The prevalence and significance of prior hepatitis B virus (HBV) infection in hepatitis C virus(HCV) cirrhosis

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AASLD ABSTRACTS

HEPATOLOGY October 2001

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HBV-COINFECTION AND ABSENCE OF HEPATOCELLULAR CARCINOMA (HCC) CORRELATE W I T H LOW MORTALITY IN HCV-POSIT1VE LIVER TRANSPLANTED PATIENTS, NO RELEVANCE OF ItLA-COMPATIBILITY. Hans L Tillmann, Andrea Berning-Haag, Angy Grundey, Heiner Wedemeier, Dongfeng Chen, Jens Rosenau, Uwe Tietge, Klaus H Boeker, Juergen Klempnauer, Christian Trautwein, Michael P Manns, Medizinische Hochschule Hannover, Hannover Germany

ROLE OF MYCOPHENOLATE MOFETIL IN RECURRENT HEPATITIS C VIRUS INFECTION AFTER LIVER TRANSPLANTATION. Ziv Ben-Ari, Liver Institute, Rabin Medical Center, Petah-Tikva Israel; Orit Papo, Department of Pathology, Rabin Medical Center, Petah-Tikva Israel;Jaqueline Sulkes, Epidemiology Unit, Rabin Medical Center, Petah-Tikva Israel; Eytan Mor, Department of Transplantation, Rabin Medical Center, Petah-Tikva Israel; Ran Tur-Kaspa, Liver Institute, Rabin Medical Center, Petah-Tikva Israel

Introduction: It has been shown that HLA-antigens are associated with different courses of hepatitis C infection in immunocompetent individuals. However, there are conflicting data on the impact of HLA-compatibility on the outcome of hepatitis C after liver transplantation (OLT). The aim of this study was to analyse the role of HLA-compatibility in relation to other possible confounding factors such as HBV-coinfection, presence of HCC, sex, HCV genotype, and liver function tests prior to OLT. Patients and Methods: 105 HCV-positive patients who underwent liver transplantation at Hannover Medical School were included. Follow up was 1 to 15 years after OLT. A hepatocellular carcinoma (HCC) was found in 30 explanted livers. HCV de novo infection occurred in 12 patients within the first three months after OLT. Survival was analysed by Kaplan-Meier and Cox regression. Results: Retransplantation was required in 24 patients, and 45 patients died. HLA-compatibility and the degree of mismatch had no influence on patient or graft-survival according to the Kaplan-Meier-analysis. The absence of HCC was associated with a much better outcome (p=0.0087), even though only 4 patients suffered from a recurrence of HCC. Surprisingly, HBV-coinfection was associated with better survival (p = 0.03), none of the eight HBV-coinfected patients died so far. Sex and HCV-genotype had no significant impact in our patients. Using univariate Cox s regression analysis for continues parameters such as liver function tests before OLT only revealed the level of albumin to be associated with graft survival (p=0.0052). Multiple regression analysis (including the parameters age, sex, presence of HCC, HCV de novo infection and HBsAg positivity, cholinesterase, ALT, bilirubin) showed a worse survival for patients with HCC (p=0.015), and better survival for patients with HCV de novo infection after transplantation ( n = 12, p=0.02) and absence of HCCs (p=0.015). Conclusion: HCV de novo infection, absence of HCC and HBV-coinfection are associated with a more benign course of HCV-positive liver transplanted patients, while HLA-compatibility is irrelevant for the survival of HCV positive patients after liver transplantation. The low mortality of HBV/HCV coinfected patients deserves further studies on viral interactions.

Background: Recurrent hepatitis C virus (HCV) infection after liver transplan-

tation is almost universal. The addition of mycophenolate mofetil to the standard induction immunosuppression following liver transplantation has been found to be safe and efficient in lowering the incidence of acute rejection. However, its effects on recurrent HCV posttransplantation remain unclear. Methods: Patients who underwent orthotopic liver transplantation for HCV infection ( n = 3 5 ) were included in the study. Group 1 (n=20) consisted of patients who received an immunosuppressive regimen of cydosporine/ tacrolimus-+prednisone-+azathioprine; group 2 ( n = 1 5 ) included patients who received mycophenolate mofetil (2.0 gr daffy orally), cyclosporine /tacrolimus-+prednisone. Recurrent HCV infection was defined as histologic lobular hepatitis, increased serum ALT level (xl.5 upper limit of normal) and detectable serum HCV RNA (by PCR). Results: Mean follow-up was 56.8--30.2 months for group 1 and 16.9-+14.9 months for group 2 (owing to the later introduction of mycophenolate mofetil). The rate of recurrent HCV infection was similar in the two groups (90% in group 1 vs. 80% in group 2), although time to recurrence was statistically significantly shorter in group 2 (mean 8.9-+2.5 months vs 16.7-+3.5 months in group 1, p <0.05). The recurrence rate was higher in the patients treated with cyclosporine (93%) compared to patients treated with taerolimus (72%) (p <0.03). There was no significant difference in the histological findings, presence of fibrosing cholestatic hepatitis, retransplantation, or death rate. No statistical significant correlation was found between the occurrence of acute rejection and the incidence and timing of recurrent HCV infection. Conclusions: The addition of myeophenolate mofetil to the immunosuppressive regimen in patients with recurrent HCV infection after liver transplantation is associated with a shorter time to recurrence, but there is no difference in outcome.

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ELEVATED AFP LEVELS IN PATIENTS UNDERGOING LIVER TRANSPLANTATION FOR HEPATITIS C CIRRHOSIS IN THE ABSENCE OF ItEPATOCELLULAR CARCINOMA. S H Sigal, S Merati, D A Robinson, M T Carrera, L Munoz, M L Schilsky, T D Schiano, S L Friedman, H C Bodenheimer, Jr., M E Schwartz, S N Thung, R Saxena, Depts of Medicine, Pathology, and Surgery, Recanati/Miller Transplantation Inst, Mt Sinai Medical Ctr, New York City, NY

THE PREVALENCE AND SIGNIFICANCE OF PRIOR HEPATITIS B VIRUS (HBV) INFECTION IN HEPATITIS C VIRUS(HCV) CIRRHOSIS. Kirti Shetty, Peter Kim, Carol A Bodian, Thomas D Schiano, Henry C Bodenheimer Jr., Albert D Min, Mount Sinai School of Medicine, New York, NY

Hepatocellular carcinoma (HCC) commonly complicates hepatitis C (HCV) cirrhosis. To screen for early and potentially treatable lesions, AFP levels are monitored. Elevated AFP levels ( > 2 0 ng/ml), however, may occasionally be observed in the absence of radiographically detectable tumor. The aim of this study is to assess the frequency and significance of elevated AFP levels in HCV cirrhosis in the absence of tumor. Methods: Patients undergoing liver transplantation (OLT) for HCV cirrhosis at Mt. Sinai Medical Center between January 1998 and June 2000 in whom HCC was excluded after review of the explanted livers were evaluated. Percent expected liver weight (weight/expected weight based on weight and height) was calculated, and histologic sections evaluated for severity of inflammation (interface hepatitis), ductular proliferation, and regeneration (2-cell thick plate basophilic hepatocytes) on a scale from 1 to 3. Clinical, biochemical and pathologic features of those with and without elevated AFP levels were compared. Results: Among 65 patients, AFP levels were normal in 55 (84.6%) (6.6+4.2; 1.5-13.9 ng/ml) and elevated in 10 (15.4%) (67.9+63.0; 20.7-185.3 ng/ml) at OLT. In those with normal values, 40 (72.7%) had normal levels (4.8+3.1 measurements) over 17.1 + 17.4 months. The other pa tients had eleva ted AFP levels on 42.2 + 24.3% of determinations (7.4 +3.1 measurements) over 26.4+ 15.6 months. In those with abnormal values, 6 (60%) had repeatedly abnormal but fluctuating levels (4.2+3.1 measurements) over 12.8+12.4 months. The other patients had elevated AFP levels on 51.3+24.6% of determinations (5.3+2.2 measurements) over 13.3+4.6 months. ALT levels (121.7+27.5 v 60.8+7.6 U/L, p=.006), AST levels (149.8+17.9 v 93.4+7.7 U/L, p=.005) and INR (2.20+.30 v 1.68+.07, p=.005) were higher in patients with elevated AFP levels compared to those with normal values at OLT. Age, other liver tests, CP score, % expected liver volume, and scores for interface hepatitis, ductular proliferation and regeneration were not different. Conclusions: Abnormal AFP levels in patients undergoing OLT for end-stage HCV cirrhosis without HCC are associated with elevated ALT and AST levels but not inflammation, ductular proliferation or regeneration. A subset of patients has repeatedly elevated but fluctuating AFP levels. The clinical and biologic significance of the elevated AFP level in this setting remains to be determined.

Prior infection with the hepatitis B virus (HBV) may be associated with persistence of HBV DNA in the serum or liver of affected individuals. This occult infection, defined as negative HBsAg, and positive hepatitis B core antibody (anti-HBc) occurs in approximately 33% of those with chronic hepatitis C virus (HCV). Anti-HBc appears to correlate well with the presence of HBV DNA in liver tissue. The complex interactions between prior HBV and concomitant HCV infections are still being elucidated. Preliminary studies suggest that HCV patients with occult HBV are more likely to develop cirrhosis, to be resistant to interferon treatment, and to develop hepatocellular carcinoma (HCC). However, much of the data regarding occult HBV is derived from regions of the world in which HBV is endemic. There is scant information available on the significance of prior HBV infection in HCV cirrhosis, encountered in a low-HBV prevalence area, such as the United States. Aims: Our aims were: (1) To assess the prevalence and risk factors for prior HBV infection, as defined by anti-HBc positivity, in patients with HCV cirrhosis undergoing liver transplantation(LT). (2) To examine the impact of previous HBV infection on patient survival, as well as on the development of HCC. Methods: We retrospectively studied all adult patients who had undergone a LT for HCV cirrhosis between 1988 and 1999, excluding those positive for HbsAg. Cases were defined as those with positive anti-HBc, and were compared to controls (anti-HBc negative) using chi square tests. Survival analysis was performed using a proportional hazards model. Results: A total of 601 patients were identified in our LT database as being HBsAg negative, and HCV antibody positive. Six patients were excluded due to lack of anti-HBc status. 313 patients (53%) were found to be anti-HBc positive. Cases were more likely to be male (61% vs 39%, p<0001), to have a history of intravenous drug use (79% vs 21%,p<0.001), and alcohol abuse (58% vs 42%, p<0.003). There were no significant differences between the two groups in terms of race, age, or history of previous blood transfusions..After adjusting for age and sex, no significant differences in survival were noted between the two groups. 26% of our patients had HCC on explant. However, there was no difference noted in the rate of HCC development between cases and controls (27% vs 25% respectively, p =NS). This study demonstrates a significant prevalence of previous HBV infection in HCV cirrhosis. Its overall impact is unclear, but may be enhanced in the immunosuppressed milieu of the post-transplant setting. Further prospective studies are required to fully elucidate its significance. Conclusions: (1) Prior HBV infection may be more prevalent in a US pre-transplant population with HCV cirrhosis, than previously believed. (2) Risk factors for prior HBV infection include male sex, intravenous drug use, and alcohol abuse. (3) In our large population with explant-proven HCC, prior HBV infection does not appear to confer an added risk of HCC development, in contrast to earlier studies.