Long-term Repeated Measurements of Hepatitis B viral Load and the Risks of Hepatocellular Carcinoma/Liver Cirrhosis
Date Issued
2011
Date
2011
Author(s)
Chen, Chuen-Fei
Abstract
Abstract
This thesis consists of two component studies to investigate long-term changes in serum levels of hepatitis B virus (HBV) DNA and the risks of hepatocellular carcinoma and liver cirrhosis. PART 1: Long-term Changes in HBV DNA Predict Risk of Hepatocellular Carcinoma Background & Aims: Serum HBV DNA levels may vary markedly in the natural progression of chronic hepatitis B. It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of HBV DNA or alanine aminotransferase (ALT). Methods: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3,160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. The group-based trajectory model was used to identify distinctive groups of long-term changes in serum HBV DNA levels over 11 years of follow-up. Multivariate-adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were estimated using Cox regression models. Results: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The hepatocellular carcinoma risk was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL, compared to those with baseline levels of HBV DNA <10,000 copies/mL (reference group; HR, 2.25; 95% CI, 0.68–7.37). Compared with the reference group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000–100,000 copies/mL, decreased to/persisted at 100,000–1,000,000 copies/mL, or decreased to/persisted at 1,000,000–10,000,000 copies/mL were 3.12 (1.09–8.89), 8.85 (3.85–20.35), and 16.78 (7.33–38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low normal, to ever high normal, to transient abnormal, to persistent abnormal (Ptrend<.001). Conclusions: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Spontaneous decrease of HBV DNA to <104 copies/mL is associated with a significantly lowered risk of hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV. PART 2: Long-term Changes in HBV DNA Predict Risk of Liver Cirrhosis Background & Aims: Chronic hepatitis B may lead to the development of liver cirrhosis. Chronic hepatitis B is a dynamic disorder with dynamic change of serum HBV DNA level. There is little known about the impact of long-term sequential changes in HBV viral load and ALT on subsequent liver cirrhosis risk. Methods: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3,106 participants in the REVEAL-HBV study. Development of liver cirrhosis was determined by ultrasounds. To confirm the complete ascertainment of cirrhosis cases, we conducted data linkage to the National Health Insurance profiles in Taiwan. The group-based trajectory model was used to identify distinctive groups of long-term changes in serum HBV DNA levels over 11 years of follow-up. Multivariate-adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were estimated using Cox regression models. Results: During 36,923 person-years of follow-up, 262 participants developed liver cirrhosis (incidence rate, 709.6/100,000 person-years). The liver cirrhosis risk was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased from 100,000 copies/mL to <10,000 copies/mL, compared to those with baseline levels of HBV DNA <10,000 copies/mL (reference group; HR, 1.38; 95% CI, 0.87–2.18). Compared with the reference group, the HRs (95% CI) for long-term levels of HBV DNA that decreased from >10,000,000 copies/mL to <10,000 copies/mL, persisted at 100,000–1000,000 copies/mL, decreased from >10,000,000 copies/mL to 100,000–1,000,000 copies/mL, or persisted at 1,000,000–10,000,000 copies/mL were 2.46 (1.19–5.13), 2.92 (1.94–4.39), 4.10 (2.51–6.72),and 4.81 (2.94–7.87), respectively. A gradient in ALT level was significantly associated with liver cirrhosis risk: from all low normal, to ever high normal, to transient abnormal, to persistent abnormal (Ptrend<.001). Conclusions: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for liver cirrhosis. For participants with the same HBV DNA levels at enrollment, greater decreases in serum HBV DNA during the follow-up were associated with lower risk of liver cirrhosis. Participants with spontaneous viral load reduction to <104 copies/mL during follow-up had different risks of liver cirrhosis depending on their HBV DNA levels at enrollment. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.
This thesis consists of two component studies to investigate long-term changes in serum levels of hepatitis B virus (HBV) DNA and the risks of hepatocellular carcinoma and liver cirrhosis. PART 1: Long-term Changes in HBV DNA Predict Risk of Hepatocellular Carcinoma Background & Aims: Serum HBV DNA levels may vary markedly in the natural progression of chronic hepatitis B. It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of HBV DNA or alanine aminotransferase (ALT). Methods: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3,160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. The group-based trajectory model was used to identify distinctive groups of long-term changes in serum HBV DNA levels over 11 years of follow-up. Multivariate-adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were estimated using Cox regression models. Results: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The hepatocellular carcinoma risk was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL, compared to those with baseline levels of HBV DNA <10,000 copies/mL (reference group; HR, 2.25; 95% CI, 0.68–7.37). Compared with the reference group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000–100,000 copies/mL, decreased to/persisted at 100,000–1,000,000 copies/mL, or decreased to/persisted at 1,000,000–10,000,000 copies/mL were 3.12 (1.09–8.89), 8.85 (3.85–20.35), and 16.78 (7.33–38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low normal, to ever high normal, to transient abnormal, to persistent abnormal (Ptrend<.001). Conclusions: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Spontaneous decrease of HBV DNA to <104 copies/mL is associated with a significantly lowered risk of hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV. PART 2: Long-term Changes in HBV DNA Predict Risk of Liver Cirrhosis Background & Aims: Chronic hepatitis B may lead to the development of liver cirrhosis. Chronic hepatitis B is a dynamic disorder with dynamic change of serum HBV DNA level. There is little known about the impact of long-term sequential changes in HBV viral load and ALT on subsequent liver cirrhosis risk. Methods: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3,106 participants in the REVEAL-HBV study. Development of liver cirrhosis was determined by ultrasounds. To confirm the complete ascertainment of cirrhosis cases, we conducted data linkage to the National Health Insurance profiles in Taiwan. The group-based trajectory model was used to identify distinctive groups of long-term changes in serum HBV DNA levels over 11 years of follow-up. Multivariate-adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were estimated using Cox regression models. Results: During 36,923 person-years of follow-up, 262 participants developed liver cirrhosis (incidence rate, 709.6/100,000 person-years). The liver cirrhosis risk was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased from 100,000 copies/mL to <10,000 copies/mL, compared to those with baseline levels of HBV DNA <10,000 copies/mL (reference group; HR, 1.38; 95% CI, 0.87–2.18). Compared with the reference group, the HRs (95% CI) for long-term levels of HBV DNA that decreased from >10,000,000 copies/mL to <10,000 copies/mL, persisted at 100,000–1000,000 copies/mL, decreased from >10,000,000 copies/mL to 100,000–1,000,000 copies/mL, or persisted at 1,000,000–10,000,000 copies/mL were 2.46 (1.19–5.13), 2.92 (1.94–4.39), 4.10 (2.51–6.72),and 4.81 (2.94–7.87), respectively. A gradient in ALT level was significantly associated with liver cirrhosis risk: from all low normal, to ever high normal, to transient abnormal, to persistent abnormal (Ptrend<.001). Conclusions: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for liver cirrhosis. For participants with the same HBV DNA levels at enrollment, greater decreases in serum HBV DNA during the follow-up were associated with lower risk of liver cirrhosis. Participants with spontaneous viral load reduction to <104 copies/mL during follow-up had different risks of liver cirrhosis depending on their HBV DNA levels at enrollment. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.
Subjects
chronic hepatitis B
hepatocellular carcinoma
liver cirrhosis
HBV DNA
ALT
group-based trajectory model
long-term follow-up study
SDGs
Type
thesis
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