Correspondence

Liver Transplantation in Hepatitis B

N Engl J Med 1994; 330:1317-1318May 5, 1994

Article

To the Editor:

Samuel et al. (Dec. 16 issue)1 report the results of a major retrospective multicenter study of liver transplantation in European patients with hepatitis B virus (HBV) infection. Of great clinical importance is the observed reduction in the risk of recurrence of HBV in recipients of liver allografts who received long-term ( ≥ 6 months) passive immunoprophylaxis with anti-hepatitis B surface antigen; no benefit was seen with short-term (2 months) immunoprophylaxis.

The mean (±SE) length of time to HBV recurrence was 3.0 ±2.6 months in patients receiving short-term immunoprophylaxis, 3.2 ±2.7 in those not given immunoprophylaxis, and 8.6 ±6.8 months in those given long-term therapy. These findings are surprising, since many of the recurrences in the group receiving short-term therapy apparently occurred while the patients were still receiving immunoprophylaxis (i.e., within two months of transplantation). Why then were there virtually no recurrences within the first two months after transplantation in the group receiving long-term immunoprophylaxis? Similarly, why was recurrence not delayed in the group given short-term therapy as compared with the control group? Perhaps the answers can be found by examining the methods used. This was a retrospective study of liver transplantation for HBV infection performed at 17 European centers between 1977 and March 1990, with data collected by questionnaires sent out in 1990. And “the protocols for immunoprophylaxis differed among centers and within them.” Thus, it is possible that patients with early recurrence of HBV infection subsequently had their therapy discontinued. Given the lack of a clearly defined immunoprophylaxis protocol, these patients were then retrospectively categorized as having no response to short-term therapy. The group receiving long-term immunoprophylaxis would then really be a subgroup of patients with an initial response to short-term (<2 months) therapy, at least in some of the 17 centers.

The intention-to-treat principle was used in the analysis of patients who died. Was the same principle applied to the analysis of early failures of immunoprophylaxis? In this study the potential benefits of this expensive prophylactic regimen may have been overestimated.

Alfredo J. Fabrega, M.D.
Raymond Pollack, M.B.
University of Illinois, Chicago, IL 60612

1 References

1. 1

   Samuel D, Muller R, Alexander G, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993;329:1842-1847
   Full Text | Web of Science | Medline

To the Editor:

. . . In the study by Samuel et al., the mortality rate at one month exceeded 10 percent in the group receiving short-term therapy and the group not receiving immunoprophylaxis, in contrast to a rate of 0 percent in the group receiving long-term therapy. Since the risk of recurrent hepatitis B during the first month in patients who did not receive immunoprophylaxis was about 2 percent and active hepatitis usually appeared more than 60 days after transplantation,1 the patients in this group were unlikely to die of HBV infection. In previous studies the mortality rate at 60 days was quite similar between patients with HBV infection and those without infection, despite the considerable differences in the long-term mortality1,2. This raises the question whether the favorable survival rate and rate of recurrent HBV in patients receiving long-term therapy were attributable to factors other than passive immunoprophylaxis in this retrospective study. Is the long-term therapy still associated with improved survival in multivariate analysis after the exclusion of patients who died one or two months after transplantation? Further well-designed prospective studies including assessments of histopathological changes in allografts are needed to confirm the encouraging results of long-term immunoprophylaxis.

Ming Wei, M.D., M.P.H.
Byrnes Medical Center, Columbia, SC 29208

2 References

1. 1

   Demetris AJ, Todo S, Van Thiel DH, et al. Evolution of hepatitis B virus liver disease after hepatic replacement: practical and theoretical considerations. Am J Pathol 1990;137:667-676
   Web of Science | Medline

2. 2

   Todo S, Demetris AJ, Van Thiel DH, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991;13:619-626
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The similarity in the mean time to HBV recurrence in the group receiving short-term immunoprophylaxis and the group not given immunoprophylaxis is due to the fact that in the short-term group, many centers gave immune globulin only during surgery and on the first day after surgery. The exact amount of immune globulin received by each group could not be calculated because of the different preparations used, but it is clear that the total amount of immune globulin received at two months was higher in the group receiving long-term therapy than in the group receiving short-term therapy. In our opinion, the lower risk of HBV recurrence observed in the group given long-term therapy is due both to the high doses of immune globulin given and to the long-term administration of immune globulin. It is conceivable that short-term administration of high doses of immune globulin will reduce the risk of HBV recurrence at two months but will not prevent recurrence, since HBV has been shown to be present after liver transplantation in extrahepatic sites.1

In response to Fabrega and Pollack: we used the intention-to-treat principle in our analyses of the patients who died and of failures of immunoprophylaxis.

Dr. Wei is correct that the mortality rate at one month was higher in the group given short-term therapy and the group given no immunoprophylaxis and that this rate was not related to the recurrence of HBV. The main reason is that in many centers long-term administration of immune globulin was used in more recent years, when postoperative mortality was lower. In Figure 4 of our article, the survival curves beyond six months are not parallel and remain higher in the group given long-term therapy -- a difference that can be explained by a lower rate of HBV recurrence in that group. In the multivariate analysis, the year of transplantation was taken into account to eliminate the effect of postoperative mortality on survival, and it showed clearly that long-term immunoprophylaxis was associated with better survival because of a lower risk of the recurrence of HBV.

Samuel Didier, M.D.
Paul Brousse Hospital, 94800 Villejuif, France

Graeme Alexander, M.D.
Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom

Henri Bismuth, M.D.
Paul Brousse Hospital, 94800 Villejuif, France

1 References

1. 1

   Feray C, Zignego AL, Samuel D, et al. Persistent hepatitis B virus infection of mononuclear blood cells without concomitant liver infection: the liver transplantation model. Transplantation 1990;49:1155-1158
   CrossRef | Web of Science | Medline