GAZETTE COMMON GROUND. CHB: A significant and prevalent disease in the US and worldwide. Inside. Screening, diagnosis, and evaluation

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1 VOL III/III COMMON GROUND GAZETTE Inside CASE 1: Screening, diagnosis, and evaluation P. 1 CASE 2: Initiating treatment P. 4 CASE 3: Managing antiviral resistance P. 5 CASE 4: Achieving the maximum effect in CHB treatment P. 6 CASE 5: Strategies for treating HBV/HIV coinfection P. 6 CASE 6: Strategies for treating pregnant women P. 8 To download references for the CHB Common Ground Gazette, VOL lli/iii, please go to or healthmatterscme A CONTINUING MEDICAL EDUCATION COMPANY This activity is jointly sponsored by Postgraduate Institute for Medicine and HealthmattersCME. This activity is supported by an independent educational grant from Gilead Sciences Medical Affairs. The American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) recently released guidelines to assist health care providers in the diagnosis and management of patients with chronic hepatitis B infection (CHB). This CME/CE-certified activity uses case studies to discuss the clinical applications of the AASLD and EASL guidelines, as well as the similarities and differences between the two sets of guidelines. CHB: A significant and prevalent disease in the US and worldwide The estimated worldwide prevalence of chronic hepatitis B infection (CHB) is 350 million. In the United States, estimates of CHB prevalence range from 1.25 million to 2 million persons and estimates of annual CHB-related deaths range from 2000 to Worldwide and in the US, a large percentage of chronically infected persons remain undiagnosed. Effective antiviral treatments for CHB are available, but decisions concerning treatment initiation, selection, duration, and monitoring can be challenging, especially in special populations. In 2009 the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) each released updated guidelines on prevention, identification, diagnosis, and treatment of CHB. CASE 1 Screening, diagnosis, and evaluation Question: Why is this patient a candidate for CHB screening? A) His age puts him at high risk for CHB B) He was born in China C) His occupation places him at risk for HBV exposure D) Screening is not needed for this patient because his ALT and AST levels are normal Screening for CHB in specified patients and settings is necessary because identifying and treating those infected can reduce further transmission and may lower the risk of liver disease and cirrhosis. Furthermore, HBV screening in patients requiring medical intervention for other conditions, such as chemotherapy for cancer, can help avoid potentially serious complications that may be associated with undiagnosed and This newsletter highlights the common ground shared by the AASLD and the EASL guidelines and discusses areas of divergence, using case studies to illustrate these similarities and differences in the clinical setting. Case 1 covers screening, diagnosis, and evaluation of CHB. Case 2 highlights important issues in initiating treatment of CHB. Case 3 discusses issues concerning antiviral resistance and strategies for long-term viral suppression and avoiding resistance. Case 4 draws attention to factors that can help achieve the maximum effect in treatment. Case 5 reviews how to treat patients with coinfection, specifically, HIV coinfection. Case 6 describes strategies for treating pregnant women with CHB. BW is a 44-year-old married man, born in China, living in the US for 30 years. He has worked as a computer software engineer for 10 years at the same company. BW recently changed health insurance plans and is visiting his new physician for a routine physical. His medical records indicate that he has been in good health with no documented conditions other than mild hypercholesterolemia, for which he recently began taking a statin. His most recent liver function tests to monitor for statin-related side effects were obtained 3 months previously and results were within the normal range. BW has no history of injection drug use or sexually transmitted disease. untreated CHB. The EASL guidelines do not provide screening and prevention recommendations; the AASLD follows the CDC 2008 recommendations for CHB screening (Table 1). While complications of CHB are more likely to emerge as patients age, there is no birth cohort risk group for HBV infection. Discussions about a birth cohort as a risk factor usually center on chronic hepatitis C virus (HCV) infection, not CHB. In the US, infection with HCV is more common among individuals born between 1945 and This patient was born in China, a country with high HBV endemicity. High endemicity is defined as hepatitis B surface antigen (HBsAg) prevalence of 8% and intermediate endemicity as HBsAg prevalence of 2%-7%. Most persons with CHB who were born in highly endemic areas, such as Southeast Asia, were infected For CME/CE information, please refer to center insert. Earn FREE CME/CE credit online. Go to and enter Course ID 7135 FROM PAPER TO PRACTICE COMPARING THE AASLD AND EASL GUIDELINES IN THE CLINICAL SETTING Table 1. AASLD recommended groups for HBV screening Blood, organ, plasma, semen, tissue donors All pregnant women Infants born to HBsAg-positive mothers Household contacts, needle-sharing or sex partners of HBV-infected persons Sources of blood or body fluid exposures that might warrant prophylaxis Persons born in regions with HBsAg prevalence 2%* *This category accounts for most patients with CHB in the US. Adapted from Lok A, McMahon B. Chronic hepatitis B update: Hepatology. 2009;50:1-36. perinatally or in early childhood. Patients infected perinatally or in early childhood are at a greater risk of progression from acute HBV to CHB than individuals infected later in life (Figure 1). These patients represent most of the CHB cases in the US (see Sidebar: CHB epidemiology in the US). Routine HBV screening is recommended for individuals born in geographic regions with intermediate to high endemicity (Eastern Europe, Asia, Africa, Middle East, and Pacific Islands) and for individuals born in the US but not vaccinated as infants whose parents were born in geographic regions with high endemicity (all of Africa; Southeast Asia, including China, Korea, Indonesia, and the Philippines; the Middle East, except Israel; South and Western Pacific Islands; the interior Amazon River basin; Haiti and the Dominican Republic). Health care workers are at occupational risk for HBV infection through needlesticks or other exposures to infected body fluids in health care settings. In 2007, approximately 0.6% of reported acute HBV cases were associated with occupational exposure. Persistently elevated liver enzyme levels are not always present in individuals with CHB. Levels of alanine aminotransferase (ALT) are persistently normal in individuals who are in the immune tolerant phase, and may be intermittently normal in a proportion of those with hepatitis B e antigen (HBeAg)-negative CHB. Significant liver disease can be present despite liver enzyme levels close to the upper limit of normal (ULN), especially in patients more than 40 years of age. Accordingly, while it is an important marker of HBV disease activity, a normal se- Please see CASE STUDY 1 page 2

2 2 COMMON GROUND GAZETTE Paul Martin, MD Letter from the Editors Dear Health Care Professional: Mark Sulkowski, MD CHB epidemiology in the US Approximately 0.3% 0.5% of US residents are chronically infected with HBV; 47% 70% of these persons were born in other countries. In contrast to areas such as Southeast Asia where HBV is endemic and typically is transmitted through perinatal or early childhood exposure, the most common route of HBV transmission in the US is adult horizontal transmission, except in recent immigrants and Native Alaskans, where vertical and childhood horizontal transmission still predominates. Certain populations in the US with risk factors for HBV exposure have higher CHB prevalence rates than the general population, including injection drug users (3%-6%), those infected with HIV (4%-17%), men who have sex with men (1%-3%), sexual contacts of HBsAg-positive persons (3.5%-9%), and household contacts of persons with CHB (3%-20%). The universal vaccination and immunoprophylaxis against HBV of newborns and children has greatly reduced the incidence of perinatal transmission, but sporadic cases continue to occur, particularly among patient groups not targeted in the initial vaccination programs. The CDC has reported several recent outbreaks of acute HBV infection among adult residents in long-term care facilities that were attributed to shared blood glucose monitoring devices. Chronic hepatitis B (CHB) remains a serious and prevalent disease worldwide that is associated with significant morbidity and mortality. Because individuals are often unaware of their infection with hepatitis B virus (HBV), CHB frequently may not be diagnosed or treated until signs and symptoms of severe liver disease become evident. Until recently, treatment options for patients with CHB were limited, but a number of effective and well tolerated medications are now available with potent antiviral activity. Sustained suppression of HBV replication by antiviral therapy can improve liver histology and may delay or prevent serious hepatic complications. As awareness of the prevalence of CHB in the US grows among clinicians, many have questions about screening, prevention, and diagnosis of this chronic disease, as well as selection, timing, and duration of treatment. Horizontal transmission Perinatal transmission Immune tolerant phase In 2009 the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) separately issued revised practice guidelines to help clinicians appreciate new research about the pathogenesis and natural history of CHB and its complications, and to review accumulated data on treatment. The AASLD guidelines provide detailed recommendations on screening, prevention, diagnosis, and treatment of CHB, while the EASL guidelines focus on management of CHB, and do not discuss screening or prevention. In addition, both sets of guidelines provide recommendations on the treatment of special populations such as pregnant women and patients with CHB who are coinfected with hepatitis C virus. The AASLD and EASL guidelines share recommendations for management of CHB, but they also have some differences. This newsletter uses a case-study approach to highlight the common ground between the guidelines and uncover key points that may affect clinical decision making. This continuing medical education (CME) activity will benefit clinicians by informing them about the most recent recommendations provided in the guidelines released by the AASLD and the EASL, and assisting them in understanding the similarities and differences between the two sets of guidelines. In turn, this CME activity will benefit patients with CHB by encouraging screening of at-risk individuals, promoting accurate and timely diagnosis, and increasing awareness of the best approaches to treatment. We hope you find this third and final newsletter in this series to be a useful part of your continuing education about this challenging and dynamic disease. Sincerely, Paul Martin, MD Professor of Medicine and Chief, Division of Hepatology Center for Liver Disease University of Miami School of Medicine Miami, FL Case Study 1 continued from page 1 rum ALT does not exclude chronic infection nor obviate the need for screening of at risk individuals. The best choice is selection B. The physician notes that although BW has lived in the US for several decades and has no known behavioral or occupational risk factors for HBV, he was born in China. The medical records for BW do not indicate that he has been vaccinated for HBV. BW requires screening for CHB. Question: What serologic tests would you order for this patient to screen for HBV? A) HBsAg and anti-hbs Mark Sulkowski, MD Associate Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, MD B) Anti-HBc C) HBV DNA D) HBeAg and anti-hbe 90% seroconvert 80% Inactive HBV carrier phase Clearance of HBeAg 0.5% per year Chronic hepatitis B HBeAg+ immune active phase Anti-HBe seroconversion 20% 20% revert Anti HBE+ immune active phase Cirrhosis 2 HCC+ Figure 1. Natural progression of HBV infection HBeAg, hepatitis B e antigen; anti-hbe, antibody to hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. 1 Transmission occurs in 90% of infants of HBsAg+/HBeAg+ mothers and 15% of infants of HBsAg+/anti-HBe+ mothers. 2 30% of those infected from 1-5 years of age and 7% of those infected at the age of 6 years. 3 About 50% of patients by 5 years and 70% of patients by 10 years will seroconvert to anti-hbe. 4 15%-25% risk of premature death from cirrhosis and HCC. Institute of Medicine of the National Academies. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC. The National Academies Press The AASLD currently recommends testing for both HBsAg and antibodies to HBsAg (anti- HBs) to screen for HBV infection, and seronegative patients should be vaccinated (see Sidebar: Review of HBV Serologic Markers). A positive result for HBsAg indicates that the patient is either acutely or chronically infected with HBV (Table 2). A positive result for anti-hbs indicates that the patient is either immune to HBV due to a previous resolved infection or from HBV vaccination. Additional serologic tests can determine the level of HBV DNA replication. Total anti-hbc is not recommended as a primary screening test for HBV by the AASLD. Although HBV DNA, HBeAg, and anti-hbe are markers of viral replication, the AASLD does not recommend testing for these as a primary screening tool. However, both the AASLD and the EASL do recommend testing for these markers of replication when evaluating diagnosed patients for treatment, and to monitor disease progression and response. The best choice is selection A. The physician ordered testing for HBsAg and anti-hbs to screen for HBV infection, as well as liver function tests to assess any liver abnormalities. BW returned for a second visit to review the results with his physician. Results: ALT: 27 U/L AST: 22 U/L Bilirubin: 1.0 INR: 1.0 Albumin: % HBsAg: positive Anti-HBs: negative Although the ALT and AST levels are in the normal range, BW tested positive for HBsAg and negative for anti-hbs, and therefore he is chronically infected with hepatitis B. Question: After discussing the test results, the physician counsels BW about preventing transmission of HBV to others. Which of the following is NOT a recommended preventive measure for CHB patients? A) Notify all household contacts, sexual partners, and needle-sharing contacts that they need to be tested for HBV B) Cover any cuts or lesions, and clean blood spills with bleach C) Do not donate blood, plasma, tissue or semen D) Avoid casual contact, such as hugging or participating in sports, with any susceptible individuals

3 COMMON GROUND GAZETTE 3 Review of HBV Serologic Markers A number of different serologic markers can be tested to diagnose CHB, monitor viral replication, and assess response to treatment. Hepatitis B surface antigen (HBsAg) n Protein on the surface of HBV which is found in the serum of infected individuals n Detected at high levels in serum during acute HBV infection or in CHB n Presence indicates the patient is infectious Hepatitis B surface antibody (anti-hbs) n Antibody to HBsAg n Presence usually indicates recovery and immunity from HBV infection n Also develops in patients successfully vaccinated against HBV Total hepatitis B core antibody (anti-hbc) n Antibody to core antigen of hepatitis B virus; the core antigen cannot be directly measured in the blood n Appears at the onset of symptoms in acute HBV infection and remains throughout life n Presence indicates previous or ongoing HBV IgM antibody to hepatitis B core antigen (IgM anti-hbc) n Immunoglobulin M antibody to the core antigen of the hepatitis B virus n Presence indicates recent acute infection with HBV ( 6 months) Hepatitis B e antigen (HBeAg) n Protein produced by the virus when it is actively replicating n Can be detected in serum during acute HBV infection and CHB n Some strains of HBV do not make e antigen and its absence does not exclude active viral replication Hepatitis B e antibody (anti-hbe) n Antibody to HBeAg n In persons who are HBeAg-positive, the development of anti-hbe during therapy indicates seroconversion, an endpoint of therapy in some patients HBV DNA n Genetic material of the hepatitis B virus n Number of HBV DNA viral copies (expressed as IU/mL) in the blood is used to detect active HBV infection and to monitor response to antiviral therapy (one IU equals ~5-6 copies) Centers for Disease Control and Prevention. Interpretation of hepatitis B serologic test results. Available at SerologicChartv8.pdf. HBV is transmitted through exposure of mucosal or percutaneous tissues to infected blood or body fluids. While blood is the most infectious body fluid because it carries the highest concentration of HBV, the virus can also be transmitted through exposure to infected saliva and semen. HBV can remain viable for a week outside the body, and may be present on razors or toothbrushes. The primary routes of HBV transmission are sexual contact, percutaneous exposure to infectious body fluids (eg, through needle sharing by injection drug users or needlestick injuries in health care settings), and perinatal exposure to a mother with CHB. In addition, close personal contact over an extended time with an infected person can lead to HBV transmission, as can contact with fluids from dermatologic lesions, contaminated surfaces, and sharing of toothbrushes or razors or similar objects. The EASL 2009 guidelines do not discuss preventive measures. The AASLD recommends vaccination for all susceptible household contacts and sexual or needle-sharing partners of persons with CHB and for those contacts who test positive only for total anti- HBc, come from areas of low HBV endemicity, and have no HBV risk factors; anti-hbc may be a false positive test result, particularly in persons from low prevalence areas with no risk factors for HBV infection. These individuals respond to hepatitis B vaccination similar to persons without any HBV seromarkers. Barrier protection should be used during sexual contact with susceptible persons. Exudates from wounds and lesions can transmit HBV; therefore all open sores should be covered to reduce the risk of transmission to susceptible persons. All blood spills must be cleaned with bleach or detergent. Persons with CHB should not donate blood, organs or semen. HBV is not transmitted by casual contact; therefore no adults and children with CHB should be excluded based on their HBsAg status from any workplace, school, or other settings where casual contact may occur. The physician counseled BW regarding lifestyle modifications, including the need to restrict or avoid alcohol use to protect his liver, the prevention of transmission, and the importance of life long monitoring. The AASLD guidelines point out that serial monitoring of HBV DNA levels is more important than any single arbitrary cutoff value in prognostication and in determining the need for treatment. The physician conducted a thorough physical examination, took a patient history and asked BW about any family members with liver disease, including hepatocellular carcinoma (HCC), and alcohol use. He also asked about smoking history, because tobacco use can increase the risk of liver cancer as well as cause substantial cardiopulmonary disease. He ordered additional laboratory tests to assess liver function, HBV DNA replication, and coinfection with HCV, hepatitis D (HDV), and HIV. He had BW vaccinated for hepatitis A, as recommended in the AASLD guidelines. In addition, BW s physician ordered an ultrasound to screen for HCC (See Sidebar: HCC risk factors and screening). Table 2. Interpretation of HBV serologic test results HBsAg Total anti-hbc IgM anti-hbc Anti-HBs Interpretation Never infected and no evidence of immunization + + Chronic infection Acute infection + + Recovered from past infection and immune + Immune (immunization) Source: Weinbaum CM, Williams I, Mast EE, et al. Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR. 2008;57(RR-8):1-20. Results: ALT: 27 U/L AST: 22 U/L HBeAg: positive Anti-HBe: negative HBV DNA: >20,000 IU/mL Anti-HCV, anti-hdv, anti-hiv: negative No evidence of HCC on ultrasound Repeat tests 6 months later showed the same results. Question: What would be your next step for this patient? A) Immediately begin antiviral treatment B) Refer for a liver biopsy C) Monitor at 3 to 6 month intervals D) Test for HBV genotype Many considerations have to be weighed before deciding when to initiate treatment for CHB. The AASLD guidelines have algorithms for managing HBeAg-positive and HBeAgnegative patients (Figure 2). HBeAg-positive patients with normal ALT levels should be monitored at 3 to 6 month intervals, with ALT levels assessed every 3 to 6 months and HBeAg status tested every 6 to 12 months. Any elevations in ALT require more frequent monitoring. Liver biopsy and antiviral treatment should be considered for patients with persistently borderline normal or slightly elevated ALT levels, especially if the patient is >40 years of age. In addition, antiviral treatment and liver biopsy should be considered for those with persistent elevations >2 times the ULN (upper limit of normal) who remain HBeAg-positive and have HBV DNA levels >20,000 IU/mL. Liver biopsy is usually not necessary in patients <30 years who are HBeAg-positive and have persistently normal ALT. The AASLD and the EASL make similar recommendations for pretreatment testing, including liver biopsy. The AASLD recommends liver biopsy as being most useful in patients who do not meet clear-cut guidelines for treatment. HBeAg-negative patients with normal ALT levels and HBV DNA <2000 IU/mL may be inactive carriers; however, ALT should be monitored every 3 months for a year to verify their status, and then every 6 to 12 months. Any elevations in ALT require more frequent monitoring and HBV DNA testing. The AASLD also recommends that patients with ALT elevations and HBV DNA between 2000 IU/mL and 20,000 IU/mL should be monitored every 3 months; liver biopsy and treatment may be considered if ALT elevations are persistent. Patients with ALT levels 2 times ULN and HBV DNA 20,000 IU/mL should be considered for treatment. Liver biopsy is optional in these patients. The EASL guidelines do not provide monitoring algorithms, but strongly recommend liver biopsy for any patient with an HBV DNA level >2000 IU/mL or elevated ALT without other clinical evidence of advanced disease. According to the EASL guidelines, a liver biopsy is useful to evaluate necroinflammatory activity and the fibrosis stage, guide HBV treatment decisions, and identify persons at high risk for HCC. Similar to the AASLD recommendations, the EASL suggests that liver biopsy is not required for patients with clear indications for HBV treatment (persistent ALT elevations >2 times ULN and serum HBV DNA levels >20,000 IU/mL) or evidence of advanced disease. Eight genotypes of HBV and multiple subgenotypes have been identified. While some evidence suggests that certain HBV genotypes/subgenotypes may be associated with a greater risk of liver disease progression or the response to therapy, results from studies with interferon and nucleos(t)ide analogues (NAs) are inconsistent. Some experts suggest that determining HBV genotype/subgenotype may be useful if treatment with pegylated interferon (pegifn) may be considered. Results from some studies indicate that genotypes A and B are associated with a better antiviral response to interferon therapy than genotypes C and D, but more population-based prospective studies examining multiple genotypes are needed. Routine testing for HBV genotype and subgenotype in clinical practice is not recommended by either the AASLD or the EASL. HCC risk factors and screening According to the AASLD, screening for HCC should be performed in all patients at high risk at baseline and then every 6 to 12 months. Ultrasonography is the preferred method for screening, and testing for alpha-fetoprotein should be used only if ultrasonography is not available. Patients at high risk for HCC include: n Asian men 40 years of age n Asian women 50 years of age n Africans > 20 years of age n those with cirrhosis n those with a family history of HCC n any HBsAg carrier 40 years of age with persistent or intermittent ALT level elevations and/or HBV DNA level >2000 IU/mL n a persistently elevated HBV DNA level is an independent risk factor for HCC in both HBeAg-negative and HBeAgpositive individuals Other risk factors include a history of reversions from anti-hbe to HBeAg, core promoter mutation, and infection with hepatitis C. In the US, HCC incidence is increasing; from 2001 to 2006, the incidence rose at an annual percentage rate of 3.5%. Asians/Pacific Islanders (7.8/100,000 persons) have the highest HCC incidence rate, followed by blacks (4.2/100,000), American Indians/Alaska Natives (3.2/100,000), and whites (2.6/100,000). The increasing incidence underscores the need for regular screening among those at risk and additional research on more costeffective screening strategies. Please see CASE STUDY 1 page 4

4 4 COMMON GROUND GAZETTE CASE 2 Initiating treatment This case follows BW, the patient from Case Study 1, through treatment decisions made by his physician. At 6 month followup, BW s ALT had risen from 27 U/L to 130 U/L. Three months later, the ALT level remained high, the HBV DNA level was >20,000 IU/ ml, and his HBeAg-positive status had not changed. Question: Is BW a candidate for antiviral treatment according to the AASLD guidelines? A) Yes, all patients with HBV DNA >2000 IU/mL should be treated B) No, he has mild CHB and does not require treatment C) Yes, his HBV DNA level and ALT level indicate therapy is needed D) No, he is too young for treatment The EASL and the AASLD differ somewhat on indications for treatment (Table 3). For HBeAg-positive patients, the AASLD guidelines recommend treatment for those who remain HBeAg-positive with HBV DNA >20,000 IU/mL after a 3-6 month period of ALT levels >2 times ULN. A liver biopsy should be considered for patients >40 years old with HBV DNA >20,000 IU/mL who Case Study 1 continued from page 3 Although the HBV DNA levels for this patient indicate a high rate of replication, and he have ALT elevations between 1 and 2 times ULN. If the biopsy results show moderate to severe liver damage, treatment should be considered. For HBeAg-negative patients, treatment should be considered for those with HBV DNA levels between 2000 and 20,000 IU/mL. The EASL recommends treating patients with HBV DNA levels >2000 IU/mL and/or ALT elevations above the ULN and with evidence of moderate to severe hepatic inflammation or fibrosis, regardless of HBeAg status. The EASL also categorizes patients with ALT levels <2 times ULN and mild histology as having mild CHB. According to the EASL, these patients may not require treatment but follow up is mandatory. Both the AASLD and the EASL recommend prompt antiviral treatment for patients with decompensated cirrhosis. To reduce the risk of antiviral resistance, is >40 years of age, his liver enzymes are normal and, according to the AASLD algorithm, he is not a candidate for immediate treatment with an antiviral or for a liver biopsy. n Table 3: Summary of AASLD and EASL criteria for treatment AASLD n HBV DNA >20,000 IU/mL after a 3-6 month period of ALT between 1-2 ULN n HBV DNA >20,000 IU/mL and >40 years old with biopsy results showing moderate/severe inflammation or significant fibrosis n HBV DNA >20,000 IU/mL after a 3-6 month period of ALT >2 ULN n HBV DNA ,000 IU/mL and ALT 1-2 ULN, treat as needed n HBV DNA 20,000 IU/mL and ALT 2 ULN, treat if persistent Cirrhosis (HBeAg-positive or negative) with detectable HBV DNA n Compensated HBV DNA >2000 IU/mL: treat HBV DNA <2000 IU/mL: consider treatment if elevated ALT n Decompensated: coordinate antiviral treatment with transplant center Cirrhosis (HBeAg-positive or negative) with undetectable HBV DNA n Compensated: observe n Decompensated: refer for transplant HBeAg-positive HBeAg-negative EASL n HBV DNA >2000 IU/mL and/or ALT levels > ULN and liver histology showing moderate to severe active hepatic necroinflammation and/or fibrosis n In patients with ALT <2 ULN and mild histology, treatment is optional n Same criteria as HBeAg-positive Cirrhosis (HBeAg-positive or negative) n Compensated cirrhosis: long-term therapy with monitoring for resistance and flares Detectable HBV DNA, even with normal ALT and/or HBV DNA levels <2000 IU/mL, may be treated n Decompensated cirrhosis requires urgent antiviral treatment in specialized liver units Sources: European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50: ; Lok A, McMahon B. Chronic hepatitis B update: Hepatology. 2009;50:1-36. Management of HbeAg-positive patients a ALT <1 ULN Q 3-6 mo ALT Q 6-12 mo HBeAg a HCC surveillance if indicated. Management of HbeAg-negative patients a ALT 2 ULN HBV DNA 20,000 IU/mL Treat if persistent, liver biopsy optional a HCC surveillance if indicated. HBsAg+ HBeAg Positive ALT 1-2 ULN Q 3-6 mo ALT Q 6 mo HBeAg Consider biopsy if persistent or age >40, Rx as needed HBsAg+ HBeAg Negative ALT 1-2 ULN HBV DNA 2,000-20,000 IU/mL Q 3 mo ALT and HBV DNA Consider biopsy if persistent, Rx as needed ALT >2 ULN Q 1-3 mo ALT, HBeAg Treat if persistent, liver biopsy optional, immediate Rx if jaundice or decompensated ALT <1 ULN HBV DNA <2,000 IU/mL Q 3 mo ALT 3, then Q 6-12 mo if ALT still <1 ULN Figure 2. AASLD algorithms for managing HBeAg-positive and HBeAg-negative patients Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatcellular carcinoma; Q, every; ULN, upper limits of normal. Source: Lok ASF, McMahon BJ. Chronic hepatitis B: update Hepatology. 2009;50(3):1-36. Reproduced with permission. the AASLD recommends avoiding treatment of patients who are younger than 30 years old and have minimal disease. The EASL states that immediate antiviral treatment is not required for patients <30 years of age with high HBV DNA levels and persistently normal ALT levels but with no indications of liver disease and no family history of HCC or cirrhosis. According to the AASLD, antiviral treatment should be considered for BW, because he is >40 years of age, has HBV DNA > 20,000 IU/mL, and persistent ALT elevations >2 times ULN. The physician decides to treat BW, and reviews oral (NA) versus subcutaneous (interferon) therapies with him. Question: Which of the following is NOT an advantage associated with NAs? A) Potent antiviral effects B) Favorable tolerability profile C) Ease of oral administration D) Risk of antiviral resistance The AASLD and the EASL agree that patient preference should be factored into treatment decisions. Patients should be informed about the advantages and disadvantages of oral therapy and pegifn. The key advantages of NAs include potent antiviral effect, favorable tolerability, and oral administration (Table 4). The main disadvantages of NAs are an indefinite length of treatment for patients who do not undergo seroconversion and variable rates of antiviral resistance. Advantages of pegifn include a finite duration of treatment for responders, no risk of antiviral resistance, and higher rates of HBeAg and HBsAg seroconversion following 48 weeks of therapy. However, the antiviral effects of pegifn are moderate, tolerance is relatively poor compared to the oral agents, and subcutaneous administration is required. Interferon is contraindicated in patients with autoimmune disease, decompensated cirrhosis, or uncontrolled psychiatric disorders (psychosis and severe depression). In addition, many experts recommend that interferon be avoided in persons with compensated cirrhosis due to the potential for liver disease flare in those with immunologic response to interferon. NAs are associated with selection of antiviral resistant mutations. Question: BW expresses a preference for treatment with an oral therapy. Which NAs are considered first-line choices for CHB? A) Tenofovir B) Entecavir C) Lamivudine D) A and B There are now seven treatment options available for HBV: five NAs adefovir, entecavir, lamivudine, telbivudine, tenofovir and standard interferon and pegifn. Long-acting pegifn has largely replaced standard interferon. Emtricitabine, an NA used in both monotherapy and combination therapy for treatment of HIV infection, is not approved by the Food and Drug Administration for the treatment of CHB but is currently under investigation for this indication, largely in combination with tenofovir. Durable viral suppression with antiviral therapy is important because the risk of HCC and cirrhosis increases with rising HBV DNA levels. The EASL guidelines summarize the virologic response rates at one year in HBeAgpositive and HBeAg-negative patients from different clinical trials, while noting that these trials used different HBV DNA assays and were not head-to-head comparisons. Because NAs are often used for long-term treatment, an agent should have an optimal resistance profile. Data from different pivotal NA clinical trials show that resistance builds with treatment time for both adefovir and

5 COMMON GROUND GAZETTE 5 Table 4. Features of oral agents (NAs) and peginf for treatment of chronic HBV Feature NAs PegINF Administration route Oral, once daily Injection, once weekly Tolerability Excellent Poor Clinical monitoring Minimal to moderate Intensive Treatment duration Indefinite for most Definite; 1 year Maximum log10 HBV DNA suppression Effective in high HBV DNA Usually Rarely ( 109 IU/mL) 1-year HBeAg seroconversion ~20% ~30% >1-year HBeAg seroconversion 30%-50% Not available Durability of HBeAg seroconversion ~80% ~80% HBsAg loss year 1 (year 2) 0%-3% (3%-5%) 3%-4% Resistance LVM++++ None TBV++ ADV++ ETV, TDF: negligible Use in compensated cirrhosis Delays decompensation Not recommended Use in decompensated cirrhosis Potentially lifesaving Contraindicated ADV, adefovir; ETV, entecavir; IU, international unit (~5-6 copies/ml); LVM, lamivudine; TBV, telbivudine; TDF, tenofovir Source: Dienstag JL. Benefi ts and risks of nucleoside analog therapy for hepatitis B. Hepatology. 2009;49:S112-S121. lamivudine. The risk of resistance with entecavir is low in patients without prior NA exposure, and there is no reported genotypic or phenotypic resistance with tenofovir to date. Telbivudine is effective, but has a low genetic barrier to resistance, and is associated with high rates of resistance in patients with high HBV DNA levels at baseline or detectable levels after 6 months of therapy. Both the AASLD and the EASL recommend tenofovir or entecavir as first-line NA monotherapy because of their efficacy and high barrier to resistance. The EASL notes that the role of monotherapy with entecavir or tenofovir could be modified if higher rates of resistance become apparent with longer treatment duration. The AASLD also recommends pegifn as a first-line option. The EASL guidelines reserve recommending pegifn for HBeAg-positive patients with the best chance of HBe seroconversion or HBeAg-negative patients who have the best chance of a sustained response off-treatment. In both groups, these are patients with baseline HBV DNA < IU/mL and ALT >3 times ULN. Lamivudine and telbivudine are not preferred agents because of the risk of resistance, unless only a short course of therapy is planned. In addition to its risk of resistance, adefovir is considered a less efficacious NA, as well as being more expensive. The AASLD recommends that adefovir only be used as a second-line agent in patients with no previous exposure to NAs. First-line options for CHB as recommended by the AASLD and the EASL are summarized in Table 5. The AASLD and the EASL both recommend te- nofovir or entecavir as first line agents for monotherapy. The physician decides to initiate treatment for BW with tenofovir because it is covered by his healthcare plan. Question: Under what conditions would you discontinue this patient s treatment with an NA? A) As soon as HBe seroconversion occurs B) When HBV DNA is undetectable for 12 months C) After at least 6 months of treatment following HBe seroconversion and with HBV DNA at undetectable levels D) If his liver histology improves The AASLD and the EASL have similar requirements for discontinuing NA therapy in HBeAg-positive patients. HBV DNA must be at undetectable levels, HBeAg seroconversion must have occurred, and NA treatment must have continued for at least an additional 6 months. Patients must be closely monitored for relapse. For HBeAg-negative patients, the AASLD recommends continuing treatment until the patient demonstrates HBsAg clearance. The EASL recommends long-term treatment for HBeAg-negative patients. After 6 months of therapy, BW has HBV DNA below detectable levels but he remains HBeAg-positive. BW will most likely need indefinite treatment with an NA. His physician continues monotherapy with tenofovir, and monitors BW every 3 to 6 months for any changes in response. n Table 5. First-line options recommended by AASLD and EASL for CHB treatment Antiviral agent AASLD EASL Tenofovir Entecavir Lamivudine X X Telbivudine X X Adefovir X X Pegylated interferon * *In HBeAg-positive patients with baseline HBV DNA <2 x106 IU/mL and ALT >3 ULN Sources: European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50: ; Lok A, McMahon B. Chronic hepatitis B update: Hepatology. 2009;50:1-36. CASE 3 Managing antiviral resistance Question: What is the most likely cause for the rising ALT level and HBV DNA level in this patient? A) HCC or cirrhosis B) Nonadherence C) Viral resistance to lamivudine D) B or C The risks of HCC and/or progression to cirrhosis are increased with persistent HBV replication. Approximately 1%-4% of patients with CHB develop HCC each year and available evidence indicates that, after diagnosis, the 5-year cumulative incidence of developing cirrhosis ranges from 8% to 20%. While this patient should be regularly screened for HCC and cirrhosis, until recently her antiviral treatment had produced sustained reductions in viral replication. Therefore, HCC or cirrhosis are not per se the most likely causes for the recent increases in HBV DNA and ALT levels. The AASLD guidelines state that the rate at which resistant mutants are selected is related to pretreatment serum HBV DNA level, rapidity of viral suppression, duration of treatment, and prior exposure to NA therapies. When patients show signs of a breakthrough infection, primary nonresponse, or partial virological response during NA therapy, their adherence to antiviral treatment should first be confirmed. This patient has been treated with lamivudine, which has a high rate of antiviral resistance with long-term use. In HBeAg-positive patients, resistance rates approach 70% with lamivudine monotherapy at 5 years. The physician determines that CG has been adherent to her lamivudine regimen and that antiviral resistance may be the cause of the rising ALT and HBV DNA levels. The physician orders resistance testing, which confirms mutations in the HBV polymerase that confer decrease susceptibility or resistance to lamivudine. In the absence of specific resistance testing, an increase in HBV DNA level in a patient who is adherent to his or her oral antiviral therapy can be interpreted as de facto evidence of the emergence of resistance. Question: What would be your approach to addressing lamivudine resistance in this patient? A) Add tenofovir and continue lamivudine B) Add tenofovir and stop lamivudine C) Add pegifn D) Stop lamivudine and switch to telbivudine CG is a 48-year-old woman who was born in sub-saharan Africa and has lived in the US for the past 9 months. She is a professor of literature at a local university. She was diagnosed with CHB while in Africa and has been treated with lamivudine for two years. Her current physician maintained CG on lamivudine because her HBV DNA remained undetectable and her ALT level was stable. CG remains HBeAg-positive. At a 3 month monitoring visit, blood tests for CG showed an elevation in ALT and HBV DNA >2000 IU/mL. Both the AASLD and the EASL have recommendations for managing resistance that may emerge during NA therapy (Table 6). For patients who develop lamivudine resistance, the AASLD recommends adding either adefovir or tenofovir, while continuing lamivudine. Continuing lamivudine reduces the risk of subsequent antiviral resistance and, in the case of adding adefovir, may also reduce the risk of hepatitis flares during the transition period. The EASL also recommends adding tenofovir, but states that adefovir should only be used as an alternative when tenofovir is unavailable. In HIV-coinfected patients, the AASLD recommends an alternative strategy of discontinuing lamivudine and switching to combination therapy with tenofovir and emtricitabine. However, emtricitabine alone or in combination with tenofovir is not indicated in the US for treatment of CHB monoinfection. Emtricitabine is currently under investigation for treatment of CHB. While some evidence suggests that combination therapy with lamivudine and pegifn produces a higher on-treatment response than lamivudine alone, sustained virologic response off-treatment in 5 large studies was no different than that to monotherapy with interferons. Combination therapy with pegifn and lamivudine is not currently recommended by either the EASL or the AASLD to manage lamivudine resistance. Lamivudine and telbivudine are both NAs, and they exhibit cross-resistance: HBV mutations that confer antiviral resistance to lamivudine will also confer resistance to telbivudine. Adding telbivudine is not an option for addressing lamivudine resistance, and the AASLD and the EASL recommend the same measures for addressing telbivudine resistance and lamivudine resistance. The best choice is selection A. Question: What is the best way to prevent development of antiviral resistance with NA therapy? A) Initiate treatment with a potent agent that has a low genetic barrier to resistance B) Initiate treatment with the most potent agent that has the highest genetic barrier to resistance C) Monitor HBeAg levels at 6 month intervals D) Begin treatment with combination therapy Physicians should attempt to prevent resistance at the initiation of treatment. Both the AASLD and the EASL guidelines recommend choosing the most potent agent with the highest genetic barrier to resistance to reduce the risk of antiviral viral resistance. In addition, both sets of guidelines emphasize the importance of monitoring HBV DNA levels every 3 to 6 months for antiviral response, as well as in patients with CHB who are not on therapy. The AASLD also states that unnecessary treatment should be avoided and that patient adherence should be reinforced. While combination therapy has been effective in reducing antiviral resistance in HIV infection, data are currently lacking to support a similar effect in CHB. The best choice is selection B. n Please see CASE STUDY 3 page 7

6 6 COMMON GROUND GAZETTE CASE 4 Achieving the maximum effect in CHB treatment Question: Which of the following is a disease characteristic that is predictive of HBeAg seroconversion with pegifn treatment? A) High viral load B) High serum ALT C) Low activity scores on liver biopsy D) Presence of cirrhosis The EASL guidelines describe disease characteristics that are predictive of HBeAg seroconversion with IFN treatment: these include a low viral load (HBV DNA <107 IU/mL), high serum ALT levels (>3 times ULN), and high activity scores on liver biopsy. The EASL also discusses treatment with standard interferon (IFN). HBeAg-positive patients who experience a decrease in HBV DNA levels to <20,000 IU/mL after 3 months of IFN therapy have a 50% chance of undergoing HBeAg seroconversion. Furthermore, HBeAg-positive patients who experience a reduction in quantitative HBsAg level at 6 months of IFN therapy may eventually seroconvert. HBeAg-negative patients may also be treated with IFN, and a reduction in HBV DNA level to <20,000 IU/mL at 3 months among such patients is associated with a 50% probability of achieving a sustained response. Although in some studies HBV genotypes A and/or B were more likely to respond to therapy with IFN or pegifn than genotypes C and D, both the AASLD and the EASL state that HBV genotype alone should not be used to determine treatment course. The predictors of positive response to interferon therapy described in the AASLD guidelines are similar to those outlined in more detail by the EASL. According to the AASLD, HBeAg-positive patients may be more likely to respond to pegifn if they have ALT levels >2 times ULN, lower HBV DNA levels, and infection with HBV genotype A. However, for HBeAg-negative patients, the AASLD guidelines state there are no established predictors of sustained response. The AASLD does not recommend interferon therapy for patients with compensated or decompensated cirrhosis. According to the EASL guidelines, IFN is contraindicated in patients with decompensated HVB-related cirrhosis, as well as those with autoimmune disease or uncontrolled psychosis or severe depression. However, IFN can be used for the treatment of well-compensated cirrhosis. The best choice is selection B. The physician decides to treat DH with pegifn, and carefully monitors the HBV DNA level for response. After 3 months of treatment, the HBV DNA level was not reduced by at least 1 log10 from baseline levels, indicating a primary nonresponse according to the EASL guidelines. The AASLD definition of primary nonresponse does not apply to DH is a 45-year-old man who was born in Russia and has lived in the US for the past 20 years. DH was recently diagnosed with CHB. His test results show he is HBeAg-positive, with a low viral load (HBV DNA <107 IU/mL), high serum ALT levels (>3 times ULN), and high activity scores on liver biopsy. DH has no evidence of decompensated cirrhosis or HCC. DH s physician discusses with him the relative advantages and disadvantages of therapy with NAs and IFN, and the patient chooses to try pegifn treatment because the treatment period is predetermined. interferon therapy. The physician decides to change DH s treatment regimen. Question: What is the recommended approach to addressing a lack of response to pegifn? A) Add lamivudine B) Add tenofovir C) Switch to treatment with a first-line NA D) Extend treatment to 72 weeks Combination therapy with pegifn and an NA is not currently recommended to address failure to respond to pegifn. The AASLD and the EASL agree that patients who do not adequately respond to interferon therapy should have interferon treatment discontinued and NA therapy initiated. Response to NA therapy is not affected by HBV genotype. Data indicate that response rates to NAs for patients who did not respond to interferon therapy are comparable to those of previously untreated patients. While some recent data suggest that 2 years of treatment with IFN in HBeAg-negative patients and with pegifn in HBeAg-negative patients with HBV genotype D may improve post-treatment response rates, this regimen is not currently recommended by the EASL or the AASLD for any CHB patients, regardless of HBeAg status or HBV genotype. The physician discontinues pegifn for DH and switches the patient to first line NA therapy. His physician closely monitors the patient for response to NA treatment. Question: How is primary nonresponse to NA therapy defined by the AASLD? A) Increase in serum ALT B) Hepatic decompensation C) Decrease in serum HBV DNA by <2 log10 IU/mL after at least 6 months of therapy D) Decrease in serum HBV DNA by < 1 log10 IU/mL from baseline at 3 months of therapy Increased ALT may be a sign of biochemical breakthrough, and hepatic decompensation can be a consequence of emerging antiviral resistance, but neither event is used to determine primary nonresponse to NA treatment. The AASLD and the EASL both recommend measuring HBV DNA serum levels to define primary nonresponse to NA treatment. The AASLD defines primary nonresponse to NA treatment as the failure to achieve a decrease in serum HBV DNA of at least 2 log10 IU/mL after at least 6 months of therapy. The EASL defines primary nonresponse to therapy with NAs or interferon as the failure to achieve a decrease in serum HBV DNA of at least 1 log10 IU/mL from baseline at 3 months of therapy. The AASLD recommends that patients who have a primary nonresponse to NA treatment should be switched to an alternative therapy or receive additional therapy, while the EASL specifies a rapid change to either tenofovir or entecavir in persons who started another oral agent. After 6 months of NA treatment, the physician notes that DH s serum HBV DNA levels were reduced from baseline by >2 log10 IU/ ml, indicating the patient was responding to treatment. The physician continued to closely monitor DH throughout treatment by testing HBV DNA and ALT levels at 3- to 6-month intervals. After 6 months of NA treatment, the patient s HBV DNA levels were undetectable by a commercially available PCR assay. Question: Early sustained suppression of viral replication to below detectable levels is important because it leads to? A) Biochemical remission B) Prevention of complications C) Improvement in liver histology D) All of the above CASE 5 Strategies for treating HBV/HIV coinfection TD is a 41-year-old white male who was recently diagnosed with HIV infection. TD is scheduled to begin HIV treatment shortly. Two recent liver panels showed an elevated ALT level. His physician noted that TD had never been vaccinated for HBV or tested for HBsAg, and screened TD for CHB. Question: What is the estimated prevalence of HBV among patients with HIV? A) <5% B) 6-13% C) 21-27% D) >35% Because HIV and HBV share routes of transmission, all patients with HIV are at risk for HBV infection and should be screened for CHB. A recent observational cohort study in the US calculated the annual prevalence of CHB in HIV-infected patients during from 7.8% to 8.6%, without a statistically significant trend. Other estimates range from 6% to 13%. Worldwide, approximately 2 million to 4 million individuals are coinfected with HIV and HBV. Other important viral coinfections in CHB are HCV and hepatitis D virus (HDV) (see Sidebar: Treatment of HCV or HDV coinfection.) The best choice is selection B. The initial test results for TD showed he was positive for HBsAg and anti-hbc, and negative for anti-hbs. His physician ordered a second round of tests, which showed high levels of HBV DNA. He followed up with a liver biopsy. Results: ALT: 65 U/L HBsAg: positive Anti-HBs: negative Total anti-hbc: positive HBeAg: positive Anti-HBe: negative HBV DNA: >20,000 IU/mL Anti-HCV: negative Elevated HBV DNA levels are an independent risk factor for cirrhosis and HCC. The end point of therapy according to the EASL is to reduce HBV DNA to as low a level as possible, ideally below the lower limit of detection of real-time PCR assays (10-15 IU/mL), to ensure a degree of virological suppression that will then lead to biochemical remission, histological improvement and prevention of complications. Liver disease remission is associated with reduction of HBV DNA to undetectable levels with either IFN or NA treatment. Sustained reduction of HBV DNA is important to decrease the risk of antiviral resistance to NAs and virologic breakthrough during therapy and sustained viral suppression increases the chance of HBsAg loss with mid- to long-term NA treatment in HBeAgpositive and HBeAg-negative patients, and the likelihood of HBe seroconversion in HBeAg-positive patients. In the AASLD recommendations, the end point of treatment of HBeAg-negative patients is not defined; the end point of treatment of HBeAg-positive patients with HBV DNA >20,000 IU/mL and ALT levels >2 times ULN is seroconversion from HBeAg to anti-hbe. n Anti-HDV: negative Liver histology: moderate to severe fibrosis Question: Why is this patient a candidate for CHB treatment? A) His ALT levels are moderately elevated B) He has moderate to severe hepatic fibrosis C) His HBV DNA levels are >20,000 IU/mL D) All of the above The EASL recommends that most coinfected patients be simultaneously treated for both HIV and HBV de novo. The AASLD guidelines state that it is reasonable to base HBV treatment decisions on whether or not HIV treatment is ongoing or planned. Both sets of guidelines agree that patients who meet the criteria for CHB should be treated. Although this patient has moderately elevated ALT levels, he has evidence of moderate to severe liver fibrosis and his HBV DNA levels are above 20,000 IU/mL. Individuals coinfected with HBV and HIV usually have higher levels of HBV DNA and lower rates of spontaneous HBeAg seroconversion. They can also develop liver damage with less liver inflammation, making ALT levels a less reliable indicator of the need for HBV treatment. Effective and prompt treatment of patients with HIV and CHB is important because they are at greater risk of liver-related mortality and cirrhosis than those without HIV coinfection. Liver disease-related deaths are now the most common non-aids-related cause of mortality in patients with HIV infection, and findings from a large-scale study suggest that most of these deaths are associated with HCV or HBV infection.

7 Question: What is the best approach to treating CHB in this patient? A) Begin HIV treatment, followed by CHB treatment B) Treat CHB first, followed by HIV treatment C) Treat CHB and HIV simultaneously D) Begin HIV treatment, monitor HBV DNA The AASLD and EASL guidelines agree that, ideally, treatment for both CHB and HIV should be initiated simultaneously in coinfected patients and should include two drugs that have activity against both HIV and HBV. Three NAs used to treat CHB are also active against HIV: lamivudine, entecavir, and tenofovir. Emtricitabine, used in combination with tenofovir for HIV, is under investigation for treatment of coinfected patients. Lamivudine has a high risk of resistance in CHB patients, and the development of resistance in coinfected patients approaches 90% at 4 years (Figure 3). Lamivudine should not be used as a monotherapy, and only in combination with tenofovir for treatment of coinfections. Tenofovir is effective against lamivudine-resistant HBV and should be added as part of a compete antiretroviral therapy (ART) regimen for coinfected patients receiving treatment for HIV who demonstrate lamivudine resistance. For coinfected patients not previously treated for HIV or HBV, the AASLD recommends combination therapy with tenofovir plus lamivudine or tenofovir plus emtricitabine. The EASL recommends tenofovir plus emtricitabine. Proportion of patients with sustained HBV DNA suppression COMMON GROUND GAZETTE Days of lamivudine therapy* Number of patients under observation Case Study 3 continued from page 5 Table 6. Treatment strategies to address the development of resistance to specific NAs AASLD EASL Prevention n Avoid unnecessary treatment n Initiate treatment with potent antiviral n Initiate treatment with potent antiviral that has low rate of drug resistance or that has low rate of drug resistance or with combination therapy with combination therapy n Switch to alternative therapy in patients with primary nonresponse n Test for serum HBV DNA (PCR assay) every 3-6 months during treatment n Check for medication compliance in patients with virologic breakthrough n Confirm antiviral resistance with genotypic testing Monitoring Treatment Lamivudine resistance n Add adefovir or tenofovir n Stop lamivudine, switch to tenofovir + emtricitabine* Adefovir resistance n Add lamivudine n Stop adefovir, switch to tenofovir + emtricitabine* n Switch to or add entecavir Entecavir resistance n Switch to tenofovir or tenofovir n Add tenofovir a + emtricitabine* Telbivudine resistance n Add adefovir or tenofovir n Add tenofovir b n Stop telbivudine, switch to tenofovir + emtricitabine* Tenofovir resistance n No recommendation n Test HBV DNA levels every 3-6 months during treatment n Assess medication adherence in patients with virologic breakthrough n Identify resistance mutations if possible n Add tenofovir; add adefovir if tenofovir is not available n Switch to tenofovir and add a second drug without cross-resistance n N236T substitution: add lamivudine, entecavir,a or telbivudine or switch to tenofovir + emtricitabine n A181T/V substitution: add entecavir a or switch to tenofovir + emtricitabine* n Resistance to tenofovir has not been described to date n Genotypic and phenotypic testing is recommended to determine crossresistance profile n Possibly add entecavir, telbivudine, lamivudine, or emtricitabine c *In HIV coinfected persons; minimal data are available in non-hiv-infected persons Durability of viral suppression unknown, especially in patients with prior lamivudine resistance Clinical data not available a The safety of entecavir + tenofovir in combination is unknown. b The safety of telbivudine + tenofivir in combination is unknown. c The safety of these drugs in combination with tenofovir is unknown. Sources: European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50: ; Lok A, McMahon B. Chronic hepatitis B update: Hepatology. 2009;50:1-36. Figure 3. Cumulative risk (Kaplan-Meier) for the development of HBV resistance to lamivudine (300 mg/d) in responders *Since the clearance of serum HBV DNA (60 days of lamivudine) Source: Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999;31: According to the AASLD, patients already on an effective ART regimen for HIV that does not include an agent active against HBV may be treated with either IFN or adefovir, depending on the patient s CD4 cell count. IFN can be used to treat patients with CD4 cell counts >500 cells/mm3, but adefovir is recommended for patients with lower CD4 cell counts or for HBeAg-negative patients. The EASL does not provide treatment recommendations for patients with CHB who are already on effective ART for HIV. The AASLD recommends that HBeAgpositive patients who are not scheduled to start ART for HIV in the near future should be treated for CHB with either pegifn or adefovir. The AASLD also recommends earlier initiation of ART for HIV in HBeAg-negative patients who are likely to need treatment for HIV in the future. The EASL recommends combination therapy with telbivudine and Treatment of HCV or HDV coinfection in CHB requires a different approach than monoinfection with HBV HCV coinfection Approximately 14% of patients with CHB in the United States are coinfected with HCV. Coinfected patients are at higher risk of cirrhosis and HCC than patients who have either HCV or CHB alone. Citing a lack of sufficient data, the AASLD guidelines do not provide recommendations on the treatment of patients with CHB who are coinfected with HCV, but do briefly review evidence for treatment of HCV infection in coinfected patients with IFN and ribavirin. The EASL guidelines recommend treating patients coinfected with HBV/HCV with pegifn and ribavirin. Reactivation of HBV may occur during or after clearance of HCV and should be treated with NAs. HDV coinfection HDV occurs only in conjunction with HBV infection or HBV replication. In most studies, NA therapy has not been effective in patients with HDV infection; neither the AASLD nor the EASL recommend treating chronic HDV with an NA alone or in combination with interferon. The AASLD states that IFN is the approved treatment for chronic HDV and mentions that available data support the use of pegifn. The EASL guidelines cite both standard IFN and pegifn as effective against HDV. Both the AASLD and the EASL recommend therapy for at least one year. Case Study 6 continued from page 8 be given to the newborn immediately after delivery. The CDC recommends that HBIG and the first dose of HBV vaccination be administered to newborns of HBsAg-positive women within 12 hours of delivery. Evidence indicates that administration of HBIG and vaccination soon after birth, followed by completion of the three-dose vaccine series, significantly reduces HBV transmission by 85% to 96% in infants born to women who are positive for both HBsAg and HBeAg. The efficacy of HBIG and HBV vaccination in adefovir for coinfected patients; the EASL guidelines do not make specific recommendations based on HBeAg status for these patients. Despite recommendations by the AASLD and the EASL, many HIV experts caution against the use of adefovir alone in persons with HIV. Adefovir is the least effective in lowering viral load, and beginning treatment with a weaker drug will leave fewer treatment options after resistance develops. Little data exists on the efficacy of pegifn in HIV. Lamivudine, emtricitabine, or telbivudine should not be prescribed as monotherapy for HBV in any coinfected patients because of the unacceptably high risk of selection for HBV-resistant mutations. Treatment for HIV and CHB should begin simultaneously, and include two drugs that have activity against both HIV and HBV. n preventing perinatal transmission in women who are HBsAg-positive/HBeAg-negative is unknown. The efficacy of immunoprophylaxis measures may be lower for women with very high HBV DNA levels. Administration of NAs to the newborn is not recommended. The EASL guidelines do not address the issue of precautions for newborns delivered to HBsAg-positive women. HBIG and HBV vaccine should be administered following delivery, to be followed by completion of the three-dose vaccine series. n

8 8 COMMON GROUND GAZETTE CASE 6 Strategies for treating pregnant women Results: ALT: 23 U/L HBsAg: positive Anti-HBs: negative HBeAg: positive Anti-HBe: negative HBV DNA: 8100 IU/mL Anti-HCV: negative Anti-HDV: negative Anti-HIV: negative NL has no signs of chronic liver disease, no hepatosplenomegaly, and an ultrasound showed no abdominal abnormalities. Question: What would your approach be to treating this patient? A) Treat with pegifn B) Treat with select NAs in the third trimester C) Treat with select NAs throughout pregnancy D) She does not require treatment because her HBV DNA level and ALT are low NL is a 25-year-old woman in general good health. She took a home pregnancy test, which showed a positive result, and visited her physician for evaluation. NL is 6 weeks pregnant. As part of the initial evaluation, her physician screened NL for HBV infection and liver function. The AASLD discusses screening and counseling HBsAg-positive pregnant women, but does not specify guidelines for their treatment. The EASL does not provide formal recommendations for treatment of HBsAgpositive pregnant women, but discusses evidence suggesting that treating women with high HBV DNA levels in the third trimester with lamivudine reduces the risk of intrauterine and perinatal transmission. The EASL guidelines mention the accumulated data on the safety of tenofovir and/or lamivudine or emtricitabine in HIV-positive pregnant women. Lamivudine, adefovir and entecavir are pregnancy category C drugs; tenofovir and telbivudine are category B drugs. Use of NAs during pregnancy remains controversial and more data are needed. Patients should be closely monitored following delivery because CHB can be exacerbated following pregnancy, even among women treated with lamivudine during the third trimester. NL does not have a very high level of HBV DNA, and does not currently require treatment. However, NL should be carefully monitored throughout her pregnancy for any evidence of HBV disease flare. Question: What steps should be taken after delivery to prevent perinatal HBV transmission? A) Administer hepatitis B immune globulin (HBIG) to the newborn B) Administer HBV vaccine to the newborn C) Administer NAs to the newborn D) Both A and B More than 90% of infants infected perina- Incidence tally with HBV will eventually develop CHB, as will 25% to 50% of children infected between ages 1-5 years. Approximately 25% of all persons infected as infants or young children will eventually die of liver cancer or cirrhosis. Implementation of HBV vaccination recommendations in the US since 1990 has markedly reduced the incidence of acute HBV in infants and children (Figure 4). However, in 2007, a total of 83 cases of perinatal transmission were reported, which most likely represents less than 1/10 of the actual number of infections that occurred. The AASLD recommends that all HBsAgpositive women advise their health care providers of their HBsAg-positive status so that HBIG and hepatitis B vaccination can Please see CASE STUDY 6 page 7 <15 yrs yrs yrs 45 yrs Year *Per 100,000 population. HealthmattersCME 29 W. 35th Street, Suite 10B New York, NY VOL III/III COMMON GROUND GAZETTE healthmatterscme A CONTINUING MEDICAL EDUCATION COMPANY This activity is jointly sponsored by Postgraduate Institute for Medicine and HealthmattersCME. This activity is supported by an independent educational grant from Gilead Sciences Medical Affairs. FROM PAPER TO PRACTICE COMPARING THE AASLD AND EASL GUIDELINES IN THE CLINICAL SETTING Figure 4. Incidence* of acute hepatitis B, by age group and year United States, Source: Centers for Disease Control and Prevention. Surveillance for Acute Viral Hepatitis United States, Surveillance Summaries, May 22, MMWR. 2009;58(No. SS-3).