To clarify the impact of adherence, we treated 122 genotype 1 high viral titer chronic hepatitis C patients with pegylated interferon (peg-IFN) and ribavirin for 48 weeks at nine referral hospitals, and evaluated the prognostic factors with a focus on the adherence to the treatment. This study included 68 (55.7%) treatment-naïve patients and 54 (44.3%) patients who did not respond to the previous treatment. Multivariate analysis revealed adherence to peg-IFN and ribavirin as the only significant predictor. Sustained virological response (SVR) rate was 72.2%, 19.0%, and 27.3% in patients given ≥80%, 60%–80%, and <60% dose peg-IFN, respectively, and was 68.6%, 41.2%, and 5.3% in those given ≥80%, 60%–80%, and <60% dose ribavirin, respectively. SVR rate sharply fell when exposure to peg-IFN was below 80% whereas it decreased in a stepwise manner as for ribavirin. Therefore, ≥80% of peg-IFN and as much as possible dose of ribavirin are desired to achieve SVR in the treatment of genotype 1 high viral titer chronic hepatitis C.
Although the combination of pegylated interferon (peg-IFN) and ribavirin (RBV) is the standard-of-care therapy for chronic hepatitis C, the sustained virological response (SVR) rate is still 40%–50% [
Until now, many host factors including younger age (40 years or less) [
Japanese elderly women were reported to be resistant to this therapy [
In this study, we treated genotype 1 high viral titer chronic hepatitis C patients with peg-IFN and RBV combination therapy, and evaluated the prognostic factors with a focus on the adherence to the treatment.
This study was performed at nine referral hospitals. Patients with hepatitis C virus (HCV) genotype 1 and high viral load (
The patients were given peg-IFN alfa-2b at a dosage of 1.5 mg/kg every week subcutaneously for 48 weeks. Daily RBV was administered orally for 48 weeks according to the labeling approved by the Japanese Ministry of Health, Labour and Welfare; 600 mg for patients
The factors associated with SVR were analyzed by logistic regression using SPSS version 16 (SPSS Japan, Tokyo, Japan). Univariate or multivariate logistic regression analyses were performed to establish the factors contributing to SVR. All reported
A total of 122 patients were enrolled into the study. Forty-five patients (36.9%) were female and
Analyzed factors included gender, age, body weight, BMI, viral load, history of IFN treatment, and adherence to the treatment. Younger age, heavier weight, lower viral load, peg-IFN adherence, and RBV adherence were significant factors associated with SVR by univariate analysis. Multivariate analysis revealed adherence to peg-IFN and adherence to RBV as a significant predictor. We performed the same analysis after stratifying treatment-naïve and previously treated patients, and found adherence to peg-IFN and RBV as only factors significantly associated with SVR (data not shown) as shown in the entire cohort.
Variables | SVR | Adjusted OR (95% C.I.) | ||
---|---|---|---|---|
Sex | .091 | .501 | ||
Female | 20/45 (44.4%) | 1.00 | ||
Male | 47/77 (61.0%) | 1.429 (0.506–4.032) | ||
Age (yr) | .019 | .398 | ||
65 | 5/16 (31.3%) | 1.00 | ||
51 | 35/68 (51.5%) | 2.655 (0.581–12.132) | ||
| 27/38 (71.1%) | 2.695 (0.574–12.659) | ||
Weight (Kg) | .028 | .116 | ||
| 31/68 (45.6%) | 1.000 | ||
65 | 36/54 (66.7%) | 3.053 (0.760–12.274) | ||
BMI | .716 | .158 | ||
24 | 30/57 (52.6%) | 1.000 | ||
| 37/65 (56.9%) | 2.747 (0.674–11.236) | ||
Viral load (IU/mL) | .015 | .174 | ||
800,000 | 41/86 (47.7%) | 1.000 | ||
100,000 | 26/36 (72.2%) | 2.137 (0.716–6.369) | ||
History of IFN treatment | .203 | .581 | ||
yes | 26/54 (48.1%) | 1.000 | ||
no | 41/68 (60.3%) | 1.316 (0.496–3.493) | ||
Peg-IFN adherence (%) | .008 | |||
| 6/22 (27.3%) | 2.637 (0.448–15.513) | .284 | |
60 | 4/21 (19.0%) | 1.000 | — | |
80 | 57/79 (72.2%) | 7.702 (1.926–30.798) | .004 | |
RBV adherence (%) | .010 | |||
| 1/19 (5.3%) | 1.000 | — | |
60 | 7/17 (41.2%) | 15.679 (1.289–190.653) | .031 | |
80 | 59/86 (68.6%) | 27.416 (3.130–240.151) | .003 |
Patients given
Scatter plot of patients with or without SVR according to administered total doses of peg-IFN and RBV. One hundred % represents a full scheduled dose. A circle and a triangle indicate a patient with SVR and one without SVR, respectively. A number represents number of patients with SVR/total number (SVR rate).
SVR rates classified by adherence to peg-IFN and RBV.
There was a trend that younger patients received greater peg-IFN dose; 72/106 (67.9%) patients younger than 65 years and 7/16 (43.8%) patients aged 65 or older received
Sixty-six patients (54.1%) received
The population of patients whose serum HCV-RNA first disappeared at week 4 (RVR), week 8, week 12 (EVR), week 24, and week 48 was 10 (8.2%), 39 (32.0%), 28 (23.0%), 20 (16.4%), and 4 (3.3%) patients, respectively. Twenty-one (17.2%) patients were positive for HCV-RNA throughout the treatment period (null response). The SVR rate of these patients who became negative for HCV-RNA at week 4 (RVR), week 8, week 12 (EVR), week 24, and week 48 was 10/10 (100%), 35/39 (89.7%), 17/28 (60.7%), 5/20 (25%), and 0/4 (0%), respectively. In 101 patients negative for HCV-RNA at the end of treatment, 34 (33.7%) patients relapsed. Relapse rate was significantly lower in patients who received
Relapse rates classified by adherence to peg-IFN and RBV.
Seventeen (13.9%) patients discontinued treatment. The reasons of premature discontinuation were general fatigue and/or appetite loss (11 patients), fundal hemorrhage (1 patient), deterioration of diabetes mellitus (1 patient), and depression (1 patient). Three patients discontinued treatment because of positive HCV-RNA at week 24. Thirty-nine (32.0%) and 33 (27.0%) patients required dose reduction of peg-IFN and RBV, respectively. Major reasons of dose reduction were neutropenia or thrombocytopenia for peg-IFN and anemia for RBV. Common adverse effects included general fatigue, appetite loss, weight loss, and pruritus. In 12 patients with advanced liver disease (METAVIR fibrosis score of 3-4), 6 (50%) and 4 (33.3%) patients required dose reduction of peg-IFN and RBV, respectively. In 75 patients with milder liver disease (METAVIR fibrosis score of 0–2), 22 (29.3%) and 20 (26.7%) patients required dose reduction of peg-IFN and RBV, respectively. There was no significant difference between these two groups in the proportion of patients who required dose reduction.
The mean age of our study population was 54.0 years, which was approximately 10 years older than patients of major studies in Western countries [
In our study, adherence to peg-IFN and RBV was the only significant factor associated with SVR. Interestingly, the SVR rate stepwisely rose by the increase of administered dose of RBV. In contrast, 80% or more dose of peg-IFN was required to achieve SVR (Figure
The difference between peg-IFN and RBV in the impact of adherence on SVR, especially within the
At least 80% dose of peg-IFN will be necessary to obtain favorable outcome. In contrast, RBV should be administered as much as possible within the planned dose. To accomplish this, RBV dose should be reduced by 200-mg decrements when anemia appears, and restored to the previous dose when anemia improves. Higher than standard dose RBV given together with standard dose peg-IFN may increase SVR rate [
Sezaki et al. reported that elderly women were resistant to peg-IFN and RBV combination therapy in Japan [
SVR rate was 74.2% when both drugs were administered
In this study, serotyping was used instead of genotyping because genotyping was not covered by the Japanese national health insurance. Serotype 1 includes genotype 1a and 1b. Because genotype 1a is rarely observed in Japan [
In conclusion, 80% or more dose of peg-IFN and as much as possible dose of RBV are desired to achieve SVR in the treatment of genotype 1 high viral titer chronic hepatitis C.