Long-Term Outcomes in Hepatitis B: The REVEAL-HBV Study
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Global distribution of hepatitis B virus disease
Chronic hepatitis B (CHB) is a worldwide public health challenge, and, despite the availability of an effective vaccine, there is still a large proportion of infected persons worldwide. The global distribution of chronic hepatitis B infection parallels the mode of infection. CHB is particularly prevalent in the Asia-Pacific and sub-Saharan Africa regions [1], [2], where infection is acquired predominantly during the perinatal period or in early childhood. Perinatal infection results in more
Natural course of chronic hepatitis B infection
The natural course of CHB infection is highly variable at the individual level but also varies with age of infection. The classic description of the natural history is shown in Fig. 1. Early life/perinatal infection is characterized by a period of “immune tolerance” during which the host coexists with the virus without apparent injury to the host. This period of immune tolerance is characterized by detectable circulating hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), the
Disease progression of chronic hepatitis B
Progression to cirrhosis in chronic HBV carriers occurs at a rate of 2% to 7% annually [9], [10], [11]. Patients who have cirrhosis are estimated to progress to decompensated cirrhosis at a rate of 3% annually, but active viral replication, as shown by the presence of HBeAg, increases the rate of progression [12], [13]. The 5-year survival rate varies from 84% in patients who have compensated cirrhosis to 14% to 28% in those who have decompensated cirrhosis [13], [14]. The risk of HCC among
Enrollment of the REVEAL-HBV study cohort
To assess demographic characteristics and risk factors for HCC, 89,293 residents age 30 to 65 years living in seven townships in Taiwan were invited to participate in this study. Between 1991 and 1992, a cohort of 23,820 volunteers was assembled. Each gave written informed consent for questionnaire interview, health examination, blood collection for serologic and biochemical assays, and follow-up of health status through health examination, medical record review, and data linkage with national
Questionnaire interview, blood collection, and laboratory testing
All the subjects were interviewed in person by trained public health nurses at enrollment using a structured questionnaire. A 10-mL blood sample was collected from each participant at study entry and at follow-up examinations. The serum samples were fractionated on the day of collection and stored at −70°C until assayed. Serologic tests performed at baseline include HBsAg and HBeAg by radioimmunoassay (Abbott Laboratories, North Chicago, Illinois); anti-HCV by enzyme immunoassay using
Ascertainment of clinical outcomes
The incidence of HCC and cirrhosis were the two major outcomes in the REVEAL-HBV study. Newly developed HCC cases were detected by follow-up health examinations, which included ultrasound and α-fetoprotein testing, or by computerized data linkage with the National Cancer Registry in Taiwan. Data linkage with the profiles on the National Death Certification System also was performed to ensure complete ascertainment. The ascertainment of Cirrhosis cases was done by performing ultrasound testing,
Frequency distribution of serum hepatitis B virus DNA level at study entry
Table 1 shows the frequency distribution of the HBV DNA level of the entire cohort (n = 3653) and subcohorts including the HBeAg seronegatives (n = 3088), the HBeAg seronegatives with normal ALT level at study entry (n = 2966), and the HBeAg seronegatives with normal ALT levels and no liver cirrhosis at study entry (n = 2925). There were 873 participants (23.9%) with undetectable HBV DNA levels (<300 copies/mL); 976 participants (26.7%) had a level of 105 copies/mL or higher. HBeAg-seronegative
Risk of liver cirrhosis by serum hepatitis B virus DNA level at study entry
During the overall follow-up of 40,038 person-years, there were 365 cases of liver cirrhosis, the majority of which (n = 261, 72%) were confirmed on two or more ultrasound examinations. Additionally four subjects had one ultrasound diagnosis of cirrhosis during follow-up with additional clinical evidence of cirrhosis. The incidence of liver cirrhosis (per 100,000 person-years of observation) in this study increased with increasing baseline HBV DNA level, from 339 in people who had HBV DNA below
Subcohort analysis of liver cirrhosis risk by serum hepatitis B virus DNA level at study entry
Several regression models were run to examine the risk of liver cirrhosis associated with baseline HBV DNA as a primary predictor in different subcohorts, including (1) all participants (n = 3582; cirrhosis cases = 365), (2) HBeAg seronegatives (n = 3037; cirrhosis cases = 230), and (3) HBeAg seronegatives with normal ALT levels at study entry (n = 2923; cirrhosis cases = 211). In each subcohort, the adjusted risk of liver cirrhosis increased with the serum HBV DNA level at study entry, as
Risk of hepatocellular carcinoma by serum hepatitis B virus DNA level at study entry
There were 41,779 person-years of follow-up under observation for the analysis of HCC risk. Through follow-up health examinations and data linkage with profiles of the National Cancer Registry and National Death Certification systems, 164 newly diagnosed HCC cases were identified. The HCC incidence rates by serum HBV DNA level at study entry are shown in Fig. 3. The incidence per 100,000 person-years increased from 108 for the undetectable HBV DNA level to 1152 for the level of 106 or more
Subcohort analysis of hepatocellular carcinoma risk by serum hepatitis B virus DNA level at study entry
As with the cirrhosis analyses, several regression models were run to examine the risk of HCC associated with baseline HBV DNA as primary predictor in different subcohorts including (1) all participants (n = 3653; HCC cases = 164), (2) HBeAg seronegatives (n = 3088; HCC cases = 94), (3) HBeAg seronegatives with normal ALT levels at study entry (n = 2966; HCC cases = 83), and (4) HBeAg seronegatives with normal ALT levels and no cirrhosis at study entry (n = 2925; HCC cases = 66). In each
Risk of hepatocellular carcinoma by serum hepatitis B virus DNA levels at entry and follow-up examinations
The investigators further examined the association between HCC risk and persistently elevated serum HBV DNA levels at study entry and last follow-up. The median time between the entry and follow-up samples was around 10 years. The multivariate-adjusted hazard ratios for developing HCC by serum HBV DNA levels at study entry and follow-up are shown in Fig. 6. In these analyses, after adjustment for other HCC risk factors, participants who had a serum HBV DNA level at entry below 104 copies/mL
Discussion
Several other published studies have evaluated the association between elevated serum HBV DNA levels and the risks of cirrhosis and HCC [19]. Some of the findings from these studies are summarized here.
A hospital-based case-control study of patients who had CHB (79 who had cirrhosis and 158 without cirrhosis) found a threefold risk of cirrhosis for a serum HBV DNA level higher than 105 copies/mL, as compared with the reference level that had a serum HBV DNA level below 103 copies/mL [26].
Most
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The REVEAL-HBV study was supported by grants from the Department of Health, Executive Yuan, ROC; and Bristol-Myers Squibb Co., USA. A grant was provided by Bristol-Myers Squibb Co. to Chien-Jen Chen for conducting the laboratory tests for this study. Dr. Iloeje is employed by Bristol-Myers Squibb Co. Dr. Yang received lecture honorarium from Bristol-Myers Squibb Co.