Good News Story: The Remarkable Hepatitis B Vaccine Story

W-Q He, GN Guo, C Li. Hepatology 2022; 75: 1566-1578. The impact of hepatitis B vaccination in the United States, 1999-2018

In the past 30 years, the hepatitis B vaccine has been included in infant immunization schedules in the U.S. The authors studied a large, comprehensive, and nationally representative data set (NHANES data from 1999-2018) to assess its efficacy.

Key findings:

  • HBV vaccination was associated with reduced risk of all-cause mortality (HR, 0.78; 95% CI, 0.68–0.90) and cancer-related mortality (HR, 0.76; 95% CI, 0.58–1.00) 
  • The highest vaccination uptake was found among those born after 1991, at 86.5%.
  • Vaccinated participants had higher prevalence of vaccine-induced immunity than the unvaccinated (47.2% vs. 7.4%). Among those born after 1991, vaccine efficacy (VE) was found at 58% (95% CI, 18%–79%) overall and 85% for those aged ≥20 years (mean age, 22), whereas no effect was found among those born prior to 1990

Context for these findings is noted in the associated editorial (pgs 1365-1367):

HBV remains one of the most deadly viruses worldwide with nearly 1 million deaths yearly and nearly 300 million people chronically-infected. The vast majority of unvaccinated children less than 1 year of age become chronically-infected. In the U.S., 98% of children acquired HBV through vertical transmission “including 26% of pediatric cases who were born in the USA or Canada”

My take: This study shows that HBV vaccine maintains strong protection for 20 years and protects against cancer and death.

Related blog posts:

Los Poblanos Ranch, Alburquerque

Lessons Learned from Children In the Hepatitis B Virus Research Network

SJ Schwarzenberg et al. JPGN 2022. 74: 431-433. Lessons Learned from Children Enrolled into the Hepatitis B Virus Research Network Multi-Center Prospective Study

This NIDDK-funded Hepatitis B Research Network (HBRN) was established in 2009 and enrolled 362 patients. 97% of participants were born in countries where HBV is endemic or in North America to mothers born from these countries.

Key points:

  • Due to revised criteria for ALT values, most pediatric patients have elevated ALT and do not meet the definition of immune-tolerant
  • Spontaneous flares (ALT >400 in males and >350 in females) in untreated children…did not lead to hepatic decompensation
  • Hepatocellular carcinoma was not identified in this cohort, though HBRN centers reported historical experiences. Only one patient developed cirrhosis over 4 years of followup.

Clinical Recommendations from Authors:

  • Screen for HBV in children with unexplained serum aminotransferases regardless of immunization history
  • Screen for HBV in children with normal aminotransferases if they or their parents are from an area where HBV is endemic or other risk factors
  • In those with HBV, monitor aminotransferases and HBV levels every 6 months
  • Obtain genotype in children with HBV
  • Consider treatment if ALT >2 x ULN over 3-6 mo. Treatment should follow AASLD guideline
  • Recommend AGAINST treatment at the start of a flare
  • Recommend counseling to promote healthy weight and avoidance of at-risk alcohol use

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Celiac Disease, Hepatitis B and Paul Harvey

Growing up, I heard a number of Paul Harvey broadcasts on the radio. Often there would be an important twist at the end and he would conclude with ‘and that’s the rest of the story.’

This came to mind after reading a recent article on celiac disease and hepatitis B infection:

N Habash et al. JPGN 2022; 74: 328-332. Celiac Disease: Risk of Hepatitis B Infection

Methods:

  • A cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009–2014) 
  • And a retrospective analysis of HBV infection in two cohorts: Mayo Clinic cohort (1998–2021) and the Rochester Epidemiology Project cohort (REP; 2010–2020)

Key findings:

  • Based on NHANES database, the rate of HBV infection in the United States was  0.33%
  • Of 93 patients with CD, 46 (49%) were vaccinated for HBV and of the remaining 19,422 without CD, 10,228 (53%) were vaccinated
  • Twenty-two (48%) vaccinated patients with CD had HBV immunity and 4405 (43.07%) vaccinated patients without CD had HBV immunity
  •  In NHANES data, there were no cases of HBV infection in patients with CD. Among the 3568 patients with CD seen at Mayo Clinic and 3918 patients with CD in the REP database, only four (0.11%) at Mayo Clinic and nine (0.23%) of the REP patients had HBV infection.

This finding is probably applicable to other conditions in which HBV immunity is ascertained.

My take: In contrast to other small studies, this study showed that the “rate of HBV vaccination and immunity was similar in individuals with and without CD.” In addition, there was no increased risk of HBV infection detected in CD patients. Thus, testing for HBV is not necessary in patients with CD.

And that’s the rest of the story.

Related blog post

Should All Pediatric Patients with Hepatitis B Undergo Routine Surveillance for Hepatocellular Carcinoma?

C Rajan et al. JPGN Reports: November 2021 – Volume 2 – Issue 4 – p e124. Open Access: Hepatocellular Carcinoma in the Absence of Cirrhosis in a Child With Inactive Chronic Hepatitis B Infection

In this case study, the authors “describe an unusual case of a child with chronic hepatitis B infection who developed HCC in the absence of active hepatitis or cirrhosis.” Based on their case report, they advocate for “regular HCC surveillance for all children with chronic hepatitis B, regardless of presence or absence of hepatitis or cirrhosis.”

However, the authors suggestions to expand surveillance to all children with hepatitis B is NOT aligned with current expert opinion (by most experts). This potential recommendation deserves (deserved) more commentary in their discussion. The AASLD recommends offering surveillance when the risk of HCC is at least 1.5% per year and the incidence is greater than 0.2% per year, which includes patients with cirrhosis and some non-cirrhotic hepatitis B carriers [7]. In a study from Taiwan (blog post: HBV Vaccination Prevents Cancer), the authors showed the beneficial effects of vaccination: HCC incidence per 105 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. This study also showed how rare HCC cases are in children; thus, showing benefit of vaccination was impressive.

The AASLD guidelines on HCC (Link to PDF: Diagnosis, Staging, and Management of
Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for
the Study of Liver Diseases
) notes the following high risk categories:

My take: This case report is helpful in emphasizing the risk of HCC in patients with HBV, even in those without significant risk factors. However, at this time most experts do not recommend surveillance in those with a low risk of developing HCC.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Celiac Disease and Lack of Response to Hepatitis B Immunization

A Aneja et al. JPGN Reports February 2021 – Volume 2 – Issue 1 – p e046: Open Access: Clinical Characteristics of Children With Celiac Disease Not Responding to Hepatitis B Vaccination in India

Methods: The study population from consisted of 3 groups—50 newly diagnosed CD children (group 1), 50 previously diagnosed CD children who were on gluten free diet (GFD) >3 months (group 2), and 100 age and gender matched healthy controls (group 3).

Key findings:

  • Positive anti-HBs response was found in 46% in newly diagnosed CD children, 60% in CD children on GFD, and 83% in healthy controls (P < 0.001)
  • Ongoing gluten intake has significant impact on protective immune response to Hepatitis B vaccine
  • 44 out of 45 (97.77%) nonresponders from CD group seroconverted after a single booster dose

My take: Check Hep B immune response in patients with celiac disease.

Related blog post: Improving Care Process in Celiac Disease

Hepatitis B: Natural History and Difficulty Treating Immunotolerant Children

S Mo et al. JPGN 2021; 73: 150-155. Natural History of Chronic Hepatitis B Infection Among Chinese Children and Young Adults: A Single-Center Experience

Key findings:

  • Of the 353 patients, there were immune-tolerant 112 (34%), HBeAg-positive immune-active 47 (14%), and inactive carrier 82 (25%). The remaining 88 patients (27%) did not fit into a particular category with 26 of 88 patients meeting the criteria for inactive carrier except for mildly elevated alanine aminotransferase
  • Among 179 patients followed for ≥5 years, the spontaneous seroconversion rate was 38% (from HBeAg-positive to HBeAg-negative along with anti-HBeAb positivity)

In their discussion, the authors make two key points:

  1. “No substantial benefit from anti-viral therapy” has been evident in children in the immuno-tolerant phase (MM Jonas et al. Hepatology 2016; 63: 307-318.)
  2. The updated AASLD guidelines “strongly recommend anti-viral therapy for HBeAg-positive pregnant women with a serum HBV DNA >200,000 IU/mL”

G Mieli-Vergani et al. JPGN 2021; 73: 156-160. Peginterferon Alfa-2a (40KD) Plus Lamivudine or Entecavir in Children With Immune-Tolerant Chronic Hepatitis B

As noted above, antiviral therapy has not been shown to be effective in children who are in the immuno-tolerant phase; however, the authors of this study explored whether combination therapy could be effective in a randomized, controlled, multicenter study (n=59).

  • Key finding: At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group)

My take: These studies reinforce the notion that children in the immuno-tolerant phase of HBV infection do not benefit from antiviral therapy. Prevention of infection is the most promising strategy.

Related blog posts:

Confirmation Bias diagram. From Steve Stewart-Williams

Why Fewer Children Have Immune-Tolerant Hepatitis B Infection Than Previously

A recent study (KB Schwarz et al. JPGN 2019; 69: 588-94) highlights the chronic hepatitis B virus (HBV) phenotypes from a large pediatric North American cohort (n=371).

  • Immune-tolerant HBV was define by HBe-Ag-positivity along with normal ALT levels.
  • Inactive carrier were HBe-Ag-negative with low HBV DNA/normal ALT.
  • Chronic hepatitis B (HBeAg positive and HBeAg negative) had high HBV DNA and abnormal ALT values.
  • Indeterminant HBV had characteristics did not allow them to classified in these four categories.

Key findings:

  • If local laboratory normative values were used 36% of children would have been classified as immune-tolerant*.  However, this drops down to 12% if updated upper limits of normal (ULN) are used based on Figure 3.
  • Using updated ULN, 62% had immune active HBeAg+ disease, 12% with immune-tolerant HBV, 4% with immune-active HBeAg-negative disease, 6% with inactive carrier, and 16% indeterminant HBV.

*There are a few discrepancies between Figure 3 and the abstract data.  The abstract states that 82% would be considered to have chronic hepatitis B (this is 62% in figure 3). The abstract states that 35% were immune-tolerant based on local lab values.

The data presented were cross-sectional data at time of patient enrollment.

My take: this study shows that very few children in this cohort were immune tolerant based on more precise ULN values.  The authors note that the cohort who were immune tolerant were largely drawn from Asian children (most often infected perinatally).

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Lincoln Park, Chicago

 

PEG-B-ACTIVE Study: Efficacy of Peginterferon for Children with Hep B

A recent randomized controlled, open-label study (S Wirth et al. Hepatology 2018; 68: 1681-94) examined the use of weekly peginterferon alfa-2a (PEG) in 161 children (3-18 yrs) with immune-active HBe-Ag-positive children.  The two main groups were for those without advanced fibrosis: a PEG group (n=101) and a placebo group (n=50).  A third group enrolled 10 patients with advanced fibrosis who all received PEG. The treatment period was 48 weeks with ongoing observation for an additional 24 weeks.

Key findings:

  • The PEG group had HBeAg seroconversion of  8% at 48 weeks and 26% at 72 weeks; the placebo group had HBeAg seroconversion of 6% at both timepoints. At 72 weeks, the odds ratio was 5.43 for the PEG group and P=0.0043.
  • HBsAg clearance rates were higher in the PEG group: 8.9% vs 0% in placebo group.
  • The authors showed response (loss of HBeAg) by age and those <5 years had the highest response 43% (6 of 14).  The rate of seroconversion was 30.2% in those <12 years compared with 20.8% in those ≥12 years.
  • The authors showed response (loss of HBeAg) those with ALT values between 2-<5 had the highest response of 35% (15 of 43).
  • Adverse events were frequent –among the 101 treated patients: 49 with pyrexia, 30 with headache, 19 with abdominal pain, 15 with influenza-like illness, 14 with vomiting, 61 with ALT >5 x ULN, 25 with ALT >10 x ULN, 19 with neutropenia (ANC <750), and two with self-limited increased thyroid-stimulating hormone. These were all much higher than in the placebo group

My take: This study does not answer the question about which treatment is optimal for hepatitis B in children–direct-acting antivirals (eg. entecavir, and tenofovir) or peginterferon.  It does shows that weekly peginterferon alfa-2a was associated with HBeAg seroconversion in 26% of recipients at week 72.  Although a high number of patients experienced adverse effects, there were no new safety signals identified.

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View from Parker Ridge, near Banff

Hep B-related Hepatocellular Carcinoma in Kids: 8 Needles in 4 Haystacks

Over a 25-year period, investigators (DB Mogul et al. JPGN 2018; 67: 437-440) from 4 medical centers identified 8 patients (8-17 years) with hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV).

The authors indicate that all of the cases were thought to have acquired HBV via vertical transmission.

Key features:

  • 3 were asymptomatic; 50% reported abdominal pain
  • Only 1 case presented to a hepatologist
  • 4 patients had ALT values <1.5 times the upper limit of normal
  • Among those with documented HBeAg (n=3), all were negative and all were positive for anti-HBeAb
  • Alphafetoprotein was elevated in 3 patients, normal in 2 patients and not documented in 3 patients.

My take: HCC rarely occurs in children with HBV.  The most effective way to reduce HCC is through prevention, particularly vaccination.  The role of regular imaging which could detect tumors earlier remains unclear (in the absence of a risk factor like cirrhosis); in this series, only one patient presented to a hepatologist.

Related blog posts:

Lake Agnes, Banff

Changing Liver Mortality Trends Since 2007

A recent study (D Kim et al. Gastroenterol 2018; 155: 1154-63) used a CDC database which captures >99% of deaths in the U.S. to analyze mortality trends from 2007 through 2016.  Full text link available online: Changing Trends in Etiology-Based Annual Liver Mortality

When looking at all-cause mortality, there has been a significant decline in deaths associated with hepatitis C (HCV) but not in deaths associated with alcoholic liver disease (ALD).  The image below shows the trend and the impact of direct-acting antivirals.  Deaths associated with nonalcholic fatty liver disease (NAFLD) and due to hepatitis B (HBV) are described in this study as well, though both together account for less than 1/4th deaths associated with ALD.  Interestingly, mortality related to NAFLD was increasing slowly over the study period.

Related blog posts: