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Outcome of liver transplantation for hepatitis B in the United States
  Liver Transplantation
Volume 10, Issue 8, August 2004
W. Ray Kim 1 2 *, John J. Poterucha 1, Walter K. Kremers 2, Michael B. Ishitani 3, E. Rolland Dickson 11
Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation Rochester, Minnesota 2Department of Health Science Research, Mayo Clinic and Foundation Rochester, Minnesota 3Division of Transplantation Surgery, Mayo Clinic and Foundation Rochester, Minnesota
Important innovations, such as hepatitis B immune globulin (HBIG) and lamivudine, have been introduced to the care of patients undergoing liver transplantation (OLT) for viral hepatitis B (HBV) (over the last 15 years). We analyzed survival of OLT recipients with HBV in the United States to examine the effect of these innovations.
A retrospective analysis was conducted based on data collected prospectively by the United Network for Organ Sharing in all adult (older than 18) patients undergoing primary OLT in the United States between 1987 and 2002. OLT recipients with HBV were identified by the principal diagnosis of acute or chronic HBV or positive results on HBV markers.
Patients were divided into Era 1 (1987-1991), Era 2 (1992-1996), and Era 3 (1997-2002). Era 1 consisted of 6,708 patients (675 with HBV), Era 2 consisted of 13,995 patients (1,005 with HBV), and Era 3 consisted of 20,730 patients (1,723 with HBV). More recent patients were older and had less advanced liver disease and shorter ischemic time. The survival of patients with HBV was significantly better for Era 2 than for Era 1 (P < .01) and for Era 3 than for Era 2 (P < .01).
There was no difference in survival between patients with HBV and all other diagnoses for Era 3 (P = .14). In the multivariable analysis, the effect of these eras persisted when other variables such as recipient and donor age, warm ischemic time, pre-OLT disease severity, and hepatocellular carcinoma (HCC) were taken into account. Unlike previous reports, fulminant disease and Asian race had no effect on patient survival.
In conclusion, these data underscore the effectiveness of therapeutic innovations that have occurred in the past two decades and indicate timely and widespread adoption of these measures by transplant centers nationwide.
Before the advent of effective means to prevent reinfection of the graft, the outcome of liver transplantation (OLT) for hepatitis B virus (HBV)-related liver disease was dismal because of virtually universal reinfection of the graft, followed by progressive destruction by recurrent hepatitis, which then led to graft failure over a relatively short period of time.[1-4] Based on these results, HBV-related liver disease once was considered to be a contraindication for OLT.[5] By the same token, HBV-related liver disease was excluded from the initial criteria for coverage by Medicare for adult liver transplants.[6]
During the 1990s, however, important innovations took place to improve the outcome of patients receiving OLT for HBV-related liver disease. Immunoprophylaxis using HBV immune globulin (HBIG) began to be used widely in Europe in the late 1980s and in the early 1990s in the United States.[7-9] Long-term administration of intravenous HBIG resulted in a significant reduction in the incidence of recurrent HBV, especially in patients in a nonreplicative phase of the infection [i.e., negative for HBV e antigen (HBeAg) and HBV-DNA].[10] The efficacy of lamivudine against HBV was first reported in 1995.[11] The subsequent institution of lamivudine in OLT candidates and recipients led to additional improvement in the outcome of OLT[12] by further reducing the recurrence of HBV infection,[13-15] rendering patients with active viral replication eligible for OLT[13][15] and altering the course of hepatitis progression in those patients in whom HBV reinfection did occur.[16][17] Finally, the availability of newer antiviral agents such as adefovir likely will improve the outcome in the future by providing therapeutic options for patients infected with HBV resistant to lamivudine.[18]
These innovations represent exciting progress over a relatively short period of time. Whether these innovations have had a demonstrable effect on the outcome of liver transplantation on a nationwide scale has not been examined. In this study, we used data from the United Network for Organ Sharing (UNOS) to examine the outcome after OLT for HBV-related liver disease in the United States. We also sought to identify factors that may have had prognostic importance in patients with HBV undergoing OLT. Our overall hypothesis was that patient survival after OLT for HBV-related liver disease improved over time beyond the degree of improvement observed for other diagnoses.
The management of patients undergoing liver transplantation for HBV-related liver disease has changed significantly in the last two decades. Before the advent of HBIG prophylaxis, patients with HBV undergoing OLT were faced with a high risk of recurrent infection and hepatitis.[2][4] The natural course of recurrent HBV under immunosuppression after OLT was much more aggressive than in nonimmunosuppressed patients. The most extreme example of aggressive recurrent HBV is fibrosing cholestatic hepatitis, which is characterized by massive accumulation of viral proteins in hepatocytes, profound cholestasis, hepatic failure, and, in most cases, death.[1][3]
Although passive immunoprophylaxis using HBIG was tested for prevention of recurrent HBV during the 1980s, it was not until the early 1990s that the efficacy of long-term administration of high-dose HBIG was demonstrated to reduce the risk of recurrent HBV.[2][19] However, even with HBIG, patients with active viral replication (e.g., HBeAg+ at the time of transplantation) continued to experience a high incidence of recurrent HBV.[10] Lamivudine was initially developed and approved in 1995 for treatment of HIV infection. However, it is also a potent inhibitor of HBV polymerase and, in the context of OLT, has been used to convert patients with replicative disease to nonreplicative status,[13][15] to prevent HBV recurrence,[20][21] and to treat patients who develop recurrent disease.[16][22] In the late 1990s, the use of lamivudine in combination with HBIG was shown to be more effective than either agent alone in the prevention of recurrence, even in patients with evidence of viral replication.[13-15] Finally, by the early 2000s, a second oral agent, adefovir dipivoxil, was made available for study purpose and then on a compassionate-use basis for the treatment of patients with HBV resistant to lamivudine, further expanding management options for OLT recipients with HBV.[18][23]
The clinical impact of these innovations has been reported by academic, high-volume centers whose patient population is enriched with HBV patients.[24][25] The significance of this work is that with the UNOS data, which, by definition, reflects what happened in the whole population, a significant improvement in the outcome for OLT for HBV was clearly demonstrable on a nationwide level. As shown in Figure 1, the 1-year survival probability in patients undergoing liver transplantation for HBV improved from 71% in Era 1, to 83% in Era 2, and to 87% in Era 3. More impressively, the 5-year survival increased from 53% to 69% to 76% over time. For Era 3, survival in HBV patients was at least comparable, if not superior, to that in patients with other diagnoses. These continual improvements suggest that advances in the prevention and treatment of recurrent HBV disease have been adopted in a timely and widespread fashion.
An earlier analysis reported that patients who underwent OLT for fulminant HBV had a higher rate of survival than those who underwent OLT for chronic disease.[7] In this analysis, the comparison between those with fulminant and chronic HBV disease in the most recent era (1997-2002) showed no difference in survival. In the previous report, the better result among those with fulminant disease was attributed to a lower recurrence rate in that group.[7] We surmise that the currently available prophylactic regimen has reduced the recurrence rate to the degree that any detectable differences in the outcome have been abolished. This, however, remains a hypothesis, because the current data did not provide detailed information about prophylactic regimens. Another factor that has been found to have prognostic significance is delta hepatitis (HDV) coinfection.[26-28] In this data set, there were only 38 records of 3,403 with HBV that had a documented HDV diagnosis, precluding a meaningful analysis. Although this likely represents incomplete detection or underreporting of HDV, it appears doubtful that it confounded the overall analysis, based on the relatively low prevalence of HBV-HDV coinfection in the U.S. population and lack of evidence for a change in the prevalence of the coinfection over time.
Another issue that has been suggested to have important prognostic significance is the race of the recipient. Jacobs et al. reported that Asians had a higher risk of recurrent HBV and higher mortality than non-Asians,[29] a finding that was supported by a later analysis with a larger (n = 64 Asians) number of subjects.[24] A subsequent report from a different center reported a lower 1-year survival for Asian recipients compared with non-Asians, although 5-year survival probability was comparable.[30] The most recent data came from a multicenter study that compared 124 Asian patients with 171 white patients.[31] There was no difference between the two races in survival up to 2 years. However, Asian recipients with recurrent disease were found to have a shorter survival time than white recipients. In the most recent era in this study, there were 362 Asian recipients of a total of 1,723 with HBV. With up to 5 years of follow-up, we found no evidence in the univariable and multivariable analyses that Asian race was associated with reduced survival. These data did demonstrate that African Americans did less well than other races. However, this effect was present for all diagnoses and was not specific for HBV (no interaction between African American race and HBV, data not shown).[32]
There are a number of limitations to this study, which are mainly related to the data. Because data collected by UNOS were principally for organ allocation and not for comprehensive follow-up of recipients, the data lacked details of clinical information. The most significant limitation with respect to this analysis was that we had no information regarding post-OLT patient management, histology, and laboratory data to directly correlate specific regimen for prophylaxis or treatment for recurrent HBV and patient outcome. Similarly, although data fields were available for markers of active replication, information on HBeAg or HBV DNA was frequently omitted. Thus, although the eras in the improvement in OLT outcome appeared to correlate with therapeutic innovations, we were not able to implicate a direct cause-and-effect relationship. In addition, the structure of the database allowed only limited information on the main diagnosis. For example, although some patients may have had HBV-related cirrhosis and HCC, both diagnoses could not be recorded concomitantly, and, in this study, HBV status in patients with HCC was identified by their serologic data. This may explain the low frequency of HCC in these data (4-9% among HBV patients), whereas analyses that had access to more clinical details reported a prevalence of HCC in excess of 20% among OLT recipients with HBV. Although these limitations may not be necessarily negligible, it appears unlikely that they led to a systematic bias to affect the main results of this analysis in terms of the time trend in outcome of OLT in patients with HBV.
In summary, the outcome of liver transplantation for HBV has improved significantly in the last two decades, commensurate with therapeutic innovations introduced during the period. Most recently, the outcome after OLT for HBV, adjusting for other variables, is comparable with, if not slightly better than, that in patients with other diagnoses. Based on the most recent data, we did not find evidence that fulminant HBV affords superior outcome to chronic HBV-related disease. We showed that race had no relationship with HBV-specific outcome. These data underscore the importance of therapeutic innovations that have occurred incrementally in the past two decades for HBV and support OLT as an appropriate treatment for patients with acute and chronic hepatic insufficiency or HCC from HBV.
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