Inst för medicin, Huddinge / Dept of Medicine, Huddinge
Doi
Abstract
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