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Significance of this study
What is already known on this subject?
Hepatitis C virus (HCV) infection is prevalent in patients receiving haemodialysis. The prognosis is greatly improved in these patients who eradicate HCV infection, whether they remain on maintenance dialysis or have had renal transplantation.
In previous small-scale, non-comparative studies, combination therapy with peginterferon plus low-dose ribavirin seemed to have higher sustained virological response (SVR) rate than peginterferon monotherapy in HCV-infected patients receiving haemodialysis. However, more patients prematurely terminated combination therapy due to severe haemolytic anaemia.
In treatment-naive haemodialysis patients with HCV genotype 1 (HCV-1) infection, a large-scale randomised study showed that patients receiving 48 weeks of combination therapy with peginterferon plus low-dose ribavirin had greater SVR rate than those receiving peginterferon monotherapy. Furthermore, most patients can tolerate combination therapy by high-dose erythropoiesis-stimulating agent (ESA) supply and timely titrating dosages of ribavirin for anaemia.
What are the new findings?
In this open-label, randomised trial, we demonstrated that in treatment-naive haemodialysis patients with HCV genotype 2 (HCV-2) infection, patients receiving 24 weeks of combination therapy with peginterferon plus low-dose ribavirin had a significantly greater SVR rate than those receiving peginterferon monotherapy.
By close monitoring the serial haemoglobin levels, high-dose ESA supply and timely titrating dosages of ribavirin to manage treatment-related anaemia, most patients can well tolerate combination therapy.
In HCV-2 patients receiving haemodialysis, those who have a baseline viral load less than 800 000 IU/mL can receive peginterferon monotherapy without compromising the SVR rate.
How might it impact on clinical practice in the foreseeable future?
Instead of peginterferon monotherapy, haemodialysis patients with HCV-2 infection should be encouraged to receive 24 weeks of peginterferon plus low-dose ribavirin therapy to achieve a higher SVR rate.
In easy-to-treat HCV-2 patients receiving haemodialysis with a low baseline viral load, peginterferon monotherapy provides comparable efficacy to combination therapy.
Hepatitis C virus (HCV) infection remains a major comorbidity in haemodialysis patients.1–3 The incidence and prevalence rates of HCV infection in haemodialysis patients are much greater than those in the general population and are attributed to high rates of nosocomial transmission.4 ,5 Compared with haemodialysis patients who do not have HCV infection, haemodialysis patients with HCV infection have increased risks of liver-related morbidity and mortality.6 Although haemodialysis patients with HCV infection who receive renal transplantation have survival advantages over those who remain on maintenance dialysis, these patients still have poor patient and graft survival, as well as have poor responses to interferon (IFN)-based therapy.7–9 In contrast, haemodialysis patients who eradicate HCV infection have improved clinical outcomes, whether they remain on maintenance dialysis or have had renal transplantation.10 ,11
In haemodialysis patients with various HCV genotype infection, the sustained virological response (SVR) and the adverse event (AE)-related treatment discontinuation rates are 33–41% and 17–30% by conventional IFN or peginterferon monotherapy, respectively.12–15 Although addition of ribavirin to IFN further improves the SVR rate in patients with HCV infection and normal renal function, ribavirin has been considered to be contraindicated in haemodialysis patients because of concern for life-threatening haemolytic anaemia. A meta-analysis evaluated addition of low-dose ribavirin (200 mg three times/week to 400 mg/day, adjusted to achieve a target ribavirin plasma concentration of 10–15 μmol/L), to conventional IFN or peginterferon for haemodialysis patients with various HCV genotype infection, and the SVR and the premature discontinuation rates due to poor response or AEs by combination therapy were 56% and 22%, respectively.16 However, previous studies were small in size and were highly heterogeneous in terms of treatment regimen, HCV genotype and study endpoint, making the efficacy and safety of combination therapy compared with monotherapy in this patient population uncertain. Recently, we demonstrated that treatment-naive haemodialysis patients with HCV genotype 1 (HCV-1) infection treated with peginterferon plus low-dose ribavirin for 48 weeks had a greater SVR rate than those treated with peginterferon monotherapy.17 Furthermore, most patients can tolerate combination therapy. However, the safety and efficacy have not been fully addressed with regard to non-genotype 1 (non-1) HCV patients. Therefore, we conducted a randomised study to compare the efficacy and safety of combination therapy of peginterferon plus low-dose ribavirin and peginterferon monotherapy for 24 weeks in haemodialysis patients with HCV-2 infection.
From 1 July 2007 to 9 May 2012, we conducted a multicentre, open-label, randomised study in eight academic centres in Taiwan. Treatment-naive haemodialysis patients with HCV-2 infection and aged between 18 and 65 years were consecutively enrolled in the Haemodialysis Low Dose Peginterferon and Ribavirin for HCV-2 Patients (HELPER-2) trial. The protocol was approved by Taiwan Joint Institutional Review Board and was conducted in accordance with the principles of Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. Each patient provided written informed consent before enrolment.
Setting and participants
Chronic HCV infection was defined as presence of anti-HCV antibody (Abbott HCV EIA 3.0, Abbott Laboratories, Abbott Park, Illinois, USA) and HCV RNA (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, limit of detection: 15 IU/mL) for ≥6 months. HCV-2 infection was confirmed by reverse hybridisation assay (Versant HCV Genotype 2.0 assay, Siemens Healthcare Diagnostics, Illinois). Patients receiving haemodialysis were defined as those with stage 5 chronic kidney disease (glomerular filtration rate <15 mL/min/1.73 m2 for ≥3 months) who received haemodialysis through vascular access.
Patients were excluded if they had haemoglobin levels <10 g/dL, neutrophil count <1.5×109 cells/L, platelet count <90×109 cells/L, non-genotype 2 HCV infection, hepatitis B virus (HBV) or HIV coinfection, daily alcohol consumption >20 g, decompensated cirrhosis, autoimmune liver diseases, neoplastic diseases, immunosuppressive therapy, drug abuse, pregnancy, poorly controlled autoimmune diseases, cardiopulmonary diseases, neuropsychiatric diseases and diabetes mellitus with retinopathy or were receiving peritoneal dialysis. Of the 461 screened patients, 284 patients were excluded and the remaining 177 patients were eligible for the study (figure 1).
Randomisation and interventions
Randomisation was computer-generated in blocks of 4 with centralised allocation and the code was secured by an independent assistant. After obtaining informed consent from the eligible patients, the site investigators faxed the document to the assistant, who confirmed the patient’s eligibility and telephoned the site investigators the treatment allocation through the assigned randomisation code. Eligible patients were randomly assigned using a 1:1 ratio to receive combination therapy of peginterferon alfa-2a 135 μg/week (Pegasys, Hoffman-LaRoche, Basel, Switzerland) plus low-dose ribavirin 200 mg/day (Copegus, Hoffman-LaRoche, Basel, Switzerland) or monotherapy of peginterferon alfa-2a 135 μg/week for 24 weeks. The randomisation was not stratified by the participating centres.
Baseline demographic data, haemogram (haemoglobin level, neutrophil count and platelet count), biochemical assays (serum albumin, bilirubin, aspartate aminotransferase [AST], alanine aminotransferase and creatinine), serologic assays (anti-HCV, HBsAg, and anti-HIV), virological assays (HCV RNA and genotype) and human genomic assay for interleukin (IL)-28B rs8099917 genotypes (ABI TaqMan allelic discrimination kit and ABI7900HT Sequence Detection System, Applied Biosystems, Life Technologies Corporation, Grand Island, New York, USA) were evaluated before enrolment.18 ,19 The stage of hepatic fibrosis was assessed by AST-to-platelet ratio index (APRI).20 ,21 Low baseline viral load was defined as a level of <800 000 IU/mL, whereas high baseline viral load was defined as a level of ≥800 000 IU/mL.17 IL-28B rs8099917 favourable genotype was defined as patients with homozygous TT genotype, whereas unfavourable genotype was defined as patients with heterozygous GT or homozygous GG genotype. Significant hepatic fibrosis (≥F2 by Metavir score) and advanced hepatic fibrosis (≥ F3 by Metavir score) were defined an APRI score of ≥0.8 and ≥1.0, respectively.20 ,21
Outcomes and follow-up
All patients received treatment for 24 weeks and post-treatment follow-up for 24 weeks. Serum HCV RNA levels were assessed at weeks 4, 12 and 24 of treatment and at week 24 post-treatment. The on-treatment virological responses (including rapid virological response [RVR], early virological response [EVR], complete early virological response [cEVR], partial early virological response [pEVR] end-of-treatment virological response [ETVR]) and the post-treatment virological response (including SVR) were defined as described in online supplementary table S1.17 Patients who had no response to treatment or had viral breakthrough during treatment were considered non-responders and treatment was stopped. For patients who prematurely discontinued treatment, the ETVR was assessed at the time of treatment discontinuation.
The primary endpoint was SVR rate, defined as undetectable serum HCV RNA 24 weeks post-treatment for patients receiving at least one dose of the study medication. Patients who were not responsive to treatment or who had viral breakthrough during treatment were considered not to have achieved SVR, regardless of the HCV RNA data at the end of follow-up. Patients who relapsed after the treatment (see online supplementary table S1) and who lacked the end of follow-up data to assess SVR were also considered not having achieved SVR. Sensitivity analyses were done for the primary endpoint.
The site investigators used a prespecified checklist to assess the severity and the causality of the constitutional and laboratory AEs at weeks 1, 2, 4, 6, 8 and then every 4 weeks until the end of follow-up. Except for anaemia, the severity of all AEs was graded according to the Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events, V.1.0. The safety summary was assessed from the beginning of treatment to the last visit for patients who prematurely discontinued treatment. Patients were withdrawn from the study if they developed serious AEs, missed receiving the allocated treatment >4 consecutive weeks or subjectively requested to terminate treatment.
The dosage of peginterferon alfa-2a was reduced in a stepwise fashion from 135 μg/week to 90 or 45 μg/week or treatment was stopped according to the severity of constitutional AEs. Dosages were reduced from 135 μg/week to 90 μg/week treatment was stopped according to laboratory AEs (the dosage was reduced to 90 μg/week if the neutrophil count was <0.75×109 cells/L or the platelet count was <50×109 cells/L; treatment was stopped if the neutrophil count was <0.50×109 cells/L or the platelet count was <25×109 cells/L). Ribavirin dosage was reduced in a stepwise fashion from 200 mg/day to 200 mg once every 2 days, 200 mg once every 3 days, 200 mg once weekly or treatment was stopped for patients if the haemoglobin level was less than 8.5 g/dL, less than 8.0 g/dL, less than 7.5 g/dL or less than 7.0 g/dL, respectively. The erythropoiesis-stimulating agent (ESA) epoetin β (Recormon, Hoffman-LaRoche, Basel, Switzerland) was also initiated at a starting dosage of 5000 IU/week when the haemoglobin level was <8.5 g/dL. Patients were seen weekly to titrate epoetin β dosage. Stepwise epoetin β dosage increments of 5000 IU/week to the maximum permitted dosage of 40 000 IU/week were given at these weekly visits until the haemoglobin level was 8.5 g/dL or greater. Epoetin β was continued until the end of treatment even if the haemoglobin level increased to 8.5 g/dL or greater. Blood transfusion was permitted if the patients developed serious AEs. Adherence to ribavirin was assessed at each visit by pill count for patients receiving combination therapy.
The secondary endpoint was the AE-related withdrawal rate for patients receiving at least one dose of the study medication.
Data were analysed by Statistical Program for Social Sciences (SPSS V.17.0; SPSS Inc., Chicago, Illinois, USA). On the basis of the assumption that the SVR rate was 34% in the monotherapy group, we estimated that a total of 172 patients would provide 90% power to detect an absolute increase in SVR with combination therapy of 22% or more (two-sided α=0.05).12–16 Patient characteristics were expressed as mean (SD) and percentage when appropriate.
The proportions for viral response and AEs between treatment groups were compared and reported by relative risk (RR) and risk difference (RD), respectively. p Values for RR were obtained by either χ2 test or Fisher's exact test; p values for RD were obtained by the Wald asymptotic test. The subgroup analyses based on the prespecified factors to predict SVR, including baseline viral load, IL-28B rs8099917 genotype, sex, APRI score and RVR, were compared by RR.17 The interactions between the prespecified factors and the allocated treatment were tested by the stratified Mantel–Haenszel test. Serial haemoglobin levels during the study period were expressed by mean (95% CI) and compared by t tests. All statistical tests were two-tailed, and the results were statistically significant when a p value was <0.05.
Role of the funding source
The study was funded by the National Center of Excellence for Clinical Trial and Research. The funding source had no role in the study design; the collection, analysis and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. All authors had access to the study data and reviewed and approved the final manuscript.
In total, 177 eligible patients were allocated to combination therapy (n=89) or monotherapy (n=88). Three patients who were allocated to combination therapy and two patients who were allocated to monotherapy did not receive any study medication and were excluded from the endpoint analyses. In total, 75 patients (87%) receiving combination therapy and 79 patients (92%) receiving monotherapy completed 24 weeks of treatment. Eighty patients (93%) in each treatment group completed 24 weeks of follow-up (figure 1). Baseline characteristics were comparable between the treatment groups (table 1). There was no imbalance of treatment assignment for each participating centre.
The mean adherence rate to ribavirin in patients receiving combination therapy was 91%. Three non-adherent patients (3%) received <80% of required ribavirin doses.
The RVR (64% vs 63%, RR: 1.02 [95% CI 0.81 to 1.28]; p=0.99), EVR (93% vs 95%, RR: 0.98 [95% CI 0.91 to 1.05]; p=0.75) and the ETVR (88% vs 90%, RR: 0.99 [95% CI 0.89 to 1.10]; p=0.99) rates were comparable between the treatment groups. The SVR rate was greater in the combination therapy group than in the monotherapy group (74% vs 44%, RR: 1.68 [95% CI 1.29 to 2.20]; p<0.001) (table 2).
We performed sensitivity analyses to assess the impact of three patients in each group who failed to achieve SVR and who were categorised as undetermined reason (table 2). As a best-case scenario, we assumed that the three combination therapy patients achieved SVR and the three monotherapy patients did not. As a worst-case scenario, we assumed that the three monotherapy patients achieved SVR and the three combination therapy patients did not. Results from the best-case scenario (78% vs 44%, RR: 1.76 [95% CI 1.34 to 2.29]; p<0.001) and the worst-case scenario (74% vs 48%, RR 1.56 [95% CI 1.21 to 2.01]; p=0.001) were consistent with the primary result for SVR.
Subgroup analyses for prespecified factors
Differences between combination therapy and monotherapy did not vary by IL-28B rs8099917 genotype, sex, APRI score or week 4 virological response (table 3). In patients with high baseline viral load, combination therapy achieved a greater SVR rate than monotherapy (76% vs 24%, RR: 3.08 [95% CI 1.80 to 5.29]); however, in patients with low baseline viral load, combination therapy had a similar SVR rate to monotherapy (73% vs 66%, RR: 1.11 [95% CI 0.83 to 1.45]; interaction p=0.001). In patients who failed to achieve RVR, the week 12 viral responses showed that all patients in both groups achieved cEVR or failed to achieve EVR. Among patients with cEVR, the SVR rates were 44% (11 of 25 patients) in the combination therapy group and 14% (4 of 28 patients) in the monotherapy group (RR: 3.08 [95% CI 1.12 to 8.45]).
In patients who achieved RVR, the SVR rate of patients receiving combination therapy was greater than those receiving monotherapy if they had high baseline viral load (100% vs 39%); the SVR rates of patients receiving combination therapy and monotherapy were comparable if they had low baseline viral load (93% vs 81%). In patients who failed to achieve RVR, the SVR rate of patients receiving combination therapy was greater than those receiving monotherapy if they had high baseline viral load (43% vs 9%); the SVR rates of patients receiving combination therapy and monotherapy were comparable if they had low baseline viral load (20% vs 20%).
We further analysed the role of cumulative ribavirin dosages and virological outcomes in 64 patients with SVR and 9 relapsers receiving combination therapy (table 4). The relapse rates were 33%, 25%, 6%, 7% and 10% in patients receiving ribavirin at a cumulative dosage of <50%, 50–60%, 60–70%, 70–80% and ≥80%, respectively.
The constitutional and laboratory AEs in treated patients are shown in table 5. Compared with patients receiving monotherapy, those receiving combination therapy were more likely to have a haemoglobin level <8.5 g/dL (RD: 62% [95% CI 50% to 73%]; p<0.001). In addition to ribavirin dosage reduction, patients receiving combination therapy required a higher dosage (mean [SD]: 13 417(7219) vs 6667 (2581) IU/week, p=0.027) but similar duration (mean [SD]: 10 (5) vs 7 (3) weeks, p=0.065) of epoetin β than those receiving monotherapy to manage anaemia (figure 2). One patient receiving combination therapy received transfusion due to anaemia-induced postural dizziness at week 12 of therapy. The haemoglobin levels were more significantly decreased in the combination therapy group than in the monotherapy group from week 4 of treatment (p<0.001) until week 8 after the end of treatment (p=0.009) (figure 3A). Patients receiving combination therapy had significant lower haemoglobin levels than patients receiving monotherapy from week 8 of treatment (p<0.001) until week 4 after the end of the treatment (p=0.006) (figure 3B).
The AE-related withdrawal rates were 6% in the combination therapy group and 3% in the monotherapy group (RD: 2% [95% CI −4% to 9%]). Three serious AEs occurred in both groups (3% vs 3%, RD: 0% [95% CI −5% to 5%]).
To our knowledge, this was the first and the largest randomised trial that demonstrated that treatment-naive haemodialysis patients with HCV-2 infection receiving peginterferon alfa-2a plus low-dose ribavirin achieved a greater SVR rate than those receiving peginterferon alfa-2a (74% vs 44%). The SVR rates in our study were comparable to previous small-scale studies in haemodialysis patients with HCV-2 infection receiving combination therapy (80 to 100%) or monotherapy (48 to 50%).22–26 Furthermore, the SVR and AE-related withdrawal rates were similar to patients receiving haemodialysis or not.27
In contrast to haemodialysis patients with HCV-1 infection who achieved a higher RVR rate by combination therapy, the RVR rates were similar in haemodialysis patients with HCV-2 infection receiving combination therapy or monotherapy.17 The different effects of ribavirin on the RVR rates in HCV-1 and HCV-2 patients may be reasoned by the improved third phase viral decay after 7–28 days of treatment only in HCV-1 patients.28 Although the EVR and ETVR were also similar between the two groups, combination therapy had a greater SVR rate than monotherapy, which might be attributed to the lower relapse rate in the combination therapy group. The addition of ribavirin may improve the SVR rate in HCV-infected patients by inducing viral mutations, blocking cellular enzymes or modulating the host immune responses.29 In line with previous reports in patients with normal renal function, we thus recommended that HCV-2 patients receiving haemodialysis should receive ribavirin at a cumulative dosage of ≥60% to reduce the relapse rates.30 ,31
Because baseline viral load, IL-28B genotype, sex, APRI score and RVR have been reported to affect the SVR rate, we further examined whether any prespecified subgroup of patients may benefit from combination therapy or monotherapy.17 ,32 Of interest, the beneficial effect of combination therapy was more pronounced in patients with baseline viral load ≥800 000 IU/mL than those with baseline viral load <800 000 IU/mL, and this phenomenon was reasoned by the substantially decreased SVR rate of monotherapy in patients with high baseline viral load.25 ,26 Peginterferon monotherapy may be preferred for patients with low baseline viral load because monotherapy had comparable SVR rate to combination therapy and it may avoid the additional toxicity of ribavirin. Compared with patients with cEVR, patients with RVR could achieve a much higher SVR rate (96% vs 44%) by 24 weeks of combination therapy. The issue of whether extending the duration of combination therapy to 48 weeks could improve the SVR rate in these patients with cEVR awaits further investigation.33
Compared with the monotherapy group, results from our study were consistent with the 95% confidence bounds of RD for AE-related withdrawal rate ranging from −4% to 9% in the combination therapy group. We could not confidently exclude the possible differences between the two treatment groups because our study was not powered to detect the differences for AE-related withdrawal rate. However, the potentially increased risk of withdrawal rate did not preclude combination therapy because such therapy may benefit patients by attaining a greater SVR rate. Although 70% of our patients receiving combination therapy required ribavirin dosage reduction and high-dose ESA, only one patient needed blood transfusion for symptomatic anaemia.17 In contrast to the conventional notion that ribavirin is contraindicated for haemodialysis patients, we demonstrated that by careful patient selection, close monitoring the haemoglobin levels and timely titrating dosages of ribavirin and ESA, most patients can tolerate combination therapy.17 ,34 However, providers should be alert to the potential risk of substantial decrease of haemoglobin levels after 4 weeks of combination therapy.
Despite the favourable treatment response for haemodialysis patients with HCV-2 infection receiving combination therapy, 26% of them still failed to achieve SVR. Compared with peginterferon plus ribavirin therapy for 24 weeks, IFN-free regimen with sofosbuvir plus ribavirin or sofosbuvir plus daclatasvir for 12 weeks can achieve an even greater SVR rate in treatment-naive patients with HCV-2 infection and normal renal function, as well as more favourable safety profiles.35 ,36 Furthermore, sofosbuvir plus ribavirin also benefited these patients who failed previous IFN-based therapy, or who were intolerant, medically ineligible or unwilling to receive IFN.37 Although the efficacy of sofosbuvir-based therapies is satisfactory in these studies, the optimised dosage of sofosbuvir plus ribavirin or sofosbuvir plus daclatasvir for haemodialysis patients with HCV-2 infection is still unknown.38 The unmet medical needs may set the stage for future clinical trials in haemodialysis patients with HCV-2 infection.
Our study has several limitations. It was an open-label trial and may introduce observer bias. However, the outcome measurements were objective, minimising this possibility. Second, because the pharmacokinetics of peginterferon alfa-2a and ribavirin has not been well established in patients on peritoneal dialysis, our findings may not be generalisable to these patients.
In conclusion, in an open-label randomised clinical trial for haemodialysis patients with HCV-2 infection, peginterferon alfa-2a plus low-dose ribavirin was generally well tolerated and produced a greater SVR rate than peginterferon alfa-2a monotherapy.
The authors thank the nurses and the patients involved in the study; Ching-Chuan Chen for central block randomisation management; Hui-Ju Lin, Yu-Lin Tan, Po-Chung Liu for clinical data management; Wan-Ting Yang for host genetic analyses; Yu-Sheng Chiu, PhD for virology analyses; the 4th Core Lab of National Taiwan University Hospital for instrumental supports.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
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