We analyzed change in outcomes during two successive 5-year periods (period I = 1992–1996 vs period II = 1997–2002) among 35 186 deceased adult liver transplant recipients reported to the United Network for Organ Sharing (UNOS) Registry. The 5-year graft survival was 67.4% in the first period and 67.5% in the second, though the 1-year survival had improved from 81.0 to 83.5%. Comparison of blended survival rates during the two study periods showed decreased long-term graft survival in period II, explicable by an increased number of hepatitis C virus cirrhosis (HCV) patients and an increase in patients with HCV antibodies (HCVab) during this later period. Analysis wherein these patients with HCV were excluded revealed the same long-term graft survival during both periods. Non-HCV patients who had HCVab also had worse 5-year graft survival. We conclude that hepatitis C prevented improved outcomes during period II and that improved, more effective, treatment for hepatitis C virus would have great positive impact on overall survival of liver transplant recipients.
The advent of cyclosporine (CsA) led to a steady improvement in both short- and long-term survival of renal grafts (1) and liver transplantation (2). Further, the introduction of tacrolimus (Tac) resulted in improvement in short-term graft survival and the decreased incidence of acute rejection (3). Given these improvements, we expected that long-term graft survival would also progressively improve along with advancements in surgical techniques, patient management and immunosuppressive drugs. Despite these improvements, studies in kidney transplantation, surprisingly, have shown that the reduction in acute rejection has not resulted in a corresponding improvement in long-term survival (4). Moreover, a recent study of liver transplants showed a decrease in graft survival in hepatitis C virus cirrhosis (HCV) patients, as well as lower survival among all patients who had anti-hepatitis C virus antibodies (HCVab) (5–7). These studies suggest that not all graft survival rates have necessarily improved over time.
To determine whether long-term liver transplantation (survival after the first year) has improved, we examined the data of the United Network for Organ Sharing (UNOS) Liver Transplant Registry. Specifically, we investigate survival rates for six primary diseases, taking into account potential confounding factors and the cause of graft failures.
Patients and Methods
We used data on liver transplants performed between January 1992 and December 2002 in the United States as reported to the UNOS Registry to examine the change in graft survival rates and cause of graft failures for two transplantation year periods. Period I was from 1992 to 1996 and period II was from 1997 to 2002. Multi-organ transplant grafts and regrafts were excluded. We limited our study to adult patients (>16 years) who received an organ from a deceased donor. The total number of liver transplants was 35 186.
Among the 72 registered primary diseases, we separately examined six main diseases: hepatitis C virus cirrhosis (HCV), hepatitis B virus cirrhosis (HBV), primary sclerosing cholangitis (PSC), primary biliraly cirrhosis (PBC), autoimmune hepatitis (AIH) and alcoholic liver disease (ALD). In addition, we also examined data on two categories of metabolic disease (alpha-1-antitripsin deficiency and Wilson's disease, etc.) and acute hepatic necrosis (AHN) (drug-induced type, hepatitis virus (A, B, C, D) and others). Patients with other types of hepatitis C virus infection-related diseases such as hepatocellular carcinoma were classified into the category of ‘hepatitis C virus-related disease.’ Among 25 901 non-HCV patients, 4037 had HCVab.
Kaplan-Meier curves and log-rank tests were used to describe and compare graft survivals and patient survival for the two time periods. Patient deaths and retransplantations were counted as graft loss. All p-values were two-sided, and p < 0.05 was considered significant. The chi-square test was used to compare distribution differences of categorical variables. The t-test was used to compare group mean differences for continuous variables. Disease prevalence-adjusted graft survival was calculated using the formula S(y)A= S(y)D1· PD1+ S(y)D2· PD2+ S(y)D3· PD3, where P is the prevalence of each disease.
Cox proportional hazard analyses were conducted to adjust for major confounding factors in each disease category. The same model was used to analyze each disease for the two time periods. Following a previous study (8), liver transplantation factors were selected and classified as follows: (i) donor age variable: 0–20, 21–40, 41–60, >60 years; (ii) recipient race: African American, non-African American; (iii) recipient age: 17–40, 41–60, >60 years; (iv) recipient sex; (v) warn ischemic time: 0–12, >12; (vi) cold ischemic time: 0–60, 61–120, >120; (vii) patient status: not hospitalized, hospitalized but not in ICU, ICU; (viii) presence of HCVab and (ix) serum creatinine level: 0–1, 1.1–1.5, >1.6. A total of 632 patients (2.2%) with missing values used in Cox were excluded to maintain the integrity of the database. Also excluded for the Cox test were 7575 grafts that survived less than 1 year. All analyses were performed with the Stata program (Ver. 7.0).
Change in graft survival rates in overall data
The comparison of liver graft survival for the two periods, 1992–1996 and 1997–2002, revealed no improvement in overall 5-year graft survival (Figure 1A). The 5-year graft survival rates in period I and period II were 67.4 and 67.5%, respectively (p = 0.2); however, the 1-year graft survival rates had improved from 81.0 to 83.5% in period II (p < 0.001). A plot of graft survival after 1 year (Figure 1B) revealed a significantly lower rate of survival in period II. The reasons for the loss in long-term survival in period II were then investigated.
During the 10-year study period, a steadily increasing number of HCV patients were transplanted, as shown in Figure 2A. As can be seen, the percentage of patients with HCV in period II rose from 18.0% in 1992 to 31.9% in 2002. The proportion of ALD patients decreased from 20.6 to 12.8%, while the percentage of those with PSC decreased from 8.8 to 6.0% and those with PBC from 9.5 to 3.8%.
During the 10 years under investigation, the highest 5-year graft survival rate was for patients with PBC (77.4%) and the lowest for the HCV group (63.5%) (Figure 2B). The rapid decline in graft survival for HCV patients is apparent when compared to patients with other diseases. Thus, transplantation of more HCV patients with the poorest graft survival could explain why overall graft survival fell in the second period, as shown in Figure 1.
Once HCV was identified as a major factor, HCV patients were compared to all other non-HCV patients. Non-HCV patients include patients whose primary diseases were hepatitis C virus-related diseases (acute hepatic necrosis type C, type C & B cirrhosis, alcoholic cirrhosis with hepatitis C, hepatocellular carcinoma and cirrhosis). The HCV patients had a markedly lower long-term graft survival rate in period II after the first year post-transplantation (Figure 3A). As shown in Figure 3A, non-HCV patients also had a lower survival in period II compared to period I. When the non-HCV patients were further divided into those who did and those who did not have HCVab in their serum, a noticeable decrease in long-term graft survival was seen among those patients with HCVab (Figure 3B). This very strong effect of hepatitis C virus infection in patients with various diseases led to poor long-term survival, which was as low as that in HCV patients. Thus, even in patients with various primary diseases, if they had been infected with hepatitis C virus, their graft survival was as low as that of patients whose primary disease was HCV.
Graft survival according to primary disease
As shown in Figures 4 and 5 and Table 1, first year graft survivals were significantly improved in most primary disease patients, except for those with PSC and PBC. Figure 4 shows 5-year graft survival on the left side and long-term graft survival after 1 year on the right side for patients with various primary diseases. Our analysis of long-term graft survival of each primary disease included HCVab negative patients only. As in the overall data, there was no improvement in 5-year graft survival for HCV, PSC, PBC and HBV. Analysis of long-term graft survival of grafts with more than 1 year of graft survival showed that period II transplants had lower survival than patients in period I who had HCV and PSC (Figure 4 right side).
Figure 5 shows 5-year graft survival on the left side and long-term graft survival after 1 year on the right side for four other primary diseases. For all these diseases, 5-year graft survival was higher in period II, although the difference was not statistically significantly different, except for ALD. Long-term graft survival after the first year did not improve in patients with any of the four diseases shown.
Differences in two periods adjusting for transplantation-related factors
Table 1 compares transplantation-related characteristics of patients in relation to main primary diseases for the two time periods. Most striking is the significant increase in overall donor age from 34.3 to 38.4 years (p < 0.001) for all the diseases. This increase in the age risk factor was also accompanied by an overall increase in recipient age for all diseases from by 48.8 to 50.4 years (p < 0.001), except for patients with PSC, PBC and metabolic diseases. The percentage of patients requiring ICU care increased overall from 16.0 to 18.9% (p < 0.001) during these two periods. HCVab positivity also increased overall from 36.0 to 44.6% (p < 0.001). The percentage of African American recipients with HCV, PSC and PBC significantly increased (Table 1), perhaps adding to the increased risk of late graft failures in these diseases. The table also reveals improvement in surgical technique with a reduction of 1.5 h in warm ischemic time (p < 0.001) and a 15 min reduction in cold ischemic time (p < 0.001).
Transplantation year (period) was not a significant variable in liver transplantation survival, except for patients with HCV and PSC (Table 1). HCV and PSC patients in period II showed significantly lower long-term graft survival rates compared to the first period.
Long-term graft survival excluding HCV, hepatitis C virus-related diseases, PSC and patients with HCVab
The decrease in long-term survival of HCV and PSC patients as well as in patients with HCVab strongly influenced overall survival outcomes. If we had excluded these patients, then graft survival would not have decreased in period II. As shown in Figure 6, exclusion of these patients from the analysis results in the same survival for period I and period II.
Computation of blended graft survival rates according to proportion of HCV patients and HCVab patients
We hypothesized that the decrease in long-term graft survival was caused by a change in the proportion of transplant patients with HCV and calculated the blended rate taking this into account. We assumed that disease composition did not change from 1992 to 2002 and that graft survival remained the same from period I to period II for HCV recipients and anti-HCVab positive recipients. Figure 7 shows a projection of the rate of graft survival over a 5-year period for the two groups. As can be seen, there is no difference for the two periods. Thus, the poor graft survival in the second period can likely be explained by the change in the proportion of HCV patients transplanted.
Figure 7 also indicates that patient survival follows the same trend as graft survival. In other words, despite second and third grafts, patient survival in period II is worse than in period I.
Causes of graft failures
Causes of graft failure in the first and second period were compared (Figure 8) for HCV patients and PSC patients whose graft survival significantly deteriorated in period II (Figure 4). HCV patients in period II had a higher incidence of recurrence of disease than those in the period I, although the difference was not significant. In period II, patients with PSC had a significantly lower incidence of chronic rejection (p = 0.04) and primary graft loss (p = 0.04), compared to period I. The recurrence rate increased from 22.2 to 27.4%, which was not significant.
Patients with HBV had recurrence as a cause of failure in 48.6% of the failures. The overall failure rate for those patients was less than that for those with HCV (Figure 2).
Despite the assumed improvement in immunosuppression and the clear improvement in 1-year graft survival from 81 to 85% in period II, our analysis of the UNOS Liver Transplant Registry data showed no improvement in the 67% 5-year survival rate (Figure 1). One reason for this lack of improvement is the increasing number of HCV patients that have received transplants, making HCV patients the largest group among all primary diseases to be transplanted. In addition to the recent demographic mix, patients with hepatitis C virus infections have a very markedly lower long-term graft survival rate among those with a history of hepatitis C virus infections, as confirmed by serologic test (Figure 3). This lower graft survival among patients with hepatitis C virus infections has been studied earlier by Forman et al. (5), who also used the UNOS Registry data, and noted by others (6,9). The impact of HCV recurrence on graft survival has been documented by many studies (10–12) and shown here to be the cause of graft failure in 55.2% of failures in period I and 61.3% of those in period II (Figure 8). Although the difference between the two periods is statistically insignificant, recurrence in HCV patients in period II is higher than in period I.
Long-term graft survival after 1 year post-transplant has not significantly improved for any of the six primary diseases (Figures 4 and 5). Transplant recipients with HBV, AIH, ALD and metabolic disease had higher 5-year graft survival rates in period II. However, there was no significant improvement in long-term graft survival, even for this population (Figure 5).
Patients with HCV and PSC showed significantly worse long-term survival rates, even after adjusting for contributing factors (Table 1). HCV recurrence is universal, and incidence of cirrhosis at 5 years can be as high as 30% (13). Neumann et al. analyzed 209 transplant patients with HCV and found that one third of patient deaths were due to HCV recurrence (6). Their univariate and multivariate analyses showed that risk factors for HCV recurrence were rejection treatment, use of OKT3, steroids and donor age (more than 40 years old). In addition, immunosuppression regimens may also play a role, since better outcomes with CsA were identified in compared to Tac, e.g. trends to later or lower hepatitis C recurrence, lower mortality and trends toward an association between Tac and hepatitis C virus-induced fibrosis (14–17). Berenguer et al. emphasized that immunocompromised HCV recipients have a faster progression of fibrosis compared to immunocompetent recipients (13). The cause of graft failures (Figure 8) indicated a decreased incidence of immunologic graft loss and increased incidence of disease recurrence.
Patients with other diseases (HBV, PBC, AIH, ALD, metabolic disease, AHN) had no significant long-term graft survival improvement, suggesting that the patient management in the first and second period, including the immunosuppressant regimen, had little impact on long-term survival after the acute phase of 1 year. Liermann et al. (18) and Jacob et al. (19) also reported no long-term survival improvement in PBC. Primary diseases with low incidences of recurrence such as HBV with prophylaxis (9), metabolic diseases and ALD (20) also showed no significant long-term graft survival improvement.
In addition to the limitations imposed by the retrospective design and despite our analysis of data on all liver transplant recipients since 1992, our analyses were performed using reported HCVab as an indicator of a history of hepatitis C virus infections. We had no data on HCV RNA testing or index of hepatitis C stage since this is not collected by UNOS. Due to these limitations, it was not possible to determine whether patients with active HCV infection are different from patients who have HCVab, but no detectable HCV RNA.
In conclusion, despite the improvement in the first-year graft survival in the recent 5 years, we found no improvement in long-term graft survival in liver transplantation. This lack of improvement could be attributed to the increase in the proportion of HCV patients transplanted (who had the worst survival). In addition, non-HCV patients with HCVab also had lower long-term graft survival. We conclude that improved treatment for hepatitis C virus-infected patients would have the greatest impact on overall survival of liver transplants.
This work was supported in part by Health Resources and Services Administration contract 231–00–0115 and funded by Terasaki Foundation Laboratory, Los Angeles, CA, USA.