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Background and Aim: Treatment end-point of therapy for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) includes HBeAg seroconversion, which ranges from 15% to 22% after 1 year of oral nucleos(t)ides according to clinical trials. Our goal was to determine the incidence and predictors of HBeAg seroconversion in such patients in routine clinical practice because they may differ than reported rates., Methods: We conducted a retrospective cohort study of 333 consecutive treatment-naïve HBeAg-positive patients who were treated for CHB between 1/2000 and 6/2010 at three gastroenterology and liver clinics in the USA. Primary study end-point was HBeAg seroconversion-loss of HBeAg and antibody to HBeAg (anti-HBe) development., Results: The majority of patients were Asian (96%). Median treatment duration prior to HBeAg seroconversion was 50 (range 26-52) weeks. Of the 333 study patients, 25% received lamivudine, 16% adefovir, 51% entecavir, and 8% tenofovir. HBeAg seroconversion at month 12 was 8.2%. On multivariate analysis inclusive of age, gender, and antiviral agents, independent predictors for HBeAg seroconversion at month 12 were hepatitis B virus DNA < 7.5 log10  IU/mL (hazard ratio [HR] = 2.59 [1.04-6.44]), P = 0.041) and alanine transaminase (ALT) > 1.5 × upper normal limit (HR = 2.86 [1.05-7.81], P = 0.040), but not the choice of nucleos(t)ides., Conclusions: The HBeAg seroconversion rate seen in clinical settings for oral nucleos(t)ides appears much lower than those reported in pivotal trials, especially in patients with lower ALT and higher HBV DNA levels. HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment end-points., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: The primary treatment endpoint for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is HBeAg seroconversion; however, data on the durability of response are inconsistent., Goals: Our goal was to investigate the rate of recurrent viremia after HBeAg seroconversion and subsequent discontinuation of therapy., Methods: We retrospectively studied 88 consecutive Asian American patients who achieved HBeAg seroconversion [loss of HBeAg and development of antibody to HBeAg (anti-HBe)] among 458 HBeAg-positive patients who received oral antiviral therapy at 3 US clinics between March 1998 and November 2010. Recurrent viremia was defined as reappearance of detectable serum hepatitis B virus DNA (>100 IU/mL) on 2 consecutive laboratory tests from previously undetectable levels., Results: Antiviral medications used at the time of HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), and combination therapy (3%). Antiviral therapy was continued after HBeAg seroconversion in 49 patients (group I) and discontinued in the other 39 patients after consolidation therapy [median=12 months (range, 1 to 55 mo)] (group II). No patients in group I experienced recurrent viremia, whereas 90% in group II did. Elevated alanine aminotransferase also occurred in 38% of group II patients [median peak alanine aminotransferase 249 IU/mL (range, 93 to 1070 IU/mL)]., Conclusions: Despite consolidation therapy, almost all patients who discontinued therapy after achieving HBeAg seroconversion and complete viral suppression experienced recurrent viremia, and close to half also experienced biochemical flares. HBeAg seroconversion does not seem to be a durable treatment endpoint for many patients, and they should be monitored carefully for virologic relapse and biochemical flares if antiviral therapy is withdrawn.

The majority of data on risk factors (RFs) for hepatocellular carcinoma (HCC) comes from studies involving populations without underlying liver disease. It is important to evaluate RFs for HCC in patients with chronic liver disease since HCC rarely occurs in those without underlying liver disease. We conducted a hospital-based case-control study of 259 incident HCC cases and 781 controls by convenience sampling between 02/2001 and 12/2009 from the liver clinic at Stanford University Medical Center. The study population was 41% White, 14% Hispanic, 3% African American, 40% Asian American, and 2% other race/ethnicity. RFs were examined through medical records and an in-person questionnaire. Alcohol and tobacco use was calculated by cumulative grams of alcohol or cumulative pack(s) of cigarette consumed over one's lifetime. Diabetes mellitus (DM) was defined by random glucose level of ≥200 mg/dL. RFs were evaluated using multivariate logistic regression. Independent predictors of HCC risk, after mutual adjustment and additional control for alcohol use, etiology of liver diseases, and DM, included age >40 (OR = 8.5 [2.6-28.3]), male gender (OR = 3.5 [2.2-5.8]), presence of cirrhosis (OR = 2.8 [1.6-4.9]), Asian ethnicity (OR = 2.8 [1.8-4.6]), AFP > 50 (OR = 4.2 [2.6-6.8]), and cumulative lifetime tobacco use of >11,000 packs (OR = 1.7 [1.0-2.9]). Heavy prolonged cigarette smoking, but not alcohol use, was a significant independent predictor for HCC in patients with underlying liver disease. Besides older age, male gender, presence of cirrhosis, and elevated AFP, Asian ethnicity and heavy cumulative tobacco use are strong independent predictors of HCC.

The goal of liver transplantation (LT) is to maximize the length and quality of a patient's life and facilitate his or her return to full productivity. The aims of this study were (1) to use the United Network for Organ Sharing (UNOS) data set to determine the proportions of recipients who were employed and unemployed within 24 months after LT between 2002 and 2008 and (2) to examine the factors associated with a return to employment. UNOS data that were collected since the adoption of the Model for End-Stage Liver Disease scoring system on February 27, 2002 were analyzed. There were 21,942 transplant recipients who met the inclusion criteria. The employment status of the recipients was analyzed within a 60-day window at the following times after transplantation: 6, 12, and 24 months. Approximately one-quarter of the LT recipients (5360 or 24.4%) were employed within 24 months after transplantation, and the remaining recipients had not returned to work. The demographic variables that were independently associated with posttransplant employment included an age of 18 to 40 years, male sex, a college degree, Caucasian race, and pretransplant employment. Patients with alcoholic liver disease had a significantly lower rate of employment than patients with other etiologies of liver disease. The recipients who were employed after transplantation had significantly better functional status than those who were not employed. In conclusion, the employment rate after LT is low, with only one-quarter of LT recipients employed. New national and individual transplant program policies are needed to assess the root causes of unemployment in recipients who wish to work after LT., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background: Combination therapy for chronic hepatitis B virus (HBV) infection is recommended for patients with antiviral resistance (AVR) or partial response (PR) to earlier antiviral therapy; however, data on outcomes are limited., Goals: To determine the rate of complete viral suppression (CVS) with combination therapy and to compare CVS among different indications and treatment regimens., Methods: A cohort of 109 consecutive patients with chronic hepatitis B from 3 liver clinics in Northern California was retrospectively studied. All patients started combination therapy between April 2004 and August 2009 for the following indications: AVR (n = 29), PR (n = 60), or others (n = 20). Combination treatments included lamivudine (LAM), adefovir (ADV), telbivudine (LdT), entecavir (ETV), tenofovir (TDF), and emtricitabine (FTC). CVS was defined as undetectable serum HBV DNA <100 IU/mL., Results: Among the patients, who were nearly all Asian (99%), 73% had ≥ 2 prior treatments and 82% had treatment failure (AVR or PR). Median treatment duration of combination therapy was 21 months (range, 6 to 50 mo). The majority (77%) achieved CVS after 6 months of various combination regimens: 80% for ETV+TDF, 76% for TDF+LAM or FTC or LdT, 75% for ETV+ADV, and 69% for ADV+LAM or LdT (P = 0.86). After 6 months of therapy, CVS was observed in a similar proportion of patients treated for PR and AVR (72% and 74%, respectively)., Conclusions: Although the majority of 109 treatment-experienced patients had prior treatment failure, high rates of CVS were rapidly achieved and did not significantly differ between indications of AVR and PR or between ETV-based and TDF-based regimens.

The goal of antiviral treatment of chronic hepatitis B is to prevent the complications of cirrhosis, hepatic decompensation, HCC, and death. Because these clinical outcomes may take a long period of time to develop, it is important to use intermediate or surrogate end points to evaluate the efficacy and response to antiviral treatment, and to determine whether treatment can be safely stopped, especially given concern for the development of antiviral resistance with NUC therapy. Although normalization of ALT and suppression of HBV DNA viral replication are associated with favorable outcomes, the durability of their response is low, and these end points are insufficient markers for stopping treatment. HBeAg seroconversion is currently used to discontinue NUC treatment in patients with HBeAg-positive chronic hepatitis B, whereas the stopping rule for HBeAg-negative disease relies on HBsAg loss. However, HBsAg loss occurs very infrequently and is not a practical end point for clinical use, although quantitative HBsAg levels may be useful in identifying patients who could achieve a sustained virologic response to treatment.

Genome-wide association studies have recently identified single nucleotide polymorphisms in proximity to the interleukin-28B (IL-28B) gene that can predict sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection who are undergoing therapy with pegylated interferon (IFN) a and ribavirin. IL-28B encodes IFN-λ3, a type III IFN involved in host antiviral immunity. Favorable variants of the 2 most widely studied IL-28B polymorphisms, rs1 2979860 and rs8099917, are strong pretreatment predictors of early viral clearance and SVR in patients with genotype 1 HCV infection. Variations in the distribution of IL-28B alleles may partly explain differences in SVR rates among ethnic groups. Further investigations have implicated IL-28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL-28B may be a key factor involved in host immunity against HCV. Clinical trials of IFN-λ as a therapeutic agent for chronic HCV infection are currently underway. The use of IL-28B polymorphisms as a predictive tool will have a major impact on treatment strategies for chronic HCV infection, particularly in the context of emerging therapies and direct-acting antiviral agents.

Unlabelled: Studies of hepatitis B virus (HBV)/hepatitis C virus (HCV) dual infection are limited. Most are small, conducted outside the United States, and compare dual infection with HCV monoinfection. The goal of this study was to characterize HBV/HCV dual infection in a large multiethnic, matched, case-control study of dual-infected and HBV-monoinfected patients at two United States centers. Using an International Classification of Disease Version 9 electronic query and chart review, we identified 115 HBV/HCV dual-infected patients with serial HBV DNA, HCV RNA, and alanine aminotransferase (ALT) levels. As a control, 115 HBV-monoinfected patients were chosen randomly and matched with cases by age ±10 years, sex, Asian versus non-Asian ethnicity, and study site. Both groups had similar sex, ethnic, and age distributions (68% male, 83% Asian, age 52 ± 14 years). The median follow-up times were 33 and 38 months for the dual-infected and monoinfected groups, respectively. More monoinfected patients received HBV antiviral therapy than dual-infected patients (43% versus 24%; P = 0.002). No significant difference was detected between the proportion of monoinfected versus dual-infected patients with ALT above 40 U/L at presentation or during follow-up. Dual infection patients exhibited very little HBV/HCV codominance at baseline and throughout follow-up: patients had either HBV viremia with low or absent HCV RNA or detectable HCV RNA with low or absent HBV DNA. Asian ethnicity was predictive of HBV dominance after adjusting for sex, age, and baseline ALT elevation (odds ratio 7.35; P = 0.01)., Conclusion: HBV/HCV dual-infected and HBV-monoinfected patients had similar clinical characteristics. Asian ethnicity is a major independent predictor of HBV-dominant disease, and HCV dominance with undetectable HBV DNA is more common in non-Asian individuals. Larger studies are needed to further characterize the natural history of HBV/HCV dual infection in Asian and non-Asian individuals., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Early diagnosis of hepatocellular carcinoma (HCC) has a significant impact on survival by implementation of effective treatment strategies, including hepatic resection, locoregional ablative therapy, and liver transplantation. The use of serum tumor markers and biopsy are particularly important for diagnosis of small hepatic lesions with atypical features on imaging studies. α-Fetoprotein remains the most frequently used tumor marker for the diagnosis of HCC. The development of novel serum biomarkers for HCC, identification of molecular markers for tissue immunohistochemistry, and emergence of new diagnostic techniques such as proteomic profiling may improve the early detection rate of HCC in the future., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV-related HCC is increasing, while the number of patients listed for HBV-related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long-term outcome of patients transplanted for HBV-related HCC in the National Institutes of Health (NIH) HBV OLT Study Group., Results: Ninety-eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV-related HCC. With a mean follow-up of 36.5 months post-OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre-OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre-OLT in predicting HCC recurrence. Serum alpha-fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p=0.003). HCC recurrence was significantly associated with decreased post-OLT survival., Conclusion: HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence., (© 2010 John Wiley & Sons A/S.)

Viral hepatitis is a major cause of chronic liver disease, liver failure, and hepatocellular carcinoma worldwide, resulting in significant morbidity and mortality. New insights into the pathogenesis and molecular biology of hepatitis viruses have led to the discovery of novel antiviral agents. Likewise, a greater understanding of the natural history of chronic infection, predictors of disease progression, and predictors of virologic response to therapy has resulted in more effective treatment strategies. Recent data have increasingly demonstrated that the ability to achieve a successful response to antiviral therapy may significantly reduce the risk of progressive liver disease and hepatocellular carcinoma. Immunization practices and the use of potent antiviral therapy may have a major impact in reducing the burden of chronic liver disease and the incidence of hepatocellular carcinoma associated with chronic hepatitis B and chronic hepatitis D. Individualized treatment strategies and the development of direct acting antiviral agents may lead to further improvements in the ability to achieve a sustained virologic response to therapy in chronic hepatitis C. With new advances in the treatment of chronic hepatitis, efforts to optimize viral suppression while reducing the potential for antiviral drug resistance will become increasingly important.

Goals: The primary aim of this study was to further evaluate the efficacy of peginterferon plus nitazoxanide without ribavirin using a 4-week lead-in., Background: The initial treatment of chronic hepatitis C with nitazoxanide used 12 weeks of nitazoxanide monotherapy before combination therapy with peginterferon with or without ribavirin., Study: This open-label pilot study enrolled 44 treatment-naive patients with chronic hepatitis C (40 with genotype 4; 3 with genotype 1; and 1 with genotype 2). The patients received oral nitazoxanide 500 mg twice daily for 4 weeks followed by nitazoxanide plus peginterferon alfa-2a 180 mug weekly for 36 weeks and were then followed for 24 weeks. The results of this study were compared with those from an overlapping historical trial using 12 weeks of nitazoxanide lead-in., Results: A sustained virologic response (SVR) was achieved in 80% of patients, which was similar to the SVR rates in the historical trial, that is, 79% and 61% in patients treated with and without ribavirin, respectively. A rapid virologic response occurred in 59% of patients, which was also similar to the rapid virologic response rates in the historical trial (64% and 54% in patients treated with and without ribavirin, respectively). All 4 patients with genotypes 1 and 2 had an SVR., Conclusions: The nitazoxanide lead-in phase before combination therapy with peginterferon can likely be reduced from 12 weeks to 4 weeks without compromising virologic response rates. In addition, treatment of chronic hepatitis C with peginterferon plus nitazoxanide without ribavirin is promising and requires further study.

Background & Aims: Cirrhosis is a prevalent and expensive condition. With an increasing emphasis on quality in health care and recognition of inconsistencies in the management of patients with cirrhosis, we established a set of explicit quality indicators (QIs) for their treatment., Methods: We organized an 11-member, multidisciplinary expert panel and followed modified Delphi methods to systematically identify a set of QIs for cirrhosis. We provided the panel with a report that summarized the results of a comprehensive literature review of data linking candidate QIs to outcomes. The panel performed independent ratings of each candidate QI by using a standard 9-point RAND appropriateness scale (RAS) (ranging from 1 = not appropriate to 9 = most appropriate). The panel members then met, reviewed the ratings, and voted again by using an iterative process of discussion. The final set of QIs was selected; QIs had a median RAS >7, and panel members agreed on those selected., Results: Among 169 candidate QIs, the panel rated 41 QIs as valid measures of quality care. The selected QIs cover 6 domains of care including ascites (13 QIs), variceal bleeding (18 QIs), hepatic encephalopathy (4 QIs), hepatocellular cancer (1 QI), liver transplantation (2 QIs), and general cirrhosis care (3 QIs). Content coverage included prevention, diagnosis, treatment, timeliness, and follow-up., Conclusions: We developed an explicit set of evidence-based QIs for treatment of cirrhosis. These provide physicians and institutions with a tool to identify processes amenable to quality improvement. This tool is intended to be applicable in any setting where care for patients with cirrhosis is provided., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients with diabetes mellitus overall experience worse health outcomes than non-diabetics, but whether this is true among recipients of liver transplantation still remains unclear. The aim of this study was to compare the mortality of diabetic and non-diabetic patients following liver transplantation., Methods: We conducted a retrospective analysis of 530 adult patients undergoing liver transplantation at Stanford University Medical Center from February 1995 to July 2006. Information on diabetes mellitus was available for 431 patients; 96 patients who had acute liver failure (n = 17), combined liver and kidney transplantation (n = 28), or died prior to discharge (n = 51) were excluded from analysis., Results: Over a mean follow-up of 4.5 years, survival was 81% in the diabetic group and 94% among controls (p = <0.0001). After controlling for age (mean +/- SD: 54.4 +/- 7.6 in diabetics, 50.1 +/- 9.6 in controls), body mass index (28.6 +/- 6.6 in diabetics, 27.1 +/- 5.4 in controls), presence of hepatitis C, and MELD score (17 +/- 9.6 in diabetics, 19 +/- 10.2 in controls), diabetes mellitus remained a significant predictor of death (HR 3.11, p = 0.01)., Conclusions: Diabetes mellitus is an independent risk factor for mortality following liver transplantation. Further investigation of this relationship should focus on the impact of more intensive pre- and post-liver transplantation glucose control, cardiovascular risk factor reduction, and the effects of accelerated atherosclerosis in the setting of immune suppression.

Objectives: Previous studies have found ethnicity to be an important predictor of outcomes of treatment with peginterferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C. Although the expected sustained virological response (SVR) rates of Hispanics and African Americans are lower than those of Caucasians, SVR rates in Asians appear to be more favorable. However, in some of these studies, hepatitis C virus (HCV) genotype was identified by INNO-LiPA assay, which can mistype the easier-to-treat HCV genotype 6 as genotype 1. Our goal was to compare SVR rates among Caucasian and Asian-American patients with genotype 1 and 2/3 infection whose HCV genotypes were accurately classified by core sequencing testing., Methods: A cohort of 269 consecutive treatment-naive HCV-infected patients with genotype 1 or 2/3 (157 Caucasians and 112 Asians) treated with PEG-IFN+RBV from January 2001 to November 2007 at four community-based gastroenterology clinics in Northern California were studied. The analysis of data was by intention-to-treat., Results: The SVR rates for patients with genotype 1 were 45% for Caucasians and 52% for Asians (P=0.37). The SVR rates for patients with genotype 2/3 infection was 77% for Asians and 74% for Caucasians (P=0.7). On multivariate logistic regression analyses adjusting for age, alanine aminotransferase (ALT), baseline viral load, HCV genotype, and treatment adherence, we did not find Asian ethnicity to predict SVR. On a separate analysis, we found that Asians who had HCV genotype 1 or 1b by the less accurate INNO-LiPA assay had significantly higher SVR rates than Caucasians with genotype 1 (64% vs. 45%, respectively, P=0.03)., Conclusions: SVR rates were similar in Asian Americans and Caucasians infected with HCV genotype 1 or 2/3 when HCV genotype classification was accurately determined.

Percutaneous liver biopsy (LB) remains an important tool in the diagnosis and management of parenchymal liver diseases. In current practice, it is most frequently performed to assess the inflammatory grade and fibrotic stage of commonly encountered liver diseases, with the diagnostic role relegated to secondary importance. The role of LB remains a vastly controversial and debated subject, with an ever-increasing burden of evidence that questions its routine application in all patients with liver dysfunction. It remains, essentially, an invasive procedure with certain unavoidable risks and complications. It also suffers shortcomings in diagnostic accuracy since a large liver sample is required for an ideal assessment, which in clinical practice is not feasible. LB is also open to observer interpretation and prone to sampling errors. In recent years, a number of noninvasive biomarkers have evolved, each with an impressive range of diagnostic certainty approaching that achieved with LB. These noninvasive tests represent a lower-cost option, are easily reproducible, and serve as suitable alternatives to assess hepatic inflammation and fibrosis. This article aims to debate the shortcomings of LB while simultaneously demonstrating the diagnostic accuracy, reliability and usefulness of noninvasive markers of liver disease thereby making the case for their utilization as suitable alternatives to LB in many, although not all, circumstances.

Chronic hepatitis C is a major cause of chronic liver disease globally, and the natural history of progression may lead to cirrhosis with liver failure, hepatocellular carcinoma, and premature liver-related death. Emerging data demonstrates that interferon-based therapy, particularly among those achieving a sustained virologic response (SVR), is associated with long-term persistence of SVR, improved fibrosis and inflammation scores, reduced incidence of hepatocellular carcinoma, and prolonged life expectancy. This reduction in the rate of progression has also been demonstrated in patients with chronic hepatitis C and cirrhosis in some but not all studies. The majority of these results are reported with standard interferon therapy, and long-term results of peginterferon plus ribavirin therapy with a higher likelihood of SVR should have a yet greater impact on the population of treated patients. The impact on slowing progression is greatest in patients with an SVR, less in relapsers, and equivocal in nonresponders. Thus, the natural history of chronic hepatitis C after completion of antiviral therapy is favorable with achievement of an SVR, although further data are needed to determine the likely incremental impact of peginterferon plus ribavirin, late long-term effects of therapy, and the benefit of treatment in patients with advanced hepatic fibrosis.

Hepatitis B virus is a major cause of chronic liver disease worldwide and is associated with an increased risk of hepatocellular carcinoma, progressive hepatic fibrosis and end-stage liver disease. Suppression of HBV replication is recognized as the primary on-treatment goal of antiviral therapy, as reduction of serum HBV DNA to low or undetectable levels is highly likely to have a positive impact on long-term clinical outcomes in HBV-associated chronic liver disease. Entecavir is an oral nucleoside analogue that effectively inhibits HBV polymerase, resulting in rapid viral suppression. Long-term data on patients receiving entecavir for chronic hepatitis B have demonstrated high potency, a low incidence of antiviral drug resistance and good tolerability, making entecavir an ideal first-line agent for the treatment of chronic hepatitis B.

Purpose: Hepatitis B virus (HBV) genotypes can affect treatment response to interferon-based therapy and disease outcomes in patients with chronic hepatitis B (CHB). Little data exist to characterize HBV genotypes in Vietnamese, one of the largest minority groups in the United States and also one with one of the highest CHB and liver cancer disease burdens. The goal of this study was to compare the distribution of HBV genotypes in Vietnamese and Chinese patients., Methods: We performed a cross-sectional study of 567 consecutive patients of Vietnamese (n = 478) or Chinese (n = 89) descent, with HBV genotype mutation analysis performed between 7/2,005 and 6/2,008 at a community gastroenterology clinic and a university-affiliated liver clinic in the United States., Results: There were no significant differences between the Vietnamese and Chinese groups in mean age (45 and 44 years), gender (58% and 61% male), HBeAg status (64% and 65% negative), median alanine aminotransferase (33 and 41 U/L), and log(10) HBV DNA (4.9 and 5.0 log(10) IU/ml), or the prevalence of precore/basic core promoter mutations (72% and 71%), respectively. Vietnamese patients had a much higher prevalence of HBV genotype B and a lower prevalence of genotype C than Chinese patients: 74% and 25% vs. 55% and 43% (P = 0.001)., Conclusions: Chinese patients with CHB often carry either B or C genotype. Vietnamese patients with CHB mostly have HBV genotype B. Additional studies are needed to further characterize the clinical significance of HBV genotype in the natural history and treatment outcomes of CHB in Vietnamese patients.

Several previous studies found that Asians transplanted for hepatitis B virus (HBV) infection had worse post-transplant outcomes than Caucasians. Data on post-transplant outcomes of African Americans and waitlist outcomes of Asian Americans and African Americans with hepatitis B are scant. The aim of this study was to compare waitlist and post-transplant outcomes among Asian Americans, African Americans, and Caucasians who had HBV-related liver disease. Data from a retrospective-prospective study on liver transplantation for HBV infection were analyzed. A total of 274 patients (116 Caucasians, 135 Asians, and 23 African Americans) from 15 centers in the United States were enrolled. African Americans were younger and more Asian Americans had hepatocellular carcinoma (HCC) at the time of liver transplant listing. The probability of undergoing transplantation and the probability of survival on the waitlist were comparable in the 3 racial groups. Of the 170 patients transplanted, 19 died during a median follow-up of 31 months. The probability of post-transplant survival at 5 years was 94% for African Americans, 85% for Asian Americans, and 89% for Caucasians (P = 0.93). HCC recurrence was the only predictor of post-transplant survival, and recurrence rates were similar in the 3 racial groups. Caucasians had a higher rate of HBV recurrence: 4-year recurrence was 19% versus 7% and 6% for Asian Americans and African Americans, respectively (P = 0.043). In conclusion, we found similar waitlist and post-transplant outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B. Our finding of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies., ((c) 2009 AASLD.)

Objectives: At present there is no clear consensus on how patients with chronic hepatitis B (CHB), high serum hepatitis B virus (HBV) DNA, and normal alanine aminotransferase (NLALT) levels should be managed. This study hypothesizes that a significant proportion of such patients may have histological disease., Methods: We carried out a retrospective study of 101 consecutive treatment-naive patients with CHB who underwent liver biopsies at a community gastroenterology clinic and had high HBV DNA and NLALT (< or = 40 U/l) levels at the time of biopsy. All patients were Asians. ALT levels were observed for a period of time before liver biopsy and were used to classify patients into two groups, namely those with only NLALT levels and those with fluctuating ALT (FLALT) levels. All patients had at least two ALT measurements during this period of time. Significant histology was defined as stage > or = 2 fibrosis or stage 1 fibrosis plus grade > or = 2 inflammation using the Batts-Ludwig scoring system., Results: In patients with NLALT levels, the proportions of those with significant histology were 0, 22, and 45% for age < or = 35, 36-50, and >50 years, respectively (n=11, n=27, n=19; P=0.033). In patients who had FLALT levels, the corresponding proportions were 22, 42, and 69% (n=9, n=22, n=13; P=0.091). After adjustments for gender, hepatitis B e antigen (HBeAg) status, and mean pre-biopsy HBV DNA levels, significant predictors of histological disease were older age (odds ratio (OR)=6.2 for age 36-50 years and OR=17.6 for age >50 years compared with age < or = 35 years, P=0.041 and P=0.003, respectively) and FLALT levels (OR=3.6, P=0.008). Sub-analysis of patients with NLALT levels using lower cutoffs (30 U/l for men and 19 U/l for women) showed similar trends., Conclusions: Patients with CHB, high HBV DNA, and NLALT levels and aged more than 35 years or those with FLALT levels may have significant histological disease (22-70%).

Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139 cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P = 0.02), and isoniazid-related hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor. Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs for MTB induction therapy (P = 0.003) and to have been diagnosed within 1 month of symptom onset (P = 0.01) and were less likely to have multiorgan disease (P = 0.01) or to have experienced episodes of acute transplant rejection (P = 0.02). Compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active MTB infection and a 4-fold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears safe and is probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring a specific contraindication. Liver Transpl 15:894-906, 2009. (c) 2009 AASLD.

Nitazoxanide, the first thiazolide, was originally developed for the treatment of Cryptosporidium parvum. More recently, antiviral activity of nitazoxanide against hepatitis B virus (HBV) and hepatitis C virus was recognized in in vitro systems. These basic studies led to phase II clinical trials that demonstrated the safety and efficacy of nitazoxanide in combination with peginterferon, with or without ribavirin, in the treatment of chronic hepatitis C genotype 4. The sustained virologic response rate was 79% and 80% in two studies, which was higher than the response rate of 50% with the standard of care with peginterferon plus ribavirin. In very preliminary studies of patients with chronic hepatitis B, nitazoxanide suppressed serum HBV DNA and led to loss of hepatitis B e antigen in the majority of patients and hepatitis B surface antigen in approximately a quarter of patients. Randomized controlled studies of naive and nonresponder patients with chronic hepatitis C genotype 1 are underway, new second generation and controlled release thiazolides are being developed, and future studies of patients with chronic hepatitis B are planned.

Background & Aims: Sustained virologic response (SVR) rates of 50%-60% have been achieved in patients with chronic hepatitis C genotype 4 treated with peginterferon plus ribavirin. The safety and efficacy of nitazoxanide plus peginterferon alfa-2a, with or without ribavirin, were evaluated in a randomized controlled trial at 2 centers in Egypt., Methods: Previously untreated patients with chronic hepatitis C and genotype 4 infection were assigned randomly to groups that were given standard of care (peginterferon alfa-2a and ribavirin for 48 weeks, n = 40), nitazoxanide monotherapy for 12 weeks followed by nitazoxanide plus peginterferon alfa-2a for 36 weeks (n = 28), or nitazoxanide monotherapy for 12 weeks followed by nitazoxanide plus peginterferon alfa-2a and ribavirin for 36 weeks (n = 28). Therapeutics included nitazoxanide (500 mg) twice daily, peginterferon alfa-2a (180 microg) once weekly, and weight-based ribavirin (1000-1200 mg/day)., Results: The percentages of rapid virologic response (RVR), defined as undetectable HCV RNA at week 4 of combination therapy, and SVR were significantly higher in patients given the triple therapy compared with the standard of care (64% vs 38%, P = .048; and 79% vs 50%, P = .023; respectively). Patients given nitazoxanide plus peginterferon alfa-2a had intermediate rates of RVR (54%) and SVR (61%). Adverse events were similar across treatment groups except for higher rates of anemia in the groups receiving ribavirin., Conclusions: The combination of nitazoxanide, peginterferon alfa-2a, and ribavirin increased the percentages of patients with RVR and SVR, compared with patients given peginterferon plus ribavirin, without an increase in adverse events.

A significant proportion of patients with chronic hepatitis C virus (HCV) infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR). Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN) is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferon-based therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients.

Chronic HBV infection is an important public health problem worldwide and in the United States. A treatment algorithm for the management of this disease, published previously by a panel of U.S. hepatologists, has been revised on the basis of new developments in the understanding of the disorder, the availability of more sensitive molecular diagnostic tests, and the licensure of new therapies. In addition, a better understanding of the advantages and disadvantages of new treatments has led to the development of strategies for reducing the rate of resistance associated with oral agents and optimizing treatment outcomes. This updated algorithm was based primarily on available evidence by using a systematic review of the literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to low or undetectable levels. Assays can now detect serum HBV DNA at levels as low as 10 IU/mL and should be used to establish a baseline level, monitor response to antiviral therapy, and survey for the development of drug resistance. Interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir are approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Although all of these agents can be used in selected patients, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir. Issues for consideration for therapy include efficacy, safety, rate of resistance, method of administration, and cost.

Nitazoxanide, the first thiazolide, was originally developed for the treatment of Cryptosporidium parvum. The antiviral activity of nitazoxanide was discovered by serendipity in patients with AIDS who were treated for cryptosporidial diarrhea and had HBV or HCV co-infection. In preliminary open-label studies of patients with chronic hepatitis B, nitazoxanide suppressed serum HBV DNA and led to loss or seroconversion of hepatitis B e antigen in the majority of patients, as well as hepatitis B surface antigen in approximately a quarter of patients. In Phase II studies of patients with chronic hepatitis C genotype 4, nitazoxanide combined with peginterferon alfa-2a, with or without ribavirin, increased the sustained virologic response rate to 79-80 versus 50% with peginterferon plus ribavirin standard of care. Randomized, controlled studies of naive and nonresponder patients with chronic hepatitis C genotype 1 and patients with chronic hepatitis B are underway, and new second generation thiazolides are being developed.

Hepatic encephalopathy (HE) is a significant cause of morbidity and mortality in patients with advanced chronic liver disease. Current therapies are associated with inconvenient side-effects, high cost, and incomplete efficacy. The quanternary ammonium compound L-acyl-carnitine has been suggested as a potent, low-cost, and safe alternative therapy for patients with cirrhosis and HE. A systematic review of the literature assessing the use of carnitine in the treatment of HE identified three high-quality human trials for review. Analysis of the selected carnitine trials compared to currently accepted therapies suggests that L-acyl-carnitine is promising as a safe and effective treatment for HE, and further trials of this drug are warranted.

Chronic liver failure is an important cause of morbidity and mortality and is the long-term consequence of many chronic liver diseases. In addition to determining the specific cause of the chronic liver disease, which may be amenable to targeted therapy, it is important to treat the sequelae of chronic liver failure effectively to improve quality of life, to prolong survival, and to provide a bridge to liver transplantation. Once a patient who has chronic liver failure develops hepatic decompensation, liver transplantation is the definitive treatment for those who qualify. Management of chronic liver failure is the focus of this article.

Background & Aims: Serum ALT remains the most accessible test available to clinicians for monitoring chronic hepatitis B virus infection, but appropriate action when ALT levels are only mildly elevated is ambiguous in standard guidelines., Methods: A retrospective study was conducted to investigate the prevalence of significant histology in a patient population with mildly elevated serum ALT levels. A total of 193 consecutive patients were selected and divided into 2 groups according to HBeAg status. Patients were further divided into cohorts on the basis of their highest ALT elevation during follow-up and whether it was 1-1.5 times the upper limit of normal (ULN), 1.5-2 times the ULN, or greater than twice the ULN. The ULN that was used is 30 U/L for men and 19 U/L for women., Results: In all cohorts there was a substantial fraction of patients with histologic disease as evaluated by liver biopsy. HBeAg-negative patients were older, had lower viral load, and had a higher prevalence of disease. After adjustments for age, HBeAg status and HBV DNA viral load were not predictors of significant histology. Age >35 years, male gender, and increasing ALT levels were predictors for significant histology on multivariate analysis., Conclusions: A substantial proportion of patients with mildly elevated ALT levels have significant histologic disease. The prevalence increased with the higher ALT levels and age.

Objectives: Infection with hepatitis C virus (HCV) genotype 6 is common in patients from parts of China and Southeast Asia. No study to date has examined the treatment response to peginterferon and ribavirin (PEG IFN + RBV) in these patients, or the effects of treatment duration on sustained virologic response (SVR) rates., Methods: We performed a retrospective study of 190 consecutive Asian-American patients who were diagnosed with HCV genotype 6 at a gastroenterology clinic in northern California between 2001 and 2004, 66 of whom were treatment-naïve and subsequently completed 24 wk of IFN + RBV or PEG IFN + RBV or 48 wk of PEG IFN + RBV therapy. The primary outcome was SVR., Results: There was no statistical difference in SVR of 31 patients treated with 24 wk of IFN + RBV and in 23 patients treated with 24 wk of PEG IFN + RBV (51.6%vs 39%, P= 0.363). The SVR in 12 patients treated with 48 wk of PEG IFN + RBV was significantly higher than that in those treated for only 24 wk (75%vs 39%, P= 0.044)., Conclusions: Treatment-eligible patients with HCV genotype 6 should be treated with a full course of 48 wk as tolerated. Larger prospective studies of patients with HCV genotype 6 are needed to confirm the optimal treatment duration with PEG IFN + RBV.

Licensed oral agents for antiviral therapy in patients with chronic hepatitis B virus (HBV) infection include lamivudine, adefovir, entecavir, and telbivudine. Emtricitabine, tenofovir, and the combination of tenofovir plus emtricitabine in 1 tablet, which are licensed for the treatment of human immunodeficiency virus infection, are additional off-label options for treating HBV infection. Preventing HBV antiviral drug resistance to nucleoside/nucleotide analogues and appropriate management when resistance occurs has become a major focus in the management of chronic hepatitis B. HBV antiviral drug resistance may be best prevented by using an agent or combination of agents with a high genetic barrier to resistance, and 2 potent nucleoside and nucleotide drugs with different resistance profiles may prove to be the optimal first-line treatment for chronic hepatitis B. Frequent assessment of quantitative serum HBV DNA remains the best approach to early detection of resistance, and antiviral therapy should be modified as soon as resistance is detected. Results from several clinical trials have shown that the addition or substitution of newer antiviral agents can restore suppression of viral replication, normalize alanine aminotransferase levels, and reverse histologic progression in patients with resistance to lamivudine, but little information exists regarding the long-term benefits of second-line treatment regimens. Despite the substantial advances in treatment made to date, new agents with novel viral targets will be needed for patients who ultimately may fail second- or third-line therapy.

Acute hepatitis A and acute hepatitis B are associated with significant morbidity, time away from work or usual activities, substantial cost to the healthcare system, and some mortality. Despite the availability of vaccines against hepatitis B and hepatitis A since 1981 and 1995, respectively, and a combined hepatitis A and B vaccine since 2001, immunization rates against these vaccine-preventable diseases are appallingly low. In particular, several groups of adults, such as men who have sex with men, heterosexuals with multiple partners, injection drug users, persons with human immunodeficiency virus infection, travelers to endemic areas, and persons with chronic liver disease, are at particularly high risk for acute hepatitis A and B or for a more severe illness or a higher rate of chronicity in the case of hepatitis B. Studies have confirmed that hepatitis A and hepatitis B vaccines are safe and immunogenic in patients in these populations, although patients with more advanced disease may respond less well. These observations have led to the recommendation that patients falling into the above risk groups undergo hepatitis A and B vaccination early in the natural history of their underlying risk behavior or diseases. Vaccination rates are low in clinical practice, and public health and educational programs are needed to overcome barriers to facilitate timely implementation of these recommendations. The use of a combined vaccination, possibly using an accelerated administration schedule, provides convenience and may increase compliance.

Chronic hepatitis B virus (HBV) carriers are at considerable risk of reactivation of HBV infection when undergoing chemotherapy or immunosuppressive therapy. Complications of HBV reactivation, including asymptomatic elevation of HBV DNA levels, acute hepatitis, acute liver failure, and delays or dose reductions in chemotherapy, are avoidable with appropriate prophylactic oral antiviral therapy. This article reviews evidence for and presents a grade A recommendation supporting primary prophylaxis among HBV carriers with lamivudine. The dose and duration of prophylaxis, risk of lamivudine resistance, and future directions of prophylactic therapy for HBV reactivation during chemotherapy are discussed. Recommendations are suggested based on expert opinion for prophylaxis with the combination of lamivudine plus adefovir or with entecavir as alternative antiviral strategies that substantially reduce or avoid the risk of HBV antiviral drug resistance.

An international group of experienced hepatologists and virologists conducted a single-day workshop to review the management of patients with chronic hepatitis B receiving treatment with oral nucleosides or nucleotides. Guidelines regarding on-treatment management and available published data on the importance of serum hepatitis B virus (HBV) DNA as a marker of outcomes were reviewed. On-treatment monitoring strategies to define early virologic responses that might be predictive of better outcomes and a reduced risk of viral resistance were proposed for further study. This treatment plan, labeled the roadmap concept, recommends monitoring of serum HBV DNA levels to identify outcomes of therapy. Primary treatment failure was defined as a reduction of serum HBV DNA levels by less than 1 log10 IU/mL from baseline at week 12. Measurement of the HBV DNA level at week 24 was considered essential to characterize virologic responses as complete, partial, or inadequate. Complete virologic response was defined as negative HBV DNA by a sensitive assay (<60 IU/mL or <300 copies/mL); partial virologic response was defined as HBV DNA levels less than 2000 IU/mL (4 log10 copies/mL), and inadequate virologic response was defined as HBV DNA levels of 2000 IU/mL or greater (4 log10 copies/mL). Strategies are proposed for managing patients in each of these categories, depending in part on the rapidity with which HBV DNA suppression is achieved and the emergence of genotypic mutations that reduce the effectiveness of a specific drug. Future studies of the use of the roadmap concept in improving outcomes of chronic hepatitis B are warranted.

Background: Living donor liver transplantation (LDLT) was extended to adults in recent years and more recently to older patients. The impact of donor age, analysis of preoperative risk factors for older LDLT recipients, and comparison of the complication rate between older and younger recipients were analyzed., Methods: Subjects included patients who underwent LDLT at Kyoto University Hospital from October 1996 to December 2005. Twenty-three donors were 60 years of age or older, and 411 were younger than 60 years of age. Fifty-two recipients were 60 years of age or older and 410 were younger than 60 years of age., Results: Postoperative recovery of liver function for donors and recipient/graft survival were not influenced by donor age. Hospital stay was longer in the donors 60 years of age or older than those younger than 60 years of age (P=0.02). The 5-year survival rates were 78.7% in recipients 60 years of age or older and 69.3% in younger recipients (P=0.26). Among preoperative risk factors for recipient survival rate, fulminant hepatic failure and preoperative status in the intensive care unit were significant (P<0.05). There were no significant differences in the incidence of postoperative complications for recipients., Conclusions: Selected right lobe donors from individuals who were 60 years of age or older showed a similar postoperative course compared with younger donors. Moreover, LDLT is feasible for patients 60 years of age or older who do not require care in the intensive care unit or do not have fulminant hepatic failure.

Survival rates after liver transplantation have improved steadily because of earlier referral and timely evaluation, judicious patient selection, improved surgical techniques, superior immunosuppressive regimens, and effective prevention of perioperative opportunistic infections. Indications and contraindications for liver transplantation are undergoing constant modifications with the goal of improving survival and functional status of patients who have end-stage liver disease or acute liver failure. Potential candidates for liver transplantation should meet minimal listing criteria and not have contraindications to liver transplantation. Currently, the Model for End-stage Liver Disease score is used for organ allocation, but it may have future application in patient-selection criteria.

Patients with hepatocellular carcinoma (HCC) receive a higher MELD score and may undergo liver transplantation (OLT) earlier compared to patients with cirrhosis, potentially decreasing waiting list mortality. However, post-OLT survival may be reduced by recurrence of HCC. We compared clinical outcomes between patients with HBV-cirrhosis and no HCC and patients with HBV-HCC. A total of 279 patients (HBV-cirrhosis = 183; HBV-HCC = 96) in the US HBV-OLT study were followed for a median of 30.2 months from listing. Patients with HCC were older, more likely to be Asian, and had less severe liver impairment than patients with HBV-cirrhosis. Despite a higher rate of OLT in patients with HCC (78.1% vs. 51.4%; P < 0.001), intention-to-treat (ITT) survival (73% vs. 78%) and survival without OLT (82% vs. 79%) at 5 years were similar for patients with and without HCC. Cox regression analysis identified higher albumin, lower MELD, no HCC at listing, and being transplanted to be associated with better ITT survival. Ninety-four patients with HCC (including 19 new HCC) and 75 with HBV-cirrhosis underwent OLT. Post-OLT survival (83% vs. 90%) and HBV recurrence (11% vs. 10%) at 3 years were similar, while disease (HBV and/or HCC) recurrence (19% vs. 10%; P = 0.043) was higher in patients with HBV-HCC vs. HBV-cirrhosis. Disease recurrence was the only independent predictor of post-OLT survival. In conclusion, despite more advanced liver disease and a lower rate of transplantation, ITT survival of patients listed for HBV-cirrhosis was comparable to those with HBV-HCC, possibly related to beneficial effects of antiviral therapy., ((c) 2006 AASLD.)

Conventional treatment of chronic hepatitis B with interferon alfa-2b, lamivudine, and adefovir is limited by low rates of sustained hepatitis B virus DNA suppression and hepatitis B e antigen (HBeAg) seroconversion, increasing rates of drug resistance to the oral agents, and poor tolerability of interferon. Recently several promising new antiviral agents have emerged that possess potent antiviral effects, less toxicity, and have little or no risk of drug resistance. Two new agents, entecavir and peginterferon alfa-2a, have received recent approval by regulatory authorities in the United States and several other countries for the treatment of adults with chronic hepatitis B. In large phase III clinical trials, these agents have demonstrated superior efficacy over lamivudine in both HBeAg-positive and HBeAg-negative patients. Drug resistance occurs at a low rate in lamivudine-refractory patients treated with entecavir or is, to date, nonexistent in nucleoside-naïve patients treated with entecavir and all patients receiving peginterferon. In addition, several novel agents in clinical development, such as emtricitabine, clevudine, telbivudine, valtorcitabine, and tenofovir, have shown promising clinical profiles in patients with chronic hepatitis B. This review summarizes the recent clinical studies of these new agents and discusses the implications of these data for the management of chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection is a significant public health problem in the United States, with 1.25 million people infected with the virus. The long-term risks of chronic HBV infection include cirrhosis and hepatocellular carcinoma, which occur in 15% to 30% of those infected at birth or early in life and may lead to liver transplantation or death. During the past few years, the development and increased availability of oral antiviral agents have made treatment simpler, safer, and more tolerable for these patients. This article focuses on 3 of these drugs--lamivudine, adefovir, and entecavir--and their use in patients with chronic HBV infection and advanced hepatic fibrosis or cirrhosis.