Viral hepatitis: A narrative review of hepatitis A–E

Table 1 Approved antivirals for adults and children for chronic hepatitis B

Drug	Adult dosing	Pediatric dosing	Potential side effects	Pregnancy category
Peg-IFN-a-2a (adult) IFN-a-2b (children)	180 mcg wkly	> 1 yr dose: 6 million IU/m2 three times wkly	Flu-like symptoms, fatigue, mood disturbances, cytopenia, autoimmune disorders in adults, anorexia, and weight loss in children	C
Entecavir	0.5 mg daily	> 2 yr dose: weight-based to 10-30 kg; above 30 kg: 0.5 mg daily	Lactic acidosis (decompensated cirrhosis only)	C
Tenofovir dipovoxil fumarate	300 daily	> 12 yr	Fanconi syndrome, osteomalacia, lactic acidosis	B
Tenofovir alafenamide	25 mg daily	-	Lactic acidosis	There are insufficient human data on use during pregnancy to inform a drug-associated risk of birth defects and miscarriage
Lamivudine	100 mg daily	2 yr dose: 3 mg/kg daily to max 100 mg	Pancreatitis lactic acidosis	C
Adefovir	10 mg daily	12 yr	Acute renal failure Fanconi syndrome lactic acidosis	C
Telbivudine	600 mg daily	-	Creatine kinase elevation and myopathy peripheral neuropathy lactic acidosis	B

Table 2 Drugs in pipeline for hepatitis B virus

drug class	Drug	Company	Phase
Core protein inhibitors	AB-506	Arbutus Biopharma	1
	ABI-H0731	Assembly Biosciences	1,2
	ABI-H2158	Assembly Biosciences	1
	EDP-514	Enanta Pharmaceuticals	1
	JNJ-6379	Johnson & Johnson	1,2
	JNJ-0440	Johnson & Johnson	1
	RO7049389	Roche	1
siRNA, antisense RNA	AB-729	Arbutus Biopharma	1
	DCR-HBVS	Dicerna Pharmaceuticals	1
	GSK/IONIS-HBV-LRx	Ionis/GlaxoSmithKline	1,2
	IONIS-HBVRx	Ionis/GlaxoSmithKline	1,2
	JNJ-3989 (ARO-HBV)	Johnson & Johnson	1,2
	RO7062931	Roche	1
	Vir-2218 (ALN-HBV02)	Vir Biotechnology/Alnylam	1
pol/RT inhibitor	Tenofovir exalidex	ContraVir Pharmaceuticals	1,2
HBsAg secretion inhibitors	REP-2139	Replicor	1,2
	REP-2165	Replicor	1,2
HBV entry inhibitor	Bulevirtide	Hepatera Ltd	1,2
TLR-7 agonists	AL-034	Johnson & Johnson/Alios	1
	RG-7854	Roche	1
	RO7020531	Roche	1
TLR-8 agonist	GS-9688	Gilead Sciences	1,2
Therapeutic vaccines	AIC-649	AiCuris	1
	INO-1800	Inovio Pharmaceuticals	1
	TG1050	Transgene	1
RIG-I and NOD2 agonist	Inarigivir	Spring Bank	1,2
Apoptosis inducer	APG-1387	Ascentage Pharma	1
FXR agonist	EYP-001	Enyo Pharma	1,2

HBV: hepatitis B virus; HBsAg: Hepatitis B surface antigen; TLR: Toll-like receptor.

Table 3 DAA therapy in pediatric population

Regimen	Patient population	Duration (wk)
Genotype 1
Ledipasvir/sofosbuvir	Prior exposure to DAA and IFN (± ribavirin) , no cirrhosis	12
	Prior exposure to DAA and IFN (± ribavirin) , compensated cirrhosis	24
Glecaprevir/pibrentasvi	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an NS5A inhibitor but no NS3/4A protease inhibitor exposure, no cirrhosis, compensated cirrhosis	16
	Age ≥ 12 yr or weighing ≥ 45 kg with prior exposure to NS3/4A protease inhibitors but no NS5A inhibitor exposure, no cirrhosis, compensated cirrhosis	12
	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, with compensated cirrhosis	12
	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, without cirrhosis	8
Genotype 2
Glecaprevir /pibrentasvir	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, without cirrhosis	8
	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, compensated cirrhosis	12
Genotype 3
Glecaprevir/pibrentasvir	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, no cirrhosis or compensated cirrhosis	16
Genotype 4
Glecaprevir/pibrentasvir	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, compensated cirrhosis	12
	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, no cirrhosis	8
Ledipasvir/sofosbuvir	Age ≥ 3 yr with prior exposure to an IFN (± ribavirin) plus an HCV protease inhibitor regimen, no cirrhosis or compensated cirrhosis	12
Genotype 5
Ledipasvir/sofosbuvir	Age ≥ 3 yr with prior exposure to an IFN (± ribavirin) plus an HCV protease inhibitor regimen, no cirrhosis or compensated cirrhosis	12
Glecaprevir/pibrentasvir	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, no cirrhosis	8
	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, with compensated cirrhosis	12
Genotype 6
Glecaprevir/pibrentasvir	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, no cirrhosis	8
	Age ≥ 12 yr or weight ≥ 45 kg with prior exposure to an IFN-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors, with compensated cirrhosis	12
Ledipasvir/sofosbuvir	Age ≥ 3 yr with prior exposure to an IFN (± ribavirin) plus an HCV protease inhibitor regimen, no cirrhosis, compensated cirrhosis	12

DAA: Direct-acting antiviral; IFN: Interferon; HCV: Hepatitis C virus.

Table 4 DAA therapy for chronic hepatitis C virus

Regimen	Patient population	Duration (wk)
Genotype 1
Daclatasvir + sofosbuvir	Decompensated cirrhosis regardless of subtype	12
	HIV/HCV coinfection when antiretroviral regimen cannot be made to accommodate recommended regimens	12
Elbasvir/grazoprevir	Treatment naive or Peg/RBV experienced regardless of cirrhosis	12
	Severe renal impairment (CKD stage 4/5)	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Glecaprevir/pibrentasvir	Treatment naive or Peg/RBV experienced without cirrhosis	8
	Treatment naive or Peg/RBV experienced with cirrhosis, and non-NS5A failures (including NS3) regardless of cirrhosis	12
	Post liver transplant without cirrhosis	12
	Severe renal impairment (CKD stage 4 or 5)	8–12
	Post kidney transplant regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Ledipasvir/sofosbuvir	Treatment naive regardless of cirrhosis	12
	Treatment naive, no cirrhosis, non-black, HIV negative, and HCV RNA <106 IU/mL	8
	Peg/RBV (± NS3 protease inhibitor) experienced without cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/RBV (± NS3 protease inhibitor) experienced	12
	Decompensated cirrhosis, prior sofosbuvir failure only	24
	Post liver transplant regardless of cirrhosis or decompensation	12
	Post kidney transplant regardless of cirrhosis	12
Sofosbuvir/velpatasvir	Treatment naive or Peg/RBV ± NS3 protease inhibitor experienced regardless of cirrhosis	12
	GT1b, non-NS5A DAA experienced regardless of cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/RBV (± NS3 protease inhibitor) experienced	12
	Decompensated cirrhosis, DAA failure (including NS5A)b	24
Sofosbuvir/velpatasvir/voxilaprevir	NS5A failures (including NS3 protease inhibitor) regardless of cirrhosis	12
	GT1a, non-NS5A failures (including NS3 protease inhibitors) regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Genotype 2
Daclatasvir + sofosbuvir	Decompensated cirrhosis	12
	Post liver transplant regardless of cirrhosis or decompensation	12
Glecaprevir/pibrentasvir	Treatment naive or Peg/RBV experienced without cirrhosis	8
	Treatment naive or Peg/RBV experienced with cirrhosis, and sofosbuvir failures regardless of cirrhosis	12
	Post liver transplant without cirrhosis	12
	Severe renal impairment (CKD stage 4 or 5)	8–12
	Post kidney transplant regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Sofosbuvir/velpatasvir	Treatment naive, or Peg/RBV or non-NS5A experienced regardless of cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/RBV or non-NS5A experienced	12
	Decompensated cirrhosis, DAA failure (including sofosbuvir ± NS5A)b	24
	Post liver transplant with decompensated cirrhosis	12
Sofosbuvir/velpatasvir/voxilaprevir	NS5A failures	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Genotype 3
Daclatasvir + sofosbuvir	Decompensated cirrhosis	12
	Post liver transplant regardless of cirrhosis or decompensation	12
Glecaprevir/pibrentasvir	Treatment naive without cirrhosis	8
	Treatment naive with compensated cirrhosis	12
	Post liver transplant without cirrhosis	12
	Severe renal impairment (CKD stage 4 or 5)	8–12
	Post kidney transplant regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Sofosbuvir + elbasvir/grazoprevir	Peg/RBV experienced with compensated cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Sofosbuvir/velpatasvir	Treatment naive without cirrhosis	12
	Treatment naive with cirrhosis or Peg/RBV experienced without cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/ RBV experienced	12
	Decompensated cirrhosis, previously exposed to DAA (including sofosbuvir ± NS5A)b	24
	Post liver transplant with decompensated cirrhosis	12
Sofosbuvir/velpatasvir/voxilaprevir	Peg/RBV experienced with cirrhosis, or DAA failure (including NS5A inhibitors) regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Genotype 4
Daclatasvir + sofosbuvir	Decompensated cirrhosis	12
	HIV/HCV coinfection when antiretroviral regimen cannot be made to accommodate recommended regimens	12
Elbasvir/grazoprevir	Treatment naive or Peg/RBV experienced with prior relapse, regardless of cirrhosis	12
	Severe renal impairment (CKD stage 4/5)	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Glecaprevir/pibrentasvir	Treatment naive or Peg/RBV experienced without cirrhosis	8
	Treatment naive or Peg/RBV experienced with cirrhosis	12
	Post liver transplant without cirrhosis	12
	Severe renal impairment (CKD stage 4 or 5)	8–12
	Post kidney transplant regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
	Treatment naive regardless of cirrhosis or Peg/RBV experienced without cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/ RBV experienced	12
	Decompensated cirrhosis, sofosbuvir failure	24
	Post liver transplant regardless of cirrhosis or decompensation	12
	Post kidney transplant regardless of cirrhosis	12
Sofosbuvir/velpatasvir	Treatment naive or Peg/RBV experienced regardless of cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/ RBV (± NS3 protease inhibitor) experienced	12
	Decompensated cirrhosis, DAA failure (including NS5A)	24
Sofosbuvir/velpatasvir/voxilaprevir	NS5A failures (including NS3 protease inhibitors) regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Sofusbuvir/ledipasvir	Treatment naive, compensated cirrhosis – not for decompensated cirrhosis	12
Genotype 5 or 6
Glecaprevir/pibrentasvir	Treatment naive or Peg/RBV experienced without cirrhosis	8
	Treatment naive or Peg/RBV experienced with cirrhosis	12
	Post liver transplant without cirrhosis	12
	Severe renal impairment (CKD stage 4 or 5)	8–12
	Post kidney transplant regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis
Ledipasvir/sofosbuvir	Treatment naive or Peg/RBV experienced regardless of cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/ RBV experienced	12
	Decompensated cirrhosis, sofosbuvir failure	24
	Post liver transplant regardless of cirrhosis or decompensation	12
Sofosbuvir/velpatasvir	Treatment naive or Peg/RBV experienced regardless of cirrhosis	12
	Decompensated cirrhosis, treatment naive or Peg/RBV (± NS3 protease inhibitor) experienced	12
	Decompensated cirrhosis, DAA failure (including NS5A)	24
Sofosbuvir/velpatasvir/voxilaprevir	NS5A failures (including NS3 protease inhibitors) regardless of cirrhosis	12
	Not for decompensated cirrhosis or post liver transplant with cirrhosis

Adapted from American Association for the Study of Liver Diseases/IDSA guidelines (https://www.hcvguidelines.org/). CKD: Chronic kidney disease; DAA: Direct-acting antiviral; HIV: Human immunodeficiency virus; HCV: Hepatitis C virus; RBV: Ribavirin; Peg: Pegylated interferon.

Table 5 Novel drug treatments for chronic hepatitis D virus

Drug	Mode of action	Administration route	Phase of study	Adverse effect
Myrcludex B	Interferes with hepatitis D virus entry into hepatocyte	Subcutaneous, daily for 6 mo	Ib, IIa	Lipase and amylase elevation in phase I but not in phase II study
	Through sodium taurocholate cotransporting	± pegylated interferon (Peg-IFN)		Elevation of taurine- and glycine-conjugated bile acids without apparent clinical consequences
	polypeptide inhibition			Thrombocytopenia, neutropenia, lymphopenia, and eosinophilia: Generally mild, transient
Lonafarnib	Farnesyltransferase inhibitor, inhibits virion assembly	Oral, 2 to 12 mo, ± ritonavir	II	Gastrointestinal toxicity (anorexia, nausea with or without vomiting, diarrhea, weight loss): Dose dependent and in lower dose cohorts generally mild and well tolerated
		± peg-IFN
Rep-2139-Ca	Nucleic acid polymer, binds with high affinity to	Intravenous infusion, once wkly	II	Hair loss, dysphagia, anorexia, dysgeusia, in hepatitis B study: Related to heavy metal exposure at the trial site
	Amphipathic proteins, which are required at various	for 4-6 mo ± peg-IFN		Administration route-related side effects: peripheral grade 1 hyperemia, fever, chills, and headache
	Stages of the viral life cycle

IFN: Interferon.