Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance

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 losing HBsAg.7 The approved dose of TAF is 25 mg orally once‐daily, with no dose adjustment needed unless creatinine clearance is <15 mL/min. In these phase 3 studies, TAF had significantly less decline than TDF in bone density and renal function at 48 weeks of treatment. In HBeAg‐positive patients, the mean decline in the estimated glomerular filtration rate was −0.6 mL/min for TAF patients, whereas the decline was −5.4 mL/min in TDF patients (P < .0001). In HBeAg‐negative patients, the mean decline in the estimated glomerular filtration rate was −1.8 mL/min in TAF patients, whereas the decline for TDF patients was −4.8 mL/min (P = .004).17 In hip and spine bone mineral density measurements, the adjusted percentage difference in spine bone mineral density for TAF versus TDF was 1.88% (95% confidence interval, 1.44‐2.31; P < .0001) for HBeAg‐positive patients and 1.64% (95% confidence interval, 1.01‐2.27; P < .0001) in HBeAg‐negative patients after 48 weeks.17 In human immunodeficiency virus (HIV)‐infected patients, TAF (N = 300) versus TDF (N = 333) containing antiretroviral therapy (ARVT) for up to 144 weeks also showed that TAF had a less negative impact on bone mineral density and renal biomarkers, with fewer patients on TAF versus TDF developing proximal tubulopathy (0 vs. 4) or requiring treatment discontinuation because of renal complications (0 vs. 12; P < .001).19 While longer‐term data in HBV‐monoinfected patients are lacking, particularly with respect to the impact on clinical outcomes such as renal disease and fracture risk, the current safety profile of TAF combined with evidence of similar antiviral efficacy led to its inclusion among the preferred HBV therapies for those patients requiring treatment. Most studies of switching from TDF to TAF come from the HIV literature. In studies of up to 96 weeks, a switch to TAF versus continued TDF treatment (as part of an antiretroviral regimen) was associated with improvements in proteinuria, albuminuria, proximal renal tubular function (mostly within the first 24 weeks), and bone mineral density.20 Collectively, these studies suggest that TAF has a better safety profile than TDF and similar antiviral efficacy in studies of up to 2 years' duration. 1 Screening, Counseling, and Prevention of Hepatitis B 1A. SCREENING The presence of HBsAg establishes the diagnosis of hepatitis B. Chronic versus acute infection is defined by the presence of HBsAg for at least 6 months. The prevalence of HBsAg varies greatly across countries, with high prevalence of HBsAg‐positive persons defined as ≥8%, intermediate as 2% to 7%, and low as <2%.21 In developed countries, the prevalence is higher among those who immigrated from high‐ or intermediate‐prevalence countries and in those with high‐risk behaviors.22 HBV is transmitted by perinatal, percutaneous, and sexual exposure and by close person‐to‐person contact (presumably by open cuts and sores, especially among children in hyperendemic areas).24 In most countries where HBV is endemic, perinatal transmission remains the most important cause of chronic infection. Perinatal transmission also occurs in nonendemic countries (including the United States), mostly in children of HBV‐infected mothers who do not receive appropriate HBV immunoprophylaxis at birth. The majority of children and adults with CHB in the United States are immigrants, have immigrant parents, or became exposed through other close household contacts.26 HBV can survive outside the body for prolonged periods.28 The risk of developing chronic HBV infection after acute exposure ranges from 90% in newborns of HBeAg‐positive mothers to 25%‐30% in infants and children under 5 to less than 5% in adults.29 In addition, immunosuppressed persons are more likely to develop chronic HBV infection after acute infection.34 Table 3 displays those at risk for CHB who should be screened for HBV infection and immunized if seronegative.23 HBsAg and antibody to hepatitis B surface antigen (anti‐HBs) should be used for screening (Table 4). Alternatively, antibody to hepatitis B core antigen (anti‐HBc) can be utilized for screening as long as those who test positive are further tested for both HBsAg and anti‐HBs to differentiate current infection from previous HBV exposure. HBV vaccination does not lead to anti‐HBc positivity. Table 3 - Groups at High Risk for HBV Infection Who Should Be Screened • Persons born in regions of high or intermediate HBV endemicity (HBsAg prevalence of ≥2%) Africa (all countries) North, Southeast, East Asia (all countries) Australia and South Pacific (all countries except Australia and New Zealand) Middle East (all countries except Cyprus and Israel) Eastern Europe (all countries except Hungary) Western Europe (Malta, Spain, and indigenous populations of Greenland) North America (Alaskan natives and indigenous populations of Northern Canada) Mexico and Central America (Guatemala and Honduras) South America (Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas) Caribbean (Antigua‐Barbuda, Dominica, Grenada, Haiti, Jamaica, Saint Kitts and Nevis, Saint Lucia, and Turks and Caicos Islands) • U.S.‐born persons not vaccinated as an infant whose parents were born in regions with high HBV endemicity (≥8%)a • Persons who have ever injected drugsa • Men who have sex with mena • Persons needing immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatological or gastroenterologic disorders. • Individuals with elevated ALT or AST of unknown etiologya • Donors of blood, plasma, organs, tissues, or semen • Persons with end‐stage renal disease, including predialysis, hemodialysis, peritoneal dialysis, and home dialysis patientsa • All pregnant women • Infants born to HBsAg‐positive mothersa • Persons with chronic liver disease, e.g., HCVa • Persons with HIVa • Household, needle‐sharing, and sexual contacts of HBsAg‐positive personsa • Persons who are not in a long‐term, mutually monogamous relationship (e.g., >1 sex partner during the previous 6 months)a • Persons seeking evaluation or treatment for a sexually transmitted diseasea • Health care and public safety workers at risk for occupational exposure to blood or blood‐contaminated body fluidsa • Residents and staff of facilities for developmentally disabled personsa • Travelers to countries with intermediate or high prevalence of HBV infectiona • Persons who are the source of blood or body fluid exposures that might require postexposure prophylaxis • Inmates of correctional facilitiesa • Unvaccinated persons with diabetes who are aged 19 through 59 years (discretion of clinician for unvaccinated adults with diabetes who are aged ≥60 years)a aIndicates those who should receive hepatitis B vaccine, if seronegative.Sources: 23. Table 4 - Interpretation of Screening Tests for HBV Infection Screening Test Results Interpretation Management Vaccinate? HBsAg Anti‐HBc Anti‐HBs + + – Chronic hepatitis B Additional testing and management needed No – + + Past HBV infection, resolved No further management unless immunocompromised or undergoing chemotherapy or immunosuppressive therapy No – + – Past HBV infection, resolved or false‐positive HBV DNA testing if immunocompromised patient Yes, if not from area of intermediate or high endemicity – – + Immune No further testing No – – – Uninfected and not immune No further testing Yes Some persons may test positive for anti‐HBc, but not HBsAg; they may or may not also have anti‐HBs, with the prevalence depending on local endemicity or the risk group.37 The finding of isolated anti‐HBc (anti‐HBc positive but negative for HBsAg and anti‐HBs) can occur for a variety of reasons. Among intermediate‐ to high‐risk populations, the most common reason is previous exposure to HBV infection; the majority of these persons recovered from acute HBV infection earlier in life and anti‐HBs titers have waned to undetectable levels, but some had been chronically infected with HBV for decades before clearing HBsAg. In the former case, the risk of hepatocellular carcinoma (HCC) or cirrhosis attributed to HBV is minimal. In the latter, these persons are still at risk of developing HCC, with an incidence rate that appears to be similar to those with inactive chronic HBV with undetectable HBV‐DNA levels.39 These individuals usually have low HBV‐DNA levels (20‐200 IU/mL, more commonly if they are anti‐HBs negative than if they are anti‐HBs positive) and are typically born in regions with high prevalence of HBV infection or have HIV or hepatitis C virus (HCV) infection.37 Much less commonly with new, more specific anti‐HBc tests, anti‐HBc may be a false‐positive test result, particularly in persons from low‐prevalence areas with no risk factors for HBV infection. Earlier anti‐HBc enzyme immunoassay and radioimmunoassay tests were less specific, more frequently yielding false‐positive results.45 Anti‐HBc may be the only marker of HBV infection during the window phase of acute hepatitis B; these persons should test positive for anti‐HBc immunoglobulin M.37 Last, reports exist of HBsAg mutations leading to false‐negative HBsAg results.37 Because of the risk for HBV transmission, screening for anti‐HBc occurs routinely in blood donors and, if feasible, in organ donors.37 Since the original anti‐HBc studies, the specificity of anti‐HBc tests has improved to 99.88% in blood donors and 96.85% in non‐HBV medical conditions.46 Individuals with HIV infection or those about to undergo HCV or immunosuppressive therapy are at risk for potential reactivation if they have preexisting HBV and should be screened for anti‐HBc.37 The majority of individuals positive for anti‐HBc alone do not have detectable HBV DNA,37 especially with older, less specific assays. For anti‐HBc–positive individuals, additional tests to detect past or current infection include immunoglobulin M anti‐HBc, antibody to hepatitis B e antigen (anti‐HBe), and HBV DNA with a sensitive assay. Detectable HBV DNA documents infectivity, but a negative HBV DNA result does not rule out low levels of HBV DNA. Additionally repeat anti‐HBc testing can be performed over time, particularly in blood donors in whom subsequent anti‐HBc negativity suggests an initial false‐positive result.37 Although reports vary depending on the sensitivity and specificity of the anti‐HBc test used and HBV prevalence in the study population, the minority of patients have an anamnestic response to HBV vaccination, with the majority having a primary antibody response to hepatitis B vaccination similar to persons without any HBV seromarkers.23 Thus, vaccination could be considered reasonable for all screening indications in Table 3. Anti‐HBc–positive HIV‐infected individuals should receive HBV vaccination (ideally when CD4 counts exceed 200/μL) because most have primary responses to HBV vaccination, with ∼60% to 80% developing anti‐HBs levels ≥10 mIU/mL after 3 or 4 vaccinations.50 Thus, limited data suggest that vaccination may be considered.48 When considering the benefit of using an anti‐HBc–positive donor organ with possible occult HBV infection, the harm of hepatitis B transmission must be weighed against the clinical condition of the recipient patient. While persons who are positive for anti‐HBc, but negative for HBsAg, are at very low risk of HBV reactivation, the risk can be substantial when chemotherapeutic or immunosuppressive drugs are administered singly or in combination (see Screening, Counseling, and Prevention of Hepatitis B, section 6D). Thus, all persons who are positive for anti‐HBc (with or without anti‐HBs) should be considered potentially at risk for HBV reactivation in this setting. Guidance Statements on Screening for Hepatitis B Infection Screening should be performed using both HBsAg and anti‐HBs. Screening is recommended in all persons born in countries with a HBsAg seroprevalence of ≥2%, U.S.‐born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (≥8%), pregnant women, persons needing immunosuppressive therapy, and the at‐risk groups listed in Table 3. Anti‐HBs–negative screened persons should be vaccinated. Screening for anti‐HBc to determine prior exposure is not routinely recommended but is an important test in patients who have HIV infection, who are about to undergo HCV or anticancer and other immunosuppressive therapies or renal dialysis, and in donated blood (or, if feasible, organs) (see Screening, Counseling, and Prevention of Hepatitis B, section 6D). 1B. COUNSELING PATIENTS WITH CHRONIC HEPATITIS B, INCLUDING PREVENTION OF TRANSMISSION TO OTHERS Patients with chronic HBV infection should be counseled regarding lifestyle modifications and prevention of transmission as well as the importance of lifelong monitoring. No specific dietary measures have been shown to have any effect on the progression of CHB per se, but metabolic syndrome and fatty liver contribute to liver‐related morbidity.54 Ingestion of more than 7 drinks of alcohol per week for women and more than 14 drinks per week for men are associated with increased risk of cirrhosis and HCC.56 Studies evaluating the risk of lesser amounts of alcohol intake are sparse,58 but the conservative approach is to recommend abstinence or minimal alcohol ingestion.59 Individuals with CHB should be immunized against hepatitis A if not already immune.61 HBsAg‐positive persons should be counseled regarding transmission to others (see Table 5). Because of increased risk of acquiring HBV infection, household members and sexual partners should be vaccinated if they test negative for HBV serological markers. For casual sex partners or steady partners who have not been tested or have not completed the full immunization series, barrier protection methods should be utilized. Transmission of HBV from infected health care workers (HCWs) to patients has been shown to occur in rare instances.62 For persons with CHB who are HCWs, the Centers for Disease Control and Prevention recommends that those who perform exposure‐prone procedures should seek counseling and advice from an expert review panel.63 If serum HBV DNA exceeds 1,000 IU/mL, antiviral therapy is recommended, and performance of exposure‐prone procedures is permitted if serum HBV DNA is suppressed to <1,000 IU/mL and maintained below that cutoff.63 Since 2013, the U.S. Department of Justice has ruled that it is unlawful for medical and dental schools to exclude applicants who are HBsAg positive. Unless prone to biting, no special arrangements need to be made for HBV‐infected children in the community other than practicing universal precautions in daycare centers, schools, sports clubs, and camps.23 Table 5 - Recommendations for Infected Persons Regarding Prevention of Transmission of HBV to Others Persons Who Are HBsAg Positive Should: Have household and sexual contacts vaccinated Use barrier protection during sexual intercourse if partner is not vaccinated or is not naturally immune Not share toothbrushes or razors Not share injection equipment Not share glucose testing equipment Cover open cuts and scratches Clean blood spills with bleach solution Not donate blood, organs, or sperm Children and Adults Who Are HBsAg Positive: Can participate in all activities, including contact sports Should not be excluded from daycare or school participation and should not be isolated from other children Can share food and utensils and kiss others Guidance Statements on Counseling of Persons Who Are HBsAg Positive HBsAg‐positive persons should be counseled regarding prevention of transmission of HBV to others (Table 5). For HCWs and students who are HBsAg positive: They should not be excluded from training or practice because they have hepatitis B. Only HBsAg‐positive HCWs and students whose job requires performance of exposure‐prone procedures are recommended to seek counseling and advice from an expert review panel at their institution. They should not perform exposure‐prone procedures if their serum HBV‐DNA level exceeds 1,000 IU/mL but may resume these procedures if their HBV‐DNA level is reduced and maintained below 1,000 IU/mL. Other than practicing universal precautions, no special arrangements are indicated for HBV‐infected children in community settings, such as daycare centers, schools, sports clubs, and camps, unless they are prone to biting. Abstinence or only limited use of alcohol is recommended in HBV‐infected persons. Optimization of body weight and treatment of metabolic complications, including control of diabetes and dyslipidemia, are recommended to prevent concurrent development of metabolic syndrome and fatty liver. Guidance Statements on Counseling of Persons Who Are HBsAg Negative and anti‐HBc Positive (With or Without anti‐HBs) Screening for anti‐HBc is not routinely recommended except in patients who have HIV infection or who are about to undergo HCV therapy or immunosuppressive treatment. Persons who are anti‐HBc positive without HBsAg are not at risk of transmission of HBV, either sexually or to close personal contacts. Persons who are positive only for anti‐HBc and who are from an area with low endemicity with no risk factors for HBV should be given the full series of hepatitis B vaccine. Persons who are positive only for anti‐HBc and have risk factors for hepatitis B (Table 3) are not recommended for vaccination unless they are HIV positive or immunocompromised. 1C. COUNSELING OF HBsAg‐POSITIVE WOMEN IN PREGNANCY AND POSTPARTUM All pregnant women should be screened for HBsAg. Pregnant women with CHB should be encouraged to discuss with their obstetrician and/or pediatrician the prevention of mother‐to‐child transmission. Hepatitis B immune globulin (HBIG) and HBV vaccine should be administered to their newborn <12 hours after delivery.23 Antiviral therapy in the third trimester is recommended for pregnant women with serum HBV DNA >200,000 IU/mL.1 A proportion of women (around 25%) have hepatitis flares with or without HBeAg seroconversion within the first months after delivery.65 Seroconversion rates of up to 17% have been described. It has been postulated that the rapid decrease in cortisol levels characteristic of the postpartum state is analogous to the steroid withdrawal therapy that has been used to elicit seroconversion. Although the flares are often mild and resolve spontaneously, cases of acute liver failure have been described in the peripartum period.66 Extending third trimester antiviral therapy from 2 to 12 weeks postpartum did not protect against postpartum flares in one study,68 supporting the AASLD guideline recommendation that antiviral therapy given for prevention of mother‐to‐child transmission be discontinued at the time of delivery or up to 4 weeks postpartum.1 A previous systematic review of any antiviral therapy in the third trimester showed a significant reduction in perinatal transmission of HBV4 with lamivudine, telbivudine, or TDF, but TDF is the preferred choice owing to its antiviral potency and concerns for resistance with the other antiviral agents. Two recent randomized, control trials of TDF versus no antiviral treatment in the third trimester confirmed significant reductions in risk of mother‐to‐child transmission of hepatitis B with TDF in women with a high level of HBV DNA.69 Elevated maternal creatine kinase levels were more frequent in TDF‐treated versus untreated women in one study, though none were assessed as clinically significant.69 Both studies found no difference in the rates of prematurity, congenita