Gastroenterology
Volume 130, Issue 3 , Pages 989-991, March 2006

Hepatitis B Virus Replication x Time Equals Trouble

  • Robert Perrillo

      Affiliations

    • Corresponding Author InformationAddress correspondence to: Robert Perrillo, MD, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121. fax: (504) 842-7466

Ochsner Clinic Foundation, New Orleans, Louisiana

Article Outline

 

Hepatitis B is the most common cause of cirrhosis and hepatocellular carcinoma in the world today. This can be explained by the high rate of hepatitis B virus (HBV) infection worldwide, with an incidence of more than 50 million new cases a year and a prevalence of over 350 million HBV carriers. In highly endemic countries most individuals acquire HBV infection as a result of exposure in the perinatal period or during early childhood. Strikingly, the lifetime risk of developing HBV-related cirrhosis or hepatocellular carcinoma has been estimated to be between 15% and 40% for males who acquire infection during early life.1 These clinical outcomes are interrelated because 80% to 90% of patients with HBV-related hepatocellular carcinoma have underlying cirrhosis.2

Variability in the rate of progression to cirrhosis may be related to differences in the clinical and serological features of disease. In untreated patients with HBeAg-positive chronic hepatitis B the incidence of cirrhosis has been calculated to vary from 2% and 5% per 100 person years with a 5-year cumulative incidence of 8%–20%.3 An even higher rate of cirrhosis has been reported in HBeAg-negative chronic hepatitis B.4 The severity of fibrosis stage at presentation correlates with the risk of cirrhosis, and the time to development of cirrhosis is longer in patients with milder forms of hepatitis.5 Repeated episodes of severe acute exacerbation that are unaccompanied by HBeAg seroconversion has been shown to predict a higher rate of cirrhosis.6 Ongoing HBV replication detected by sustained or intermittent HBV DNA positivity by direct hybridization assays and older age also have been shown to correlate with a greater risk of cirrhosis.7 The significance of increasing age as a risk factor may reflect the prolonged duration of the underlying liver disease in conjunction with the accumulation of exposure to environmental risk factors such as aflatoxin in highly endemic areas.8

Many studies have demonstrated a link between viral replication, liver injury, and disease complications in chronic hepatitis B. Serum HBV DNA level has been shown to directly correlate with histologic grading and stage of disease, and a response to antiviral therapy reduces progression of fibrosis.9, 10 Also, patients with genotype C have been shown to have delayed HBeAg seroconversion, longer periods of viremia, a greater risk of progressive disease, and a correspondingly higher rate of cirrhosis and hepatocellular cancer.11 Another important line of evidence that links viral replication to disease complications comes from large, longitudinal cohort studies of Asian patients.12, 13 In a study from Taiwan, the incidence rates for hepatocellular carcinoma in males were 1169 cases per 100,000 person-years among those positive for both HBsAg and HBeAg at the time of enrollment, 324 for persons positive for HBsAg only, and 39 for those who were negative for both.13 The relative risk was 60.2 in the group positive for both markers and 9.6 for those with HBsAg alone. Further study by the authors indicated that serum ALT at baseline was also independently predictive for risk of hepatocellular carcinoma, implying that chronic necroinflammation may also contribute to the development of hepatocellular carcinoma.

At the current time much of the information on the long-term risk of HBV replication has come from tertiary care centers and have not been population-based studies. The data, therefore, could be affected by patient selection bias. Moreover, the studies have used relatively insensitive signal amplification or hybridization assays to detect HBV DNA, which do not allow one to determine if values below 105 copies (approximately 2 × 104 IU/mL) are associated with a lower risk of disease complications. In this issue of Gastroenterology, Iloeje et al14 present the results of a large population-based survey of 3583 Taiwanese residents living in 7 townships. The patient mix included relatively equal numbers of males and females between the ages of 30 and 65 years, and unlike previous studies the authors used polymerase chain testing for quantification of HBV DNA in serum. During a mean follow-up time of 11 years, 365 subjects were newly diagnosed with cirrhosis. A major finding of this study was that the cumulative incidence of cirrhosis increased with the HBV DNA level and varied from nearly 5% for individuals with non-detectable HBV DNA to 36% for persons in whom the level was greater to or equal to 106 copies/mL. Cox proportional hazards models indicated that when adjusting for HBeAg status, gender, age, serum ALT, and other variables, serum HBV DNA was the strongest predictor of progression to cirrhosis with relative risk values of 2.5, 5.6, and 6.5 when HBV DNA levels were equal to or greater than 104, 105, and 106 copies/mL, respectively.

At first look, this study provides very compelling evidence that HBV DNA level is strongly correlated with the risk of cirrhosis and implies that lower levels than those incorporated in current treatment guidelines (≥ 105 copies/mL) might serve as a useful threshold for antiviral therapy.15, 16, 17 These data are reminiscent of additional findings in the study by Yang et al13 in which the adjusted odds ratio of developing hepatocellular carcinoma in HBeAg-negative persons also varied according to HBV DNA level. However, the reader should be reminded that the large cohort studies by Yang and Iloeje are limited by the fact that replication markers were only evaluated at the time of enrollment. Thus, no information is given about the duration of viral replication as it relates to the clinical endpoints. Serum samples were obtained every 6 to 12 months in the study by Iloeje; thus, testing for HBV DNA at predefined intervals and at the time of the diagnosis of cirrhosis would have been helpful in clarifying to what extent the duration and sustainability of viral replication affects progression to cirrhosis. Also, we are given no information on the risk of cirrhosis as it relates to particular genotypes. Presumably, the vast majority of patients were genotype Ba or genotype C, and the latter has been associated with a higher risk of cirrhosis and hepatocellular carcinoma in individuals over the age of 50 in Taiwan.18 Another potential limitation is that the diagnosis of cirrhosis was based on ultrasonographic criteria alone which is not sensitive enough to detect all cases (approximately 80% sensitivity).19 Thus, the platelet count and prothrombin time of the cirrhotic and non-cirrhotic patients would have been useful information to further substantiate the diagnosis of cirrhosis. Finally, while the multivariate model indicated that HBV DNA level was the best predictor for cirrhosis, the ALT data reported in the study does not allow one to properly address whether or not more intense necroinflammation, as reflected by higher ALT levels, increases the risk further in a patient with high serum HBV DNA. Instead of reporting ALT in a dichotomous fashion (ie, elevated or non-elevated), dividing ALT levels into quartiles (eg, < 1 × ULN, > 1 but < 2 × ULN, 2-5 × ULN, and greater than 5 × ULN) would have been one way of further studying this possible association.

Chronic hepatitis B is a dynamic disorder with periods of HBV replication-induced liver injury interspersed with periods of relative quiescence or more intense viral replication and worsened cellular injury. Therefore, the relative risk of cirrhosis (and other complications) as it relates to HBV replication status can not be most accurately delineated through cross-sectional survey, case cohort studies, or case control studies in which viral replication is measured at one interval. To better define the question of how continuing viral replication affects disease progression, a long-term population-based follow-up study on a randomly selected, large cohort with repeated measurements of HBV infection markers and aminotransferase levels would be needed. Ideally, all of the major genotypes (A to D) should be represented, and a liver biopsy or serum test for fibrosis markers at predefined intervals should provide confirmation of extent of disease.20

Such a study would be a large undertaking demanding significant resources and international participation. Also, a prospective natural history study would have to incorporate adequate patient safeguards that address the need for therapeutic intervention because antiviral therapy has been shown to improve liver histology, forestall disease progression and even reduce the incidence rate for hepatocellular carcinoma.21, 22, 23 Thus, the primary endpoint would have to be time to reaching a predefined indicator of disease progression (eg, change in fibrosis score) other than cirrhosis. Despite these seeming obstacles, a long-term follow up of HBV carriers with periodic assessments of viral replication, disease status, and predefined criteria for treatment could lead to earlier treatment and has the potential to prevent future complications as well as save lives.

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References 

  1. Maddrey WC . Hepatitis B (an important public health issue) . J Med Virol . 2000;61:362–366
  2. Nair S , Perrillo RP . Hepatitis B and D . In:  Zakim D ,  Boyer T editor. 4th ed. Hepatology. A textbook of liver disease . 2: Philadelphia: Saunders; 2003;p. 959–1016
  3. Fattovich G . Natural history of hepatitis B . J Hepatol . 2003;39:S50–S58
  4. Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients (a long-term cohort study) . J Hepatol . 2002;36:263–270
  5. Ikeda K, Saithor S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis (a prospective study of 2215 patients) . J Hepatol . 1998;28:930–938
  6. Liaw Y-F , Tai D-I , Chu C-M , Chen T-J . The development of cirrhosis in patients with chronic type B hepatitis (a prospective study) . Hepatology . 1988;8:493–496
  7. Fattovich G, Brollo L, Giustina F, Noventa F, Pontisso P, Alberti A, et al. Natural history and prognostic factors for chronic hepatitis type B . Gut . 1991;32:294–298
  8. Kensler TW , Egner PA , Wang JB , Zhu YR , Zhang BC , Lu PX . Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas . Gastroenterology . 2004;127:S310–S318
  9. Yuen M-F, Ng IO-L, Fan S-T, Yuan H-J, Wong DK-H, Yuen JC-H, et al. Significance of HBV DNA levels in liver histology of HBeAg and anti-HBe positive patients with chronic hepatitis B . Am J Gastroenterol . 2004;99:2032–2037
  10. Mommeja-Marin H , Mondou E , Blum R , Rousseau F . Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection (analysis and review of the literature) . Hepatology . 2003;37:1309–1319
  11. Fung SK , Lok ASF . Hepatitis B virus genotypes (do they play a role in the outcome of HBV infection?) . Hepatology . 2004;40:790–792
  12. Yu M-W, Hsu F-C, Sheen I-S, Chu C-M, Lin D-Y, Chen C-J, et al. Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers . Am J Epidemiol . 1997;145:1039–1047
  13. Yang H-I, Lu S-N, Liaw Y-F, You S-L, Sun C-A, Wang L-Y, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma . N Engl J Med . 2002;347:168–174
  14. Iloeje UH , Yang H-I , Su J , Jen C-L , Chen C-J . Predicting cirrhosis risk based on the level of circulating hepatitis B viral load . Gastroenterology . 2006;130:678–686
  15. Lok ASF , McMahon BJ . Chronic hepatitis B (update of recommendations) . Hepatology . 2004;39:857–861
  16. Liaw Y-F, Leung N, Guan R, Lau GKK, Merican I, McCaughan G, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B (A 2005 update) . Liver International . 2005;25:472–489
  17. EASL Jury . EASL international consensus conference on hepatitis B (consensus treatment) . J Hepatol . 2003;39:533–540
  18. Kao JH , Chen PJ , Lai MY , Chen DS . Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B . Gastroenterology . 2000;118: 554–549
  19. Lin D-Y , Sheen I-S , Chiu C-T , Lin S-M , Kuo Y-C , Liaw YF . Ultrasonographic changes of early liver cirrhosis in chronic hepatitis B (a longitudinal study) . J Clin Ultrasound . 1993;21:303–308
  20. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C . Hepatology . 2003;38:518–526
  21. Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B . N Engl J Med . 1996;334:1422–1427
  22. Van Zonneveld M, Honkoop P, Hansen BE, Niesters HG, Murad SD, de Man RA, et al. Long-term follow-up of alpha interferon treatment of patients with chronic hepatitis B . Hepatology . 2004;39:804–810
  23. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease . N Engl J Med . 2004;351:1521–1531

 Dr. Perrillo is a consultant to Gilead Sciences, Roche Pharmaceuticals, and Bristol Myers Squbb.

PII: S0016-5085(06)00196-X

doi:10.1053/j.gastro.2006.01.070

Refers to article:

  • Predicting Cirrhosis Risk Based on the Level of Circulating Hepatitis B Viral Load , 23 November 2005

    Uchenna H. Iloeje, Hwai–I. Yang, Jun Su, Chin–Lan Jen, San–Lin You, Chien–Jen Chen, The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group
    Gastroenterology March 2006 (Vol. 130, Issue 3, Pages 678-686)

Gastroenterology
Volume 130, Issue 3 , Pages 989-991, March 2006

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