Duodenal Permeability Is Associated With Mucosal Microbiota in Compensated Cirrhosis.

INTRODUCTION: Several complications of decompensated cirrhosis are believed to result from increased intestinal permeability. However, little is known about the relationship between mucosal bacteria and epithelial permeability in cirrhosis. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with compensated cirrhosis. METHODS: We obtained duodenal tissue biopsies from patients with compensated cirrhosis and controls. Patients were excluded if they used antibiotics or immunosuppression. The composition of mucosal microbiota was determined by 16S rRNA gene sequencing and epithelial permeability by transepithelial electrical resistance (TEER) and tight junction protein expression. RESULTS: We studied 24 patients with compensated cirrhosis and 20 controls. Patients with cirrhosis were older than controls (62 vs 52 years, P = 0.02) but had a similar number of extrahepatic comorbidities (2.2 vs 1.4, P = 0.13). Patients with compensated cirrhosis had lower duodenal TEER (i.e., increased epithelial permeability; 13.3 Ω/cm 2 ± 3.4 vs 18.9 Ω/cm 2 ± 7.1; P = 0.004). Patients with compensated cirrhosis trended toward a distinct mucosal microbiota community structure relative to controls ( P = 0.09). Clustering analysis identified two unique enterotypes. These enterotypes differed in bacterial composition and also TEER. A beta-binomial model found 13 individual bacteria associated with TEER, including Lactobacillus and Bifidobacterium taxa. Thirty-six taxa were associated with tight junction protein expression, including Lactobacillus and Bifidobacterium. DISCUSSION: Compensated cirrhosis is characterized by increased duodenal epithelial permeability with a distinct mucosal microbial community. Intriguingly, bacteria previously associated with health were protective of duodenal permeability.

Psychometric properties of the PROMIS short form measures in a U.S. cohort of 961 patients with chronic hepatitis C prescribed direct acting antiviral therapy.

BACKGROUND: To better understand symptoms experienced by patients infected with chronic hepatitis C virus (HCV), valid and reliable patient-reported outcome (PRO) measures are needed. AIM: To assess the reliability and validity of 10 patient-reported outcomes measurement information system (PROMIS) measures and the Headache Impact Test-6 (HIT-6) in a large national sample of patients with HCV. METHODS: Pre-treatment data from 961 patients with HCV starting direct acting antiviral therapy at 11 U.S. liver centers were analyzed. Internal reliability was evaluated using Cronbach's alpha coefficient; frequency distributions were examined for floor and ceiling effects; structural validity was investigated via item-response-theory models; convergent validity was evaluated using correlations with theoretically-similar items from the HCV-PRO and memorial symptom assessment scale (MSAS); and known-groups validity was investigated by observing PRO differences by liver disease status and number of comorbidities. RESULTS: The HIT-6 and the majority of the PROMIS measures yielded excellent reliability (alphas ≥ 0.87). Ceiling effects were infrequent ( < 4%), while 30%-59% of patients reported no symptoms (floor effects). The data supported structural validity of the HIT-6 and most PROMIS measures. The PROMIS measures showed moderate to strong correlations with theoretically-similar items from the HCV-PRO and MSAS (0.39-0.77). Trends were observed between worse PRO scores and advanced cirrhosis and greater number of comorbidities, lending support for known-groups validity. CONCLUSIONS: The psychometric properties of the HIT-6 and PROMIS measures performed satisfactorily in this large cohort of patients with HCV starting direct acting antiviral therapy. Opportunities exist for further refinement of these PROs. Evaluation of performance over time and in under-represented subgroups is needed.

[Proper patient education improves hepatitis C patients' disease-related knowledge and antiviral treatment acceptance in rural China].

Objective: To evaluate the affect of hepatitis C virus (HCV) education in chronic hepatitis C patients' disease related knowledge and antiviral treatment acceptance in rural china. Methods: Rural HCV patients of attended CHC project of HCV education. Doctor delivered subsequent interactive lecture, and patients completed pre- and post-education questionnaires before and after taking the lectures. Results: 151 CHC patients were included. Mean age was 57.3 years old, 50.3% were male, 51.0% of the students had primary school education or illiterate, and 76.2% had a monthly income below RMB 3,000. 98.0% of patients defined their baseline HCV knowledge as "nothing" or "a little bit". A multivariate analysis reveled baseline knowledge scores were associated with age and household income. After education, mean knowledge score (range: 0-28) increased from 13.1 to 23.0 (P < 0.001) and average percent of patients with correct answers from the topic rose from 46.8% to 82.1% (P < 0.001), and patients' antiviral treatment acceptance increased from 33.9% to 65.6% (P < 0.001). Conclusion: A rural Chinese patients had less education, HCV education delivered on the preferred format of patients substantially improved hepatitis C patients' disease-related knowledge and antiviral treatment acceptance in rural china.

The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. AIM: To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. METHODS: Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria. RESULTS: One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. CONCLUSIONS: HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.

Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment.

Antiviral drug resistance hepatitis B virus (HBV) variants (HBV-DR) occur spontaneously in chronic hepatitis B (CHB) patients and after exposure to nucleos(t)ide analogues (NUCs). We determined the prevalence of HBV-DR variants among participants of the Hepatitis B Research Network (HBRN) Cohort Study conducted at 21 sites in the United States (US) and Canada. Samples obtained from 1342 CHB participants aged ≥18 years, and who were currently not receiving NUCs, were tested for HBV-DR variants by Sanger sequencing. In addition, next generation sequencing (NGS) was used to characterize HBV-DR variants from 66 participants with and 66 participants with no prior NUC exposure matched for HBV genotype and HBV DNA level. Half the participants were men, 75% Asian, 26% HBeAg positive. Primary HBV-DR variants were detected by Sanger sequencing in 16 (1.2%) participants: 2/142 (1.4%) with and 14/1200 (1.2%) without prior NUC exposure; only 1 of these 16 had a secondary variant. In total, 23 (1.7%) participants had secondary variants, including 1 with prior NUC experience. In the subset of 132 participants, NGS detected HBV-DR variants in a higher proportion of participants: primary variants in 18 (13.6%) (8 [12.1%] with, and 10 [15.2%] without prior NUC therapy) and secondary variants in 10 (7.6%) participants. Based on Sanger sequencing, prevalence of primary HBV-DR variants is low (1.2%) among adults with CHB in US/Canada. The similar low prevalence of HBV-DR variants in participants with and without NUC treatment suggests transmission of these variants is uncommon.

All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

BACKGROUND: Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. AIM: To assess efficacy of all-oral HCV therapy in advanced liver disease. METHODS: Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. RESULTS: Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. CONCLUSIONS: All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

Dynamic prediction of risk of liver-related outcomes in chronic hepatitis C using routinely collected data.

Accuracy of risk assessments for clinical outcomes in patients with chronic liver disease has been limited given the nonlinear nature of disease progression. Longitudinal prediction models may more accurately capture this dynamic risk. The aim of this study was to construct accurate models of short- and long-term risk of disease progression in patients with chronic hepatitis C by incorporating longitudinal clinical data. Data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial were analysed (n = 533 training cohort; n = 517 validation cohort). Outcomes included a composite liver outcome (liver-related death, decompensation, hepatocellular carcinoma (HCC) or liver transplant), decompensation, HCC and overall mortality. Longitudinal models were constructed for risk of outcomes at 1, 3 and 5 years and compared with models using data at baseline only or baseline and a single follow-up time point. A total of 25.1% of patients in the training and 20.8% in the validation cohort had an outcome during a median follow-up of 6.5 years (range 0.5-9.2). The most important predictors were as follows: albumin, aspartate aminotransferase/alanine aminotransferase ratio, bilirubin, alpha-fetoprotein and platelets. Longitudinal models outperformed baseline models with higher true-positive rates and negative predictive values. The areas under the receiver-operating characteristic curve for the composite longitudinal model were 0.89 (0.80-0.96), 0.83 (0.76-0.88) and 0.81 (0.75-0.87) for 1-, 3-, and 5-year risk prediction, respectively. Model performance was retained for decompensation and overall mortality but not HCC. Longitudinal prediction models provide accurate risk assessments and identify patients in need of intensive monitoring and care.

Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US - the ENUMERATE study.

BACKGROUND: Entecavir (ETV) has been shown to be safe and efficacious in randomised controlled trials in highly selected patients with hepatitis B virus (HBV) infection. AIM: To determine the safety and effectiveness of ETV in 'real-world' HBV patients in the United States (US). METHODS: Treatment-naïve HBV patients ≥18 years old who received ETV for ≥12 months between 2005 and 2013 were included in a retrospective, cohort study. Rates of ALT normalisation, undetectable HBV DNA, HBeAg and HBsAg loss/seroconversion, adverse events (AE) and clinical outcomes were evaluated. RESULTS: Of 841 patients, 658 [65% male, 83% Asian; median age 47 years] met the inclusion criteria. 36% were HBeAg+ and 9.3% cirrhotic. 89% had abnormal ALT. Baseline median HBV DNA was 5.8 log 10 IU/mL. Median duration of ETV treatment was 4 years. Rates of ALT normalisation at 1, 3 and 5 years were 37.2%, 48.7% and 56.2% in HBeAg+ and 39.6%, 46.8% and 55.6% in HBeAg- patients. HBV DNA was undetectable at 1, 3 and 5 years in 34.6%, 64.7% and 84.6% in HBeAg+ patients, and 81.9%, 90.3% and 96.2% in HBeAg patients. Five-year cumulative probability of HBeAg loss and seroconversion was 46% and 33.7% and HBsAg loss was 4.6%. ETV was discontinued due to adverse events in 1.2% of patients. Hepatic decompensation occurred in 0.8%, liver cancer in 2.7% and death in 0.6%. CONCLUSION: Entecavir treatment was safe in a large cohort of US patients, but ALT normalisation and hepatitis B virus DNA suppression rates were lower than previously reported in clinical trials.

Changes in characteristics of hepatitis C patients seen in a liver centre in the United States during the last decade.

With the approval of 2 direct-acting antivirals (DAAs) in 2011 and anticipation of interferon (IFN)-free regimens, more hepatitis C virus (HCV) chronically infected patients are now seeking treatment. To describe the characteristics of newly referred HCV patients in 2011-2012 (Era-2) and compare them to those seen in 1998-1999 (Era-1). Retrospective data were collected from HCV patients newly referred to our tertiary liver clinics. Advanced liver disease was defined as cirrhosis (based on histology or Aspartate aminotransferase-platelet-ratio index (APRI) >2), hepatic decompensation or hepatocellular carcinoma (HCC). A total of 1348 patients (538 in Era-1, 810 in Era-2) were included. Compared to Era-1, Era-2 patients were older (median age 56 vs 45 years), more likely to be black (17.2% vs 11.6%) and had a longer interval between diagnosis and referral (median 4 vs 2 years). Genotype (GT) 1 predominated in both Eras with a significant increase in GT1a from 39.9% in Era-1 to 53.8% in Era-2. A higher per cent of patients in Era-2 were treatment experienced, but 77% had never received treatment. Era-2 patients were more likely to have advanced disease at referral (61.6% vs 51.5%, P < 0.001), with an eightfold higher prevalence of HCC (21.6% vs 2.6%, P < 0.001). HCV patients newly referred in recent years were older, predominantly infected with GT1a and had more advanced liver disease yet only a quarter had received HCV treatment. Reduction in HCV disease burden will require development of treatment regimens targeted towards patients in the current Era as well as increase in diagnosis and referral of patients for treatment.

Systematic review: identifying patients with chronic hepatitis C in need of early treatment and intensive monitoring--predictors and predictive models of disease progression.

BACKGROUND: Advances in hepatitis C therapies have led to increasing numbers of patients seeking treatment. As a result, logistical and financial concerns regarding how treatment can be provided to all patients with chronic hepatitis C (CHC) have emerged. AIM: To evaluate predictors and predictive models of histological progression and clinical outcomes for patients with CHC. METHODS: MEDLINE via PubMed, EMBASE, Web of Science and Scopus were searched for studies published between January 2003 and June 2014. Two authors independently reviewed articles to select eligible studies and performed data abstraction. RESULTS: Twenty-nine studies representing 5817 patients from 20 unique cohorts were included. The outcome incidence rates were widely variable: 16-61% during median follow-up of 2.5-10 years for fibrosis progression; 13-40% over 2.3-14.4 years for hepatic decompensation and 8-47% over 3.9-14.4 years for overall mortality. Multivariate analyses showed that baseline steatosis and baseline fibrosis score were the most consistent predictors of fibrosis progression (significant in 6/21 and 5/21, studies, respectively) while baseline platelet count (significant in 6/13 studies), aspartate and alanine aminotransferase (AST/ALT) ratio, albumin, bilirubin and age (each significant in 4/13 studies) were the most consistent predictors of clinical outcomes. Five studies developed predictive models but none were externally validated. CONCLUSIONS: Our review identified the variables that most consistently predict outcomes of patients with chronic hepatitis C allowing the application of risk based approaches to identify patients in need of early treatment and intensive monitoring. This approach maximises effective use of resources and costly new direct-acting anti-viral agents.

New mobile technologies and visual acuity.

Mobile devices have shown promise in visual assessment. Traditional acuity measurement involves retro-illuminated charts or card-based modalities. Mobile platforms bring potential to improve on both portability and objectivity. The present research activity relates to design and validation of a novel tablet-based infant acuity test. Early results in an adult cohort, with various levels of artificially degraded vision, suggest improved test-retest reliability compared with current standards for infant acuity. Future pragmatic trials will assess the value of this emerging technology in pediatric visual screening.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

IL28B genetic variants and gender are associated with spontaneous clearance of hepatitis C virus infection.

Single nucleotide polymorphisms (SNPs) near the IL28B gene have been shown to be associated with response to treatment for chronic hepatitis C and also with spontaneous clearance of hepatitis C virus (HCV) infection. We analysed the association between IL28B genetic variants and spontaneous clearance of HCV infection in 376 HCV-infected Chinese paid plasma donors. Genotyping of eight SNPs near the IL28B region was performed by the iPLEX system (MassARRAY(®) SNP Genotyping; Sequenom) in all donors, and sequencing was performed on all 80 donors who cleared HCV and on 160 of 296 donors who did not clear HCV to validate the genotypes. Eighty (21.3%) donors spontaneously cleared HCV. Four SNPs were significantly associated with spontaneous HCV clearance: rs8099917 TT (vs GT), rs8105790 TT (vs CT), rs12980275 AA (vs AG) and rs10853728 CC (vs CG or GG) with OR (95% CI) 15.27 (2.07-112.50), 14.88 (2.02-109.72), 7.92 (1.88-33.32) and 2.32 (1.22-4.42) respectively. No association between the other four IL28B SNPs including rs12979860 and spontaneous HCV clearance was found. Women had a higher rate of spontaneous HCV clearance than men [56/213 (26.3%) vs 24/163 (14.6%), P = 0.007], and this was true even after stratification for IL28B genotypes with OR of 1.9-2.2 among those with favourable genotypes. Our results confirmed that IL28B polymorphism is associated with spontaneous clearance of HCV in Chinese subjects, but the SNPs that predict HCV clearance in Chinese subjects were different from those reported in Caucasians. Women were more likely to clear HCV infection regardless of IL28B genotypes.

Adherence to nucleos(t)ide analogues for chronic hepatitis B in clinical practice and correlation with virological breakthroughs.

Medication adherence is important for the success of nucleos(t)ide analogue (NUC) treatment for chronic hepatitis B. The aims of this study were to determine adherence to NUCs and factors associated with NUC adherence and to correlate NUC adherence with the occurrence of virological breakthroughs in patients with chronic hepatitis B. Consecutive patients with chronic hepatitis B receiving NUC were asked to complete a survey every 3 months. Adherence was also assessed by healthcare providers in the clinic. Adherence rate was defined as the per cent of days the patients took their hepatitis B virus medications during the last 30 days. A total of 111 patients were studied. The mean age was 47.7 years, 73.9% were men, 57.7% were Asian, 42.3% had postgraduate education and 80% had private insurance. Sixty-nine (74.1%) patients reported 100% adherence in the survey, while 78 (83.9%) reported 100% adherence to their healthcare providers. Patients with 100% adherence based on the survey were older (P = 0.02), more likely to be men (P = 0.006), and had higher annual household income (P = 0.04) than those with <100% adherence. In the 80 patients who completed three surveys, viral breakthrough was observed in 1/46 (2.2%) with 100% adherence on all three surveys, 1/18 (5.6%) with <100% adherence on one survey and 3/16 (18.8%) with <100% adherence on ≥2 surveys, (P = 0.06). In conclusion, adherence to NUC therapy in our patients with chronic hepatitis B was high but self-reporting of adherence to healthcare providers may be inflated. Patients with chronic hepatitis B with better adherence to NUC therapy had a trend towards a lower rate of viral breakthroughs.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

Variation in organ quality between liver transplant centers.

A wide spectrum of quality exists among deceased donor organs available for liver transplantation. It is unknown whether some transplant centers systematically use more low quality organs, and what factors might influence these decisions. We used hierarchical regression to measure variation in donor risk index (DRI) in the United States by region, organ procurement organization (OPO) and transplant center. The sample included all adults who underwent deceased donor liver transplantation between January 12, 2005 and February 1, 2009 (n = 23,810). Despite adjusting for the geographic region and OPO, transplant centers' mean DRI ranged from 1.27 to 1.74, and could not be explained by differences in patient populations such as disease severity. Larger volume centers and those having competing centers within their OPO were more likely to use higher risk organs, particularly among recipients with lower model for end-stage liver disease (MELD) scores. Centers using higher risk organs had equivalent waiting list mortality rates, but tended to have higher post-transplant mortality (hazard ratio 1.10 per 0.1 increase in mean DRI). In conclusion, the quality of deceased donor organ patients receive is variable and depends in part on the characteristics of the transplant center they visit.

Characteristics of chronic hepatitis B patients who underwent liver biopsies.

Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10-year period were reviewed. Significant liver disease was defined as Knodell HAI ≥ 7 and/or Ishak fibrosis ≥ 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety-three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log(10) copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied.

Endpoints of hepatitis B treatment.

The goal of hepatitis B treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma. Ideally, clinical studies should demonstrate that hepatitis B therapies can prevent liver-related complications; however, these clinical endpoints evolve over years or decades. Therefore, clinical trials have relied on intermediate endpoints to evaluate the efficacy of treatment and to determine when treatment can be stopped. Intermediate endpoints that have been used include biochemical, histological, virological, and serological endpoints. This review will discuss the validity of these intermediate endpoints as surrogates of clinical endpoints, and the rates at which these intermediate endpoints can be achieved with currently available therapies.

Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation.

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre-OLT and HBIG regimens post-OLT. Data from the NIH HBV-OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1-81) post-OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log(10) copies/mL, 74% were receiving antiviral therapy. Twenty-five patients experienced virologic breakthrough before OLT. Post-OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high-dose, IV low-dose, intramuscular low-dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT.