Phases of chronic infection: AASLD/IDSA 2025 definitions

Phase	Quoted definition
Immune-tolerant	“HBeAg-positive, HBV DNA ≥10,000,000 IU/mL and normal ALT (<25 IU/mL in women, <35 IU/mL in men)”
Immune active, HBeAg-positive	“HBeAg-positive and ALT ≥2xULN and HBV DNA ≥20,000 IU/mL”
Immune active, HBeAg-negative	“HBeAg-negative and ALT ≥2xULN and HBV DNA ≥2000 IU/mL”
Inactive	“HBeAg-negative, HBV DNA <2000 IU/mL and normal ALT”
Indeterminate	“HBeAg-positive or negative with HBV DNA level and/or ALT level outside those with immune-tolerant, immune active or inactive CHB”

“Up to 40% of adults with CHB do not meet one or more criteria for a defined phase and are in indeterminate phases.2,3 Indeterminate phases are more common in persons who are HBeAg-negative than HBeAg-positive.” (opens the source at this quote in a new tab)
“Transition from the immune-tolerant to immune active phase of CHB may occur in childhood, adolescence, or adulthood, with the average age of transition around 30 years.” (opens the source at this quote in a new tab)
“While some individuals in the indeterminate phase may transition to an immune active or an inactive phase, many remain in the indeterminate phase for years. Several cohort studies suggest that individuals who remain in the indeterminate phase are at risk of HCC.” (opens the source at this quote in a new tab)

Phases of chronic infection: EASL 2025 serologic profile and untreated disease progression

Marker	HBeAg-positive chronic HBV infection	HBeAg-positive chronic hepatitis B	HBeAg-negative chronic HBV infection	HBeAg-negative chronic hepatitis B
HBsAg	“High”	“Intermediate to high”	“Low, usually <1,000 IU/ml”	“Intermediate, usually >1,000 IU/ml”
ALT	“Normal”	“Elevated”	“Normal”	“Elevated”
Liver disease progression (if untreated)	“None/minimal”	“Moderate to severe”	“None”	“Mild to severe”

“Chronic HBV infection is a dynamic and complex condition that progresses through distinct phases (Table 4), each characterised by unique virological, immunological and clinical features.” (opens the source at this quote in a new tab)
“A significant proportion of individuals with chronic HBV infection cannot be easily classified into the four phases outlined in the 2017 EASL CPGs,5 which are also adopted in this new guideline.” (opens the source at this quote in a new tab)

Clinical outcomes in the indeterminate phase

“The annual incidence rate of HCC in patients in the indeterminate phase was 0.32% (95% CI 0.21-0.48%, I2 = 85.7%), and those of cirrhosis and hepatic decompensation were 0.67% (95% CI 0.30-1.49%, I2 = 94.3%) and 0.34% (95% CI 0.17-0.69%, I2 = 51.8%), respectively. The pooled prevalence of moderate-to-severe liver inflammation, significant fibrosis, advanced fibrosis, and cirrhosis was 40.7%, 39.7%, 17.9%, and 7.2%, respectively.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Transition from inactive infection to HBeAg-negative hepatitis

“The annual incidence of HBeAg-negative immune active hepatitis among inactive carriers is estimated to be 0.37%.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

“A higher risk of reactivation, i.e. progression from HBeAg-negative infection to HBeAg-negative hepatitis, exists with HBV DNA <2,000 IU/ml and HBsAg >1,000 IU/ml.” (opens the source at this quote in a new tab)

Spontaneous HBsAg loss: approximately 1% per year in pooled cohorts

“The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79-1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49-5.93), 8.16% at 10 years (95% CI, 5.24-11.72), and 17.99% at 15 years (95% CI, 6.18-23.24).” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P < .01).” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote
“In a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate, approximately 1%).” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

“Spontaneous HBsAg loss has been reported to occur at the rate of roughly 1% per year, but this rare event does not occur at a linear rate (128, 129). In a study of 1076 patients with CHB in Taiwan, cumulative probabilities of spontaneous HBsAg loss were 8.1% after 10 years and increased to 44.7% after 25 years (129).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Spontaneous HBsAg loss: higher rates in HBeAg-negative infection with low HBsAg, lower rates on nucleos(t)ide analogue therapy

“The annual incidence of HBsAg loss in this population is approximately 2%, increasing further (up to 7%) in older individuals and those with low HBsAg levels (<100 or <250 IU/ml).” (opens the source at this quote in a new tab)
“This rate is significantly higher than in NA-treated patients with chronic HBV infection, where the reported average annual rate is ≤0.33%.” (opens the source at this quote in a new tab)
“Although spontaneous HBsAg seroclearance is unusual in chronic HBV infection, its likelihood increases with age and annual HBsAg monitoring is recommended to detect such events.” (opens the source at this quote in a new tab)

Cirrhosis incidence in untreated chronic infection

“The reported incidence rates of cirrhosis in chronic HBV infection have come mostly from tertiary care centers, and range from 2% to 7% annually.5–9 In contrast, in a study of 1506 asymptomatic HBV carriers, the cirrhosis incidence rate was 0.7% annually.” (opens the source at this quote in a new tab)
“The 3582 patients under study were followed up for a mean of 11 years and contributed 40,038 person-years of observation and by June 30, 2004; a total of 1053 (29.4%) participants dropped out of follow-up evaluation. There were 365 (10%) patients newly diagnosed with cirrhosis.” (opens the source at this quote in a new tab)

Hepatocellular carcinoma incidence by baseline viral load in the REVEAL-HBV cohort

“There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41 779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100 000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100 000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively.” (opens the source at this quote in a new tab)

Hepatocellular carcinoma incidence in untreated immune-tolerant and treated immune-active U.S. Veterans

“A total of 591 U-IT and 555 T-IA CHB patients were identified (mean age 56.4-57.5 years, 45%-50% non-Hispanic white, 37%-40% African American, 9%-10% Asian, 25%-29% concurrent diabetes, 35%-39% with FIB-4 > 3.25). Over a median follow up of 6.4 years (IQR 3.0-10.4), incidence of HCC was significantly lower in U-IT patients vs. T-IA patients (0.28 vs. 0.54 per 100 person-years; HR 0.52, 95% CI 0.32-0.83, p = 0.007). However, the risk of cirrhosis or all-cause mortality was similar between both T-IA and U-IT CHB patients.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Mortality in the United States: hepatitis B-related deaths reported in national surveillance

“There were 1,769 hepatitis B-related deaths reported during 2023.” (opens the source at this quote in a new tab)

“The age-adjusted hepatitis B-related death rate during 2023 (0.44 deaths per 100,000 population) remained stable compared to 2022.” (opens the source at this quote in a new tab)
“In 2023, hepatitis B-related death rates among non-Hispanic Asian/Pacific Islander persons and non-Hispanic Black persons were 8.5 times and 2.7 times as high as the rate among non-Hispanic White people, respectively.” (opens the source at this quote in a new tab)

Mortality in the United States: death certificate analysis, 2000 to 2019

“A total of 35 280 decedents with hepatitis B listed as the cause of death were identified, including 17 483 deaths during 2010 to 2019. Decedents were 63.3% US-born, and 25.8% of decedents were Asian or Pacific Islander and 46.5% of decedents were White; 28.4% of decedents were listed as having hepatitis C virus (HCV) or HIV coinfection.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Liver cancer was the predominant UCOD among non-US–born decedents (37.9% of decedents). From 2000 to 2009 compared with 2010 to 2019, the hepatitis B–listed mortality rate significantly decreased nationally (change, −18.97%) and in 14 states; significant increases were observed in West Virginia (change, 83.78%) and Kentucky (change, 69.44%).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Mortality in the United States: premature death and underreporting in the Chronic Hepatitis Cohort Study

“Of 4389 CHB patients followed for a mean of 5.38 years, 492 (11%) CHB patients died after a mean follow-up of 3.00 years.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“CHB patients died at an average age of 59.8 years” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“14 years younger than the general U.S. population” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“and at higher rates for all causes (relative risk [RR] = 1.85, 95% confidence interval [CI], 1.851–1.857) and liver-related causes (RR = 15.91, 95% CI, 15.81–16.01). Only 19% of CHB decedents and 40% of those dying of liver disease had hepatitis B reported on their death certificates.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Projected U.S. liver-related deaths, 2019 to 2030

“The annual incidence of decompensated cirrhosis is projected to increase by 20% from 2019 to 2030 from 1700 (UI: 1100–2700) to 2100 (UI: 1300–3300) cases, hepatocellular carcinoma (HCC) annual incidence is forecasted to increase by 31% from 6500 (4500–9600) 8500 (UI: 5900–12,500) cases, and liver related deaths are expected to increase by 25% from 7900 (UI: 5500–11,600) to 9900 (UI: 6600–14,900) deaths annually.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Global mortality: approximately 1.1 million HBV-related deaths in 2024

“In 2024, hepatitis B resulted in an estimated 1.1 million deaths, mostly from cirrhosis and hepatocellular carcinoma (primary liver cancer).” (opens the source at this quote in a new tab)

“Globally in 2024, there were an estimated 1.1 million (95% uncertainty interval [UI]: 0.9–1.3 million) HBV-related deaths” (opens the source at this quote in a new tab)
“Globally, the annual number of HBV-related deaths increased by 17% between 2015 and 2024” (opens the source at this quote in a new tab)

“HBV-related diseases resulted in 555 000 global deaths (487 000 to 630 000) in 2019.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

“HBV-related deaths are projected to rise globally from 858,000 in 2015 to 1,149,000 in 2030, alongside increasing HCC incidence (from 644,000 to 857,000) and cases of decompensated cirrhosis (from 296,000 to 403,000), assuming that current levels of diagnosis and treatment remain unchanged.” (opens the source at this quote in a new tab)