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Racial Differences in HBV Liver Transplant Linked to Underlying Disease
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MedPage Today
August 28, 2009
Action Points
* Explain to patients that race does not appear to influence the waitlist or outcomes after liver transplantation.
* The study showed that recurrence of liver cancer was the only significant predictor of an increased risk of mortality after transplantation.
* The presence of HBVeAg at transplantation was the only predictor of HBV recurrence.
Caucasian liver transplant recipients have a significantly greater risk of hepatitis B recurrence than Asian- and African-American recipients, according to a review of recent transplantation experience in HBV-infected patients.
Otherwise, the study found few, if any disparities attributable to race.
Caucasian recipients had a four-year HBV recurrence rate of 19%, which was two to three times greater than the recurrence rate of Asian- and African-American recipients, Anna S. Lok, MD, of the University of Michigan, and colleagues reported in the September issue of Liver Transplantation. The authors expressed surprise at this finding.
The presence of hepatitis B envelope antigen (HBeAg) was the only predictor of HBV recurrence.
In contrast to some previous studies, the latest review showed no race-related disparities in waitlist time or post-transplant survival. Most differences were attributed to the underlying cause of the original liver disease. Patients with liver cancer, for example, had lower survival rates.
"Our research showed transplant indication and Model for End-stage Liver Disease (MELD) score for endstage cirrhosis patients were the only predictors of transplantation, but race was not," the authors said.
"Analysis indicated that hepatocellular carcinoma recurrence was the only predictor of post-transplant mortality, while race, indication for transplant, and HBV recurrence were not," they added.
Several previous studies had yielded conflicting data on liver transplantation outcomes by race.
One study showed worse outcomes among races other than Caucasians or African-Americans and attributed the results to transplantation involving patients with HBV infection or hepatocellular carcinoma (Hepatology 2007; 46: 1491-97).
"These data indicate that racial differences in [post-transplant] outcome observed in some studies may be related to differences in the predominant cause of liver disease," the authors said.
Until recently, outcome data for HBV-infected liver recipients had been scant. The NIH-sponsored HBV-Orthotic Liver Transplantation study specifically examined outcomes in patients transplanted because of end-stage liver disease related to HBV infection.
The large number of patients enrolled made it possible to to compare waitlist times and post-transplant outcomes by race.
The authors analyzed data on 274 participants in the NIH study. They comprised 116 Caucasians, 135 Asians, and 23 African-Americans. The probability of transplantation one, three, and five years after waitlisting increased from 48% to 63% for Caucasians, 48% to 66% for Asian-Americans, and 53% to 88% for African-Americans.
Irrespective of race, patients with acute liver failure spent the least time on the waitlist, followed by patients with hepatocellular carcinoma and those with end-stage cirrhosis.
From 2001 to 2007, 170 of the 274 patients received liver transplants. The five-year survival was 94% for African-Americans, 85% for Asian-Americans, and 89% for Caucasians.
Recurrence of liver cancer was the only predictor of survival. Asian-Americans were three times as likely to have hepatocellular carcinoma when they were waitlisted (47%), versus 16% of African-Americans and 17% of Caucasians.
Overall, 8% of transplanted patients had HBV recurrence. The probability of recurrence four years after transplantation was 6% among African-Americans, 7% among Asian-Americans, and 19% among Caucasians. In univariate analysis, Caucasians had a higher incidence of HBV recurrence P=0.043).
By Cox regression analysis, HBeAg status at listing was the only independent predictor of post-transplantation HBV recurrence (P=0.003), although the results showed a trend toward race as an influencing factor (P=0.057).
A limitation of the study was the smaller number of African-American patients, which raised the possibility that fewer were referred, or they were referred too late in their illness to qualify for transplantation.
In an accompanying editorial, Charles D. Howell, MD, of the University of Maryland in Baltimore, said evaluation of potential racial disparities in liver transplant outcomes should continue to clarify differences observed among various studies.
"More study is necessary to determine whether the disparity between African-Americans, Asians, and Caucasians in outcomes of liver transplantation for HBV persists in the most recent era," he wrote.
The study was suppported by NIH. Roche Molecular Diagnostics provided kits for HBV DNA assays.
Neither the authors nor Howell reported relevant disclosures.
from Charles Howell editorial:
"The conclusion that Caucasians, Asian Americans and African Americans with hepatitis B can be managed similarly in the transplant setting seems intuitive. However, aside from the MELD allocation policy and HBV treatment guidelines, the medical management and health care that patients received were not described. The observational study design makes it difficult to identify other variables and medical management that led to excellent long-term outcomes, such as pretransplant management and the selection of patients with acute liver failure and HCC. The results indicate that Asians and Caucasians can expect similar outcomes on the wait list as well as after transplantation, but the OLT study group cohort includes too few African Americans to adequately address disparities between African Americans and Caucasians. More study is necessary to determine whether the disparities between African Americans and Caucasians in outcomes of liver transplantation for HBV identified in 1997-2001 persist in the most recent era."
Liver transplantation outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B
Liver Transplantation Sept 2009
Natalie Bzowej 1 2 3 4 5 6 7, Steven Han 2, Bulent Degertekin 3, Emmet B. Keeffe 4, Sukru Emre 5 *, Robert Brown 6, Rajender Reddy 7, Anna S. Lok 3 *, National Institutes of Health Hepatitis B Virus Orthotopic Liver Transplantation Study Group
1California Pacific Medical Center, San Francisco, CA
2University of California, Los Angeles, CA
3Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI
4Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA
5Mount Sinai Medical Center, New York, NY
6Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York, NY
7University of Pennsylvania, Philadelphia, PA
email: Anna S. Lok (aslok@med.umich.edu)
"In summary, in this large retrospective-prospective study involving 274 patients with HBV listed for liver transplantation in the United States, we found similar waitlist and post-transplant outcomes among Caucasians, Asian Americans, and African Americans. There were some differences among these 3 racial groups. Asian Americans were significantly more likely to be listed for HCC, but HCC recurrence rates were similar to those of Caucasians and African Americans. African Americans were significantly younger and had a higher rate of transplantation, which is likely related to the higher proportion with acute liver failure. A surprising finding was a higher rate of HBV recurrence among Caucasians. This finding is inexplicable and needs to be validated. We acknowledge that the number of African Americans included in this study is small (23 in total and 17 transplanted), and patients who are approved for listing for liver transplantation may not represent the patient population at large. Nevertheless, our data indicate that Caucasians, Asian Americans, and African Americans with hepatitis B can be managed similarly in the transplant setting and can expect to have similar outcomes on the waiting list and after transplantation."
Abstract
Several previous studies found that Asians transplanted for hepatitis B virus (HBV) infection had worse post-transplant outcomes than Caucasians. Data on post-transplant outcomes of African Americans and waitlist outcomes of Asian Americans and African Americans with hepatitis B are scant. The aim of this study was to compare waitlist and post-transplant outcomes among Asian Americans, African Americans, and Caucasians who had HBV-related liver disease. Data from a retrospective-prospective study on liver transplantation for HBV infection were analyzed. A total of 274 patients (116 Caucasians, 135 Asians, and 23 African Americans) from 15 centers in the United States were enrolled. African Americans were younger and more Asian Americans had hepatocellular carcinoma (HCC) at the time of liver transplant listing. The probability of undergoing transplantation and the probability of survival on the waitlist were comparable in the 3 racial groups. Of the 170 patients transplanted, 19 died during a median follow-up of 31 months. The probability of post-transplant survival at 5 years was 94% for African Americans, 85% for Asian Americans, and 89% for Caucasians (P = 0.93). HCC recurrence was the only predictor of post-transplant survival, and recurrence rates were similar in the 3 racial groups. Caucasians had a higher rate of HBV recurrence: 4-year recurrence was 19% versus 7% and 6% for Asian Americans and African Americans, respectively (P = 0.043). In conclusion, we found similar waitlist and post-transplant outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B. Our finding of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies. Liver Transpl 15:1010-1020, 2009
Article Text
Conflicting data exist as to whether race affects outcomes after orthotopic liver transplantation (OLT) in the United States. Results from 1 center found no significant difference in patient survival between African Americans and Caucasians after solid organ transplantation, including liver transplantation.[1] In contrast, a retrospective analysis of the United Network of Organ Sharing (UNOS) database of over 14,000 OLT procedures performed between 1988 and 1996 revealed that 2- and 5-year patient survival was significantly lower for both African Americans and Asians compared to white Americans and Hispanics.[2] This study found that the racial difference in post-OLT survival was related to the etiology of liver disease, with lower survival rates among African Americans with hepatitis C or acute liver failure and among Asians with hepatitis B virus (HBV). A second analysis of the UNOS database, which included more than 17,000 OLT procedures performed during the same period (1990-1996), also concluded that post-OLT survival was lower in minority races.[3] However, a recent analysis of 2823 patients transplanted in 4 centers between 1985 and 2000 found no difference in post-OLT patient or graft survival among racial groups.[4] In this study, a significantly increased risk of mortality was observed among patients of other races (not Caucasian or African American) transplanted before 1994, and this was attributed to the poor outcome of patients transplanted for hepatitis B or hepatocellular carcinoma (HCC). These data indicate that racial differences in post-OLT outcome observed in some studies may be related to differences in the predominant cause of liver disease.
Several studies have compared outcomes of Caucasians and Asians transplanted for HBV infection. Three early studies found that Asians who had liver transplants for hepatitis B had higher rates of post-OLT mortality.[5-7] Data from these single-center studies were confirmed by analysis of the large databases cited previously.[2][4] Studies conducted after the introduction of hepatitis B immune globulin (HBIG) and lamivudine were more encouraging. A retrospective study of 70 Asians and 99 whites transplanted in the late 1990s found that post-OLT survival and HBV recurrence were comparable between the 2 groups.[8] Similarly, an analysis of the UNOS database of all adult patients transplanted for HBV between 1997 and 2002 found that post-OLT survival of Asians was similar to that of other races.[9] These data indicate that outcomes of Asians and Caucasians after liver transplantation for HBV infection in the recent era are comparable, but there are very little data on the outcomes of African Americans who had liver transplantation for hepatitis B. To date, most studies have focused on post-OLT outcomes; whether transplantation rates and outcomes on the waiting list are comparable among racial groups is unclear. Furthermore, most studies have not included data on HBV markers and HBV prophylactic regimen, factors that may affect post-OLT HBV recurrence and survival.
The National Institutes of Health (NIH) - sponsored HBV-OLT study is a multicenter retrospective-prospective study on the outcomes of liver transplant patients with HBV infection. The large number of enrolled patients permitted a comparison of post-OLT outcomes as well as outcomes on the waiting list among Caucasians, Asian Americans, and African Americans in an era in which oral nucleos/tide analogues and HBIG are available. This study also allowed a comparison of the clinical and virological characteristics of the patients in these racial groups.
Abbreviations
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; NIH, National Institutes of Health; NS, not significant; OLT, orthotopic liver transplantation; SD, standard deviation; UNOS, United Network of Organ Sharing.
DISCUSSION
This large study included 274 patients listed for liver transplantation for HBV infection in 15 centers distributed across the United States, providing a good representation of HBV patients in this country. We found that Asians constituted half (49.2%) of the study population. This is not surprising because hepatitis B is endemic in Asian countries and many studies have reported a high prevalence (10%-15%) of chronic HBV infection among Asian Americans.[13-15] The National Health and Nutrition Examination Survey found that the prevalence of HBV infection is 4-fold higher among African Americans versus whites.[16] It is surprising to see that a low percentage of patients listed for liver transplantation for HBV infection were African Americans. This discrepancy may be related to differences in access to transplantation.[17] We found that African Americans listed for end-stage cirrhosis had similar MELD scores and those listed for HCC had similar tumor staging at listing in comparison with Caucasians and Asian Americans. However, this does not preclude the possibility that fewer African Americans are referred to liver transplant centers or the possibility that more African Americans are referred too late and are not eligible for listing. Interestingly, African Americans were significantly younger at listing. This is surprising because African Americans likely acquired HBV infection during childhood or adult life, while Asian Americans likely acquired HBV infection perinatally or during early childhood. These data suggest that African Americans with chronic HBV infection may have a more rapidly progressive course.
Asian Americans were 3 times as likely to be listed for HCC as Caucasians or African Americans. The higher propensity for HCC may be related to a longer duration of HBV infection among Asian Americans, in whom infection likely occurred at a younger age, or to other factors such as HBV genotype, host genetics, or environmental factors (eg, aflatoxin). Many studies have shown that HBV genotype C, which is common in Asian countries and among Asian Americans, is associated with a higher risk of HCC than HBV genotype B.[18-21] A previous analysis of a subset of patients in the NIH HBV-OLT study for whom HBV genotype data were available showed that patients with genotype C infection were significantly more likely to have HCC at listing than those with genotype non-C (A, B, or D).[22] Once listed, the rate of new HCC diagnosis was similar in all 3 racial groups, underscoring the importance of HCC surveillance for all patients with HBV-related cirrhosis, regardless of race.
Despite differences in age at infection and therefore duration of infection, the prevalence of HBeAg, the percentage of patients with detectable serum HBV DNA, and the mean serum HBV DNA levels at listing were similar in the 3 racial groups. Persistence of HBeAg and high serum HBV DNA levels after a longer duration of infection may have contributed to the high rate of HCC among Asian Americans.[23][24] Similar percentages of patients in all 3 groups were receiving antiviral therapy at listing and at the time of transplant, and this indicated that there was no racial barrier to access to antiviral therapy.
Previous studies found that African Americans were less likely to be transplanted[17][25][26]; however, in this study, we found that African Americans were more likely to be transplanted, but the number of African Americans included was small. Moreover, the anomalous finding may be related to the fact that more African Americans were listed with acute liver failure, and those with end-stage cirrhosis had slightly higher MELD scores at listing. Multivariate Cox regression analysis showed that transplant indication was a significant predictor of time to transplant, but race was not. This finding confirms that the current system of organ allocation (sickest first) is fair across racial groups. Our study also showed that outcomes on the waiting list (waitlist mortality as well as dropout rate) were comparable among Caucasians, Asian Americans, and African Americans.
In accordance with the results of Lee et al.'s study,[4] racial disparity in post-transplant survival was not observed among patients who underwent OLT in an era when nucleos/tide analogues and HBIG prophylaxis are routinely used and the Milan criteria are applied to patients with HCC.[27] In fact, our study found a very high rate of post-transplant survival among African Americans: a 5-year probability of 94% versus 85% for Asian Americans and 89% for Caucasians. The only independent risk factor for mortality after liver transplant was recurrence of HCC. Although the rate of HCC recurrence was similar among the 3 racial groups, a higher proportion of patients transplanted for HCC may explain the slightly lower rate of post-transplant survival among Asian Americans. The disparity in the proportion of patients transplanted for HCC might have contributed to a higher rate of post-OLT mortality among Asian Americans in the era prior to the application of the Milan criteria.
A surprising finding was a higher HBV recurrence rate among Caucasians. Three studies performed in the 1990s reported similar or higher HBV recurrence rates among Asian Americans. One study of 15 Asians and 29 non-Asians reported a significantly higher rate of HBV recurrence among Asians: 72% versus 32% (P < 0.05).[6] Another study of 15 Asians and 20 non-Asians did not observe any difference in HBV recurrence rates between the 2 groups.[7] A third study of 70 Asians and 99 whites reported similar rates of HBV recurrence: 11% versus 12%.[8] In the current study, the probability of HBV recurrence 4 years post-transplant was 19% among Caucasians, 7% among Asian Americans, and 6% among African Americans (P = 0.043) despite similar HBeAg and HBV DNA status (at listing and at transplant), use of antiviral therapy pre-transplant, occurrence of virological breakthrough/confirmed genotypic resistance to antiviral therapy pre-transplant, and use of antiviral and HBIG prophylaxis post-transplant.
In summary, in this large retrospective-prospective study involving 274 patients with HBV listed for liver transplantation in the United States, we found similar waitlist and post-transplant outcomes among Caucasians, Asian Americans, and African Americans. There were some differences among these 3 racial groups. Asian Americans were significantly more likely to be listed for HCC, but HCC recurrence rates were similar to those of Caucasians and African Americans. African Americans were significantly younger and had a higher rate of transplantation, which is likely related to the higher proportion with acute liver failure. A surprising finding was a higher rate of HBV recurrence among Caucasians. This finding is inexplicable and needs to be validated. We acknowledge that the number of African Americans included in this study is small (23 in total and 17 transplanted), and patients who are approved for listing for liver transplantation may not represent the patient population at large. Nevertheless, our data indicate that Caucasians, Asian Americans, and African Americans with hepatitis B can be managed similarly in the transplant setting and can expect to have similar outcomes on the waiting list and after transplantation.
Editorial
Racial disparities in liver transplantation for hepatitis B: To be or not to be
Charles D. Howell *
University of Maryland School of Medicine, Baltimore, MD
email: Charles D. Howell (chowell@medicine.umaryland.edu)
*Correspondence to Charles D. Howell, University of Maryland School of Medicine, 22 South Greene Street, Room N3W50, Baltimore, MD 21201
See Article on Page 1010
Telephone: 410-328-1358; FAX: 410-328-1897
Article Text
Several studies have documented significant racial disparities in access to and outcomes of liver transplantation in the United States. A study of United Network for Organ Sharing (UNOS) data from 1994 to 1998 by Reid et al.[1] found underrepresentation of African Americans, 18 to 70 years old, on the liver recipient wait list relative to their proportion in the general US population as well as their higher age-adjusted mortality from cirrhosis. In addition, African Americans patients had more severe liver disease when they were placed on the wait list, were more likely to be removed from the list because of death or becoming too ill, and were less likely to undergo transplantation within 4 years of being placed on the wait list. African Americans patients had a shorter waiting time for orthotopic liver transplantation (OLT), which was consistent with more severe and advanced liver disease at listing. These results suggested that African Americans face barriers to referral for liver transplantation that are likely to include decreased access to care related to higher poverty rates and lower rates of private health insurance in comparison with Caucasians or whites. However, racial disparities in health status and health care quality persist for many disorders after adjustments for education level, household income, and health payer status. Disparities in post-liver transplantation outcomes have also been documented in Asian patients. Nguyen and Thuluvath[2] found lower 2-year graft and patient survival rates after transplantation in Asian and African American patients with respect to Caucasians between 1988 and 1996 that differed by liver disease etiology. African Americans with hepatitis C virus (HCV), cryptogenic cirrhosis, and acute liver failure had worse outcomes than whites; in contrast, Asians with hepatitis B virus (HBV), primary biliary cirrhosis, acute liver failure, and cryptogenic cirrhosis had lower survival rates than whites.
Abbreviations
HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; UNOS, United Network for Organ Sharing.
A better understanding of the sources of disparities in access and outcomes of liver transplantation is necessary for the development of effective strategies to eliminate them and improve the health status of patients with end stage liver disease residents. A recent report by Moylan et al.[3] showed that some disparities between African Americans and Caucasians in outcomes on the liver transplantation wait list before 2002 can be attributed to UNOS organ allocation policy. The authors compared the outcomes in African Americans and white patients who were placed on the liver transplantation list before (1996-2000) and after (2002-2006) implementation of the Model for End-Stage Liver Disease (MELD) liver donor allocation policy.[3] Moylan et al. confirmed the disparities reported by Reid et al.[1] among patients placed on the wait list in the prior MELD era (1996-2000). In contrast, the odds of dying or becoming too sick for liver transplantation and the odds of receiving liver transplantation within 3 years under MELD did not differ by race. The MELD allocation policy also corrected a disparity between Asian-Pacific Islanders and Caucasians in the probability of receiving liver transplantation for primary hepatocellular carcinoma (HCC).[4] Yet, racial disparities in liver transplantation persist. African Americans with cirrhosis who were transplanted between 2002 and 2006 had a higher median MELD score, which indicates ongoing barriers to referral for liver transplantation in the MELD era. African Americans transplanted between 2002 and 2006 also continued to experience lower graft and patient survival rates than Caucasians.[5] Compared to Caucasians, African American patients were more likely to undergo transplantation for HCV and acute liver failure and to have a higher MELD score at transplantation and were less likely to undergo live donor transplantation. African American patients with HCV had a significantly lower survival rate that was abolished by adjustments for the higher MELD scores and older age of African Americans. Graft survival was lower in African Americans who underwent transplantation for most indications. Still, African Americans were more likely to have recurrent disease, particularly HCV, and allograft rejection as causes for graft loss than whites, but were less likely to undergo repeat liver transplantation. These results suggest that earlier referral and better therapy to prevent and treat recurrent HCV and allograft rejection might improve the outcomes of liver transplantation for African Americans. Hispanics were also more likely to undergo liver transplantation for HCV from 2002 to 2006 but remarkably had better posttransplant patient and graft survival rates than Caucasians.[5]
Prior to the use of hepatitis B immune globulin (HBIG) treatment to prevent recurrent infection, both patient survival and graft survival following liver transplantation for HBV were inferior to survivals following liver transplantation for all other indications except HCC. Consequently, HBV was deemed to be a contraindication to liver transplantation at some centers. The lower posttransplant survival in HBV-positive recipients has been completely abolished over the past 2 decades by HBIG monotherapy starting in the late 1980s and early 1990s, and HBIG combined with oral nucleoside treatment in the late 1990s. Indeed, a recent study of UNOS data by Kim et al.[6] found no differences in outcomes of liver transplantation for HBV between Asians and Caucasians transplanted in the United States during the era of HBIG and oral nucleoside therapy (1997-2001). African American patients had a lower survival rate and African American race was associated with lower patient survival in a proportional hazards regression model. The basis for this difference was not apparent. Less is known about racial differences in organ allocation and the outcomes of liver transplantation for HBV infections during the MELD era.
In this issue of Liver Transplantation, Bzowej et al.[7] and the National Institutes of Health HBV OLT study group present the results of a combined retrospective-prospective observational study of the outcomes of HBV infection among Caucasian, Asian, and African American patients who were placed on the UNOS liver transplantation recipient wait list between 1996 and 2005 (n = 274) and who had liver transplantation performed between 2001 and 2007 (n = 170). Most patients (80%) in the current study received transplantation under the MELD allocation policy. Patients were followed for a mean of 22 months after listing and for 31 months after transplantation. End-stage cirrhosis was the indication for transplantation in 62%, HCC was the indication in 30%, and acute liver failure was the indication in 7%. In comparison with Asians and African Americans, end-stage liver cirrhosis was a more common indication for listing among Caucasians; HCC was more common among Asian patients, and acute liver failure was more prevalent among African Americans. The races did not differ with respect to other variables at listing or at transplantation. There were no racial differences in the probability of liver transplantation up to 5 years after listing. All patients with acute liver failure received liver transplantation within 8 days of listing, and patients with HCC were transplanted at a higher rate than patients with end-stage liver disease. Only the liver transplant indication and MELD score were associated with the probability of liver transplantation in a Cox regression model. In addition, there were no significant racial differences in HCC incidence or liver-related mortality while patients were on the wait list. Furthermore, there were no differences in posttransplant survival rates between the 3 races. Patient survival rates at 1 and 5 years ranged from 90% to 94% and 85% to 94%, respectively. Recurrent HCC was the only variable associated with posttransplant mortality in a multivariable model. Recipient race was not a significant variable in the probability of liver transplantation.
The availability of HBV serological tests, serum HBV DNA and resistance data, guidelines for HBV treatment before and after transplantation, and information on HBV recurrence after transplantation were unique features of the study. Sixty percent were receiving antiviral therapy with lamivudine and/or adefovir dipivoxil at the time of listing. The duration of treatment and the specific regimens used prior to listing are not discussed, but most treated patients appeared to have incomplete HBV DNA suppression. Serum HBV DNA was detected in 60% at listing and at the time of liver transplantation. The mean titer was 10,000 HBV DNA copies/mL at listing, and 60% had more than 105 copies per milliliter at the time of transplantation. This probably explains the high HBV breakthrough and genotypic resistance rates detected before transplantation. Ninety-seven percent of the patients were treated with HBIG plus an oral agent after transplantation. Despite a high rate of active HBV replication prior to transplantation, only 8% of the patients experienced recurrent HBV infection after transplantation. This is consistent with prior studies showing lower recurrence rates in patients who receive a combination of HBIG and an oral agent instead of monotherapy.[8] Consequently, recurrent HBV infection was not an important factor in patient and graft survival. For unclear reasons, recurrent HBV was significantly higher in Caucasian patients, especially at 2 and 4 years after transplantation. In a multivariable analysis, HBV recurrence was associated with hepatitis B e antigen status at listing but not with race, pretransplant serum HBV DNA concentration, transplantation after the approval of adefovir by the Food and Drug Administration, or transplant center. Other potential causes for HBV recurrence such as the use of dual therapy versus monotherapy with HBIG or oral nucleoside, variability in patient compliance with the HBIG/oral therapy, and HBIG serum dynamics were not examined. Also, HCC recurred in only 8% with no racial difference, despite the observation that more than 50% of tumors exceeded the Milan criteria at the time of transplantation. Factors associated with HCC recurrence such as the tumor stage at listing and transplantation were not analyzed.
The results are consistent with a previous study by Moylan et al.[3] of patients on the UNOS liver transplant wait list who underwent transplantation according to the MELD liver donor allocation policy. MELD allocation policy selected HBV patients for liver transplantation on the basis of the severity of liver disease and the risk of liver-related mortality. Analogously to Kim et al.,[6] Bzowej et al.[7] also found similar survival rates in Caucasians and Asians who underwent liver transplantation for HBV between 1997 and 2001 when treatment with HBIG combined with lamivudine was available. However, the finding that African Americans had posttransplant survival similar to that of Asian and Caucasian patients contradicts Kim's results in a study of 1200 patients. This difference between the studies can probably not be explained by differences in organ allocation policy in the United States before and after 2002.[5] On the other hand, only 23 African Americans patients were listed and 17 African Americans were transplanted in the study by Bzowej et al.; this sample was too small for dependable conclusions. Thus, the results concerning African American patients must be received with caution. The study has several additional shortcomings. The partial retrospective study design is a potential source of selection bias. Enrollment required informed consent from the patients. Therefore, patients with HBV who denied consent during the prospective period (2001-2006) and patients who were removed from the wait list because they became too ill or because of HCC progression or death during the retrospective period (1996-2001) were excluded. In addition, the follow-up period was relatively short; less than 50% of the patients were followed for more than 2 years either on the wait list or after transplantation. Longer term follow-up and inclusion of more African American patients will be necessary to determine whether these short-term trends in pretransplant and posttransplant outcomes, such as a new HCC diagnosis on the wait list, recurrent HBV and HCC, and survival, will be maintained.
The conclusion that Caucasians, Asian Americans and African Americans with hepatitis B can be managed similarly in the transplant setting seems intuitive. However, aside from the MELD allocation policy and HBV treatment guidelines, the medical management and health care that patients received were not described. The observational study design makes it difficult to identify other variables and medical management that led to excellent long-term outcomes, such as pretransplant management and the selection of patients with acute liver failure and HCC. The results indicate that Asians and Caucasians can expect similar outcomes on the wait list as well as after transplantation, but the OLT study group cohort includes too few African Americans to adequately address disparities between African Americans and Caucasians. More study is necessary to determine whether the disparities between African Americans and Caucasians in outcomes of liver transplantation for HBV identified in 1997-2001 persist in the most recent era.
A better understanding of the sources of disparities in access and outcomes of liver transplantation is necessary for the development of effective strategies to eliminate them and improve the health status of patients with end stage liver disease residents. A recent report by Moylan et al.[3] showed that some disparities between African Americans and Caucasians in outcomes on the liver transplantation wait list before 2002 can be attributed to UNOS organ allocation policy. The authors compared the outcomes in African Americans and white patients who were placed on the liver transplantation list before (1996-2000) and after (2002-2006) implementation of the Model for End-Stage Liver Disease (MELD) liver donor allocation policy.[3] Moylan et al. confirmed the disparities reported by Reid et al.[1] among patients placed on the wait list in the prior MELD era (1996-2000). In contrast, the odds of dying or becoming too sick for liver transplantation and the odds of receiving liver transplantation within 3 years under MELD did not differ by race. The MELD allocation policy also corrected a disparity between Asian-Pacific Islanders and Caucasians in the probability of receiving liver transplantation for primary hepatocellular carcinoma (HCC).[4] Yet, racial disparities in liver transplantation persist. African Americans with cirrhosis who were transplanted between 2002 and 2006 had a higher median MELD score, which indicates ongoing barriers to referral for liver transplantation in the MELD era. African Americans transplanted between 2002 and 2006 also continued to experience lower graft and patient survival rates than Caucasians.[5] Compared to Caucasians, African American patients were more likely to undergo transplantation for HCV and acute liver failure and to have a higher MELD score at transplantation and were less likely to undergo live donor transplantation. African American patients with HCV had a significantly lower survival rate that was abolished by adjustments for the higher MELD scores and older age of African Americans. Graft survival was lower in African Americans who underwent transplantation for most indications. Still, African Americans were more likely to have recurrent disease, particularly HCV, and allograft rejection as causes for graft loss than whites, but were less likely to undergo repeat liver transplantation. These results suggest that earlier referral and better therapy to prevent and treat recurrent HCV and allograft rejection might improve the outcomes of liver transplantation for African Americans. Hispanics were also more likely to undergo liver transplantation for HCV from 2002 to 2006 but remarkably had better posttransplant patient and graft survival rates than Caucasians.[5]
Prior to the use of hepatitis B immune globulin (HBIG) treatment to prevent recurrent infection, both patient survival and graft survival following liver transplantation for HBV were inferior to survivals following liver transplantation for all other indications except HCC. Consequently, HBV was deemed to be a contraindication to liver transplantation at some centers. The lower posttransplant survival in HBV-positive recipients has been completely abolished over the past 2 decades by HBIG monotherapy starting in the late 1980s and early 1990s, and HBIG combined with oral nucleoside treatment in the late 1990s. Indeed, a recent study of UNOS data by Kim et al.[6] found no differences in outcomes of liver transplantation for HBV between Asians and Caucasians transplanted in the United States during the era of HBIG and oral nucleoside therapy (1997-2001). African American patients had a lower survival rate and African American race was associated with lower patient survival in a proportional hazards regression model. The basis for this difference was not apparent. Less is known about racial differences in organ allocation and the outcomes of liver transplantation for HBV infections during the MELD era.
In this issue of Liver Transplantation, Bzowej et al.[7] and the National Institutes of Health HBV OLT study group present the results of a combined retrospective-prospective observational study of the outcomes of HBV infection among Caucasian, Asian, and African American patients who were placed on the UNOS liver transplantation recipient wait list between 1996 and 2005 (n = 274) and who had liver transplantation performed between 2001 and 2007 (n = 170). Most patients (80%) in the current study received transplantation under the MELD allocation policy. Patients were followed for a mean of 22 months after listing and for 31 months after transplantation. End-stage cirrhosis was the indication for transplantation in 62%, HCC was the indication in 30%, and acute liver failure was the indication in 7%. In comparison with Asians and African Americans, end-stage liver cirrhosis was a more common indication for listing among Caucasians; HCC was more common among Asian patients, and acute liver failure was more prevalent among African Americans. The races did not differ with respect to other variables at listing or at transplantation. There were no racial differences in the probability of liver transplantation up to 5 years after listing. All patients with acute liver failure received liver transplantation within 8 days of listing, and patients with HCC were transplanted at a higher rate than patients with end-stage liver disease. Only the liver transplant indication and MELD score were associated with the probability of liver transplantation in a Cox regression model. In addition, there were no significant racial differences in HCC incidence or liver-related mortality while patients were on the wait list. Furthermore, there were no differences in posttransplant survival rates between the 3 races. Patient survival rates at 1 and 5 years ranged from 90% to 94% and 85% to 94%, respectively. Recurrent HCC was the only variable associated with posttransplant mortality in a multivariable model. Recipient race was not a significant variable in the probability of liver transplantation.
The availability of HBV serological tests, serum HBV DNA and resistance data, guidelines for HBV treatment before and after transplantation, and information on HBV recurrence after transplantation were unique features of the study. Sixty percent were receiving antiviral therapy with lamivudine and/or adefovir dipivoxil at the time of listing. The duration of treatment and the specific regimens used prior to listing are not discussed, but most treated patients appeared to have incomplete HBV DNA suppression. Serum HBV DNA was detected in 60% at listing and at the time of liver transplantation. The mean titer was 10,000 HBV DNA copies/mL at listing, and 60% had more than 105 copies per milliliter at the time of transplantation. This probably explains the high HBV breakthrough and genotypic resistance rates detected before transplantation. Ninety-seven percent of the patients were treated with HBIG plus an oral agent after transplantation. Despite a high rate of active HBV replication prior to transplantation, only 8% of the patients experienced recurrent HBV infection after transplantation. This is consistent with prior studies showing lower recurrence rates in patients who receive a combination of HBIG and an oral agent instead of monotherapy.[8] Consequently, recurrent HBV infection was not an important factor in patient and graft survival. For unclear reasons, recurrent HBV was significantly higher in Caucasian patients, especially at 2 and 4 years after transplantation. In a multivariable analysis, HBV recurrence was associated with hepatitis B e antigen status at listing but not with race, pretransplant serum HBV DNA concentration, transplantation after the approval of adefovir by the Food and Drug Administration, or transplant center. Other potential causes for HBV recurrence such as the use of dual therapy versus monotherapy with HBIG or oral nucleoside, variability in patient compliance with the HBIG/oral therapy, and HBIG serum dynamics were not examined. Also, HCC recurred in only 8% with no racial difference, despite the observation that more than 50% of tumors exceeded the Milan criteria at the time of transplantation. Factors associated with HCC recurrence such as the tumor stage at listing and transplantation were not analyzed.
The results are consistent with a previous study by Moylan et al.[3] of patients on the UNOS liver transplant wait list who underwent transplantation according to the MELD liver donor allocation policy. MELD allocation policy selected HBV patients for liver transplantation on the basis of the severity of liver disease and the risk of liver-related mortality. Analogously to Kim et al.,[6] Bzowej et al.[7] also found similar survival rates in Caucasians and Asians who underwent liver transplantation for HBV between 1997 and 2001 when treatment with HBIG combined with lamivudine was available. However, the finding that African Americans had posttransplant survival similar to that of Asian and Caucasian patients contradicts Kim's results in a study of 1200 patients. This difference between the studies can probably not be explained by differences in organ allocation policy in the United States before and after 2002.[5] On the other hand, only 23 African Americans patients were listed and 17 African Americans were transplanted in the study by Bzowej et al.; this sample was too small for dependable conclusions. Thus, the results concerning African American patients must be received with caution. The study has several additional shortcomings. The partial retrospective study design is a potential source of selection bias. Enrollment required informed consent from the patients. Therefore, patients with HBV who denied consent during the prospective period (2001-2006) and patients who were removed from the wait list because they became too ill or because of HCC progression or death during the retrospective period (1996-2001) were excluded. In addition, the follow-up period was relatively short; less than 50% of the patients were followed for more than 2 years either on the wait list or after transplantation. Longer term follow-up and inclusion of more African American patients will be necessary to determine whether these short-term trends in pretransplant and posttransplant outcomes, such as a new HCC diagnosis on the wait list, recurrent HBV and HCC, and survival, will be maintained.
The conclusion that Caucasians, Asian Americans and African Americans with hepatitis B can be managed similarly in the transplant setting seems intuitive. However, aside from the MELD allocation policy and HBV treatment guidelines, the medical management and health care that patients received were not described. The observational study design makes it difficult to identify other variables and medical management that led to excellent long-term outcomes, such as pretransplant management and the selection of patients with acute liver failure and HCC. The results indicate that Asians and Caucasians can expect similar outcomes on the wait list as well as after transplantation, but the OLT study group cohort includes too few African Americans to adequately address disparities between African Americans and Caucasians. More study is necessary to determine whether the disparities between African Americans and Caucasians in outcomes of liver transplantation for HBV identified in 1997-2001 persist in the most recent era.
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