Hepatitis B: Standard and Novel Treatment Options

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

ADV

adefovir dipivoxil

ALT

alanine aminotransferase

APASL

Asian Pacific Association for the Study of the Liver

CBC

complete blood count

cccDNA

covalently closed circular DNA

EASL

European Association for the Study of the Liver

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

IFN

interferon

LAM

lamivudine

NA

nucleos(t)ide analogue

PEG

pegylated

TAF

tenofovir alafenamide fumarate

TDF

tenofovir disoproxil fumarate

TSH

thyroid‐stimulating hormone

ULN

upper limit of normal

USTA

US Treatment Algorithm

The main goals of therapy for chronic hepatitis B virus (HBV) infection are to prevent the development of cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and death from HBV‐related liver disease.1 Despite decades of advancements in HBV therapy, a complete sterilizing cure with eradication of intrahepatic covalently closed circular DNA (cccDNA) and integrated HBV DNA remains unattained to this point. Instead, achieving a functional cure with undetectable hepatitis B surface antigen (HBsAg) and HBV DNA with HBsAb seroconversion, along with resolution of residual liver injury and a decrease in the risk for HCC, appears to be a tangible goal.1

The decision to treat chronic HBV is based on clinical assessments of liver disease and risk for disease progression. All current treatment guidelines recommend treating patients with evidence of acute liver failure, decompensated cirrhosis, or severe exacerbation of chronic HBV.2, 3, 4, 5 For patients who have not progressed to cirrhosis, treatment decision is based on the presence or absence of hepatitis B e antigen (HBeAg), HBV DNA level, and degree of alanine aminotransferase (ALT) elevation. The exact cutoff values for HBV DNA and definition of normal ALT vary according to different guidelines (Table 1). Notably, the American Association for the Study of Liver Diseases (AASLD) recommends using an upper limit of normal (ULN) for ALT as 35 U/L for men and 25 U/L for women, which might be different from ULNs from local laboratories.2 In 2008, a retrospective cohort analysis of 369 patients suggested that incorporation of serum albumin ≤3.5 mg/dL and platelet count ≤130,000/mm³ to the treatment criteria could substantially increase identification of patients at risk for serious liver complications or HCC.6 Additional patient‐specific factors such as age, family history of HCC, occupational risks, family planning, and personal preferences are taken into consideration as well.2

Table 1.

Overview of Chronic HBV Treatment Guidelines

Guideline	HBeAg Positive			HBeAg Negative
	HBV DNA, IU/mL	ALT	Liver Disease	HBV DNA, IU/mL	ALT	Liver Disease
AASLD (2018)	>20,000	≥2× ULNa	N/A	≥2000	≥2× ULN	N/A
	Detectable	N/A	Cirrhosis	Detectable	N/A	Cirrhosis
EASL (2017)	>2000	> ULN	Moderate inflammation or fibrosis	>2000	> ULN	Moderate inflammation or fibrosis
	>20,000	>2× ULN	N/A	>20,000	>2× ULN	N/A
	Detectable	N/A	Cirrhosis	Detectable	N/A	Cirrhosis
APASL (2016)	>20,000	>2× ULN	N/A	>2000	>2× ULN	N/A
	>2000	N/A	Compensated cirrhosis	>2000	N/A	Compensated cirrhosis
	Detectable	>2× ULN		Detectable	>2× ULN
	Detectable	N/A	Decompensated cirrhosis	Detectable	N/A	Decompensated cirrhosis
USTA (2015)	≥2000	> ULN	N/A	≥2000	> ULN	N/A
	Detectable	N/A	Cirrhosis	Detectable	N/A	Cirrhosis

^aULN (AASLD: 35 U/L for men and 25 U/L for women; EASL and APASL: 40 U/L).

Abbreviations: APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; N/A, Not Applicable; USTA, US Treatment Algorithm.

Currently, two classes of antiviral therapies have been approved for treatment of HBV: interferons (IFNs) and nucleos(t)ide analogues (NAs) (Table 2). IFN‐α was the first treatment approved for chronic HBV infection and has several mechanisms of action including decreased transcription of HBV pregenomic RNA, degradation of cccDNA, enhanced cell‐mediated immunity, and clearance of infected hepatocytes.7 Pegylated (PEG) IFN‐α is preferred over standard IFN‐α because of longer half‐life, less frequent dosing, and more sustained efficacy. The advantages of IFN therapy compared with NAs include a finite duration of treatment with higher rate of durable response and higher rates of HBeAg and HBsAg loss, especially in genotype A infection. However, IFN therapy is less effective at suppressing viral replication compared with NAs, requires parenteral administration, and is contraindicated in patients with pregnancy, decompensated cirrhosis, or severe exacerbations of hepatitis. Moreover, its use is further limited by adverse events including flu‐like symptoms, myelosuppression, worsening of underlying mood disorders, as well as exacerbation/unmasking of autoimmune diseases.7 Thus, IFN has not been widely used for HBV.

Table 2.

Approved HBV Therapies in Adults and Children

Drug	Dosage in Adults	Dosage in Children	Pregnancy Category	Potential Side Effects	Monitoring on Treatment
Preferred Agents
TAF	25 mg daily	N/A	B Insufficient human data on use during pregnancy	Lactic acidosis, nephrotoxicity, hepatotoxicity, pancreatitis	Creatinine, phosphate, urinalysis at baseline, then as clinically indicated; Liver function tests at baseline and for several months Lactic acid if clinical concern Test for HIV before treatment initiation
Entecavir (ETV)	0.5 or 1.0 mg daily	≥2 years: weight based to 10‐30 kg; >30 kg: 0.5 mg daily	C	Lactic acidosis	Lactic acid if clinical concern
TDF	300 mg daily	≥12 years: 300 mg daily	B	Nephropathy, Fanconi syndrome, osteomalacia, lactic acidosis	Creatinine clearance at baseline/annually If at risk for renal impairment, serum phosphate, urine glucose, protein at least annually Consider bone density study at baseline/during treatment Lactic acid if clinical concern Test for HIV before treatment initiation
PEG‐IFN‐2a	180 μg weekly	N/A	C	Adults: flu‐like symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders Children: anorexia and weight loss	CBC (every 1‐3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications
Not Recommended
LAM	100 mg daily	≥2 years: 3 mg/kg daily to maximum 100 mg	C	Pancreatitis Lactic acidosis	Amylase/lipase, lactic acid if clinical concern
Telbivudine	600 mg daily	N/A	B	Creatine kinase elevations and myopathy Peripheral neuropathy Lactic acidosis	Creatine kinase, lactic acid, nerve conduction study if clinical concern
ADV	10 mg daily	≥12 years: 10 mg daily	C	Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus Lactic acidosis	Creatinine clearance at baseline/annually If at risk for renal impairment, serum phosphate, urine glucose, protein at least annually Consider bone density study at baseline/during treatment Lactic acid if clinical concern
IFN‐a‐2b	N/A	≥1 year: 6 million IU/m2 three times per week	C	Adults: flu‐like symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders Children: anorexia and weight loss	CBC (every 1‐3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications

Abbreviations: CBC, complete blood count; TSH, thyroid‐stimulating hormone.

NAs target the viral polymerase reverse transcriptase domain and currently are the only approved class of direct‐acting small‐molecule antiviral drugs against HBV.1, 2, 8 This class includes lamivudine (LAM), telbivudine, entecavir (ETV), adefovir dipivoxil (ADV), tenofovir disoproxil fumarate (TDF), and the very recently approved tenofovir alafenamide fumarate (TAF).1, 8 Overall, NAs are administered orally, have negligible adverse effects, and can be used in decompensated cirrhosis or acute liver failure, which make them preferred over PEG‐IFN in most cases. However, the requirement for indefinite therapy in many cases is associated with concerns regarding long‐term costs, risk for nonadherence, and adverse effects.2

ETV and TDF have higher potency and relatively low frequency of resistance compared with the other NAs, and they are both recommended as first‐line therapies.2 Due to well‐documented cross‐resistance between ETV and LAM, ETV is not preferred as first line in patients with prior treatment exposure to LAM. The rate of ETV resistance can increase up to 51% after 5 years of ETV treatment in LAM‐resistant HBV, compared with 1.2% in treatment‐naive patients.9 Since its approval in 2008, TDF has demonstrated potent antiviral activity with no resistance throughout 8 years of use, and it has become the preferred agent in the setting of LAM or ETV resistance. Several recent randomized controlled trials have shown that TDF monotherapy provides similar antiviral efficacy in patients with drug‐resistant HBV when compared with the combination of TDF and ETV.10 However, long‐term therapy with TDF has been associated with development of renal dysfunction, decreased bone mineral density, and Fanconi‐like syndrome.10, 11, 12, 13

TAF, the newest approved agent in the class of NAs, is a prodrug of tenofovir designed to have greater plasma stability compared with TDF, thereby allowing for more efficient delivery to target cells at a substantially lower dose.11, 12 Given at a dose of 25 mg, TAF results in circulating concentrations of tenofovir about 90% lower compared with the standard 300 mg dose of TDF, which offers the potential for an improved safety profile. Recently, two multicenter, double‐blinded, phase 3, noninferiority studies comparing TAF with TDF in patients with HBeAg‐positive and HBeAg‐negative chronic HBV both showed that TAF was noninferior to TDF in suppressing viral replication and normalizing ALT, with significantly better outcomes on bone mineral density and renal function after 48 weeks of treatment (Table 3).11, 12 Furthermore, patients who were switched to TAF after 96 weeks of TDF therapy were found to have significant improvement in their creatinine clearance and bone mineral density 48 weeks after the switch, while maintaining high rates of virological control and ALT normalization.13 Notably, patients with decompensated cirrhosis or significant renal impairment (estimated glomerular filtration rate <50 mL/min) were not assessed in these studies, so TAF is currently approved only for patients with compensated cirrhosis (Child‐Pugh class A).11, 12 Nevertheless, TAF has become one of the recommend first‐line agents for HBV.

Table 3.

Outcomes of Multicenter, Double‐Blinded, Phase 3, Noninferiority Studies Comparing TAF with TDF in HBeAg‐Positive and HBeAg‐Negative Patients

	HBeAg‐Positive11				HBeAg‐Negative12
	TAF 25 mg (n = 581)	TDF 300 mg (n = 292)	Difference in Proportions (95% CI)	P	TAF 25 mg (n = 285)	TDF 300 mg (n = 140)	Difference in Proportions (95% CI)	P
HBV DNA <29 IU/mL	371 (64%)	195 (67%)	−3.6% (−9.8 to 2.6)	0.25	268 (94%)	130 (93%)	1.8% (−3.6 to 7.2)	0.47
HBeAg loss	78/565 (14%)	34/285 (12%)	1.8% (−3.0 to 6.5)	0.47	N/A	N/A	N/A	N/A
HBeAg seroconversion	58/565 (10%)	23/285 (8%)	2.1% (−2.0 to 6.3)	0.32	N/A	N/A	N/A	N/A
HBsAg loss	4/576 (1%)	1/288 (<1%)	0.4% (−1.1 to 1.8)	0.52	0	0	0	–
HBsAg seroconversion	3/576 (1%)	0	0.5% (−0.7 to 1.7)	0.22	0	0	0	–
ALT normalization (by central laboratory normal range)	384/537 (72%)	179/268 (67%)	4.6% (−2.3 to 11.4)	0.18	196/236 (83%)	91/121 (75%)	8.0% (−1.3 to 17.2)	0.076
ALT normalization (by AASLD normal range)	257/572 (45%)	105/290 (36%)	8.7% (1.8‐15.6)	0.014	137/276 (50%)	44/138 (32%)	17.9% (8.0‐27.7)	0.0005

HBV has a complex life cycle involving viral proteins and host factors, which are potential targets of therapeutic intervention. A wide range of next‐generation direct antiviral agents with distinct mechanisms are currently in development, which include viral entry inhibitors, transcription inhibitors, inhibitors of viral RNase H, modulators of capsid assembly, inhibitors of HBsAg secretion, RNA interference gene silencers, and antisense oligonucleotides.8 Compounds that exert antiviral activities through host factors and immunomodulation, such as host targeting agents, programmed cell death protein 1/programmed death ligand‐1 inhibitors, and Toll‐like receptor agonists, are also being studied.8