Prospective study on peripheral and intrahepatic immune cells derived from chronic hepatitis B patients during and after long-term treatment with direct antivirals

Globally 257 million people are chronically infected with hepatitis B virus
(HBV). In these patients the immune system is incapable of clearing the virus.
The levels of HBV DNA, ALT and hepatitis B envelope antigen (HBeAg) vary
greatly between patients, and may fluctuate in the same patient. The long-term
consequences of chronic HBV infection can be severe, since patients are at
increased risk for developing liver fibrosis, cirrhosis and/or hepatocellular
carcinoma. To better describe the disease state of the patient and to guide
treatment strategies, a clinical distinction into four phases was made based on
variations in serum HBV DNA, ALT and HBeAg levels. These four clinical HBV
phases are known as the immune tolerant (IT), immune active (IA), inactive
carrier (IC) and HBeAg-negative hepatitis (ENEG) phase. The molecular events
characterizing each phase and determining the transition between clinical
phases are still poorly understood.
Permanent immune control occurs only in a minority of chronic HBV patients,
either spontaneously or following chronic treatment with direct antivirals.
Currently, HBsAg conversion or loss in serum is seen as the most useful
clinical hallmark for a transition to a state where the host immune system
prevents further proliferation of the virus and avoids a reactive inflammatory
state which is a major driver of fibrosis, cirrhosis and hepatocellular
carcinoma. However, this situation occurs infrequent in NA(s) treated patients
and therefore it is of importance to identify additional predictors for
sustained response.
A complementary longitudinal study will be performed by the same investigators
as the HBV-FNAB-001 study on patients with liver samples before and after
stopping of chronic suppressive treatment with direct antivirals. In this
approach the link between immune cell states and functional control will be
made through the comparison of liver cell changes in successful controllers and
in patients with different timing and extent of viral and clinical relapse.

To identify correlations between immune changes at the cellular or molecular
level in the serial FNAB and blood samples before and after withdrawal of
treatment, and * in case of relapse - to identify correlations between the
degree of immune control (or lack thereof) and the timing and intensity of
virological and clinical relapse.

Part 2 prospective multi-center study in about 20 CHB patients on NA treatment
at 3 sites (Erasmus MC Rotterdam, University Hospital Toronto and Massachusetts
General Hospital, Boston).

Patients enrolled in this study will not directly benefit from this study as
this is an exploratory study to identify correlates between intrahepatic immune
changes at the cellular or molecular level and viral control.
Per patient 3 or 4 FNABs will be collected. This is a minimally invasive
technique to obtain safe and repeated liver samples. The procedure is well
tolerated by patients and has been performed for many years by our team without
any complications related to the procedure. Moreover, it can be performed on
any patient without anaesthesia or other preparations. Furthermore, blood
collections will be performed for each patient at each visit. Depending if
patient is a responder or relapser six is the maximal number of blood
collections in this study and blood collection does not pose an extra risk for
the patient.
If a subject is identified as clinical relapser a safety follow up of 6 months
will follow. No study materials will be taken during the 6 month safety follow
up.