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Hepatitis B: Explosion of New Knowledge; Comments by E Keefe
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Gastroenterology Nov 2007
Emmet B. Keeffe
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
See "Entecavir therapy up to 96 weeks in patients with HBeAg-positive chronic hepatitis B," by Gish RG, Lok AS, Chang TT, on page 1437; "Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients," by Lampertico P, Vigano M, Manenti E, et al, on page 1445; "Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F," by Livingston SE, Simonetti JP, Bulkow LR, et al on page 1452; and "Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B," by Chu CM, Liaw YF on page 1458.
As regular readers of Gastroenterology and Clinical Gastroenterology and Hepatology appreciate, a steady flow of publications in both journals continues to expand our knowledge of the natural history and management of chronic hepatitis B virus (HBV) infection. This explosion of new knowledge is appropriate and much needed, because chronic hepatitis B is an important public health problem globally and in the United States. It is estimated that worldwide up to 400 million people have chronic HBV infection,1, 2 and treatment options to control active viral replication and disease progression continue to expand.3, 4, 5 Although the prevalence of HBV infection in the United States is lower than in many other countries, an estimated 1.25 million individuals are infected.6 However, this prevalence figure is likely to be an underestimate; the immigrant Asian American population, with high background rates of HBV infection, has increased significantly over the last decade to approximately 13 million individuals in 2005.7 Asians and Asian Americans infected early in life have a long-term risk for the development of cirrhosis and/or hepatocellular carcinoma (HCC) that ranges from 15% to 25%.1
Natural History
The natural history of chronic HBV infection has been divided into 4 phases: immune tolerance, immune clearance, inactive hepatitis B surface antigen (HBsAg) carrier state, and reactivation.2 The immune tolerance phase is present in children and young adults and characterized by the presence of hepatitis B e antigen (HBeAg), high serum HBV DNA levels, and persistently normal alanine aminotransferase (ALT) levels. This phase is present in those infected early in life, but generally absent when infection occurs in adulthood, as in Caucasians and African Americans. This period of immune tolerance is followed by an immune clearance phase (HBeAg-positive chronic hepatitis B) that lasts for a variable period of time; it is characterized by high HBV DNA levels as before, but now elevated ALT levels and features of chronic hepatitis on liver biopsy. Clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) results in transition to the inactive HBsAg carrier state; serum HBV DNA is <2000 IU/mL (∼104 copies/mL) and ALT levels are normal. However, some patients under immune pressure develop viral mutations (precore or core promoter) that do not produce HBeAg, but continue to replicate at high levels and cause various degrees of liver damage. This fourth reactivation phase of chronic HBV infection, referred to as HBeAg-negative chronic hepatitis B, is characterized by fluctuation of serum HBV DNA levels, typically from 2000 to 2,000,000 IU/mL, persistently or intermittently elevated ALT levels, and progressive liver damage on liver biopsy.
Treatment
Patients in the immune clearance or reactivation phases are candidates for therapy.2, 3, 4, 5 Over the past 15 years, treatment options for chronic hepatitis B have expanded to include 4 licensed oral nucleoside or nucleotide agents, including lamivudine, adefovir, entecavir, and telbivudine, and 2 immune modulating agents, including interferon alfa-2b and peginterferon alfa-2a.3, 4, 5 In addition, phase III studies of tenofovir versus adefovir in patients with HBeAg-positive and HBeAg-negative disease show superiority of tenofovir that will likely lead to licensure of this agent in 2008 for the treatment of chronic hepatitis B.8, 9 The impact of these increasing treatment options is only beginning to be recognized, but there is a growing literature showing that antiviral therapy is associated with improved long-term outcomes in patients with chronic hepatitis B.3, 4, 5, 10, 11 However, the development of antiviral drug resistance associated with the use of the oral agents is a potential limitation to their long-term effectiveness.12
In this issue of Gastroenterology, 2 papers further expand our knowledge of the natural history of chronic HBV infection,13, 14 a third paper confirms the safety and efficacy of extended entecavir therapy with a low rate of resistance,15 and a fourth paper demonstrates the effectiveness of the combination of lamivudine plus adefovir for treatment of lamivudine resistance.16 In a prospective cohort study of 1158 Alaska Native persons, Livingston et al13 showed that the time to HBeAg clearance was significantly longer in persons with genotype C as compared with those with genotypes A, B, D, and F. The age at which 50% of persons cleared HBeAg was <20 years of age for those infected with genotype A, B, D, and F versus 47.8 years of age for those with genotype C. Although a limitation of this study is the lack of serum HBV DNA and ALT measurements throughout the entire study period, there are several important implications of the findings of this report. Women with genotype C chronic HBV infection of childbearing ages are more likely to be HBeAg positive and have high serum HBV DNA levels, and are therefore more likely to infect their offspring. In addition, the much longer period of active viral replication, particularly if associated with the immune clearance phase with high ALT levels and active histologic disease, puts individuals with genotype C a greater risk for the development of cirrhosis and HCC. This hypothesis is supported by seminal cohort studies from Taiwan showing that higher baseline HBV DNA levels predict a greater incidence of both cirrhosis and HCC over a period of 12-13 years of follow-up.17, 18 Livingston et al13 also demonstrated that persons with genotypes C and F were more likely to revert back to detectable HBeAg after losing HBeAg than individuals infected with other genotypes. This study, as well as other studies over the past several years,19, 20 indicates that genotype C is associated with several more adverse outcomes when compared with genotype B or other genotypes (Table 1). These observations raise the controversial issue of whether or not clinicians should include testing for HBV genotype as part of the baseline evaluation of patients with chronic HBV infection. Many practitioners are already embracing this testing strategy, and it is possible that future guidelines will make this recommendation, as the presence of genotype C may direct more aggressive management such as earlier therapy or initiation of surveillance programs for detection of HCC at a younger age.
In the second paper in this issue of Gastroenterology regarding the natural history of HBV infection, Chu and Liaw14 studied reactivation of hepatitis B, as defined by a positive HBV DNA by hybridization assay (detection sensitivity 1.4 X 105 copies/mL, or ∼25,000 IU/mL) and >2-fold elevation of ALT, in 133 HBeAg-positive carriers who had undergone HBeAg seroconversion. There were 75 men and 58 women; 108 subjects had genotype B and 25 genotype C. The strength of this study is that all patients were followed from the immune tolerant phase through immune clearance with HBeAg seroconversion to an inactive carrier state. During a mean follow-up of 5.8 years after HBeAg seroconversion, reactivation occurred in 3.3% of patients per year, and the cumulative probabilities of reactivation were 15.1%, 29.8%, and 32.8% after 5, 10, and 15 years of follow-up, respectively. Multivariate analysis demonstrated that reactivation correlated with genotype C, confirming the observations of Livingston et al,13 as well as male gender, ALT >5 times the upper limits of normal during the HBeAg phase, and age ≥40 years at the time of HBeAg seroconversion. Genotype was the most significant predictor of reactivation, with patients having genotype C 3.8 times more likely to reactivate than those with genotype B.
In the third hepatitis B paper in this issue of Gastroenterology, Gish et al15 expand on previously published 1-year pivotal studies of entecavir21, 22 and demonstrate that entecavir therapy through 96 weeks has continued and incremental benefit for patients with HBeAg-positive chronic hepatitis B, with safety comparable to lamivudine and a very low rate of resistance. In the original pivotal study of patients with HBeAg-positive chronic hepatitis B,21 709 patients were randomized to entecavir 0.5 mg (n = 354) or lamivudine 100 mg (n = 355) once daily. Protocol-defined virologic responders (serum HBV DNA <0.7 MEq/mL [∼140,000 IU/mL] but no loss of HBeAg) were the subjects of the current study, and included 243 patients receiving entecavir and 164 patients receiving lamivudine into the second year. The cumulative rates for entecavir-treated versus lamivudine-treated patients with HBV DNA <300 copies/mL (∼50 IU/mL) were 80% versus 39%, respectively (P < .0001), but HBeAg seroconversion rates were not different (31% and 25%, respectively). No patient developed virologic breakthrough owing to entecavir resistance.
The study design of the entecavir pivotal trials has been a subject of debate, predominantly related to the cohort of patients who were categorized as "nonresponders" at week 48 based on serum HBV DNA ≥0.7 MEq/mL (∼140,000 IU/mL) and discontinued therapy per protocol.21, 22 This design has been felt to underestimate the potential of entecavir therapy to result in the selection of antiviral drug-resistant mutants because therapy was not continued in these subjects. However, preliminary report of a 4-year assessment of the rate of resistance with entecavir therapy in nucleoside-naive and lamivudine-refractory patients provides some reassurance regarding this concern.23 In this study, all patients with detectable HBV DNA at weeks 48, 96, 144, 192, or the end of dosing were genotyped and subsequently phenotyped if they experience a virologic breakthrough. Of the 663, 278, 149, and 120 nucleoside-naive patients treated with entecavir and monitored for resistance in years 1, 2, 3, and 4, respectively, a total of 3 patients (<1%) had evidence of entecavir substitutions and only 2 patients experienced virologic breakthrough. In lamivudine-refractory patients, virologic breakthrough owing to entecavir resistance was observed in 1%, 10%, 16%, and 15% of patients during years 1, 2, 3, and 4, respectively. Thus, entecavir continues to demonstrate a high genetic barrier to resistance in nucleoside-naive patients, with a cumulative probability of a virologic breakthrough in 0.8% of patients. However, in lamivudine-refractory patients, the cumulative probability of a virologic breakthrough was 40%.
Finally, in the fourth hepatitis B paper in this issue of Gastroenterology, Lampertico et al16 demonstrate a low rate of resistance to adefovir when this drug is used in combination with lamivudine in Caucasian patients with preexisting lamivudine resistance. In this study, 145 lamivudine-resistant patients were treated with adefovir 10 mg in addition to continued lamivudine 100 mg daily. During 42 months of treatment, the 4-year cumulative rate of de novo detection of the adefovir resistance mutation rtA181T was 4%, and no patient experienced virologic or clinical breakthrough. The results of this study are far superior to several prior reports showing that 20%-25% of patients with lamivudine resistance treated with adefovir monotherapy subsequently develop adefovir mutations during 2 years of therapy. This important study provides further evidence to support current recommendations for an "add" rather than "switch" strategy in patients with lamivudine resistance.3, 4, 5
In summary, the natural history of chronic hepatitis B through the 4 phases of infection-immune tolerance, immune clearance, inactive carrier, and reactivation-is variable in individual patients, and patients with genotype C appears to have several more adverse outcomes when compared to patients with other genotypes (Table 1). The treatment of chronic hepatitis B continues to improve, and long-term follow-up data of entecavir treatment provides confidence that this drug represents an important advance based on its high potency and low rate of antiviral drug resistance, pointing to a high genetic barrier to resistance. Finally, patients with lamivudine resistance should be treated with an "add" rather than "switch" strategy, using adefovir, or possibly tenofovir, as an alternative option.
References
1. Ganen D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med. 2004;350:1118-1129. CrossRef
2. Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. MEDLINE | CrossRef
3. Keeffe EB, Dieterich DT, Han SB, et al.. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962. Abstract | Full Text | Full-Text PDF (310 KB) | MEDLINE | CrossRef
4. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539. MEDLINE | CrossRef
5. Lok ASF. Navigating the maze of hepatitis B treatments. Gastroenterology. 2007;132:1586-1594. Full Text | Full-Text PDF (244 KB) | MEDLINE | CrossRef
6. McQuillan GM, Coleman PJ, Kruszon-Moran D, et al.. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health. 1999;89:14-18. MEDLINE
7. US Census Bureau State and County Quickfacts: 01 February 2005. Available at: http://quickfacts.census.gov/qfd/states/00000.html. Accessed September 16, 2007.
8. Phase III study evaluating Gilead's Viread for the treatment of chronic hepatitis B virus meets primary endpoint [press release on the Internet]. Updated June 6, 2007. Available at: www.gilead.com/pr_1012569. Accessed September 16, 2007.
9. Second phase III study evaluating Gilead's Viread for the treatment of chronic hepatitis B virus meets primary endpoint [press release on the Internet]. Updated June 25, 2007. Available at: www.gilead.com/pr_1018988. Accessed September 16, 2007.
10. Liaw YF, Sung JJ, Chow WC, et al.. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531. CrossRef
11. Arora G, Keeffe EB. Chronic hepatitis B with advanced hepatic fibrosis or cirrhosis: impact of antiviral therapy. Rev Gastroenterol Disord. 2007;7:63-73.
12. Ghany M, Liang TJ. Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. Gastroenterology. 2007;132:1574-1585. Abstract | Full Text | Full-Text PDF (3214 KB) | MEDLINE | CrossRef
13. Livingston SE, Simonetti JP, Bulkow LR, et al.. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology. 2007;133:1452-1457. Abstract | Full Text | Full-Text PDF (208 KB) | CrossRef
14. Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology. 2007;133:1458-1465. Abstract | Full Text | Full-Text PDF (521 KB) | CrossRef
15. Gish RG, Lok AS, Chang TT, et al.. Entecavir therapy up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133:1437-1444. Abstract | Full Text | Full-Text PDF (303 KB) | CrossRef
16. Lampertico P, Vigano M, Manenti E, et al.. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445-1451. Abstract | Full Text | Full-Text PDF (538 KB) | CrossRef
17. Chen CJ, Yang HI, Su J, et al.. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73. CrossRef
18. Iloeje UH, Yang HI, Su J, et al.. Predicting cirrhosis risk based on level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686. Abstract | Full Text | Full-Text PDF (181 KB) | MEDLINE | CrossRef
19. Kramvis A, Kew M, Francois G. Hepatitis B virus genotypes. Vaccine. 2005;23:2409-2423. CrossRef
20. Liu CH, Kao JH. Hepatitis B virus genotypes: what should the clinician know?. Current Hepatitis Reports. 2007;6:17-23.
21. Chang TT, Gish RG, de Man R, et al.. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010. CrossRef
22. Lai CL, Shouval D, Lok AS, et al.. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011-1020. CrossRef
23. Colonno RJ, Rose RE, Pokornowski K, et al.. Four year assessment of ETV resistance in nucleoside-naive and lamivudine refractory patients. J Hepatol. 2007;46:S294;[abstract 781]. Full-Text PDF (149 KB) | CrossRef
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