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. 2025 Jul 1;25(1):881.
doi: 10.1186/s12879-025-11213-w.

Disease progression & treatment need in sub-genotype C4 hepatitis B infection: a retrospective cohort study in the Northern Territory, Australia

Genevieve E Martin  1   2   3 , Kelly Hosking  1   2 , Kelly Banz  2 , Catherine Gargan  2 , Geoff Stewart  2 , Belinda Greenwood-Smith  2 , Penelope Ramsay  2   4 , Jaclyn Tate-Baker  2 , Christine Connors  2 , Paula Binks  1 , Melita McKinnon  1 , Prashanti Manchikanti  4 , George Garambaka Gurruwiwi  1 , Nicole Allard  5 , Ashleigh Qama  5 , Jessica Michaels  6 , Emily Vintour-Cesar  1 , Robert Batey  2 , Catherine Marshall  1   2 , Peter Nihill  2 , Tammy-Allyn Fernandes  2 , Karen Fuller  7 , Steven Y C Tong  3   8 , David Boettiger  1   9 , Benjamin Cowie  3   5   8 , Joshua S Davis  1   10 , Sarah Mariyalawuy Bukulatjpi  4 , Jane Davies  11   12 ; Hep B PAST Partnership
Collaborators, Affiliations

Disease progression & treatment need in sub-genotype C4 hepatitis B infection: a retrospective cohort study in the Northern Territory, Australia

Genevieve E Martin et al. BMC Infect Dis. .

Abstract

Background: In the Northern Territory (NT) of Australia, First Nations people with chronic hepatitis B (CHB) are infected with a unique sub-genotype, C4, which contains mutations linked to progressive fibrosis and hepatocellular carcinoma. This cohort study aimed to investigate disease progression in C4 sub-genotype infection and estimate how many untreated individuals may benefit from antiviral therapy with broadening treatment indications.

Methods: Included individuals were part of Hep B PAST, a co-designed program to improve the cascade of care for people living with CHB in the NT. Disease phase and cirrhotic status were determined algorithmically using clinical and laboratory data at two time points. Loss of HBV antigens was assessed longitudinally. Treatment need was assessed cross-sectionally in the cohort at study completion. Key outcomes were estimated rates of HBsAg/HBeAg loss in sub-genotype C4 infection and quantification of how many untreated individuals qualify for therapy under current Australian and expanded global treatment guidelines.

Results: HBsAg and HBeAg loss occurred at a rate of 1·04 and 8·06 events/100 person-years respectively (7342·6 and 545·6 years follow up). 783 people living with CHB were included (40% female, median age 48 years). Of these, 16% had cirrhosis (an additional 6% having FibroScan > 7 kPa, meaning 22% had cirrhosis or significant fibrosis) and 25% were prescribed antivirals. Only 6·7% of untreated individuals were treatment eligible under current guidelines. Using the 2024 World Health Organisation guidelines, this increased to 50% due mostly to fibrosis and population prevalence of diabetes.

Conclusions: Despite advanced liver disease in people living with CHB in the NT, rates of antigen loss in sub-genotype C4 hepatitis B infection are similar to other genotypes. Further work is needed to understand drivers of cirrhosis and significant fibrosis in this population.

Keywords: Chronic hepatitis B; First Nations health; Hepatitis B virus; Liver cirrhosis; Viral genotype.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Human Research Ethics Committee (HREC) of NT Health and Menzies School of Health Research: 2018–3242. Following extensive community consultation and with Indigenous Reference Group input into the consent processes, a hybrid consent model was used for different aspects of the Hep B PAST program [17]. In line with HREC approval, service level informed consent was provided for all individuals included in this work. Every individual known to be living with chronic hepatitis B was included as part of their usual care through a service which provided service level informed consent, with the option to opt-out on an individual basis. If service level informed consent was not provided, individual written informed consent could be sought. All research was conducted in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Loss of hepatitis B antigens. Kaplan–Meier plots showing (A) loss of HBsAg and (B) loss of HBeAg over first 15 years of follow up. 95% confidence intervals are shaded in grey
Fig. 2
Fig. 2
Changes in disease phase and treatment status. Alluvial plot showing comparison of number of individuals by treatment/disease status at baseline and study completion. Data flows represent the changes in status between time points and are proportional to the number of individuals. Individuals are classified as unknown if insufficient information was available to assign disease phase. Alternate names for phases as follows: phase I (HBeAg positive chronic infection, or immune tolerant), phase II (HBeAg positive chronic hepatitis or immune clearance), phase III (HBeAg negative chronic infection or immune control) and phase IV (HBeAg negative chronic hepatitis or immune escape). Data used in construction of figure is shown in Supplementary Table 3
See this image and copyright information in PMC

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