Henri Bismuth

Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation.

BACKGROUND/AIMSnSeveral genotypes of hepatitis C virus (HCV) have been identified by phylogenetic analysis, but their clinical relevance remains elusive. Liver transplantation for HCV-related cirrhosis offers a unique opportunity for prospective studies of this issue.nnnMETHODSnSixty anti-HCV-positive liver recipients with precise virological and histological assessments were included. HCV genotype was determined with both type-specific capsid primers and a line probe genotyping assay.nnnRESULTSnHCV genotype 1b was the predominant type before transplantation (40 of 60 patients); after liver transplantation, acute and chronic active hepatitis developed more frequently in these patients than in patients infected by other genotypes (31 of 40 and 24 of 40 vs. 8 of 20 and 4 of 20 patients). Actuarial rates of acute hepatitis and chronic active hepatitis were 77% and 59%, respectively, 3 years after transplantation in patients infected by type 1b and 40% (P = 0.008) and 22% (P = 0.004) in those infected by other types. There was no statistical relation between the level of HCV viremia and HCV genotypes both before and after transplantation. In contrast, after transplantation, serum HCV RNA values were significantly increased in patients who developed hepatitis after transplantation.nnnCONCLUSIONSnThis study provides direct evidence that HCV 1b is associated with more aggressive recurrent liver disease than other genotypes.

Hepatitis viruses and liver transplantation

Acute and chronic liver diseases related to hepatitis viruses are the main indications for liver transplantation. The risk of viral reinfection after transplantation is the main limiting factor in these indications. The risk of viral B reinfection is: 80% in the absence of prophylaxis; is related to the presence of active viral B replication prior to transplantation; is higher in patients with chronic liver disease, rather than with fulminant hepatitis; and is higher in patients with hepatitis B virus (HBV)‐related liver disease alone rather than in those with HBV‐hepatitis delta virus (HDV) infection. Posttransplant long‐term passive antibody to hepatitis B (anti‐HB) immunoprophylaxis reduces the risk of HBV recurrence to 30% in patients with HBV cirrhosis, and to less than 10% in those with fulminant hepatitis B. Patients with HBV‐HDV liver disease receiving passive anti‐HB immunoprophylaxis are at low risk of HBV recurrence (10–15%), but at high risk of HDV recurrence (80%). However, HDV reinfection of the graft has no clinicopathological consequence in the absence of concomitant HBV reinfection. The five year survival of patients transplanted for HBV cirrhosis and for HDV cirrhosis at the Hepatobiliary Center, Hǒpital Paul Brousse is 72% and 85%, respectively. Hepatitis B virus reinfection of the graft is characterized by a high level of viral replication, and a chronic outcome. Antiviral treatments such as ganciclovir, adenine arabinoside monophosphate, famcyclovir, and lamivudine have a place after transplantation and may stop HBV replication. ganciclovir, famcyclovir and lamivudine should be continued for several months and in some cases indefinitely. Hepatitis C virus reinfection is almost constant, assessed by the persistence of hepatitis C virus (HCV)‐RNA in the serum in 90% of cases. Acute lobular hepatitis appeared in 75% of patients at a median of 4 months post transplantation with a range of between 23 days and 4 years. In our series, the 5 year actuarial rate of HCV acute hepatitis on the graft, chronic hepatitis, and cirrhosis, is 75, 60, and 8%, respectively. Hepatitis C virus RNA level is dramatically increased after transplantation and seems to correlate with the occurrence of acute hepatitis on the graft. A positive relation between genotype 1b and prevalence and severity of HCV hepatitis on the graft have been suggested in European series. There is no demonstrated way to prevent HCV reinfection. The use of interferon for the treatment of HCV hepatitis on the graft was disappointing due to a poor antiviral effect and the occurrence of chronic rejection episodes in some patients. Promising results of the combination of interferon and ribavirine have been reported and need confirmation. The 5 year survival of patients transplanted for viral C cirrhosis at the Hepatobiliary Center, Hǒpital Paul Brousse is 78%. In conclusion, patients with HBV cirrhosis and without HBV replication are candidates for liver transplantation. Long‐term passive anti‐HB prophylaxis is the best way to prevent HBV recurrence. Patients with HBV replication should be included in protocols using combinations of antiviral treatments and passive anti‐HB immunoprophylaxis. Viral C reinfection is frequent, but medium‐term survival is good. However, long‐term graft and patient survival remains unknown and methods to prevent and treat HCV reinfection on the graft are needed.

Current status of auxiliary partial orthotopic liver transplantation for acute liver failure

I read with great interest the review article by Rela et al. recently published in Liver Transplantation. This is a very interesting review of the subject in which a large part is devoted to historical steps that led to this concept that aims at taking advantage of the possibility of recovery of the native liver and the potential for withdrawal of the liver graft, hence discontinuation of immunosuppression and actual cure. In their historical narration, Rela et al. rightly report that initial attempts at auxiliary transplantation included heterotopic positioning of the graft, below or beside the native liver, avoiding partial hepatectomy of the native liver. In that section of the article, they state that Stampfl et al. reported in 1990 the first case of heterotopic auxiliary liver transplantation (HALT) for acute liver failure (ALF). Indeed, this was the first successful case that served as a bridge to regular orthotopic full graft transplantation at postoperative day 27. However, I reported the first case of HALT for ALF performed in March 1980 that was published in French in 1982 and then in English as part of the first series of partial liver grafts in 1985. This was a case of ALF due to drug toxicity of antiepileptic valproic acid in a 17-year-old girl. After the initial recovery, the patient developed agranulocytosis that required withdrawal of immunosuppression, and she died of graft rejection at postoperative day 22. In this case, space difficulties encountered in full graft HALT led us to use our technique of partial graft consisting of reducing the graft by ex vivo hepatectomy, a technique we first used successfully in pediatric liver transplantation and is since known as “reduced-sized liver transplantation.” This is just a friendly reminder in view of the comprehensive historical part of this article and to revive an old and maybe unfairly overlooked publication.

Risk of liver retransplantation for viral hepatitis

The risk of viral recurrence after liver transplantation for viral related liver disease is high. Viral reinfection is characterized by a viral reactivation, high amount of virus, difficulty to control viral replication in these immunosuppressed patients, occurrence of graft disease, and sometimes graft failure. For these reasons, retransplantation for viral recurrence is controversial due to the high risk of recurrence on the second graft and to the overall poor results in a context of organ shortage.