C Blackwell Munksgaard 2004 Copyright
American Journal of Transplantation 2004; 4: 1375–1378 Blackwell Munksgaard
doi: 10.1111/j.1600-6143.2004.00504.x
Case Report
Severe Hepatitis C Infection in a Renal Transplant Recipient Following Hepatitis C Genotype Mismatch Transplant Thomas Schusslera , Catherine Staffeld-Coitb , James Easonc and Satheesh Naira,∗ Sections of a Hepatology, b Nephrology, and c Abdominal Organ Transplantation, Ochsner Clinic Foundation, New Orleans, LA ∗ Corresponding author: Satheesh Nair,
[email protected] We report a case of a 32-year-old female with histologically and clinically inactive chronic hepatic C infection, who received a cadaveric renal transplant from a hepatitis C-positive donor with a different genotype. The genotype mismatch (genotype 1 to genotype 2) and change to tacrolimus-based immunosuppression resulted in severe hepatitis C infection characterized by a 10-fold increase in transaminase levels and grade 3 inflammation histologically. Our report highlights the risk of genotype-mismatch transplants in solid organ transplantation. Key words: Hepatitis C genotype, renal transplant Received 8 December 2003, revised and accepted for publication 24 March 2004
Introduction Transmission of hepatitis C virus (HCV) infection via solid organ transplantation is well known. Several centers use healthy organs from HCV-positive donors to HCV-positive recipients to overcome the paucity of donor organs. Among six major genotypes of HCV worldwide, genotype 1 is the commonest type in the United States with nearly 75% prevalence (1). Because of the widespread prevalence of genotype 1, most HCV to HCV transplants are between genotype 1. While HCV to HCV transplantation is not considered unsafe, there are no known studies of the impact of genotype mismatch transplant. In this report we outline the course of recurrent HCV following a genotype-mismatch HCV transplant. This report is especially important because several large multicenter trails on antiviral treatment have highlighted the differences in therapeutic responses between genotype 1 and 2 (2).
Case Report A 32-year-old Caucasian female with a history of HCV infection for 15 years was referred to the hepatology clinic for abnormal liver function tests. She had acquired HCV in 1988, at the time of a living-related kidney transplant for focal segmental glomerulosclerosis. Her brother, who had a history of multiple blood transfusions and abnormal transaminases, was the donor. He was later diagnosed to have HCV once the tests for HCV became available. Three years after the initial transplant, she returned to peritoneal dialysis owing to allograft failure from chronic rejection. She was subsequently placed on the transplant waiting list. A serological screen at the time of listing revealed that she was HCV antibody positive. Her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were normal on multiple occasions. Three years into dialysis (6 years after the initial transplant) she underwent a cadaveric renal transplant from a non HCV donor. Her transaminase levels remained normal. After her second allograft developed recurrent disease, she was placed on the waiting list for a third transplant. As she had persistent HCV antibody, she underwent a liver biopsy in January 2002, which did not show any inflammation or fibrosis (Figure 1). Her hepatitis C viral load was 7.8 million copies/mL (bDNA assay). Genotype was 2a. Even at that time, her transaminase levels had remained normal. A decision was made not to treat owing to absence of significant biochemical or histological disease. In November 2002, she underwent a third cadaveric renal transplant from an HCV antibody-positive donor. The third kidney donor was a 34-year-old male who was HCVpositive. His AST and ALT were normal. The cause of death was related to a motor vehicle accident. The liver was used after a biopsy showed no significant disease, and the recipient of the liver was doing well clinically. The kidney transplant was a 4-antigen mismatch, and immunosupression was induced with steroids, tacrolimus, mycophenolate, and three doses of thymoglobulin. Immunosuppression based on four drugs was used owing to early graft loss in the two previous transplants. Clinically, she did well after the transplant with normalization of her renal function, but at 6 weeks ALT and AST levels started 1375
Schussler et al.
Figure 1: Histological examination of liver biopsy specimen 8 months before the most recent transplant showed expansion of the portal triad with lymphocytes (Grade 1) hepatitis and minimal steatosis. A trichrome stain was negative for fibrosis.
Figure 2: Histological examination of a liver biopsy specimen 9 months after the most recent transplant needle biopsy revealed nodular aggregates of lymphocytes and steatosis (H&E stain).
increasing. Her serum bilirubin was 1.2 mg/dL, albumin was 4.5 g/dL, and prothrombin time was 12.5 s (INR 1.1). HCV antibody and HCV RNA by PCR remained positive. HCV viral load was 157 000 IU/mL. However, her genotype at this time was genotype 1a as opposed to the genotype 2a detected a year earlier before the most recent transplant. Ultrasound examination of the liver was normal. As her transaminase levels remained elevated in the range of 400–500 IU/L for > 6 months after the latest transplant, a liver biopsy was performed. Her serum bilirubin at this time was 1.8 mg/dL, and serum albumin was 4.0 g/dL. Her HCV PCR was 3.8 million units/mL. In contrast to the prior biopsy, the present one showed significant hepatocyte dropout and swelling. The overall inflammation was grade 3 and fibrosis was stage 2 (Knodell scoring system) (Figures 2 and 3), suggesting a severe hepatitis C infection. Figure 4 depicts her transaminase levels over the last several years. Because of the severe nature of her HCV infection and the potential for rapid progression in the light of immunosuppression, treatment with pegylated interferon and ribavirin was contemplated. However, because of concern of precipitating allograft rejection and her prior history of rejection, it was finally decided not to offer the treatment. The patient is being weaned off prednisone and mycophenolate with a plan to maintain her on tacrolimus monotherapy. Her AST and ALT levels remain elevated at 400–500 IU/L. A repeat liver biopsy is planned for next year to assess the progression of the disease, and if significant fibrosis is seen, further treatment will be considered.
1376
Figure 3: Histological examination 9 months after the most recent transplant. The trichrome stain demonstrated portal fibrosis with early periportal extension. (Stage I fibrosis).
Discussion Abnormalities in transaminases are seen in 7–24% of all renal transplant recipients (3), and in one half of the cases liver disease has been attributed to HCV (3,4). In fact, liver failure is the cause of death in at least 8–28% of long-term survivors following renal transplant (3,4). It is a common practice in the United States to use HCV-positive donors for solid organ transplant and offer them to HCV-positive recipients. Although several reports have highlighted an
American Journal of Transplantation 2004; 4: 1375–1378
HCV Genotype Mismatch in Renal Transplantation 500 IU/L 450
HCV PCR 3.8 million IU/ml Genotype 1a
400 350
Liver Biopsy Grade 3 Hepatitis Stage 2 fibrosis
HCV PCR 157,000 IU/ml Genotype 1a
300 250 200 150
Ist RT HCV +
100
2nd RT HCV -
HCV PCR 7.8 million copies/ml) Genotype 2a Biopsy No Hepatitis
3rd RT (HCV + donor)
50 0
1988 1994 1996 1998 2000 2002 2002 2003 2003 November December April October
Immunosuppression
Cyclosporine
Tacrolimus
RT =Renal transplant
Figure 4: Course of transaminase levels (ALT) over the last several years.
increased risk of subfulminant and fibrosing cholestatic hepatitis in patients receiving HCV-positive organs, their overall graft and patient survival have not differed from recipients of HCV-negative organs (5–8). On the other hand, the ability to receive an HCV-positive organ considerably shortens the waiting time and may enhance survival (9), especially in centers with a long waiting time for cadaveric transplants. In a HCV-positive donor to a HCV-positive recipient, the mechanisms as well as the kinetics of superinfection of different HCV genotypes, subtypes, or quasispecies and their contribution to hepatitis are poorly understood. Viral interference, genetic recombination, mutation, resortment, and viral load with viral competition can potentially influence the clinical course (10). In addition, as in naive patients, host immune factors may play a role. It is also not clear whether in the setting of organ transplantation, HLA matching or mismatching influences the host immune response to the infection (11). The coexistence of circulating quasispecies that share up to 10% nucleotide difference has been demonstrated in patients infected with a single genotype (10). Superinfection has been observed in individuals at high risk for HCV infection, including transplant patients, injection drug users, and patients on hemodialysis (10). Genotype analysis in six HCV-positive liver donor/recipient pairs has shown that one genotype predominated after transplantation (10). There was a trend for genotype 1a to dominate superinfected liver transplant recipients 4 months after transplant. The simultaneous coexistence of two different HCV strains was not detected in this study. Baseline characteristics such as age, sex, viral load, and ALT level were not predictive of the final genotype. In this study, recombination by sequencing was not seen. Another study of HCV-positive donor/recipient pairs by Vargas et al. also demonstrated the predominance of a specific genotype, 1b, in 23 patients after orthotopic liver transplant (11). American Journal of Transplantation 2004; 4: 1375–1378
As in our patient, the superinfection in these two studies was a rapid process with genotype predominance within months (10,12). It is not very clear whether it is the predominance of a different genotype or change in the type and degree of immunosuppression that precipitated the severe infection after the latest transplant. Our patient had chronic HCV for at least 15 years without any histological activity and with normal transaminase levels, despite being on immunosuppresive drugs such as cyclosporine and prednisone for several years. However, the most recent transplant, with a different genotype and tacrolimus-based immunosuppression, triggered acute hepatitis, resulting in a significant increase in transaminase levels and severe hepatocyte injury. The host immune system and its interaction with HCV is an important determinant of severity of HCV infection, and one can only speculate that a different genotype and/or immunosuppressive regimen might have affected this balance and precipitated a severe hepatitis. The data on interaction with HCV and immunosuppressive agents are not very clear owing to a lack of large trials with uniform immunosuppressive regimen (13). Heavier tacrolimus-based immunosuppression, especially induction with thymoglobulin, may be associated with severe HCV infection. A 5-year follow-up study from Europe on post liver transplant HCV infection showed that patients who received tacrolimusbased regimen had a worse outcome (14). On the other hand, long-term follow up of the ‘U.S. Multicenter FK506 Liver Study Group’ showed no difference between the tacrolimus or cyclosporine group (15). There is some interest in the use of cyclosporine-based immunosuppression in liver transplant recipients with recurrent HCV, especially in view of the antiviral properties of cyclosporine in cultured hepatocytes (16). In addition, cyclosporine may also augment response to interferon (17). Treatment of post renal transplant HCV infection is difficult owing to the risk of inducing rejection of renal allograft with interferon. But in situations where there is severe HCV infection with a likelihood of rapid progression of liver disease, such as in our patient, having a genotype 2 or 3 offers distinct advantages. Antiviral therapy is much more efficacious and the duration of treatment is shorter. In addition, one may achieve good response with a lower dose of pegylated interferon in genotype 2 or 3 (18). This case illustrates that the genotype of the recipient should be considered when using a HCV-positive donor for renal transplantation. As it is not logistically possible to obtain the genotype information on the donor who is HCV-positive at the time of procurement, a policy of not using HCV-positive donors for recipients with genotype 2 or 3 should be considered. As genotypes 2 and 3 represent only 20–25% of HCV patients, this is unlikely to influence organ availability significantly. Also uniform guidelines regarding the use of immunosuppressive agents need to be developed in HCV-positive patients. 1377
Schussler et al.
References 10. 1. Pereira BJ, Wright TL, Schmid CH, Levey AS.A controlled study of hepatitis C transmission by organ transplantation. The New England Organ Bank Hepatitis C Study Group. Lancet 1995; 345: 484–487. 2. Alter MJ, Kruszon-Moran D, Nainan OV et al. The prevalence of hepatitis C virus infection in the United States through 1994. N Engl J Med 1988; 1999: 341:556–341: 562. 3. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–982. 4. Pereira BJ, Levey AS, Hepatitis Cvirus infection in dialysis and renal transplantation. Kidney Int 1997; 51: 981–999. 5. Pereira BJ, Hepatitis C. Infection and post-transplantation liver disease. Nephrol Dial Transplant 1995; 10: 58–67. 6. Schmid CH, Levey AS, Pereira BJ, Hepatitis Cvirus genotype does not affect patient survival among renal transplant candidates. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1999; 56: 700–706. 7. Morales JM, Campistol JM, Castellano G et al. Transplantation of kidneys from donors with hepatitis C antibody into recipients with pre-transplantation anti-HCV. Kidney Int 1995; 47: 236–240. 8. Ali MK, Light JA, Barhyte DY et al. Donor hepatitis C virus status does not adversely affect short-term outcomes in HCV+ recipients in renal transplantation. Transplantation 1998; 66: 1694– 1697. 9. Thysell H, Hermodsson S, Blohme I, Hepatitis C. Superinfection in hepatitis C virus (HCV) -infected patients transplanted
1378
11.
12.
13. 14.
15.
16.
17.
18.
with an HCV-infected kidney. Transplantation 1995; 60: 642– 647. Lyra AC, Yusim K, Everhart JE et al. Liver transplantation with hepatitis C virus–infected graft: interaction between donor and recipient viral strains. Hepatology 2003; 38: 25–33. Feray C, Shouval D, Samuel D. Will transplantation of an hepatitis C-infected graft improve the outcome of liver transplantation in HCV patients? Gastroenterology 1999: 117: 263–265. Vargas HE, Laskus T, Wang LF et al. Outcome of liver transplantation in hepatitis C virus–infected patients who received hepatitis C virus–infected grafts. Gastroenterology 1999; 117: 149–153. Everson GT. Impact of immunosuppressive therapy on recurrence of hepatitis C. Liver Transpl 2002; 8: 19–27. Berenguer M, Prieto M, San Juan F et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002; 36: 202–210. Wiesner RH. Long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation 1998; 66: 493–499. Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003; 38: 1282–1288. Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C. controlled trial. J Gastroenterol 2003; 38: 567–572. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C. a randomized trial. Lancet 2001; 358: 958–965.
American Journal of Transplantation 2004; 4: 1375–1378
