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BACKGROUND AND AIMS: Outcomes of persons with chronic hepatitis B virus (HBV) infection in the era of antiviral therapy (AVT) are not well characterized. We determined the incidence and factors associated with clinical outcomes in a multiethnic, North American cohort of adults with chronic HBV infection, who were not on AVT at enrollment. APPROACH AND RESULTS: Adults with chronic HBV infection, not receiving AVT, and without a history of decompensation, HCC, or liver transplantation (LT), were prospectively followed. Participants with known human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis D virus (HDV) coinfection were excluded. During follow-up, treatment could be initiated per standard of care. Clinical outcomes included: incident cirrhosis, decompensation, HCC, OLT, and HBV-related death. Among 1,418 participants analyzed, 51.5% were women, median age was 41.1 years, 75% were Asian, 10% White, 13% Black, 24% HBeAg(+), and 1.5% cirrhosis at baseline. During the study, 274 started treatment, 83 had an alanine aminotransferase flare, 118 of 330 initially HBeAg(+) became HBeAg(−), and 90 of 1,329 became HBsAg(−). After 6,641 person-years follow-up, 8 participants (4 of 21 with baseline cirrhosis) had 12 clinical outcomes (2 decompensation, 5 HCC, 2 OLT, and 3 HBV-related deaths) and 19 of 1,397 had incident cirrhosis. Twenty-one of 26 participants had first outcome before treatment, none had become HBsAg(−), whereas 5/9 HBeAg(+) had become HBeAg(−) at time of first outcome. Cumulative percentage of clinical outcomes was 16% at year 4 in participants with baseline cirrhosis and 2% (including incident cirrhosis) at year 7 in those without. CONCLUSIONS: Incidence of adverse outcomes was low in this closely monitored, large cohort of North American adults with predominantly inactive, chronic HBV without cirrhosis. Our data highlight the benefits of HBsAg loss and the importance of early diagnosis and treatment to prevent cirrhosis and other complications of chronic HBV infection.

BACKGROUND AND AIMS Emerging data from a single-center study suggests that a 30% relative reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline may be associated with histologic improvement in nonalcoholic steatohepatitis (NASH). There are limited multicenter data comparing an active drug versus placebo on the association between the quantity of liver fat reduction assessed by MRI-PDFF and histologic response in NASH. This study aims to examine the association between 30% relative reduction in MRI-PDFF and histologic response in obeticholic acid (OCA) versus placebo-treated patients in the FLINT (farnesoid X receptor ligand obeticholic acid in NASH trial). APPROACH AND RESULTS This is a secondary analysis of the FLINT trial including 78 patients with MRI-PDFF measured before and after treatment along with paired liver histology assessment. Histologic response was defined as a 2-point improvement in nonalcoholic fatty liver disease activity score without worsening of fibrosis. OCA (25 mg orally once daily) was better than placebo in improving MRI-PDFF by an absolute difference of -3.4% (95% confidence interval [CI], -6.5 to -0.2%, P value = 0.04) and relative difference of -17% (95% CI, -34 to 0%, P value = 0.05). The optimal cutoff point for relative decline in MRI-PDFF for histologic response was 30% (using Youden's index). The rate of histologic response in those who achieved less than 30% decline in MRI-PDFF versus those who achieved a 30% or greater decline in MRI-PDFF (MRI-PDFF responders) relative to baseline was 19% versus 50%, respectively. Compared with MRI-PDFF nonresponders, MRI-PDFF responders demonstrated both a statistically and clinically significant higher odds 4.86 (95% CI, 1.4-12.8, P value

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy.

Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD.A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category.Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62).Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.

BACKGROUND & AIMS: Noninvasive methods are needed to determine disease stage in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the diagnostic performance of several widely available fibrosis models for the assessment of hepatic fibrosis in patients with NAFLD. METHODS: We performed a retrospective analysis of data from individuals enrolled in the NIDDK NASH Clinical Research Network, from 2004 through 2018. Using biopsy as the reference standard, we determined the diagnostic performance of the aspartate aminotransferase (AST):platelet ratio (APRI), FIB-4, ratio of AST:alanine aminotransferase (ALT) and the NAFLD fibrosis score (NFS) in a cross-sectional study of 1904 subjects. The ability of these models to detect changes in fibrosis stage was assessed in a longitudinal data set of 292 subjects with 2 biopsies and accompanying laboratory data. Outcomes were detection of fibrosis of any stage (stages 0 to 4), detection of moderate fibrosis (stages 0–1 vs 2–4), and detection of advanced fibrosis (stages 0–2 vs 3–4). Diagnostic performance was evaluated using the C-statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) analyses. RESULTS: In the cross-sectional study, FIB-4 and NFS outperformed other non-invasive models for detecting advanced fibrosis; the C-statistics were 0.80 for FIB-4 and 0.78 for NFS. In the longitudinal study, 216 patients had non-advanced fibrosis at baseline and 35 patients progressed to advanced fibrosis after median follow up of 2.6 years. After we adjusted for fibrosis stage and model score at initial biopsy, change in APRI, FIB-4, and NFS were significantly associated with change in fibrosis. A unit change in APRI, FIB-4, or NFS was associated with changes in fibrosis stage of 0.33 (95% CI, 0.20-0.45; P

Background/Aims The role of HCV-specific CD4 + T cells and regulatory T cells in influencing the outcome of antiviral therapy is incompletely defined. Methods CD4 + IFN-γ ELISPOT assays ( n =58) and flow cytometric analysis of FoxP3-expressing T regulatory cells ( n =62) were performed on patients from the Virahep-C study at baseline, during and after cessation of antiviral therapy. Results Total HCV-specific IFN-γ CD4 + T cell ELISPOT responses did not increase with therapy, but rather decreased by 8 weeks and remained below baseline 24 weeks after cessation of therapy. There were no statistically significant differences with respect to viral kinetics, race and virologic outcome. In contrast, viral relapse after treatment was associated with a three-fold increase in HCV-specific responses. The frequency and phenotype of regulatory T cells during therapy were not significantly different in terms of race, viral kinetic groups or virologic outcome. Conclusions A contraction of HCV-specific CD4 + T cell responses was found during treatment with recovery of responses in patients experiencing virologic relapse after treatment. The levels of FoxP3-expressing regulatory T cells did not vary by race and were not predictive of virologic outcome. Work is ongoing to explore the contribution of mechanisms independent of CD4 + T cells in therapy-induced viral clearance.

To test the hypothesis that children with chronic hepatitis B living in the US and Canada would have international origins and characteristic hepatitis B virus (HBV) genotypes and laboratory profiles.Clinical characteristics of children enrolled in the Hepatitis B Research Network were collected from 7 US and Canadian centers.Children (n = 343) with an age range of 1.0-17.8 years were enrolled; 78% of the children were Asian, 55% were adopted, and 97% had international origins with either the child or a parent born in 1 of 31 countries. The majority had HBV genotype B (43%) or C (32%), and the remainder had genotype A (5%), D (16%), E (4%), or multiple (1%). Children with genotype B or C were more likely to be Asian (98% and 96%), more consistently hepatitis B envelope antigen positive (95% and 82%), had higher median HBV DNA levels (8.2 and 8.3 log10 IU/mL), and less frequently had elevated alanine aminotransferase values (43% and 57%) compared with children with other genotypes. The percentage of hepatitis B envelope antigen positivity and of those with HBV DNA ≥6 log₁₀ IU/mL declined with age.The majority of children in the Hepatitis B Research Network have HBV genotypes that reflect their international origins. Clinical and laboratory data differ substantially by patient age and HBV genotype. Use of these data can help drive the development of optimal strategies to manage and treat children with chronic hepatitis B.

Summary Background The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. Methods We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Findings Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 2·2, 95% CI 1·4 to 3·3; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Interpretation Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. Funding National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. We collected data from 3 large US studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. We found that pre-menopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than post-menopausal women (P

Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor MonitorTM polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of −4.1 log10 and −4.3 log10 copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV. (Hepatology 2003;38:1419-1427.)