Summary Background Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection ...remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. Methods After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805 ) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system). Findings Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0·0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (≥1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0·0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. Interpretation In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. Funding Gilead Sciences.
Laboratory and pathological predictors of future histological progression in primary biliary cirrhosis (PBC) are needed for routine practice and clinical trials. We sought to develop clinically ...meaningful markers for those with predominantly early disease at risk of progressive liver damage.
Patients with PBC (n=69) with a follow-up liver biopsy performed approximately 10 years after initial histological diagnosis were identified and reviewed.
Histological progression in the stage of fibrosis observed in paired liver biopsies from the same patient was associated with the absence of biochemical response to ursodeoxycholic acid (UDCA) at 2 years: alkaline phosphatase (ALP) >1.67 × ULN (upper limit of normal) (P=0.001, odds ratio (OR) 12.14, 95% confidence interval (CI) 2.69-54.74) when defined as an increase in one stage and ALP > 1.76 × ULN (P=0.03, OR 5.07, 95% CI 1.17-21.95) when defined as an increase in two stages. Ductopenia (>50% loss), as formally evaluated through blinded biopsy review of liver tissue obtained at initial diagnosis in a subset of 34 patients, predicted histological progression (P=0.012), along with biochemical response to UDCA (P=0.002). The presence of interface hepatitis in the same biopsies did not.
Patients with PBC who fail to show a biochemical response to UDCA or who have ductopenia on baseline biopsy progress histologically during extended follow-up. Such patients may benefit from novel treatments, with our exploratory data providing a means of identifying these individuals early in their disease.
Cholestatic liver disorders are caused by genetic defects, mechanical aberrations, toxins, or dysregulations in the immune system that damage the bile ducts and cause accumulation of bile and liver ...tissue damage. They have common clinical manifestations and pathogenic features that include the responses of cholangiocytes and hepatocytes to injury. We review the features of bile acid transport, tissue repair and regulation, apoptosis, vascular supply, immune regulation, and cholangiocytes that are associated with cholestatic liver disorders. We now have a greater understanding of the physiology of cholangiocytes at the cellular and molecular levels, as well as genetic factors, repair pathways, and autoimmunity mechanisms involved in the pathogenesis of disease. These discoveries will hopefully lead to new therapeutic approaches for patients with cholestatic liver disease.
In this randomized comparison of treatment with tenofovir disoproxil fumarate or adefovir dipivoxil for 48 weeks in patients with chronic hepatitis B, tenofovir was more likely to result in viral ...suppression. The follow-up period was not long enough to assess the resistance patterns, risks, and benefits of long-term treatment.
In this randomized comparison of treatment with tenofovir disoproxil fumarate or adefovir dipivoxil for 48 weeks in patients with chronic hepatitis B, tenofovir was more likely to result in viral suppression.
Chronic hepatitis B virus (HBV) infection is a major health problem.
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Since most patients with chronic HBV infection require long-term therapy,
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there is a need for new drugs with potent antiviral activity and established long-term safety, as well as a proven low rate of HBV antiviral resistance, a high genetic barrier (i.e., requiring more than one amino acid substitution to confer resistance to HBV treatment), or both.
The ultimate goal of treatment of chronic HBV infection is to prevent liver complications. This goal is seldom achieved through hepatitis B surface antigen (HBsAg) loss and seroconversion, which are associated . . .
On‐treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG‐IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown ...limited external validity. We analyzed 803 HBeAg‐positive patients treated with PEG‐IFN in three global studies with available HBsAg measurements. A stopping‐rule based on absence of a decline from baseline was compared to a prediction‐rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG‐IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value NPV: 97%‐100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%‐98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). Conclusion: HBsAg is a strong predictor of response to PEG‐IFN in HBeAg‐positive CHB. HBV genotype‐specific stopping‐rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype. (Hepatology 2013;53:872–880)
Secondary sclerosing cholangitis (SSC) is a disease that is morphologically similar to primary sclerosing cholangitis (PSC) but that originates from a known pathological process. Its clinical and ...cholangiographic features may mimic PSC, yet its natural history may be more favorable if recognition is prompt and appropriate therapy is introduced. Thus, the diagnosis of PSC requires the exclusion of secondary causes of sclerosing cholangitis and recognition of associated conditions that may potentially imitate its classic cholangiographic features. Well‐described causes of SSC include intraductal stone disease, surgical or blunt abdominal trauma, intra‐arterial chemotherapy, and recurrent pancreatitis. However, a wide variety of other associations have been reported recently, including autoimmune pancreatitis, portal biliopathy, eosinophillic and/or mast cell cholangitis, hepatic inflammatory pseudotumor, recurrent pyogenic cholangitis, primary immune deficiency, and AIDS‐related cholangiopathy. This article offers a comprehensive review of SSC. (HEPATOLOGY 2006;44:1063–1074.)
Peginterferon (PEG‐IFN) treatment of hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and ...hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG‐IFN treatment affects serological and virological response. A total of 214 HBeAg‐positive CHB patients treated with PEG‐IFN±lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non‐WT (detectable mutants at PC/BCP) by line‐probe assay. Response was assessed at 6 months posttreatment and through long‐term follow‐up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non‐WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non‐WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non‐WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio OR 2.90, 95% confidence interval CI: 1.15‐7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26‐24.63, P = 0.013) and patients with non‐A genotypes with detectable mutants had a low probability of response. Conclusion: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG‐IFN for HBeAg‐positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG‐IFN therapy. (HEPATOLOGY 2012;56:67–75)
The hepatic complications of chronic hepatitis C (CHC) usually occur only after progression to cirrhosis has taken place. Progression to cirrhosis, however, is extremely variable and depends on a ...broad set of host and viral factors that modify the rate at which fibrosis develops in a given individual. Despite their inherent limitations, studies of the natural history of CHC have identified several nonmodifiable factors associated with disease progression. These include age at acquisition of infection, sex, and race. More recent reports suggest important roles for host genetic polymorphisms and viral factors. Of greater immediate relevance to patients and their clinicians are the potentially modifiable factors, which include excessive alcohol consumption; smoking (tobacco and marijuana); insulin resistance; and coinfection with hepatitis B virus, human immunodeficiency virus type 1, or schistosomiasis. Unfortunately, to date, there are no reliable predictive models that can accurately estimate the risk of CHC disease progression.
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•HCC incidence varies markedly by etiology of cirrhosis.•THRI is simple to use, has good predictive ability, and has been externally validated.•THRI may help to refine HCC ...surveillance guidelines for patients with cirrhosis.
Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. We aimed to assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk.
A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system was evaluated in an external cohort for validation.
Of 2,079 patients with cirrhosis and ≥6months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p<0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low-risk (<120points), medium-risk (120–240) and high-risk (>240) groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with primary biliary cirrhosis, hepatitis B viral and hepatitis C viral cirrhosis (n=1,144), with similar predictive ability (Harrell’s c statistic 0.77) in the validation and derivation cohorts.
HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis.
HCC incidence varies markedly depending on the underlying cause of cirrhosis. Herein, using readily available clinical and laboratory parameters we describe a risk score, THRI, which has a good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis.
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