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NDT Advance Access originally published online on January 3, 2006
Nephrology Dialysis Transplantation 2006 21(4):1046-1052; doi:10.1093/ndt/gfk023
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Does hepatitis C virus affect the reactivation of hepatitis B virus following renal transplantation?

Tzung-Hai Yen1,4, Chiu-Ching Huang3, Hsin-Hung Lin3, Jeng-Yi Huang1, Ya-Chun Tian1, Chih-Wei Yang1, Mai-Szu Wu1, Ji-Tseng Fang1, Chun-Chen Yu1, Yang-Jen Chiang2 and Sheng-Hsieh Chu2

1 Department of Nephrology and 2 Department of Urology, Chang Gung Memorial Hospital, Taipei, 3 Department of Medicine, China Medical University Hospital, Taichung, Taiwan and 4 Histopathology Unit, Cancer Research UK, London Research Institute, London, UK

Correspondence and offprint requests to: Chiu-Ching Huang, MD, Department of Medicine, China Medical University Hospital, No 2, Yuh-Der Road, Taichung 404, Taiwan. Email: cch{at}www.cmuh.org.tw



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Hepatitis B virus (HBV) is endemic in Taiwan. Transplantation followed by long-term immunosuppressive medications may precipitate HBV reactivation. Interference of hepatitis C virus (HCV) with HBV gene expression and replication has been confirmed in many studies involving non-transplant populations. This study investigates the incidence of HBV reactivation following renal transplantation and compares the clinical outcome, especially the liver outcome, of patients with or without HCV co-infection.

Methods. Fifty-one of 512 renal transplant recipients were positive for hepatitis B surface antigen before surgery, and were followed for 81.6±7.5 (4–120) months. Seventeen of 51 patients acquired HCV before transplantation and six patients acquired HCV after renal transplantation.

Results. At the end of this assessment, we had 28 patients who suffered HBV reactivation and another 23 patients who suffered no HBV reactivation. Initially, we found a significant difference of HCV carriage (P<0.05) between patients with (seven out of 28 or 25%) or without (21 out of 23 or 91.3%) HBV reactivation. Further inspection showed that 21 of the 28 patients without HCV co-infection and seven of the 23 patients with HCV co-infection suffered HBV reactivation. After comparison, we found a lower incidence of HBV reactivation in patients with HCV co-infection than in patients without HCV co-infection (P<0.05). In contrast to the latter, we found that patients with HCV co-infection suffering HBV reactivation tended to have a late onset of HBV reactivation (P<0.05). Otherwise, there was no difference in hepatitis severity, in terms of peak alanine aminotransferase, total bilirubin levels and hepatitis reactivation-related death, between these two groups of patients. Finally, a multivariable analysis also revealed that HCV carriage was indeed an independent variable leading to the reduced incidence of HBV reactivation in patients with HCV co-infection.

Conclusion. HCV might affect the reactivation of HBV by decreasing the incidence or delaying the onset of HBV reactivation in renal transplant recipients carrying both HBV and HCV.

Keywords: co-infection; HBV; HCV; reactivation; renal transplantation



   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Both hepatitis B virus (HBV) and hepatitis C virus (HCV) are common pathogens that cause chronic hepatitis in patients with end-stage renal disease. HBV is endemic in Taiwan: the carrier rate of hepatitis B surface antigen (HBsAg) in the general population is ~15–20%. Consequently, numerous Taiwanese dialysis patients are also chronic carriers of HBV. The prevalence of anti-HCV in haemodialysis patients varies dramatically, ranging from 5 to >50%. The annual seroconversion rate of the HCV antibody is ~15% for Taiwanese dialysis patients [1]. Since HBV and HCV utilize the same transmission routes, co-infection may occur and even persist in the same patient. Transplantation, followed by long-term immunosuppressive drug therapy, is often associated with HBV reactivation. Our previous study of anti-HCV-positive renal transplant recipients revealed that co-infection of HBV and HCV may cause aggressive liver disease and cirrhosis; HCV infection alone has a more benign clinical outcome [2]. Our recent data also revealed that patients with anti-HCV antibody had a higher incidence of chronic hepatitis, chronic allograft dysfunction and post-transplantation nephrotic syndrome. Long-term graft survival was low. However, patients with anti-HCV antibodies had better patient survival compared with patients without HCV over 15 years of follow-up. Patients with anti-HCV antibodies without clinical chronic hepatitis were associated with the longest patient survival [3]. Nevertheless, a further question remains unanswered: does HCV affect the reactivation of HBV following renal transplantation? This question regarding viral interference between HBV and HCV following transplantation and long-term immunosuppression is the focus of this investigation.

This study examines the incidence of HBV reactivation following renal transplantation and compares the differences in clinical outcome, especially liver outcome, between patients with or without HCV co-infection. The response to viral suppression therapy with lamivudine, in conjunction with HBV genotypic resistance, was also investigated.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Hospital records of all renal transplant recipients at Chang Gung Memorial Hospital, Taiwan, were reviewed. The follow-up status for each case was obtained from out-patient clinics. From December 1984 to December 2002, 512 uraemic patients on maintenance dialysis underwent renal transplantation. Fifty-one of 512 patients were positive for HBsAg prior to surgery and were followed for a period of 81.6±7.5 (range 4–120) months. All 51 patients have their sera collected prospectively every 3 months and tested for liver function, hepatitis B serological markers, HBV DNA and anti-HCV antibody. HCV RNA was tested whenever necessary. We did not routinely perform HCV genotyping. Seventeen of 51 patients acquired HCV before transplantation and six patients acquired HCV after renal transplantation. At the end of the assessment, we had 28 patients who suffered HBV reactivation and another 23 patients who suffered no HBV reactivation.

Immunosuppressive protocol
All patients, except for two patients who underwent transplantation before the availability of cyclosporin, were on a cyclosporin-based dual regimen (cyclosporin and prednisolone). The maintenance trough serum cyclosporin levels were kept between 75 and 150 ng/ml. The two patients, one from the group of patients without HCV co-infection and the other from the group of patients with HCV co-infection, were prescribed an azathioprine-based regimen (azathioprine, 2 mg/kg/day and prednisolone). Patients with the initial cyclosporin medication received the same cyclosporin maintenance immunosuppressive medication throughout. Likewise, patients with the initial azathioprine medication continued to receive the same azathioprine maintenance immunosuppressive medication. No patient received induction therapy with anti-lymphocyte globulin, anti-thymocyte globulin, OKT3 or interleukin-2 receptor blocker. Acute rejection was treated with methylprednisolone 0.5 g every 12 h intravenously for 3 days.

Definition of clinical events
Hepatitis was defined as a ≥2-fold increase in alanine aminotransferase (ALT), which exceeds the normal upper limit [2]. HBV reactivation was defined as (i) progressive increment of the serum HBV DNA level to >2.83 x 108 copies/ml (1000 pg/ml) in patients with normal ALT levels or (ii) HBV DNA level >2.83 x 107 copies/ml (100 pg/ml) in patients with increased ALT levels and/or a liver biopsy specimen showing significant hepatitis and in the absence of other systemic infections. Severe hepatitis with hepatic decompensation was defined as a clinical syndrome comprising both of the following features: (i) obvious constitutional symptoms with jaundice and (ii) blood coagulation disorders, such as prolonged prothrombin time (>3 s) with or without ascites [4]. Hepatic failure was defined as severe hepatitis associated with hepatic encephalopathy [4]. HBV reactivation with hepatic failure was defined as the combination of clinical findings of HBV reactivation and hepatic failure. HCV reactivation was defined as increased ALT levels with detectable HCV RNA but with the absence of HBV DNA in patients’ sera. Fibrosing cholestatic hepatitis was diagnosed according to Zylberberg et al. [5], which was characterized (i) clinically by a rapidly progressive hepatic failure, a mildly elevated serum ALT level and high HBV replication and (ii) pathologically by an extensive periportal fibrosis associated with marked cholestasis, a mild inflammatory cellular infiltrate and an absence of liver cirrhosis. Acute rejection was defined by as clinical diagnosis or with pathological evidence [2]. Graft failure was defined when either the recipient needed renal replacement therapy or when the recipient died with a functioning or non- functioning graft [2].

Hepatitis viral markers
The viral markers HBsAg, HBs antibody (anti-HBs), IgM anti-HBc, hepatitis B e antigen (HBeAg), HBe antibody (anti-HBe) and anti-hepatitis D virus (anti-HDV) were assayed using commercially available radioimmunoassay kits (Ausria II, Ausab, Corab M, HBeAg-RIA and anti-delta; Abbott Laboratories, Chicago, IL). Serum anti-HCV was assayed using a first- (before 1992), second- (1992 to 1998) or third- (after 1998) generation enzyme immunoassay (Ax SYM HCV III; Abbott Laboratories). Serum IgM anti-HDV was assayed using an enzyme immunoassay (Deltassay IgM; Cambridge Biotech Ltd, Dublin, Ireland). Serum HBV DNA was assayed using a hybrid-capture amplification assay with a detection sensitivity of 0.5 pg/ml (Digene HBV test, Hybrid Capture II; Digene Corp.). Serum HCV RNA was assayed with a combined RT–PCR assay (Amplicor HCV test; Roche Diagnostic System Inc., Branchburg, NJ); its detection sensitivity is 10–100 copies/ml.

Lamivudine treatment
Lamivudine therapy, 100 mg/day orally, was prescribed on a rescue-only basis, i.e. as soon as possible after detection of HBV reactivation. The effects of lamivudine treatment on serum HBV DNA suppression, ALT normalization and HBeAg seroconversion were monitored regularly. The emergence of tyrosine–methionine–aspartate–aspartate mutant HBV and its effect were also determined if necessary. Lamivudine was maintained as long as the patient was on an immunosuppressive regimen. No patients received lamivudine treatment on a prophylactic basis.

Statistical analysis
Data were expressed as mean±SEM unless otherwise stated. All statistical analyses were performed using SPSS 11.0 for Mac OSx (SPSS Inc., Chicago, IL). Data were routinely tested for normality of distribution and equality of SDs before running the analysis. For comparison of the different variables between patients with or without HCV co-infection, we used the Student's t-test for quantitative variables and {chi}2 or Fisher exact test for categorical variables. The cumulative incidence of patient and graft survival was calculated with the Kaplan–Meier method, and the difference was determined by the log rank test. Since there was a significant difference in ‘age’ between patients with or without HCV co-infection, we therefore performed a multivariable analysis (via binary logistic regression) for patients with or without HBV reactivation, aiming to investigate whether HCV carriage was indeed an independent variable leading to the reduced incidence of HBV reactivation. The criterion for significance was the 95% confidence interval (CI) to reject the null hypothesis.



   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Comparison of patients with or without HBV reactivation
At the end of this assessment, we had 28 patients who had HBV reactivation and 23 patients who had no HBV reactivation (Table 1). None of the 51 HBV-positive patients had circulating HBV DNA at transplantation. After analysis (taking HBV reactivation as a dependent variable), we did not find any significant difference in independent variables for age of transplantation, gender, duration of dialysis, times of transplantation, types of donor, pre-transplant liver functions, pre-transplant HBV markers, pre-transplant HDV marker, pre-transplant liver ultrasound and immunosuppressive regimen. However, we found a significant difference in HCV carriage (P<0.05) between patients with (seven out of 28 or 25%) or without (21 out of 23 or 91.3%) HBV reactivation.


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  		Table 1. Comparison of patients with or without HBV reactivation

 
Comparison of patients with or without HCV co-infection
Using the same baseline variables, we tried to compare patients with or without HCV co-infection (Table 2). We found that patients with HCV co-infection tended to be older. Otherwise, they did not differ much from patients without HCV co-infection in terms of age of transplantation, gender, duration of dialysis, number of transplantations, type of donor, pre-transplant liver functions, pre-transplant HBV markers, pre-transplant HDV marker, pre-transplant liver ultrasound and immunosuppressive regimen.


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  		Table 2. Comparison of patients with or without HCV co-infection

 
Comparison of general outcome of patients with or without HCV co-infection
We did not find any significant differences (all P>0.05) in general outcomes, for example proportions of patients with and without acute rejection or corticosteroid-resistant acute rejection, patient death and graft failure (Table 3, Figure 1).


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  		Table 3. Comparison of general outcome of patients with or without HCV co-infection

 

Figure 1
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  		Fig. 1. The results of log rank comparisons of patient (A) and graft (B) survival curves for patients with (HBV+/HCV+) and without HCV (HBV+/HCV–) co-infection. There were no significant differences (both P>0.05) between these two groups.

 
Comparison of liver outcome of patients with or without HCV co-infection
Table 4 summarizes the results. Twenty-one of the 28 patients without HCV co-infection developed HBV reactivation after transplantation. Seven of the 28 patients developed HBV reactivation causing acute exacerbation with hepatic failure, and three of these were prescribed lamivudine therapy immediately after detection of HBV reactivation. However, six of these seven patients still died of hepatic failure. Liver biopsies performed in one surviving patient revealed fibrosing cholestatic hepatitis. The other six patients did not undergo a liver biopsy due to prolonged bleeding time during hepatic failure. Fourteen of the 28 patients without HCV co-infection experienced HBV reactivation causing acute hepatitis without hepatic failure. Ten of these 14 patients were prescribed lamivudine therapy; lamivudine was not administered to four patients because of financial problems in one case and normal ALT levels in the other three cases. All 14 patients enjoyed a full recovery. Furthermore, seven of the 28 patients without HCV co-infection had no HBV reactivation. Taken together, reactivation of HBV developed 20.2±5.5 months after transplantation, inducing peak ALT levels of 216.5±42.7 IU/l and peak total bilirubin levels of 9.8±3.0 mg/dl. Liver biopsies were performed in eight patients—four showed minimal hepatitis, three displayed chronic lobular hepatitis and one exhibited fibrosing cholestatic hepatitis (Figure 2).


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  		Table 4. Comparison of liver outcome of patients with or without HCV co-infection

 

Figure 2
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  		Fig. 2. Sections of liver biopsies (H&E stain, left; HBsAg stain, middle; and HBcAg stain, right) of patient Wu, one of the 28 patients without HCV co-infection who developed fibrosing cholestatic hepatitis. This patient survived after rescue therapy with lamivudine.

 
Seven of the 23 patients with HCV co-infection displayed HBV reactivation causing acute hepatitis. One of these seven patients suffered fulminant hepatic failure and died of hepatic complications; the remaining six showed HBV reactivation but recovered following supportive care. At follow-up, two of these six patients displayed hepatoma—one died of hepatoma with distant bone metastasis and the other had a small hepatoma and survived following a hepatectomy. Lamivudine therapy was prescribed for four of the seven patients after HBV reactivation was detected; three did not receive lamivudine because this drug was unavailable at the hospital upon their admission. Conversely, three of 23 patients with HCV co-infection developed HCV reactivation rather than HBV reactivation. Reactivation of HCV occurred at 33 months after renal transplantation in one case, and at 30 and 145 months in the other two cases. The HCV RNA was positive in these three patients. Notably, the liver function tests were only minimally abnormal in these three patients: ALT levels were 52, 46 and 95 IU/l, respectively. All three achieved full recovery following supportive medications. Thirteen out of the 23 patients with HCV co-infection experienced neither HBV nor HCV reactivation. Taken together, reactivation of HBV developed 86.9±36.5 months after transplantation, inducing peak ALT levels of 196.7±56.3 IU/l and peak total bilirubin levels of 6.5±3.4 mg/dl. Post-mortem liver necropsy in one patient who died of hepatic failure revealed fibrosing cholestatic hepatitis. Liver biopsies were performed in two patients, revealing chronic active hepatitis with bridging necrosis.

In summary, we found a lower incidence of HBV reactivation in patients with HCV co-infection than without HCV co-infection (P<0.05). In contrast to patients without HCV co-infection, we found that patients with HCV co-infection suffering HBV reactivation tended to have a late onset of HBV reactivation (P<0.05). Otherwise, there was no difference in hepatitis severity, in terms of peak ALT and total bilirubin levels, and hepatitis reactivation-related death between these two groups of patients (P>0.05).

Multivariable analysis of independent variables leading to the reduced incidence of HBV reactivation in patients with HCV co-infection
Using anti-HCV, age of transplantation (<35, 35–55 and >55), gender (male/female), number of transplantations (first/second), type of donor (cadaver/living), liver function tests (normal/abnormal), liver ultrasound (normal to mild/moderate to severe parenchymal change), anti-HDV, immunosuppressive medications (cyclosporin-/azathioprine-based regimen) as independent variables and HBV reactivation as the dependent variable, we then performed a multivariable analysis (via binary logistic regression) to investigate whether HCV carriage was indeed an independent variable leading to the reduced incidence of HBV reactivation in patients with HCV co-infection. We found that HCV is the only independent variable which appears in the logistic regression equation. The results showed Omnibus tests of model coefficients: {chi}2 = 10.452, at 1 df, P = 0.001. The model summary showed –2 log likelihood = 59.758, Cox and Snell R2 = 0.185, Nagelkerke R2 = 0.248. The variables in the equation were B = 0.963, SE = 0.315, Wald = 9.364, at 1 df, P = 0.002, eB = 2.619. All the other independent variables have P>0.05 and do not appear in the logistic regression equation, thus supporting our argument that HCV was responsible for the reduced incidence of HBV reactivation in our study.



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Our data suggested that the influence of HCV on the natural history of HBV reactivation was to decrease the incidence and delay the onset of HBV reactivation in renal transplant recipients carrying both HBV and HCV.

Several mechanisms could account for HBV reactivation after kidney transplantation and long-term immunosuppressive therapy. First, immunosuppressed patients may be more susceptible to HBV reactivation because immunosuppressive drugs impair the T- and B-cell functions essential in controlling HBV infections [6]. Another possible mechanism producing hepatocellular injury was the direct cytopathic effect of HBV, resulting from accelerated viral replication, which leads to hepatocyte lysis. This has been suggested in fibrosing cholestatic hepatitis following organ transplantation. A previous study showed that high-level accumulation of intracellular large surface antigen was extremely cytotoxic to hepatocytes in experimental animal models [7]. Furthermore, HBV DNA contains a glucocorticoid-responsive element, which enhances viral replication [8]. Administration of corticosteroids may therefore directly or indirectly lead to accelerated HBV replication with induction of hepatocyte injury.

Interference of HCV with HBV gene expression and replication has been investigated in many studies involving the non-transplant population. The general consensus is that concurrent HCV and HBV infections are associated with a fulminant course of acute hepatitis [9], with more severe forms leading to rapid progression of chronic liver disease [10]. Conversely, and most importantly, some researchers have reported that HCV may exert an inhibitory effect on HBV [11–16].

Fattovich et al. evaluated 184 HBsAg patients with chronic hepatitis for anti-HCV and identified a subgroup with anti-HBe-positive, HBV DNA-negative, HDV-negative chronic hepatitis B, in which HCV is a primary factor in the development of liver disease [11]. Pontisso et al. investigated HBV and HCV genomic sequences in the serum and liver of 55 patients with chronic liver disease who were positive for anti-HCV and HBV markers. They found a reciprocal inverse relationship between HBV and HCV replication; patients with HCV and HBV antibodies typically have no HBV DNA persistence in the liver [12]. Their subsequent evaluation on the genotype of HCV in 34 consecutive cases with positive HBsAg and anti-HCV in their serum also showed that HCV-1 inhibited HBV replication more efficiently than HCV-2. Cirrhosis was frequently found in patients with dual HBV and HCV-2 infection [15]. Sato et al. investigated 82 chronic HBsAg carriers and demonstrated that hepatitis C virus was the primary cause of active hepatitis in most patients with HBV and HCV co-infection [13].

Liaw et al., at Chang Gung Memorial Hospital, Taiwan compared 41 patients with persistent ALT elevation (hepatitis group) and 82 age- and sex-matched patients with normal ALT (control group) after HBsAg clearance. They found that HCV might usurp the role of HBV in chronic hepatitis and become the primary cause of continuing hepatitis or ALT elevation after HBV/HBsAg clearance [14]. Chu et al., in evaluating assays of HBV replication and antigen expression in HBsAg carriers with concurrent HCV or HDV infection, also revealed that HCV and HDV suppressed HBV replication, but that HCV also substantially suppressed HBV surface protein expression. Carriers of HBsAg with concurrent HCV infection therefore have low-level viraemia and intracellular HBsAg [16]. In a follow-up study, Liaw et al. compared the clinical features of acute and long-term outcomes of acute HCV superinfection with a cohort of acute HDV superinfection and a matched active chronic hepatitis B control group. They concluded that acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase. The long-term prognosis following acute HCV superinfection is much worse than that following HDV superinfection or active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or hepatocellular carcinoma [4].

In contrast, most researchers agree that for the renal transplant population, concurrent HBV and HCV infection might lead to aggressive liver disease and cirrhosis [2,17–20]. There has been no literature report of any similar inhibition of HCV over HBV after renal transplantation, as is common in the non-transplant population. This study is the first to point out this fact.

None of the 51 patients had circulating HBV DNA at transplantation. In this hospital, we always choose not to perform renal transplantation in patients with active HBV replication. This practice aims to avoid the catastrophic complications of fulminant hepatitis following transplantation and long-term immunosuppressive medications. However, we are not certain if the absence of active HBV replication at transplantation could explain the influence of inhibition of HCV over HBV in this study.

In summary, we observed a decrease in the incidence and a delayed onset of HBV reactivation in renal transplant recipients carrying both HBV and HCV. However, the retrospective nature of the study, small patient population, absence of a protocol liver biopsy in the pre-transplant and post-transplant periods, the small number of liver biopsies and a relatively short follow-up period after transplantation limit the certainty of our conclusion. As HBV is endemic in Taiwan, we try to extrapolate the experience gained from the non-transplant population to our renal transplant recipients and aim to check if there is any similar viral interaction in our study population. We suggest larger and longer observation in the future to delineate the complex interactions between HCV, HBV and long-term immunosuppressive medications following renal transplantation.



   Acknowledgments
 
We are indebted to the following individuals at Cancer Research UK, London, UK: Professor Richard Poulsom and Professor Robert Goodlad for their critical comments, Dr Sharan Love for the statistical advice and Mr Denis Alférez and Miss Nikki Mandir for helping with preparation of the manuscript.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Huang CC. Hepatitis in patients with end-stage renal disease. J Gastroenterol Hepatol 1997; 12: S236–S241[Medline]
  2. Huang CC, Liaw YF, Lai MK, Chu SH, Chuang CK, Huang JY. The clinical outcome of hepatitis C virus antibody-positive renal allograft recipients. Transplantation 1992; 53: 763–765[Medline]
  3. Lin HH, Huang CC, Huang JY et al. Impact of HCV infection on first cadaveric renal transplantation, a single center experience. Clin Transplant 2004; 18: 261–266[CrossRef][Medline]
  4. Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 2004; 126: 1024–1029[Medline]
  5. Zylberberg H, Carnot F, Mamzer MF, Blancho G, Legendre C, Pol S. Hepatitis C virus-related fibrosing cholestatic hepatitis after renal transplantation. Transplantation 1997; 63: 158–160[Medline]
  6. Milich DR. T- and B-cell recognition of hepatitis B viral antigens. Immunol Today 1988; 9: 380–386.[CrossRef][Medline]
  7. Chisari FV, Filippi P, Buras J et al. Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci USA 1987; 84: 6909–6913[Abstract/Free Full Text]
  8. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci USA 1986; 83: 1627–1631[Abstract/Free Full Text]
  9. Chu CM, Sheen IS, Liaw YF. The role of hepatitis C virus in fulminant viral hepatitis in an area with endemic hepatitis A and B. Gastroenterology 1994; 107: 189–195[Medline]
  10. Fong TL, Di Bisceglie AM, Waggoner JG, Banks SM, Hoofnagle JH. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology 1991; 14: 64–67[Medline]
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  12. Pontisso P, Ruvoletto MG, Fattovich G et al. Clinical and virological profiles in patients with multiple hepatitis virus infections. Gastroenterology 1993; 105: 1529–1533[Medline]
  13. Sato S, Fujiyama S, Tanaka M et al. Coinfection of hepatitis C virus in patients with chronic hepatitis B infection. J Hepatol 1994; 21: 159–166[CrossRef][Medline]
  14. Liaw YF, Tsai SL, Chang JJ et al. Displacement of hepatitis B virus by hepatitis C virus as the cause of continuing chronic hepatitis. Gastroenterology 1994; 106: 1048–1053[Medline]
  15. Pontisso P, Gerotto M, Ruvoletto MG et al. Hepatitis C genotypes in patients with dual hepatitis B and C virus infection. J Med Virol 1996; 48: 157–160[Medline]
  16. Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection. J Clin Microbiol 1998; 36: 2084–2086[Abstract/Free Full Text]
  17. Pouteil-Noble C, Tardy JC, Chossegros P et al. Co-infection by hepatitis B virus and hepatitis C virus in renal transplantation: morbidity and mortality in 1098 patients. Nephrol Dial Transplant 1995; 10 [Suppl 6]: 122–124
  18. Breitenfeldt MK, Rasenack J, Berthold H et al. Impact of hepatitis B and C on graft loss and mortality of patients after kidney transplantation. Clin Transplant 2002; 16: 130–136[CrossRef][Web of Science][Medline]
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Received for publication: 2. 3.05
Accepted in revised form: 5.12.05


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