested with the Student t-test and the Chi-square test for dichotomous and categorical variables. The result of analysis was considered statistically significant for a
A total of 49 patients (27 males and 22 females), who were treated for 48 weeks or more, were enrolled in this study. Based on the initial RBV dose, these patients were divided into two groups: Group A (≥15 mg/kg/day,
We also analyzed the relationship between the body weight of patients and the initial RBV dose. Most of the patients enrolled in our study (81.6%) weighed less than 70 kg, and half of these patients weighed 60 kg or less. The initial RBV dose (15.69 vs. 11.02 mg/kg/day,
Suppression of HCV RNA continued to be effective in both patient groups. Thus, EVR (92.0 vs. 83.3%,
Adverse events were reported by 79.6% (39/49) of patients (
The reasons for RBV dose reduction were identified for all patients who completed treatment. Among the patients who completed 48 weeks of treatment, 20 patients (14 patients in Group A and 6 patients in Group B) had RBV dose reductions for safety reasons, including both adverse events (flu-like symptoms) and laboratory abnormalities (neutropenia and anemia). The RBV dose reduction rate was significantly higher for Group A than for Group B (60.9 vs. 23.1%) (
In Korea, a high endemic area for hepatitis B virus infection, about five to nine hundred thousand people are chronically infected with HCV, and at least 10-17% of these people get the hepatocellular carcinoma.
In this report we present a detailed analysis of the impact of RBV dose reductions on SVR rates in patients naive to treatment, infected with HCV genotype 1 and treated with Peg-IFN α-2b and RBV combination therapy. The European Association for the Study of the Liver (EASL) clinical practice guidelines recommended that Peg-IFN α-2b should be used at a weight-based dose of 1.5 µg/kg per week and patients infected with HCV genotype 1 should receive the weight-based dose of RBV of 15 mg/kg body weight per day. The choice of this regimen was based upon the results of three pivotal, randomized, clinical trials that demonstrated the superiority of this combination treatment over standard IFN alfa and RBV combination therapy.
In the Korean Association for the Study of the Liver (KASL) guidelines, weight-based RBV (1,000 mg for patients weighing <75 kg or 1,200 mg for patients weighing ≥75 kg) combined with Peg-IFN α-2b therapy was recommended for patients with genotype 1 CHC. A previous Korean report showed combination therapy efficacy comparable to that of studies in Western countries. Dosage modification was performed in 39% (29/75) of patients without producing a significant reduction in SVR.
It has been known that the mean body weight of patients in Korea is relatively lower than in the western countries. Based on the current Korean guidelines, it is possible that the recommended dose of RBV may be too high in low-weight patients, resulting in more frequent dose reduction due to adverse events. The aim of this study was therefore to evaluate the possibility of an over-dose RBV treatment when we treat the patients according to the current Korean guidelines and to evaluate whether relatively high-dose RBV (≥15 mg/kg/day) causes RBV dose reduction more frequently. In our study, we referred to the EASL guideline,
In order to minimize the effect of Peg-IFN, we included only one kind of Peg-IFN, which is Peg-IFN α-2b, and limited the cases to those administered for over 48 weeks. A randomized trial determined that the optimal duration of treatment should be based on the viral genotype and established that patients with genotype 1 should be treated for 48 weeks with Peg-IFN alfa plus standard weight-based RBV.
Dose reductions were less common in patients who received less than 15 mg/kg/day of RBV as their initial dose (23.1%). According to our findings, high-dose RBV (>15 mg/kg/day) appeared not to increase the virologic response, but rather prompted dose reduction more frequently (60.9%, 14/23). SVR was not significantly different between the two groups, but the dose reduction rate for anemia was significantly higher in the group administered at a dose of over 15 mg/kg/day. Most of the enrolled patients in our study (81.6%) weighed less than 70 kg, and half of these patients weighed 60 kg or less.
There were some limitations in this study. First, this study was a retrospective study and examined only a small number of patients. Second, although we included patients who received Peg-IFN α-2b over 48 weeks in this study, we may have overlooked the impact of the total dose of Peg-IFN α-2b during therapy. Third, there was no evidence to support that treatment withdrawal or serious side effects frequently occurred in high-dose RBV treated patients (Group A) compared to low-dose RBV treated patients (Group B). Fourth, RBV bioavailability displays wide inter-individual variability and its plasma concentrations correlate poorly with the daily RBV dose. After adjustment for body weight, therapeutic drug monitoring of RBV has been considered a feasible option for improving RBV dose titrations.
An important part of this study was to assess the RBV dose effect on the response to combination treatment with Peg-IFN alfa-2b. Based on our findings, we suggest that a lower dose of RBV than that proposed by the Korean standard guideline may be sufficiently effective and may decrease the need for dose reductions during treatment. However, because lowering the RBV dose can potentially decrease the SVR, further studies are needed to determine the optimal initial RBV dose required to maintain a virological response in genotype 1 chronic hepatitis C in Korean patients.
The authors have no conflicts to disclose.
chronic hepatitis C
early virologic response
peginterferon alfa 2b
ribavirin
sustained virologic response
Initial ribavirin dose relative to body weight.
Baseline clinical characteristics of the investigated patients
Characteristic | Group A (RBV dose ≥15 mg/kg/day) | Group B (RBV dose <15 mg/kg/day) (N=26) | |
---|---|---|---|
Mean age | 42.26 ±14.26 | 45.85 ±9.27 | 0.297 |
Sex – no. (%) | |||
Male | 7 (30.4) | 20 (76.9) | 0.020 |
Female | 16 (69.6) | 6 (23.1) | |
Body weight (kg) | 57.16 ±6.26 | 70.47 ±10.84 | 0.000 |
BMI (kg/m2) | 21.84 ±1.70 | 25.05 ±2.91 | 0.000 |
ALT, IU/L | 81.48 ±100.78 | 138.08 ±201.52 | 0.229 |
HCV RNA, ×105 | 39.67 ±54.30 | 52.21 ±61.63 | 0.456 |
Initial RBV dose (mg/kg/day) | 17.22 ±1.6 | 12.72 ±1.76 | 0.000 |
Mann-Whitney test;
Fisher’s exact test.
ALT, alanine aminotransferase; BMI, body mass index; HCV RNA, hepatitis C virus RNA; RBV, ribavirin.
Clinical outcomes after treatment with combination therapy
Group A (n=23) | Group B (n=26) | ||
---|---|---|---|
EVR rate | 21 (91.3) | 22 (84.6) | 0.634 |
SVR rate | 19 (82.6) | 19 (73.1) | 0.506 |
Recurrence rate | 1 (4.3) | 1 (3.8) | 1.000 |
Dose reduction rate | 14 (60.9) | 6 (23.1) | 0.010 |
Values are presented as no. (%).
Fisher’s exact test.
EVR, early virologic response; SVR, sustained virologic response.
Frequencies of adverse events and dose modifications
Adverse events | Group A |
Group B |
|||
---|---|---|---|---|---|
n (%) | Dose modification, n (%) | n (%) | Dose modification, n (%) | ||
Flu-like symptoms | 14 (28.6) | 4 (8.2) | 9 (18.4) | 3 (6.1) | 0.352 |
Anemia | 14 (28.6) | 13 (26.5) | 7 (14.3) | 6 (12.2) | 0.022 |
Neutropenia | 5 (10.2) | 3 (6.1) | 11 (22.4) | 3 (6.1) | 1.000 |
Nausea | 4 (8.2) | 0 (0.0) | 6 (12.2) | 0 (0.0) | 0.731 |
Itching sensation | 2 (4.1) | 0 (0.0) | 6 (12.2) | 0 (0.0) | 0.254 |
Rash | 2 (4.1) | 1 (2.0) | 4 (8.2) | 0 (0.0) | 0.671 |
Thyroid dysfunction | 2 (4.1) | 0 (0.0) | 4 (8.2) | 0 (0.0) | 1.000 |
Depression | 2 (4.1) | 0 (0.0) | 2 (4.1) | 0 (0.0) | 0.215 |
Insomnia | 2 (4.1) | 0 (0.0) | 2 (4.1) | 0 (0.0) | 0.215 |
Thrombocytopenia | 2 (4.1) | 0 (0.0) | 1 (2.0) | 0 (0.0) | 0.469 |
Fisher’s exact test.