Breakthroughs and challenges in the management of pediatric viral hepatitis

Table 1 Pediatric studies of different combinations of direct-acting antivirals

Drug regimen	Age range in yr	Sample size	Genotype(s)	Number of patients with SVR12, %	Ref.
Sofosbuvir/ledipasvir	12-17	100	1	98/100 (98)	Balistreri et al[25]
	6-11	92	1, 3, 4	91/92 (99)	Murray et al[26]
	3-5	34	1, 4	33/34 (97)	Schwarz et al[27]
Sofosbuvir plus ribavirin	12-17	52	2, 3	51/52 (98)	Wirth et al[33]
	6-11	41		41/41 (100)	Rosenthal et al[34]
	3-5	13		12/13 (92)	Rosenthal et al[34]
Sofosbuvir/velpatasvir	12-17	102	1, 2, 3, 4	97/102 (95)	Sokal et al[35]
	6-11	73		68/73 (93)	Sokal et al[35]
	3-5	41		34/41 (83)	Sokal et al[35]
Glecaprevir/pibrentasvir	12-17	47	1, 2, 3, 4	47/47 (100)	Jonas et al[36]
	6-11	32		31/32 (97)	Jonas et al[37]
	3-5	16		15/16 (96)	Jonas et al[37]
Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin	12-17	38	1, 4	38/38 (100)	Leung et al[134]
	6-11	26	1	25/26 (95)	Rosenthal et al[135]
Elbasvir/grazoprevir	12-17	22	1, 4	22/22 (100)	Wirth et al[136]
	6-11	17		17/17 (100)	Wirth et al[136]
	3-5	18		18/18 (100)	Wirth et al[136]
Sofosbuvir/velpatasvir/voxilaprevir	12-17	21	1, 2, 3, 4	21/21 (100)	Bansal et al[137]
Sofosbuvir plus daclatasvir	15-17	13	4	13/13 (100)	El-Sayed et al[138]
	13-17	10		10/10 (100)	El-Shabrawi et al[139]
	12-17	30		29/29 (100)	Yakoot et al[140]
	8-17	40	1, 4	39/39 (100)	Abdel Ghaffar et al[141]
	7-13	14	3	14/14 (100)	Padhi et al[57]

SVR12: Sustained virological response 12 wk after the end of treatment.

Table 2 Direct-acting antiviral regimens approved for treatment of chronic hepatitis C virus infection in children and adolescents

Regimen	Genotype and duration of treatment	Formulations	Dosage
Sofosbuvir/ledipasvir	GT 1, 4, 5, 6: 12 wk	Tablet (FDC) 400/90 mg	> 35 kg: 400/90 mg/d
	GT 1, treatment-experienced, cirrhosis: 24 wk		17-35 kg: 200/45 mg/d
			< 17 kg, older than 3 yr of age: 150/33.75 mg/d
		Tablet (FDC) 200/45 mg
		Pellets 200/45 mg and 150/33.75
Sofosbuvir + ribavirin	GT 2: 12 wk	Sofosbuvir: tablet 400 mg	Sofosbuvir: > 35 kg: 400 mg/d
	GT 3: 24 wk		17-35 kg: 200 mg/d
		Tablet 100 mg	< 17 kg, older than 3 yr of age: 200 mg if ≥ 17 kg
		Capsules 50 mg containing granules
			150 mg/d if < 17 kg. Ribavirin: 15 mg/kg per day in two divided doses
Sofosbuvir/velpatasvir	All GTs: 12 wkdecompensated cirrhosis: 12 wk + ribavirin	Tablet (FDC) 400/100 mg	> 30 kg: 400/100 mg/d
			17-30 kg, older than 6 yr of age: 200/50 mg/d. Ribavirin: 15 mg/kg per day in two divided doses
		Tablet (FDC) 200/50 mg
Glecaprevir/pibrentasvir	All GTs: 8 wk	Tablet (FDC) 100/40 mg/d	12-17 yr or > 45 kg: 300/120 mg/d
	All GTs, cirrhosis: 12 wk
	GT 3 treatment-experienced: 16 wk

FDC: Fixed-dose combination; GT: Genotype.

Table 3 Antiviral drugs approved for adolescents and children with chronic hepatitis B virus infection

Drug	Use in children	Dose	Formulation
Interferon-α-2b	≥ 1 yr	6 million IU/m2 3 times a week	Subcutaneous injections
Pegylated interferon-α-2a	≥ 3 yr	180 µg/1.73 m2 once a week	Subcutaneous injections
Lamivudine	≥ 3 yr	3 mg/kg daily (max 100 mg)	Oral solution (5 mg/mL)
			tablets (100 mg)
Entecavir	≥ 2 yr	10-30 kg: 0.015 mg/kg daily (max 0·5 mg)	Oral solution (0.05 mg/mL)
			tablets (0.5 mg and 1 mg)
Adefovir	≥ 12 yr	10 mg daily	Tablets (10 mg)
Tenofovir disoproxil fumarate	≥ 12 yr (FDA)	300 mg daily	Oral powder (40 mg per 1 g)
	≥ 2 yr (EMA)		tablets (150, 200, 250 and 300 mg)
Tenofovir alafenamide	≥ 12 yr (EMA)	25 mg daily	Tablets (25 mg)

EMA: European Medicines Agency; FDA: Food and Drug Administration.

Table 4 Summary of results of clinical trials of hepatitis B antiviral therapy in children

	Interferon-α-2b	Lamivudine	Adefovir	Tenofovir DF	Entecavir	Pegylated interferon-α-2a
Number treated	144	191	173	52	120	101
Duration of treatment in wk	24	52	48	72	48	48
Age, median (range)	5 (1-17)	9 (2-17)	11	15.5 (12-17)	12 (2-17)	11 (3-7)
Virological response as HBeAg negative HBV DNA undetectable (% treated vs placebo)	26 (vs 11)	23 (vs 13)	10.6 (vs 0)	21.2 (vs 0)	24.2 (vs 3.3)	19.8 (vs 2)
HBsAg negative (% treated vs placebo)	10 (vs 1)	2 (vs 0)	0.8 (vs 0)	1.9 (vs 0)	5.8 (vs 0)	8.9 (0)
Ref.	Sokal et al[97]	Jonas et al[98]	Jonas et al[99]	Murray et al[100]	Jonas et al[101]	Wirth et al[102]

HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen.

Table 5 Investigational drugs for chronic hepatitis B infection

Class	Compound	Mechanism	Known side effects	Route	Status	Ref.
Entry inhibitors	Bulevirtide	Blocks entry via interaction with NTCP	Injection site reactions, cholestasis	Subcutaneous (iv)	Approved for CHD (HBV/HDV) Phase II for HBeAg-CHB	European Association for the Study of the Liver[117] and Bogomolov et al[118]
Capsid assembly modulators	JNJ-56136379	Prevents encapsidation of pgRNA Prevents formation of cccDNA	Hypertransaminasemia	Oral	Phase II for CHB ± NA	Zoulim et al[105]
Capsid assembly modulators	ABI-H0731 (Vebicorvir)	Prevents packaging of pgRNA into capsids	Skin rash, dizziness	Oral	Phase II for CHB ± NA	Yuen et al[106]
HBsAg secretion inhibitors	REP-2139	Inhibits the secretion of HBsAg subviral particles	Fever, chills, hypertransaminasemia, leukopenia	iv	Phase II for CHB + NA Phase II for CHD + peg-IFN-α	Bazinet et al[109,110]
HBsAg secretion inhibitors	REP-2165	Inhibits the secretion of HBsAg subviral particles	Fever, chills, hypertransaminasemia, leukopenia	iv	Phase II for CHD + peg-IFN-α	Bazinet et al[110]
RNA interference	JNJ-3989	Silences the mRNA viral transcripts reducing HBsAg	-	iv	Phase II for CHB	Yuen et al[111] and Gane et al[112]
RNA interference	VIR-2218	Silences the mRNA viral transcripts reducing HBsAg	-	iv	Phase II for CHB	VIR Biotechnology[113]
RIG-1 agonist	Inarigivir (SB9200)	Activates PRR RIG-1 and IFN-I response	Headache, dizziness, UTI, ILI, GI symptoms, hypertransaminasemia	Oral	Phase II for CHB + NA	Yuen et al[114]
Immune modifier	Selgantolimod (GS-9688)	TLR8 agonist	Nausea, vomiting, chills, headache, UTI	Oral	Phase II for CHB + NA	Gane et al[116]

CHB: Chronic hepatitis B; CHD: Chronic hepatitis D; GI: Gastrointestinal.; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; ILI: Influenza-like illness; NA: Nucleotide analogue; peg-IFN-: Pegylated interferon α; UTI: Urinary tract infection.