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When to Start and Stop Hepatitis B Treatment: Can One Set of Criteria Apply to All Patients Regardless of Age at Infection?

Bulent Degertekin, MD; and Anna S.F. Lok, MD
[+] Article and Author Information

From the University of Michigan Health System, Ann Arbor, MI 48109.


Grant Support: By Ufuk University Faculty of Medicine, Ankara, Turkey (Dr. Degertekin), and the Tuktawa Fund for Liver Research and Education at the University of Michigan (Dr. Lok). Dr. Lok is supported in part by National Institutes of Health contract N01 DK-9-2323 and grants U01 DK57577 and U01 DK62498.

Potential Financial Conflicts of Interest: Consultancies: A.S.F. Lok (Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix, Innogenetics, Pharmasset, Roche, Schering-Plough); Grants received: A.S.F. Lok (Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix, Innogenetics, Roche, Schering-Plough).

Requests for Single Reprints: Anna S.F. Lok, MD, Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, Ann Arbor, MI 48109-0362; e-mail, aslok@med.umich.edu.

Current Author Addresses: Drs. Degertekin and Lok: Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, Ann Arbor, MI 48109-0362.


Ann Intern Med. 2007;147(1):62-64. doi:10.7326/0003-4819-147-1-200707030-00011
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Existing guidelines for the treatment of hepatitis B virus (HBV) infection recommend that only patients with active or advanced liver disease and high serum HBV DNA levels be treated and that, in patients who are initially seropositive for hepatitis B e antigen (HBeAg), treatment can be stopped 6 months after HBeAg seroconversion (13). In this issue, Lai and Yuen (4) raise concern that those recommendations are inappropriate for patients with perinatal HBV infection. They propose that patients with normal alanine aminotransferase (ALT) levels who acquire infection early in life should also be treated and that HBeAg-positive patients should continue treatment after HBeAg seroconversion. The 2007 update of the American Association of the Study of Liver Disease guidelines (5) address some of Lai and Yuen's concerns by recommending that treatment also be considered for patients with intermittent or mildly elevated ALT levels; those who remain HBeAg- positive with high serum HBV DNA levels after 40 years of age; and HBeAg-negative patients with HBV DNA levels of 10 000 to 100 000 copies/mL (2000 to 20 000 IU/mL), particularly if liver histologic examination shows significant inflammation or fibrosis (5). Here, we put other aspects of their proposal in the context of existing evidence.

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HBeAg Seroconversion as Treatment End Point
Posted on October 3, 2007
Ching-Lung Lai
The University of Hong Kong
Conflict of Interest: None Declared

TO THE EDITOR: We write in response to the comments in the Editorial by Degertekin and Lok (1) to our article (2).

The Editorial states that ¡§although HBV replication after HBeAg seroconversion can be reactivated ¡K, an occurrence of 30% over 10 years does not justify continuing treatment for patients¡¨ (1). A 30% occurrence rate is very high. The risk of myocardial infection with hypercholesterolemia in a placebo-controlled trial is 7.9% at 5 years (3); no physician would consider stopping the treatment for hypercholesterolemia once the lipid levels are normalized. More importantly, the Editorial only considers the risk of reactivation of viral replication, whereas the most serious risks in the hepatitis B e antigen (HBeAg)-negative patients are the risks for the development of cirrhosis complications and hepatocellular carcinoma (HCC), both occurring more often in HBeAg-negative patients with HBV DNA levels greater than 10000 copies/mL, and are independent of the HBeAg status of the patients (4).

The Editorial further states that ¡§transition (from the inactive carrier state to HBeAg-negative hepatitis) is not unique to patients with perinatal hepatitis B virus (HBV) infection; in fact it is most commonly associated with genotype D, which is usually acquired during childhood or during adulthood¡¨ (1). This is not true. A recent study of 173 children from Northern Greece, all with genotype D, shows that 61.8% of Thracian Muslims acquire the HBV infection from infected mothers and another 26.2% acquired it horizontally through family contact, i.e., 87% are infected during early childhood, similar to the Asians (5). This explains the high risk for the development of cirrhosis complications and HCC in these populations.

Finally the Editorial states that ¡§HBeAg seroconversion seems an appropriate treatment in most patients¡K This is particularly true when a strict definition of HBeAg seroconversion ¡V namely, HBeAg loss, HBe antibody detection, a nondetectable (or very low) serum HBV DNA level, and normalization of (ALT) values ¡V is used as the treatment end point¡¨ (1). This ¡§strict¡¨ definition of HBeAg seroconversion is no where implied in the 2007 Guidelines of the American Association for the Study of Liver Diseases, where HBV DNA level is not mentioned as an end point. Adopting this ¡§strict¡¨ definition is indeed what we advocate: that HBeAg seroconversion is not an ideal sole criteria for a treatment end point, but should be accompanied by low HBV DNA levels (preferably to below the threshold of detectability by polymerase chain reaction) and ALT normalization (2).

Ching-Lung Lai, MD, Man-Fung Yuen, MD, PhD, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.

Potential Financial Conflicts of Interest: None disclosed.

References

1. Degertekin B, Lok AS. When to start and stop hepatitis B treatment: can one set of criteria apply to all patients regardless of age at infection? Ann Intern Med. 2007;147:62-4. [PMID: 17606963]

2. Lai CL, Yuen MF. The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria and end points. Ann Intern Med. 2007;147:58-61. [PMID: 17606962]

3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-7. [PMID: 7566020]

4. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of Hepatocellular Carcinoma Across a Biological Gradient of Serum Hepatitis B Virus DNA Level. JAMA. 2006;295:65-73. [PMID: 16391218]

5. Zacharakis G, Koskinas J, Kotsiou S, Pouliou E, Papoutselis M, Tzara F, et al. Natural history of chronic hepatitis B virus infection in children of different ethnic origins: a cohort study with up to 12 years' follow-up in northern Greece. J Pediatr Gastroenterol Nutr. 2007;44:84-91. [PMID: 17204959]

Conflict of Interest:

None declared

In Response
Posted on October 14, 2007
Anna S Lok
University of Michigan
Conflict of Interest: None Declared

Dear Editor

We appreciate the comments of Drs. Lai and Yuen on our editorial (1).

We agree that life-long maintenance therapy would be preferred when safe, affordable and effective treatment is available to prevent disease recurrence. However, the safety of life-time use of nucleos/tide analogue therapies for hepatitis B has not been established. Adefovir is associated with a small risk of nephrotoxicity. Entecavir at high doses in rodents was associated with a variety of tumors, prompting the manufacturer to pledge a 10-year follow-up study to establish its long-term safety in humans. Furthermore, currently available hepatitis B treatments are very expensive; and efficacy of these treatments in maintaining viral suppression is diminished by the selection of drug- resistant mutations during long-term therapy. Even in cancers that have the propensity for late recurrence, treatment is discontinued after disease remission or after a finite duration of consolidation therapy (2).

We are in complete agreement that cirrhosis and hepatocellular carcinoma are the key outcomes of chronic hepatitis B virus (HBV) infection. However, as Drs. Lai and Yuen indicated, persistently high HBV DNA level is the most important predictor of these outcomes. Thus, the risk of adverse outcomes after treatment discontinuation is related to the risk of reactivation of viral replication.

Drs. Lai and Yuen cited a recent paper in Greek children showing that 21 of 34 Muslim Thracians (62%) had an HBV-infected mother. However, this study did not determine if the mothers were the source of infection and if the infection was acquired perinatally. In this same study, only 47 of 121 Christian Thracians (39%) had an HBV-infected mother (3). Other studies from Italy and Greece, where HBV genotype D is preponderant reported increase in prevalence of chronic HBV infection with age, with the highest prevalence in those above the age of 40, supporting that HBV infection in these countries is mostly acquired during childhood and adult life (4,5).

While the strict definition of hepatitis B e antigen (HBeAg) seroconversion was not spelled out in the 2007 American Association for the Study of Liver Diseases Practice Guidelines, a recent analysis of 74 patients who lost HBeAg after 48 weeks of entecavir therapy found that 70 had HBeAg seroconversion, 71 had undetectable HBV DNA by PCR assay, and 63 had normalization of aminotransferases; supporting that the vast majority of patients who achieve HBeAg seroconversion during nucleos/tide analogue therapy meet the strict definition of HBeAg seroconversion (6).

Bulent Degertekin, MD and Anna SF Lok, MD Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA

References

1- Degertekin B, Lok AS. When to start and stop hepatitis B treatment: can one set of criteria apply to all patients regardless of age at infection? Ann Intern Med. 2007 Jul 3;147(1):62-4. [PMID: 17606963]

2- Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001 May 2;93(9):684-90. [PMID: 11338583]

3- Zacharakis G, Koskinas J, Kotsiou S, Pouliou E, Papoutselis M, Tzara F, et al. Natural history of chronic hepatitis B virus infection in children of different ethnic origins: a cohort study with up to 12 years' follow-up in northern Greece. J Pediatr Gastroenterol Nutr. 2007;44:84-91. [PMID: 17204959]

4- Stroffolini T, Guadagnino V, Chionne P, Procopio B, Mazzuca EG, Quintieri F, Scerbo P, Giancotti A, Nistico S, Foca A, Tosti ME, Rapicetta M. A population based survey of hepatitis B virus infection in a southern Italian town. Ital J Gastroenterol Hepatol. 1997 Oct;29(5):415-8. [PMID: 9494849]

5- Sypsa V, Hadjipaschali E, Hatzakis A. Prevalence, risk factors and evaluation of a screening strategy for chronic hepatitis C and B virus infections in healthy company employees. Eur J Epidemiol. 2001;17(8):721- 8. [PMID: 12086089]

6- Gish, R.G., Lok, A.S., Chang, T.T., de Man, R.A., Gadano, A., Sollano, J., Han, K.H., Chao, Y.C., Lee, S.D., Harris, M., Yang, J., Colonno, R., Brett- Smith, H., Entecavir Therapy up to 96 Weeks in Patients with HBeAg-Positive Chronic Hepatitis B, Gastroenterology (2007), DOI: 10.1053/j.gastro.2007.08.025.

Conflict of Interest:

None declared

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