Sustained Virologic Response and Clinical Outcomes in Patients with Chronic Hepatitis C and Advanced Fibrosis

Context Most studies of hepatitis C treatment report effects on surrogate measures, such as liver enzymes and viral load. Contribution The authors compared clinical outcomes in patients with chronic hepatitis C and advanced fibrosis who did and did not have sustained virologic response to treatment. They found that sustained virologic response decreased patients' hazard of liver failure. Caution Sustained virologic response also seemed to be associated with a reduction in liver cancer and liver-related death, but not enough events occurred in the sustained virologic response group to detect differences between groups in these other outcomes. Implication Sustained virologic response to chronic hepatitis C treatment is associated with a reduction in clinical events, mainly liver failure. The Editors More than 170 million people are chronically infected with the hepatitis C virus (HCV) (1). Patients with chronic hepatitis C may develop decompensated liver disease and hepatocellular carcinoma (HCC). This risk is highest in patients with advanced fibrosis. The effectiveness of treatment for chronic hepatitis C is usually evaluated by the number of patients who reach sustained virologic response, which is a surrogate marker. Several large studies have suggested that successful treatment with pegylated interferon and ribavirin may halt and even reverse hepatic fibrosis. Camm and colleagues (2) found that sustained virologic response was associated with a reduction in fibrosis in 1013 patients with chronic hepatitis C who had had pre- and posttreatment liver biopsies and had received interferon or pegylated interferon. Among 3010 patients for whom pre- and posttreatment biopsy results were available in Poynard and associates' study (3), reversal of fibrosis occurred in 12% of those treated for 24 weeks with standard interferon and up to 24% of those treated with an optimal schedule of pegylated interferon and ribavirin. Although Poynard and associates observed regression of cirrhosis in 49% of their patients after successful treatment, a clinical benefit of pegylated interferon treatment has not yet been demonstrated for patients who have already developed advanced fibrosis or cirrhosis. Until now, reports of the long-term benefit of standard interferon therapy for patients with cirrhosis have been disappointing, because few patients achieved sustained virologic response (4). Large studies from Japan indicate that persons treated before cirrhosis develops experience the maximum benefit of sustained virologic response (5). Because sustained virologic response rates after therapy with pegylated interferon plus ribavirin are higher than those after interferon monotherapy, studies are needed to evaluate the effect of the former therapy on solid clinical end points, such as liver failure, HCC, and survival, and to establish whether sustained virologic response leads to an improved long-term outcome in this high-risk population. We therefore sought to investigate whether sustained virologic response, compared with nonresponse, leads to an improved clinical outcome for patients with chronic hepatitis C and advanced fibrosis. Methods We enrolled all consecutive patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6) that was treated with an interferon-based regimen between 1990 and 2003 at 5 large hepatology units of tertiary care centers in Europe and Canada. Patients were excluded if they were co-infected with hepatitis B virus or HIV. Patients with decompensated liver disease were not eligible for treatment and were therefore not included in the study. Approval was obtained from the ethics committees of each participating study site. Local investigators identified all eligible patients, and the principal investigator then visited each center to enter the individual patient data from the chart into a central database in a standardized and predefined manner. We obtained data on patient sex and age and details of the treatment (duration, interferon vs. pegylated interferon, ribavirin, and treatment-naive vs. previous nonresponse). Age was determined at the start of the last treatment. Virologic data (genotype, baseline viral load, antihepatitis B core antigen positivity), biochemical data (bilirubin, albumin), and hematologic data (platelet count, prothrombin time/quick time) were measured in the certified laboratories of participating hospitals and were corrected centrally for local normal values. Local pathologists, who all had extensive experience in scoring samples from patients with viral hepatitis, scored liver biopsy samples. To assess HCV RNA status, all participating centers used commercial polymerase chain reaction tests from Roche Diagnostics (Basel, Switzerland) with a detection limit of 100 to 500 IU/mL. Before these tests became commercially available in 1994, they used nested in-house polymerase chain reaction tests, in which plasma HCV RNA was analyzed in duplicate by polymerase chain reaction using 2 sets of primers derived from the 5 noncoding region followed by a hybridization assay; this method is described elsewhere for the different centers (69). These sensitive HCV RNA tests were also used to define the absence of detectable HCV RNA at 24 weeks after the end of treatment. Patients who did not respond or who had relapse with detectable virus at this time were classified as nonresponders. Clinical Events The primary outcomes of the study were the composite of death (liver-related and nonliver-related), liver failure, and HCC and each outcome individually. Patients who had more than 1 event contributed only 1 (the first that occurred) to analyses of the association between sustained virologic response and any event. Liver transplantation counted as liver-related death at the time of transplantation, but patients who survived the procedure were regarded as alive in the analysis of overall death. Liver failure was defined as ascites confirmed by ultrasonography or computed tomography, bleeding esophageal varices, jaundice with a bilirubin level greater than 35 mol/L, or hepatic encephalopathy. Hepatocellular carcinoma was confirmed by cytohistologic examination or was diagnosed if 2 coincident imaging techniques (ultrasonography, computed tomography, or magnetic resonance imaging) showed a focal lesion larger than 2 cm with arterial hypervascularization, or if 1 imaging technique showed a focal lesion larger than 2 cm with arterial hypervascularization in the presence of an -fetoprotein level greater than 400 ng/mL. For HCC, the date of the event was when the diagnosis was confirmed histologically or radiographically. If follow-up was incomplete, the treating physician contacted the patient. If the patient could not be reached, the treating physician contacted the patient's general practitioner to complete the follow-up. Statistical Analysis Baseline clinical characteristics were compared by using MannWhitney U and chi-square tests. Logistic regression was used to analyze which of the following baseline factors were associated with response to interferon-based treatment: age; sex; previous nonresponse; treatment duration; treatment including ribavirin; treatment with pegylated interferon versus standard interferon; fibrosis stage; genotype; pretreatment bilirubin level, platelet count, and albumin level; viral load; treatment period (1990 to 1997 or 1998 to 2005); and treatment center. The Appendix shows our covariate and model selection strategy and regression diagnostics. Twenty-four weeks after the end of treatment was used as time 0 for classifying patients as responders or nonresponders, because the definition of sustained virologic response is undetectable serum HCV RNA by sensitive molecular tests at that time. The KaplanMeier method was used to estimate the effect of sustained virologic response on clinical events, and groups were compared by using log-likelihood tests. Separate Cox proportional hazards models were developed to determine which baseline factors were associated with development of any clinical event, overall death, liver-related and nonliver-related death, liver failure, and HCC. The final models included sustained virologic response, age, sex, previous nonresponse, bilirubin level, albumin level, platelet count, and treatment center as covariates and were stratified by treatment period (1990 to 1997 or 1998 to 2005) to represent evolution in the evaluation and treatment of hepatitis C since 1990 (and especially since the introduction of ribavirin in 1998). The reported hazard ratios for bilirubin level, albumin level, and platelet count are the relative increases in hazard associated with increases of 10 mol/L for bilirubin level, 10 g/L for albumin level, and 10 109 cells/L for platelet count. Antihepatitis B core antigen positivity was a risk factor for HCC, but the hazard of HCC associated with antihepatitis B core antigen positivity was not proportional over time; we therefore stratified the analysis of risk for HCC by serum antihepatitis B core antigen positivity. Because baseline bilirubin level, albumin level, or platelet count was missing in 28.5% of patients, we used multiple imputation to impute missing values (10, 11); the Markov chain Monte Carlo method with a single chain (PROC MI in SAS software [SAS Institute, Cary, North Carolina]) was applied to construct 10 complete data sets. All baseline factors, time-related factors, and events related to the analyses were entered into the imputation procedure and, if necessary, transformed to conform to the multivariate normality assumption. Cox analysis (PROC PHREG) or logistic regression analysis (PROC LOGISTIC) was then run on each data set, and the results and inference were combined by using PROC MIANALYZE. All statistical analyses were performed by using SAS software, version 9.1. 3. Role of the Funding Source The Netherlands Organisation for Health Research and Developme