Abstract
Potential conflict of interest: Dr. Hwang received grants from Merck and Gilead. Dr. Chang advises Arbutus. Dr. Lok received grants from Gilead and Bristol‐Myers Squibb. Dr. Jonas consults for Gilead and received grants from Bristol‐Myers Squibb and Roche. Dr. Brown consults and received grants from Gilead. Dr. Bzowej received grants from Gilead, Allergan and Cirius. Dr. Terrault received grants from Gilead and Bristol‐Myers Quibb. Dr. Wong is a member of the United States Preventive Services Task Force (USPSTF). This article does not necessarily represent the views and policies of the USPSTF. The funding for the development of this Practice Guidance was provided by the American Association for the Study of Liver Diseases. This practice guidance was approved by the American Association for the Study of Liver Diseases on December 4, 2017. Purpose and Scope of the Guidance This AASLD 2018 Hepatitis B Guidance is intended to complement the AASLD 2016 Practice Guidelines for Treatment of Chronic Hepatitis B1 and update the previous hepatitis B virus (HBV) guidelines from 2009. The 2018 updated guidance on chronic hepatitis B (CHB) includes (1) updates on treatment since the 2016 HBV guidelines (notably the use of tenofovir alafenamide) and guidance on (2) screening, counseling, and prevention; (3) specialized virological and serological tests; (4) monitoring of untreated patients; and (5) treatment of hepatitis B in special populations, including persons with viral coinfections, acute hepatitis B, recipients of immunosuppressive therapy, and transplant recipients. The AASLD 2018 Hepatitis B Guidance provides a data‐supported approach to screening, prevention, diagnosis, and clinical management of patients with hepatitis B. It differs from the published 2016 AASLD guidelines, which conducted systematic reviews and used a multidisciplinary panel of experts to rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development and Evaluation system in support of guideline recommendations.1 In contrast, this guidance document was developed by consensus of an expert panel, without formal systematic review or use of the Grading of Recommendations Assessment, Development, and Evaluation system. The 2018 guidance is based upon the following: (1) formal review and analysis of published literature on the topics; (2) World Health Organization guidance on prevention, care, and treatment of CHB5; and (3) the authors' experience in acute hepatitis B and CHB. Intended for use by health care providers, this guidance identifies preferred approaches to the diagnostic, therapeutic, and preventive aspects of care for patients with CHB. As with clinical practice guidelines, it provides general guidance to optimize the care of the majority of patients and should not replace clinical judgement for a unique patient. This guidance does not seek to dictate a "one size fits all" approach for the management of CHB. Clinical considerations may justify a course of action that differs from this guidance. Interim Data Relevant to the AASLD 2018 Hepatitis B Guidance Since the publication of the 2016 AASLD Hepatitis B Guidelines, tenofovir alafenamide (TAF) has been approved for treatment of CHB in adults. TAF joins the list of preferred HBV therapies, along with entecavir, tenofovir disoproxil fumarate (TDF), and peginterferon (peg‐IFN; Tables 1 and 2)6 (section: Updated Recommendations on the Treatment of Patients With Chronic Hepatitis B). Additionally, studies on the use of TDF for prevention of mother‐to‐child transmission led to TDF being elevated to the level of preferred therapy in this setting (section 1C of Screening, Counseling, and Prevention of Hepatitis B). Table 1 - Approved Antiviral Therapies in Adults and Children Drug Dose in Adultsa Use in Childrena Pregnancy Categoryb Potential Side Effectsb Monitoring on Treatmentc Preferred Peg‐IFN‐α‐2a (adult) IFN‐α‐2b (children) 180 mcg weekly ≥1 year dose: 6 million IU/m2 three times weeklyd C Flu‐like symptoms, fatigue, mood disturbances, cytopenia, autoimmune disorders in adults, anorexia and weight loss in children Complete blood count (monthly to every 3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications Entecavir 0.5 mg dailye ≥2 years dose: weight‐based to 10‐30 kg; above 30 kg: 0.5 mg dailye C Lactic acidosis (decompensated cirrhosis only) Lactic acid levels if there is clinical concern Test for HIV before treatment initiation Tenofovir dipovoxil fumarate 300 mg daily ≥12 years B Nephropathy, Fanconi syndrome, osteomalacia, lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and protein at least annually Consider bone density study at baseline and during treatment in patients with history of fracture or risks for osteopenia Lactic acid levels if there is clinical concern Test for HIV before treatment initiation Tenofovir alafenamide 25 mg daily — There are insufficient human data on use during pregnancy to inform a drug‐associated risk of birth defects and miscarriage. Lactic acidosis Lactic acid levels if clinical concern Assess serum creatinine, serum phosphorus, creatinine clearance, urine glucose, and urine protein before initiating and during therapy in all patients as clinically appropriate Test for HIV before treatment initiation Nonpreferred Lamivudine 100 mg daily ≥2 years dose: 3 mg/kg daily to max 100 mg C Pancreatitis Lactic acidosis Amylase if symptoms are present Lactic acid levels if there is clinical concern Test for HIV before treatment initiation Adefovir 10 mg daily ≥12 years C Acute renal failure Fanconi syndrome Lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and urine protein at least annually Consider bone density study at baseline and during treatment in patients with history of fracture or risks for osteopenia Lactic acid levels if clinical concern Telbivudine 600 mg daily — B Creatine kinase elevation and myopathy Peripheral neuropathy Lactic acidosis Creatine kinase if symptoms are present Clinical evaluation if symptoms are present Lactic acid levels if there is clinical concern aDose adjustments are needed in patients with renal dysfunction.bIn 2015, the U.S. Food and Drug Administration replaced the pregnancy risk designation by letters A, B, C, D, and X with more specific language on pregnancy and lactation. This new labeling is being phased in gradually, and to date only TAF includes these additional data.cPer package insert.dPeg‐IFN‐α‐2a is not approved for children with chronic hepatitis B, but is approved for treatment of chronic hepatitis C. Providers may consider using this drug for children with chronic HBV. The duration of treatment indicated in adults is 48 weeks.eEntecavir dose is 1 mg daily if the patient is lamivudine experienced or if they have decompensated cirrhosis.Abbreviation: TSH, thyroid stimulating hormone. Table 2 - Efficacy of Approved First‐Line Antiviral Therapies in Adults with Treatment‐Naïve Chronic Hepatitis B and Immune‐Active Disease (Not Head‐to‐Head Comparisons) HBeAg Positive Peg‐IFNa Entecavirb Tenofovir Disoproxil Fumarateb Tenofovir Alafenamidec % HBV‐DNA suppression (cutoff to define HBV‐DNA suppression)d 30‐42 (<2,000‐40,000 IU/mL) 8‐14 (<80 IU/mL) 61 (<50‐60 IU/mL) 76 (<60 IU/mL) 73 (<29 IU/mL) % HBeAg loss 32‐36 22‐25 — 22 % HBeAg seroconversion 29‐36 21‐22 21 18 % Normalization ALT 34‐52 68‐81 68 — % HBsAg loss 2‐7 11 (at 3 years posttreatment) 4‐5 8 1 HBeAg Negative Peg‐IFN Entecavir Tenofovir Disoproxil Fumarateb Tenofovir Alafenamidec % HBV‐DNA suppression (cutoff to define HBV‐DNA suppression)e 43 (<4,000 IU/mL) 19 (<80 IU/mL) 90‐91 (<50‐60 IU/mL) 93 (<60 U/mL) 90 (<29 IU/mL) % Normalization ALTf 59 78‐88 76 81 % HBsAg loss 4 6 (at 3 years posttreatment) 0‐1 0 <1 References: (6‐16).aAssessed 6 months after completion of 12 months of therapy.bAssessed after 3 years of continuous therapy.cAssessed after 2 years of continuous therapy.dHBV DNA <2,000‐40,000 IU/mL for peg‐IFN; <60 IU/mL for entecavir and tenofovir disoproxil fumarate; <29 IU/mL for tenofovir alafenamide.eHBV DNA <20,000 IU/mL for peg‐IFN; <60 IU/mL for entecavir and tenofovir disoproxil fumarate; <29 IU/mL for tenofovir alafenamide.fALT normalization defined by laboratory normal rather than ≤35 and ≤25 U/L for males and females. TAF, like TDF, is a nucleotide analogue that inhibits reverse transcription of pregenomic RNA to HBV DNA. TAF is more stable than TDF in plasma and delivers the active metabolite to hepatocytes more efficiently, allowing a lower dose to be used with similar antiviral activity, less systemic exposure, and thus decreased renal and bone toxicity. A phase 3 trial of 873 hepatitis B e antigen (HBeAg)‐positive patients (26% with past nucleos(t)ide analogue [NA] therapy) randomized to TAF 25 mg daily or TDF 300 mg daily in a 2:1 ratio found similar 48‐week responses, with serum HBV DNA <29 IU/mL in 64% versus 67%, alanine aminotransferase (ALT) normalization in 72% versus 67%, HBeAg loss in 14% versus 12%, and hepatitis B surface antigen (HBsAg) loss in 1% versus 0.3% in the TAF and TDF groups, respectively.17 Week 96 follow‐up results likewise showed that 73% and 75% had serum HBV DNA <29 IU/mL, 22% and 18% lost HBeAg, and 1% and 1% lost HBsAg in TAF and TDF patients, respectively.6 Analogously, a phase 3 trial of 426 HBeAg‐negative patients (21% with past NA therapy) randomized to TAF 25 mg daily or TDF 300 mg daily in a 2:1 ratio found comparable 48‐week normalization in 83% versus 75% in the TAF and TDF groups, respectively. However, no patient in either group lost HBsAg.18 Week 96 follow‐up results also showed serum HBV DNA <29 IU/mL in 90% of TAF patients and 91% of TDF patients, with 1 TAF‐treated patient lo