Tag Archives: hepatitis B

Sorting Out Discrepancies in Hepatitis B Testing

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A recent study (J Pediatrics 2014; 165: 773-8) highlighted the clinical problem of discrepant hepatitis B virus (HBV) testing in pregnant women.

Design: The Centers for Disease Control and Prevention analyzed a nonrandom sample of discordant cases of HBV reported by US Perinatal Hepatitis B Prevention Program.  Discordant cases indicated that there were differences between an initial HBsAg result and a subsequent test.  Among 142 cases, 89 had sufficient information to determine accuracy of the initial test.

Key finding: 14 (15.7%) of these cases were true positives, the remainders were false-positives.

How did authors sort out cases?

Negative testing for “total anti-HBc or no detectable HBV DNA result indicating no HBV infection…A positive total anti-HBc indicates current or past HBV infection, is not elicited by vaccination, and usually persists for life.”

Pointers regarding serology:

  • IgM anti-HBc -acute or recent infection and can persist for more than 6 months.
  • HBV DNA confirms active infection and can detect infection at levels below those of HBsAg assays.  This can occur either due to “occult HBV infection” or due to a mutant HBV strain that results in non-reactive test for HBsAg.
  • There were at least 11 HBsAg assays that have been FDA-approved –most but not all of them will confirm results before reporting.

It is important to sort out patients with discrepant HBV serology.  In infants who are not identified with HBV testing (false-negatives), this results in suboptimal post exposure prophylaxis and increased likelihood of chronic HBV.  Whereas, infants with false-positive results, incur unnecessary prophylaxis and costs.  The authors note that “total anti-HBc was the most useful single test to resolve HBsAg discrepancies.

Also noted: J Pediatr 2014; 165: 767-72.  “Factors Affecting the Natural Decay of Hepatitis B Surface Antigen in Children with Chronic Hepatitis B Virus Infection during Long-Term Followup”  This study followed 349 Taiwanese children over 20 years and noted annual HBsAg clearance of 0.58% (42 cleared HBsAg).  Spontaneous clearance was more common in HBeAg-seroconverters, infants with low initial HBsAg level <1000 IU/mL, and to those born to non-HBsAg-carrier mothers.

Clinical Science Year in Review in Pediatric GI – NASPGHAN 2014

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For many participants at NASPGHAN, the “year in review” presentations are a highlight.  This year was no exception.

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

William Balistreri –Clinical Science Year in Review 

Lay press remains excellent source of information.

Benefit of microbiome. (from NPR) Now there is elephant poop coffee -$645/lb ($70/cup).  Link: No. 1 Most Expensive Coffee Comes From Elephant’s No. 2 : The ... Collecting elephant poop is probably a less ideal job than what most of us have.  As for coffee, “make mine de-crap.”

Elephant Microbiome Collector

Topic of the year: Hepatitis C

  • 25 years since identification of Hepatitis C in 1989
  • Now approaching cure (Related blog post: Wiping out Hepatitis C | gutsandgrowth). All-oral highly effective regimen –newest regimen as easy as one pill per day for 8-12 weeks. Direct-acting antivirals (DAAs). Moving past 1st generation of DAAs: telaprevir/boceprevir with interferon/ribavirin.(refs = Pawlotsky, Gastroenterology 146:1176, 2014 and Schmidt, Clinical Gastroent Hepatol 12:728, 2014)
  • New drugs for HCV –just in time –increasing risk of HCV complications. Ann Intern Med 2014; 160: 293.
  • Goal –SVR –sustained virological response
  • Reviewed large number of articles: Sofosbuvir, Simeprevir, Sofosbuvir/Ledipasvir (Harvoni).  3-D regimen: ABT-450, ABT-267, ABT-333 –will be approved in coming weeks (Related blog post:Have You Heard of Harvoni? | gutsandgrowth)
    • Gane, NEJM 368:34, 2013
    • Zeuzem, NEJM 370:1993,2014
    • Kowdley, N Engl J Med 370:1879, 2014
    • Lawitz, Lancet 383:515, 2014
    • Feld, New England Journal of Medicine, 370:1594, 2014
  • Mild side effects with newer drug therapies
  • Awaiting pediatric studies.
  • Costly $1000/pill –“if dog swallows it,” may have to look for it in the stool
  • Stay updated with recommendations: www.hcvguidelines.org  (AASLD/IDSA)

Hepatitis B –success of vaccination.

  • Preventing perinatal transmission with HBIG/vaccine. JAMA 2013; 310: 974. Those born after 1984, with much lower HCC. Ann Intern Med 2014; 160: 828; Hepatology 2014; 60: 448
  • Give antivirals (eg. telbivudine) for HBeAg-positive mothers prior to delivery. (Related blog post: Hepatology Update -Summer 2014 | gutsandgrowth) Greenup, Journ of Hepatology 61:502, 2014 AND Zhang, Hepatology 60:468, 2014
  • Antiviral therapy lowers the risk of HCC. Hepatology 2014; 147: 143 (Wu et al).
  • Make sure children with IBD are being screened for hepatitis B. ~13% may not be immune. Moses, Am J Gastro 107:133, 2012

Trend of the Year: Social Media

  • Genome sequencing –tremendous advance. Families may push for this option on their own.
  • Magnets –banned. Social media allowed this problem to be quickly identified. (Related blog post: Buckyball Recall –It’s Official | gutsandgrowth)
  • Social media allows family to share information and get answers. Internet blogging allows families to reach out to scientists.
    • Schumacher, Pediatrics 133:e1345, 2014
    • Enns, Genetics in Medicine, March 2014
  • BiliCam –can take picture with mobile phones.

Biliary Atresia

Threat of the Year: Obesity along with NAFLD

  •  NAFLD can have significant liver histologic abnormalities even with normal ALT levels. J Pediatr 2014; 164: 707.
  • Clinical burden of NAFLD is not restricted to liver-related morbidity or mortality Armstrong, HEPATOLOGY 59:1174, 2014. Also, concern for obstructive sleep apnea and cardiovascular disease.  Sundaram, J Pediatr 164:699, 2014. Pacifico, HEPATOLOGY 59:461, 2014
  • Elastography is promising tool. Xanthakos, J Peds 164:186, 2014
  • Current treatment –lifestyle changes. Snacking contributes to fatty liver. Sleep curtailment is associated with obesity. Spaeth. SLEEP 36:981, 2013, Taveras, Pediatrics 133:1013, 2014, Mitchell, Pediat 131:e1428, 2013
  • Increased antibiotics in early life associated with obesity due to alteration of microbiome. Bailey, JAMA Pediatrics, Sept 29, 2014
  • Suggestion for future: “Diet Water.”

Diet Water.jpg

For those who want to learn more from Dr. Balistreri directly, I would recommend the Aspen Conference:

Aspen Meeting

Related link: Dr. Balistreri’s Review of the Growth and Development of the Pediatric Gastroenterology Specialty.

 

Don’t Give Up Too Soon (with Hepatitis B treatment)

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A recent study shows that ongoing treatment with entecavir is usually effective in “primary nonresponders” (Hepatology 2014; 59: 1303-10).

This study retrospectively reviewed a study with 1254 treatment-naive patients who received entecavir (ETV) 0.5 mg/day for >6 months. Only 16 (1.28%) patients were considered “primary nonresponders.”  The latter was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD or <1 log drop after 3 months by EASL.

Key findings:

  • The probability of achieving a virologic response (HBV DNA <15 IU/mL) was 95.8% at 54 months among these “nonresponders”
  • Primary nonresponders did not have ETV resistance; however, 13 (1%) of the entire cohort developed ETV resistance.
  • In this treatment cohort, the 5-year cumulative risk of hepatocellular carcinoma (HCC) was 2.5%.  Previous studies have shown that HBV suppression lowers the risk of HCC.

Take-home message: 

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.

 

Liver Update: Headlines and Links Only

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  1. From AGA: Hepatic failure flagged as unexpected boceprevir safety signal in adverse event review. GI & Hep News: http://ow.ly/rSCEF 
  2. From NY Times: Spike in Harm to Liver Is Tied to Dietary Aids nyti.ms/JPN9fK 
  3. From Jeff Schwimmer (The Liver Post): First case report of Liver Cancer in a child with Nonalcoholic Fatty Liver Disease. He is only 7 years-old. http://goo.gl/6dJbzs 
  4. “Recurrence of Hepatopulmonary Syndrome Post-Orthotopic Liver Transplantation in a Patient with Noncirrhotic Portal Hypertension” Hepatology 2013; 58: 2205-06.
  5. “Management of Hepatitis B: Our Practice and How It Relates to the Guidelines” Clin Gastroenterol Hepatol 2014; 12: 16-26.  Terrific review and insights.
  6. “Acute Liver Failure” NEJM 2013; 369: 2525-34.
  7. “Cesarean Section Reduces Perinatal Transmission of Hepatitis B Virus Infection from Hepatitis B Surface Antigen-Positive Women to Their Infants” Clin Gastroenterol Hepatol 2013; 11: 1349-55. Retrospective, nonrandomized study -“performing elective cesarean section only in highly viremic mothers with pre-delivery HBV DNA levels ≥1,000,000 copies/mL may be advisable.”

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Liver fibrosis in determining treatment for Hepatitis B

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A recent editorial reviews current guidelines and makes the point that while patients with advanced fibrosis should receive antiviral treatment, treatment is also recommended for patients with high levels of HBV DNA and active liver disease (Clin Gastroenterol Hepatol 2013; 11: 1500-02).  The related study (Clin Gastroenterol Hepatol 2013; 11: 1493-99) indicated that guidelines do not predict accurately which patients have ≥F2 fibrosis.  The editorial argues that the study’s conclusions are “misguided” because ALT and HBV DNA are not used solely for identifying patients with fibrosis.

Key points:

  • 18-47% of HBV-related HCC occurs in the absence of cirrhosis.
  • Guidelines “agree that treatment should be initiated in non-cirrhotic patients with serum HBV DNA >20,000 IU/mL and alanine aminotransferase (ALT) levels higher than 2 times upper limit of normal (ULN) or histologic evidence of moderate-to-severe inflammation or fibrosis.”
  • For HBeAg-negative patients, AASLD guidelines suggest a lower threshold for HBV DNA (>2000 IU/mL) along with ALT >2 times ULN or ALT 1-2 times ULN with concerning liver biopsy (particularly in age >40 years).
  • “Since treatment does not eradicate the virus…and in many instances [is] lifelong treatment, we agree with Sanai et al that criteria for initiating hepatitis B treatment in guidelines must be carefully weight to avoid unnecessary treatment.”

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Do antivirals lower the risk of Hepatocellular Carcinoma in HBV?

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Meaningful endpoints of therapy are often difficult to demonstrate in clinical studies due to the length of followup that may be needed.  For patients infected with hepatitis B virus (HBV), most clinical studies use surrogate biologic, virologic and histologic markers rather than endpoints like hepatocellular carcinoma (HCC) and death.  In addition, long-term randomized trials with untreated controls are difficult to justify given the success of current treatments in improving these surrogate markers.

A recent Japanese study (Hepatology 2013; 58: 98-107 and editorial pg 18) reports data on a large entecavir-treated cohort (n=472) which was matched with a historical control (retrospective control group, n=1143).  The authors used propensity score matching to eliminate any baseline differences.

Findings:

  • Cumulative incidence of HCC rate at 5 years was 3.7% (for entecavir group) and 13.7% (for controls)
  • Using regression analysis and adjusting for known HCC risk factors, patients treated with entecavir had a hazard ratio of 0.37 for developing HCC.
  • Patients with more risk factors for HCC (eg. older, more active disease, cirrhosis) obtained greater benefit from entecavir treatment (shown in Figure 4 in manuscript)
  • The authors also showed that entecavir-treated patients also had less risk of developing HCC than lamivudine-treated patients
  • Entecavir-treated patients had low rates of resistance (0.8%) at 3.2 years of treatment

Take-home message: suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC.  In noncirrhotic patients, the magnitude of risk reduction is less.  Thus, patients with active disease should be treated.

Causes of Death with Hepatitis B in U.S.

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A recent study followed 6,689 patients with hepatitis B virus (HBV) between 1996-2005 and analyzed causes of death (Hepatology 2013; 58: 21-30, editorial pg 6). This study used a large prospectively-collected database.

The patients were all part of Kaiser Permanente Northern California health plan.  Patients were not eligible if they were coinfected with HIV or HCV.  Causes of death were divided into HBV-related (eg. decompensated cirrhosis [DCC], hepatocellular carcinoma [HCC]) and other causes, including cancer and cardiovascular.

Among this cohort, 68.3% were Asian-Pacific Islander (API) descent, and 11.8% were white (non-hispanic); the remainder were other or unknown descent.  The cohort had a mean age of 41 years.

Findings:

  • Males had higher overall 10-year death rates than females for total deaths (8.9% versus 4.1%) and for HBV-related deaths (4.8% versus 1.2%).
  • 46.7% of all deaths were HBV-related.
  • Death rate rose with increasing age; approximately 40% of deaths after age 40 were HBV-related.
  • Among HBV-related deaths, the death rate from HCC was twice the rate of DCC
  • “We did not find that subjects of API descent origin were at higher risk of death from HBV-related complications.”  This was unexpected because presumably “they are often infected in childhood and therefore have disease of longer duration.”
  • Limitations included absence of data on alcohol, cigarettes and coffee.  In addition, the study period occurred when treatment options for HBV were more limited.

The accompanying editorial notes wide variability in mortality outcome data depending on the study setting.   “Studies in patients with incidentally detected HBV infection, mostly conducted in blood donors in Western countries, tend to portray a benign course…with…their incidence of complications of chronic liver disease, HCC, or liver-related mortality is not significantly higher than that in hepatitis B surface antigen-negative healthy controls.”  In China, the lifetime risk for an infected patient to die from an HBV-related cause “has been estimated to be up to 50% in men and 15% in women.”

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Looking at the Tenofovir Data Another Way

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In last Friday’s post, this blog reviewed 5-year data on tenofovir usage which showed that tenofovir could reverse fibrosis/cirrhosis.  Another study using the same cohort examined the efficacy of tenofovir in patients with high viral load (HVL) at baseline (Hepatology 2013; 58: 505-13).

From an initial total of 641 patients enrolled in GS-US-174-0102 (n=375) and GS-US-174-0103 (n=266), the authors identified 129 (20%) with HVL.  HVL was defined as having ≥9 log10 copies/mL.  After an initial 48 weeks of randomization between tenofovir (HVL n=82) or adefovir (HVL n=47), patients received an additional 192 weeks of therapy with tenofovir in an open label extension.

Results:

  • By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL
  • High HVL patients took longer to achieve undetectable HBV DNA, but by week 96 the results were similar in both groups
  • Patients who received tenofovir during the initial 48 weeks achieved undetectable HBV DNA quicker than those who had received adefovir initially
  • There were similar rates of histologic regression in both HVL and non-HVL patients

This study evaluated only patients in the ‘immune clearance’ phase of HBV and therefore cannot be extrapolated to those in the immune tolerant phase.

Changing the Outcome for Hepatitis B

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Much of hepatology relies on surrogate markers to convey whether treatments are effective.  For hepatitis B virus (HBV), some of these markers include serology (eg. development of HBV e antibody), improvements in biochemistry (eg. transaminases) as well as histology.  Of these, improved histology is likely to have the most bearing on clinical outcomes like progression to end-stage liver disease and hepatocellular carcinoma.  A previous study of lamivudine has indicated that regression of fibrosis can reduce the rate of hepatocellular carcinoma (NEJM 2004; 351: 1521-31).

As such, the results of long-term use of agents like tenofovir have been awaited.  Since tenofovir along with entecavir are considered 1st line agents, their use has become commonplace for the treatment of HBV.  Now 5-year data are available in a large cohort (Lancet 2013; 381: 468-75).

The data from this study was derived from an open-label cohort that followed 48-week double-blind comparison trials. 489 patients completed 240 weeks of treatment.  348 patients had biopsy results available at baseline and at week 240.

Key findings:

  • 304 (87%) of those with biopsies at study completion had histologic improvement.
  • 176 (51%) had regression of fibrosis
  • 71 of 96 (74%) who had cirrhosis at baseline no longer had cirrhosis (≥1 unit decrease in Ishak fibrosis score)
  • 3 of 252 without cirrhosis at baseline progressed to cirrhosis at week 240
  • No evidence of resistance to tenofovir was evident.  Nearly all patients on tenofovir had undetectable HBV DNA
  • Adverse safery events were rare

As with all studies looking at liver histology, there were limiting factors including potential sampling errors and variable interpretation.  The authors sought to minimize this by using an independent pathologist.   Another strength of the study was the broad range of patients to make these findings broadly applicable.

Take-home message: Tenofovir treatment for 5 years is safe and effective.  Long-term suppression of HBV can lead to regression of fibrosis and reversal of cirrhosis.

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