Jeanne Serpaggi

Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C.

Context Few studies have documented histologic regression of cirrhosis. Contribution This study describes 96 patients with chronic hepatitis C and biopsy-proven cirrhosis who were treated with an interferon-based regimen and who had at least 1 post-treatment liver biopsy. Eighteen patients had biopsy-proven regression of cirrhosis. Patients with regression had better 10-year survival rates than did patients without regression (100% vs. 74%). Implication Cirrhosis may be reversible in some patients with chronic hepatitis C. The Editors Single or multifactorial damage to the liver ultimately leads to cirrhosis and its complications, especially hepatocellular carcinoma (13). Different types of evidencehistologic; morphologic (as assessed by abdominal ultrasonography or digestive endoscopy); and biochemical (as assessed by measurement of hyaluronate, procollagen III peptide, prothrombin time, and platelets), including analyses of native liverssupport the idea that cirrhosis can be reversed, provided that the underlying disease is controlled (58). Nevertheless, whether cirrhosis regresses is still debated (9, 10). To provide definitive support for this concept, we evaluated the relation between histologic regression of cirrhosis and clinical outcome in patients treated for chronic hepatitis C. Methods Study Design We established a cohort of 143 patients with biopsy-proven cirrhosis (METAVIR F4) who received specific treatment between 1988 and 2001 at a single hepatology unit in a tertiary care center in France and who underwent a second liver biopsy to assess the effect of treatment on cirrhosis (Appendix Figure) (6, 8, 11). All patients in this cohort currently undergo prospective follow-up and are seen by a senior hepatologist at least every 6 months. The institutional review board of our hospital approved the past and present studies, and all patients gave informed consent. Appendix Figure. Study flow diagram. We included patients who met the following criteria: ChildPugh class A cirrhosis related to chronic hepatitis C; absence of hepatitis B co-infection; absence of immunosuppression (HIV-associated infection, long-term hemodialysis, organ transplantation, immunosuppressive therapy); and treatment with conventional -interferon or pegylated interferon, with or without ribavirin. The exclusion criteria were age older than 70 years at the time of diagnosis of cirrhosis and previous liver-related complications. Sustained virologic response was defined as undetectable hepatitis C virus RNA on the latest available assaying technique and normal alanine aminotransferase level 24 weeks after the end of treatment and during follow-up. Patients who did not fulfill these criteria were classified as nonresponders and did not receive long-term treatment. Liver disease was staged and graded according to the METAVIR score (12), which combines an activity stage from 0 to 3 and a fibrosis grade from 0 to 4 (4 corresponds to cirrhosis). Regression of cirrhosis was defined as a decrease in the score from 4 to 2 or fewer METAVIR fibrosis units to avoid the 15% rate of false-negative results in patients with F3 disease (13, 14). Patients underwent clinical and biological evaluation, including measurement of aminotransferase, bilirubin, albumin, prothrombin time, platelet, and hepatitis C viral load at each visit. All patients were screened for hepatocellular carcinoma with ultrasonography and had -fetoprotein measured every 6 months. The diagnosis of hepatocellular carcinoma followed the guidelines of the European Association for the Study of the Liver (15). Hepatic encephalopathy was defined clinically (16). Ascites was diagnosed by clinical examination and ultrasonography. The source of gastroesophageal bleeding was confirmed by endoscopy. Outcome Measures Our main goal was to evaluate the effect of regression of cirrhosis on a composite end point of liver-related complications (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, liver transplantation) and death from liver-related causes. For patients with more than 1 event, only the first event was analyzed. The incidence of liver-related deaths or transplantation was analyzed as a secondary end point. Statistical Analysis Total duration of follow-up was calculated from the date of the first liver biopsy until death, last consultation, or liver transplantation until November 2006. Eight patients (8%) were not followed in our unit as of this date after a median follow-up of 96 months (range, 36 to 127 months). These patients were censored at the time of the last visit. The time from diagnosis of cirrhosis (time of the index biopsy) to liver-related complications or to the date when the data were censored was plotted according to groups by using KaplanMeier estimates, and P values were computed with the log-rank test. All P values are 2-sided, and the type I error was set at 5%. Continuous values are presented as medians and interquartile ranges and categorical variables as counts and proportions. The differences between groups were assessed with the Fisher exact test and the MannWhitney U test. All statistical analyses were performed by using SPSS software, version 16 (SPSS, Chicago, Illinois). Role of the Funding Source This study was funded by the French Agence Nationale de la Recherche (ANR). The funding source had no role in the design, analysis, or interpretation of the study or in the decision to submit the manuscript for publication. Results Sample Ninety-six patients fulfilled the inclusion criteria (Table 1). All had ChildPugh class A biopsy-proven cirrhosis at enrollment and thereafter received specific therapy. The median interval between the first liver biopsy and treatment was 2 months (interquartile range, 0 to 6 months). Sixty-one patients (64%) received interferon monotherapy, 34 (35%) received interferon and ribavirin, and 1 (1%) received pegylated interferon and ribavirin. Eighty-two patients (85%) did not respond to the first treatment course; of these, 47 (49%) received at least 1 more treatment course. Thirty-nine patients (41%) achieved a sustained virologic response, and 57 (59%) did not. Table 1. Patient Characteristics at Baseline Histologic Outcome The median interval between the end of treatment and the second liver biopsy was 17 months. The median length of the liver biopsy samples was 15 mm (interquartile range, 10 to 20 mm) both before and after treatment (P= 0.86, Wilcoxon signed-rank test). In terms of fibrosis scores, 69 liver biopsies (71.9%) showed persistent cirrhosis (METAVIR fibrosis stage 4), 9 (9.4%) showed extensive fibrosis (stage 3), 10 (10.4%) showed intermediate fibrosis (stage 2), 7 (7.3%) showed moderate fibrosis (stage 1), and 1 (1%) showed no fibrosis (stage 0). Of the 18 patients with regression of cirrhosis on the second liver biopsy (METAVIR fibrosis stage 0, 1, or 2), 17 (94.4%) had long-term response to therapy and 1 had biochemical response (normal liver function tests and no detectable activity on liver biopsy but persistent viremia) to antihepatitis C therapy. Clinical Outcome The median follow-up was 118 months (interquartile range, 86 to 138 months), and total follow-up was 900 patient-years. The time from achievement of sustained virologic response to the end of follow-up was similar between patients with and those without regression of cirrhosis (P= 0.38). During follow-up, 27 (35%) patients with persistent cirrhosis developed at least 1 cirrhosis-related complication (Table 2). The incidence of liver-related complications, including hepatocellular carcinoma, was lower in patients with a sustained virologic response (Figure, top). Nevertheless, 4 patients with hepatitis Crelated cirrhosis developed a liver-related event, including variceal bleeding (1 patient) and hepatocellular carcinoma (3 patients); all had antihepatitis B core antigen antibodies. In contrast, patients with regression of cirrhosis had no complications (Figure, bottom). The incidence of cirrhosis-related complications per 100 patient-years was 1.14 in patients with sustained virologic response and 4.63 in those without sustained virologic response (P= 0.009); respective values in patients with and those without regression of cirrhosis were 0 and 4 (P= 0.002). Table 2. Clinical Outcomes, by Virologic and Histologic Response Figure. KaplanMeier estimates of time to a liver-related event and death in patients with or without a sustained virologic response ( top ) and in patients with or without regression of cirrhosis ( bottom ). Liver-related events were hepatocellular carcinoma, hepatic encephalopathy, variceal bleeding, ascites, spontaneous bacterial peritonitis, and liver transplantation. During follow-up, 22 patients (23%) without regression died (n= 16 [17%]) or underwent a liver transplantation (n= 6 [6%]), whereas neither of these events occurred in the 18 patients with regression (P= 0.010). The incidence of liver-related death or liver transplantation per 100 patient-years was 0.85 in patients with sustained virologic response and 3.43 in those without sustained virologic response (P= 0.004, log-rank test); respective values in patients with and those without cirrhosis were 0 and 2.96 (P= 0.025, log-rank test). Among the 6 patients who had liver transplantation, 5 survived and 1 died during the perioperative period. Four patients died of nonliver-related causes. One patient with regression of cirrhosis died of myocardial infarction. Discussion During more than 10 years of follow-up in 96 patients with treated hepatitis Crelated cirrhosis, 18 patients achieved histologically proven regression. The absence of liver-related morbidity and mortality in these patients supports the concept of cirrhosis reversal. Persistence of cirrhosis carries a risk for hepatocellular carcinoma, which warrants regular screening. Regression of hepatitis Crelated cirrhosis after treatment ranges from 10% to

Efficacy and safety of adefovir dipivoxil in kidney recipients, hemodialysis patients, and patients with renal insufficiency.

Background. This study analyzes the biochemical, serological, and virological efficacy and the safety of adefovir dipivoxil in patients with renal disturbances. Methods. Twelve patients with lamivudine-resistant hepatitis B virus (HBV) chronic infection were treated for a median time of 15 (3–19) months. The daily dosage was 10 mg initially and then adjusted according to renal function. Results. Median (range) ALT values remained stable: 55 (13–117) and 37 (17–266) UI/L. After the 12th month, the median decline in serum HBV DNA was from 8.76 (6.3–9.7) to 2.97 (1.15–5.65) log10 Eq/ml (median decline of –5.5 log10). No virologic breakthrough was observed. One of the six HBeAg-positive patients lost HBe Ag but without HBe seroconversion; none had HBs Ag loss. There were no significant clinical and biochemical adverse effects. In the 11 nonhemodialysed patients, the creatinine clearance significantly improved from 70 (30–100) to 88 (38–125) ml/mn (P=0.01) and the mean serum creatinine levels increased only slightly from 114 (91–839) to 130 (81–561) &mgr;mol/ml (NS). Serum phosphorus remained stable. The urinary level of protein decreased from 0.16 (0.08–8.63) to 0.12 (0.01–0.74) g/day (NS). Conclusions. Adefovir dipivoxil is safe for the treatment of chronic hepatitis B in patients with varying degrees of renal dysfunction and lamivudine-resistant HBV and results in biochemical and virological efficacy similar to that reported in the general population.

Diagnostic accuracy of the fibrotest in hemodialysis and renal transplant patients with chronic hepatitis C virus.

Background. An accurate diagnosis of hepatitis C virus (HCV)-related liver lesions is mandatory in dialysis patients and kidney recipients to better define the treatment of and contraindications to kidney transplantation. The aim of this study was to assess the diagnostic accuracy of the fibrotest (a noninvasive method to assess liver fibrosis in HCV on a scale from 0 to 1) in hemodialysis and renal transplant patients infected by chronic HCV. Methods. In all, 110 patients with biopsy-proven HCV (60 renal transplant recipients and 50 hemodialysis patients), determined using the METAVIR scoring system, were studied. Results. Forty-six percent of patients had fibrosis ≥F2. A positive predictive value of a score >0.6 for the presence of significant fibrosis by comparison with liver biopsy was 71%, and an negative predictive value of <0.2 for excluding significant fibrosis was 77%, respectively. The areas under the ROC curves for the diagnosis of significant fibrosis were 0.66, 0.47, and 0.71 in the global population, hemodialysis patients, and renal transplant patients, respectively. In all, 75% of patients were correctly classified using the fibrotest. If biopsy was restricted to scores in the intermediate range (<0.6 and >0.2), the index could reduce the indication for biopsy by 47%. The results did not differ significantly in hemodialysis and renal transplant patients. Conclusion. The fibrotest has a diagnostic value in hemodialysis and renal transplant patients which is similar to that reported in the general population (75%) and its use could avoid 32% of liver biopsies if it were interpreted in detail in nephrology patients.