Treatment of hepatitis C virus infection in patients with end-stage renal disease

Authors

  • Chen-Hua Liu,

    1. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
    2. Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
    3. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Jia-Horng Kao

    Corresponding author
    1. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
    2. Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
    3. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Professor Jia-Horng Kao, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei 10002, Taiwan. Email: kaojh@ntu.edu.tw

Abstract

Hepatitis C virus (HCV) infection is a major health problem in patients with end-stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses.

Introduction

Despite the introduction of blood-product screening, the increased use of erythropoietin, as well as the adoption of universal precautions and strict infection controls, hepatitis C virus (HCV) infection still remains a major health problem in patients with end-stage renal disease (ESRD). The annual incidence of HCV infection in these patients ranges from 0.2% to 6.2%, which is approximately 100–1000 times higher than that in the general population (Table 1).1–19 After exposure to HCV, there is a mean incubation period of 8 weeks before the onset of symptoms. Although some patients might present with fatigue, anorexia, or abdominal discomfort during acute HCV infection, most are asymptomatic, with mild-to-moderate, elevated serum alanine aminotransferase (ALT) levels. ALT values range from two to 20 times the upper limit of normal (ULN).4,20,21 The diagnosis of acute HCV infection in patients with ESRD is confirmed by the detection of serum HCV-RNA and the documentation of anti-HCV seroconversion.

Table 1.  Incidence and prevalence of hepatitis C virus infection in patients with end-stage renal disease
StudyCountryReference yearAnnual incidence (%)No. patients
Kobayashi et al.1Japan19981.01179
Furusyo et al.2Japan20012.59169
Kumagai et al.3Japan20050.332744
Liu et al.4Taiwan20101.361031
Fabrizi et al.5USA19992.10120
Fabrizi et al.6USA20051.3872
Schneeberger et al.7The Netherlands20000.504567
Jadoul et al.8Belgium19931.70399
Izopet et al.9France20050.401323
Lombardi et al.10Italy19990.837456
Petrosillo et al.11Italy20010.953492
Sypsa et al.12Greece20056.20562
Espinosa et al.13Spain20020.22781
Moreira et al.14Brazil20033.72281
Santos et al.15Brazil20075.52433
Hmaied et al.16Tunisia20060.50395
Ben Othman et al.17Tunisia20042.34276
Fissell et al.18France Germany Italy Japan Spain UK and USA20043.10308
StudyCountryReference yearPrevalence (%)No. patients
Furusyo et al.2Japan200137.2269
Iwasaki et al.22Japan200023.9142
Kao et al.23Taiwan199523.0328
Dai et al.24Taiwan200224.785
Sivapalasingam et al.25USA200223.3227
Kalantar-Zadeh et al.26USA200712.01590
Méndez-Sánchez et al.27Mexico20045.0149
Schneeberger et al.7Netherlands20003.42286
Jadoul et al.28Belgium20046.81710
Salama et al.29France200016.31323
Lombardi et al.10Italy199922.510097
Petrosillo et al.11Italy200130.03492
Da Porto et al.30Italy199215.7387
Sypsa et al.12Greece200529.0562
Hinrichsen et al.31Germany20027.02796
Covic et al.32Moldavia199975.0148
Yoshida et al.33Brazil199214.5110
Mahmoud et al.34Egypt199960.0133
Daw et al.35Libya200220.5200
Diouf et al.36Senegal200080.015

Without effective medical interventions, 65–92% of ESRD patients with acute hepatitis C become chronically infected.2,4,20,21 Therefore, the high, acute HCV infection and chronicity rates after acute infection contribute to the high prevalence of HCV infection in ESRD patients. The reported prevalence rates of chronic HCV infection among ESRD patients ranges from 3.4%to 80% with great geographic variation (Table 1).2,7,10–12,22–36 The higher incidence and prevalence rates of HCV infection among ESRD patients suggest the possible routes of nosocomial transmission, such as contamination of the hands of staff members, sharing items between patients, dialyzer reuse, and contamination of dialysis machines.37–41 ESRD patients with chronic HCV infection usually have an apparent indolent clinical course with only mildly-elevated serum ALT levels.

Natural history of HCV infection in ESRD patients

The natural history of chronic HCV infection in ESRD patients remained unclear during the early years of HCV infection. This is because the morbidity and mortality rates in ESRD patients were generally higher than those in the general population, making the long-term consequences of HCV infection difficult to clarify. However, recent studies have clearly shown that HCV-infected ESRD patients on maintenance dialysis are at increased risk of liver-related mortality.13,26,42–51 In addition, HCV infection adversely decreases the heath-related quality of life in these patients.52 Although ESRD patients with chronic hepatitis C receiving renal transplantation (RT) usually have a higher survival rate than those on maintenance dialysis, several studies indicate that these patients have a poorer patient and graft survival after RT.53–60 However, HCV-infected patients have accelerated hepatic fibrosis and deterioration of hepatic necroinflammation after RT, suggesting that immunosuppression following RT could worsen the course of liver disease.61–64

Diagnosis and evaluation of HCV infection in ESRD patients

Serological assays

There are two types of anti-HCV assays using structural and non-structural (NS) HCV proteins to detect HCV antibodies: enzyme immunoassay (EIA) and recombinant immunoblotting assay (RIBA). EIA is more commonly used due to its simplicity and reduced cost. EIA-1 (first-generation EIA) contained a single recombinant antigen in the HCV NS4 region, and was flawed by high false-negative and false-positive rates. The following two successive generations of EIA (EIA-2 and EIA-3), containing additional antigens in the core, NS3, NS4, and NS5 regions, further increase the sensitivity and specificity. Such commercial assays are now widely used in clinical practice. Although RIBA is considered reproducible and confirmative to diagnose HCV infection for positive EIA samples, it is rarely used after the introduction of sensitive molecular assays to detect (or quantify) circulating HCV-RNA.

In ESRD patients receiving maintenance dialysis, previous studies showed that the false-negative rates of EIA-2 were 2.6% and 7%, respectively, to diagnose HCV infection, taking HCV-RNA as the reference standard.41,65 The EIA-3 provided excellent accuracy, with 0–0.23% false-negative rates. Thus, EIA-3 is an effective screening tool for HCV infection in patients with ESRD.66,67

Virological assays

HCV-RNA is the direct marker of HCV replication. It can be used to estimate the level of viral replication in the liver and to monitor the effectiveness of treatment response to antiviral therapy. HCV-RNA can be determined qualitatively or quantitatively on the basis of different molecular biological techniques. In addition, the HCV genotype is the intrinsic characteristic of the infected HCV strains, and remains stable during the course of chronic HCV infection. The evaluation of HCV-RNA and the genotype can help clinicians determine the optimal duration and dosage of interferon (IFN)-based therapy.

Several studies have found that the HCV-RNA level is transiently decreased during hemodialysis, but gradually returns to baseline level within 48 h.68–70 Various mechanisms, including the adsorption of HCV onto the dialysis membrane, destruction of HCV particles, escape of HCV into the dialysate, or increased plasma IFN-α levels during the dialysis, might be associated this particular phenomenon.71,72 It is recommended that the viral load should be determined prior to hemodialysis to avoid the possibility of underestimation. Although the distribution of HCV genotypes varies widely among different geographic regions, HCV genotypes 1 and 2 predominate in ESRD patients with chronic hepatitis C, regardless of geographic areas.73–76

Biochemical assays

Although the serum ALT level is used to screen liver diseases in the general population, it is known that ESRD itself lowers ALT levels.77,78 Thus, the optimized cut-off ALT level to detect HCV viremia is approximately 0.4–0.45 times the ULN of the conventional level (typically 40 IU/L).79,80

Invasive and non-invasive tests to evaluate liver histology

Compared to non-uremic HCV patients, ESRD patients with chronic hepatitis C have milder hepatic necroinflammation and fibrosis.81–83 A longer duration of infection, advanced age at infection, elevated serum aspartate aminotransferase (AST), and severe hepatic necroinflammation on liver biopsy are associated with significant hepatic fibrosis.83,84

Clinically, percutaneous liver biopsy is the gold standard to assess the liver histology in ESRD patients with chronic hepatitis C, by which physicians can evaluate the eligibility for RT, the long-term prognosis and the necessity for IFN-based therapy.85,86 However, liver biopsy is limited by poor patient acceptance, potentially serious bleeding events, and sampling and interpretation errors. These issues have stimulated a search for non-invasive means to predict the severity of liver histology.87–89

Two studies indicated that the AST : platelet ratio index (APRI), based on simple blood tests, is useful in predicting the severity of hepatic fibrosis in ESRD patients with chronic hepatitis C.90,91 However, the major strength of APRI is to exclude patients with significant hepatic fibrosis (≥F2) when the cut-off level is set at <0.40; this saves, at most, 50% of patients from being correctly diagnosed without the need for liver biopsy. The recently-introduced transient elastography (Fibroscan; Echosense, Paris, France) shows superior diagnostic accuracy to APRI, with 69% and 82% of ESRD patients with mild (≥F1) and significant (≥F2) hepatic fibrosis correctly diagnosed without the need for liver biopsy.92

Definition of HCV virological response following IFN-based therapy

The goal of HCV treatment is to decrease liver-related morbidity and mortality. Because the evolution to end-stage liver disease in ESRD patients with chronic HCV infection usually takes several decades, it is difficult to show the beneficial effect of treatment on the prevention of liver-related complications. Sustained viral suppression, rather than long-term clinical outcome, is therefore defined as the surrogate end-point of IFN-based therapy. Table 2 shows the definition of virological responses to treatment in chronic hepatitis C. The most important is sustained virological response (SVR), defined as undetectable HCV-RNA, 24 weeks after the completion of therapy by a sensitive HCV-RNA assay. This end-point is generally believed to be a ‘virological cure’, although some patients might still develop liver-related complications (particularly hepatocellular carcinoma) years after achieving SVR, especially those with advanced fibrosis and other risk factors for liver disease (alcohol, diabetes, occult hepatitis B virus infection). A rapid virological response (RVR), defined as undetectable HCV-RNA at week 4 of treatment, and early virological response (EVR), defined as an undetectable polymerase chain reaction (PCR; complete EVR [cEVR]) or ≥2 log reduction of HCV-RNA at week 12 of treatment to the baseline viral level (but still PCR positive; partial EVR). RVR and cEVR are strong positive predictors of SVR in chronic hepatitis C patients with normal renal function.93

Table 2.  Definitions of virological responses in patients with hepatitis C virus (HCV) infection treated with interferon-based therapy
Virological responseDefinition
  1. EVR, early virological response; RVR, rapid virological response.

RVRUndetectable HCV-RNA at week 4 of treatment by a sensitive, qualitative or quantitative HCV-RNA assay
EVR≥2 log reduction of HCV-RNA at week 12 of treatment compared to baseline level by a quantitative HCV-RNA assay
Complete EVRUndetectable HCV-RNA at week 12 of treatment in the absence of an RVR
Partial EVR≥2 log reduction of HCV-RNA but without undetectable HCV-RNA at week 12 of treatment in the absence of an RVR
End-of-treatment virological responseUndetectable HCV-RNA at the end of treatment by a sensitive, qualitative or quantitative HCV-RNA assay
Sustained virological responseUndetectable HCV-RNA at week 24 at the end of treatment by a sensitive, qualitative or quantitative HCV-RNA assay

Treatment of ESRD patients with acute HCV infection

IFN monotherapy

IFN-α monotherapy has been used successfully to treat non-uremic patients with acute hepatitis C. Treatment with conventional IFN at a dose of 3–6 million units (MU) three times per week for 4–24 weeks had an overall SVR rate of 32–98%.94–96 In ESRD patients with acute hepatitis C, the overall SVR rate in patients who received conventional IFN at a dose of 3–10 MU three times per week for 12–48 weeks was 26–86%, which was higher than those who did not receive IFN therapy (5.6–12.5%) (Table 3).97–101 The treatment-related withdrawal rate was 0–22%, depending on different treatment dosages and durations. Patients who received a higher dose of IFN and had a lower HCV E1/NS1 single-strand conformational polymorphism band number were predictive of SVR.98,101

Table 3.  Efficacy and safety of conventional or pegylated interferon monotherapy in end-stage renal disease patients with acute hepatitis C
StudyNo. patientsAntiviral agentDose and durationSustained virological response (%)Withdrawal rate (%)
  1. MU, million units.

Süleymanlar et al.973IFN-α-2a4.5 MU three times per week for 16 weeks1000
Gürsoy et al.9836IFN-α-2b3 MU three times per week for 12 weeks (n = 16)
6 MU three times per week for12 weeks (n = 20)
26
50
17
Urbánek et al.9918IFN-α-2b10 MU/day for 3 weeks, and 3 MU three times weekly for 12 weeks720
Al-Harbi et al.1009IFN-α3 MU three times per week for 12 weeks8622
Rocha et al.10123IFN-α3 MU three times per week for 48 months (n = 16)
3 MU three times per week for 2 weeks, 5 MU three times per week for 2 weeks, 5 MU daily for 4 weeks, and 5 MU three times per week for 16 weeks (n = 7)
38
57
13
Engel et al.10210Pegylated IFN-α-2b1 µg/kg/week for 24 weeks4010
Liu et al.435Pegylated IFN-α-2a135 µg/week for 24 weeks896

Pegylated IFN monotherapy

The use of pegylated IFN-α-2b at a dose of 1–1.66 µg/kg/week for 12–24 weeks further increased the SVR rate to 82–95% in non-uremic patients with acute hepatitis C.103,104 However, there have been a few studies that have evaluated the safety and efficacy of pegylated IFN for ESRD patients with acute hepatitis C. Engel et al. identified 32 ESRD patients with acute hepatitis C, 10 of whom received pegylated IFN-α-2b at a dose of 1 µg/kg/week for 24 weeks. The SVR rate was 40%, and one of the 10 treated patients died during the treatment because of pneumonia and fistula formation.102 In 2008, we evaluated 35 such patients, all of whom received pegylated IFN-α-2a at a dose of 135 µg/week for 24 weeks. The SVR rate in the treated patients was 89%, which was significantly higher than those of the non-treatment historical controls (17%); the premature withdrawal rate was 5.7%.4 Among patients who received 80% of the scheduled treatment dosage and duration, the SVR rate was 90%. In contrast, baseline ALT levels, HCV-RNA levels, and the genotype did not influence SVR. A 16-week HCV-RNA surveillance rule after the onset of acute hepatitis C is ideal to determine the necessity of IFN treatment in this situation.4

Treatment of ESRD patients with chronic HCV infection

IFN monotherapy

The SVR and treatment-related withdrawal rates of conventional IFN monotherapy (3–6 MU, three times per week) for 24–48 weeks are generally ≤20% and 5–10% in non-uremic patients with chronic hepatitis C.94 The treatment of ESRD patients with chronic hepatitis C by conventional IFN monotherapy at a dose of 1–6 MU daily to three times per week for 12–48 weeks resulted in SVR rates of 20–71%. The treatment-related withdrawal rates were 0–53% (Table 4).105–128 Four meta-analysis studies showed that approximately one-third of ESRD patients with chronic hepatitis C who received conventional IFN monotherapy can achieve an SVR.129–133 However, the corresponding treatment-related withdrawal rates ranged from 20% to 30%. The higher SVR and treatment-related withdrawal rates for conventional IFN monotherapy in ESRD patients than those in non-uremic patients might be explained by altered IFN pharmacokinetics, specifically decreased renal clearance and higher IFN serum concentrations.133 A low baseline HCV-RNA level, mild liver histology, and treating patients by IFN at a dose of 3 MU for at least 6 months are predictive of SVR.110,128,150 Patients who achieve an RVR have a high probability of achieving an SVR; those who fail to clear HCV-RNA at weeks 4–8 of treatment have a low likelihood of achieving an SVR.109,119,128,150

Table 4.  Efficacy and safety of conventional or pegylated interferon (IFN) monotherapy in end-stage renal disease patients with chronic hepatitis C
StudyNo. patientsAntiviral agentDose and durationSustained virological response (%)Withdrawal rate (%)
  1. MU, million unit; NA, not available.

IFN     
 Koenig et al.10537IFN-α5.0 MU 3 times/week for 16 weeks3035
 Pol et al.10619IFN-α-2b3.0 MU 3 times/week for 24 weeks205
 Raptopoulou-Gigi et al.10719IFN-α-2b1.0 or 3.0 MU 3 times per week for 24 weeks6331
 Fernández et al.10814IFN-α-2b1.5–3.0 MU 3 times/week for 24 weeks2121
 Izopet et al.10923IFN-α-2b3.0 MU 3 times/week for 24 weeks (n = 12)
3.0 MU 3 times/week for 48 weeks (n = 11)
42
64
0
27
 Chan et al.11011IFN-α-2b3.0 MU 3 times/week for 24 weeks27NA
 Uchihara et al.1119IFN-α-2b/natural IFN-α-2b3.0–6.0 MU/day for 2 weeks, and 3.0 MU 3 times/week for 22 weeks2033
 Benci et al.11210Leukocyte IFN-α1.0 MU 3 times per week for 48 weeks2010
 Djordjevićet al.1136IFN-α-2b3.0 MU 3 times/week for 12 weeks330
 Boran et al.11410IFN-α-2b10.0 MU/day for 2 weeks, and 3.0 MU 3 times/week for 6 weeks30NA
 Campistol et al.11519IFN-α-2b3.0 MU 3 times/week for 24 weeks4253
 Huraib et al.11617IFN-α-2b3.0 MU 3 times/week for 48 weeks716
 Hanrotel et al.11712IFN-α-2a3.0 MU 3 times/week for 48 weeks338
 Casanovas-Taltavull et al.11829Lymphoblastoid IFN-α3.0 MU 3 times/week for 24 weeks, and 1.5 MU 3 times/week for 24 weeks6224
 Degos et al.11937IFN-α-2b3.0 MU 3 times/week for 48 weeks1951
 Espinosa et al.12013IFN-α3.0 MU 3 times/week for 48 weeks4623
 Kamar et al.12155IFN-α3.0 MU 3 times/week for 24 or 48 weeks38NA
 Ozdemir et al.12220IFN-α3.0–6.0 MU 3 times/week for 24–48 weeks40NA
 Mahmoud et al.12318IFN-α-2b3.0 MU 3 times/week for 24 weeks4411
 Rivera et al.12420IFN-α-2b3.0 MU 3 times/week for 24–48 weeks40NA
 Buargub et al.12535IFN-α3.0 MU 3 times/week for 48 weeks2634
 Rocha et al.12646IFN-α3.0 MU 3 times/week for 48 weeks2237
 Grgurevićet al.12715IFN-α3.0 MU 3 times/week for 24 weeks (n = 8),
5.0 MU 3 times/week for 12 weeks, and 5.0 MU per week for 12 weeks (n = 7)
50
29
0
29
 Liu et al.12825IFN-α-2a3.0 MU 3 times/week for 24 weeks2020
Pegylated IFN     
 Annicchiarico et al.1348Pegylated IFN-α-2b0.6–1.1 µg/week for 24 weeks3333
 Teta et al.1353Pegylated IFN-α-2a180.0 µg/week for 48 weeks6733
 Rivera et al.1237Pegylated IFN-α-2a135.0 µg/week for 48 weeksNA14
 Sporea et al.13610Pegylated IFN-α-2a180.0 µg/week for 48 weeks300
 Kokoglu et al.13712Pegylated IFN-α-2a135.0 µg/week for 48 weeks750
 Covic et al.13878Pegylated IFN-α-2a135 µg/week for 48 weeks1414
 Russo et al.13916Pegylated IFN-α-2b1.0 µg/kg/week for 48 weeks (n = 9), and 0.5 µg/kg/week for 48 weeks (n = 7)22
0
56
28
 Casanovas-Taltavull et al.14012Pegylated IFN-α-2a135.0 µg/week for 48 weeks2525
 Amarapurkar et al.1416Pegylated IFN-α-2b1.0 µg/kg/week for 24 weeks50NA
 Sikole et al.14214Pegylated IFN-α-2a135.0 µg/week for 48 weeks3621
 Chan et al.1436Pegylated IFN-α-2a135.0 µg/week for 48 weeks3333
 Espinosa et al.14416Pegylated IFN-α-2a
Pegylated IFN-α-2b
135.0 µg/week for 48 weeks (n = 9)
1.5 µg/kg/week for 24 weeks (n = 7)
0
57
29
44
 Ayaz et al.14522Pegylated IFN-α-2a135.0 µg/week for 48 weeks6523
 Liu et al.12825Pegylated IFN-α-2a135.0 µg/week for 24 weeks480
 Akhan et al.14612Pegylated IFN-α-2a135.0 µg/week for 48 weeks500
 Kose et al.14733Pegylated IFN-α-2a135.0 µg/week for 48 weeks796
 Tan et al.14834Pegylated IFN-α-2b0.5 µg/kg/week for 4 weeks, and 1.0 µg/kg/week for 20–44 weeks5033
Meta-analysis     
 Fabrizi et al.129269IFN-α1.5–6.0 MU/day to 3 times per week for 12–48 weeks3717
 Russo et al.130213IFN-α3.0–5.0 MU 3 times per week for 24–48 weeks3330
 Fabrizi et al.131645IFN-α
Pegylated IFN-α
1.0–6.0 MU/day to 3 times/week for 8–48 weeks (n = 529), 135.0–180.0 µg times/week for 48 weeks (α-2a), or 0.5–1.0 µg/kg times/week for 48 weeks (α-2b) (n = 116)39
31
19
27
 Gordon et al.132546IFN-α
Pegylated IFN-α ± ribavirin
1.0–6.0 MU/day to 3 times/week for 16–48 weeks (n = 459), 135.0–180.0 µg/week for 24–48 weeks (α-2a), or 0.5–1.0 µg/kg/week for 48 weeks (α 2b) (n = 87)41
37
26
28
 Fabrizi et al.149254Pegylated IFN-α135.0–180.0 µg/week (α-2a) or 0.5–1.1 µg/kg/week for 24–48 weeks (α-2b)3323

Pegylated IFN monotherapy

The SVR and treatment-related withdrawal rates of pegylated IFN monotherapy (pegylated IFN-α-2a at a dose of 180 µg/week; pegylated IFN-α-2b at a dose of 0.5–1.5 µg/kg/week) for 48 weeks were 18–39% and 3–7% in non-uremic patients with chronic hepatitis C.151,152 Two pharmacokinetic studies showed that the effective concentration in ESRD patients treated with pegylated IFN-α-2a or IFN-α-2b at a dose of 135–180 µg/week or 1 µg/kg/week was comparable to that in non-uremic patients treated with pegylated IFN-α-2a or IFN-α-2b at a dose of 180 µg/week or 1.5 µg/kg/week.153,154 The treatment of ESRD patients with chronic hepatitis C by pegylated IFN monotherapy at a dose of 135–180 µg/week or 0.5–1.1 µg/kg/week for 24–48 weeks resulted in SVR rates of 0–79%, and treatment-related withdrawal rates of 0–56% (Table 4).124,128,134–148 Three meta-analysis studies showed that the SVR and treatment-related withdrawal rates in patients receiving pegylated IFN were 31–37% and 23–28%, which are comparable to conventional IFN.131,132,149 Although patients treated with either conventional or pegylated IFN have similar efficacy and safety on the basis of meta-analysis studies, one head-to-head, randomized trial showed that the overall efficacy and safety in patients treated with pegylated IFN were superior to those treated with conventional IFN.128

Similar to ESRD patients who receive conventional IFN monotherapy, a low baseline HCV-RNA level and RVR are positive predictors for SVR in those receiving pegylated IFN monotherapy.128

IFN and ribavirin therapy

The use of ribavirin in combination with conventional IFN greatly improves SVR rates to 31–43% in non-uremic patients with chronic hepatitis C.155,156 Ribavirin is considered contraindicated for the treatment of ESRD patients with chronic hepatitis C because of the risk of life-threatening hemolytic anemia. However, several studies showed that using low-dose ribavirin (200 mg three times per week to 400 mg daily) to keep target concentrations of 10–15 µmol/L in combination with conventional IFN and high-dose erythropoietin (20 000–30 000 IU/week) was feasible for treating ESRD patients with chronic hepatitis C. SVR and treatment-related withdrawal rates after 24–48 weeks of combination therapy ranged between 17% and 63%, and 0% and 33%, respectively (Table 5).157–159 Although these pilot studies showed it might be safe to administrate low-dose ribavirin under close hemoglobin surveillance and high-dose erythropoietin supply, ribavirin is generally not recommended for routine clinical use, unless further large-scale trials confirm its safety profile in ESRD patients.

Table 5.  Efficacy and safety of conventional or pegylated interferon (IFN) plus low-dose ribavirin in end-stage renal disease patients with chronic hepatitis C
StudyNo. patientsAntiviral agentDose and durationSustained virological response (%)Withdrawal rate (%)
  • Relapsers to previous IFN-based monotherapy. MU, million unit; NA, not available.

IFN + ribavirin     
 Bruchfeld et al.1576IFN-α-2b + ribavirin3 MU 3 times/week (IFN), and 200–400 mg/qd (ribavirin) for 28 weeks1733
 Tan et al.1585IFN-α-2b + ribavirin3 MU 3 times/week (IFN), and 200–600 mg/qd (ribavirin) for 24 weeksNA20
 Mousa et al.15920IFN-α + ribavirin3 MU (IFN), and 200 mg (ribavirin) 3 times/week for 24 weeks (n = 9)
3 MU (IFN), and 200 mg (ribavirin) 3 times/week for 48 weeks (n = 11)
67
36
0
0
Pegylated IFN + ribavirin     
 Bruchfeld et al.1606Pegylated IFN-α-2a or -2b + ribavirin135 µg/week (pegylated IFN-α 2a) or 50 µg/week (pegylated IFN-α-2b), and 200–400 mg/qd (ribavirin) for 48 (genotype 1/4) or 24 (genotype 2) weeks5033
 Rendina et al.16135Pegylated IFN-α-2a + ribavirin135 µg/week (pegylated IFN), and 200 mg/qd (ribavirin) for 48 (genotype 1) or 24 (genotype non-1) weeks9714
 Carriero et al.16214Pegylated IFN-α 2a + ribavirin135 µg/week (pegylated IFN), and 200 mg/qd (ribavirin) for 48 weeks2971
 Van Leusen et al.1637Pegylated IFN-α-2a + ribavirin135 µg/week (pegylated IFN), and 200 mg/other day (ribavirin) for 48 (genotype 1/4) or 24 (genotype 2/3) weeks710
 Hakim et al.16415Pegylated IFN-α-2a + ribavirin135 µg/week (pegylated IFN) and 200 mg/week to 3 times/week (ribavirin) for 48 weeks733
 Liu et al.16535Pegylated IFN-α-2a + ribavirin135 µg/week (pegylated IFN), and 200 mg/qd (ribavirin) for 48 (genotype 1) or 24 (genotype 2) weeks6017

Pegylated IFN and ribavirin therapy

Combination therapy with pegylated IFN and ribavirin has improved the SVR rate and is the current standard of care to treat non-uremic patients with chronic hepatitis C.166,167 However, only a few studies have assessed the efficacy and safety of pegylated IFN plus low-dose ribavirin to treat ESRD patients with chronic hepatitis C (Table 5).160–164 SVR and treatment-related withdrawal rates after 24 or 48 weeks of combination therapy ranged between 7% and 97%, and 0% and 71%, respectively. These patients needed to receive high-dose erythropoietin (10 000–40 000 IU/week) to maintain adequate dosage for ribavirin during the treatment to achieve excellent on-treatment viral suppression.160,161 Furthermore, patients with HCV genotype 2 or 3 infection have higher SVR rates than those with genotype 1 or 4 infection.

Retreatment for prior relapsers to IFN monotherapy

Although the safety and efficacy of conventional or pegylated IFN plus ribavirin to retreat non-uremic patients with chronic hepatitis C who failed to respond to prior IFN-based monotherapy are well established, only two studies have addressed this issue in ESRD patients. Djordjevićet al. retreated four patients who relapsed from 12 weeks of conventional IFN monotherapy at a dose of 3 MU three times per week by the same protocol for another 24 weeks. Despite all the patients having good viral suppression, ALT normalization, and tolerance during the retreatment, none had an SVR.113

In 2009, we retreated 35 patients who relapsed from 24 weeks of conventional or pegylated IFN monotherapy with 135 µg/week pegylated IFN and daily 200 mg ribavirin for 48 (HCV genotype 1) or 24 (HCV genotype 2) weeks.165 The overall SVR rate was 60%, and the SVR rate in the HCV genotype 2 patients was superior to that in the HCV genotype 1 patients (80% vs 52%). The treatment-related withdrawal rate was 17%. Twenty-six (74%) patients had to receive erythropoietin at a mean dose of 15 000 IU/week to manage anemia during combination therapy. Low baseline HCV-RNA and RVR were independent predictors for SVR.

Treatment of ESRD patients with HCV infection following RT

Antiviral therapy for HCV infection following RT is currently limited by its unsatisfactory safety and efficacy. The results of one meta-analysis, which included 102 RT recipients with chronic hepatitis C who received conventional IFN monotherapy or conventional IFN plus ribavirin therapy, showed that the overall SVR and treatment-related withdrawal rates were 18% and 35%, respectively.168 However, many studies included in the meta-analysis did not provide clear efficacy end-points, leading to unclear SVR rates. In addition, treatment interruption was most frequently associated with acute allograft rejection, resulting in graft dysfunction or graft loss.55,168–170 Although results with ribavirin or amantadine monotherapy, and ribavirin plus amantadine combination therapy showed improvements in serum ALT levels without detrimental effects on renal graft function, these regimens did not have any beneficial effects on viral suppression or liver histology.171–174 Taking these lines of evidence together, IFN-based therapy should only be initiated in RT recipients under specific clinical conditions, such as fibrosing cholestatic hepatitis, when the risk of not treating HCV infection outweighs the risk of graft loss.

Long-term outcome after IFN-based therapy

ESRD patients with HCV infection who achieve an SVR are shown to have greater improvements in liver histology and quality of life than those who fail to achieve an SVR after IFN-based therapy.116,128,175,176 Furthermore, patients with an SVR have decreased liver histology progression at the post-RT stage.175 Several studies indicated that patients with an SVR can maintain long-term, undetectable serum HCV-RNA and normalized ALT levels, either at maintenance dialysis or after RT.121,122,177

Conclusions

HCV infection still remains a major health problem that can cause substantial liver-related morbidity and mortality in patients with ESRD. Universal precautions against nosocomial blood-borne infections, routine ALT, and anti-HCV surveillance should be strictly adhered to in order to prevent and detect acute HCV infection. Conventional and pegylated IFN monotherapy are both effective and safe for the treatment of ESRD patients with acute hepatitis C. Careful surveillance of serum HCV-RNA levels during the first 16 weeks of acute hepatitis C is helpful AS to avoid unnecessary therapy for the small proportion with acute, self-limiting hepatitis C.

Approximately one-third of ESRD patients with chronic hepatitis C treated with conventional or pegylated IFN monotherapy achieve an SVR. The combined use of low-dose ribavirin plus conventional or pegylated IFN can further increase the SVR rates for treatment-naïve or treatment-relapse (after conventional or pegylated IFN monotherapy) ESRD patients with chronic hepatitis C by improving on-treatment viral suppression and reducing off-treatment relapse. However, close monitoring of hemoglobin levels and high-dose erythropoietin are needed to prevent severe anemia during the treatment period. Determination of pretreatment serum HCV-RNA levels, HCV genotype, and stage of hepatic fibrosis, as well as the monitoring of on-treatment serum HCV-RNA kinetics, are recommended to guide the optimal therapy.

IFN-based therapy is generally not recommended for treating HCV infection after RT because it might cause graft dysfunction or loss. The beneficial effects on sustained viral suppression, biochemical remission, histological improvement, and quality of life can be maintained in patients with an SVR either during dialysis or after RT. Most IFN-based therapeutic studies for ESRD patients with HCV infection are too small to adequately address safety and efficacy issues, and the long-term outcome of ESRD patients with HCV infection after IFN-based therapy remains unclear. Large-scale, well-conducted studies are necessary to answer these interesting and important issues.

Acknowledgments

The study was supported by grants from the National Taiwan University Hospital, the National Science Council, and the Department of Health, Executive Yuan, Taiwan.

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