Maternal knowledge of the risk of vertical transmission and offspring acquisition of hepatitis B.

INTRODUCTION AND OBJECTIVES: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. MATERIALS AND METHODS: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. RESULTS: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02). CONCLUSIONS: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5-15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

Gender Differences in Hepatology Medical Literature.

BACKGROUND: Studies suggest that gender differences in academic medicine exist. Men frequently have better measures of performance such as number of publications, number of citations, remuneration, and funding. AIMS: To evaluate whether a gender disparity in authorship exists. METHODS: We recorded the gender of first and senior authors of original papers, editorials/reviews from liver-related manuscripts in Gastroenterology, Hepatology, Transplantation, American Journal of Gastroenterology, and Liver Transplantation from January 2014 to 2016. RESULTS: Of 2424 articles reviewed, we excluded 232 (10%) due to inability to determine gender. Among papers analyzed, 72.0% were original and 28.1% reviews/editorials with 65.1% of first authors being male and 34.9% female. Only 20.3% of papers with multiple authors had a female senior author. The proportion of male first and senior authorship between original papers and reviews/editorials was comparable. 72% of original papers had a male as first or senior author, but only 28% females. 71% of review/editorial papers had a male as first or senior author, but only 29% females. When the senior author of an original paper was female, 47.1% of first authors were male and 52.9% female. When the senior author was male, 67.1% of first authors were male and 32.9% female (p < 0.00001). CONCLUSIONS: A significant gender difference exists in Hepatology publications. Female authorship mirrors the percentage of female AASLD membership; however, female senior authorship remains disproportionate. In general, funding for male authors is greater. Fewer women are first authors when the senior author is male, highlighting the importance of female mentorship in Hepatology.

Deferred treatment with a fixed-dose combination of sofosbuvir-velpatasvir for chronic hepatitis C virus genotype 1, 2, 4 and 6 infection.

Sofosbuvir-velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single-arm, open-label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir-velpatasvir among patients randomized to the placebo group in the ASTRAL-1 study. Patients received sofosbuvir-velpatasvir (400/100 mg) once daily for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12 weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%-99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%-100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%-100%) with genotype 2, 19/19 (100%; 95%CI, 82%-100%) with genotype 4 and 8/9 (89%; 95% CI, 52%-100%) with genotype 6. All (19/19; 95%CI, 82-100) patients with cirrhosis and all (31/31, 95%CI, 89-100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir-velpatasvir for 12 weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721).

Total Alanine Aminotransferase (ALT) Flares in Pregnant North American Women With Chronic Hepatitis B Infection: Results From a Prospective Observational Study.

INTRODUCTION: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. METHODS: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy. RESULTS: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation. DISCUSSION: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Pan-Genotypic Hepatitis C Treatment with Glecaprevir and Pibrentasvir for 8 Weeks Resulted in Improved Cardiovascular and Metabolic Outcomes and Stable Renal Function: A Post-Hoc Analysis of Phase 3 Clinical Trials.

INTRODUCTION: Chronic hepatitis C (CHC) infection is associated with extrahepatic manifestations (EHMs) which can affect renal, cardiovascular and other comorbidities. The effect of CHC treatment with short-duration regimens on these EHMs is not well defined. Hence, we examined longitudinal estimated glomerular filtration rate (eGFR), triglycerides and glucose values to assess the impact of short-duration CHC therapy on renal, cardiovascular and metabolic diseases, respectively. METHODS: We conducted analyses of all patients without cirrhosis treated with glecaprevir and pibrentasvir (G/P) for 8 weeks in two phase 3 clinical trials. In addition, one phase 3 trial was carried out to explore the effects of treatment on renal EHMs in patients with advanced renal impairment at baseline. As a sensitivity analysis, we included all CHC patients treated with G/P for 8 or 12 weeks enrolled across five phase 3 trials. Adjusting for baseline demographics and clinical properties via mixed regression models enabled evaluation of changes in EHMs through end of treatment. RESULTS: G/P treatment for 8 weeks resulted in statistically significant declines in triglycerides (- 28.6 mg/dl) and glucose (- 11.2 mg/dl), while there was no statistically significant decline in eGFR. Biomarker improvements were greatest among patients with elevated triglycerides and elevated glucose at baseline. Similar effects were observed across all patients treated with G/P for 8 or 12 weeks. CONCLUSION: Short-duration treatment with G/P resulted in stable renal function and improvements in cardiovascular and metabolic EHM markers, especially in patients with severe EHMs at baseline. FUNDING: AbbVie Inc.

Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1.

BACKGROUND: Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. METHODS: This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. FINDINGS: 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93-99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. INTERPRETATION: Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. FUNDING: Gilead Sciences.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Isolated anti-HBc: The Relevance of Hepatitis B Core Antibody-A Review of New Issues.

Hepatitis B core antibody (anti-HBc) is considered the most sensitive serological marker for history of hepatitis B virus (HBV) infection. In a subset of anti-HBc carriers, anti-HBc is present in the absence of hepatitis B surface antigen and hepatitis B surface antibody-a serological pattern known as "isolated anti-HBc" (IAHBc). IAHBc has been of clinical interest over the past several years, with growing data to suggest its role as a serological marker for occult HBV infection (OBI). This article reviews the clinical significance and association of IAHBc with hepatitis C virus (HCV) co-infection, risk of HBV reactivation during direct-acting antiviral therapy for HCV as well as immune suppression, and development of hepatocellular carcinoma (HCC). Hepatitis B core-related antigen is also highlighted as an emerging laboratory assay that may identify OBI and predict HCC development in non-cirrhotic patients receiving nucleoside/nucleotide analog therapy.

Effect of Hepatitis C Treatment with Ombitasvir/Paritaprevir/R + Dasabuvir on Renal, Cardiovascular and Metabolic Extrahepatic Manifestations: A Post-Hoc Analysis of Phase 3 Clinical Trials.

INTRODUCTION: We analyzed phase 3 trial data of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) ± ribavirin (RBV) in genotype 1 chronic hepatitis C patients to investigate the impact of 3D ± RBV on renal, cardiovascular and metabolic extrahepatic manifestations (EHMs), including persistency 52 weeks post treatment and differential impact by EHM disease severity. METHODS: Estimated glomerular filtration rate (eGFR), fasting triglyceride and fasting glucose values from clinical trials were used to assess renal, cardiovascular and metabolic EHMs, respectively. Two placebo-controlled trials were used to study the effect of treatment, while the pooled sample of treated patients was used to study the persistency and differential effect of treatment by baseline EHM disease severity, as defined by baseline values of respective EHM biomarkers. Changes in EHM outcomes from baseline were assessed with mixed models adjusting for patient baseline demographic and clinical characteristics. RESULTS: Treatment with 3D ± RBV resulted in statistically significant declines from baseline of triglycerides and glucose and no statistical change in eGFR. By 52 weeks post treatment patients with elevated triglycerides (-35.3 mg/dl), pre-diabetes (-4.4 mg/dl), diabetes (-34.2 mg/dl) and CKD stage 3 (+1.6 ml/min/1.73 m2) at baseline experienced a statistically significant improvement in their respective EHM values. Patients with CKD stages 2, 4 and 5 experienced no statistically significant change in eGFR from baseline. CONCLUSION: Treatment with 3D ± RBV resulted in improvement or no worsening of cardiovascular, metabolic and renal EHM markers, especially in patients with severe EHMs at baseline, which persisted until 52 weeks post treatment. FUNDING: Abbvie Inc.

Management of Chronic Hepatitis B in Pregnancy.

Chronic hepatitis B virus (HBV) infection due to mother-to-child transmission during the perinatal period remains an important global health problem. Despite standard passive-active immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine in neonates, up to 8.5% of newborns still acquire HBV infection. Thus, management of chronic HBV during pregnancy and strategies to prevent mother-to-child transmission are important steps in eradicating or reducing the global burden of chronic HBV infection. To date, the management of HBV infection in pregnancy still needs careful attention because of some controversial aspects, including the influence of pregnancy on the course of HBV replication, safety of antiviral prophylaxis with nucleus(t)ide analogs, postpartum flares of hepatitis after delivery, and the safety of breastfeeding. In this review, we highlight these important issues of preventive strategies in the perinatal period.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

BACKGROUND: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. METHODS: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. RESULTS: In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

The Braden Scale, A standard tool for assessing pressure ulcer risk, predicts early outcomes after liver transplantation.

The Braden Scale is a standardized tool to assess pressure ulcer risk that is reported for all hospitalized patients in the United States per requirements of the Center for Medicare and Medicaid Services. Previous data have shown the Braden Scale can predict both frailty and mortality risk in patients with decompensated cirrhosis. Our aim was to evaluate the association of the Braden Scale score with short-term outcomes after liver transplantation (LT). We performed a retrospective cohort study of deceased donor LT recipients at 2 centers and categorized them according to the Braden Scale at hospital admission as low (>18), moderate (16-18), or high risk (<16) for pressure ulcer. We created logistic and Poisson multiple regression models to evaluate the association of Braden Scale category with in-hospital and 90-day mortality, length of stay (LOS), nonambulatory status at discharge, and discharge to a rehabilitation facility. Of 341 patients studied, 213 (62.5%) were low risk, 59 (17.3%) were moderate risk, and 69 (20.2%) were high risk. Moderate- and high-risk patients had a greater likelihood for prolonged LOS, nonambulatory status, and discharge to a rehabilitation facility, as compared with low-risk patients. High-risk patients additionally had increased risk for in-hospital and 90-day mortality after LT. Multiple regression modeling demonstrated that high-risk Braden Scale score was associated with prolonged LOS (IRR, 1.56; 95% confidence interval [CI], 1.47-1.65), nonambulatory status at discharge (odds ratio [OR], 4.15; 95% CI, 1.77-9.71), and discharge to a rehabilitation facility (OR, 5.51; 95% CI, 2.57-11.80). In conclusion, the Braden Scale, which is currently assessed in all hospitalized patients in the United States, independently predicted early disability-related outcomes and greater LOS after LT. Liver Transplantation 23 1153-1160 2017 AASLD.

Management of Cirrhotic Patients After Successful HCV Eradication.

OPINION STATEMENT: Chronic hepatitis C (HCV) is a hepatotropic virus which, when untreated, can lead to progressive inflammation and fibrosis resulting in cirrhosis, hepatocellular carcinoma (HCC), and decompensations related to end-stage liver disease. The relatively recent introduction of all oral, interferon-free, direct-acting antiviral medications against HCV has transformed the management of these patients. Previous treatment regimens were prolonged, poorly tolerated, and frequently did not result in cure. Current therapies achieve sustained viral response (SVR) in the vast majority of patients including those with decompensated liver disease; a previously challenging population to treat. These successes will result in significant numbers of cirrhotic patients requiring management after SVR. Although many complications of cirrhosis are improved in this setting, regular follow-up of HCC, esophageal varices, and other sequelae of cirrhosis will be necessary. This chapter will review the management of cirrhosis in HCV patients achieving cure.

Hepatitis B and Risk of Non-Hepatocellular Carcinoma Malignancy.

Chronic hepatitis B infection (CHB) is a known risk factor for malignancy. Unlike hepatocellular carcinoma (HCC), less is known about the risk of non-HCC malignancy. However, epidemiology and pathologic evidence suggests a strong association between non-Hodgkin lymphoma and CHB. Data regarding the risk of other malignancies, such as pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma, are mixed. Surveillance and appropriate treatment of infection and malignancy in these patients is essential. Further study of these associations is needed and may bring new insights in the pathogenesis and treatment of these diseases.

Hepatitis B in the Female Population.

Chronic hepatitis B infection in the female population has implications not just for the individual but for her children as well. This article discusses the natural history of hepatitis B and how it plays an important role in hepatitis B virus (HBV) transmission, the current strategies and new strategies to control HBV and reduce transmission, and the updated guidelines for the management of HBV.