Bart J. Veldt

Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis

CONTEXT Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death. OBJECTIVE To assess the association between sustained virological response (SVR) and all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis. DESIGN, SETTING, AND PATIENTS An international, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada of 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis (Ishak score 4-6). Complete follow-up ranged between January 2010 and October 2011. MAIN OUTCOME MEASURES All-cause mortality. Secondary outcomes were liver failure, HCC, and liver-related mortality or liver transplantation. RESULTS The 530 study patients were followed up for a median (interquartile range [IQR]) of 8.4 (6.4-11.4) years. The baseline median (IQR) age was 48 (42-56) years and 369 patients (70%) were men. The Ishak fibrosis score was 4 in 143 patients (27%), 5 in 101 patients (19%), and 6 in 286 patients (54%). There were 192 patients (36%) who achieved SVR; 13 patients with SVR and 100 without SVR died (10-year cumulative all-cause mortality rate, 8.9% [95% CI, 3.3%-14.5%] with SVR and 26.0% [95% CI, 20.2%-28.4%] without SVR; P < .001). In time-dependent multivariate Cox regression analysis, SVR was associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.26; 95% CI, 0.14-0.49; P < .001) and reduced risk of liver-related mortality or transplantation (HR, 0.06; 95% CI, 0.02-0.19; P < .001), the latter occurring in 3 patients with SVR and 103 without SVR. The 10-year cumulative incidence rate of liver-related mortality or transplantation was 1.9% (95% CI, 0.0%-4.1%) with SVR and 27.4% (95% CI, 22.0%-32.8%) without SVR (P < .001). There were 7 patients with SVR and 76 without SVR who developed HCC (10-year cumulative incidence rate, 5.1%; 95% CI, 1.3%-8.9%; vs 21.8%; 95% CI, 16.6%-27.0%; P < .001), and 4 patients with SVR and 111 without SVR experienced liver failure (10-year cumulative incidence rate, 2.1%; 95% CI, 0.0%-4.5%; vs 29.9%; 95% CI, 24.3%-35.5%; P < .001). CONCLUSION Among patients with chronic HCV infection and advanced hepatic fibrosis, sustained virological response to interferon-based treatment was associated with lower all-cause mortality.

Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.

Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00‐1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63‐1.04; P = 0.095). During a median follow‐up of 4.0 years (interquartile range, 2.0‐6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5‐year occurrence of HCC being 11.4% (95% CI, 3.0‐19.8) and 5.0% (95% CI, 2.2‐7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35‐7.97; P = 0.009). Conclusion: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC. (HEPATOLOGY 2008;47:1856–1862.)

Interleukin‐28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin‐28B (IL28B) gene region, encoding interferon (IFN)‐λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty‐five patients received IFN‐based antiviral therapy. The CC IL28B variant was less common in the chronic HCV‐infected recipients than in non‐HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi‐square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D‐non‐CC/R‐non‐CC = 3/19 [16%] versus D‐CC/R‐non‐CC = 11/22 [50%] versus D‐non‐CC/R‐CC = 5/12 [42%] versus R‐CC/D‐CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver‐related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN‐based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;)

Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy

Background: The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world. Aims: To assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy. Methods: Meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C. Results: A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0–7.4) among sustained virological responders; all late relapses occurred within four years after treatment. Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0–2.3) and none developed hepatocellular carcinoma (HCC). Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3–2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5–17.7) and 7.1% (95% CI 0–15.0), respectively. Conclusions: Five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up.

Insulin resistance, serum adipokines and risk of fibrosis progression in patients transplanted for hepatitis C.

In the nontransplant setting diabetes mellitus is a risk factor for disease progression in patients with chronic hepatitis C virus (HCV) infection. The impact of early insulin resistance on the development of advanced fibrosis, even in the absence of clinically apparent diabetes mellitus, is not known.

Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection.

Recurrent hepatitis C virus (HCV) infection is a major cause of morbidity and mortality after liver transplantation for HCV‐related end stage liver disease. Although previous studies have shown a short‐term effect of interferon‐based treatment on fibrosis progression, it is unclear whether this translates to improved graft survival. We evaluated whether treatment of recurrent HCV leads to an improved graft survival. Cohort study included consecutive HCV patients who underwent liver transplantation between 1 January 1995 and 1 January 2005 in the Mayo Clinic, Rochester, MN. Two hundred and fifteen patients were included in the study. During a median follow‐up of 4.4 years (interquartile range 2.2–6.6), 165 patients (77%) had biopsy‐proven recurrent HCV infection confirmed by serum HCV RNA testing. Seventy‐eight patients were treated. There were no differences in MELD‐score, fibrosis stage or time towards HCV recurrence between treated and untreated patients at time of recurrence. There was a trend for greater frequency of acute cellular rejection among untreated patients. The incidence of graft failure was lower for patients treated within 6 months of recurrence compared to patients not treated within this time‐period (log rank p = 0.002). Time‐dependent multivariate Cox regression analysis showed that treatment of recurrent HCV infection was statistically significantly associated with a decreased risk of overall graft failure (hazard ratio 0.34; CI 0.15–0.77, p = 0.009) and a decreased risk of graft failure due to recurrent HCV (hazard ratio 0.24; CI 0.08–0.69, p = 0.008). In conclusion, although a cause and effect relationship cannot be established, treatment of recurrent HCV infection after liver transplantation is associated with a reduced risk of graft failure.

A Practical Guide to the Management of HCV Infection Following Liver Transplantation

Hepatitis C‐associated liver failure is the most common indication for liver transplantation, with virological recurrence near ubiquitous. Approximately 30% of HCV‐infected recipients will die or lose their allograft or develop cirrhosis secondary to hepatitis C recurrence by the fifth postoperative year, with the proportion increasing with duration of follow‐up. Strategies for minimizing the frequency of severe HCV recurrence include avoidance of older donors, early diagnosis/treatment of CMV and minimization of immunosuppression, particularly T‐cell depleting therapies and pulsed corticosteroid treatment of acute cellular rejection. Patients should be offered treatment with peginterferon and ribavirin before LT if MELD ≤ 17 or as soon as histological evidence of recurrence of HCV is apparent post‐LT. Because of the high frequency of hemotoxicity and renal insufficiency, ribavirin should be dosed according to renal function.

Differential expression of lumican and fatty acid binding protein-1: New insights into the histologic spectrum of nonalcoholic fatty liver disease†

The basis of hepatocellular injury and progressive fibrosis in a subset of patients with nonalcoholic fatty liver disease (NAFLD) is poorly understood. We sought to identify hepatic proteins that are differentially abundant across the histologic spectrum of NAFLD. Hepatic protein abundance was measured in liver samples from four groups (n = 10 each) of obese (body mass index >30 kg/m2) patients: (1) obese normal group (normal liver histology), (2) simple steatosis (SS), (3) nonalcoholic steatohepatitis (NASH)‐mild (steatohepatitis with fibrosis stage 0‐1), and (4) NASH‐progressive (steatohepatitis with fibrosis stage 2‐4). Hepatic peptides were analyzed on an API Qstar XL quadrupole time‐of‐flight mass spectrometer using Analyst QS software. Linear trends tests were performed and used to screen for differential abundance. Nine known proteins were expressed with differential abundance between study groups. For seven proteins differential abundance is likely to have been on the basis increased hepatic lipid content and/or inflammation. Lumican, a 40‐kDa keratin sulfate proteoglycan that regulates collagen fibril assembly and activates transforming growth factor‐beta and smooth muscle actin, was expressed similarly in obese normal and SS but was overexpressed in a progressive manner in NASH‐mild versus SS (124%, P < 0.001), NASH‐progressive versus NASH‐mild (156%, P < 0.001) and NASH‐progressive versus obese normal (178%, P < 0.001). Fatty acid binding protein‐1 (FABP‐1), which is protective against the detergent effects of excess free fatty acids, facilitates intracellular free fatty acid transport and is an important ligand for peroxisome proliferator‐activated receptor–mediated transcription, was overexpressed in SS when compared to the obese normal group (128%, P < 0.001), but was paradoxically underexpressed in NASH‐mild versus SS (73%, P < 0.001), NASH‐progressive versus NASH‐mild (81%, P < 0.001), and NASH‐progressive versus obese normal (59%, P < 0.001). Conclusion: Histologically progressive NAFLD is associated with overexpression of lumican, an important mediator of fibrosis in nonhepatic tissues, whereas FABP‐1 is paradoxically underexpressed in NASH, suggesting a new potential mechanism of lipotoxicity in NAFLD. Further studies are needed to determine the biologic basis of lumican and/or FABP‐1 dysregulation in NAFLD. (HEPATOLOGY 2009;49:1375–1384.)

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

The course of posttransplant hepatitis c infection: Comparative impact of donor and recipient source of the favorable IL28B genotype and other variables

Background and Aims The IL28B genotype has been linked to sustained virological response (SVR) in hepatitis C virus (HCV). Its role on disease biology and progression is less clear. We characterized the effects of IL28B genotype on HCV recurrence, allograft histology, rate of SVR, and survival after liver transplantation (LT) in HCV. Methods Consecutive patients who underwent LT with HCV were studied. The rs12979860 genotype from both the donor was and recipient was determined. Measured endpoints included histologic HCV recurrence (inflammatory grade and fibrosis stage), acute cellular rejection, SVR, retransplantation, and death. Results The study cohort comprised 272 consecutive LT in 255 patients. C-allele frequency was 56% in recipients and 70% in donors (P<0.001). Recipient IL28B CC genotype was associated with lower alanine aminotransferase levels and viral load at recurrence and a lower frequency of F≥2 on liver biopsy at 1 year after LT, when compared with the non–CC genotype (P=0.012). The opposite was observed in LT with donor CC genotype (P=0.003). Both recipient and donor CC genotype favored SVR, and when the two of them occurred together, the SVR rate reached 90%. Survival analysis after 5.5 years of follow-up showed a higher rate of progression to cirrhosis (hazard ratio, 5.96; 95% confidence interval, 1.29–27.6), liver-related death, or retransplantation among liver transplant recipients with a CC genotype donor. Conclusions The IL28B genotype is predictive not only of SVR but also of the histologic diagnosis of posttransplant hepatitis C, with donor CC genotype favoring inflammation and fibrosis, and adverse outcomes during long-term follow-up. A favorable effect of donor CC genotype is manifest only after antiviral therapy.