S Nagai et al. Clin Gastroenterol Hepatol 2019; 17: 2759-68. For patients who underwent liver transplantation during 2016–2017, a significantly lower proportion of patients with NASH survived for 1 year after transplantation than patients with HCV (P = .004) or ALD (P < .001). 1-year patient survival rates: NASH 90.4%, HCV 92.8%, ALD 93.5%. Full Text: Increased Risk of Death in First Year After Liver Transplantation Among Patients With Nonalcoholic Steatohepatitis vs Liver Disease of Other Etiologies
JE Squires et al. JPGN 2020; 70: 79-86. Using a prospective, longitudinal database, this study from ChiLDReN network with 93 children with biliary atresia and native liver found that NO increased prevalence of neurodevelopmental delays. Markers of advanced liver disease (high bilirubin/GGT for those ≤5 yrs, and portal hypertension for those >5 years) did negatively affect neurodevelopmental measures.
C Jaramillo et al. JPGN 2020; 70: 87-92. This pilot study with 21 patients found that degree of fibrosis, quantified by collagen hybridizing peptide, at time of Kasai, was associated with the risk of requiring a liver transplantation by age 4 years. Total bilirubin >2 mg/dL and Albumin ❤ g/dL at 3 months post-Kasai were also associated significantly with need for liver transplantation.
H-S Chen et al. Hepatology 2019; 70: 1903-12. In this study from Taiwan with 182 children (median age of 10.6 at enrollment) with hepatitis B and a normal ALT, a baseline anti-HBc titer of >500 IU/mL was associated with spontaneous HBeAg seroconversion with hazard ratio of 2.81. Over the median follow-up of 19.8 years, 85 subjects (46.7%) had HBeAg seroconversion. Thus, anit-HBc reflects anti-HBV immune response in the HBeAg-positive patients with normal ALT.
NA Terrault et al. Hepatology 2018; 67: 1560-99. Here’s the full link: Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance
Some of the key points:
Table 4 (pg 1565): provides a refresher on interpretation of serology
Table 5 (pg 1567): Children and Adults Who Are HBsAg Positive:
- Can participate in all activities, including contact sports
- Should not be excluded from daycare or school participation and should not be isolated from other children
- Can share food and utensils and kiss others
Figure 1 (pg 1571) Treatment algorithms.
- For both HBsAg-positive/HBeAg-positive and HBsAg-positive/HBeAg-negative patients, treatment is recommended if ALT ≥2 x ULN.
- For both groups, treatment is NOT recommended for those with ALT ≤ULN and low HBV DNA levels (<20,000 IU/mL for HBeAg-positive and <2,000 IU/mL for HBeAg-negative).
- In those who do not fall into these categories, ongoing monitoring is recommended
Figure 1 from AASLD Guidance Link
Guidance Statements for HCC Screening in HBsAg‐Positive Persons
- All HBsAg‐positive patients and high risk adults (see page 1574) with cirrhosis should be screened with US examination with or without AFP every 6 months.
- There are insufficient data to identify high‐risk groups for HCC in children. However, it is reasonable to screen HBsAg‐positive children and adolescents with advanced fibrosis (F3) or cirrhosis and those with a first‐degree family member with HCC using US examination with or without AFP every 6 months.
- In adults: The AASLD recommends peg‐IFN, entecavir, or tenofovir (TDF) as preferred initial therapy for adults with immune‐active CHB
- In children: The AASLD suggests antiviral therapy in HBeAg‐positive children (ages 2 to <18 years) with both elevated ALT and measurable HBV‐DNA levels, with the goal of achieving sustained HBeAg seroconversion.
- The AASLD suggests antiviral therapy to reduce the risk of perinatal transmission of HBV in HBsAg‐positive pregnant women with an HBV‐DNA level >200,000 IU/mL..The only antivirals studied in pregnant women are lamivudine, telbivudine, and TDF. Of these 3 options, TDF is preferred to minimize the risk of emergence of viral resistance during treatment. Interim studies show high efficacy of TDF in preventing mother‐to‐child transmission.
- The infants of all HBsAg‐positive women should receive immunoprophylaxis (HBV vaccination with or without hepatitis B immunoglobulin, per World Heath Organization and Centers for Disease Control and Prevention recommendations)
Treatment & prevention of HBV reactivation in patients receiving immunosuppressive or cytotoxic drugs (section 6 pages 1577-9)
- HBsAg and anti‐HBc (total or immunoglobulin G) testing should be performed in all persons before initiation of any immunosuppressive, cytotoxic, or immunomodulatory therapy.
- HBsAg‐positive, anti‐HBc–positive patients should initiate anti‐HBV prophylaxis before immunosuppressive or cytotoxic therapy.
- HBsAg‐negative, anti‐HBc–positive patients could be carefully monitored with ALT, HBV DNA, and HBsAg with the intent for on‐demand therapy, except for patients receiving anti‐CD20 antibody therapy (e.g., rituximab) or undergoing stem cell transplantation, for whom anti‐HBV prophylaxis is recommended.
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Mother-to-child transmission of hepatitis B virus (HBV) accounts for the majority of cases of chronic HBV infection. HBV infection affects more than 250 million people worldwide and in many cases results in cirrhosis or hepatocellular carcinoma. As such, there has been interest in preventing perinatal transmission.
The most recent study (C Jourdain et al. NEJM 2018; 378: 911-23) again showed that tenofovir administration to pregnant women with HBV can prevent transmission. This study enrolled 331 women. Key findings:
- 0% (0/147) infants in the tenofovir group developed HBV infection compared to 2% (3/147) in the control group. This did not reach statistical significance
- The placebo group received HBV vaccination and hepatitis B immune globulin 1.2 hours and 1.3 hours after birth (median time). This rapid provision of treatment along with completion of four doses of HBV vaccine likely helped keep the placebo group HBV infection rate low
In the related editorial (G Dusheiko. pg 952-3), it is noted that “current levels of evidence supporting antiviral therapy with TDF [tenofovir] (or possbily lamivudine or telbivudine) to reduce levels of maternal HBV DNA during pregnancy have been accepted by the” AASLD.
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Recently the AASLD Postgraduate Course discussed emerging treatments for nonalcoholic fatty liver disease/nonalchoholic steatohepatitis. From AASLD News: Emerging Treatments for NASH
- Quentin Anstee: “It is important to remember that our patients with fatty liver disease will most likely die of cardiovascular disease, not liver disease.”
Four principles in treating nonalcoholic fatty liver disease (NAFLD) to address both cardiovascular and liver risks.
- Target obesity with lifestyle changes and, possibly, bariatric surgery.
- Target metabolic syndrome to reduce cardiovascular disease risk using medications with additional liver-directed benefits.
- Target liver disease to prevent progression of steatohepatitis to fibrosis and cirrhosis.
- Minimize downstream complications such as hepatocellular carcinoma.
More than 60 phase 3 trials are underway –Primary Therapeutic Targets:
- PPAR signaling (insulin signaling, glucose and lipid metabolism, energy homeostasis, inflammation)
- FXR signaling (insulin sensitivity, glucogenesis, lipogenesis)
- ASK1 signaling (apoptosis)
- CCR2/CCR5 signaling (inflammation and fibrogenesis).
As part of the Hepatitis B Research Network (HBRN), 343 children were enrolled in 7 U.S. and Canadian centers. A recent study (KB Schwarz et al. J Pediatr 2015; 167: 1287-94) provides data on HBV epidemiology and a related commentary by Brian McMahon (1186-7) provides some useful advice on what is needed to further reduce HBV infection.
88 children were not enrolled. More than half of these patients refused to participate, the other reasons included language barriers or inability to comply with follow-up.
- 78% of the subjects in this study were Asian
- 55% were adopted. This high adoption rate likely skews some of the data because (according to the associated editorial) “children with HBV in the US..most are likely to be children of parents who immigrated to the US from endemic countries and not adoptees.”
- 97% had international origins with either the child or a parent born abroad
- HBV genotype B was most common (43%) followed by genotype C (32%), D (16%), A (5%), E (4%) or multiple (<1%).
In the editorial, Dr. McMahon notes that ascertaining the rate of a birth dose of HBV vaccine would be of interest. In many countries, vaccination is started at ≥2 months and this is unlikely to prevent HBV transmission. Two important public health issues for North America:
- “First, all pregnant women, especially those foreign-born, need to be screened for HBsAg and if positive, their infants should receive HBV vaccine and hepatitis B immune globulin immediately after birth.”
- “Second, all foreign-born children and adults who immigrate to the US or Canada should be tested for HBsAg.”
My take: This study provides an up-to-date snapshot of tertiary care for children with HBV in North America. There are many opportunities to curtail (or hopefully eliminate) the impact of HBV in our communities and around the world.
AASLD Guideline (Nov 2015): Treatment of Chronic HBV
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San Diego Zoo
While entecavir and tenofovir have been in use for many years in adult hepatology for hepatitis B virus (HBV) infection, a well-designed study supporting their use in pediatrics has been lacking until now. Recently, a study (M Jonas et al. Hepatology 2015; DOI: 10.1002/hep.28015) has shown that entecavir is effective for pediatric HBV
Link to full study. Randomized Controlled Trial of Entecavir Versus Placebo in Children with HBeAg-positive Chronic Hepatitis B
Here’s the abstract:
This ongoing, randomized phase III study assesses the safety and efficacy of entecavir versus placebo in nucleos(t)ide-naive children (2 to <18 years) with HBeAg-positive chronic hepatitis B (CHB). Blinded treatment was administered for a minimum of 48 weeks. After Week 48, patients with HBeAg seroconversion continued blinded treatment; those without, switched to open-label entecavir. The primary endpoint was HBeAg seroconversion and HBV DNA <50 IU/mL at Week 48. A total of 180 patients were randomized (2:1) and treated. Baseline median age was 12 years, with approximately 50% of children aged >12 to <18, and 25% each aged ≥2 to ≤6 and >6 to ≤12. Rates for the primary endpoint at Week 48 were significantly higher with entecavir than placebo (24.2% [29/120] versus 3.3% [2/60]; P=0.0008). Furthermore, higher response rates were observed with entecavir compared with placebo for the key Week 48 secondary endpoints: HBV DNA <50 IU/mL (49.2% [59/120] versus 3.3% [2/60]; P < 0.0001), alanine aminotransferase normalization (67.5% [81/120] versus 23.3% [14/60]; P < 0.0001), and HBeAg seroconversion (24.2% [29/120] versus 10.0% [6/60]; P = 0.0210). Among entecavir-randomized patients there was an increase in all efficacy endpoints between Weeks 48 and 96, including an increase from 49% to 64% in virologic suppression. The cumulative probability of emergent entecavir resistance through Years 1 and 2 of entecavir was 0.6 and 2.6%, respectively. Entecavir was well tolerated with no observed differences in adverse events or changes in growth compared with placebo. Conclusion: In childhood CHB, entecavir demonstrated superior antiviral efficacy to placebo with a favorable safety profile. These results support the use of entecavir as a therapeutic option in children and adolescents with CHB.
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From Brooklyn Bridge
Wu Q et al. Clin Gastroenterol Hepatol 2015; 13: 1170-76. This was a prospective study of 450 Hepatitis B e antigen-positive pregnant women with HBV DNA levels greater than 10 to the 6th IU/mL. 279 women received telbivudine 600 mg daily starting between 24 to 32 weeks of gestation until delivery or up to a month thereafter; this treatment group was compared to 171 controls women unwilling to take the medication. All infants received vaccinations after birth along with hepatitis B immune globulin. None of the infants in the treatment arm acquired hepatitis B (negative HBsAg at 6 months) compared with 14.7% of infants in the control arm who were positive for infection. no serious adverse effects were noted in the women receiving telbivudine or their infants.
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