S Kemme et al. JPGN 2021; 72: 194-201. Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series This small case series (n=4) with HAAA found that this condition was poorly responsive to steroids, azathioprine and tacrolimus; however, Anti-Thymocyte Globulin (ATG) was associated with sustained biochemical remission of the hepatitis. Two patients underwent hematopoietic stem cell transplantation. All patients had extensive investigations. All had evidence of systemic hyperinflammation (with markedly-elevated ferritin and soluble IL-2 R levels) and CD8+ T cell predominant liver tissue infiltration.
Workup: In the well and stable premature with elevated DB, “aminotransferases, AP, GGT, glucose, T4, TSH, UC, urine CMV PCR, and US with Doppler evaluation should be obtained…Coagulation studies in well babies with other evidence of good synthetic function are not necessary.” Empiric ursodeoxycholic acid may be given with weekly evaluation.
Genetic testing: “Genetic panels are indicated in babies with no obvious risk factors after the first tier of studies…In critically ill babies with multisystem disease, critical whole exome sequencing (WES) is faster and provides broader results.”
Sepsis: Babies with sudden increase in DB and ALT should be evaluated for sepsis (including urosepsis) and CMV.
Nutritional support: Infants should be “supported with MCT and vitamin supplementation.”
Severe liver disease: “Babies with coagulopathy and marked elevation of aminotransferases who have multiorgan failure in the first few days of life need to be evaluated for perinatal complications, severe metabolic disease, and gestational alloimmune liver disease (GALD). In this period, ischemic shock or infectious disease is much more common than primary liver disease, but the presentations can overlap.”
Liver biopsy: “Liver biopsy should be pursued in babies whose cholestasis is not improving and the diagnosis is unclear.”
Etiology: Infection, genetic disease, cardiac dysfunction, large heme loads, and hypothyroidism are common causes of liver dysfunction in the NICU. Common findings included trisomy 21-associated liver dysfunction (n=12), and thyroid disease. 6 patients had type 2 Abenathy shunts -only one required closure. Two patients had biliary atresia. Other liver diseases identified included GALD (n=2), PFIC2, Alagille, Alpha-one-antitrypsin, Cystic Fibrosis, and Niemann-Pick.
Wahid N et al. AASLD 2020, Abstract 153. Summary from GI & Hepatology News: Liver-related deaths decline after Medicaid-expansion under ACA. “Beginning around 2015, liver-related deaths began to decline in expansion states by a mean of –0.6%, while they continued on an upward trajectory in the nonexpansion states…“It’s a no-brainer that the lack of insurance accessibility for the most vulnerable people in the United States meant that they were dying of cirrhosis instead of being transplanted,” said Elliot Benjamin Tapper, MD, of the University of Michigan, Ann Arbor.”
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.
After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH
Deterioration of liver function (bilirubin, INR) after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.
The cumulative incidence of waitlist mortality was 5.2%. Median waitlist time was 83 days.
In multivariable analysis (n = 2253), increasing bilirubin level ( P < .001), portal vein thrombosis ( P = .03), and ventilator dependence ( P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing ( P = .009) was associated with a lower risk of waitlist mortality.
Two recent studies have suggested that tenofovir may be more effective for hepatitis B virus (HBV) infections.
T C-F Yip et al. Gastroenterol 2020; 158: 215-25.
J Choi et al. JAMA Oncol 2019; 5: 30-6. (Reviewed in a commentary by P Lampertico, M Colombo. Gastroenterol 2019; 157: 1682-88)
In the first retrospective study from Hong Kong, the authors analyzed 29,350 consecutive treated-patients (mean age 52.9 years). 1309 were treated with tenofovir disoproxil fumarate (TDV) and 28,041 were treated with entecavir. Key findings:
TDF-treated patients were younger (mean age 43.2 years vs. 53.4 years) and had less cirrhosis at baseline (2.9% vs. 13.6%).
After a median follow-up of 3.6 years, 8 TDF-treated patients (0.6%) and 1386 (4.9%) of entecavir-treated patients developed hepatocellular carcinoma (HCC). The authors note that TDF maintained a lower rate of HCC after propensity score weighting (hazard ratio of 0.36)
The second study was a nationwide population cohort database with >24,000 patients –all with ALT >80. Key finding:
HCC was significantly lower in TDF group than in the entecavir group, the percent person-years being 0.64 compared to 1.06; though, there was not a lower mortality rate or a lower liver transplantation rate.
The commentary associated with the latter study makes the following points:
Both TDF and entecavir could prevent “the incidence and mortality of HCC …in >85% of patients who received [them] for years.”
Studies comparing TDF and entecavir have come up with conflicting results. “Three studies in Korea, the U.S, and Europe reported no differences between NAs even after patient matching by a propensity score.”
“Cumulatively, all these studies deliver the reassuring message of a robust risk reduction of liver cancer taking place in patients with chronic hepatitis B who experience prolonged virus suppression after NA therapy, but currently they fail to provide convincing evidence that one NA is superior to the other one in determining such clinical benefit.”
My take: Tenofovir may be better but the answer is not definitive; due to lack of randomization, there may still be confounding variables in which sicker patients are receiving entecavir and this could be contributing to the difference in outcomes. Also, in patients with bone disease and renal impairment, tenofovir alafenamide (TAF) or entecavir is recommended.
P Rosenthal et al. Hepatology 2019; 69: 2326-37. This study examined the efficacy and safety of combined entecavir and Peginterferon for immune-tolerant chronic hepatitis B-infected children (n=60). 48 weeks after completing treatment (week 96), 2 children (3%) achieved the primary outcome of undetectable HBeAg with HBV DNA levels <1000 IU/mL. These two children were also HBsAg negative/anti-HBs positive. In the other children (55 completed study), the ALT and HBV DNA levels were similar to baseline. 37 children experienced adverse events. My take: Entecavir/peginterferon is not very effective in immune-tolerant children infected with chronic HBV.
DL Thomas. NEJM 2019; 380: 2041-50. This article reviews the pathway to the global elimination of chronic hepatitis. Currently, it is estimated that hepatitis C virus (HCV) and hepatitis B virus (HBV) kill more than 1 million persons each year. “In fact, by 2040, deaths from chronic hepatitis are projected to exceed the combined mortality associated with HIV infection, tuberculosis, and malaria.”
JR Dillman et al. J Pediatr 2019; 212: 60-5. This study with 41 patients and 13 patients with biliary atresia prospectively assessed ultrasound shear wave elastography (SWE). The authors found that SWE with a cut-off value of >1.84 m/s had 92% sensitivity and 79% specificity. Also, in their cohort, GGT >320 had a sensitivity of 100% and specificity of 78%.
Z Younossi et al. Hepatology 2019; 69: 2672-82. This review provides a global perspective of NAFLD. 25% of the world’s population is currently thought to have NAFLD with highest prevalence in South America at 30.45% and lowest in Africa at 13.5%. This article usggest North America to have 24.1% prevalence rate.
YH Yeo et al. Hepatology 2019; 69: 1385-97. The prevalence of high risk individuals in the U.S. who are susceptible (not immune) to hepatitis B has decreased from 83% to 69% from 2003 to 2014. That still leaves 64 million who would benefit from HBV vaccination.
M Sharma et al.Hepatology 2019; 69: 1657-75. This meta-analysis compared therapies for primary prevention of esophageal varices and concluded that nonselective beta-blocker (NSBB) monotherapy may decrease all-cause mortality and carried a lower risk of serious complications than variceal band ligation (VBL). However, the commentary (1382-84 by L Laine) reaches a different conclusion. “Current recommendations for primary prevention with VBL or NSBB or carvediolo still appear to be acceptable…using a shared decision-making approach” to weigh issue such as daily medication or periodic endoscopy.
J Nguyen et al. J Pediatr 2019; 207: 90-6. This study modeled the cost-effectiveness of early treatment with direct-acting antiviral therapy in adolescents with hepatitis C infection. With pangenotypic agenst, the cost would be $10000 to $21000 per QALY gained.
S Trinh et al. Clin Gastroenterol Hepatol 2019; 17: 948-56. This retrospective hepatitis B study examined the changes in renal function between 239 tenofovir disoproxil fumarte (TDF) treated patients and 171 entecavir treated patients. Key finding: TDF was not associated with higher risk of worsening renal function in this cohort with a mean followup of 43-46 months in patients with baseline normal renal function. In patients with renal impairment, deterioration of renal function was noted in TDF-treated patients. Thus, TDF should be avoided in patients with impaired renal function.
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.
The large randomized pediatric entecavir study for Hepatitis B virus (HBV) is now in print: MM Jonas et al. Hepatology 2016; 63: 377-87. Full link to this study on previous blog: Pediatric Entecavir Data This study has led to FDA approval for use of entecavir in children as young as 2 years. One interesting aspect of the study was the 2.6% drug resistance rate in the second year of the study. This further validates current recommendations to treat children with “immune active” phases (e.g. abnormal transaminases and abnormal histology).
H Roberts et al.Hepatology 2016; 63: 388-97. This study provides prevalence data for chronic HBV, 1988-2012. During 2011-12, there were approximately 850,000 Americans with chronic HBV infections. Migration of persons from HBV endemic countries has “largely contributed to prevalence rates remaining constant since 1999.”
JM Wilder et al. Hepatology 2016; 63: 437-44. This study showed that ledipasvir/sofosbuvir was similarly effective in black and non-black patients, with SVR12 rates of 95% and 97% respectively. This is important because older interferon-based treatments were much less effective in black patients.
TB Dick et al. Hepatology 2016; 63: 634-43. This review provides in-depth guidance regarding drug-drug interactions relevant to the new direct-acting antiviral agents used to treat Hepatitis C viral infection.
A recent post (New Hepatitis B Treatment Guidelines -AASLD) described the updated treatment recommendations. When these guidelines were published, a separate review devoted specifically to pediatrics was published (Hepatology 2016; 63: 307-18).
Some of the key points:
This pediatric review included 14 studies with 1425 children. The authors note that 7 of these trials had a high risk of bias. Also, the studies are limited by relying on surrogate markers of long-term outcomes as clinical outcomes like cirrhosis, HCC, and death are rare in childhood.
Among oral agents, entecavir and lamivudine are approved for use in children ≥ 2 years, whereas adefovir and tenofovir are approved for use in children ≥ 12 years. Both lamivudine and adefovir are associated with frequent development of viral resistance
For children with elevated ALT (>1.5 times upper limit of normal [ULN]), treatment is recommended:
9A. 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.
Why not treat everyone?
Children with immune-tolerant HBV infection (normal or near-normal ALT [< 1.5-2 times ULN] along with high HBV DNA [>10 million IU/mL]), “are not typically candidates for treatment because treatment with any of the currently available drugs has not been demonstrated to improve HBeAg seroconversion compared with no treatment.”
Children with ALT >10 time ULN may be in the process of spontaneous seroconversion “and should be observed for several months before treatment” is initiated.
“Prolonged treatment with nucleoside or nucleotide analogs in children who are in immune-tolerant phase has not been associated with substantial benefit and carries a risk of developing antiviral drug resistance…An exception may be those…undergoing immunosuppressive therapy.”
9A. 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.
“Most studies required ALT elevation (>1.3 times ULN) for at least 6 months with HBV DNA elevations for inclusion. Given that HBV DNA levels are typically very high during childhood (>106 IU/mL), there is no basis for a recommendation for a lower-limit value with respect to treatment. However, if a level <104 IU/mL is observed, therapy might be deferred until other causes of liver disease and spontaneous HBeAg seroconversion are excluded.”
“Duration of treatment with oral antivirals that has been studied is 1-4 years. It may be prudent to use HBeAg seroconversion as a therapeutic endpoint when oral antivirals are used, continuing treatment for an additional 12 months of consolidation, as recommended in adults. It is currently unknown whether a longer duration of consolidation would reduce rates of virological relapse.”
“Children who stop antiviral therapy should be monitored every 3 months for at least 1 year for recurrent viremia, ALT flares, and clinical decompensation.”
9B. The AASLD recommends against use of antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with persistently normal ALT, regardless of HBV DNA level.
Another nice summary of current treatment recommendations: P Martin et al. Clin Gastroenterol Hepatol 2015; 13: 2071-87. Table 5 lists recommendations for treatment of HBeAg-positive.
The main group needing treatment (entecavir, tenofovir, or PEGinterferon alfa-2a) are those with HBV DNA >2000 IU/mL and elevated ALT. Table 6 lists recommendations for those with HBeAg-negative. Main group needing treatment are the same (HBV DNA >2000 IU/mL and elevated ALT).
With both groups (HBe-Ag negative and positive), “consider liver biopsy or transient elastography” if elevated HBV DNA >2000 and normal ALT. If histologic disease present, consider treatment.
One point the authors make about therapy regards duration: “Historically, HBeAg seroconversion was considered a durable response, and discontinuation of antiviral therapy was recommended after a period of consolidation therapy of 6-12 months from the time of HBeAg seroconversion. However, patients who discontinue therapy …can experience recurrent viremia and ALT flares. Thus, long-term therapy is justified.”
For HBeAg negative patients who have compensated liver disease, loss of HBsAg for 6-12 months may be discontinued from therapy.
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
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.