Funding: The study was supported by grants from the National Taiwan University Hospital, the National Science Council and Department of Health, Executive Yuan, Taiwan.
Competing interests: None.
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Chronic hepatitis C virus (HCV) infection is common in dialysis patients, with the reported prevalence and annual incidence ranging from 3 to 80% and 2.9%, respectively.1–4 Although dialysis patients with HCV infection usually present with mild symptoms and mild elevation of serum alanine aminotransferase (ALT) levels, previous studies have shown that these patients harbour higher liver-related morbidity and mortality rates at the dialysis stage,5–8 and poor graft and patient survival after renal transplantation.9–11
Pegylated interferon and ribavirin have become the mainstay therapy for chronic hepatitis C patients with normal renal function, with an overall sustained virological response (SVR) rate of 54–61%.12 However, ribavirin is currently considered contraindicated in dialysis patients due to the risk of severe haemolytic anaemia.13–15 In dialysis patients with chronic hepatitis C, two meta-analyses indicated that the SVR rates were 33–37% with standard interferon α 1–6 million units (MU) for 6–12 months. However, the corresponding drop-out rates ranged from 17 to 29.6%.16 17 Recently, small non-randomised studies on the use of pegylated interferon α showed that patients receiving pegylated interferon α-2a 135–180 μg once per week had a more favourable SVR rate (33–75%) than those receiving pegylated interferon α-2b 0.5–1.0 μg/kg once per week (12.5%).18–21
With these lines of evidence, the recent Asian Pacific Association for the Study of the Liver (APASL) consensus statements on the diagnosis, management and treatment of HCV infection recommends that only standard interferon monotherapy is used for the treatment of dialysis patients with chronic hepatitis C because there was no report at the time of better efficacy and safety of pegylated interferon.22 We thus conducted a randomised trial to evaluate the efficacy and safety of pegylated interferon α-2a versus standard interferon α-2a in treatment-naïve dialysis patients with chronic hepatitis C.
MATERIALS AND METHODS
Dialysis patients aged between 18 and 65 years who were naïve to interferon-based therapy and fulfilled the following criteria were eligible for this study: presence of anti-HCV antibody (Abbott HCV EIA 2.0, Abbott Diagnostic, Chicago, IL) and HCV RNA for more than 6 months, receiving regular dialysis therapy, and with creatinine clearance of less than 10 ml/min/1.73 m2 of body surface area.
Patients were excluded from the study if they had neutropenia (neutrophil count <1500/mm3), thrombocytopenia (platelet count <90 000/ml3), co-infection with hepatitis B virus (HBV) or HIV, chronic alcohol abuse (daily alcohol consumption >20 g/day), autoimmune liver diseases, decompensated cirrhosis (Child–Pugh class B or C), neoplastic diseases, organ transplantation or immunosuppressive therapy, evidence of drug abuse, poorly controlled autoimmune diseases, cardiopulmonary diseases, neuropsychiatric disorders and diabetes mellitus, or were unwilling to take contraception during the study.
This randomised, controlled clinical trial was conducted in four centres (National Taiwan University Hospital, Far Eastern Memorial Hospital, Chiayi Christian Hospital and St. Martin De Porres Hospital) in Taiwan from July 2005 to January 2007. The protocols were approved by the Ethical Committee of each participating centre, and all patients provided written informed consent before enrolment. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. Eligible patients were randomly assigned in a 1:1 ratio to receive either once weekly, subcutaneous injection of 135 μg pegylated interferon α-2a (Pegasys, F. Hoffmann-LaRoche, Basel, Switzerland) or thrice weekly, subcutaneous injection of 3 MU standard interferon α-2a (Roferon, F. Hoffmann-LaRoche, Basel, Switzerland) for 24 weeks. Randomisation was performed by a computer-generated random number table. Participants received the study drugs on an outpatient basis for 24 weeks and then were followed for 24 weeks after the cessation of therapy. Furthermore, they received outpatient visits to assess the efficacy and safety at weeks 1, 2, 4, 6 and 8 of the study and then monthly until the end of follow-up.
Laboratory tests, including haemogram, coagulation profiles and serum ALT levels, were assessed at each outpatient visit. Serum HCV RNA levels were evaluated quantitatively at baseline and at week 12 of the study (Cobas Amplicor HCV Monitor v2.0, Roche Molecular Systems, Pleasanton, CA; with a detection cut-off level of 600 IU/ml) and qualitatively at weeks 4, 24 and 48 of the study (Cobas Amplicor HCV v2.0, Roche Molecular Systems, Pleasanton, CA; with a detection cut-off level of 50 IU/ml). HCV genotyping was performed at baseline by a reverse hybridisation technique (Inno-LiPA HCV II, Innogenetics, Ghent, Belgium). The rapid virological response (RVR) was defined as undetectable HCV RNA by a sensitive qualitative test at week 4 of the study. The early virological response (EVR) was defined as at least a 2-log decrease of HCV RNA level by a quantitative test from baseline to week 12 of the study, and the end of treatment virological response (ETVR) was defined as undetectable HCV RNA by a sensitive qualitative test at week 24 of the study. Liver biopsies at baseline and at the end of follow-up were performed using 16-gauge Temno Evolution™ biopsy needles (Allegiance, McGaw Park, IL) 30–60 min after the infusion of 0.3 μg of deamino-8-d-arginine vasopressin (DDAVP) per kilogram of body weight.23 All biopsy specimens were assessed according to the modified histological activity index (HAI) score24 by one experienced pathologist who was unaware of the clinical status of study subjects. The HAI scores range from 0 to 24, with inflammation scores graded from 0 (none) to 18 (severe) and fibrosis scores graded from 0 (none) to 6 (cirrhosis).
Assessment of efficacy
The primary efficacy end point was SVR, defined as undetectable HCV RNA by a sensitive qualitative test at week 48 of the study by intention-to-treat (ITT) analysis. The secondary efficacy end point was histological response, defined as a decrease of at least 2 points in the post-treatment to pretreatment liver biopsies by the modified HAI score.
Assessment of safety
Participants received laboratory tests and evaluation of adverse events on an outpatient basis to assess safety. They were considered withdrawn from the study if they missed four consecutive weeks of therapy or if the investigators were concerned about the safety of the treatment. Patients who withdrew from the study because of intolerance to adverse events were encouraged to receive outpatient visits without therapy until the end of the follow-up. Dosage reduction to pegylated interferon α-2a 90 μg once weekly, standard interferon α-2a 1.5 MU thrice weekly or cessation of treatment was determined according to the severity of adverse events and the laboratory abnormalities (dosage reduction, neutrophil count <750/mm3 or platelet count <50 000/ml3; cessation of treatment, neutrophil count <500/mm3 or platelet count <30 000/ml3). If the laboratory abnormalities and the severity of adverse events improved or resolved after dosage reduction or treatment cessation, a return to the initial dose was permitted. The primary safety end point was the treatment-related withdrawal rate, defined as premature cessation of therapy or loss to follow-up off therapy due to treatment-related adverse events.
Statistical analyses were performed using the Statistical Program for Social Sciences (SPSS 11.0 for windows; SPSS Inc., Chicago, IL). The estimated sample size of 52 patients (26 in each group) was based on a type I error rate of α = 0.05, and a type II error rate of β = 0.20 for a primary two-sided test, with the assumption of a 35% difference in SVR rates (52% SVR in the pegylated interferon α-2a group vs 17% SVR in the standard interferon α-2a group). The independent Student t test was used to compare quantitative variables, and χ2 test or Fisher’s exact test was used for qualitative variables. ITT analyses for efficacy and safety were performed on the basis of the patients who received at least one dose of the study medication except for changes from baseline in histological findings (secondary efficacy end point). Per-protocol (PP) analysis for efficacy was performed on the basis of the patients who completed the follow-up study. The secondary efficacy end point was analysed only in patients who had undergone pretreatment and post-treatment liver biopsies. The relatedness of pretreatment and on-treatment variables to SVR was examined by univariate analysis, multivariate logistic regression analysis and χ2 test. A p value <0.05 was considered statistically significant. All statistical tests were two-tailed.
Of the 66 patients screened, 16 did not meet the inclusion criteria and were excluded from the study. The reasons for exclusion were undetectable HCV RNA in seven, presence of hepatocellular carcinoma in two, decompensated cirrhosis in one, HCV and HBV co-infection in two, poorly controlled diabetes mellitus in one, severe heart diseases in one and reluctance to receive treatment in two (fig 1). The baseline characteristics of the eligible patients with pegylated interferon α-2a or standard interferon αa-2a were comparable (table 1). Treatment was completed in 100% and 84%, and follow-up was completed in 100% and 88%, in patients receiving pegylated interferon α-2a and standard interferon α-2a, respectively. The reasons for incomplete treatment were intolerable adverse events in four, and for incomplete follow-up were intolerable adverse events in two and death due to cardiogenic pulmonary oedema 4 weeks off therapy in one.
Table 2 shows the virological responses in dialysis patients who received pegylated interferon α-2a or standard interferon α-2a by ITT and PP analyses. There were no significant differences between pegylated interferon α-2a and standard interferon α-2a groups for RVR rates (60% vs 44%, p = 0.40, ITT analysis; 60% vs 45%, p = 0.39, PP analysis), EVR rates (92% vs 88%, p = 1.00, ITT analysis; 92% vs 86%, p = 0.65, PP analysis) and SVR rates (48% vs 20%, p = 0.07, ITT analysis; 48% vs 23%, p = 0.13, PP analysis). In contrast, patients receiving pegylated interferon α-2a had a significantly higher ETVR rate than those receiving standard interferon α-2a (92% vs 60%, p = 0.02, ITT analysis; 92% vs 64%, p = 0.03, PP analysis).
Pretreatment and post-treatment paired liver biopsies were available in 41 patients (82%). Histological improvement occurred after either pegylated interferon α-2a or standard interferon α-2a therapy, but did not show statistical differences in either inflammatory scores (p = 0.14), fibrosis scores (p = 0.28), total scores (p = 0.13) or percentage of a decrease of at least 2 points of total scores (p = 0.12). In contrast, patients who achieved SVR had a statistically significant improvement of inflammatory scores (p<0.001), fibrosis scores (p = 0.004), total scores (p<0.001) and percentage of a decrease of at least 2 points of total scores (p<0.001) compared with those who did not achieve SVR (table 3).
Fever was more frequently observed in patients receiving standard interferon α-2a than in those receiving pegylated interferon α-2a (44% vs 12%, p = 0.03) (table 4). Other constitutional symptoms were comparable in both groups. None of them needed dose reduction or cessation of treatment due to neutropenia. More patients receiving standard interferon α-2a needed dose modification than those receiving pegylated interferon α-2a due to thrombocytopenia, but the difference was not statistically significant (20% vs 12%, p = 0.70). Four patients stopped standard interferon α-2a at weeks 12, 16, 16 and 20 of treatment, respectively, due to treatment-related adverse events (retinal haemorrhage, fever, fatigue and dermatitis), but two of them completed follow-up. Two patients receiving standard interferon α-2a had treatment-related serious adverse events: one had retinal haemorrhage with impaired visual acuity at week 12 of treatment and one died from cardiogenic pulmonary oedema 4 weeks off therapy. None of the patients receiving pegylated interferon α-2a stopped treatment prematurely or had serious adverse events during treatment and follow-up. The treatment-related withdrawal rate of patients receiving pegylated interferon α-2a was significantly lower than that of patients receiving standard interferon α-2a (0% vs 20%, p = 0.04).
Predictors of a sustained virological response
Table 5 shows the pretreatment and on-treatment predictors for SVR. Baseline HCV RNA level with a cut-off level of 800 000 IU/ml and age with a cut-off level of 40 years were significantly associated with SVR (p = 0.0001 and 0.01, respectively), and treatment with pegylated interferon α-2a or standard interferon α-2a was marginally significantly associated with SVR (p = 0.07). Factors in the univariate analysis with a p value <0.10 entered into multivariate logistic regression analysis to search for independent factors predictive of SVR. Both baseline HCV RNA level ⩾800 000 IU/ml (odds ratio (OR) 0.04, 95% CI 0.01 to 0.41, p = 0.007) and treatment with pegylated interferon α-2a (OR 6.52, 95% CI 1.31 to 32.47, p = 0.02) were independently associated with SVR. By week 4, 52% of patients treated with either pegylated interferon α-2a or standard interferon α-2a had RVR. While 65% of the patients with RVR achieved SVR, none of the patients without RVR achieved SVR (p<0.001).
With the high incidence and prevalence,1–4 higher liver-related co-morbidity at the dialysis stage,5–8 poor graft and patient survival,9–11 and poor response to interferon-based therapy at the post-transplantation stage,25–28 dialysis patients with chronic hepatitis C are encouraged to receive antiviral therapy at the dialysis stage rather than at the post-transplantation stage. Although small-scale clinical trials showed that standard interferon or pegylated interferon in combination with ribavirin may achieve a high SVR in dialysis patients, severe adverse events frequently occurred29–33 and routine use of ribavirin is not recommended.13–15 22 34Two meta-analyses indicated that the overall SVR rates of standard interferon monotherapy were 33–37% in dialysis patients; however, varied dosage, duration and response rates were observed.16 17 Similarly, wide variation of treatment responses (12.5–75%) and adverse events were also observed with pegylated interferon α-2a or α-2b monotherapy.18–21 We thus conducted a randomised trial to compare the efficacy and safety of pegylated versus standard interferon α-2a directly in this special clinical setting. Although univariate analysis failed to show the superiority of pegylated interferon α-2a over standard interferon α-2a in achieving SVR, multivariate analysis clearly demonstrated the better treatment response of pegylated interferon α-2a. This discrepancy may be explained by the relatively small cohort of patients, which precluded an even distribution of all potential confounding factors affecting SVR. It is known that the baseline HCV RNA level serves as an important predictor of SVR.35 36 After adjusting baseline viral load, patients receiving pegylated interferon α-2a had a significantly higher SVR rate than those receiving standard interferon α-2a. Furthermore, the treatment-related withdrawal rate in the standard interferon α-2a group was higher than that in the pegylated interferon α-2a group. Taking these results together, for the first time we demonstrated that 24-week pegylated interferon α-2a was better than standard interferon α-2a for treatment-naïve dialysis patients with chronic hepatitis C in terms of efficacy and safety.
Our study showed that patients who received standard interferon α-2a were inferior to patients who received pegylated interferon α-2a in achieving ETVR by either ITT or PP analyses. None of the four patients in the standard interferon α-2a group who stopped treatment prematurely at week 12–20 of treatment due to adverse events had ETVR, although all of them had EVR. In sharp contrast, all patients in the pegylated interferon α-2a group could tolerate the treatment well without premature discontinuation, and, therefore, all of them who had EVR had ETVR. Because of the greater peak-to-trough drug concentration in patients with standard interferon than those with pegylated interferon,37 dialysis patients with standard interferon may experience more severe adverse events that preclude complete treatment. Therefore, virological relapse occurs early after stopping the treatment. This fact also highlights that dialysis patients with chronic hepatitis C should receive pegylated interferon-based therapy.
Contrary to the concept that HCV genotype 1 and significant hepatic fibrosis are associated with a poor SVR rate to interferon monotherapy in HCV patients with normal renal function,35 36 our results failed to show the significance of these factors in predicting SVR. Instead, baseline HCV RNA level was the only independent predictor for SVR. This may be explained by the limited patient numbers in our study, or the inferior augmentation of host immunity with interferon therapy in dialysis patients, which resulted in similar viral suppression across different genotypes and fibrosis stages.38–40 Further larger studies are needed to examine the role of HCV genotype and hepatic fibrosis for SVR in these patients.
Early prediction of virological response to interferon monotherapy during treatment can help docors to identify patients who are unlikely to achieve SVR, and allow discontinuation of treatment to relieve patient discomfort and to save additional medical cost. In this study, none of the patients without RVR could achieve SVR at the end of follow-up. Furthermore, treatment failure was also observed in all dialysis patients receiving 1.5–3 MU standard interferon for 12 months who had detectable serum HCV RNA at month 2 of treatment.41 To decide whether to receive an extended duration of treatment beyond 24 weeks in patients based on RVR and month 2 serum HCV RNA level should be individualised and needs further confirmation.
Although our data showed that dialysis patients with chronic hepatitis C who received 24 weeks of pegylated interferon monotherapy had a virological response comparable with that of chronic hepatitis C patients with normal renal function who received 48 weeks of pegylated interferon monotherapy,35 the overall SVR rate was far from satisfactory. Further large studies focusing on the treatment duration and the addition of ribavirin to achieve a higher SVR rate without compromising patient tolerance and safety are awaited to optimise treatment in this special clinical setting.
In conclusion, pegylated interferon α-2a is superior to standard interferon α-2a in treatment-naïve dialysis patients with chronic hepatitis C. High pre-treatment HCV RNA level and failure to achieve RVR are predictors of poor response to interferon monotherapy.
Funding: The study was supported by grants from the National Taiwan University Hospital, the National Science Council and Department of Health, Executive Yuan, Taiwan.
Competing interests: None.
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