Downloaded from gut.bmj.com on June 11, 2014 - Published by group.bmj.com
Gut Online First, published on June 11, 2014 as 10.1136/gutjnl-2014-307398 Commentary
Viral factors and predicting disease outcomes in chronic hepatitis B Peter Revill, Stephen Locarnini One of the conundrums of chronic infection with the hepatitis B virus (HBV) is identifying those individual patients who are at risk for the development of the serious sequelae of cirrhosis and hepatocellular carcinoma (HCC). It has been estimated that 25–40% of patients with chronic hepatitis B (CHB) who acquire the virus early in life (perinatal or early horizontal transmission from an HBeAg-positive source) will eventually develop these serious and disastrous consequences.1 Viral factors associated with the outcome of CHB include hepatitis B e antigen (HBeAg) status, HBV DNA and HBsAg levels (>2000 IU/mL) in serum, HBV genotype and HBV variants, all of which have been shown to positively enhance the risk for disease progression.2–4 The viral variants considered significant risk factors include the basal core promoter (BCP) mutants A1762T/G1764A which have been strongly associated with the development of HCC.5 However, these viral factor associations are not absolute and the need for a viral biomarker that achieves such a goal in patients with CHB is very strong. Dr Tai-Chung Tseng and colleagues6 from Taiwan provide compelling evidence that the presence of BCP mutants A1762T/ G1764A in patients 1 year after HBeAg seroconversion significantly increases risk of cirrhosis in Asian subjects. Moreover, using a quantitative molecular analysis based on pyrosequencing, they also found that patients harbouring a higher percentage (≥45%) of A1762T BCP mutant, had a higher risk for liver cirrhosis than those with a lower A1762T BCP mutant percentage (45%), significant necroinflammatory damage may have already occurred, resulting in bridging fibrosis. The finding that liver cirrhosis risk in genotype B and C patients can now be stratified by the different proportions of BCP mutants provides a compelling argument for the development of new criteria for therapeutic intervention with potent and specific antiviral therapy. These findings strongly indicate that patients with a high percentage of BCP mutants and genotype B/C HBV infection should be candidates for antiviral treatment in order to prevent cirrhosis. Current clinical practice guidelines (CPG) recommend initiating antiviral therapy in HBeAg-negative non-cirrhotic patients on the basis of high viral loads and elevated serum alanine transaminase (ALT).11–13 The detection and enumeration of BCP mutants could now be considered a standard part of the routine work-up for Asian patients with CHB due to their now recognised potential pathological significance. Current molecular methodologies based on pyrosequencing/next-generation sequencing
Revill P, et al.Article Gut Monthauthor 2014 Vol (or 0 No their 0 1 Copyright employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from gut.bmj.com on June 11, 2014 - Published by group.bmj.com
Commentary are not as yet widely available in the routine diagnostic clinical laboratory. To date, their use has found only limited application, in particular, clinical situations in helping to shape clinical decision making in the context of the choice and timing of antiviral therapy. For example, no longer using or recommending lamivudine therapy in the third trimester of pregnancy because of the concern for the selection of drug-resistant mutants by the time of delivery, and their possible transmission to the neonate,14 but rather using high genetic barrier drugs such as tenofovir in this setting. It remains to be determined if these key findings of Tseng and colleagues6 for the role of levels of BCP mutants as an important pathogenomic viral biomarker for increased risk of cirrhosis in Asian patients are also applicable to other HBV genotypes, such as genotype A1 (sub-Saharan Africa), A2 (North America), D (Mediterranean and Eastern European region, Central Asia), E (West Africa) and F (Central America). HBV genotypes have different propensity to select BCP and precore mutations. For example, the G1896A precore mutation rarely emerges in HBV genotype A, in which BCP mutations predominate. Future studies on the association of BCP mutations with development of cirrhosis are warranted across all HBV genotypes, to determine whether integration of a quantitative BCP mutant
2
assay warrants further consideration for inclusion in current CPGs.
Contributors SL and PR contributed equally to the generation of this commentary.
5
6
Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
7
To cite Revill P, Locarnini S. Gut Published Online First: [ please include Day Month Year] doi:10.1136/ gutjnl-2014-307398 Received 20 May 2014 Revised 21 May 2014 Accepted 22 May 2014
8
9
▸ http://dx.doi.org/10.1136/gutjnl-2014-306977
10
Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-307398 11
REFERENCES 1 2
3
4
Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582–92. 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. Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013;57:441–50. Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012;142:1140–9 e3; quiz e13–4.
12
13 14
Liu CJ, Chen BF, Chen PJ, et al. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis 2006;194:594–9. Tseng T-C, Liu C-J, Yang H-C, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut Published Online First: 24 Apr 2014. doi:10.1136/gutjnl-2014-306977 Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010;51:1933–44. Revill P, Yuan Z. New insights into how HBV manipulates the innate immune response to establish acute and persistent infection. Antivir Ther 2013;18:1–15. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J Hepatol 1990;10:29–34. Tedder RS, Bissett SL, Myers R, et al. The ‘Red Queen’ dilemma—running to stay in the same place: reflections on the evolutionary vector of HBV in humans. Antivir Ther 2013;18:489–96. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167–85. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531–61. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661–2. Ayres A, Yuen L, Jackson KM, et al. Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations. J Viral Hepat 11 Dec 2013. Epub ahead of print.
Revill P, et al. Gut Month 2014 Vol 0 No 0
Downloaded from gut.bmj.com on June 11, 2014 - Published by group.bmj.com
Viral factors and predicting disease outcomes in chronic hepatitis B Peter Revill and Stephen Locarnini Gut published online June 11, 2014
doi: 10.1136/gutjnl-2014-307398
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/06/11/gutjnl-2014-307398.full.html
These include:
References
This article cites 11 articles http://gut.bmj.com/content/early/2014/06/11/gutjnl-2014-307398.full.html#ref-list-1
P
Gut Online First, published on June 11, 2014 as 10.1136/gutjnl-2014-307398 Commentary
Viral factors and predicting disease outcomes in chronic hepatitis B Peter Revill, Stephen Locarnini One of the conundrums of chronic infection with the hepatitis B virus (HBV) is identifying those individual patients who are at risk for the development of the serious sequelae of cirrhosis and hepatocellular carcinoma (HCC). It has been estimated that 25–40% of patients with chronic hepatitis B (CHB) who acquire the virus early in life (perinatal or early horizontal transmission from an HBeAg-positive source) will eventually develop these serious and disastrous consequences.1 Viral factors associated with the outcome of CHB include hepatitis B e antigen (HBeAg) status, HBV DNA and HBsAg levels (>2000 IU/mL) in serum, HBV genotype and HBV variants, all of which have been shown to positively enhance the risk for disease progression.2–4 The viral variants considered significant risk factors include the basal core promoter (BCP) mutants A1762T/G1764A which have been strongly associated with the development of HCC.5 However, these viral factor associations are not absolute and the need for a viral biomarker that achieves such a goal in patients with CHB is very strong. Dr Tai-Chung Tseng and colleagues6 from Taiwan provide compelling evidence that the presence of BCP mutants A1762T/ G1764A in patients 1 year after HBeAg seroconversion significantly increases risk of cirrhosis in Asian subjects. Moreover, using a quantitative molecular analysis based on pyrosequencing, they also found that patients harbouring a higher percentage (≥45%) of A1762T BCP mutant, had a higher risk for liver cirrhosis than those with a lower A1762T BCP mutant percentage (45%), significant necroinflammatory damage may have already occurred, resulting in bridging fibrosis. The finding that liver cirrhosis risk in genotype B and C patients can now be stratified by the different proportions of BCP mutants provides a compelling argument for the development of new criteria for therapeutic intervention with potent and specific antiviral therapy. These findings strongly indicate that patients with a high percentage of BCP mutants and genotype B/C HBV infection should be candidates for antiviral treatment in order to prevent cirrhosis. Current clinical practice guidelines (CPG) recommend initiating antiviral therapy in HBeAg-negative non-cirrhotic patients on the basis of high viral loads and elevated serum alanine transaminase (ALT).11–13 The detection and enumeration of BCP mutants could now be considered a standard part of the routine work-up for Asian patients with CHB due to their now recognised potential pathological significance. Current molecular methodologies based on pyrosequencing/next-generation sequencing
Revill P, et al.Article Gut Monthauthor 2014 Vol (or 0 No their 0 1 Copyright employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from gut.bmj.com on June 11, 2014 - Published by group.bmj.com
Commentary are not as yet widely available in the routine diagnostic clinical laboratory. To date, their use has found only limited application, in particular, clinical situations in helping to shape clinical decision making in the context of the choice and timing of antiviral therapy. For example, no longer using or recommending lamivudine therapy in the third trimester of pregnancy because of the concern for the selection of drug-resistant mutants by the time of delivery, and their possible transmission to the neonate,14 but rather using high genetic barrier drugs such as tenofovir in this setting. It remains to be determined if these key findings of Tseng and colleagues6 for the role of levels of BCP mutants as an important pathogenomic viral biomarker for increased risk of cirrhosis in Asian patients are also applicable to other HBV genotypes, such as genotype A1 (sub-Saharan Africa), A2 (North America), D (Mediterranean and Eastern European region, Central Asia), E (West Africa) and F (Central America). HBV genotypes have different propensity to select BCP and precore mutations. For example, the G1896A precore mutation rarely emerges in HBV genotype A, in which BCP mutations predominate. Future studies on the association of BCP mutations with development of cirrhosis are warranted across all HBV genotypes, to determine whether integration of a quantitative BCP mutant
2
assay warrants further consideration for inclusion in current CPGs.
Contributors SL and PR contributed equally to the generation of this commentary.
5
6
Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
7
To cite Revill P, Locarnini S. Gut Published Online First: [ please include Day Month Year] doi:10.1136/ gutjnl-2014-307398 Received 20 May 2014 Revised 21 May 2014 Accepted 22 May 2014
8
9
▸ http://dx.doi.org/10.1136/gutjnl-2014-306977
10
Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-307398 11
REFERENCES 1 2
3
4
Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582–92. 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. Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013;57:441–50. Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012;142:1140–9 e3; quiz e13–4.
12
13 14
Liu CJ, Chen BF, Chen PJ, et al. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis 2006;194:594–9. Tseng T-C, Liu C-J, Yang H-C, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut Published Online First: 24 Apr 2014. doi:10.1136/gutjnl-2014-306977 Thompson AJ, Nguyen T, Iser D, et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010;51:1933–44. Revill P, Yuan Z. New insights into how HBV manipulates the innate immune response to establish acute and persistent infection. Antivir Ther 2013;18:1–15. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J Hepatol 1990;10:29–34. Tedder RS, Bissett SL, Myers R, et al. The ‘Red Queen’ dilemma—running to stay in the same place: reflections on the evolutionary vector of HBV in humans. Antivir Ther 2013;18:489–96. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167–85. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531–61. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661–2. Ayres A, Yuen L, Jackson KM, et al. Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations. J Viral Hepat 11 Dec 2013. Epub ahead of print.
Revill P, et al. Gut Month 2014 Vol 0 No 0
Downloaded from gut.bmj.com on June 11, 2014 - Published by group.bmj.com
Viral factors and predicting disease outcomes in chronic hepatitis B Peter Revill and Stephen Locarnini Gut published online June 11, 2014
doi: 10.1136/gutjnl-2014-307398
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/06/11/gutjnl-2014-307398.full.html
These include:
References
This article cites 11 articles http://gut.bmj.com/content/early/2014/06/11/gutjnl-2014-307398.full.html#ref-list-1
P
