Eliminating viral hepatitis in children after liver transplants: How to reach the goal by 2030

Table 1 Risk factors of de novo hepatitis B infection in children after liver transplantation

Risk factors
Positive anti-HBc donor[40]
Positive-intrahepatic HBV DNA[40]
Liver graft HBV DNA > 1000 copies[40]
Intraoperative fresh-frozen plasma transfusion > 400 mL[40]
Positive-anti-HBc recipients[40]
Pre-operative anti-HBs < 1000 mIU/mL[40,43,48]
Post-operative anti-HBs < 100-200 mIU/mL[48,53]
Hepatitis B surface mutation (within the “a” determinant region[54])

Anti-HBc: Hepatitis B core antibody; anti-HBs: Hepatitis B surface antibody.

Table 2 Antiviral agents for hepatitis B infection in children[44]

Medication	Licensing	Dose and duration	HBsAg loss (%)	Resistance (%)
IFN-α-2b	≥ 1 yr	6 million IU/m2 three times weekly for 6 mo	1-2	0
Lamivudine	≥ 2 yr	3 mg/kg daily for ≥ 1 yr	0	19-64
Entecavir	≥ 2 yr	0.25-0.5 mg daily for ≥ 1 yr	0.52	0.7-1.2
Tenofovir dipovaxil fumarate	≥ 12 yr	300 mg daily for ≥ 1 yr	0.02	0
Adefovir	≥ 12 yr	10 mg daily for ≥ 1 yr	0	0.9-20

HBsAg: Hepatitis B surface antigen.

Table 3 Recommended direct-acting antiviral regimens for children who are naïve to or experienced with direct-acting antiviral therapy[101,102]

Age	Genotype	No cirrhosis/ cirrhosis	Recommended regimens of DAAs	Duration (wk)
12-17 yr	Pan-genotypes	No cirrhosis	Sofosbuvir 400 mg/ velpatasvir 100 mg	12
		Compensated cirrhosis (Child-Pugh A)	Glecaprevir 300 mg/pibrentasvir 120 mg	8-12
12-17 yr or BW ≥ 35 kg	1, 4, 5, 6	No cirrhosis	Sofosbuvir 400 mg/ledipasvir 90 mg	12
		Compensated cirrhosis (Child-Pugh A)	Sofosbuvir 200 mg/velpatasvir 50 mg (BW ≥ 17 kg)
3-11 yr	Pan-genotypes	No cirrhosis	Sofosbuvir 150 mg/velpatasvir 37.5 mg (BW < 17 kg)	12
		Compensated cirrhosis (Child-Pugh A)	Glecaprevir 250 mg/pibrentasvir 100 mg (BW 30-44 kg); Glecaprevir 200 mg/pibrentasvir 80 mg (BW 20-29 kg); Glecaprevir 150 mg/pibrentasvir 60 mg (BW 12-19 kg)	12; 8-16; 8-16; 8-16;

BW: Body weight.

Table 4 Studies of children infected with hepatitis E virus after liver transplantation

Ref.	Year	Country	Participants	Seroprevalence of HEV infection	Methods		Comments
					HEV IgM/G	HEV RNA
1[130]	2012	Canada	Gr 1; N: 66 with normal LFT, aged 13.7 yr (1.8-25.5); Gr 2; N: 14 with transaminitis, aged 17.4 yr (5.9-19.8)	Gr 1: 10/66 (15%) with IgG +, none had IgM, HEV RNA +; Gr 2: 12/14 (86%) with IgG+; 9/12 (75%) with IgM+; 1/12 (0.8%) with HEV RNA +	Feldan Bio Inc, Saint-Augustin	Serum nested RT-qPCR	All in Gr 2 showed a trend toward chronic hepatitis and fibrosis; An 8-yr-old girl had chronic HEV infection (genotype 3) for > 10 yr and developed cirrhosis
2[131]	2012	Germany	N: 41 liver-transplanted children, aged 8.8 ± 4.2 yr	2/41 (4.9%) IgG +0/41 stool HEV RNA +	Mikrogen	Stool RT-qPCR	No case with chronic HEV infection
3[132]	2013	Germany	N: 22 liver-transplanted children, aged 6.7 yr (1.4-17.2)	1/22 (0.45%) IgG + by Wantai assay and HEV RNA + in serum	Wantai assay	Serum or stool PCR	10-year-old boy with HEV infection that had persistent transaminitis after 2-mo immunosuppressive reduction. Ribavirin 15 mg/kg/d was started for 6 mo. Normal LFT and undetectable serum and stool HEV RNA at day 42 of treatment.
4[139]	2014	Brazil	One liver-transplanted child: case report	HEV IgG/IgM and HEV RNA in serum and liver tissue at 6-10 yr after liver transplantation	Mikrogen	Liver and serum RT-PCR	A 4-yr-old girl with transaminitis from ACR at 6 yr after LT, had transaminitis off and on and HEV IgG/IgM and HEV RNA was detected 9-10 yr after LT. Chronic HEV infection was successful treatment with ribavirin for 10 mo.
5[133]	2015	France	84 liver-transplanted children, aged 12.3 yr	8/84 (8.3%) HEV IgG+	Wantai assay	Ceeram Tools® kit for HEV-RNA detection	None had HEV IgM/RNA +; No case of chronic infection
6[140]	2020	France	80 liver-transplanted children, aged 3.5 ± 4 yr	6/80 (8%) with HEV IgG+	Wantai assay	Ceeram Tools® kit for HEV-RNA detection	None had HEV IgM/RNA +; No case of chronic infection; 4/6 had undetectable HEV IgG after follow-up (3-42 mo)
7	2021	Thailand	30 liver-transplanted children with transaminitis, aged 1.2-17.6 yr	14/30 (45.2%) with HEV IgG+, 4 (13%) with HEV IgM+ and one case with HEV RNA in stool	Euroimmun kit	Stool PCR	All of them had persistence of HEV IgM from 5 to 44 mo and transaminitis from 4 to 30 mo before HEV testing. The previous treatment included graft rejection, de novo autoimmune hepatitis and CMV viremia.

Ref: Reference; Gr: Group; RT-qPCR: Real-time polymerase chain reaction; HEV: Hepatitis E virus; ACR: Acute cellular rejection; MP: MP Biomedicals, formerly Genelabs Diagnostics, Singapore; Wantai assay: Wantai Biologic Pharmacy Enterprise, Beijing, China; LT: Liver transplantation; CMV: Cytomegalovirus.

Table 5 Diagnostic tests for hepatitis E infection[144,145]

Detection	Technique	Specimen
Virus or its components (direct method)	HEV nucleic acid: (1) RT-PCR; (2) Realtime RT-PCR; and (3) Loop-mediated isothermal amplification assay. HEV RNA: (1) In situ hybridization; (2) HEV viral protein (antigen); (3) EIA; and (4) IHC.	Serum, stool, bile, liver tissue
Host immune response (indirect method)	Specific anti-HEV antibodies (IgM and IgG) (sensitivity 72%-98% and specificity 78%-96%): (1) Indirect EIA; (2) Immunochromatographic assays; (3) Double-antigen sandwich-based EIAs; (4) μ capture EIAs for IgM anti-HEV; (5) Specific cellular immune response; and (6) ELISpot assays.	Serum, peripheral blood mononuclear cells

HEV: Hepatitis E virus; RT-PCR: Reverse transcription polymerase chain reaction; ELISpot: Enzyme-linked immune absorbent spot; EIA: Electroimmunoassay; IHC: Immunohistochemistry.