Tag Archives: hepatitis B

HBV: translating advances from adults to pediatrics

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Given the increased difficulties of conducting research in the pediatric population, it can take a long time for pediatric patients to benefit from the research advances demonstrated in adults.  Fortunately, with hepatitis B virus (HBV) the lag time has not been excessive.  A specific example has been a recent study demonstrating the effectiveness of tenofovir in the pediatric population (Hepatology 2012; 56: 2018-26).

In this double-blind, placebo-controlled study,  adolescents with chronic HBV were randomized into tenofovir 300 mg (n=52) or placebo (n=54) once daily for 72 weeks.  101 patients completed the 72 weeks of treatment.  In this population, 85% had received prior HBV therapy and 91% were HBeAg-positive at baseline.  Patients included in the study had to have ALT >2 x ULN or history of this w/in 24 months along with HBV DNA>10 to the 5th copies/mL.  The inclusion criteria required a weight of >35 kg.

Findings:

  • Virologic response (HBV DNA <400 copies/mL): 89% in tenofovir group and 0% in placebo group
  • No resistance noted through 72 weeks.  All cases of virologic breakthrough were associated with non-adherence but no genotypic or phenotypic resistance.
  • Normalization of ALT: among patients with baseline elevation, normalization occurred in 74% of tenofovir group compared with 31% of placebo group
  • Serologic response: 21% of tenofovir group and 15% of placebo group experienced loss of HBeAg by week 72
  • Adverse effects were more frequently noted in placebo group.  No patients met the safety endpoint of a 6% decrease in spine bone mineral density

Since suppression of HBV DNA is a limited surrogate endpoint for the development of long-term sequelae much longer followup is needed to determine the impact of this nucleotide analogue.  In adults, this agent has been associated with reversal of cirrhosis.

Across the globe, 350 million people live with chronic HBV infection and 600,000 die each year due to HBV infection.  About 25% of children with HBV develop cirrhosis or cancer of liver later in life.  Given the magnitude of the problem, the most promising approach remains prevention with vaccination.  Treatment to prevent complications in those already infected is likely to be offered to a tiny fraction of those who might benefit.

Related blog entries:

More on entecavir and tenofovir

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In a previous post (Extended data with entecavir & annotated HBV management …) good news on the long term use of entecavir was reported.  Another large study indicates that  entecavir (ETV) monotherapy generally produces equivalent results to combination therapy with tenofovir (TDF) (Gastroenterol 2012; 143: 619-28).

The authors report their experience with a randomized open-label multi center study with 379 nucleos(t)ide-naive patients; 264 were HBeAg-positive and 115 were HBeAg-negative.  At week 96, among all patients, virology response defined as HBV DNA <50 IU/mL was 76.4% in the ETV group and 83.2% in the ETV-TDF group.

In multiple comparisons, the combination group tended to have better virological response  except in the HBeAg-negative group (91.1% ETV vs. 89.8% in ETV-TDF).  The other comparisons included the HBeAg-positive group (69.8% ETV vs. 80.4% ETV-TDF), low baseline HBV DNA (<10 to the 8th IU/mL) (83% in both groups), and the high baseline HBV DNA (62.0% ETV vs. 78.8% ETV-TDF).  Yet, the only group where this was statistically significant was those with high baseline HBV DNA, n= 164 (>10 to the 8th IU/mL).

Biological response was greater in the ETV monotherapy, 81.9% compared with 69% in the combination group.  Among HBeAg+ patients, loss of e antigen was comparable: 38.9% in ETV compared with 29.7% in ETV-TDF.  In this group, seroconversion to HBeAb+ occurred in 32.5% of ETV compared with 21.7% of combination patients.

Safety: five patients in combination group and two patients in ETV monotherapy group discontinued treatment due to adverse events.  Three deaths occurred in the combination group (either on treatment or during followup), with the following causes: cardiac arrest, bile duct tumor, and liver failure.  In the patient with liver failure, she had responded to therapy but experienced a breakthrough at week 48.  At week 100, she was switched to commercial treatment.  Five days later she was hospitalized and died within 1 week.  No resistance to either drug was identified.  Thus, the authors speculate that nonadherence was an important factor.  Also, during the course of the study, five malignancies were diagnosed, including 3 with HCC.

HBV in the Joseon Dynasty

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Investigators have found evidence of Hepatitis B virus (HBV) in the mummified remains of a Korean child from the 16th century (Hepatology 2012; 56: 1671-80).

There are at least 10 HBV genotypes (A-J) and several sub genotypes; each have a specific geographical distribution.  Genotypes are defined by an >8% sequence divergence whereas as sub genotypes have 4-8% sequence divergence.  The HBV in this study corresponds to C2 clade.

While the technical aspects are fascinating, the other important contribution of this article is to the understanding of the evolutionary history of HBV.   There are two theories with regard to the origin of HBV, which may have occurred 100,000 years ago.  One suggests a primate origin with subsequent cross-species transmission.  Another theory suggests a common ancestor of HBV for primates and humans.

In this study, the mummy-derived HBV has the same genotype C which is currently predominant in Korea (>95%); and C2 sub genotype is the most common sub genotype.

The studies conclusions regarding the identification of the subtype is supported by the process of testing the samples in three independent laboratories.  The genetic diversity noted in the sample is likely related to natural evolutionary processes.

Additional references:

Lessons about HBV in NYC

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Hepatitis B infection remains a leading cause of cirrhosis and liver cancer worldwide.  In the U.S., the prevalence is estimated at 0.3-0.5% of the population.  An updated look at the epidemiology comes from NYC (MMWR 2012; 61: 6-9).  Investigators randomly selected 180 HBV cases (2008-2010) and investigated them.

Findings/take-home points:

  • Two-thirds were Asian.
  • In 70%, the clinician did not know any of patient risk factors
  • In 62%, the clinician did not know hepatitis A vaccination status (despite recommendations)
  • Main reasons for testing: 27% birth country prevalence, 12% elevated liver tests, 2% hepatitis signs/symptoms
  • Only 75% received counseling regarding transmission

As a result of this investigation, the department of health initiated multiple changes:

  • Clinicians were contacted regarding HAV vaccinations
  • Booklet for patients developed: How to Tell Others You Have Chronic Hepatits B
  • Patient education booklet developed: Hepatitis B: the Facts

These booklets (in five languages) can be ordered in bulk and free of charge within NYC and also online at

Hepatitis B The Facts, Eng.qxp:For Internet, 5.5×8.5 – NYC.gov

Hep B Guide to Telling 7 11_Hep B Chronic – NYC.gov

Other useful links:

DO YOU NEED A HEPATITIS B TEST? – NYC.gov

Unrelated link -but worth a look (thanks to Larry Saripkin for showing me this useful training video):

“dont go ninjin nobody that dont need ninjin” Kung Fu Hillbilly – Training Video – YouTube

More on perinatal HBV

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In addition to a recent blog entry (How to stop HBV vertical transmission), several other recent articles add information about HBV vertical transmission:

  • Gastroenterology 2012; 142: 773-81.  Data from 2386 Taiwanese children born to HBsAg-positive mothers were examined.  HBeAg-positivity increased the likelihood of having an HBV-infected infant (9.26%) despite appropriate immunization & HBIG.  Since HBeAg-posiitivity is associated with higher HBV DNA levels, this is logical based on previous studies. Fulminant HBV developed in 1 of 1050 children who did not receive HBIG; in this study, the majority of mothers with HBeAg-negative HBV did not receive HBIG.
  • Pediatrics 2012; 129: 609-16.  This study examined HBV prevention in the U.S. from 1994-2008.  The CDC created the US Perinatal Hepatitis B Prevention Program (PHBPP) to accelerate progress at eliminating perinatal HBV transmission.  While the number of infants born to HBsAg-positive women with HBV increased from 19,208 to 25,600, the incidence of infants with chronic hepatitis B virus infection among tested infants decreased from 2.1% in 1999 to 0.8% in 2008.  This is due to the fact that 94.4% of PHBPP-managed infants received HBV vaccine and HBIG within 1 day of birth.  Yet, gaps remain.  The number of infants who completed the vaccine series by 12 months actually declined from 86% (1994) to 77.7% (2008). And, in 2008 only one-quarter of CDC’s 25,6000 infants born to HBsAg-positive women had known serologic outcomes.

Related previous post: Looking for trouble

How to stop HBV vertical transmission

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A review and a study this month help delineate a strategy to lower the rate of HBV transmission (Clin Gastro Hepatol 2012; 10: 452-59 & 520-526).  Overall, using HBIG and HBV vaccine within 12 hours of birth (followed by two additional doses of vaccines within 6-12 months) prevents about 95% of HBV transmission from HBsAg-positive mothers to their infants.  This has made a huge difference.  Yet, among mothers with high levels of viremia, HBV is still transmitted in 8-30%.  As such, this review proposes an algorithm to reduce mother to child transmission (MTCT).

The key risk factor is HBV DNA levels >200,000 IU/mL; the most effective way to reduce transmission from highly-viremic mother to infancts is the use of antiviral therapy.  The authors recommend that in addition to the usual preventive measures (HBIG/HBV vaccine within 12 hours of birth), that efforts to lower MTCT include use of either lamivudine (pregnancy category C), telbivudine (pregnancy category B), or tenofovir (pregnancy category B) at the 3rd trimester in the following:

  • Infected women with high HBV DNA levels
  • Infected women who have had children who have failed previous prophylaxis
  • Infected women with threatened pre-term labor

In addition, elective C-section should be considered if HBV DNA >20 million IU/mL at full term.

The second citation refers to an open-label prospective study of 88 HBe-Ag positive women.  All women had HBV DNA >6 log10 copies/mL and increased ALT.  Telbivudine (600 mg/day) was administered to 53 women starting between 12 and 30 weeks gestation; there were 35 control patients who all received HBIG/HBV vaccine.  In the treatment group, none of the infants developed HBV infection.  In the control group, the transmission rate was 8.6%.  No significant adverse effects were noted; specifically, no congenital malformations were noted.

Related blog entry/additional references: