Survival Rates Stall for HCV Patients after Liver Graft

BALTIMORE, May 7 -- For patients with hepatitis C virus (HCV) infection, the likelihood of surviving over a three-year period after a liver transplant has not improved in 10 years, said researchers here.

However, patients who were not HCV-infected showed significant improvement in patient and graft survival during the same period, reported Paul J. Thuluvath, M.D., of Johns Hopkins, and colleagues.

Their study, reported in the May issue of Liver Transplantation, covered three three-year periods from 1991 to 2001.

Hepatitis C virus-induced liver disease is the most common indication for liver transplantation in the U.S., Dr. Thuluvath said. However, he noted, previous studies from Europe have shown that recipients with HCV have a 10% to 15% lower five-year graft and patient survival compared with non-HCV controls.

To determine whether this difference held for patients transplanted in the U.S., the Hopkins team turned to data from the United Network for Organ Sharing.

Their database included 28,193 patients who underwent a liver transplant from January 1991 through October 2001. Of these, 5,708 who had hepatitis C were eligible for the study, as were 16,116 patients without HCV.

On the basis of time of transplantation, patients were divided into three groups: 1991-1993 (period 1), 1994-1997 (period 2), and 1998-2001 (period 3).

The overall three-year patient survival rate, adjusted for confounding variables, was lower for HCV patients compared with non-HCV patients (78.5% vs. 81.4%, hazard ratio 1.14, 95% confidence interval 1.05 to 1.23, P=0.001), the researchers said.

Patient survival rates remained unchanged during the three study periods at 77.4% for period 1, 79.6% in period 2, and 78.5% in period 3, the researchers reported. Graft survival rates also remained unchanged from period to period at 72.8%, 71.0%, and 69.8%, respectively.

By contrast, the graft and patient survival rates of patients not infected with HCV improved markedly during the two study periods from 1994 to 2001, compared with the first period (1991 to 1993).

Dr. Thuluvath acknowledged limitations of the study that included missing or partial data for recipient and donor liver histology, complications after transplant, treatment for rejection episodes, and maintenance immunosuppressive regimens.

Moreover, the investigators said, it is often difficult to make a firm distinction between rejection and recurrence when they coexist, leading to over- or under-treatment.

Despite some of the study's weaknesses, the large UNOS data set used for this study was robust enough to compare trends in survival, the researchers said.

Results of an Italian transplant-survival study in HCV-infected patients, covering roughly the same time span and published in the same issue of the journal, seemed to produce different results.

We noted a "trend for better patient survival [among those infected with HCV] in recent years," wrote Luca S. Belli, M.D., of Niguarda Hospital in Milan, and colleagues.

They acknowledged, however, that the cumulative probability of developing severe recurrent disease remained unchanged.

In the Milan study, the researchers conducted a multicenter retrospective analysis of 502 consecutive HCV-positive transplant recipients from January 1990 through December 2002. Patients came from hospitals in Milan and Padua, Italy, and from London.

Protocol liver biopsies were obtained at one, three, five, seven, and 10 years after transplant in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow-up longer than one year were considered for the analysis of predictors of disease progression.

The overall survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for better patient survival over the years emerged from all three centers after Kaplan-Meier analysis, the researchers reported.

However, they noted, the cumulative probability of developing HCV-related recurrent severe fibrosis in the cohort of 354 patients who survived at least one year remained unchanged.

Multivariate analysis indicated that older donors (P=0.0001) and female gender of the recipient (P=0.02) were the two major risk factors for the development of severe recurrent disease, while the use of antilymphocytic preparations was associated with a less aggressive course (P=0.03).

Two of the prognostic factors, donor age and recipient gender and their combination showed an important synergy, Dr. Belli said. A female recipient not only has a much higher probability of severe recurrent disease than a male recipient but her risk increases with the increasing age of the donor, reaching almost 100% when the donor is 60 or older.

In conclusion, the researchers said, although a trend for a better patient survival was observed in more recent years, the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence.

In an accompanying editorial, Marina Berenguer, M.D., Ph.D., of Hospital La Fe in Valencia, Spain, considered the conflicting data from these and other studies, and said that advanced donor age together with steroid pulse therapy and excess immunosuppression can explain differences in outcomes.

"The association with worse outcomes in recent years," she said, "and the controversy that seems to surround this observation, is likely due to differences in distribution of these variables from study to study, from center to center, and from year to year."

Although more effective antivirals will likely change disease management, such effective antivirals are not yet close at hand for HCV patients having liver transplantation. In the absence of such therapies, she said, "we are obliged to make sure through a better understanding of factors associated with outcome that we are minimizing harm to patients with our current management strategies."

Most importantly, she added, using large, controlled multicenter trials to determine which are the least harmful immunosuppressive regimens will eventually lead to improved results.