Our multicenter cohort study demonstrates that HCV(+)D are not “risk-free”. Although prior UNOS-based studies found no association between donor HCV-antibody status and survival (2
), these studies could not evaluate the clinically significant outcome of fibrosis progression or account for key post-transplant events (i.e., acute rejection, HCV treatment). Specifically, we found that liver transplantation with HCV(+)D grafts was associated with an overall 58% increased adjusted risk of advanced fibrosis compared to HCV(−)D grafts.
Importantly, this increased risk of advanced fibrosis associated with HCV(+)D grafts was most apparent among recipients of grafts from donors > 45 years – a finding that persisted even after adjustment for other independent predictors of advanced fibrosis. This substantiates findings from a prior single-center study that reported more severe fibrosis in the recipients of older (≥50 years; n=9) compared to younger HCV(+)D grafts (<50 years; n=20) (5
). As regenerative capacity of hepatocytes is age-dependent (11
), hepatocytes that have previously been injured by chronic inflammation in an older donor may have decreased ability to repair and proliferate compared to a younger donor. Additionally, age may be a surrogate for the presence of hepatic fibrosis in HCV(+)D, which has recently been reported to be an important predictor of severe HCV recurrence (12
). Lastly, older donor livers may have higher rates of baseline clinical fibrosis prior to implantation.
Consistent with UNOS-registry based studies (2
), rates of mortality and graft loss did not differ significantly by HCV-antibody status in our cohort. One explanation is that recipients of HCV(+)D grafts live for several years after the development of advanced recurrent disease so that differences in patient and graft survival require a longer duration of follow-up to become apparent. Alternatively, increased attention on the part of the provider to post-transplant management of HCV(+)D graft recipients with rapid recurrence, including changes in immunosuppression, less aggressive treatment of acute rejection, and early initiation or longer duration of antiviral treatment, may attenuate differences in graft survival between HCV(+)D and HCV(−)D graft recipients. Additional studies with long-term follow-up and more granular post-transplant event data are needed to further explore these hypotheses.
Consistent with prior UNOS-based studies, we found that there were significant differences in baseline characteristics of HCV(+)D versus HCV(−)D. This perhaps reflects the demographics of the HCV-antibody positive individuals in the United States, as African-Americans, relative to individuals of other race/ethnicities, have a disproportionately higher prevalence of HCV-antibody positivity and rates of tobacco use (i.e., may be at increased risk of cerebrovascular death) (13
). In addition, a recent study demonstrated that HCV-antibody positive individuals (with or without viremia) experience a higher mortality rate ratio in all groups above 30 years (e.g., 30–44, 44–59, ≥60) compared to HCV-antibody negative individuals (13
). These factors, in addition to their high proportion of national-share distribution likely due to their HCV-antibody positivity, explain the higher DRI associated with grafts from HCV(+)D.
Unlike in the DRI, however, grafts from African-American donors are associated with a decreased
risk of advanced fibrosis in our analyses. Although these grafts were associated with a higher risk of graft loss in the donor risk index (15
) – which included recipients of all etiologies of liver disease – there is a growing body of evidence to suggest that the donor risk index may not be predictive of graft loss in HCV-infected liver transplant recipients (16
). In the non-transplant setting, African-Americans with chronic HCV infection experience slower rates of progression to cirrhosis (18
), and whether these same protective immunologic and genetic factors play a role in the post-transplant setting warrant more detailed investigation.
One limitation of our study is the lack of detailed donor data, including donor biopsies and donor HCV RNA. Unfortunately, data on donor fibrosis were not reported in the UNOS registry, the source of our donor data; only macrovesicular and microvesicular steatosis was reported, and these data were available for <20% of our entire cohort. In a European-based multi-center study, 43% of the 63 HCV(+)D were aviremic and over 50% had stage 1 fibrosis (12
). However, the mean donor age in their cohort was 57.3 years, over a decade older than the donors in our cohort, so these findings may not be applicable in a U.S.-based cohort. In addition, the standard practice at each of the five centers was to accept only grafts from HCV(+)D without any evidence of fibrosis. Acceptance of grafts from HCV(+)D with minimal fibrosis was considered only for donors without any additional risk factors for poor post-transplant outcome such as older donor age or donation after cardiac death. Therefore, we believe that it is unlikely that there was a substantial
difference in baseline fibrosis between younger and older HCV(+)D. A second limitation is our lack of donor HCV viremic status. Since some proportion of the HCV(+)D in our study were not viremic and not at risk for potentially affecting HCV disease progression in the recipient, we would expect that reclassification of these aviremic HCV(+)D graft recipients would further strengthen the association between donor HCV-antibody status and post-transplant fibrosis severity.
Our study has important implications for the use of HCV(+)D grafts. We advise caution when using grafts from HCV(+)D, especially older ones. Recipients of HCV(+)D grafts should undergo close monitoring for the early development of advanced fibrosis, and this monitoring approach may be tailored if future studies demonstrate that donor fibrosis or donor HCV viremia further modify recipient outcomes. In light of more effective HCV therapy with direct-acting antiviral agents, further studies are warranted to determine whether early HCV treatment modifies this risk and whether recipients of HCV(+)D grafts should be selected based upon their genotype and ability to tolerate antiviral therapy. Most importantly, given the negative impact of advanced recurrent disease on health-related quality of life post-transplant (20
) and the higher risk with use of HCV(+)D, our study reminds us of the need to carefully balance the risk of wait-list mortality with the risk of post-transplant complications when utilizing HCV(+)D organs.