HEPATOLOGY, July 1998, p. 265-267, Vol. 28, No. 1
Chronic Carriers of Hepatitis B Virus Who Clear Hepatitis B Surface Antigen: Are They Really "Off the Hook"?
Worldwide there are approximately 350 million carriers of Hepatitis B virus (HBV).1 As many as one million of these carriers develop hepatocellular carcinoma (HCC) each year, and countless others develop end-stage liver disease. In most of the world, the majority of carriers are infected either in infancy or during the first 5 years of life through either perinatal exposure or close person-to-person contact with other infected children. In developed countries, such as the United States, many people who become Hepatitis B surface antigen (HBsAg)-positive carriers are believed to have been infected as adults predominately through sexual exposure or by injection drug use.
Over the past couple of decades, a great deal has been learned about the serological course of chronic HBV. After a child or infant is first infected and becomes a carrier of HBsAg, he/she has high levels of HBV DNA in his/her sera and will be positive for Hepatitis B e antigen (HBeAg) for many years. Whereas many people who are HBeAg positive have active liver disease, as evidenced by elevated liver transaminase levels and chronic hepatitis on biopsy, others who are infected in early childhood, especially children from Asia, have normal transaminase levels and are asymptomatic carriers. Years later the majority of carriers eventually lose HBeAg and develop antibody to HBeAg. In most of these persons undergoing seroconversion from HBeAg to antibody to HBeAg, levels of HBV DNA decrease substantially, even undetectable in some, and chronic hepatitis improves.1 The rate of clearance of HBeAg averages between 8% and 12% per year. One study comparing age and sex to clearance of HBeAg showed that clearance was higher in women than in men and in younger persons than in older persons.2 In some of the carriers who are cleared of HBeAg, reactivation of hepatitis can occur as evidenced by the reappearance of HBeAg and rise in transaminase levels.3 In some carriers who lose HBeAg, a mutation in the pre-core region of the HBV genome occurs; that mutation results in the inability of the virus to make HBeAg.4 These persons can have high levels of HBV DNA and active liver disease on biopsy. Whereas the majority of carriers of HBV are HBsAg positive for life, some carriers are eventually cleared of HBsAg and may develop antibody to HBsAg. An Alaskan, population-based study of 1,400 HBsAg-positive carriers, who were followed for a total of 7,815 carrier years, showed that the rate of clearance of HBsAg in these carriers was 0.3% per year.5 Clearance of HBsAg was significantly higher in women than in men and in older than in younger carriers.
In this issue of HEPATOLOGY, Huo et al.6 present data on 1,335 chronic carriers of Hepatitis B followed for a mean period of 33 months.6 HBsAg was cleared in 58 carriers defined by a negative test on two consecutive samples. Two persons had received anti-viral therapy and one had cirrhosis; that left 55 persons who were untreated and had no evidence of clinical cirrhosis at the time of HBsAg clearance. Of those 55 people, 22 developed anti-HBs levels above 10 SRU, 10 had levels < 10 SRU, and the other 13 never developed antibody to HBsAg. The authors found HBV DNA in 16 of 51 (31.4%) persons after they had been cleared of HBsAg. However, in 75% of these individuals, HBV DNA was found <2 months after the loss of HBsAg; it is uncertain if these persons were tested for HBV DNA at a time more distant from their loss of HBsAg. During a mean follow-up of 23 months after clearance of HBsAg (range, 1-180 months), 18 (32.7%) of these 55 persons developed a liver complication. Of those 55 patients, 11 developed HCC, 6 developed liver cirrhosis, and 1 developed subfulminant hepatitis.
Twenty-three persons who had cleared HBsAg had other hepatotrophic viruses, besides Hepatitis B, including Hepatitis C virus, Hepatitis D virus, and acute Hepatitis A. Six of these persons with other hepatrophic viruses developed a liver complication. Thus, only 32 patients who cleared HBsAg were solely infected with HBV. The authors should have removed patients with other hepatrophic viruses from the analysis. Of the persons who developed HCC, seven of the nine who underwent tumor resections had underlying cirrhosis. Because the authors did not report that liver biopsies were done before the clearance of HBsAg, it is conceivable that the cirrhosis in these patients was present before seroconversion and, therefore, put them at significant risk of developing HCC. Also, as the mean time from clearance of HBeAg to the development of a serious liver complication was short and as the period of time between the beginning of HCC and clinical presentation can be long, some of the persons who developed HCC may have been incubating this tumor before seroconversion.
Despite these concerns, this paper shows that some chronic HBV carriers who were cleared of HBsAg can have serious liver complications later in life. Why is this possible? Persons who develop acute HBV and clear HBsAg within a few months are unlikely to have serious complications later caused by HBV. However, when a persons fails to clear HBsAg after acute HBV and then becomes a chronic carrier, the integration of HBV into genome of the human hepatocyte invariably occurs in all carriers. Studies have shown that integrated HBV DNA can result in chromosomal rearrangement and deletions, which, in turn, could result in the expression of oncogenes or deletion of genes regulating hepatocyte growth (suppressor genes).7 In addition, during the active phase of HBsAg carriage, when persons are HBeAg-positive, significant liver damage leading to cirrhosis can occur. Cirrhosis per se has been shown to be a risk factor for HCC. When chronic HBV becomes less active, some people can be left with compensated cirrhosis. Either the development of cirrhosis and/or the prior integration of HBV DNA in carriers before the clearance of HBsAg could result in an increased risk for development of HCC. In the classic, Taiwanese epidemiologic study by Palmer Beasley's group of 3,454 HBsAg-positive and 19,253 HBsAg-negative people, the relative risk of developing HCC was 100 in HBsAg-positive versus -negative persons.8 However there was an increased relative risk of 5 in people who were antiibody to Hepatitis B core antigen-positive in comparison with those who were negative for all HBV seromarkers. Could these persons in Beasley's study who were HBsAg-negative/antibody to Hepatitis B core antigen-positive be former carriers as those described by Huo et al.6 who had cleared HBsAg and later developed HCC? To answer the question regarding the risk of HCC and other liver complications in carriers who are cleared of HBsAg, large prospective studies are needed following both carriers who have cleared HBsAg and those who have not. These studies should exclude persons who are co-infected with other hepatatrophic viruses, such as Hepatitis C virus and Hepatitis D virus which could confound the outcome. Huo et al.'s large cohort of carriers in Taiwan would be an ideal group to continue to follow if persons with Hepatitis C virus and Hepatitis D virus are eliminated or analyzed separately. Until more data become available, however, we are left with the real possibility that carriers who clear HBsAg may still be at substantial risk for HCC and other liver complications. As recommended for HBsAg carriers, these "former carriers" who cleared HBsAg should be followed with periodic surveillance with alpha-fetoprotein and/or ultrasound to attempt to detect HCC in an early, potentially resectable stage.9 In addition to the risk of liver related complications in HBV carriers who cleared HBsAg, these persons may be able to transmit HBV, as evidenced by studies demonstrating rare transmission of HBV from persons who are HBsAg-negative but antibody to Hepatitis B core antigen-positive to HBV-seronegative persons via blood transfusion, or organ donation.
Whereas previous data suggests that the natural history of HBV carriage in Asians differs from that of Europeans, there is little comparative data to clarify the characteristics and extent of those differences. Whereas liver cancer may be a more frequent complication of chronic HBV carriage in Asians than in Westerners, presumably because infection occurred mainly in childhood in Asia versus adulthood in Westerners, cirrhosis occurs in both groups. For example, two studies on HBsAg carriers, one from Asia and one from the Netherlands, both showed that cirrhosis and liver failure was associated with failure to clear HBeAg.10,11 On the other hand, a study of HBsAg-positive asymptomatic blood donors from Italy, who were predominately HBeAg-negative/antibody to HBeAg-positive showed a relatively benign course over a mean 11-year follow-up.12 More prospective studies on the natural history of chronic HBV in Asia and Western countries are needed to clarify the risks of complications in these different population groups.
What about carriers who are treated with anti-viral therapy and who are cleared of HBV DNA? Carriers who respond best to interferon alfa are those who are HBeAg positive, have low levels of HBV DNA, have liver transaminase levels > 1.5 times normal, and have a biopsy showing active hepatitis. Only a minority of carriers will meet these criteria, as most adult carriers are HBeAg negative and many HBeAg-positive carriers infected early in life in areas endemic for HBV have normal transaminase levels. In addition, HBeAg-positive carriers in endemic areas, such as Asia, appear to respond less well to interferon.13 The proportion of carriers who clear HBeAg with anti-viral therapy and who, subsequently, lose HBsAg is higher than those who lose HBsAg without therapy.14,15 Are these successfully treated persons at a risk of future liver complications? The recent studies are not well designed, consisting of a relatively small number of participants with insufficient follow-up for answering this question. It appears that HBV carriers who fail to clear HBeAg are at a much higher risk of developing end stage liver disease than those who clear HBeAg even if clearance occurs naturally. 16 Treatment with interferon clearly accelerates the clearance of HBeAg, and clearance of HBeAg appears to decrease the risk of end stage liver disease.16,17 However, one study following interferon treated and untreated carriers for a mean of 7 years showed that the clearance of HBeAg over time was the same for both groups.17 Furthermore, what little follow-up data on treated patients is available does not demonstrate a clear difference between the treated and untreated carriers in the subsequent development of HCC. What is needed are large well-designed prospective studies of HBsAg-positive carriers who are successfully treated with anti-viral agents compared with carriers who have failed anti-viral therapy and untreated controls. In this age of outcome measurements in health care delivery this information is extremely important because substantial dollars are being spent on the development and testing of new anti-viral agents for HBV and the treatment of carriers with currently licensed anti-viral drugs. Unfortunately, funding for these important natural history studies is limited. Nevertheless, we should encourage these studies, or we may never learn if anti-viral therapy in chronic HBV infection truly reduces the subsequent risk of HCC and other serious liver related sequelae.
Brian J. McMahon M.D.
Director, Viral Hepatitis Program
Alaska Native Medical Center
Abbreviations: HBV, Hepatitis B virus; HCC, hepatocellular carcinoma; HBsAg, Hepatitis B surface antigen; HBeAg, Hepatitis B e antigen.
From the Alaska Native Medical Center, Anchorage, Alaska.
Received May 11, 1998; accepted May 19, 1998.
Address reprint requests to: Brian J. McMahon, M.D., Centers for Disease Control and Prevention, Arctic Investigations Program, 4055 Tudor Centre Drive, Anchorage, AK 99508-5902. Fax: (907) 729-3429.
1. Lee W. Hepatitis B Virus Infection. N Engl J Med 1997; 337: 1733-1745[Medline].
2. Alward WLM, McMahon BJ, Hall DB, Heyward WL, Francis DP, Bender TR. The serologic course of Hepatitis B surface antigen and e antigen and the development of primary hepatocellular carcinoma in asymptomatic carriers of Hepatitis B virus. J Infect Dis 1985; 151: 604-609[Medline].
3. Davis G, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of chronic Hepatitis B virus infection. Gastroenterology 1984; 86: 230-235[Abstract].
4. Brown JL, Carman WF, Thomas HC. The clinical significance of molecular variation within the Hepatitis B virus genome. HEPATOLOGY 1992; 15: 144-148[Medline].
5. McMahon BJ, Alberts SR, Wainwright RB, Bulkow L, Lanier AP. Hepatitis B-related sequelae. Prospective study in 1400 Hepatitis B surfaceantigen-positive Alaska Native carriers. Arch Intern Med 1990; 150: 1051-1054[Medline].
6. Huo T-I, Wu J-C, Lee P-C, Chau G-Y, Lui W-Y. Tsay S-H, Ting L-T, et al. Sero-clearance of Hepatitis B surface antigen in chronic carriers not necessarily implies a good prognosis. HEPATOLOGY 1998; 28: 231-236[Abstract/Full Text].
7. Tabor E. Tumor suppressor genes, growth factor genes, and oncogenes in Hepatitis B virus-associated hepatocellular carcinoma. J Med Virol 1994; 42: 357-365[Medline].
8. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-1956[Medline].
9. McMahon BJ, London T. Workshop on screening for hepatocellular carcinoma. J Natl Cancer Inst 1991; 83: 916-919[Medline].
10. Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. HEPATOLOGY 1988; 8: 493-496[Medline].
11. De Jongh FE, Janssen HLA, De Man RA, Hop WCJ, Schalm SW, Van Blankenstein M. Survival and prognostic indicators in Hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992; 103: 1630-1635[Abstract].
12. de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, Rumi MG, et al. The natural history of asymptomatic Hepatitis B surface antigen carriers. Ann Intern Med 1993; 118: 191-194[Medline].
13. Lok ASF, Chung H-T, Vincent WS, Ma OCK. Long-term follow-up of chronic Hepatitis B patients treated with interferon alfa. Gastroenterology 1993; 105: 1833-1838[Abstract].
14. Korenman J, Baker B, Waggoner J, Everhart, Di Bisceglie AM, Hoofnagle JH. Long-term remission of chronic Hepatitis B after alpha-interferon therapy. Ann Intern Med 1991; 114: 629-634[Medline].
15. Evans AA, Fine M, London WT. Spontaneous seroconversion in Hepatitis B e antigen-positive chronic Hepatitis B: Implications for interferon therapy. J Infect Dis 1997; 176: 845-850[Medline].
16. Niederau C, Heintges T, Lange S, Goldman G, Niederau CM, Mohr L, Haussinger D. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic Hepatitis B. N Engl J Med 1996; 334: 1422-1427[Medline].
17. Fattovich G, Giustina G, Realdi G, Corroacher R, Schalm SW, the European Concerted Action on Viral Hepatitis (EUROHEP). Long-term outcome of Hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. HEPATOLOGY 1997; 26: 1338-1342[Abstract].
Copyright © 1998 by the American Association for the Study of Liver Diseases.
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