Journal of Viral Hepatitis, 2014
doi:10.1111/jvh.12370
REVIEW
Treating Immune-tolerant Hepatitis B T.-C. Tseng1,2 and J.-H. Kao3,4,5,6
1
Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The
2
Buddhist Tzuchi Medical Foundation, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan; 3Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; 4Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; 5Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; and 6Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan Received August 2014; accepted for publication October 2014
SUMMARY. Hepatitis B virus (HBV) infection is a major cause
of cirrhosis and hepatocellular carcinoma worldwide. On the basis of virus–host interactions, the natural history of HBV carriers can be divided into four chronological phases. In the first immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication activity, normal ALT levels as well as minimal liver disease. Ample evidence has shown that patients in the immune tolerance phase have very low viral evolution and minimal risk of fibrosis progression. However, recent immunological studies argued that HBV-specific immune responses already exist in a proportion of immune-tolerant patients and the immune activities are comparable to those in the immune clearance phase. Regarding antiviral therapy, whether these immune-tolerant patients are indicated for treatment remains debated. Previous studies showed that HBeAg-positive patients with normal or near-normal ALT
INTRODUCTION Although safe and effective vaccines have been available for nearly three decades, hepatitis B virus (HBV) infection is still an important public health problem [1]. The clinical manifestations of HBV infection range from acute or fulminant hepatitis to various forms of chronic infection, including inactive carrier state, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) [1].
NATURAL HISTORY AND DISEASE PROGRESSION OF CHRONIC HEPATITIS B Chronic HBV infection is hyperendemic in Asia. HBV carriers in this area usually acquire the virus perinatally or in early childhood by the age of 2 years. Therefore, Correspondence: Dr. Jia-Horng Kao, Director and Distinguished Professor, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei 10002, Taiwan. E-mail: [email protected]
© 2014 John Wiley & Sons Ltd
levels, who are assumed to be in the immune tolerance phase, have a lower HBeAg seroconversion rate receiving either pegylated interferon or nucleos(t)ide analogue treatment. The latest clinical trial focusing on-treatment response of immune-tolerant patients with tenofovir disoproxil fumarate-based therapy also confirmed the results. The HBeAg seroconversion rates are 50 000 IU/mL) [15–17]. The liver histology shows no or limited liver fibrosis and hepatitis B core antigen (HBcAg) is predominantly in the nucleus of hepatocytes by immunohistochemical staining [14]. As the liver cell damage/fibrosis is very limited, it is expected to be associated with a very low risk of HCC. However, there is no cohort study to prove or disprove this inference. © 2014 John Wiley & Sons Ltd
Treating immune-tolerant hepatitis B
Virological characteristics Hepatitis B virus mutants develop during the course of persistent infection because of the spontaneous error of the viral reverse transcription step. The viral mutants are selected and become the major viral strains under the pressure of host immunity if better replication fitness is shown. Two common HBV mutants, one with a stop codon mutation in the precore region (PC) (G1896A) and one with a dual mutation in the basal core promoter (BCP) (A1762T/G1764A), have been reported to be associated with the possible progression to advanced liver disease [18–20]. In vitro, these two mutants are shown to abolish or reduce the production of HBeAg [21]. In a cross-sectional study using population sequencing, Chan et al. [22] showed that 69% of HBeAg-positive patients with normal ALT level have the wild-type virus for both the PC and BCP regions, which is higher than HBeAgpositive patients with elevated ALT (33%) and HBeAgpositive patients with liver cirrhosis (11%). However, it is unclear whether the HBeAg-positive patients with a snapshot normal ALT level can really represent immune-tolerant patients. In addition, the lack of quantification data of these viral mutants limits the possibility of assessing their clinical usefulness. Another longitudinal study by Wang et al. [23] analysed 7 patients with a long-term follow-up (>17 years). These patients were enrolled at the age of < 10 years, and all of them had ALT levels
doi:10.1111/jvh.12370
REVIEW
Treating Immune-tolerant Hepatitis B T.-C. Tseng1,2 and J.-H. Kao3,4,5,6
1
Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The
2
Buddhist Tzuchi Medical Foundation, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan; 3Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; 4Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; 5Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; and 6Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan Received August 2014; accepted for publication October 2014
SUMMARY. Hepatitis B virus (HBV) infection is a major cause
of cirrhosis and hepatocellular carcinoma worldwide. On the basis of virus–host interactions, the natural history of HBV carriers can be divided into four chronological phases. In the first immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication activity, normal ALT levels as well as minimal liver disease. Ample evidence has shown that patients in the immune tolerance phase have very low viral evolution and minimal risk of fibrosis progression. However, recent immunological studies argued that HBV-specific immune responses already exist in a proportion of immune-tolerant patients and the immune activities are comparable to those in the immune clearance phase. Regarding antiviral therapy, whether these immune-tolerant patients are indicated for treatment remains debated. Previous studies showed that HBeAg-positive patients with normal or near-normal ALT
INTRODUCTION Although safe and effective vaccines have been available for nearly three decades, hepatitis B virus (HBV) infection is still an important public health problem [1]. The clinical manifestations of HBV infection range from acute or fulminant hepatitis to various forms of chronic infection, including inactive carrier state, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) [1].
NATURAL HISTORY AND DISEASE PROGRESSION OF CHRONIC HEPATITIS B Chronic HBV infection is hyperendemic in Asia. HBV carriers in this area usually acquire the virus perinatally or in early childhood by the age of 2 years. Therefore, Correspondence: Dr. Jia-Horng Kao, Director and Distinguished Professor, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei 10002, Taiwan. E-mail: [email protected]
© 2014 John Wiley & Sons Ltd
levels, who are assumed to be in the immune tolerance phase, have a lower HBeAg seroconversion rate receiving either pegylated interferon or nucleos(t)ide analogue treatment. The latest clinical trial focusing on-treatment response of immune-tolerant patients with tenofovir disoproxil fumarate-based therapy also confirmed the results. The HBeAg seroconversion rates are 50 000 IU/mL) [15–17]. The liver histology shows no or limited liver fibrosis and hepatitis B core antigen (HBcAg) is predominantly in the nucleus of hepatocytes by immunohistochemical staining [14]. As the liver cell damage/fibrosis is very limited, it is expected to be associated with a very low risk of HCC. However, there is no cohort study to prove or disprove this inference. © 2014 John Wiley & Sons Ltd
Treating immune-tolerant hepatitis B
Virological characteristics Hepatitis B virus mutants develop during the course of persistent infection because of the spontaneous error of the viral reverse transcription step. The viral mutants are selected and become the major viral strains under the pressure of host immunity if better replication fitness is shown. Two common HBV mutants, one with a stop codon mutation in the precore region (PC) (G1896A) and one with a dual mutation in the basal core promoter (BCP) (A1762T/G1764A), have been reported to be associated with the possible progression to advanced liver disease [18–20]. In vitro, these two mutants are shown to abolish or reduce the production of HBeAg [21]. In a cross-sectional study using population sequencing, Chan et al. [22] showed that 69% of HBeAg-positive patients with normal ALT level have the wild-type virus for both the PC and BCP regions, which is higher than HBeAgpositive patients with elevated ALT (33%) and HBeAgpositive patients with liver cirrhosis (11%). However, it is unclear whether the HBeAg-positive patients with a snapshot normal ALT level can really represent immune-tolerant patients. In addition, the lack of quantification data of these viral mutants limits the possibility of assessing their clinical usefulness. Another longitudinal study by Wang et al. [23] analysed 7 patients with a long-term follow-up (>17 years). These patients were enrolled at the age of < 10 years, and all of them had ALT levels
