AASLD guidelines for treatment of chronic hepatitis B

Potential conflict of interest: Dr. Jonas consults and received grants from Gilead. She received grants from Bristol‐Myers Squibb and Roche. Dr. Chang advises Genentech, Alnylam, and Arbutus. Dr. Terrault consults for Bristol‐Myers Squibb and received grants from Gilead. Dr. Bzowej received grants from Gilead, Synageva, and Ocera. The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases. This Practice Guideline was approved by the AASLD on August 1, 2015. This Practice Guideline published with accompanying Reviews by Lok et al., Jonas et al., and Brown et al. See Editorial on Page 31 Objectives and Guiding Principles Guiding Principles This document presents official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the treatment of chronic hepatitis B (CHB) virus (HBV) infection in adults and children. Unlike previous AASLD practice guidelines, this guideline was developed in compliance with the Institute of Medicine standards for trustworthy practice guidelines and uses the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.1 Multiple systematic reviews of the literature were conducted to support the recommendations in this practice guideline. An enhanced understanding of this guideline will be obtained by reading the applicable portions of the systematic reviews. This guideline focuses on using antiviral therapy in chronic HBV infection and does not address other related and important issues, such as screening, prevention, and surveillance. For broader issues related to diagnosis, surveillance, and prevention as well as treatment in special populations (e.g., liver transplant recipients) that are not addressed by this guideline, the previous AASLD guideline2 and recent World Health Organization (WHO) guideline3 are excellent additional resources. Objectives Guideline developers from the AASLD formulated a list of discrete questions that physicians are faced with in daily practice. These questions were: Should adults with immune active CHB be treated with antiviral therapy to decrease liver‐related complications? Should adults with immune‐tolerant infection be treated with antiviral therapy to decrease liver‐related complications? Should antiviral therapy be discontinued in hepatitis B e antigen (HBeAg)‐positive persons who have developed HBeAg seroconversion on therapy? Should antiviral therapy be discontinued in persons with HBeAg‐negative infection with sustained HBV DNA suppression on therapy? In HBV‐monoinfected persons, does entecavir therapy, when compared to tenofovir therapy, have a different impact on renal and bone health? Is there a benefit to adding a second antiviral agent in persons with persistent low levels of viremia while being treated with either tenofovir or entecavir? Should persons with compensated cirrhosis and low levels of viremia be treated with antiviral agents? Should pregnant women who are hepatitis B surface antigen (HBsAg) positive with high viral load receive antiviral treatment in the third trimester to prevent perinatal transmission of HBV? Should children with HBeAg‐positive CHB be treated with antiviral therapy to decrease liver‐related complications? Target Audience This guideline is intended primarily for health care professionals caring for patients with CHB. Additionally, this guideline may assist policy makers in optimizing the care of individuals living with CHB. Background Burden of Disease Globally, an estimated 240 million persons have CHB with a varying prevalence geographically, highest in Africa and Asia.4 In the United States, the National Health and Nutrition Examination Survey (1999 to 2008) identified approximately 704,000 adults with CHB,5 but with adjustments for hepatitis B infection among foreign‐born persons, the upper estimate of CHB in the United States may be as high as 2.2 million.6 Globally, deaths from cirrhosis and hepatocellular carcinoma (HCC) were estimated at 310,000 and 340,000 per year, respectively.7 To reduce the morbidity and mortality of CHB in the United States and worldwide, there is a need for continued efforts to identify infected individuals through targeted screening, prevent new infections through vaccination, and monitor and treat those at risk for complications of their CHB, including surveillance for HCC.8 Natural History in Adults and Children CHB has been traditionally characterized into four phases (Table 1), reflecting the dynamic relationship between viral replication and evolution and the host immune response. These phases are of variable duration and not every person infected with CHB will evolve through all phases. Given the dynamic nature of CHB infection, serial monitoring of HBV DNA and alanine aminotransferase (ALT) levels is important to characterize the phase of infection. A single ALT and HBV DNA level are insufficient to assign phase of infection and/or need for treatment. Of note, some persons will be in the “gray zones,” meaning that their HBV DNA and ALT levels do not fall into the same phase. Longitudinal follow‐up of ALT and HBV DNA levels and/or assessment of liver histology can serve to clarify the phase of infection. Immune‐tolerant phase: In this highly replicative/low inflammatory phase, HBV DNA levels are elevated, ALT levels are normal (<19 U/L for females and <30 U/L for males), and biopsies are without signs of significant inflammation or fibrosis. The duration of this phase is highly variable, but longest in those who are infected perinatally. With increasing age, there is an increased likelihood of transitioning from immune‐tolerant to the HBeAg‐positive immune‐active phase. HBeAg‐positive immune‐active phase: Elevated ALT and HBV DNA levels in conjunction with liver injury characterize this phase. Median age of onset is 30 years among those infected at a young age. The hallmark of transition from the HBeAg‐positive immune‐active to ‐inactive phases is HBeAg seroconversion. The rate of spontaneous seroconversion from HBeAg to antibody to HBeAg (anti‐HBe) is less than 2% per year in children younger than 3 years of age and increases during puberty and among adults to 8% and 12% per year, respectively. Inactive CHB phase: In this phase, HBV DNA levels are low or undetectable, ALT levels are normal, and anti‐HBe is present. Liver histology shows minimal necroinflammation, but variable fibrosis reflecting previous liver injury during the HBeAg‐positive immune‐active phase. Among persons who undergo spontaneous HBeAg seroconversion, 67%‐80% will continue to remain in the inactive CHB phase. Approximately 4%‐20% of inactive carriers have one or more reversions back to HBeAg positive. HBeAg‐negative immune reactivation phase: Among those who seroconvert from HBeAg to anti‐HBe positive, 10%‐30% continue to have elevated ALT and high HBV DNA levels, and roughly 10%‐20% of inactive carriers may have reactivation of HBV replication and exacerbations of hepatitis after years of quiescence. Most of these persons harbor HBV variants in the precore or core promoter region, and liver histology shows necroinflammation and fibrosis. Persons with HBeAg‐negative CHB tend to have lower serum HBV DNA levels than those with HBeAg‐positive CHB and are more likely to experience a fluctuating course. Table 1 - Phases of CHB Infection ALT HBV DNA HBeAg Liver Histology Immune‐tolerant phase Normal Elevated, typically >1 million IU/mL Positive Minimal inflammation and fibrosis HBeAg‐positive immune‐active phase Elevated Elevated ≥20,000 IU/mL Positive Moderate‐to‐severe inflammation or fibrosis Inactive CHB phase Normal Low or undetectable <2,000 IU/mL Negative Minimal necroinflammation but variable fibrosis HBeAg‐negative immune reactivation phase Elevated Elevated ≥2,000 IU/mL Negative Moderate‐to‐severe inflammation or fibrosis Resolved CHB infection is defined by clearance of HBsAg with acquisition of antibody to HBsAg. Approximately 0.5% of persons with inactive CHB will clear HBsAg yearly; most will develop antibody to HBsAg (anti‐HBs). Low levels of HBV DNA are transiently detected in the serum in the minority of persons achieving seroclearance.10 Clearance of HBsAg, whether spontaneous or after antiviral therapy, reduces risk of hepatic decompensation and improves survival. Risk of liver‐related complications is variable. Among untreated adults with CHB, cumulative 5‐year incidence of cirrhosis is 8%‐20%, and among those with cirrhosis, 5‐year cumulative risk of hepatic decompensation is 20%, and risk of HCC is 2%‐5%.12 Viral, host, and environmental factors influence risks of cirrhosis and HCC13 (Table 2). HBV DNA levels, ALT levels, and HBeAg status are among the most important determinants of risk of progression to cirrhosis,15 whereas HBV DNA levels (>2,000 IU/mL), HBeAg status, and cirrhosis are key predictors of HCC risk.15 A biological gradient of risk has been shown in adults with HBV DNA levels above 2,000 IU/mL; a higher HBV DNA level is associated with progressively higher rates of cirrhosis and HCC.15 Table 2 - Host, Viral/Disease, and Environmental Factors Associated With Cirrhosis and HCC Cirrhosis HCC Host >40 years of age Male sex Immune compromised >40 years of age Male sex Immune compromised Positive family history Born in Sub‐Saharan Africa Viral/disease High serum HBV DNA (>2,000 IU/mL) Elevated ALT levels Prolonged time to HBeAg seroconversion Development of HBeAg‐negative CHB Genotype C Presence of cirrhosis High serum HBV DNA (>2,000 IU/mL) Elevated ALT Prolonged time to HBeAg seroconversion Development of HBeAg‐negative CHB Genotype C Environmental Concurrent viral infections (HCV, HIV, and HDV) Heavy alcohol use Metabolic syndrome (obesity, diabetes) Concurrent viral infections (HCV, HIV, and HDV) Heavy alcohol use Metabolic syndrome (obesity, diabetes) Aflatoxin Smoking Diagnosis, Staging and Monitoring of Persons With CHB The initial evaluation of persons with CHB should include a thorough history and physical examination, with special emphasis on risk factors for coinfection, alcohol use, and family history of HBV infection and liver cancer. Laboratory tests should include assessment of liver disease activity and function, markers of HBV replication, and tests for coinfection with hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) in those at risk (Table 3). Owing to the fluctuating nature of CHB, the accuracy of one high HBV DNA level at a single time point in predicting prognosis is poor and regular monitoring of disease status is imperative to determine need for antiviral therapy. The upper limits of normal (ULNs) for ALT values based on healthy subjects are lower than laboratory values derived from all populations, including those with subclinical liver disease.19 Table 3 - Initial Evaluation of HBsAg‐Positive Patient History/Physical Examination Routine Laboratory Tests Serology/Virology Imaging/Staging Studies All patients Symptoms/signs of cirrhosis Alcohol and metabolic risk factors Family history of HCC Vaccination status CBC including platelet count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, INR HBeAg/anti‐HBe HBV DNA quantitation Anti‐HAV to determine need for vaccination Abdominal ultrasound Vibration‐controlled transient elastography or serum fibrosis panel (APRI, FIB‐4, or FIbroTest) Select patients Tests to rule out other causes of chronic liver diseases if elevated liver test(s) AFP, GGT HBV genotype Anti‐HDV Anti‐HCV Anti‐HIV in those who have not undergone one‐time screening (ages 13‐64) Liver biopsy Abbreviation:s INR, international normalized ratio; GGT, gamma‐glutamyl transpeptidase. Determination of the stage of liver disease is important in guiding antiviral therapy decisions and need for surveillance. Liver biopsy provides an assessment of the severity of necroinflammation and fibrosis, rules out other causes of liver disease, and may be especially useful for persons who lack clear‐cut indications for treatment. Whereas liver biopsy is regarded as the best method to assess the severity of inflammatory activity and fibrosis, noninvasive methods to assess fibrosis severity are also useful. Acute‐on‐chronic exacerbations of hepatitis B may lead to overestimation of fibrosis stage by noninvasive tests, and different cutoffs for significant and advanced fibrosis depending on ALT levels have been proposed.20 Serum markers of fibrosis, such as aspartate aminotransferase (AST)‐to‐platelet ratio index (APRI), FIB‐4, FibroTest, and vibration‐controlled transient elastography, have only moderate accuracy in identifying persons with significant fibrosis (fibrosis stage 2 or greater on the Metavir scale), but good diagnostic accuracy in excluding advanced fibrosis21 and may be useful aids in decision making. Antiviral Therapy The goals of antiviral treatment are to decrease the morbidity and mortality related to CHB. The achievement of a sustained suppression of HBV replication has been associated with normalization of serum ALT, loss of HBeAg with or without detection of (anti‐HBe), and improvement in liver histology. Historically, the term “cure” was avoided in treatment of CHB, given that persistence of covalently closed circular DNA (cccDNA), the transcriptional template of HBV,23 in the nucleus of hepatocytes, even in persons with serological markers of resolved infection, poses a lifelong risk for reactivation of infection. However, an immunological cure may be defined by HBsAg loss and sustained HBV DNA suppression and a virological cure defined by eradication of virus, including the cccDNA form. The latter is not currently an attainable goal. There are six therapeutic agents approved for the treatment of adults with CHB in the United States and five therapeutic agents approved for the treatment of children with CHB (Table 4). Side effects are more frequent with interferon (IFN) therapy than with nucleos(t)ide analogs (NAs) therapy. Overall, all NAs have an excellent safety profile across a wide spectrum of persons with CHB, including those with decompensated cirrhosis and transplant recipients.25 The side effects listed in Table 4 for NAs are infrequent. For persons with HDV coinfection, the only effective treatment is pegylated interferon (Peg‐IFN). For persons with HIV coinfection, treatment of HBV needs to be coordinated with HIV therapy given that several HBV drugs have anti‐HIV activity (tenofovir, entecavir, lamivudine, and telbivudine).26 Table 4 - Approved Antiviral Therapies in Adults and Children Drug Dose in Adultsa Use in Childrena Pregnancy Category Potential Side Effectsb Monitoring on Treatmentb Peg‐IFN‐2a(adult) IFN‐α‐2b (children) 180 μg weekly ≥1 year Dose: 6 million IU/m2 TIWc C Flu‐like symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders in adults Anorexia and weight loss in children CBC (monthly to every 3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications Lamivudine 100 mg daily ≥2 years Dose: 3 mg/kg daily to max 100 mg C Pancreatitis Lactic acidosis Amylase if symptoms Lactic acid levels if clinical concern Telbivudine 600 mg daily — B Creatine kinase elevations and myopathy Peripheral neuropathy Lactic acidosis Creatine kinase if symptoms Cinical evaluation if symptoms Lactic acid levels if clinical concern Entecavir 0.5 or 1.0 mg dailyd ≥2 years Dose: weight‐based to 10‐30 kg; above 30 kg 0.5 mg daily[Link] C Lactic acidosis Lactic acid levels if clinical concern Adefovir 10 mg daily ≥12 years 10 mg daily C Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus 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 persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern Tenofovir 300 mg daily ≥12 years 300 mg daily 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 persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern aDoses need to be adjusted in persons with renal dysfunction.bPer package insert.cPeg‐IFN‐α‐2a is not approved for children with CHB, 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.dEntecavir dose in adults is 1 mg daily if lamivudine or telbivudine experienced or decompensated cirrhosis.Entecavir doses in treatment‐naïve children older than 2 and at least 10 kg are: 0.15 mg (10‐11 kg), 0.2 mg (>11‐14 kg), 0.25 mg (>14‐17 kg), 0.3 mg (>17‐20 kg), 0.35 mg (>20‐23 kg), 0.4 mg (>23‐26 kg), 0.45 mg (>26‐30 kg), and 0.5 mg (>30 kg). For treatment‐experienced children older than 2 and at least 10 kg, the entecavir doses are: 0.30 mg (10‐11 kg), 0.4 mg (>11‐14 kg), 0.5 mg (>14‐17 kg), 0.6 mg (>17‐20 kg), 0.7 mg (>20‐23 kg), 0.8 mg (>23‐26 kg), 0.9 mg (>26‐30 kg), and 1.0 mg (>30 kg).Abbreviations: CBC, complete blood counts; TSH, thyroid‐stimulating hormone. Biochemical, serological, virological, and histological endpoints are used to assess the success of therapy (Table 5). Assessments are performed on continuous therapy (NAs)27 and after therapy discontinuation (Peg‐IFN).2 The best predictor of sustained remission off‐treatment is HBsAg loss, but this is infrequently achieved with current therapies. Table 5 - Efficacy of Approved Preferred Antiviral Therapies in Adults With Treatment‐Naïve CHB and Immune Active Disease (Not Head‐to‐Head Comparisons) Peg‐IFNa (%) Entecavirb (%) Tenofovirb (%) HBeAg‐Positive HBV DNA suppressionc 30‐42 (<2,000‐40,000 IU/mL) 8‐14 (<80 IU/mL) 61 (<50‐60 IU/mL) 76 (<60 IU/mL) HBeAg loss 32‐36 22‐25 — HBeAg seroconversion 29‐36 21‐22 21 Normalization ALT[Link] 34‐52 68‐81 68 HBsAg loss 2‐7 (6 mos post‐treatment) 11 (at 3 yrs post‐treatment) 2‐3 (1 yr) 4‐5 (2 yrs) 3 (1 yr) 8 (3 yrs) (References) 31 36 30 HBeAg‐Negative HBV DNA suppressiond 43 (<4,000 IU/mL) 19 (<80 IU/mL) 90‐91 93 Normalization ALT[Link] 59 78‐88 76 HBsAg loss (%) 4 (6 mos post‐treatment) 6 (at 3 yrs post‐treatment) 0‐1 (1 yr) 0 (1 yr) (References) 40 42 39 aAssessed 6 months after completion of 12 months of therapy.bAssessed after 2‐3 years of continuous therapy.cHBV DNA <2,000‐40,000 IU/mL for Peg‐IFN; <60 IU/mL for entecavir and tenofovir.dHBV DNA <20,000 IU/mL for Peg‐IFN; <60 IU/mL for entecavir and tenofovir.ALT normalization defined by laboratory normal. Methods of Guideline Development The specific questions specified a priori for evaluation by the guidelines committee are shown in Table 6. Table 6 - Clinical Questions Evaluated Question Population Intervention Comparison Outcome(s) 1 Immune‐active CHB Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, loss of HBsAg 2 Immune‐tolerant CHB, adults Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, loss of HBsAg 3 HBeAg‐positive immune‐active chronic hepatitis, with HBeAg seroconversion on therapy Continued antiviral therapy Stopping antiviral therapy Cirrhosis, HCC, reactivation, seroreversion, decompensation, loss of HBsAg 4 HBeAg‐negative immune‐active chronic hepatitis, with viral suppression on antiviral therapy Continued antiviral therapy Stopping antiviral therapy Reactivation, decompensation, loss of HBsAg 5 CHB on treatment with oral therapy Tenofovir Entecavir Renal function, hypophosphatemia, bone health 6 CHB on treatment with oral therapy with persistent viremia Continue therapy Change or switch therapy HBV resistance, clinical flare, decompensation, loss of HBeAg 7 CHB with cirrhosis, with HBV DNA <2,000 IU/mL Antiviral therapy No treatment Decompensation, HCC, death 8 Pregnant women with CHB Antiviral therapy in third trimester No treatment CHB in the infant, safety HBeAg‐positive CHB, Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, HBeAg seroconversion, loss of HBsAg A and the of A of AASLD with an with in systematic reviews to the these key and the systematic the (Table In this the of in is as or low based on the of and risk of and The based recommendations on the of of and values and and clinical are as to most patients with minimal or to the of patients values and are with the of are to recommendations to to five of the key questions are as an to this For the questions with and are after Table 7 - The the of Study Initial of of when Risk of when High (e.g., (e.g., Dose gradient Low All the low of the of a Recommendation of of and Patient values and and of the of Recommendation Most in this the of and only a Health care Most should receive the of The can be as a policy in most The of in this the of but Health care to patients a decision that is with their values using decision aids and decision making. There is a need for and of of Persons With CHB The AASLD antiviral therapy for adults with immune‐active CHB or HBeAg to decrease the risk of liver‐related of of The AASLD entecavir, or tenofovir as initial therapy for adults with immune‐active CHB. of Low of Immune‐active CHB is defined by an of ALT or of significant histological disease elevated HBV DNA above 2,000 IU/mL or above IU/mL The for ALT in healthy adults is 30 U/L for and 19 U/L for There is insufficient for or use of ALT other than ALT ≥2 The decision to treat persons with ALT above the but of severity of liver disease by biopsy or noninvasive Therapy is for persons with immune‐active CHB and cirrhosis if HBV DNA of ALT factors in the decision to treat persons with immune‐active CHB but ALT and HBV DNA are: age is associated with higher likelihood of significant histological Family history of HCC treatment of and HBsAg may months to years after treatment discontinuation is a risk for drug Presence of for treatment of liver disease severity of HBV DNA should be with immune‐active disease and the cutoffs should be as a but not for treatment. of antiviral to of one therapy in achieving risk in liver‐related However, in and entecavir as the most important was the lack of with factors that need to be in between entecavir, and tenofovir for therapy of treatment side effects (Table 4). is in persons with autoimmune disease, disease, cytopenias, disease, and decompensated history of lamivudine is not in this Family A therapy with or use of oral antiviral that is in is best (Table 4). HBV A and B are more likely to HBeAg and HBsAg loss with than is for For persons treated with 48 duration is used in most and is This treatment duration HBeAg seroconversion rates of and sustained off‐treatment HBV DNA suppression <2,000 IU/mL in of persons who HBeAg to anti‐HBe The of and NAs has not higher rates of off‐treatment serological or virological and is not of therapy for therapy is variable and by HBeAg status, duration of HBV DNA and of All NAs dose in persons with creatinine clearance Evaluation for stage of disease using noninvasive methods or liver biopsy is useful in guiding treatment decisions including duration of therapy. with does not the risk of HCC, and surveillance for HCC should continue in persons who are at Background CHB is a dynamic disease characterized by variable of immune activity that in the development of cirrhosis, liver and liver‐related death in a of Elevated serum ALT and HBV DNA levels are of risk of liver factors include older age, a family history of HCC, alcohol use, HIV infection, HBV genotype and HBV precore and core promoter The of HBV therapy is to prevent liver‐related morbidity and Persons in the immune‐active phases of infection positive and elevated ALT, histological of liver injury inflammation and/or and elevated HBV DNA levels with a greater risk of liver disease and associated and The profile is in Table A total of 42 were to treatment and of cirrhosis, HCC, decompensation, or were and were a total of provided in persons with cirrhosis, and provided in persons with decompensated specific antiviral compared to treatment and compared therapy to treatment. A to antiviral was not to the of per The of was higher for low to low to of per was lower than per For specific the of was and highly variable. The of the treatment in liver‐related cirrhosis, decompensation, HCC, and and of risk across and among to of the lower of the Antiviral therapy to was associated with significant risk in cirrhosis in risk and a risk in HCC and