doi:10.1111/j.1440-1746.2010.06488.x

A D VA N C E S I N C L I N I C A L P R A C T I C E

jgh_6488

228..239

Treatment of hepatitis C virus infection in patients with end-stage renal disease Chen-Hua Liu*,†,‡ and Jia-Horng Kao*,†,‡ *Department of Internal Medicine and †Hepatitis Research Center, National Taiwan University Hospital, and ‡Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

Key words dialysis, end-stage renal disease, hepatitis C virus, interferon, ribavirin. Accepted for publication 8 August 2010. Correspondence Professor Jia-Horng Kao, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei 10002, Taiwan. Email: [email protected]

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 antiHCV seroconversion. Without effective medical interventions, 65–92% of ESRD patients with acute hepatitis C become chronically infected.2,4,20,21 228

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 mildlyelevated 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,

Journal of Gastroenterology and Hepatology 26 (2011) 228–239 © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd

C-H Liu and J-H Kao

Table 1

Hepatitis C virus therapy in uremics

Incidence and prevalence of hepatitis C virus infection in patients with end-stage renal disease

Study

Country

Reference year

Annual incidence (%)

No. patients

Kobayashi et al.1 Furusyo et al.2 Kumagai et al.3 Liu et al.4 Fabrizi et al.5 Fabrizi et al.6 Schneeberger et al.7 Jadoul et al.8 Izopet et al.9 Lombardi et al.10 Petrosillo et al.11 Sypsa et al.12 Espinosa et al.13 Moreira et al.14 Santos et al.15 Hmaied et al.16 Ben Othman et al.17 Fissell et al.18

Japan Japan Japan Taiwan USA USA The Netherlands Belgium France Italy Italy Greece Spain Brazil Brazil Tunisia Tunisia France Germany Italy Japan Spain UK and USA

1998 2001 2005 2010 1999 2005 2000 1993 2005 1999 2001 2005 2002 2003 2007 2006 2004 2004

1.01 2.59 0.33 1.36 2.10 1.38 0.50 1.70 0.40 0.83 0.95 6.20 0.22 3.72 5.52 0.50 2.34 3.10

179 169 2744 1031 120 72 4567 399 1323 7456 3492 562 781 281 433 395 276 308

Study 2

Furusyo et al. Iwasaki et al.22 Kao et al.23 Dai et al.24 Sivapalasingam et al.25 Kalantar-Zadeh et al.26 Méndez-Sánchez et al.27 Schneeberger et al.7 Jadoul et al.28 Salama et al.29 Lombardi et al.10 Petrosillo et al.11 Da Porto et al.30 Sypsa et al.12 Hinrichsen et al.31 Covic et al.32 Yoshida et al.33 Mahmoud et al.34 Daw et al.35 Diouf et al.36

Country

Reference year

Prevalence (%)

No. patients

Japan Japan Taiwan Taiwan USA USA Mexico Netherlands Belgium France Italy Italy Italy Greece Germany Moldavia Brazil Egypt Libya Senegal

2001 2000 1995 2002 2002 2007 2004 2000 2004 2000 1999 2001 1992 2005 2002 1999 1992 1999 2002 2000

37.2 23.9 23.0 24.7 23.3 12.0 5.0 3.4 6.8 16.3 22.5 30.0 15.7 29.0 7.0 75.0 14.5 60.0 20.5 80.0

269 142 328 85 227 1590 149 2286 1710 1323 10097 3492 387 562 2796 148 110 133 200 15

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 nonstructural (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,

Journal of Gastroenterology and Hepatology 26 (2011) 228–239 © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd

229

Hepatitis C virus therapy in uremics

C-H Liu and J-H Kao

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 HCVRNA 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. HCVRNA 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-a 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 230

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 (ⱖF2) when the cut-off level is set at