Lower Observed Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Patients Treated With Entecavir: Results of the ENUMERATE Study.

OBJECTIVES: Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence. METHODS: The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases. RESULTS: Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was significantly lower than predicted by the fourth year (SIR, 0.37; 95% confidence interval: 0.166-0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a significantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confidence interval: 0.35-0.905). CONCLUSIONS: Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.

A long-term study of the effects of antiviral therapy on survival of patients with HBV-associated hepatocellular carcinoma (HCC) following local tumor ablation.

The ultimate goal of antiviral therapy for chronic hepatitis B (CHB) is prevention of hepatocellular carcinoma (HCC). Earlier we reported favorable effects of antiviral therapy on survival of HCC patients following curative tumor ablation (Int J Cancer online 14 April 2010; doi: 10.1002/ijc.25382). It was the first observation made in the United States. We now report 12 year follow-up of this patient group. CHB patients with no prior antiviral therapy with a single HCC (≤ 7 cm) were studied. All patients underwent local tumor ablation as their first option. Patients diagnosed before 1999 received no antiviral treatment while those diagnosed after 1999 received antiviral treatment. Survival between the treated and untreated groups was compared. Among 555 HCC patients seen at our clinic between 1991 and 2013, 25 subjects were eligible. Nine subjects (all male patients, median age 53 years [46-66]) did not receive antiviral therapy while 16 (14 male patients, median age 56 years [20-73]) received treatment. Between the two groups, there was no difference in their median tumor size and levels of alpha-fetoprotein and albumin. However, the survival was significantly different (P = 0.001): the median survival of the untreated was 16 months (3-36 months) while that of the treated was 80 months (15-152 months). Fourteen of 16 treated patients are alive to date with two longest survivors alive for ≥ 151 months. In conclusion, concomitant antiviral therapy for CHB patients with HCC reduces and prevents new/recurrent tumor and improves survival. This novel treatment strategy offers an alternative to liver transplantation in patients with HBV-associated HCC.

Education and counseling in the methadone treatment setting improves knowledge of viral hepatitis.

The aim of this study was to evaluate the effectiveness of an educational method of providing viral hepatitis education for methadone maintenance patients. Four hundred forty participants were randomly assigned to either a control or a motivationally-enhanced viral hepatitis education and counseling intervention. Viral hepatitis A (HAV), B (HBV), and C (HCV) knowledge tests were administered at baseline, following each of two education sessions (post-education), and at a 3-month follow-up assessment. Results indicated a significant increase in knowledge of HAV, HBV, and HCV over time. No differences were found in knowledge between the intervention groups in knowledge acquisition regarding any of the hepatitis viruses suggesting that a motivational interviewing style may not augment hepatitis knowledge beyond standard counseling. A two-session viral hepatitis education intervention effectively promotes hepatitis knowledge and can be integrated in methadone treatment settings.

A randomized trial of a hepatitis care coordination model in methadone maintenance treatment.

OBJECTIVES: We evaluated the efficacy of a hepatitis care coordination intervention to improve linkage to hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination and clinical evaluation of hepatitis C virus (HCV) infection among methadone maintenance patients. METHODS: We conducted a randomized controlled trial of 489 participants from methadone maintenance treatment programs in San Francisco, California, and New York City from February 2008 through June 2011. We randomized participants to a control arm (n = 245) and an intervention arm (n = 244), which included on-site screening, motivational-enhanced education and counseling, on-site vaccination, and case management services. RESULTS: Compared with the control group, intervention group participants were significantly more likely (odds ratio [OR] = 41.8; 95% confidence interval [CI] = 19.4, 90.0) to receive their first vaccine dose within 30 days and to receive an HCV evaluation within 6 months (OR = 4.10; 95% CI = 2.35, 7.17). A combined intervention adherence outcome that measured adherence to HAV-HBV vaccination, HCV evaluation, or both strongly favored the intervention group (OR = 8.70; 95% CI = 5.56, 13.61). CONCLUSIONS: Hepatitis care coordination was efficacious in increasing adherence to HAV-HBV vaccination and HCV clinical evaluation among methadone patients.

Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901.

OBJECTIVE: To review long-term safety data from the rollover study ETV-901, focusing on adverse events (AEs) with a potential nucleos(t)ide association. METHODS: The open-label study ETV-901 (AI463901) assessed the safety of entecavir in chronic hepatitis B patients who received entecavir, lamivudine or adefovir monotherapy in previous entecavir Phase II/III studies. Long-term cumulative safety results are based on reported AEs, regardless of causal relationship. RESULTS: Median exposure to entecavir in study ETV-901 was 184 weeks. Commonly reported AEs (≥ 10%) were upper respiratory tract infection, headache and nasopharyngitis. Most AEs were mild to moderate; 203 (19%) patients reported grade 3 - 4 AEs, with 45 (4%) considered related to entecavir. There were 14 (1%) discontinuations due to AEs. On-treatment alanine aminotransferase (ALT) flares were reported in 32 (3%) patients and were associated with a reduction in hepatitis B virus DNA of more than 2 log(10) copies/ml in 25/32 patients. AEs potentially associated with nucleos(t)ide analogs were infrequent, the most common being myalgia (n = 54; 5%) and neuropathy-related AEs (hypoparesthesia and hyperparesthesia, polyneuropathy; n = 42; 4%). CONCLUSIONS: Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. AEs potentially associated with nucleos(t)ide use occurred at low rates.

The management of chronic hepatitis B in Asian Americans.

Hepatitis B virus (HBV) infection is common with major clinical consequences worldwide. In Asian Americans, the HBsAg carrier rate ranges from 7 to 16%; HBV is the most important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Patients are first diagnosed at different stages of clinical disease, which is categorized by biochemical and virologic tests. Patients at risk for liver complications should be identified and offered antiviral therapy. The two antiviral agents recommended for first-line treatment of chronic hepatitis B (CHB) are entecavir and tenofovir. The primary goal of therapy is sustained suppression of viral replication to achieve clinical remission, reverse fibrosis, and prevent and reduce progression to end-stage liver disease and HCC. Asian patients with chronic hepatitis, either HBeAg-positive or -negative, with HBV DNA levels >10(4) copies/mL (>2,000 IU/mL) and alanine aminotransferase (ALT) values above normal are candidates for antiviral therapy. HBeAg-negative patients with HBV DNA >10(4) copies/mL (>2,000 IU/mL) and normal ALT levels but who have either serum albumin ≤3.5 g/dL or platelet count ≤130,000 mm(3), basal core promoter mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive antiviral therapy. Considerations for treatment include pregnant women with high viremia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg-positive patients with risk factors, lifelong surveillance for HCC with alpha-fetoprotein testing and abdominal ultrasound examination at 6-month intervals is required. These recommendations are based on a review of relevant literature and the opinion of a panel of Asian American physicians with expertise in hepatitis B treatment.

Detection of esophageal varices using CT and MRI.

BACKGROUND AND AIMS: The development of esophageal varices in cirrhotic patients carries a significant risk of hemorrhage and associated morbidity/mortality. Universal endoscopic screening, however, is invasive and expensive. Conversely, cirrhotic patients often have imaging findings which suggest portal hypertension. The aim of this study was to evaluate the ability of CT and/or MRI to detect esophageal varices compared to EGD. METHODS: Medical records from 2000 to 2007 were retrospectively reviewed. CT and/or MRI images were included if performed within 90 days of EGD. Two blinded, experienced radiologists were asked to review images for the presence of esophageal varices, as well as other findings associated with portal hypertension. Sensitivity, specificity, PPV and NPV were calculated using EGD findings as the gold standard. RESULTS: A total of 195 patients and 142 patients met criteria for CT and MRI, respectively. The sensitivity of CT to detect EGD varices was 58-89%, but increased to 65-100% when specifically looking at large endoscopic varices. Overall specificity was 68-82%, but increased to 97-100% when applying ≥4 mm varices criteria. CT was superior to MRI in the detection of endoscopic varices; the addition of other portal hypertension stigmata did not improve results. CONCLUSIONS: The exclusion of large endoscopic varices by CT, using standardized criteria, may obviate the need or frequency of EGD screening in select patient populations. Alternatively, CT findings highly suggestive of esophageal varices in cirrhotic patients may warrant further investigation and/or treatment. Further studies are needed to validate these findings.

Retreatment of patients nonresponsive to pegylated interferon and ribavirin with daily high-dose consensus interferon.

Background. Current treatment of chronic hepatitis C with pegylated interferon and ribavirin has the ability to eliminate viral infection in about half of the patients treated. Therapeutic options, for those with remaining chronic hepatitis, will remain limited until novel antivirals become available in the future. Consensus interferon is currently available and has demonstrated clinical efficacy with superior invitro antiviral activity, but the maximum tolerated dose is not defined. Methods. We assessed the efficacy of daily high-dose (24 ug) consensus interferon with weight-based (1000-1200 mg daily) ribavirin in HCV genotype 1-infected non-responder patients. Results. Six adverse events were documented in five patients, and the trial was terminated with no subject achieving viral clearance. Conclusions. The occurrence of serious adverse events effectively defined the upper limit of acceptable dose, while also revealing that this dose did not offer enhanced sustained viral clearance.

Hepatic lipogranulomas in patients with chronic liver disease: association with hepatitis C and fatty liver disease.

AIM: To study the significance and clinical implication of hepatic lipogranuloma in chronic liver diseases, including fatty liver disease and hepatitis C. METHODS: A total of 376 sequential, archival liver biopsy specimens were reviewed. Lipogranuloma, steatosis and steato-fibrosis were evaluated with combined hematoxylin and eosin and Masson's trichrome staining. RESULTS: Fifty-eight (15.4%) patients had lipogranuloma, including 46 patients with hepatitis C, 14 patients with fatty liver disease, and 5 patients with other diseases. Hepatic lipogranuloma was more frequently seen in patients with hepatitis C (21%) and fatty liver disease (18%), and its incidence was significantly higher than that in control group (P < 0.0002 and P < 0.007, respectively). In addition, 39 out of the 58 patients with lipogranuloma were associated with steatosis and/or steato-fibrosis. Of the 18 lipogranuloma patients with clinical information available for review, 15 (83%) had risk factors associated with fatty liver disease, such as alcohol use, obesity, hyperlipidemia, and diabetes mellitus. Although the incidence of these risk factors was greater in patients with lipogranuloma than in control group (60%), it did not reach statistical significance. CONCLUSION: Hepatic lipogranuloma is not limited to mineral oil use and commonly associated with hepatic steatosis, hepatitis C and fatty liver disease. With additional histological features of steato-fibrosis, lipogranuloma can also be used as a marker of prior hepatic steatosis.

Trends in the indication and method of liver biopsy for hepatitis B and C.

BACKGROUND AND AIMS: Liver biopsy plays a crucial role in assessing inflammation and fibrosis in chronic hepatitis. The aim of this study was to compare the indications and methods for performing a liver biopsy over a 15-year period when there were evolving strategies and increasing therapeutic options for the treatment for chronic hepatitis B (HBV) and C (HCV). METHODS: We reviewed all percutaneous liver biopsies performed at our center from 1992 to 2007 using a pathology database. Variables collected included indication for biopsy, use of real-time ultrasound (US) guidance, and complications associated with the biopsy. RESULTS: A total of 3,572 total liver biopsies were performed between 1992 and 2007 with a gradual increase in annual liver biopsies from 1992 to 2001. After a peak in 2003, there was a gradual decline in liver biopsies performed. The number of liver biopsies done for HCV peaked in 2003, followed by an annual decrease until 2006, while the number of annual biopsies done for HBV increased during the same period. In addition, the proportion of liver biopsies performed with real-time US-guidance increased steadily since 1997. CONCLUSIONS: Changes in liver biopsy trends at our center may be related to several factors, including the evolving treatment strategies for HCV and HBV. Percutaneous liver biopsies were increasingly performed using real-time US-guidance over the past decade, a change that may reflect practice patterns around the country.

Histologic evidence of active liver injury in chronic hepatitis B patients with normal range or minimally elevated alanine aminotransferase levels.

GOALS: To evaluate the proportion of patients with histologic evidence of active liver disease (HEALD) who have chronic hepatitis B (CHB) and normal/minimally elevated serum alanine aminotransferase (ALT). Sub-analysis was performed to determine whether HEALD based upon liver biopsy better correlates with ALT using modified ALT (30 men/19 women) upper limit of normal (ULN) criteria compared with local conventional laboratory. BACKGROUND: There are limited data on CHB with normal range ALT (NRALT). We designed a study to evaluate histologic damage in this cohort of patients. STUDY: A retrospective, multicenter study evaluated CHB patients with normal/minimally elevated ALT [< or = 1.2 x ULN (hepatitis B e antigen positive) or < or = 1.5 x ULN (hepatitis B e antigen negative)]. Liver biopsy specimens were reviewed by an independent histopathologist. HEALD was defined as Knodell necroinflammatory score greater than 5 and Ishak fibrosis stage greater than 1. RESULTS: Forty-five patients met criteria: median age of 40 years; 51% males; 73% Asian; and 67% hepatitis B e antigen negative. Median hepatitis B virus DNA was 6.04 log10 copies/mL, aspartate aminotransferase (AST) 30 IU/L, and ALT 42 IU/L; and 40% of the patients had ALT greater than ULN. Overall, 20% had HEALD and among patients with NRALT, 4 of 27 (15%) and 0 of 5 (0%) had HEALD through conventional or modified ALT ULN, respectively. CONCLUSIONS: One fifth of patients with CHB and normal/minimally elevated ALT had HEALD. Among the subset of patients with NRALT, 15% (4 of 27) had HEALD when using conventional laboratory compared with 0% (0 of 5) patients by modified ALT ULN criteria. Use of the modified ALT ULN will likely improve accuracy in identifying patients who may have HEALD compared with conventional laboratory ULN.

Prevalence of diverticulosis in recurrent Clostridium difficile infection.

AIM: To re-evaluate the theory that colonic diverticulosis is associated with relapse of Clostridium difficile associated disease (CDAD) in light of data suggesting increasing rates of CDAD infection and relapse. METHODS: Charts were reviewed for patients with recurrent CDAD who had also had a prior colonoscopy or flexible sigmoidoscopy. An age and gender matched control group was used to compare the prevalence of diverticulosis. RESULTS: Twenty-two patients met the study criteria, and the prevalence of diverticulosis in patients with CDAD relapse was 23% compared to 32% in age and sex matched controls (P = 0.44). A significant proportion of patients with CDAD relapse had co-morbidities associated with immune suppression. CONCLUSION: Diverticulosis does not appear to be associated with CDAD relapse.

Utilization of platelet count spleen diameter ratio in predicting the presence of esophageal varices in patients with cirrhosis.

GOALS: To assess whether the platelet count/spleen diameter ratio is a useful noninvasive predictor of esophageal varices. BACKGROUND: Current guidelines recommend that all patients with cirrhosis undergo screening endoscopy for the presence of varices. Recent studies have focused on using noninvasive techniques to stratify cirrhotic patients according to their risk of having varices. One study examining the platelet count/spleen diameter ratio using a cut-off value of 909, yielded a negative predictive value of 100% for the presence of varices. STUDY: A retrospective analysis of 137 patients with cirrhosis over the age of 18 that underwent screening endoscopy for varices between January 2003 and October 2005. The data collected were age, sex, etiology of cirrhosis, spleen diameter, prothrombin time/international normalized ratio, total bilirubin, platelet count, albumin, Child-Pugh score, and endoscopic findings. RESULTS: There were 137 patients with 87 (63.5%) men and a mean age of 56 years. Seventy-six (55%) patients had esophageal varices. The mean age, sex, and etiology of cirrhosis were similar between those with and without varices. Using a platelet count/spleen diameter ratio with a cut-off value of 909, yielded a negative predictive value of only 73% and a positive predictive value of 74%. CONCLUSIONS: The platelet count/spleen diameter ratio with a cut-off value of 909 may not be sufficiently accurate in predicting the presence of esophageal varices. Upper endoscopy remains the method of choice to screen for the presence of varices.

Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir.

UNLABELLED: This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-naïve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-naïve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated. CONCLUSION: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.

Bile Duct Dilatation in Patients With Chronic Viral Hepatitis on Maintenance Methadone Therapy.

Methadone maintenance therapy (MMT) is commonly used in the treatment of opioid dependence. Several small-scale reports have suggested that methadone may lead to nonobstructive dilatation of the common bile duct (CBD). We present the first large study to retrospectively evaluate this hypothesis in asymptomatic patients with chronic hepatitis on long-term MMT. Methods: Charts of all adult patients with chronic hepatitis with and without MMT between 2002 and 2007 at Beth Israel Medical Center were reviewed. Data collected included age, gender, CBD size, presence of cirrhosis, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, and dose and duration of methadone use. Patients with a history of pancreatitis and cholecystectomy were excluded. Results: CBD size in the MMT group (n=215) was significantly increased compared to controls (n=108; 5.87 mm vs 3.79 mm; P<.0001). CBD dilatation (CBD ≥8 mm) was seen in 26.1% and 2.78% of MMT and control groups, respectively (P<.0001), and was significantly associated with duration of methadone use (P=.01), but not with methadone dose (P=.83). Multivariate logistic regression showed that patients on MMT are 17.5 times more likely to develop CBD dilatation (odds ratio, 17.5). Conclusion: Chronic MMT is associated with CBD dilatation and should be considered in the differential diagnosis of asymptomatic CBD dilatation. Less invasive studies such as magnetic resonance cholangiopancreatography or endoscopic ultrasound should be considered over endoscopic retrograde cholangiopancreatography in patients without clinical or laboratory evidence suggesting biliary obstruction.

Chronic hepatitis C virus and celiac disease, is there an association?

Celiac disease (CD) has been epidemiologically associated with chronic hepatitis C (HCV), and CD activation after the initiation of interferon (IFN-alpha) in patients with HCV is documented. However, clear association of CD and HCV is lacking. A prospectively maintained database of 878 CD patients showed a prevalence of 0.68% (six patients). Symptoms of diarrhea, weight loss, and depression prompted the diagnosis of CD during or after IFN-alpha therapy in four cases. Also, 294 subjects with liver disease (195 with HCV, 80 normal controls and 19 disease controls) were prospectively screened for CD. The mean age of the subjects was 50.1 years (SD 12.3), 58% males:42% females. A total of 30% received IFN-alpha therapy (16% at the time of testing for CD). Two HCV patients (1%) had positive tTG-IgA but these had negative endomysial antibody (EMA) and normal duodenal biopsies. CD prevalence is not increased in patients with HCV. Routine screening of CD in HCV patients is not warranted, however, the presence of CD should be considered in the setting of clinical deterioration during or after IFN-alpha therapy.

Oral antivirals for chronic hepatitis B.

Four oral antiviral agents have been approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B: lamivudine, adefovir, entecavir, and telbivudine. This article reviews the durability of response, dose regimen, predictors of response, safety, and problems with resistance of these four agents and of promising agents currently in phase III clinical trials for the treatment of patients who have hepatitis B e antigen-positive and -negative chronic hepatitis B.