African Americans (AAs) are disproportionately affected by chronic hepatitis C virus (HCV) infections and constitute 20% of the US HCV-infected population.1 Natural history studies have indicated that AAs are less likely to spontaneously clear HCV after exposure1 and are less likely to achieve successful eradication of the virus with antiviral therapy2-4; this results in higher rates of chronic infection. However, studies also suggest that chronically infected AAs are less likely to progress to cirrhosis than non-AAs who have the disease for the same estimated time.5-8 The natural history of HCV disease in AA recipients of liver transplantation (LT) and the factors influencing the risk of advanced fibrosis are largely unknown.
In the United States, approximately 10% of HCV-positive patients undergoing LT are AA.9 Previous studies have shown that patient and graft survival rates are lower for AA transplant recipients versus non-AA transplant recipients (including recipients with HCV).10-12 Using United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) data from 1998 to 2007, a recent study found that HCV-positive AAs with race-mismatched donors had a 41% higher mortality rate than HCV-positive AA recipients with race-matched donors.9 In another study that used UNOS/OPTN data from 2003 to 2005 and did not stratify patients by their HCV status, AA donor race was not found to be an independent predictor of graft failure once adjustments were made for center effects and other potential confounders.13 Furthermore, the reduced survival rate of HCV-infected AA transplant recipients has been assumed to be due to worse HCV disease outcomes, but there have been no previous studies evaluating HCV-specific graft outcomes in AAs versus non-AAs. The Consortium to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C) is a multicenter cohort of 4 large US transplant centers that is focused on defining the predictors of HCV disease severity and HCV-associated graft failure. Its findings are used here to evaluate the role of recipient-donor race mismatch in AA transplant recipients.
AA, African American; CMV, cytomegalovirus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HLA, human leukocyte antigen; HR, hazard ratio; IL-28, interleukin-28; IQR, interquartile range; KIR, killer cell immunoglobulin-like receptor; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OPTN, Organ Procurement and Transplantation Network; rAA/dAA, African American recipient/African American donor; rAA/dNonAA, African American recipient/non–African American donor; rNonAA/dAA, non–African American recipient/African American donor; rNonAA/dNonAA, non–African American recipient/non–African American donor; SVR, sustained virological response; UNOS, United Network for Organ Sharing.
PATIENTS AND METHODS
This multicenter, retrospective cohort study included all adult patients (18 years old or older) who underwent LT for the first time for HCV-related disease between March 1, 2002 and December 31, 2007 at University of California San Francisco, New York Presbyterian Hospital/Columbia, Virginia Commonwealth University Medical Center, or Baylor University Medical Center. Anti-HCV and HCV RNA tests were used to establish the presence of HCV infections. The exclusion criteria included HCV RNA negativity immediately after LT, graft loss within 30 days of LT, and a coinfection with human immunodeficiency virus. The institutional review boards at each of the participating study centers approved this study.
Donor characteristics, including age, race, sex, cause of death, and positivity for HCV antibodies, and peritransplant factors, including warm and cold ischemia times, were obtained from the UNOS/OPTN database. Recipient demographic, virological, and clinical data, including immunosuppressive medications at the last follow-up, were collected retrospectively by reviews of individual health records. Acute cellular rejection was defined as biopsy-proven rejection requiring treatment with high-dose bolus corticosteroids or anti-lymphocyte therapy. A cytomegalovirus (CMV) infection was defined as an infection requiring anti-CMV therapy. HCV treatment dates and the response status were obtained, and the achievement of sustained virological response (SVR) was defined as negative HCV RNA findings at least 6 months after treatment discontinuation. Each center used a standard immunosuppression regimen; however, the immunosuppression regimens were not uniform among the sites.
Study Endpoints and Covariates
The primary outcome was the presence of advanced fibrosis, which was defined as bridging fibrosis or cirrhosis on a liver biopsy sample. The biopsy results were based on the assessments of local pathologists. Ninety-two percent of the 1093 study patients were biopsied during the study period, and the biopsy samples were used for analyses of disease severity. All patients were included in the analyses of the secondary endpoints of all-cause graft loss (defined as death and/or retransplantation) and graft loss with advanced recurrent HCV disease.
For the analysis of AA recipient race, the comparator group consisted of non-AAs, which included Caucasians, Asians, Hispanics, and members of other races. For the analysis of AA recipient-donor match versus AA recipient-donor mismatch, the matched group consisted of African American recipient/African American donor (rAA/dAA) matches, and the unmatched group consisted of African American recipient/non–African American donor (rAA/dNonAA) mismatches. In these regression models, non-AA recipients with or without race-matched donors were used as the reference group. An additional analysis was performed in which non-AA recipients were divided into 2 groups: a non–African American recipient/African American donor (rNonAA/dAA) group and a non–African American recipient/non–African American donor (rNonAA/dNonAA) group.
Descriptive statistics are presented as medians and interquartile ranges (IQRs) or proportions as appropriate. For comparisons of AA and non-AA groups, chi-square tests have been used for dichotomous variables, and Wilcoxon rank-sum tests have been used for continuous variables.
The cumulative rates of advanced fibrosis were estimated with Kaplan-Meier methods, and the groups were compared with log-rank tests; P < 0.05 was considered statistically significant. Cox proportional hazards regression was used to examine the predictors of graft survival and advanced fibrosis. The primary predictor variables were AA recipient race and AA recipient-donor race mismatch. Other recipient, donor, and transplant-related factors were examined in univariate models, and those covariates with P < 0.10 were evaluated in multivariate models. Models were built with the backward elimination of covariates; P < 0.05 was used as the criterion for inclusion in the final model. All final models were adjusted for center effects through the inclusion of the center as a covariate in the analyses. Because of the limited number of HCV-associated graft losses among AA recipient-donor–matched patients versus AA recipient-donor–mismatched patients, multivariate models were not evaluated. Sensitivity analyses limited to only Caucasian and AA recipient and donor race groups were performed.
Statistical analyses were performed with Stata 11 (Stata Corp., College Station, TX).
This study included 1093 patients, and 122 (11%) were AA. The 971 non-AA patients were Caucasian [707/1093 (65%)], Hispanic [188 (17%)], or Asian [27 (2%)] or were classified as other race [49 (4%)]. Twenty-one patients, including 3 AAs, suffered graft loss within 30 days of LT, and they were not included in this study. Donor race data were incomplete for 4 AA patients (0.4%) and 38 non-AA patients (3.5%); these patients were excluded from analyses of the primary predictors of AA recipient-donor mismatch, but they were included in analyses involving AA recipient race alone. Twenty-seven of the 122 AAs (22%) were in the race-matched group (rAA/dAA), and 91 (75%) were in the mismatched group (rAA/dNonAA); donor race data were missing for 4 (3%).
The median follow-up for the study cohort was 3.05 years (IQR = 1.81-4.74 years), and there was no difference in the duration of follow-up between AAs (2.99 years, IQR = 1.35-4.36 years) and non-AAs (3.06 years, IQR = 1.95-4.83 years, P = 0.15). There was no difference in the median duration of follow-up by racial subgroups: 3.80 years for the rAA/dAA group (IQR = 2.11-5.00 years), 2.67 years for the rAA/dNonAA group (IQR = 1.22-4.36), 3.08 years for the rAA/dNonAA group (IQR = 1.87-4.94), and 3.00 years for the rNonAA/dAA group (IQR = 1.64-4.47, P = 0.18). The median number of biopsies per patient was 3.0 (IQR = 2.0-4.0), and there was no difference between AA and non-AA patients [3.0 (IQR = 2.0-4.0) versus 3.0 (IQR = 2.0-4.0), P = 0.51]. AA recipients and non-AA recipients were similar except for the proportions undergoing combined transplantation (the liver and another organ), the median laboratory Model for End-Stage Liver Disease (MELD) scores at LT, the proportions with AA donors, and the median warm ischemia times (Table 1). The race-matched group (rAA/dAA) and the race-mismatched group (rAA/dNonAA) were similar except for the cold ischemia times [7.1 hours (IQR = 5.4-7.5 hours) versus 7.8 hours (IQR = 6.2-9.4 hours), P = 0.05].
Table 1. Characteristics of AA and Non-AA LT Recipients
AAs (n = 122)
Non-AAs (n = 971)
The data are presented as medians and IQRs.
One patient underwent combined liver-heart transplantation, whereas all the other patients underwent combined liver-kidney transplantation.
At least 1 episode of acute rejection before advanced fibrosis (%)
HCV treatment (%)
HCV treatment before advanced fibrosis (%)
CMV treatment (%)
All-cause graft failure (%)
HCV-related graft failure (%)
Advanced fibrosis (%)
Rates and Factors Associated With Advanced Fibrosis
In all, 113 AA patients (93%) and 888 non-AA patients (91%) were biopsied during the study period, and these patients were included in the analysis of advanced fibrosis. Patients who were not biopsied differed from patients who were biopsied at least once as follows: they had shorter follow-up times, more hepatocellular carcinoma (HCC) at the time of transplantation, fewer episodes of treated acute rejection, and a lower rate of HCV treatment (data not shown).
In all, 47 AAs (39%) and 241 non-AAs (25%) developed advanced fibrosis during the study period (P < 0.01). The unadjusted cumulative rate of advanced fibrosis was higher for AAs versus non-AAs (56% and 40% at 4 years, respectively, P < 0.01) p <0.01). There was no difference between the percentage of rAA/dNonAA and rAA/dAA patients developing advanced fibrosis (P = 0.89). The unadjusted cumulative rates of advanced fibrosis by recipient-donor race groups is shown in Fig. 1). AA recipient race was associated with a significantly higher rate of advanced fibrosis in a univariate model [hazard ratio (HR) = 1.59, 95% CI = 1.16-2.19, P < 0.01] and an adjusted model (HR = 1.47, 95% CI = 1.06-2.03, P = 0.02; Table 2). In comparison with non-AA recipients (with donors of any race), AA recipient-donor race mismatch was a significant predictor of advanced fibrosis in a univariate model (HR = 1.61, 95% CI = 1.13-2.30, P < 0.01) and a multivariate model (HR = 1.48, 95% CI = 1.03-2.12, P = 0.03), but AA recipient-donor match was not (Table 3) in a multivariate model using the rNonAA/dNonAA group as the reference, rNonAA/dAA was found to be protective against advanced fibrosis (HR = 0.43, 95% CI = 0.26-0.70, P < 0.01), and the association with AA recipient-donor race mismatch (HR = 1.31, 95% CI = 0.90-1.91, P = 0.15) was attenuated.
Table 2. Predictors of Advanced Fibrosis for AA and Non-AA Recipients (n = 1001)
The rates of HCV treatment were similar for AAs and non-AAs, but the response rates differed, with 66 treated non-AAs (26%) and 5 treated AAs (13%) achieving SVR (P = 0.05). The SVR rates for AAs with recipient-donor race match and AAs with recipient-donor mismatch were 11% (n = 1) and 15% (n = 4), respectively (P > 0.99). The achievement of SVR was associated with lower rates of advanced fibrosis, but it did not significantly change the association between race and the risk of advanced fibrosis in multivariate models. When treated patients were excluded from the analysis, the association between race and the risk of advanced fibrosis remained in a univariate model (HR = 1.48, 95% CI = 1.06-2.28, P = 0.05) and a multivariate model (HR = 1.24, 95% CI = 1.05-1.56, P = 0.04).
Among the patients who were biopsied at least once during the study period and were treated for HCV, 25 AAs (64%) and 180 non-AAs (71%) were biopsied before they received HCV treatment (P = 0.34). When the analysis was limited to biopsy samples taken before HCV treatment, the independent association between race and the risk of advanced fibrosis remained (HR = 1.92, 95% CI = 1.04-3.56).
In a sensitivity analysis restricted to Caucasian and AA donors and recipients, 102 AAs (15%) and 591 Caucasians (85%) were compared. Both AA race (HR = 1.56, 95% CI = 1.07-2.26, P = 0.02) and AA recipient-donor race mismatch (HR = 1.56, 95% CI = 1.02-2.40, P = 0.04) remained independent predictors of advanced fibrosis. In another sensitivity analysis, we restricted the outcome to stage 2 or higher fibrosis within 1 year of LT so that we could evaluate patients for rapid fibrosis progression. The unadjusted cumulative rate for stage 2 or higher fibrosis was not greater for AAs versus non-AAs (P = 0.09), nor was there a difference between the rAA/dNonAA and rAA/dAA groups (P = 0.22). However, both AA race (HR = 1.39, 95% CI = 1.02-1.88, P = 0.04) and AA recipient-donor race mismatch (HR = 1.42, 95% CI = 1.01-2.00, P = 0.04) were independent predictors of stage 2 or higher fibrosis within 1 year in multivariate models.
Rates and Factors Associated With Graft Failure
Forty-one AAs (34%) and 266 non-AAs (27%) experienced graft failure or death during the study period. In comparison with non-AAs, AAs had higher rates of cardiovascular death (4.1% versus 1.4%, P = 0.05) and HCV-associated graft failure or death (19% versus 9%, P < 0.01). The unadjusted cumulative rates of all-cause graft loss did not differ between AAs and non-AAs (17% and 10% at 4 years, respectively, log-rank P = 0.09), but the rates of graft failure with advanced HCV were significantly higher for AAs versus non-AAs (log-rank P < 0.01). The highest rate of HCV-associated graft loss was seen in the AA recipient-donor–mismatched group. The 4-year cumulative estimates of HCV-related graft failure were 0% for the rAA/dAA group, 21% for the rAA/dNonAA group, 12% for the rNonAA/dAA group, and 10% for the rNonAA/dNonAA group (Fig. 2). In multivariate models, AA race was an independent predictor of HCV-related graft failure (HR = 2.41, P < 0.01; Table 4).
Table 4. Predictors of HCV-Related Graft Failure for AAs and Non-AAs (n = 1093)
In multivariate models of all-cause graft loss and mortality, the glomerular filtration rate at transplant, the donor age, the use of cyclosporine at the last follow-up, HCV treatment, SVR, and CMV treatment were independent predictors of all-cause graft failure, but AA race was not (HR = 1.35, 95% CI = 0.97-1.88, P = 0.08). In multivariate analyses using recipient-donor race mismatch as the primary predictor, rAA/dNonAA was a strong and independent predictor of all-cause graft failure (HR = 1.62, P < 0.01), whereas rAA/dAA was protective (HR = 0.24, P = 0.05; Table 5). The median time to graft loss for patients meeting the endpoint of advanced fibrosis was 0.99 years (IQR = 0.13-2.53 years). The unadjusted cumulative rate of graft loss after advanced fibrosis was higher in AAs versus non-AAs (P = 0.01) and was highest in the rAA/dNonAA group (P < 0.01).
Table 5. Predictors of All-Cause Graft Failure in Race-Mismatched Recipient-Donor Groups (n = 1054)
Glomerular filtration rate at transplant (mL/minute/1.73 m2)
HCC at transplant
Donor age by decade (years)
Non-anoxia donor cause of death
Cyclosporine use at last follow-up
A sensitivity analysis that was limited to only Caucasians and AAs showed that AA race remained an independent predictor of HCV-related graft failure in adjusted models (HR = 3.06, P < 0.01), but it did not remain an independent predictor of all-cause graft failure (HR = 1.35, P = 0.11). AA recipient-donor race mismatch was predictive of all-cause graft failure (HR = 1.72, P < 0.01) in adjusted models.
This is the first study to examine the effects of AA race and AA recipient-donor race mismatch on HCV disease severity and HCV-associated graft loss in transplant recipients. We have shown that AA recipients with HCV disease have a 47% higher rate of bridging fibrosis or cirrhosis in comparison with non-AA recipients, and AA recipients with a non-AA donor have a higher risk of advanced fibrosis than those with AA donors. Additionally, AA recipients have significantly higher rates of HCV-associated graft loss, and AAs with race-mismatched donors appear to be at greater risk than AAs with race-matched donors.
Our study confirms and extends the findings of a previous OPTN-based study by Pang et al.,9 who showed that AA recipient-donor race mismatch (versus match) was associated with reduced graft survival. However, our study establishes the link between advanced disease and graft loss. Our study differs from the previous study by Pang et al.: we used a contemporary cohort of the MELD era, and we did not restrict the analysis to AAs and Caucasians. However, our sensitivity analysis comparing the results for AAs and Caucasians suggests that the AA recipient-donor race mismatch effect on advanced fibrosis and graft failure is not specific to Caucasian donors but is more generalizable to all non-AA donors.
The reason for the increased advanced fibrosis associated with AA recipient-donor race mismatch in HCV-infected AAs is unknown. We speculate that it may be related to protective genetic factors associated with the donor liver. The importance of donor and recipient interleukin-28B (IL-28B) polymorphisms has been highlighted by recent studies. Recipients with favorable alleles have been shown to have less inflammatory activity on post-LT biopsy samples14 and higher rates of response to antiviral therapy.14-17 Interestingly, single-nucleotide polymorphisms of IL-28 in both the donor and the recipient have been found to be predictive of posttransplant outcomes.15, 16 Although IL-28B polymorphisms are critical to our understanding of HCV-associated outcomes after LT and especially the response to HCV treatment, they are unlikely to explain the race match and mismatch effects seen in AAs. Population studies have shown that AAs have a substantially lower frequency of the favorable IL-28B alleles in comparison with Caucasians.18 If HCV disease outcomes are influenced by the IL-28B genotype, one could hypothesize that AAs with AA donors are more likely overall to have unfavorable IL-28B genotypes than AAs with non-AA donors, and yet this group had the best outcomes. Thus, other recipient and donor genetic factors [including but not limited to killer cell immunoglobulin-like receptor (KIR) receptors and ligands]19 and/or viral factors15 are likely to be important.
Natural killer cells and KIRs modulate the immunological response to HCV, with KIRs specifically recognizing human leukocyte antigen (HLA) class I antigens present on target cells. The effector function of natural killer cells is influenced by inhibitory KIR interactions with self-HLA class I ligands, with HLA-C being the most predominant. Previous studies have found that a decrease in the number of HLA-C allele mismatches correlates with a decrease in the number of rejection episodes.20, 21 Furthermore, mismatched KIR–HLA-C ligands in recipient-donor pairs favor progression to advanced fibrosis with recurrent HCV disease, but only in the presence of KIR2DL3.19 One could hypothesize that mismatched KIR–HLA-C ligands underscore the race mismatch effect that we have shown. However, further studies examining KIR–HLA-C and race mismatch are needed to further examine this hypothesis.
Although an evaluation of recipient-donor mismatch in non-AA recipients was not the focus of our study, an apparently protective effect of AA donor race (versus non-AA race) against the risk of advanced fibrosis was also seen in non-AA recipients. Differences in donor quality (eg, the donor cause of death and the donor age) were explored post hoc but were not found to explain this association (data not shown). Thus, other unmeasured donor or transplant-related factors are likely at play.
In our study, the achievement of SVR was protective against HCV-associated graft failure and all-cause graft failure, as shown in other studies.22, 23 Treatment rates were similar for AAs and non-AAs, but rates of SVR were higher in non-AAs versus AAs.2-4 This differential rate of response to therapy is partially explained by IL-28B polymorphisms24; interestingly, IL-28B polymorphisms may be even stronger predictors of response in LT recipients versus nontransplant patients,14 and this may suggest an interaction between the actions associated with IL28B type and immunosuppression. Because of the recognized importance of treatment responses to the achievement of long-term graft survival, new treatment options with efficacy in patient groups with unfavorable IL-28B genotypes (eg, AAs) are essential.
In most epidemiological studies, the gold standard for race classification has been the use of self-identified race.25, 26 In this study, recipient and donor race data were obtained from the UNOS/OPTN database, which does not require the self-designation of race; thus, some misclassification bias may exist. However, this limitation is not unique to this study but rather is common to all studies of race that use UNOS/OPTN data.2, 4-10, 13 Moreover, among members of a self-identified race, genetic heterogeneity is recognized because of variable admixtures with other racial groups.27, 28
There are some limitations to our study. First, because of its retrospective nature and lack of systematic data collection, some factors of potential importance to disease progression, such as donor steatosis or diabetes, recipient/donor IL-28B polymorphisms, and detailed immunosuppression information, are lacking. Second, because of the relatively small sample size, interactions could not be statistically examined. Third, despite the inclusion of 4 large US transplant programs, the total number of AAs in the study (particularly those matched to AA donors) is modest and limits our ability to perform an extensive multivariate analysis of recipient-donor–matched and recipient-donor–mismatched subgroups. However, the proportion of AAs in our cohort is very consistent with the proportion of AAs undergoing LT in the United States, so we believe our results are generalizable. Fourth, there is a possibility of misclassification bias within a race group. Despite these limitations, this is the largest cohort of patients with biopsy data evaluating disease severity after transplantation, and it includes detailed information on other cofactors known to influence disease progression, such as donor age, acute rejection, and HCV treatment.
In conclusion, this study shows that AAs have higher rates of advanced fibrosis and graft loss associated with HCV than non-AAs, and AAs with recipient-donor race mismatch represent the highest risk group. The importance of donor selection is highlighted by our results, and the use of high-quality donors (ie, younger donors, race-matched donors, or donors with a low donor risk index) may be a strategy for minimizing the risk of disease progression, especially in high-risk groups such as AAs. We do not advocate the routine matching of recipients and donors according to race, but it may be a factor to be weighed favorably when a graft is being assessed for an AA recipient, particularly if the graft is coming from an extended criteria donor. Our results also argue for closer monitoring of disease progression in AA LT recipients, possibly through the more frequent use of liver biopsy, and for the earlier consideration of antiviral therapy. Clearly, there is also a need for antiviral therapies with improved efficacy for all transplant recipients, but among AAs, this is particularly critical because of their truncated timeline for the development of recurrent cirrhosis.