Year : 2014 | Volume : 25 | Issue : 1 | Page : 1-8
Hossein Khedmat1, Mohsen Amini1, Mohammad Ebrahim Ghamar-Chehreh1, Shahram Agah2
1 Baqiyatalah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Colorectal Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Date of Web Publication 7-Jan-2014
Despite the introduction of strict hygienic precautions preventing infection spread of hepatitis C virus (HCV) in dialysis settings, this infection is still prevalent among dialysis patients due to procedures making the patients vulnerable to infection through blood contamination. Treatment of HCV infection in dialysis patients is also less successful than that in the non-uremic population due to contraindication of using ribavirin, a main drug, in the infected patients. In this review article we aim to investigate the feasibility of the current antiviral therapies in dialysis patients infected with HCV infection.
How to cite this article:
Khedmat H, Amini M, Ghamar-Chehreh ME, Agah S. Hepatitis C virus infection in dialysis patients. Saudi J Kidney Dis Transpl 2014;25:1-8
How to cite this URL:
Khedmat H, Amini M, Ghamar-Chehreh ME, Agah S. Hepatitis C virus infection in dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2014 Jan 12];25:1-8. Available from: http://www.sjkdt.org/text.asp?2014/25/1/1/124455
The World Health Organization estimates the global prevalence of chronic infection with hepatitis C virus (HCV) to be 3%, with wide epidemiological variation.  In patients under going maintenance hemodialysis (HD), the prevalence of HCV infection substantially increases to up to 90%, , and this disease has been shown to be associated with severe complications from chronic hepatitis to fatal cirrhosis and hepatocellular carcinoma.  Furthermore, there are other malignancies associated with
HCV infection in some patient populations.  Moreover, data on the natural history of HCV infection in kidney disease patients demonstrate that these patients may have significant liver disease on liver biopsy, despite normal serum liver enzymes,  and it also reportedly impairs the quality of life of chronic HD patients.  Accordingly, eradication of HCV infection in this specific population is highly recommended. 
Interferon-based therapy, a standard treatment for HCV infection, has many drawbacks in HD patients, such as poor tolerance and marginal response.  Prescription of ribavirin in HD patients is generally contraindicated due to a risk of hemolytic anemia.  Pegylated interferon (PEG-IFN), which has a large polyethylene glycol moiety bound to IFN, has higher stability and prolonged systemic bio-availability  with more efficiency compared with regular IFN.  However, data on the efficiency and safety of PEG-IFN in end-stage renal disease (ESRD) patients are limited. There are also newly introduced agents, including telaprevir and boceprevir, which have been successfully employed to manage HCV infection in the non-dialysis context. , However, there is an absolute scarcity of data on the efficacy and/or safety of these drugs in dialysis patients, although one study suggested that renal dysfunction does not affect the serum levels of boceprevir. 
We aim in this review article to discuss the course and management of HCV-positive patients on maintenance HD.
HCV Infection Course in HD Patients
Because of the chronic nature of HCV infection and the high rate of morbidities and mortalities in dialysis patients owing to their renal disease, the long-term evaluation of the natural history of HCV infection in this patient population has several limitations. However, evidence suggests that HCV infection increases all-cause mortality in dialysis patients, ,,,, and this risk of death exists irrespective of the type of dialysis.  In a meta-analysis, Fabrizi et al.  reported that the presence of anti-HCV antibody was an independent factor for death, with a relative risk of 1.57 in patients on maintenance dialysis. They also reported that dialysis patients with HCV infection are significantly more likely to develop hepatocellular carcinoma and liver cirrhosis.  On the other hand, renal transplantation has been recommended for HCV-positive dialysis patients because of its survival advantage over patients remaining in the waiting list,  although, not surprisingly, viral replication of HCV has been shown to adversely affect renal graft survival.  The proposed explanation for this observation is that HCV-induced hepatic necro-inflammation would be accelerated, especially after renal transplantation, due to immunosuppression therapy. 
Diagnosis of HCV Infection in ESRD Patients
There are two types of assays that measure the anti-HCV antibodies: Enzyme immunoassay (EIA) and recombinant immunoblotting assay (RIBA). Although RIBA is a known confirmative test for the diagnosis of HCV infection in case of positive EIA samples, molecular assays detecting circulating HCV-RNA have thoroughly replaced it. It has been demonstrated that the false-negative rates of EIA-2 were too high, rendering the HCV-RNA polymerization as the gold standard test to confirm the HCV infection. , However, the EIA-3, as a serological assay, has a high sensitivity in patients on maintenance dialysis and can be effectively used for HCV diagnosis in the HD population. 
Detection of serum aminotransferase levels in HCV-infected HD patients is of less value because it is suggested that ESRD itself lowers the aminotransferase levels; however, some authors suggested different cut-off levels for them in this patient population. , Although some authors suggested some clinical values for elevated aminotransferase levels in dialysis patients, multivariable analysis in one of them showed no independently significant relationship. 
The distribution of HCV genotypes widely varies in different geographical areas, although HCV genotype 1 predominates in dialysis patients with chronic HCV infection, regardless of geographic area. ,, Detection of HCV-RNA is the direct method of evaluating HCV infection. Moreover, this method enables us to estimate the viral replication rate in the liver; thus, it is a reliable test to assess the response to antiviral treatment and helps physicians determine the optimal duration and dosage of anti-viral agents. Most studies indicate that the HCV-RNA levels decrease transiently during HD sessions.  Several mechanisms have been suggested for this observation, including the adsorption of HCV onto the dialysis membrane, destruction of HCV particles, escape of HCV into the dialysate and an increase of plasma IFN-α levels during dialysis. , However, recent studies have reported different observations such as a steady state or an increasing rate of HCV-RNA concentration during HD sessions. , Interestingly, this observation was independent from HD procedures, dialysis membrane, heparin concentration and uremic toxins. 
Role of Histological Evaluation of the Liver
The histopathological evaluation of a liver biopsy specimen is of substantial value in determining the severity of liver fibrosis and necro-inflammation in chronic HCV infection. This also rules out other disorders, including the very prevalent non-alcoholic fatty liver disease, which may be able to induce similar damages to the liver.  However, liver biopsies are limited by complications including potentially mass bleeding events, patients' unwillingness and technical errors in obtaining the specimen or its evaluation. Compared with HCV patients with normal renal function, dialysis patients with HCV infection have milder hepatic necro-inflammation and fibrosis. The predictors of a hepatic damage in this patient population include a longer duration of infection, advanced age at infection, elevated serum aspartate aminotransferase (AST) and severe hepatic necro-inflammation on liver biopsy.  Clinical relevance of evaluating liver histopathology in dialysis patients includes the necessity for IFN-based therapy, the long-term prognosis and the eligibility for kidney transplantation. ,,
For dialysis patients on a transplantation waiting list, the Kidney Disease Improving Global Outcomes (KDIGO) recommends liver biopsies in the HCV-infected patients, while the American Association for the Study of Liver Diseases (AASLD) limits the biopsies to only the dialysis patients with genotypes 1 and 4 HCV infection. 
There is an increased risk of bleeding in patients with chronic kidney disease because of platelet dysfunction and anticoagulation therapies. Accordingly, the preferred method of a liver biopsy in HD patients is the trans-jugular or transfemoral routes. Moreover, through this method, one can also estimate the hepatic venous pressure gradient as well as the portal hypertension.
Treatment of Acute Infection with Hepatitis C Virus
Despite the introduction of a new generation of anti-HCV agents, IFN-α is still considered a very effective treatment in dialysis patients developing acute HCV infection according to recent publications. In a recent meta-analysis of eight clinical studies including 173 unique patients, Fabrizi et al  reported that IFN-based therapy of acute hepatitis C in dialysis populations results in a sustained virological response (SVR) in almost half of the patients. The patients who received higher doses of IFN developed higher rates of SVR. ,
In non-uremic patients, PEG-IFN-α-2b increases the SVR rate up to 94% in acute hepatitis C infection.  Nevertheless, data on the efficacy of PEG-IFN in dialysis patients are limited and suggestive of less-promising results than in non-uremic individuals. A recent study by Liu et al  on 35 HD patients who developed acute hepatitis C and did not have spontaneous HCV clearance by 16 weeks concluded that treatment with PEG-IFN-α-2a at a dosage of 135 μg weekly for 24 weeks was associated with almost 90% virological response, while this rate in 36 control patients who did not receive therapy was only 17%. In another study, 32 ESRD patients with acute HCV infection were followed and ten of them received PEG-IFN-α-2b, and only 40% developed SVR and one died. 
Treatment of Chronic Hepatitis C Virus Infection in Dialysis Patients
[Table 1] summarizes the data of previous metaanalyses on the treatment of chronic HCV infection in HD patients. Despite the introduction of more potent drugs and combination therapies of HCV infection in dialysis patients, IFN monotherapy is still considered a very effective therapeutic option in patients on maintenance dialysis. Conventional IFN monotherapy at a dose of 1-6 MU daily or three times per week for 12-48 weeks has been associated with SVR rates of 20-71% in dialysis patients. ,,, The predictive factors of SVR in these patients include a low baseline HCV-RNA level, mild liver histology and treating patients by IFN at a dose of 3 MU for at least six months., Previous review articles have excellently included articles published earlier on the efficacy and safety of IFN monotherapy for chronic HCV infection in dialysis patients.  In our review, we only found one more article published recently to add. Fucuta Pereira Pda et al,  evaluating 40 HD patients, reported septal fibrosis or cirrhosis in 38% of patients. HCV-RNA was undetectable at Week 12 in 68% and SVR was observed in 30% of patients.
Table 1: Meta-analyses investigating efficacy of chronic HCV treatment in dialysis patients.
Peg-IFN has also been extensively used to treat chronic HCV infection in HD patients. Among recent studies, Kose et al.  investigated the largest patient population. PEG-IFN-α-2a 135 mcg/week was given for 48 weeks, which was administered in 41 patients, of whom 38 completed the study. Virological response rates for Weeks 12 and 72 were 60% and 50%, respectively. Furthermore, Alsaran et al. treated 13 patients with PEG-IFN for 48 weeks, with no drop-out. After 24 weeks of therapy, 76% of patients responded to therapy and 24% of patients were resistant. Six months after termination of therapy, nine (69%) patients had SVR.  [Table 2] summarizes the recent studies investigating anti-HCV therapy in ESRD patients.
Table 2: Recent studies investigating treatment of HCV infection in dialysis patients.
Resistant Cases of Hepatitis C Virus-Infected Dialysis Patients to Interferon Therapy
Although treatment of HCV infection with IFN-based regimens in dialysis patients has been reportedly considered a safe and feasible method of therapy, many ESRD patients with HCV infection show resistance toward it. Intolerance to IFN due to its side-effects is the most significant cause of resistance to this therapy. There is a wide spectrum of side-effects associated with IFN therapy, which includes loss of appetite, fatigue, dry skin, influenzalike symptoms and gastrointestinal disturbances as well as neuropsychiatric symptoms and hematological abnormalities.  These side-effects often result in discontinuation or dose reduction of the drug, which can endanger viral response in HCV-infected dialysis patients. , The incidence of these side-effects can be as high as 30% in patients using PEG-IFN, with lower rates in those using standard IFN.  Data on the efficacy and safety of PEG-IFN in ESRD patients are more limited and future studies are required to extend our knowledge on this issue.
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