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Immunogenetic factors, HCV genotypes, and HCV recurrence after liver transplantation
Immunogenetic Factors, HCV Genotypes, and HCV Recurrence After Liver Transplantation L.S. Belli, C. Zavaglia, A.B. Alberti, G.F. Rondinara, L. De Carlis, E. Silini, F. Poli, M. Scalamogna, C. Tinelli, D. Forti, and G. Ideo
H
EPATITIS C virus is well documented to recur in the majority of patients with pretransplant infection and also to cause histologically proven hepatitis in about 40% to 65% of viremic patients within the first year. Factors such as genotype (particularly genotype 1b), type and amount of immunosuppression, and steroid pulses have been proposed as important determinants of progressive posttransplant liver disease. Yet the role played by host immune reactions has rarely been addressed. Since HLA-DRB1*11 has been associated with less advanced liver disease in nontransplant patients with chronic hepatitis C,1,2 we have investigated the distribution of HLA-DRB1*11 alleles in 89 HCV-positive liver transplant recipients and their possible association with the frequency, timing, and progression of recurrent disease. In addition, the role of other factors such as HLA match between donor and recipient, HCV genotype, and number of steroid pulses was also evaluated. METHODS Eighty-nine patients with HCV-related cirrhosis and surviving at least 3 months after grafting were analyzed in the present study. The median follow-up time was 44 months (range 6 to 115 months). HLA-DNA typing for HLA-DRB1 antigens was performed by the PCR-SSO. All patients underwent liver biopsies at least at yearly intervals. Immunosuppression consisted of quadruple drug induction (antithymocyte globulins, CsA, steroids, and azathioprine) followed by early CsA monotherapy (between 1 and 3 months after grafting). Kaplan–Meier analysis and chi-square tests were used when indicated.
RESULTS
Recurrent hepatitis was observed in 45 patients (45 of 89 5 51%) and the diagnosis of recurrent hepatitis was performed within 6 months of transplant in most cases (32 of 45 5 71%). Overall, ten patients progressed to stages 3 or 4 within the observation period. Of these 10 patients, 3 died of end-stage liver disease and 1 was successfully retransplanted. After Kaplan–Meier analysis, patients carrying the HLADRB1*11 (subtype 1104) allele showed significantly less recurrent hepatitis when compared with patients who were negative for the same antigen (P 5 .048). In addition, none of the 10 patients with the more severe forms of recurrent © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
Fig 1. HLA-DRB1 mismatch. Kaplan–Meier analysis concerning time to recurrent hepatitis.
hepatitis (stages 3 or 4) was HLA-DRB1*11 positive. Patients mismatched for both alleles at the DRB1 locus showed a significantly higher disease recurrence rate when compared with patients having either one or zero mismatches (P 5 .00019) (Fig 1). HCV genotype 1b and steroid pulses for acute rejection episodes were not significant risk factors for disease recurrence. DISCUSSION
Our findings suggest that HLA-DRB1*11 antigens confer protection from HCV disease recurrence after liver transplantation. Indeed, liver graft recipients carrying HLADRB1*11 (subtype 1104) developed significantly fewer cases of recurrent hepatitis than patients with different HLA-DRB1 alleles. In addition, the few patients with recurrent disease, despite their HLA-DRB1*11 background, had a particularly benign course over the years. It is clearly difficult to understand why these HLA-DRB1*11positive patients who have reached the end stage of their HCV-related liver disease before grafting. Nevertheless this From the Liver Transplantation Unit, Niguarda Hospital, Milan, Italy (L.S.B., C.Z., A.B.A., G.F.R., L.D.C., D.F., G.I.); Department of Pathology and Statistics, IRCCS Policlinico San Matteo, Pavia, Italy (E.S., C.T.); and Center for Transplant Immunology, IRCCS Ospedale Policlinico, Milan, Italy (F.P., M.S.). Address reprint requests to Dr. L.S. Belli, Ospedale San Giuseppe, Medicina IV Piano, Via San Vitiore, 201000 Milan, Italy. 0041-1345/98/$–see front matter PII S0041-1345(98)01719-9 483
Transplantation Proceedings, 31, 483–484 (1998)
484
observation might have some practical consequences in our geographic area where the prevalence of this allele is very high being encountered in almost 50% of healthy individuals and in 25% of our liver transplant candidates. It might in fact allow for identification of a subgroup of HCVpositive recipients that will benefit most from liver grafting. Even more striking is evidence that complete HLA mismatch at the DRB1 locus seems to be a strong risk factor for disease recurrence. Although the relationship between HLA mismatch and recurrent hepatitis has already been addressed by other investigators,3 our finding showing such a strong correlation between HLA-DRB1 mismatch and recurrent hepatitis has not yet been reported. Certainly, there are some elements that can justify these discrepancies at least in part, including the methodology used for HLA-DR typing. Gane and coworkers utilized a
BELLI, ZAVAGLIA, ALBERTI ET AL
combination of serologic and DNA-based techniques, whereas, in our study, DNA typing was available to all patients. Another element pertains to population characteristics. Patients analyzed in the aforementioned study differed in regard to ethnic origin and HCV genotype prevalence. Finally, our immunosuppression protocol, characterized by early corticosteroid withdrawal, may have influenced the expression of recurrent disease.
REFERENCES 1. Zavaglia C, Belli LS, Alberti A, et al: Am J Gastroenterol 92:725, 1997 2. Zavaglia C, Martinetti M, Silini E, et al: J Hepatol 28:1, 1998 3. Gane EJ, Portman BC, Naoumov NV, et al: N Engl J Med 334:815, 1996
H
EPATITIS C virus is well documented to recur in the majority of patients with pretransplant infection and also to cause histologically proven hepatitis in about 40% to 65% of viremic patients within the first year. Factors such as genotype (particularly genotype 1b), type and amount of immunosuppression, and steroid pulses have been proposed as important determinants of progressive posttransplant liver disease. Yet the role played by host immune reactions has rarely been addressed. Since HLA-DRB1*11 has been associated with less advanced liver disease in nontransplant patients with chronic hepatitis C,1,2 we have investigated the distribution of HLA-DRB1*11 alleles in 89 HCV-positive liver transplant recipients and their possible association with the frequency, timing, and progression of recurrent disease. In addition, the role of other factors such as HLA match between donor and recipient, HCV genotype, and number of steroid pulses was also evaluated. METHODS Eighty-nine patients with HCV-related cirrhosis and surviving at least 3 months after grafting were analyzed in the present study. The median follow-up time was 44 months (range 6 to 115 months). HLA-DNA typing for HLA-DRB1 antigens was performed by the PCR-SSO. All patients underwent liver biopsies at least at yearly intervals. Immunosuppression consisted of quadruple drug induction (antithymocyte globulins, CsA, steroids, and azathioprine) followed by early CsA monotherapy (between 1 and 3 months after grafting). Kaplan–Meier analysis and chi-square tests were used when indicated.
RESULTS
Recurrent hepatitis was observed in 45 patients (45 of 89 5 51%) and the diagnosis of recurrent hepatitis was performed within 6 months of transplant in most cases (32 of 45 5 71%). Overall, ten patients progressed to stages 3 or 4 within the observation period. Of these 10 patients, 3 died of end-stage liver disease and 1 was successfully retransplanted. After Kaplan–Meier analysis, patients carrying the HLADRB1*11 (subtype 1104) allele showed significantly less recurrent hepatitis when compared with patients who were negative for the same antigen (P 5 .048). In addition, none of the 10 patients with the more severe forms of recurrent © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
Fig 1. HLA-DRB1 mismatch. Kaplan–Meier analysis concerning time to recurrent hepatitis.
hepatitis (stages 3 or 4) was HLA-DRB1*11 positive. Patients mismatched for both alleles at the DRB1 locus showed a significantly higher disease recurrence rate when compared with patients having either one or zero mismatches (P 5 .00019) (Fig 1). HCV genotype 1b and steroid pulses for acute rejection episodes were not significant risk factors for disease recurrence. DISCUSSION
Our findings suggest that HLA-DRB1*11 antigens confer protection from HCV disease recurrence after liver transplantation. Indeed, liver graft recipients carrying HLADRB1*11 (subtype 1104) developed significantly fewer cases of recurrent hepatitis than patients with different HLA-DRB1 alleles. In addition, the few patients with recurrent disease, despite their HLA-DRB1*11 background, had a particularly benign course over the years. It is clearly difficult to understand why these HLA-DRB1*11positive patients who have reached the end stage of their HCV-related liver disease before grafting. Nevertheless this From the Liver Transplantation Unit, Niguarda Hospital, Milan, Italy (L.S.B., C.Z., A.B.A., G.F.R., L.D.C., D.F., G.I.); Department of Pathology and Statistics, IRCCS Policlinico San Matteo, Pavia, Italy (E.S., C.T.); and Center for Transplant Immunology, IRCCS Ospedale Policlinico, Milan, Italy (F.P., M.S.). Address reprint requests to Dr. L.S. Belli, Ospedale San Giuseppe, Medicina IV Piano, Via San Vitiore, 201000 Milan, Italy. 0041-1345/98/$–see front matter PII S0041-1345(98)01719-9 483
Transplantation Proceedings, 31, 483–484 (1998)
484
observation might have some practical consequences in our geographic area where the prevalence of this allele is very high being encountered in almost 50% of healthy individuals and in 25% of our liver transplant candidates. It might in fact allow for identification of a subgroup of HCVpositive recipients that will benefit most from liver grafting. Even more striking is evidence that complete HLA mismatch at the DRB1 locus seems to be a strong risk factor for disease recurrence. Although the relationship between HLA mismatch and recurrent hepatitis has already been addressed by other investigators,3 our finding showing such a strong correlation between HLA-DRB1 mismatch and recurrent hepatitis has not yet been reported. Certainly, there are some elements that can justify these discrepancies at least in part, including the methodology used for HLA-DR typing. Gane and coworkers utilized a
BELLI, ZAVAGLIA, ALBERTI ET AL
combination of serologic and DNA-based techniques, whereas, in our study, DNA typing was available to all patients. Another element pertains to population characteristics. Patients analyzed in the aforementioned study differed in regard to ethnic origin and HCV genotype prevalence. Finally, our immunosuppression protocol, characterized by early corticosteroid withdrawal, may have influenced the expression of recurrent disease.
REFERENCES 1. Zavaglia C, Belli LS, Alberti A, et al: Am J Gastroenterol 92:725, 1997 2. Zavaglia C, Martinetti M, Silini E, et al: J Hepatol 28:1, 1998 3. Gane EJ, Portman BC, Naoumov NV, et al: N Engl J Med 334:815, 1996