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Efficacy and safety of pegylated interferon base treatment in patients with chronic hepatitis C on dialysis
European Journal of Internal Medicine 26 (2015) 292–296
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Efficacy and safety of pegylated interferon base treatment in patients with chronic hepatitis C on dialysis Sang Bong Ahn a, Dae Won Jun b,⁎, Sang Gyune Kim c, Sae Hwan Lee c, Hyun Phil Shin d, Won Hyeok Choe e, Ja Kyung Kim f, Kyu Sik Jung f, Do Young Kim f, Jae-Jun Shim g, Soo Young Park h, Yeon Seok Seo i, Won Kim j, Jae Il Chung k a
Department of Internal Medicine, Eulji University College of Medicine, Republic of Korea Department of Internal Medicine, Hanyang University College of Medicine, Republic of Korea c Department of Internal Medicine, Soonchunhyang University, Bucheon Hospital, Republic of Korea d Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Republic of Korea e Department of Internal Medicine, Konkuk University School of Medicine, Republic of Korea f Department of Internal Medicine, Yonsei University School of Medicine, Republic of Korea g Department of Internal Medicine, Kyung Hee University School of Medicine, Republic of Korea h Department of Internal Medicine, Kyungpook National University Hospital, Republic of Korea i Department of Internal Medicine, Korea University School of Medicine, Republic of Korea j Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea k Sahmyook Medical Center, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 12 January 2015 Received in revised form 7 March 2015 Accepted 28 March 2015 Available online 13 April 2015 Keywords: Hepatitis C Pegylated interferon Dialysis Renal insufficiency
a b s t r a c t Introduction: Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) on dialysis are difficult to treat and show higher dropout rates during treatment. The aim of this study was to analyze the treatment outcomes in patients with CHC and underlying end-stage renal disease on dialysis in Korea. Methods: A retrospective multi-center study of 35 patients with CHC and underlying ESRD on regular dialysis from 13 centers were analyzed. We investigated the tolerability and efficacy of pegylated interferon therapy with or without ribavirin on dialysis patients. Results: Twenty patients (57%) were genotype 1. Sixteen patients (46%) were treated with pegylated interferon monotherapy. Nineteen patients (54%) were treated with pegylated interferon and ribavirin. The overall sustained virological response (SVR) rate was 65.7% in all subjects. Thirteen patients (37%) dropped out before completion of treatment, and six patients (46.2%) showed SVR despite premature termination of treatment. Twenty patients (90.9%) achieved SVR among the 22 patients who completed the scheduled course. The most common side effects were anemia and neutropenia. The patients receiving ribavirin treatment showed a higher dropout rate (52.6% vs. 18.8%, p = 0.04) and higher SVR rate (68.4% vs. 62.5%, p = 0.07) compared to the pegylated interferon mono-treatment group. Conclusions: The difficulty in treating HCV patients with ESRD was attributed to higher dropout rate. However, despite the high dropout rate (37%), the SVR rate in genotype 1 was 65% and in genotypes 2 and 3 was 66%. Patients who completed the treatment showed a high SVR rate of 89.5%. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction The incidence rate of hepatitis C virus (HCV) infection among patients on hemodialysis is high, with a prevalence ranging between 3.3% and 16.8% according to the geographic area [1]. The overall incidence rate of HCV infection has been reported to be 1.47 per 100 patients per year [2]. According to the ‘Dialysis Outcome and ⁎ Corresponding author at: 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Department of Internal Medicine, Hanyang University College of Medicine, Republic of Korea. Tel.: +82 2 2290 8338; fax: +82 2 972 0068. E-mail address: [email protected] (D.W. Jun).
Practice Patterns Study’ survey, the mean prevalence of anti-HCV positivity was 13.5% in patients on maintenance dialysis [3]. The prevalence rate of HCV in hemodialysis patients in South Korea has been reported to be 5–15% [4,5]. However, hepatitis C infection is very rarely treated among hemodialysis patients. One multicenter international study reported that only 1% (48/4589) of HCV-infected patients on hemodialysis were receiving antiviral medication [6]. HCV patients with underlying end-stage renal disease (ESRD) on hemodialysis are difficult to treat and are associated with poor tolerance of interferon, more complications, and a higher dropout rate, which may ultimately affect the treatment outcomes [7,8]. The efficacy and safety of interferon-based therapy in HCV patients with hemodialysis remain
http://dx.doi.org/10.1016/j.ejim.2015.03.011 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
S.B. Ahn et al. / European Journal of Internal Medicine 26 (2015) 292–296
unclear, although a number of small clinical trials have been undertaken. Currently, there have only been two reported randomized trials on HCV patients with ESRD on hemodialysis. These studies showed a SVR for genotype 1 of 64% in the group receiving conventional pegylated interferon and ribavirin (PR) combination therapy, and a SVR of 33% in the pegylated interferon monotherapy group. The SVR of the genotype 2 groups was 74% in the PR group and 44% in the monotherapy arm [9]. Although there is satisfactory evidence for pegylated interferon base treatment in patients with chronic hepatitis C (CHC) on dialysis from randomized controlled trials, the clinical data is very limited. Many physicians still hesitate to treat CHC in patients with ESRD because of the low treatment efficacy and high rate of adverse events. The aim of our study was to analyze the efficacy and safety of clinical pegylated interferon base treatment in patients with CHC on dialysis. 2. Methods We retrospectively analyzed the data from 35 ESRD with CHC patients who were treated with pegylated interferon from 13 medical centers in Korea. We collected data including sex, age, genotype, ribavirin dose, laboratory findings, duration of treatment, and complications. Thirty-four patients were maintained on hemodialysis and one patient was maintained on peritoneal dialysis for ESRD during the treatment period. Hemodialysis was carried out routinely three times a week. The diagnosis of CHC was based on positive HCV RNA by RT PCR, with or without elevated serum alanine aminotransferase (ALT) levels. Seventeen patients were treated with peginterferon alfa-2a and 18 patients were treated with peginterferon alfa-2b. The dosage of peginterferon was varied between 50 μg and 180 μg. Sixteen patients were treated without ribavirin. Nineteen patients were treated with ribavirin. The median dose of ribavirin was 182 ± 185 mg (80–800 mg). Treatment was discontinued when patients had uncontrolled complications. Genotype 1 patients received pegylated interferon base treatment for 48 weeks, and patients with genotypes 2 and 3 received 24 weeks of treatment. The primary outcome of this study was measuring the sustained virological response (SVR) for treatment efficacy. SVR was defined as the disappearance of HCV viremia (HCV RNA) by PCR for at least 6 months after the completion of therapy. Secondary end-points included the dropout rate as a measure of tolerability and the end-oftreatment virological response (ETR). The ETR was defined as the absence of HCV viremia by PCR at the end of the treatment with or without completing treatment depending upon the viral genotype. We also assessed the treatment response with the rapid virological response (RVR) and the complete early virological response (EVR) at 4 and 12 weeks as assessed by undetectable HCV RNA. 3. Results 3.1. Characteristics of patients and treatment methods Our study included 35 dialysis patients (22 men and 13 women) with HCV infection with a mean age of 48.9 ± 10.8 years old. The number of patients with genotypes 1, 2, and 3 were 20 (57%), 14 (40%), and 1 (3%) respectively. There were 17 patients who were treated with peg-interferon α-2a, and 18 patients who were treated with peg-interferon α-2b. Nineteen patients had ribavirin as their initial treatment and the average dosage was 131 mg/day (Tables 1, 2). 3.2. Treatment response and dropout rates Sixteen patients (46%) were treated only with pegylated interferon. Nineteen patients (54%) were treated with interferon and ribavirin. RVR at 4 weeks was achieved in 24 patients (68%). EVR and ETR were achieved in 27 patients (77%). Twenty-three patients (85%) had SVR among the 27 patients who had ETR. The overall SVR rate was 65.7%
293
Table 1 Characteristics of the study population. Characteristics Sex (M:F) Age (year) Genotype 1/2/3 Interferon (Peg α-2a/Peg α-2b) With/without ribavirin Ribavirin dose (mg)
22:13 48.9 ± 10.8 20/14/1 17/18 19/16 182 ± 185
in all subjects (genotype 1: 65.0%, non-genotype 1: 66.7%). Thirteen patients (37.1%) dropped out before the completion of treatment. However, of these patients, six (46.2%) showed SVR despite premature termination of treatment (genotype 1: 55.5%, non-genotype 1: 25.0%). Twenty-two patients completed the scheduled treatment. Twenty patients (90.9%) achieved SVR among the 22 patients who completed the scheduled course of treatment (Tables 3, 4). 3.3. Factors affecting the sustained virological response (SVR) Only RVR seemed to have a statistically significant effect on SVR (p = 0.03) (Table 5). The positive predictive value of RVR was 95.0%, and the negative predictive value was 66.7%. HCV genotype, pretreatment viral load, sex, and age were not independent risk factors for SVR. The rate of SVR did not differ between different types of pegylated interferon (pegylated interferon α-2a and pegylated interferon α-2b). 3.4. Outcome with and without ribavirin The dropout rate was higher in the ribavirin group than in the interferon mono-treatment arm (52.6% vs. 18.8%, p = 0.04). Combination treatment with ribavirin showed a marginal benefit in SVR as compared to interferon monotherapy (68.4% vs. 62.5%, p = 0.07) (Table 6). 3.5. Tolerability and safety Thirteen patients (37.1%) dropped out of the treatment. Anemia was the most frequent cause of discontinuation of therapy (17.1%). Mean hemoglobin level drop from 12.4 mg/dl at the initiation of ribavirin treatment to 9.9 mg/dl after the 12 weeks of ribavirin therapy (Fig. 1). Four patients discontinued treatment due to neutropenia and thrombocytopenia (11.4%). The mean glomerular filtration rates and serum creatinine levels did not change during treatment. 4. Discussion It has been reported that interferon and ribavirin combination therapy allows for a SVR rate of ~45% in genotype 1-infected patients treated for 48 weeks, and a SVR rate of 76–85% in patients with genotypes 2 and 3 treated for 24 weeks in the general population [10–12]. In this study, we found that the SVR rate in hemodialysis patients with HCV infection was 65.7%, which, as suspected, was not lower than the rate in the overall population. A recent meta-analysis of 14 observational studies on dialysis patients with HCV infection reported that the summary estimate for the adjusted relative risk of mortality was 1.35 (1.25–1.47, 95% confidence interval) [13]. Other multicenter studies have also showed that the association between HCV infection and mortality was significant (RR, 1.17; p b 0.0159) [14]. Therefore, the treatment of HCV in patients on hemodialysis is crucial for better prognoses. Due to the risk of allograft rejection, the use of interferon is contraindicated in renal transplant patients. Hence, the treatment of patients with ESRD and CHC is feasible only prior to kidney transplantation [15]. However, physicians are reluctant to treat HCV infection in patients with underlying ESRD on hemodialysis in clinical practice. Clinicians
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Table 2 Patients baseline characteristics. Case
Sex (M/F)
Age (year)
Body weight (kg)
Cirrhosis (N/Y)
Genotype
RNA (IU/ml)
Interferon type
Interferon dose (μg)
Ribavirin dose (mg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
M M F M F F M M M M F F M M M F F M M M F F F M F M M M M M M M F F M
54 55 57 33 50 35 38 53 43 41 36 49 56 31 44 26 38 58 53 62 57 54 56 60 39 45 54 44 51 44 78 58 64 53 44
54.7 72.5 55 62.5 41.3 63.6 40 65 62 75.4 42 43.2 52.8 78.9 66.5 51.5 44.5 59 83 64.5 48 52.3 47 63 50 58 58.2 94 70 55.4 58.2 56.7 71.1 54.6 60.3
N N N N N N N N Y N N N N N N N N Y N N N N N N N N N N N N Y Y Y N N
2 2 2 2 1 1 2 2 3 1 1 1 1 1 2 1 1 1 2 1 2 1 2 1 1 1 1 1 2 2 1 2 1 2 1
1,170,000 886,000 955,000 18,500,000 745,000 316,000 224,000 178,000 8,610,000 936 4407 2,096,979 2,300,300 3036 3321 486,882 531,268 35,814 193,000 69,000,000 744,000 550,000 9,880,000 NA NA 17,600 1,410,000 1,310,000 2,590,000 2,640,000 3,210,000 136,000 63,141 13,818 265,000
1 1 1 1 1 1 2 1 2 2 2 2 2 2 2 1 2 2 1 1 1 1 1 2 2 2 1 1 1 2 1 2 2 2 2
135 135 135 135 135 135 50 135 80 100 80 80 80 100 80 180 80 80 135 135 135 135 180 160 50 80 135 180 135 80 135 80 100 80 80
0 0 0 0 0 0 0 0 400 100 100 100 100 100 100 100 100 100 0 0 200 0 200 100 0 0 0 0 0 400 0 0 200 80 0
often hesitate to use interferon (with/without ribavirin), which is the first-line drug for HCV infection, in dialysis patients because of their concern over side effects. A questionnaire conducted on the treatment indications for HCV in dialysis patients identified characteristics such as few complications, under 60 years of age, and more than 10 years of survival expected on hemodialysis [16]. However, the treatment of HCV in patients on hemodialysis is recommended based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplantation, and comorbidities. In this study, we observed that the HCV treatment response (SVR) in hemodialysis patients, including those who dropped out of treatment, was not lower than the general population. Despite the high dropout rate, 46.2–85.7% of our patients achieved a SVR, which suggests a reasonable outcome if these patients start and adhere to treatment. One explanation could be that the excretion of interferon and ribavirin might be lowered due to declining renal function. Some studies have suggested that patients with hepatitis C on dialysis usually have a lower viral load [17] and increased endogenous interferon release from circulating white blood cells [18]. Also from our study, we have found out that patient with genotype 1 who were treated with interferon monotherapy had a higher rate of SVR compare to other studies. One meta-analysis study reported that a mean SVR of 37% in chronic hepatitis C patients on dialysis after interferon
therapy [19]. Sustained biochemical and virological response rates were 0%–67% and 15.8%–64%, respectively. However, some studies have reported higher rate of SVR in case of interferon monotherapy. Kokoglu et al. reported the result of 83.4% virological end of treatment response in hemodialysis patients with HCV infection [20]. They treated the patients with peg-interferon 135 μg/week for 48 weeks. Celal et al. reported that 64.7% SVR rate on hemodialysis patients with chronic hepatitis C by treatment with peginteferon alpha-2a [21]. In this study, most enrolled patients was genotype Ib (86.4%). The SVR rate in genotype 1 was 69.5% in Korean chronic hepatitis C patients [22]. We suspect that higher rate of SVR seen in Korean chronic hepatitis C patients might be related to various reasons such as a specific racial characteristics, or by selecting good compliance patients to interferon therapy and bias resulting from small group sample size. For pharmacokinetic reasons, the accumulation of ribavirin metabolites in erythrocytes and erythroblasts during treatment can enhance anemia due to renal failure by the exacerbation of the hemolytic anemia. As a result, a complication of ribavirin is severe anemia. Ribavirin is thus contraindicated in chronic kidney disease with a creatinine clearance of less than 50 ml/min [23]. The KDIGO guidelines suggest monotherapy with standard interferon that is dose-adjusted for a GFR of less than 15 ml per min per 1.73 m2 in HCV-infected patients on hemodialysis [24]. Patients on dialysis can take either interferon alpha
Table 3 Response to treatment.
Intention-to-treat analysis (n = 35) Per-protocol analysis (n = 22) Patients who dropped out (n = 13) N (%).
Overall SVR
Genotype 1
Non-genotype 1
23/35 (65.7%) 20/22 (90.9%) 6/13 (46.2%)
13/20 (65%) 10/11 (90.9%) 5/9 (55.5%)
10/15 (66.7%) 10/11 (90.9%) 1/4 (25%)
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Table 4 Patients treatment results. Case
Interferon type
Interferon dose (μg)
Ribavirin dose (mg)
Baseline hemoglobin (g/dl)
Hemoglobin at the end of treatment (g/dl)
Complete the treatment schedule (Y/N)
RVR (Y/N)
EVR (Y/N)
ETR (Y/N)
SVR (Y/N)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2b PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2b PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b
135 135 135 135 135 135 50 135 80 100 80 80 80 100 80 180 80 80 135 135 135 135 180 160 50 80 135 180 135 80 135 80 100 80 80
0 0 0 0 0 0 0 0 400 100 100 100 100 100 100 100 100 100 0 0 200 0 200 100 0 0 0 0 0 400 0 0 200 80 0
10.7 12.2 13.9 11 12.5 13.3 9.9 8.8 13.7 13.5 12.2 10.9 8 15.4 13.8 13.4 13.2 9.6 9.9 9.5 10.2 10.5 12.3 15.3 12.8 12 9.9 15.1 9.4 14.4 13 13.7 12.1 11.4 10.9
11.1 11.9 8.1 11.3 10.9 10.5 8.8 8.6 9.7 9.6 10 8.4 10.1 12.4 10.7 14.4 NA 8.2 9.1 5 10.6 7.8 10.9 11.7 13.4 9.9 11.9 11.9 9.2 12 6.7 11.2 9.5 10.4 11.6
Y Y Y N N Y Y Y Y N N Y N N Y Y N Y Y N N Y N Y Y Y Y Y N Y N Y N Y Y
Y Y Y Y N Y N Y Y Y N Y N Y Y Y N Y Y Y NA Y NA NA Y NA Y Y Y Y N Y NA Y Y
Y Y Y Y N Y N Y Y Y Y Y N Y Y Y NA Y Y Y NA Y NA Y NA Y Y Y NA Y Y Y Y Y Y
Y Y Y NA N Y N Y Y Y NA Y NA Y Y Y NA Y Y Y NA Y NA Y Y Y Y Y NA Y NA Y NA Y Y
Y Y NA NA N N N Y Y Y NA NA NA Y Y Y NA Y Y Y NA Y NA Y NA Y Y Y Y Y Y Y Y Y Y
or peginterferon alpha, although combination therapy with ribavirin is not recommended in the Korean Association for the Study of the Liver (KASL) HCV treatment guidelines [25]. However, numerous studies have been carried out to evaluating the treatment response with low-dose ribavirin combination therapy. One study showed that increasing the dose of ribavirin resulted in serious drug side effects, such as blood transfusions (47%), and there was a high dropout rate (71.4%), with ribavirin discontinued due to severe anemia or death (2/15). The authors recommended administrating 200 mg of ribavirin daily [26]. In our study, we used an average ribavirin dose of 131 mg. In this first multicenter, randomized study comparing pegylated interferon with or without ribavirin for 48 weeks in genotype 1 HCV-infected hemodialysis patients, the SVR rate was significantly higher in the combination group compared with the monotherapy group (64% vs. 33%, p b 0.001). Patients receiving ribavirin had more anemia than the monotherapy group (72% vs. 6%, p b 0.001) [9].
Although the difference was not statistically significant, the SVR was higher in the group receiving ribavirin treatment and we were able to confirm that the complication rate (e.g. anemia) in the ribavirin group was higher. Despite the small number of patients enrolled (19 patients), the HCV-infected patients on hemodialysis receiving low-dose interferon monotherapy reported a good SVR rate (91.7%) and a low dropout rate (8.3%). Interferon monotherapy could be an effective treatment option for hemodialysis patients with CHC [27]. One study found that the dropout rate for conventional interferon treatment in dialysis patients was 19% compared to the 5–9% dropout rate in non-CKD patients [28]. Our study showed similar results, with 18.8% of the patients dropping out in the monotherapy group. However, when ribavirin was added to the treatment, the dropout rate increased to 52.6%. This suggests that even though the treatment response can be increased with ribavirin in HCV-infected patients on hemodialysis, this can be accompanied by serious side effects and a higher dropout rate. In addition, physician should also be aware that fatal cardiovascular events can be exacerbated by using ribavirin in these patients. These
Table 5 Factors affecting the sustained virological response (SVR). Univariate analysis Sex Cirrhosis Genotype HCV-RNA Interferon Ribavirin Rapid viral response Complete treatment p b 0.05 by chi square test.
0.06 0.54 0.66 0.66 0.60 0.07 0.01 0.80
Table 6 Sustained virological response (SVR) with/without ribavirin.
Dropout rate Rapid viral response Early viral response Sustained viral response Serious Adverse Event p b 0.05 by Fisher's exact test.
With ribavirin (n = 19)
Without ribavirin (n = 16)
p value
10/19 (52.6%) 11/19 (57.9%) 15/19 (78.9%) 13/19 (68.4%) 12/19 (63.1%)
3/16 (18.8%) 12/16 (75%) 12/16 (75%) 10/16 (62.5%) 6/16 (37.5%)
0.04 0.35 0.46 0.07 0.14
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Fig. 1. Mean hemoglobin levels from baseline to the end of treatment for patients with interferon with ribavirin treatment.
factors can result in physician reluctance to use combination therapy in dialysis patients with HCV. If there is concern about complications such as anemia, monotherapy is a suitable treatment option. Our study has some limitations. First, since it was a retrospective multi-center study, different interferon and ribavirin dosages were used in different centers. Second, there is the possibility of bias in that patients who were able to tolerate treatment were selected enrolled. Most of the patients undergoing treatment could be considered younger and healthier than general dialysis patients. Nevertheless, this study is of considerable value because it includes data from actual clinical practice. 5. Conclusion In hemodialysis patients, the decision to treat HCV infection should be based on the benefits and risks of therapy, including comorbidities, life expectancy, and planning for kidney transplantation. Our retrospective study suggests that antiviral therapy based on pegylated interferon with or without ribavirin should be considered in all HCV-infected patients on dialysis in order to achieve SVR, with the goal to not only avoid subsequent hepatic deterioration but also to limit the risks of HCV-related post-transplant de novo glomerulonephritis. Despite the high dropout rate, the SVR rate in our study was 65.7%. The SVR rate was higher in the group receiving ribavirin treatment, although a SVR rate of 62.5% was seen in patients receiving interferon monotherapy. Patients who completed the treatment showed a high SVR rate of 89.5%. The use of peg-interferon with/without ribavirin is more challenging in HCV patients with ESRD. Conflict of interest The authors declare that they have no competing interests. Acknowledgments This work was supported by a research fund from Hanyang University (HY-2013-C). References [1] Chan TM, Lok ASF, Cheng IKP, Chan RT. Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays. Hepatology 1993;17:5–8.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Efficacy and safety of pegylated interferon base treatment in patients with chronic hepatitis C on dialysis Sang Bong Ahn a, Dae Won Jun b,⁎, Sang Gyune Kim c, Sae Hwan Lee c, Hyun Phil Shin d, Won Hyeok Choe e, Ja Kyung Kim f, Kyu Sik Jung f, Do Young Kim f, Jae-Jun Shim g, Soo Young Park h, Yeon Seok Seo i, Won Kim j, Jae Il Chung k a
Department of Internal Medicine, Eulji University College of Medicine, Republic of Korea Department of Internal Medicine, Hanyang University College of Medicine, Republic of Korea c Department of Internal Medicine, Soonchunhyang University, Bucheon Hospital, Republic of Korea d Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Republic of Korea e Department of Internal Medicine, Konkuk University School of Medicine, Republic of Korea f Department of Internal Medicine, Yonsei University School of Medicine, Republic of Korea g Department of Internal Medicine, Kyung Hee University School of Medicine, Republic of Korea h Department of Internal Medicine, Kyungpook National University Hospital, Republic of Korea i Department of Internal Medicine, Korea University School of Medicine, Republic of Korea j Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea k Sahmyook Medical Center, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 12 January 2015 Received in revised form 7 March 2015 Accepted 28 March 2015 Available online 13 April 2015 Keywords: Hepatitis C Pegylated interferon Dialysis Renal insufficiency
a b s t r a c t Introduction: Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) on dialysis are difficult to treat and show higher dropout rates during treatment. The aim of this study was to analyze the treatment outcomes in patients with CHC and underlying end-stage renal disease on dialysis in Korea. Methods: A retrospective multi-center study of 35 patients with CHC and underlying ESRD on regular dialysis from 13 centers were analyzed. We investigated the tolerability and efficacy of pegylated interferon therapy with or without ribavirin on dialysis patients. Results: Twenty patients (57%) were genotype 1. Sixteen patients (46%) were treated with pegylated interferon monotherapy. Nineteen patients (54%) were treated with pegylated interferon and ribavirin. The overall sustained virological response (SVR) rate was 65.7% in all subjects. Thirteen patients (37%) dropped out before completion of treatment, and six patients (46.2%) showed SVR despite premature termination of treatment. Twenty patients (90.9%) achieved SVR among the 22 patients who completed the scheduled course. The most common side effects were anemia and neutropenia. The patients receiving ribavirin treatment showed a higher dropout rate (52.6% vs. 18.8%, p = 0.04) and higher SVR rate (68.4% vs. 62.5%, p = 0.07) compared to the pegylated interferon mono-treatment group. Conclusions: The difficulty in treating HCV patients with ESRD was attributed to higher dropout rate. However, despite the high dropout rate (37%), the SVR rate in genotype 1 was 65% and in genotypes 2 and 3 was 66%. Patients who completed the treatment showed a high SVR rate of 89.5%. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction The incidence rate of hepatitis C virus (HCV) infection among patients on hemodialysis is high, with a prevalence ranging between 3.3% and 16.8% according to the geographic area [1]. The overall incidence rate of HCV infection has been reported to be 1.47 per 100 patients per year [2]. According to the ‘Dialysis Outcome and ⁎ Corresponding author at: 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Department of Internal Medicine, Hanyang University College of Medicine, Republic of Korea. Tel.: +82 2 2290 8338; fax: +82 2 972 0068. E-mail address: [email protected] (D.W. Jun).
Practice Patterns Study’ survey, the mean prevalence of anti-HCV positivity was 13.5% in patients on maintenance dialysis [3]. The prevalence rate of HCV in hemodialysis patients in South Korea has been reported to be 5–15% [4,5]. However, hepatitis C infection is very rarely treated among hemodialysis patients. One multicenter international study reported that only 1% (48/4589) of HCV-infected patients on hemodialysis were receiving antiviral medication [6]. HCV patients with underlying end-stage renal disease (ESRD) on hemodialysis are difficult to treat and are associated with poor tolerance of interferon, more complications, and a higher dropout rate, which may ultimately affect the treatment outcomes [7,8]. The efficacy and safety of interferon-based therapy in HCV patients with hemodialysis remain
http://dx.doi.org/10.1016/j.ejim.2015.03.011 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
S.B. Ahn et al. / European Journal of Internal Medicine 26 (2015) 292–296
unclear, although a number of small clinical trials have been undertaken. Currently, there have only been two reported randomized trials on HCV patients with ESRD on hemodialysis. These studies showed a SVR for genotype 1 of 64% in the group receiving conventional pegylated interferon and ribavirin (PR) combination therapy, and a SVR of 33% in the pegylated interferon monotherapy group. The SVR of the genotype 2 groups was 74% in the PR group and 44% in the monotherapy arm [9]. Although there is satisfactory evidence for pegylated interferon base treatment in patients with chronic hepatitis C (CHC) on dialysis from randomized controlled trials, the clinical data is very limited. Many physicians still hesitate to treat CHC in patients with ESRD because of the low treatment efficacy and high rate of adverse events. The aim of our study was to analyze the efficacy and safety of clinical pegylated interferon base treatment in patients with CHC on dialysis. 2. Methods We retrospectively analyzed the data from 35 ESRD with CHC patients who were treated with pegylated interferon from 13 medical centers in Korea. We collected data including sex, age, genotype, ribavirin dose, laboratory findings, duration of treatment, and complications. Thirty-four patients were maintained on hemodialysis and one patient was maintained on peritoneal dialysis for ESRD during the treatment period. Hemodialysis was carried out routinely three times a week. The diagnosis of CHC was based on positive HCV RNA by RT PCR, with or without elevated serum alanine aminotransferase (ALT) levels. Seventeen patients were treated with peginterferon alfa-2a and 18 patients were treated with peginterferon alfa-2b. The dosage of peginterferon was varied between 50 μg and 180 μg. Sixteen patients were treated without ribavirin. Nineteen patients were treated with ribavirin. The median dose of ribavirin was 182 ± 185 mg (80–800 mg). Treatment was discontinued when patients had uncontrolled complications. Genotype 1 patients received pegylated interferon base treatment for 48 weeks, and patients with genotypes 2 and 3 received 24 weeks of treatment. The primary outcome of this study was measuring the sustained virological response (SVR) for treatment efficacy. SVR was defined as the disappearance of HCV viremia (HCV RNA) by PCR for at least 6 months after the completion of therapy. Secondary end-points included the dropout rate as a measure of tolerability and the end-oftreatment virological response (ETR). The ETR was defined as the absence of HCV viremia by PCR at the end of the treatment with or without completing treatment depending upon the viral genotype. We also assessed the treatment response with the rapid virological response (RVR) and the complete early virological response (EVR) at 4 and 12 weeks as assessed by undetectable HCV RNA. 3. Results 3.1. Characteristics of patients and treatment methods Our study included 35 dialysis patients (22 men and 13 women) with HCV infection with a mean age of 48.9 ± 10.8 years old. The number of patients with genotypes 1, 2, and 3 were 20 (57%), 14 (40%), and 1 (3%) respectively. There were 17 patients who were treated with peg-interferon α-2a, and 18 patients who were treated with peg-interferon α-2b. Nineteen patients had ribavirin as their initial treatment and the average dosage was 131 mg/day (Tables 1, 2). 3.2. Treatment response and dropout rates Sixteen patients (46%) were treated only with pegylated interferon. Nineteen patients (54%) were treated with interferon and ribavirin. RVR at 4 weeks was achieved in 24 patients (68%). EVR and ETR were achieved in 27 patients (77%). Twenty-three patients (85%) had SVR among the 27 patients who had ETR. The overall SVR rate was 65.7%
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Table 1 Characteristics of the study population. Characteristics Sex (M:F) Age (year) Genotype 1/2/3 Interferon (Peg α-2a/Peg α-2b) With/without ribavirin Ribavirin dose (mg)
22:13 48.9 ± 10.8 20/14/1 17/18 19/16 182 ± 185
in all subjects (genotype 1: 65.0%, non-genotype 1: 66.7%). Thirteen patients (37.1%) dropped out before the completion of treatment. However, of these patients, six (46.2%) showed SVR despite premature termination of treatment (genotype 1: 55.5%, non-genotype 1: 25.0%). Twenty-two patients completed the scheduled treatment. Twenty patients (90.9%) achieved SVR among the 22 patients who completed the scheduled course of treatment (Tables 3, 4). 3.3. Factors affecting the sustained virological response (SVR) Only RVR seemed to have a statistically significant effect on SVR (p = 0.03) (Table 5). The positive predictive value of RVR was 95.0%, and the negative predictive value was 66.7%. HCV genotype, pretreatment viral load, sex, and age were not independent risk factors for SVR. The rate of SVR did not differ between different types of pegylated interferon (pegylated interferon α-2a and pegylated interferon α-2b). 3.4. Outcome with and without ribavirin The dropout rate was higher in the ribavirin group than in the interferon mono-treatment arm (52.6% vs. 18.8%, p = 0.04). Combination treatment with ribavirin showed a marginal benefit in SVR as compared to interferon monotherapy (68.4% vs. 62.5%, p = 0.07) (Table 6). 3.5. Tolerability and safety Thirteen patients (37.1%) dropped out of the treatment. Anemia was the most frequent cause of discontinuation of therapy (17.1%). Mean hemoglobin level drop from 12.4 mg/dl at the initiation of ribavirin treatment to 9.9 mg/dl after the 12 weeks of ribavirin therapy (Fig. 1). Four patients discontinued treatment due to neutropenia and thrombocytopenia (11.4%). The mean glomerular filtration rates and serum creatinine levels did not change during treatment. 4. Discussion It has been reported that interferon and ribavirin combination therapy allows for a SVR rate of ~45% in genotype 1-infected patients treated for 48 weeks, and a SVR rate of 76–85% in patients with genotypes 2 and 3 treated for 24 weeks in the general population [10–12]. In this study, we found that the SVR rate in hemodialysis patients with HCV infection was 65.7%, which, as suspected, was not lower than the rate in the overall population. A recent meta-analysis of 14 observational studies on dialysis patients with HCV infection reported that the summary estimate for the adjusted relative risk of mortality was 1.35 (1.25–1.47, 95% confidence interval) [13]. Other multicenter studies have also showed that the association between HCV infection and mortality was significant (RR, 1.17; p b 0.0159) [14]. Therefore, the treatment of HCV in patients on hemodialysis is crucial for better prognoses. Due to the risk of allograft rejection, the use of interferon is contraindicated in renal transplant patients. Hence, the treatment of patients with ESRD and CHC is feasible only prior to kidney transplantation [15]. However, physicians are reluctant to treat HCV infection in patients with underlying ESRD on hemodialysis in clinical practice. Clinicians
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Table 2 Patients baseline characteristics. Case
Sex (M/F)
Age (year)
Body weight (kg)
Cirrhosis (N/Y)
Genotype
RNA (IU/ml)
Interferon type
Interferon dose (μg)
Ribavirin dose (mg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
M M F M F F M M M M F F M M M F F M M M F F F M F M M M M M M M F F M
54 55 57 33 50 35 38 53 43 41 36 49 56 31 44 26 38 58 53 62 57 54 56 60 39 45 54 44 51 44 78 58 64 53 44
54.7 72.5 55 62.5 41.3 63.6 40 65 62 75.4 42 43.2 52.8 78.9 66.5 51.5 44.5 59 83 64.5 48 52.3 47 63 50 58 58.2 94 70 55.4 58.2 56.7 71.1 54.6 60.3
N N N N N N N N Y N N N N N N N N Y N N N N N N N N N N N N Y Y Y N N
2 2 2 2 1 1 2 2 3 1 1 1 1 1 2 1 1 1 2 1 2 1 2 1 1 1 1 1 2 2 1 2 1 2 1
1,170,000 886,000 955,000 18,500,000 745,000 316,000 224,000 178,000 8,610,000 936 4407 2,096,979 2,300,300 3036 3321 486,882 531,268 35,814 193,000 69,000,000 744,000 550,000 9,880,000 NA NA 17,600 1,410,000 1,310,000 2,590,000 2,640,000 3,210,000 136,000 63,141 13,818 265,000
1 1 1 1 1 1 2 1 2 2 2 2 2 2 2 1 2 2 1 1 1 1 1 2 2 2 1 1 1 2 1 2 2 2 2
135 135 135 135 135 135 50 135 80 100 80 80 80 100 80 180 80 80 135 135 135 135 180 160 50 80 135 180 135 80 135 80 100 80 80
0 0 0 0 0 0 0 0 400 100 100 100 100 100 100 100 100 100 0 0 200 0 200 100 0 0 0 0 0 400 0 0 200 80 0
often hesitate to use interferon (with/without ribavirin), which is the first-line drug for HCV infection, in dialysis patients because of their concern over side effects. A questionnaire conducted on the treatment indications for HCV in dialysis patients identified characteristics such as few complications, under 60 years of age, and more than 10 years of survival expected on hemodialysis [16]. However, the treatment of HCV in patients on hemodialysis is recommended based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplantation, and comorbidities. In this study, we observed that the HCV treatment response (SVR) in hemodialysis patients, including those who dropped out of treatment, was not lower than the general population. Despite the high dropout rate, 46.2–85.7% of our patients achieved a SVR, which suggests a reasonable outcome if these patients start and adhere to treatment. One explanation could be that the excretion of interferon and ribavirin might be lowered due to declining renal function. Some studies have suggested that patients with hepatitis C on dialysis usually have a lower viral load [17] and increased endogenous interferon release from circulating white blood cells [18]. Also from our study, we have found out that patient with genotype 1 who were treated with interferon monotherapy had a higher rate of SVR compare to other studies. One meta-analysis study reported that a mean SVR of 37% in chronic hepatitis C patients on dialysis after interferon
therapy [19]. Sustained biochemical and virological response rates were 0%–67% and 15.8%–64%, respectively. However, some studies have reported higher rate of SVR in case of interferon monotherapy. Kokoglu et al. reported the result of 83.4% virological end of treatment response in hemodialysis patients with HCV infection [20]. They treated the patients with peg-interferon 135 μg/week for 48 weeks. Celal et al. reported that 64.7% SVR rate on hemodialysis patients with chronic hepatitis C by treatment with peginteferon alpha-2a [21]. In this study, most enrolled patients was genotype Ib (86.4%). The SVR rate in genotype 1 was 69.5% in Korean chronic hepatitis C patients [22]. We suspect that higher rate of SVR seen in Korean chronic hepatitis C patients might be related to various reasons such as a specific racial characteristics, or by selecting good compliance patients to interferon therapy and bias resulting from small group sample size. For pharmacokinetic reasons, the accumulation of ribavirin metabolites in erythrocytes and erythroblasts during treatment can enhance anemia due to renal failure by the exacerbation of the hemolytic anemia. As a result, a complication of ribavirin is severe anemia. Ribavirin is thus contraindicated in chronic kidney disease with a creatinine clearance of less than 50 ml/min [23]. The KDIGO guidelines suggest monotherapy with standard interferon that is dose-adjusted for a GFR of less than 15 ml per min per 1.73 m2 in HCV-infected patients on hemodialysis [24]. Patients on dialysis can take either interferon alpha
Table 3 Response to treatment.
Intention-to-treat analysis (n = 35) Per-protocol analysis (n = 22) Patients who dropped out (n = 13) N (%).
Overall SVR
Genotype 1
Non-genotype 1
23/35 (65.7%) 20/22 (90.9%) 6/13 (46.2%)
13/20 (65%) 10/11 (90.9%) 5/9 (55.5%)
10/15 (66.7%) 10/11 (90.9%) 1/4 (25%)
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Table 4 Patients treatment results. Case
Interferon type
Interferon dose (μg)
Ribavirin dose (mg)
Baseline hemoglobin (g/dl)
Hemoglobin at the end of treatment (g/dl)
Complete the treatment schedule (Y/N)
RVR (Y/N)
EVR (Y/N)
ETR (Y/N)
SVR (Y/N)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2b PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2a PegINF alpha-2a PegINF alpha-2a PegINF alpha-2b PegINF alpha-2a PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b PegINF alpha-2b
135 135 135 135 135 135 50 135 80 100 80 80 80 100 80 180 80 80 135 135 135 135 180 160 50 80 135 180 135 80 135 80 100 80 80
0 0 0 0 0 0 0 0 400 100 100 100 100 100 100 100 100 100 0 0 200 0 200 100 0 0 0 0 0 400 0 0 200 80 0
10.7 12.2 13.9 11 12.5 13.3 9.9 8.8 13.7 13.5 12.2 10.9 8 15.4 13.8 13.4 13.2 9.6 9.9 9.5 10.2 10.5 12.3 15.3 12.8 12 9.9 15.1 9.4 14.4 13 13.7 12.1 11.4 10.9
11.1 11.9 8.1 11.3 10.9 10.5 8.8 8.6 9.7 9.6 10 8.4 10.1 12.4 10.7 14.4 NA 8.2 9.1 5 10.6 7.8 10.9 11.7 13.4 9.9 11.9 11.9 9.2 12 6.7 11.2 9.5 10.4 11.6
Y Y Y N N Y Y Y Y N N Y N N Y Y N Y Y N N Y N Y Y Y Y Y N Y N Y N Y Y
Y Y Y Y N Y N Y Y Y N Y N Y Y Y N Y Y Y NA Y NA NA Y NA Y Y Y Y N Y NA Y Y
Y Y Y Y N Y N Y Y Y Y Y N Y Y Y NA Y Y Y NA Y NA Y NA Y Y Y NA Y Y Y Y Y Y
Y Y Y NA N Y N Y Y Y NA Y NA Y Y Y NA Y Y Y NA Y NA Y Y Y Y Y NA Y NA Y NA Y Y
Y Y NA NA N N N Y Y Y NA NA NA Y Y Y NA Y Y Y NA Y NA Y NA Y Y Y Y Y Y Y Y Y Y
or peginterferon alpha, although combination therapy with ribavirin is not recommended in the Korean Association for the Study of the Liver (KASL) HCV treatment guidelines [25]. However, numerous studies have been carried out to evaluating the treatment response with low-dose ribavirin combination therapy. One study showed that increasing the dose of ribavirin resulted in serious drug side effects, such as blood transfusions (47%), and there was a high dropout rate (71.4%), with ribavirin discontinued due to severe anemia or death (2/15). The authors recommended administrating 200 mg of ribavirin daily [26]. In our study, we used an average ribavirin dose of 131 mg. In this first multicenter, randomized study comparing pegylated interferon with or without ribavirin for 48 weeks in genotype 1 HCV-infected hemodialysis patients, the SVR rate was significantly higher in the combination group compared with the monotherapy group (64% vs. 33%, p b 0.001). Patients receiving ribavirin had more anemia than the monotherapy group (72% vs. 6%, p b 0.001) [9].
Although the difference was not statistically significant, the SVR was higher in the group receiving ribavirin treatment and we were able to confirm that the complication rate (e.g. anemia) in the ribavirin group was higher. Despite the small number of patients enrolled (19 patients), the HCV-infected patients on hemodialysis receiving low-dose interferon monotherapy reported a good SVR rate (91.7%) and a low dropout rate (8.3%). Interferon monotherapy could be an effective treatment option for hemodialysis patients with CHC [27]. One study found that the dropout rate for conventional interferon treatment in dialysis patients was 19% compared to the 5–9% dropout rate in non-CKD patients [28]. Our study showed similar results, with 18.8% of the patients dropping out in the monotherapy group. However, when ribavirin was added to the treatment, the dropout rate increased to 52.6%. This suggests that even though the treatment response can be increased with ribavirin in HCV-infected patients on hemodialysis, this can be accompanied by serious side effects and a higher dropout rate. In addition, physician should also be aware that fatal cardiovascular events can be exacerbated by using ribavirin in these patients. These
Table 5 Factors affecting the sustained virological response (SVR). Univariate analysis Sex Cirrhosis Genotype HCV-RNA Interferon Ribavirin Rapid viral response Complete treatment p b 0.05 by chi square test.
0.06 0.54 0.66 0.66 0.60 0.07 0.01 0.80
Table 6 Sustained virological response (SVR) with/without ribavirin.
Dropout rate Rapid viral response Early viral response Sustained viral response Serious Adverse Event p b 0.05 by Fisher's exact test.
With ribavirin (n = 19)
Without ribavirin (n = 16)
p value
10/19 (52.6%) 11/19 (57.9%) 15/19 (78.9%) 13/19 (68.4%) 12/19 (63.1%)
3/16 (18.8%) 12/16 (75%) 12/16 (75%) 10/16 (62.5%) 6/16 (37.5%)
0.04 0.35 0.46 0.07 0.14
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Fig. 1. Mean hemoglobin levels from baseline to the end of treatment for patients with interferon with ribavirin treatment.
factors can result in physician reluctance to use combination therapy in dialysis patients with HCV. If there is concern about complications such as anemia, monotherapy is a suitable treatment option. Our study has some limitations. First, since it was a retrospective multi-center study, different interferon and ribavirin dosages were used in different centers. Second, there is the possibility of bias in that patients who were able to tolerate treatment were selected enrolled. Most of the patients undergoing treatment could be considered younger and healthier than general dialysis patients. Nevertheless, this study is of considerable value because it includes data from actual clinical practice. 5. Conclusion In hemodialysis patients, the decision to treat HCV infection should be based on the benefits and risks of therapy, including comorbidities, life expectancy, and planning for kidney transplantation. Our retrospective study suggests that antiviral therapy based on pegylated interferon with or without ribavirin should be considered in all HCV-infected patients on dialysis in order to achieve SVR, with the goal to not only avoid subsequent hepatic deterioration but also to limit the risks of HCV-related post-transplant de novo glomerulonephritis. Despite the high dropout rate, the SVR rate in our study was 65.7%. The SVR rate was higher in the group receiving ribavirin treatment, although a SVR rate of 62.5% was seen in patients receiving interferon monotherapy. Patients who completed the treatment showed a high SVR rate of 89.5%. The use of peg-interferon with/without ribavirin is more challenging in HCV patients with ESRD. Conflict of interest The authors declare that they have no competing interests. Acknowledgments This work was supported by a research fund from Hanyang University (HY-2013-C). References [1] Chan TM, Lok ASF, Cheng IKP, Chan RT. Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays. Hepatology 1993;17:5–8.
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