Management of Chronic Hepatitis B: An Overview of Practice Guidelines for Primary Care Providers

Steven-Huy Han; Tram T. Tran

doi:10.3122/jabfm.2015.06.140331

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Figure 1.
Treatment algorithm for patients with chronic hepatitis B (CHB) who have hepatitis B e antigen (HBeAg)–positive disease (A), HBeAg-negative disease (B), or cirrhosis (C). The strength of all recommendations is A (based on guidelines for management of CHB from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver^10–12). Alanine aminotransferase (ALT) upper limit of normal (ULN): 19 IU/mL in women, 30 IU/mL in men. Sensitive real-time polymerase chain reaction (PCR): lower limit of detection, ∼5-10 IU/mL; lower limit of quantification, ∼30 IU/mL. *See the text for definition of patients at high risk of hepatocellular carcinoma (HCC). ETV, entecavir; HBV, hepatitis B virus; Peg-IFN-α, pegylated interferon-α; TDF, tenofovir.

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Table 1. Characteristics and Clinical Prognosis of the Different Phases of Chronic Hepatitis B Infection

CHB Phase	Serum HBV DNA (IU/mL)	HBeAg	Anti-HBeAg	HBsAg, log₁₀ (IU/mL)	ALT^*	Liver Disease	Precore/Core Promoter HBV Variant	Age (Years)	Prognosis
Immune tolerant	>2 × 10^6–7	+	−	4.5–5.0	Normal	None/minimal	WT	<20–25	No or minimal liver disease development as long as ALT remains normal
Immune clearance (HBeAg-positive disease)	2 × 10^4–5	+	−	3.0–4.5	Persistently or intermittently elevated (>2× ULN), ALT flares possible (>5× ULN)	Possible necroinflammation; may lead to fibrosis or cirrhosis if HBeAg-positive phase is prolonged	WT > mutant	20–40	Favorable prognosis if HBeAg seroconversion occurs (inactive carrier state) The shorter the duration of the immune clearance phase, the better the prognosis and the lower the risk of liver disease development or progression
Inactive carrier	<2 × 10³	−	+	1.5–3.0	Normal	Necroinflammation may disappear; halt of any liver disease progression	WT > mutant (stable inactive carriers)	>35–40	Favorable prognosis, unless advanced fibrosis/cirrhosis has developed during the HBeAg-positive phase
Inactive carrier	<2 × 10³	−	+	1.5–3.0	Normal		Mutant > WT (patients who will undergo reactivation)	>35–40
Reactivation (HBeAg-negative disease)	Fluctuating, >2 × 10^3–4	−	+	2.5–4.0	Persistently or intermittently elevated	Advanced	Mutant >> WT	>35–40	May lead to fibrosis progression or cirrhosis

Data compiled from Liaw et al,¹¹ Liaw,²² and Kwon and Lok.²³
↵* Alanine aminotransferase (ALT) upper limit of normal: 19 IU/mL in women, 30 IU/mL in men.
CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; ULN, upper limit of normal; WT, wild type.

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Table 2. Summary of Anti–Hepatitis B Virus Treatment Indications as Recommended by Major Practice Guidelines

	Practice Guidelines
	AASLD¹⁰	APASL¹¹	EASL¹²
HBeAg-positive	∙ HBV DNA >20,000 IU/mL ∙ ALT >2× ULN ∙ No spontaneous HBeAg seroconversion after 3–6 months' observation	∙ HBV DNA ≥20,000 IU/mL ∙ ALT ≥2× ULN	∙ HBV DNA >20,000 IU/mL ∙ ALT >2× ULN
	∙ HBV DNA >20,000 IU/mL ∙ ALT ≤2× ULN ∙ Moderate or worse liver inflammation or significant fibrosis (on biopsy^*)	∙ HBV DNA ≥20,000 IU/mL ∙ ALT ≥1 to <2× ULN ∙ Moderate or worse liver inflammation or fibrosis (on biopsy or noninvasive fibrosis assessment^*)	∙ HBV DNA >2000 IU/mL ∙ ALT >1× ULN ∙ Moderate or worse liver inflammation or moderate fibrosis (using a standardized scoring system^{^†})
	∙ HBV DNA >2000 IU/mL ∙ Cirrhosis	∙ HBV DNA ≥2000 IU/mL ∙ Advanced fibrosis/cirrhosis	∙ Detectable HBV DNA ∙ Cirrhosis
HBeAg-negative	∙ HBV DNA >20,000 IU/mL ∙ ALT >2× ULN	∙ HBV DNA ≥2000 IU/mL ∙ ALT >2× ULN	∙ HBV DNA >20,000 IU/mL ∙ ALT >2× ULN
	∙ HBV DNA >2000 IU/mL ∙ ALT ≥1–2× ULN ∙ Moderate or worse liver inflammation or significant fibrosis (on biopsy)	∙ HBV DNA ≥2000 IU/mL ∙ ALT ≥1 to <2× ULN ∙ Moderate or worse liver inflammation or fibrosis (on biopsy or noninvasive fibrosis assessment^*)	∙ HBV DNA >2000 IU/mL ∙ ALT >1× ULN ∙ Moderate or worse liver inflammation or moderate fibrosis
	∙ HBV DNA >2000 IU/mL ∙ Cirrhosis	∙ HBV DNA ≥2000 IU/mL ∙ Advanced fibrosis/cirrhosis	∙ Detectable HBV DNA ∙ Cirrhosis

↵* Assessment of liver disease is recommended if the patient is 40 years or older.
↵† Assessment of liver disease is recommended if the patient is 30 years or older. Biopsy is to be considered in patients of older age and/or with fluctuating/minimally elevated alanine aminotransferase (ALT) concentrations or family history of hepatocellular carcinoma.
AASLD, American Association for the Study of Liver Diseases; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ULN, upper limit of normal.

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Table 3. Recommendations for the Management of Chronic Hepatitis B Infection in Special Patient Populations

Patient Population	Key Issues	Recommendations
Decompensated liver disease^*	∙ Higher risk of cirrhosis, HCC, and mortality ∙ Often associated with comorbidities such as renal dysfunction, protein malnutrition, or vitamin deficiencies	∙ Treatment is indicated irrespective of HBV DNA levels to improve clinical status ∙ Recommended agents: ETV and TDF (well tolerated and shown to improve liver status) ∙ Regular monitoring of renal function and lactic acidosis recommended during ETV or TDF therapy ∙ IFNs contraindicated; they may increase risk of sepsis and decompensation
HCV, HDV, or HIV coinfection	∙ Multiple viruses to be managed ∙ Higher risk of cirrhosis, HCC, and mortality	∙ Treatment should target the dominant virus ∙ In HIV coinfection, LVD and TDF are active against both HBV and HIV; ETV is not recommended unless the patient also receives HAART ∙ Peg-IFN only drug effective against HDV ∙ Some reports of renal toxicity with TDF in HBV/HIV-coinfected patients
LT recipients	∙ Risk of HBV reactivation	∙ Anti-HBV prophylaxis before and/or after LT recommended ∙ HBIg with or without LVD historically is the most common approach; however, there is no consensus on HBIg dose and duration (that is, long-term low dose vs. short-term high dose; HBIg withdrawal; on-demand HBIg on NUC maintenance) ∙ Alternative prophylactic regimens: ETV or TDF, alone or combined with HBIg
Immune-suppressive or chemotherapy	∙ Risk of HBV reactivation	∙ In HBsAg-positive patients, preemptive NUC therapy should be initiated at the onset of immunesuppressive or chemotherapy to prevent HBV reactivation ∙ In anti-HBc-positive patients receiving rituximab, anti-HBV prophylaxis is recommended
Pregnancy	∙ Risk of perinatal infection from highly viremic mothers ∙ Risk of fetal damage	∙ IFN-based therapy is contraindicated because of its antiproliferative effect ∙ LdT and TDF are classified as category B (no risk in animal studies but unknown in humans) ∙ LVD, ADV, and ETV are classified as category C (teratogenic in animals, unknown in humans)
Pediatric patients	∙ Infection at an early age is associated with an increased risk of long-term complications ∙ Long-term safety and drug resistance are important concerns	∙ Recommended to initiate treatment if ALT persistently >2× ULN ∙ IFNs given parenterally and associated with temporarily disrupted growth⁴³

Data compiled from refs. 10–12.
↵* Defined as child B or C cirrhosis, or Child–Turcotte–Pugh score ≥7.
ADV, adefovir; ALT, alanine aminotransferase; ETV, entecavir; HAART, highly active antiretroviral therapy; HBc, hepatitis B core antigen; HBIg, hepatitis B immunoglobulin; HBsAg, hepatitis B s antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; IFN, interferon; LdT, telbivudine; LT, liver transplant; LVD, lamivudine; NUC, nucleo(s)tide analog; Peg-IFN, pegylated interferon; TDF, tenofovir; ULN, upper limit of normal.

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Table 4. Approved Treatments for Chronic Hepatitis B

Agent (Trade Name)	Route	Class	Dosage		Duration	Resistance	Side Effects
Agent (Trade Name)	Route	Class	Adults	Children	Duration	Resistance	Side Effects
Interferons
Interferon α-2b (Intron A)	Subcutaneous	—	5 × 10⁶ IU daily or 10 × 10⁶ IU 3 times weekly	3 × 10⁶ IU/m², 3 times weekly, up to a maximum of 10 × 10⁶ IU weekly^*	HBeAg-positive: 16−24 weeks HBeAg-negative: 48 weeks	—	Influenza-like symptoms, fatigue, headache, malaise, emotional lability (anxiety, irritability)
Pegylated-interferon α-2a (Pegasys)^{^†}	Subcutaneous	—	180 μg weekly	Not indicated in patients <18 years old	48 weeks	—
Nucleo(s)tide analogs
ETV (Baraclude)^{^†}	Oral	NUC	0.5 mg daily in NUC-naïve patients^{^‡} 1.0 mg daily in LVD-experienced patients^{^‡} (≥16 years old)	Indicated for patients aged ≥2 years and weighing ≥10 kg Patients ≤30 kg: weight-based dosing of oral solution LVD-naïve: 3–9 mL daily LVD-experienced: 6–18 mL daily Patients >30 kg LVD-naïve: 10 mL (0.5 mg) solution or one 0.5-mg tablet daily LVD-experienced: 20 mL (1 mg) solution or one 1-mg tablet daily	≥1 year HBeAg-positive: until HBeAg seroconversion^* with maintained undetectable HBV DNA (plus ≥6–12 months' consolidation therapy) HBeAg-negative: until maintained undetectable HBV DNA (plus ≥6–12 months' consolidation therapy)	1% at year 5	Negligible
TDF (Viread)^{^†}	Oral	NUC	300 mg daily^{^‡} (patients ≥12 years)	Not indicated for patients <12 years old		None up to year 5	Potential nephrotoxicity
LdT (Tyzeka; Sebivo)	Oral	NUC	600 mg daily^{^‡} (patients ≥16 years)	Not indicated for patients <16 years old		17% at year 2	Negligible
ADV (Hepsera)	Oral	NUC	10 mg daily^{^‡} (patients ≥12 years)	Not indicated for patients <12 years old		29% at year 5	Potential nephrotoxicity
LVD (Epivir, Zeffix)	Oral	NUC	100 mg daily^{^‡}	Patients aged 2–17 years: weight-based dosing, oral solution or tablets; 3 mg/kg daily (maximum 100 mg daily)^*		24% at year 1 70% at year 5	Negligible

Data compiled from Lok and McMahon,¹⁰ European Association for the Study of the Liver clinical practice guidelines,¹² US prescribing information for Baraclude (Bristol-Myers Squibb, 2014); Viread (Gilead Biosciences, 2013); Tyzeka (Novartis, 2013); Hepsera (Gilead Biosciences, 2012); Epivir (ViiV Healthcare, 2013); Pegasys (Genentech/Roche, 2014); and Intron A (Merck, 2011).
↵* Use in pediatric patients approved in the United States but not in the European Union. Hepatitis B e antigen (HBeAg) loss and anti-HBe-positivity on 2 occasions 1–3 months apart.
↵† Recommended first-line agents.
↵‡ Dose adjustment is required in patients with impaired renal function (creatinine clearance <50 mL/min).
ADV, adefovir; ETV, entecavir; HBV, hepatitis B virus; LdT, telbivudine; LVD, lamivudine; NUC, nucleo(s)tide analog; TDF, tenofovir.