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.
- 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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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.
- 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
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.
- 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.
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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.
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O Jeanniard-Malet et al. JPGN 2017; 64: 524-7. This survey of 28 centers in France assessed clinical practice with regard to primary prophylaxis in portal hypertension. More than 75% use endoscopy to screen for varices in patients with chronic liver conditions. “In cases of grade 2 varices with red marks and grade 3 varices >90% of centres perform sclerotherapy or endoscopic variceal ligation.”
Y-D Ren et al. Hepatology 2017; 65: 1765-8. FMT for chronic HBV? This small study with 5 patients who received fecal microbiota transplantation in an effort to clear HBeAg. There were 13 controls. Patients in both group received either ongoing entecavir or tenofovir antiviral therapy (& had received for at least 3 years). FMT was given every 4 weeks (1 to 7 treatments). HBeAg declined gradually after each round. Three patients in the FMT arm cleared HBeAg compared with none in the control arm. Two of the three cleared HBeAg after on FMT and the third after two rounds of FMT.
Y Sun et al. Hepatology 2017; 65: 1438-50. In this report, the authors propose to augment the liver biopsy classification in patients with Hepatitis B. Their goal is to provide more information about dynamic changes regarding fibrosis using three terms:
- Predominantly progressive: thick/broad/loose/pale septa with inflammation
- Predominantly regressive: delicate/thin/dense/splitting septa
Using this new designation, they characterized 71 paired liver biopsies before and after entecavir for 78 weeks. Before treatment: 58%, 29%, and 13% for progressive, regressive and indeterminate; after treatment: 11%, 11%, and 78% respectively.
Rodin Museum, Gates of Hell
Two recent studies show that HBsAg levels may help determine therapeutic decisions:
- WP Brower et al. Clin Gastroenterol Hepatol 2016; 14: 1481-89
- Y-C Hsu et al. Clin Gastroenterol Hepatol 2016; 14: 1490-98.
The first study was a retrospective study of 292 HBeAg-negative patients with chronic hepatitis B virus (HBV) infection. This cohort had normal ALT values and HBV DNA <20,000 IU/mL. Patients were considered to be carriers of inactive HBV if their HBV DNA was <2000 IU/mL and serum levels of ALT remained normal.
Key findings with regard to likelihood of having inactive HBV at following year:
- “odds were 97% for initial level of HBsAg <100 IU/mL”
- “odds were 85% for patients with initial levels 100-1000 IU/mL and 76% for patients with initial levels >1000 IU/mL”
Also, “patients with HBV activity who had levels of HBV DNA <5000 IU/mL and decreases in HBsAg of 0.5 log IU/mL or more for 1 year had a high probability of becoming carriers of inactive HBV in the next year.” Figure 2 in an easy graphic form shows cumulative probabilities of becoming inactive or active HBV over the three-year period.
In the second study, Hsu et al performed a prospective study of 161 consecutive patients with undetectable HBV DNA following 3 or more years of entecavir. After stopping therapy, patients were monitored for relapse.
- 49.2% of patients had a clinical relapse (defined by elevation of both HBV DNA >2000 IU/mL and by elevated ALT >2-fold ULN)
- 81.7% had virological relapse (HBV DNA >2000 IU/mL).
- All patients with HBeAg-positivity had clinical relapse and were retreated.
- For HBeAg negative patients at end of treatment, 39.2% had a clinical relapse & 77.4% had a virological relapse.
- Serum HBsAg level predicted relapse among HBeAg-negative patients: 11 patients with HBsAg <10 IU/mL did not relapse. The lower the serum level of HBsAg at the end of treatment, the lower the rate of clinical relapse (see Figure 1). Of those with HBsAg 100-1000, there was ~25% clinical relapse at 30 months f/u and more than 50% virological relapse.
My take: HBsAg level is becoming important in truly determining who has inactive HBV and reflects the likely natural history. It is expected that using HBsAg levels will be increasingly used to determine management of HBeAg-negative HBV.
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Editorial: MH Nathanson, N Terrault Hepatology 2016; 64: 328-29. This very unusual editorial explains a published erratum of 2010 paper reversing a claim that patients with Hepatitis B who had achieved HBsAg clearance had markedly decreased rates of hepatocellular carcinoma (37 cases per 100,000 person-years). After correction of the arithmetic error, the rate of HCC in this population was actually 442 cases per 100,000 person-years. The editorial does reiterate that studies have shown lower HCC among those with low HBV DNA which is a prerequisite for HBsAg clearance. Exact risk is difficult in this population due to infrequent development of HBsAg loss and infrequent development of HCC. The message: While loss of HBsAg may lower HCC risk, there remains a need for HCC surveillance.
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Wild Goose Island, Glacier Natl Park