Monitoring the intrahepatic innate immune responses in chronic HBV patients treated with tenofovir

Today more than 350 million people are chronically infected with HBV. These
individuals exhibit a 20% incidence of liver cirrhosis and a 100-fold increased
risk of developing hepatocellular carcinoma. HBV causes approximately 1 million
deaths annually worldwide. Chronic HBV infection is the result of a complex
interaction between a replicating non-cytopathic virus and a down-regulated
antiviral immune response. HBV specific T cell responses are usually weak or
absent in chronic HBV patients. The reason for the T cell hyporesponsiveness or
tolerance is not clear.
Cells of the innate immune system, such as natural killer (NK) cells and
dendritic cells (DC), represent the first line of defense against viral
infections. NK cells contribute to anti-viral defenses by direct cytotoxicity
of virus-infected cells and by the production of cytokines that can control
viral replication. Recent advances in the understanding of NK cell biology have
highlighted the important role of NK cells in controlling adaptive responses.
The requirement of NK cells in the initiation of T cell responses arises from
their interaction with DCs. Defective T cell or DC activity observed in chronic
HBV-infection may therefore represent a bystander effect of viral NK cell
inhibition.
Despite the fact that NK cells comprise up to 50% of the intrahepatic
lymphocytes, their role in HBV infection is relatively unknown. The few studies
that have investigated the intrahepatic immune responses during HBV infection
showed important differences between circulating and intrahepatic HBV-specific
T cell responses.
Hence, these data highlight the importance of monitoring intrahepatic immune
responses in addition to peripheral immune responses. Using the
minimally-invasive technique of fine-needle aspiration biopsy (FNAB), it is now
possible to obtain safe and frequent liver samples to monitor local antiviral
immune responses in chronic HBV patients during antiviral therapy.
Reduction of the HBV viral load by treatment with the nucleotide analogue
adefovir dipivoxil did partially restore the function and frequency of DC and
decreased the number of Tregs. Tenofovir is a novel highly specific and potent
inhibitor of HBV replication in vitro. In recent clinical trials, tenofovir
demonstrated superior antiviral activity over adefovir dipivoxil and
significant viral load reduction was established within 12 weeks.

Our hypothesis is: HBV interferes with the function of intrahepatic innate
immune cells, especially NK cells.

Since NK cells play a major role in anti-viral immunity and NK cells comprise a
large proportion of the intrahepatic immune cells, we would like to investigate
the effect of tenofovir-induced viral load reduction on the NK cell-mediated
immune response in chronic HBV patients by addressing the following
immunological research question:

What is the effect of tenofovir-induced viral reduction on the frequency,
phenotype and function of intrahepatic and peripheral blood-derived NK cells of
chronic HBV patients?

Monocenter, translational open label study with one arm of 15 chronic HBV
patients.

Since extra blood is drawn at the same time as te collection blood for regular
bloodtesting, there is no additive risk involved in the retrieval of extra
blood.
Normally, a venapuncture can give the patient the sensation of minor pain and
cause a small swelling, bruise and/or infection. Furthermore, a FNAB can also
give the patient the sensation of minor pain and cause a small swelling, bruise
and/or infection. Other burdens or risks have not occured in our clinic, nor
have they been described in the international literature.