Risk of hepatocellular carcinoma, liver-related complications, and death in persons living with chronic hepatitis B and D

Chronic hepatitis B virus (HBV) infection affects 257 million individuals and is a leading cause of liver-related morbidity and mortality. Hepatitis D virus (HDV) is a satellite virus, that needs HBV for packing and propagation, hence infecting only individuals with HBV infection. It is estimated that around 9-19 million individuals are living with chronic hepatitis Delta (CHD), hence it is the least common among viral hepatides. CHD demonstrates a severe course of liver disease than CHB. The treatment options are still limited, and approved therapies are at a high price. This thesis aims to characterize the natural course of HBV and HDV infection in a low-endemic setting, predictors of disease progression, and the effect of therapy on the disease course.

In Study I, we identified 337 patients with positive anti-HDV antibody from 11 infectious disease clinics in Sweden assembling a nationwide cohort. During a mean follow-up of 6.5 years, HDV RNA replication was significantly associated with a composite outcome of any liver-related decompensation, HCC, and liver transplantation. The response to IFN therapy was suboptimal; 18.8% had a virological response defined as negative or more than 2 log decline of HDV RNA level and a more benign disease course was seen in virological responders compared to non-responders. HDV RNA replication was independently associated with liver decompensation events, undergoing liver transplantation, and a trend toward higher HCC risk.

In Study II, we conducted a systematic review and meta-analysis of published peerreviewed cohort studies examining the risk of HCC in patients with HBV/HDV infection compared to peers with HBV mono-infection. The pooled relative risk was 2.12 (95% confidence interval CI 1.14-3.95), with a particularly higher risk in patients with HIV/HBV/HDV co-infection and substantial heterogeneity between studies.

In Study III, we present the HDV cascade of care during three decades at Karolinska University Hospital (KUH) as a secondary care referral facility in the Southern Stockholm region. In 4095 patients with positive HBsAg, (90.4%, n=3703) have undergone an anti- HDV test. Anti-HDV positive was prevalent in (83.7%, n=310) and (65.2%, n=202) patients who had HDV RNA replication. Older age, cirrhosis, and getting a late anti-HDV diagnosis were independently associated with any prevalent liver outcome. Despite the high screening rate reaching 95%, 8% of persons meeting the criteria of the American Association for the Study of the Liver (AASLD) as “high-risk” of infection did not receive any screening test and 28% of persons with cirrhosis received a remote screening test (after two years). Persons with concurrent HIV and HBV infection were less likely to receive a screening test.

In Study IV, we analyze a nationwide cohort of African-born Swedish residents with CHB without cirrhosis (n=3865), followed for a mean of 12 years from the date of HBV diagnosis in Sweden to the incidence of HCC. The cohort was compared to individuals without HBV in 1 to ≤3 on age, sex, and county of residence to persons from the same area of birth (n=8,488) and in 1 to ≤ 10 on age, sex, and county of residence with a cohort from the general population (n=39,278). African-born men with CHB were significantly younger at HCC development compared to women and peers from comparator cohorts. The costeffectiveness surveillance threshold at 0.2% was exceeded at age 54 years (IR=0.20/100PYs, 95%CI 0.10-0.40) in men and at age 59 years (IR=0.21/100 PYs, 95%CI 0.10-0.45) in women, while at 20-40 years in the presence of concomitant HDV and HCV co-infection in men. The probability of HCC was more pronounced at younger ages in men compared to women. African-born men with CHB had 10.6 times higher risk to develop HCC compared to African-born peers without HBV and a 35.3 times higher risk than the general population. The study provides absolute and relative estimates of HCC development in a nationwide large cohort of African-born first-generation persons with CHB, without cirrhosis at baseline living in a different environmental setting.

To conclude, HDV RNA replication, older age, and cirrhosis in patients with anti-HDV positive are independent predictors of progressive liver disease and need for liver transplantation. Lack of response to IFN therapy might be associated with a worse disease outcome. Based on our pooled analyses, HDV infection is associated with two-times higher risk to develop HCC, compared to HBV mono-infection with a higher risk in persons with triple HIV/HBV/HDV infection. Nine out of 10 patients with CHB received an anti-HDV test at KUH. Delayed HDV diagnosis was independently associated together with older age and cirrhosis with a liver-related outcome. Liver cirrhosis is a fertile ground for cancer development, but some people with CHB can develop cancer without cirrhosis. Costeffectiveness analysis to surveil persons with CHB without cirrhosis identified a threshold of 2 per 1000 persons per year to conduct a semi-annual ultrasound examination. Nevertheless, the age to start liver cancer surveillance, in persons of African origin is different across guidelines due to few studies examining this risk in this population for a long time. It is unclear if the current 0.2% cost-effectiveness threshold for HCC surveillance in persons without cirrhosis might miss a population of younger patients with co-morbidities who are at increased risk to develop HCC. Our research highlights the need for cost-effectiveness studies in contemporary cohorts of persons living with CHB particularly in African-born men given the substantial number of HCCs occurring at younger ages in this population.

List of scientific papers

I. Kamal H, Westman G, Falconer K, Duberg AS, Weiland O, Haverinen S, Wejstål R, Carlsson T, Kampmann C, Larsson SB, Björkman P, Nystedt A, Cardell K, Svensson S, Stenmark S, Wedemeyer H, Aleman S. Long-Term Study of Hepatitis Delta Virus Infection at Secondary Care Centers: The Impact of Viremia on Liver-Related Outcomes. Hepatology. 2020 Oct;72(4):1177-1190.
https://doi.org/10.1002/hep.31214

II. Kamal H, Fornes R, Simin J, Stål P, Duberg AS, Brusselaers N, Aleman S. Risk of hepatocellular carcinoma in hepatitis B and D virus co-infected patients: A systematic review and meta-analysis of longitudinal studies. J Viral Hepat. 2021 Oct;28(10):1431-1442.
https://doi.org/10.1111/jvh.13577

III. Habiba Kamal, Karin Lindahl, Michael Ingre, Caroline Gahrton, Kerstin Karkkonen, Piotr Nowak, Jan Vesterbacka, Per Stål, Heiner Wedemeyer, Ann-Sofi Duberg, Soo Aleman. The cascade of care for patients with chronic hepatitis delta in Southern Stockholm, Sweden for the past 30 years [Submitted]

IV. Habiba Kamal, Michael Ingre, Per Stål, Gabriel Westman, Daniel Bruce, Heiner Wedemeyer, Ann-Sofi Duberg and Soo Aleman Age and sex-specific risks for hepatocellular carcinoma in African-born persons with chronic hepatitis B and without cirrhosis [Submitted]