In this large, multi-center cohort study of 1,264 U.S. patients transplanted for HCV-related liver disease, rates of advanced recurrent disease, mortality, overall and HCV-specific graft loss were significantly higher in women than in men. Additionally, recipient female gender was consistently
found to be an independent predictor of each of these four clinically relevant outcomes. Our results confirm and extend the findings of Belli, et al, who initially reported this gender difference in recurrent HCV disease in a study that included 93 females from three centers in Italy.(9
) Further validation of our findings is a recently published analysis of UNOS data from the post-MELD era by Thuluvath et al that found that HCV-infected females experienced an increased risk of death compared to HCV-infected male recipients.(11
) Importantly, our large, U.S.-based center-level study, which includes detailed biopsy data and post-transplant events (e.g., episodes of acute rejection, HCV treatment), offers a potential explanation for this gender difference in mortality – women die more frequently than men secondary to more aggressive recurrent HCV.
Although women were slightly older than men at transplant, had an increased likelihood of undergoing living donor transplantation, had lower rates of hepatocellular carcinoma, and higher rates of acute rejection, our multivariable analyses demonstrate that these differences alone did not account for the gender difference in outcomes. Nor did the gender of the donor significantly affect the association between recipient gender and outcomes in either bivariable or multivariable analyses, with the exception of HCV-specific graft loss where female donor gender strengthened the female recipient gender effect. Futhermore, as there were no gender differences among those who were excluded from our study for early graft loss (<31 days) or HCV aviremia, cohort selection bias is less likely to have contributed to the observed female gender effect.
Could our findings reflect a gender-specific etiologic effect on HCV-disease progression? Certainly. Epidemiologic studies have shown that women infected with chronic HCV experience slower fibrosis progression and lower rates of cirrhosis than men.(1
) Liver transplantation may “naturally select” for those women with chronic HCV who have genetic, virologic, and immunologic factors that lead to a higher risk of cirrhosis and also more rapidly progressive disease post-transplantation. Our study was not designed to test this hypothesis, but studies of HCV-infected patients evaluating cirrhotic females versus non-cirrhotic females versus males may shed further light on this issue.
Regardless of etiology, understanding the specific factors contributing to this gender difference is critical to improving post-transplant outcomes for all HCV-infected recipients. Our findings suggest that women may need to be monitored more closely for disease progression than under current practice. In particular, given our analyses demonstrating that donor age and treated acute rejection are the dominant predictors of poor outcome among females, women receiving older donor liver grafts or have had early acute rejection may need to be targeted for earlier post-transplant antiviral therapy or receive less aggressive treatment for acute rejection.
Interestingly, we found that antiviral therapy prior to the development of advanced fibrosis was associated with a 27% decreased risk of advanced fibrosis compared with patients who did not receive antiviral therapy prior to this outcome. While some studies have reported that the benefit of post-transplant antiviral treatment in HCV-infected liver transplant recipients is generally limited to those who achieve SVR,(13
) exploratory analyses of our data revealed that the protective effect was independent of SVR. Furthermore, antiviral therapy in the post-transplant setting in our cohort was protective against death and graft loss, a finding that is similar to the survival benefit seen in other more recently published studies.(15
) Although we found no significant differences in the baseline characteristics of the patients who received treatment compared with those who did not, whether our findings represent a true protective effect of treatment as opposed to a bias towards treating healthier patients certainly warrants further investigation. However, caution in interpreting these treatment-related associations in our study is needed, as we lack detailed information regarding dose, duration and tolerability of antiviral therapy in the treated patients, and these factors may influence treatment benefits.
There are several limitations to our study. Certain post-transplant metabolic factors, notably diabetes, have been shown to be important predictors of recurrent disease progression, but accurate information on post-transplant diabetes and insulin resistance are difficult to ascertain in a retrospective study such as ours. Second, the cause of graft failure was missing in 13% of our cohort, but without any evidence of a selection bias by gender. However, our sensitivity analysis confirmed a hazard of similar direction and magnitude of HCV-specific graft failure associated with female gender, and this does not change the association between gender and overall graft failure that we observed. In addition, while liver biopsies were not performed as part of a standard protocol among each of five centers, there were no gender differences in the median number of biopsies, time to the first biopsy, time from the first biopsy to the biopsy showing advanced fibrosis, so it is unlikely that this limitation accounts for the gender effect. These limitations underscore the importance of a developing a future prospective multi-center study to confirm our findings using this retrospective cohort as a stepping stone.
We acknowledge that there are inherent limitations to this multi-center study owing mainly to the heterogeneity of the centers’ practices for post-transplant care with respect to immunosuppression and HCV treatment. We carefully evaluated cyclosporine versus tacrolimus-based regimens in our multivariate models and found that their effect on the association between gender and each of the four outcomes was qualitatively similar to models that were adjusted for center effect. Therefore, we elected to adjust each multivariate model for center effect alone, as this statistical technique has the advantage of accounting for such recognized differences in addition to other potential confounders that we could not measure directly.
However, the multi-center nature of this study is also its strength. CRUSH-C is the largest and most contemporary cohort to examine gender effects on the natural history of HCV following transplantation. Given the relatively small numbers of outcomes among the female subgroup of HCV-infected transplant recipients, prior smaller, single-center studies were extremely limited in performing adjusted analyses to assess the relationship between female gender and HCV-specific outcomes.
In conclusion, female gender represents an important risk factor for advanced recurrent HCV disease and graft loss. Our retrospective study provides provocative evidence to support a long-term, prospective cohort study using standard immunosuppression regimens, protocol liver biopsies, and post-transplant treatment algorithms to determine whether modification of donor factors, immunosuppression, and post-transplant therapeutics may serve to equalize HCV-specific outcomes in women and men. Clearly, gender is important in post-transplant outcomes for HCV-infected liver transplant recipients but whether gender-specific algorithms for post-transplant management can optimize outcomes remains to be determined.