Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME

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1 Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME Chia C. Wang, MD, MS Anna S. F. Lok, MD Kris V. Kowdley, MD Supported by an independent educational grant from Gilead Sciences Medical Affairs View this activity online at:

2 Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME This article is part of a CME certified activity. The complete activity is available at: CME/CE Released: 10/20/2011; Valid for credit through 10/20/2012 Target Audience This activity is intended for gastroenterologists. Goal The goal of this activity is to further educate physicians who manage hepatitis B virus (HBV) in defining treatment goals, reducing time to appropriate initiation of treatment, and increasing the use of predictors of response and continued monitoring strategies to individualize care within the framework of optimal long-term disease management and reduction of liver-related morbidity and mortality. Learning Objectives Upon completion of this activity, participants will be able to: 1. Summarize the goals of HBV therapy and endpoints for treatment based on patient-specific characteristics 2. Integrate factors involved in disease progression, baseline predictors of treatment response, and on-treatment predictors of treatment response into the development of individualized treatment strategies 3. Differentiate among types of treatment response to actively and effectively care for patients receiving HBV antiviral therapy, including determination of when to stop or alter therapy Credits Available Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s) All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Accreditation Statements For Physicians Medscape, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC, designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Medscape, LLC staff have disclosed that they have no relevant financial relationships. For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact CME@medscape.net Pg.2

3 Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit, you must receive a minimum score of 70% on the post-test. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape Education encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing Edit Your Profile at the top of your Medscape homepage. *The credit that you receive is based on your user profile. Hardware/Software Requirements To access Medscape Education users will need A computer with an Internet connection. Internet Explorer 6.x or higher, Firefox 2.x or higher, Safari 2.x or higher, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader. Authors and Disclosures As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines relevant financial relationships as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Authors Chia C. Wang, MD, MS Clinical Assistant Professor of Medicine, University of Washington; Infectious Diseases Physician, Virginia Mason Medical Center, Seattle, Washington Disclosure: Chia C. Wang, MD, MS, has disclosed no relevant financial relationships. Dr. Wang does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the US Food and Drug Administration (FDA) for use in the United States. Dr. Wang does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Pg.3

4 Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME Anna S. F. Lok, MD Professor, Department of Internal Medicine; Alice Lohrman Andrews Research Professor in Liver Disease; Director, Clinical Hepatology; Associate Chair for Clinical Research, Department of Internal Medicine, University of Michigan, Ann Arbor Disclosure: Anna S. F. Lok, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Bristol-Myers Squibb Company; Gilead Sciences, Inc.; GlaxoSmithKline; Bayer HealthCare Pharmaceuticals; Roche Received grants for clinical research from: Bristol-Myers Squibb Company; Gilead Sciences, Inc.; GlaxoSmithKline; Roche; Merck & Co., Inc. Dr. Lok does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr. Lok does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Kris V. Kowdley, MD Director, Center for Liver Disease, Virginia Mason Medical Center; Clinical Professor of Medicine, University of Washington School of Medicine, Seattle, Washington Disclosure: Kris V. Kowdley, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Novartis Pharmaceuticals Corporation; Vertex Pharmaceuticals Incorporated; Pharmasset, Inc.; Merck & Co., Inc.; Gilead Sciences Received grants for clinical research from: Bristol-Myers Squibb Company; Intercept; Abbott Laboratories; Pharmasset, Inc.; Merck & Co., Inc.; Mochida Pharmaceutical Co., Ltd.; Conatus Pharmaceuticals Dr. Kowdley does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr. Kowdley does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Editor Julia Muino Scientific Director, Medscape, LLC Disclosure: Julia Muino has disclosed no relevant financial relationships. Pg.4

5 Introduction There are 7 approved therapies for chronic hepatitis B virus (HBV) infection: 2 formulations of interferon (IFN) (standard and pegylated IFN [PEG-IFN]) and 5 nucleos(t)ide analogs (NUCs): lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. Although these therapies are effective in suppressing HBV replication, they do not eradicate the virus. Most patients, therefore, require a long duration of treatment and sometimes lifelong treatment to derive clinical benefit. Given that treatment is expensive and may be associated with drug resistance and adverse effects -- and because not all patients with chronic HBV infection progress to cirrhosis or hepatocellular carcinoma (HCC) -- questions regarding HBV treatment remain. Guidelines from professional organizations and recommendations from consensus conferences provide a framework to guide physicians in deciding when to start treatment, which treatment to use, and when to stop treatment. [1-4] Guidelines, however, are just that, and treatment decisions should be made jointly by the patient and physician after careful consideration not only of clinical features, hepatitis B e antigen (HBeAg) status, serum HBV DNA, and alanine aminotransferase (ALT) levels, and liver histology (when available), but also individual circumstances such as family history of HCC, occupational requirements, plans for starting a family (in women), and comorbid conditions such as those that may preclude the use of IFN or increase the likelihood of adverse events. In clinical practice, other considerations, such as the patient s perceived risk for adverse outcomes if they opt to defer treatment, cost (or copay), and willingness to undergo parenteral therapy or to adhere to many years of oral therapy, may influence a patient s decision of both when to start treatment and the choice of therapy (Table 1). This review focuses on individualized treatment strategies. Table 1. Factors to Consider in Treatment Decisions Factors in disease progression Age Gender Duration of infection HBV replication: HBeAg status, HBV DNA level Liver disease: ALT level, histology (inflammation and fibrosis), clinical evidence of portal hypertension, cirrhosis Factors associated with treatment response Activity of liver disease: ALT level, histology (inflammation) HBV replication: HBeAg status, HBV DNA level HBV genotype (IFN treatment only) Factors specific to the individual patient Symptoms Age Plans to start a family in women of reproductive age Occupational requirements Family history of HCC Patient s perception of risk for adverse outcomes if hepatitis B is left untreated Patient s perception of likelihood of treatment response and benefit Cost and healthcare coverage Patient preference: willingness to commit to IFN therapy or a long course of oral medications ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; IFN = interferon Adapted from Degertekin B, et al. Hepatology. 2009;49(Suppl1):S129-S137. Pg.5

6 Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME Choosing Appropriate Drug Therapy Once a decision to initiate treatment is made, the next step is to choose the appropriate drug. The decision regarding whether to use NUC or IFN is based on patient characteristics and patient preferences (Table 2). Table 2. Comparison of Pegylated Interferon and Nucleos(t)ide Analogs Consideration Route of administration Duration of treatment Antiviral activity Drug resistance Immunomodulatory activity HBeAg seroconversion HBsAg loss Predictors of response Adverse events Decompensated liver disease Compensated cirrhosis Pregnancy Pegylated Interferon Parenteral, SC injection 1 year Modest NA Yes ~ 30% after 1 year treatment ~ 3% after 1 year ~ 10% after 3-5 years of post-treatment follow-up High ALT, low HBV DNA Genotype A (HBeAg-positive patients) Frequent (flu-like symptoms, fatigue, bone marrow suppression, depression) Contraindicated Selected cases, use with care Class C, contraindicated Nucleos(t)ide Analogs Oral A few years to lifelong Modest: ADV Strong: LAM Strongest: ETV, TDF, TBV 0%-20% after 1 year Low: ETV, TDF Higher: ADV, TBV Highest: LAM No ~ 20% after 1 year treatment 40%-50% after 5 years continuous treatment 0%-3% after 1 year 0%-8% after 4-5 years continuous treatment High ALT, low HBV DNA Rare (nephrotoxicity [ADV, TDF]; myositis, myalgia [TDF]; lactic acidosis [class effect]) Indicated Indicated LAM, ADV, ETV: class C TDF, TBV: class B LAM, TDF: safe in humans based on registry data ADV = adefovir dipivoxil; ALT = alanine aminotransferase; ETV = entecavir; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; LAM = lamivudine; SC = subcutaneous; TBV = telbivudine; TDF = tenofovir disoproxil fumarate Data from Lok AS, et al. Hepatology. 2007;5: [1] Pg.6

7 Interferon The main advantage of IFN is that it is administered for a finite duration. IFN also seems to be associated with a higher rate of hepatitis B surface antigen (HBsAg) loss, although this benefit is seen mainly in patients with genotype A infection. Clinical trials showed that a 1-year course of IFN results in a higher rate of HBeAg seroconversion than a similar duration of lamivudine treatment, [5] but in clinical practice, NUCs are administered for longer than 1 year, and similar or higher rates of HBeAg seroconversion can be achieved after 3-5 years of continuous NUC treatment. [6-9] Pretreatment factors that have been shown to predict IFN-related response in HBeAg-positive patients include high ALT (a surrogate for host immune response to HBV), low HBV DNA, and HBV genotype A. [10] These data have led to development of models to guide decisions regarding IFN treatment. Recently, decline in HBsAg titer at week 12 or 24 during PEG-IFN treatment had been suggested to predict sustained response off-treatment, and it may be used to decide whether to continue treatment. [11] These algorithms have not, however, been validated prospectively, and the optimal cutoff values have not been determined. Retrospective analysis of data from the registration trial of PEG-IFN alpha-2a with or without lamivudine in HBeAg-negative patients showed that patient age and gender, HBV genotype, and pretreatment ALT and HBV DNA levels were associated with sustained response off-treatment, but the predictive accuracy has not been validated and appears to be dependent on genotype. [12] Decline in HBsAg titer during PEG-IFN treatment had also been demonstrated to predict sustained response, and a working group suggested that suboptimal decline in HBsAg titer and HBV DNA after 12 weeks of treatment should be used as a stopping rule in HBeAg-negative patients, particularly those with genotype D infection. [11] Nucleos(t)ide Analogs Major advantages of NUCs include ease of administration (oral), potent antiviral activity, and favorable safety profile. The main disadvantages of NUCs include risk for drug resistance and the need for a long duration of treatment (often lifelong). Of the 5 approved NUCs, entecavir, tenofovir, and telbivudine have more potent antiviral activity followed by lamivudine and then adefovir dipivoxil. Entecavir and tenofovir have a higher genetic barrier to resistance (ie, lower rates of drug resistance) followed by adefovir dipivoxil, telbivudine, and then lamivudine. The most consistent predictor of response to NUC in HBeAg-positive patients is high pretreatment ALT. [13,14] Predictors of response to NUC in HBeAg-negative patients have not been established. Unlike IFN, response to NUC is similar across the major HBV genotypes (A-D). Although all 5 NUC agents approved for hepatitis B are well tolerated, lactic acidosis has been reported in a case series of entecavir treatment in patients with severe liver decompensation [15] ; myalgia, myositis, and peripheral neuropathy in patients receiving telbivudine [16] ; and nephrotoxicity and renal tubular dysfunction in patients receiving adefovir dipivoxil or tenofovir. [17,18] Tenofovir and telbivudine are categorized as class B drugs regarding safety in pregnancy, with the other NUCs as well as IFN categorized as class C drugs. Based on data from the antiretroviral pregnancy registry, lamivudine and tenofovir appear to be safe even when used in the first trimester of pregnancy. [19] Comment Currently, monotherapy with a NUC or PEG-IFN is recommended as initial therapy. Although combination therapy has potential advantages, neither combination of PEG-IFN+NUC or combination of 2 NUCs had been shown to induce higher rates of sustained response. The main advantage of combination therapies is a reduction in rate of lamivudine resistance compared with lamivudine monotherapy. Given the low rate of resistance to entecavir or tenofovir, the benefit of de novo combination therapy involving either of these drugs is limited. [8,9] IFN should not be used in patients who have decompensated cirrhosis, severe exacerbations of chronic hepatitis B, immunosuppression, or medical or psychiatric contraindications. IFN may be used with caution in patients with compensated cirrhosis provided they have normal hepatic synthetic function and no evidence of portal hypertension. IFN is most appropriate for young patients, those who are reluctant to commit to a long duration of treatment, and HBeAg-positive patients who have high pretreatment ALT levels or genotype A infection. Pg.7

8 Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME NUCs are most appropriate for patients who have decompensated liver disease or contraindications to IFN, and those who are willing to commit to long durations of treatment. Of the 5 approved NUCs, entecavir and tenofovir have the best profile regarding safety, efficacy, and drug resistance. Tenofovir is preferred in patients who might be contemplating pregnancy and in those who might have been exposed to lamivudine or telbivudine in the past. Tenofovir can be administered with or without food and is more convenient for patients who have difficulty in adhering to their medication regimen. Entecavir is preferred in patients who have other medical conditions, such as diabetes or hypertension that are associated with increased risk for renal insufficiency. Lamivudine and telbivudine should not be used because of the high rates of drug resistance unless cost is a limiting factor and the anticipated duration of treatment is short (eg, prophylaxis in patients who will be receiving immunosuppressive therapies). Adefovir dipivoxil should not be used because of its weak antiviral activity. When to Discontinue Treatment Ideally, antiviral therapy should be continued until HBsAg loss, but the likelihood of this occurring is low: HBsAg loss occurs in approximately 10% of patients 3-5 years after completing a 1-year course of PEG-IFN, and in up to 10% of patients after 4-5 years of continuous NUC therapy. [5-9] Interferon Recommended duration of PEG-IFN treatment is 48 weeks for both HBeAg-positive and HBeAg-negative patients. Recent studies suggest that on-treatment decline in HBsAg titer may be used to define early stop rules, but this strategy must be validated in prospective clinical studies. Nucleos(t)ide Analogs NUCs are often administered indefinitely because of the high risk for viral relapse when treatment is discontinued. Treatment can, however, be stopped in patients who have achieved the desired endpoint. For HBeAg-positive patients with precirrhotic liver disease, treatment can be discontinued 12 months after achieving HBeAg seroconversion. Although some studies demonstrated that durability of NUC-related HBeAg seroconversion is low, many of these studies involved small numbers of patients or inadequate duration of consolidation therapy. One study found that the 5-year cumulative rate of relapse after discontinuation of lamivudine was only 9% in patients with 12 months of consolidation therapy. [20] Some experts argue that treatment should be continued indefinitely because reactivation of HBV replication and progression to HBeAg-negative hepatitis will occur in most, if not all, patients, but long-term follow-up studies showed that some patients can remain in the inactive carrier state for decades. These data indicate that if patients are well monitored, disease progression can be prevented if treatment is reinitiated when HBV DNA, ALT levels, or both become elevated. Committing all patients to lifelong treatment because of possible future reactivation would be akin to lifelong cancer chemotherapy to prevent future relapse in patients who have achieved remission. The therapeutic endpoint is unclear for HBeAg-negative precirrhotic patients. Treatment is often continued indefinitely, but may be stopped in those who achieved HBsAg loss. Preliminary data from one small study suggest that treatment can be stopped in selected patients who maintain viral suppression for 3-5 years. These data have not, however, been validated. [21] For patients who had decompensated liver disease or cirrhosis, lifelong treatment is recommended because of concerns about fatal flares when treatment is discontinued. Treatment may be stopped, however, in selected patients with compensated cirrhosis who have lost HBsAg or have completed an adequate duration of consolidation therapy after HBeAg seroconversion (in those who were previously HBeAg positive) provided they are closely monitored and treatment reinstituted in the presence of viral rebound or ALT elevation. This recommendation is supported by studies that demonstrate regression of cirrhosis in patients with maintained viral suppression after 3-5 years of NUC therapy. [22] Although it has been suggested that patients with inadequate or slow decline in HBV DNA during the first weeks of NUC monotherapy should receive an additional NUC, this approach was derived from studies of lamivudine and telbivudine. Studies of entecavir and tenofovir (which have high genetic barriers to resistance) found that HBV DNA levels continued to decline in patients with slow initial response, and rates of drug resistance were low in patients who remained on the same treatment. [9,23] Summary Decisions regarding when to start treatment, which therapies to use, and when to stop treatment must take into consideration not only viral or disease factors, but also individual patient circumstances and preferences to achieve optimal results. Supported by an independent educational grant from Gilead Sciences. Pg.8

9 References 1. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;5: Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med. 2009;50: European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009;50: Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2: Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135: Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125: Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48: Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51: Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140: Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137: Chan HL. Hepatitis B surface antigen quantification: Why and how to use it in A core group report. J Hepatol Jun 28. [Epub ahead of print] 12. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56: Abstract 13. Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36: Abstract 14. Wu IC, Lai CL, Han SH, et al. Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsyproven histological damage. Hepatology. 2010;51: Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50: Liaw YF, Gane E, Leung N, et al; the GLOBE Study Group. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136: Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al; Adefovir Dipivoxil 438 Study Group. Long-term therapy with adefovir dipivoxil for HBeAgnegative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131: Verhelst D, Monge M, Meynard JL, et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis. 2002;40: The Antiretroviral Pregnancy Registry. Accessed September 14, Lee HW, Lee HJ, Hwang JS, et al. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology. 2010;51: Hadziyannis S, Sevastianos V, Rapti I. Outcome of HBeAg-negative chronic hepatitis B (CHB) 5 years after discontinuation of long term adefovir dipivoxil (ADV) treatment. J Hepatol. 2009;50(Suppl 1):S9-S Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52: Zoutendijk R, Reijnders JG, Brown A, et al; VIRGIL Surveillance Study Group. Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naïve patients with a partial virological response. Hepatology. 2011;54: Pg.9