By Ana Espino | Published on July 29, 2025 | 3 min read
#HepatitisB #Immunity #InfectiousDiseases
Chronic hepatitis B (CHB) remains a
major public health issue, affecting more than 296 million people worldwide.
Despite the implementation of effective vaccination campaigns, the
hepatitis B
virus (HBV) continues to cause severe
liver complications, including cirrhosis
and hepatocellular carcinoma.
Current treatment relies on two main approaches: pegylated interferon (PEG-IFN-α) and nucleos(t)ide analogues
(NUCs). While these agents help control viral load and stabilize the disease,
they lead to functional cure in less than 1% of cases per year. This low
efficacy is largely due to their inability to restore a complete and lasting
antiviral immune response. Indeed, many key cells of the immune
system—particularly dendritic cells (DCs), monocytes, NK cells, and so-called
unconventional T cells—exhibit deep phenotypic and functional alterations in
patients with chronic HBV.
These immune dysfunctions represent a major obstacle to achieving a durable
virological response and complete viral clearance. They reflect a virus-induced
state of tolerance and the difficulty of reactivating an effective immune
response despite treatment. This review explores how antiviral therapies affect
the function of altered immune cells in chronic hepatitis B. By analyzing the
effects of NUCs, PEG-IFN-α, and novel immunomodulators, the aim is to identify key immune targets
for developing more effective future combination strategies.
Antiviral treatment: a successful
immune system reboot?
This review analyzes the results of multiple clinical trials on the effects of
PEG-IFN-α, various NUCs
(entecavir, TDF, LDT…), and novel agents such as TLR agonists (e.g.,
selgantolimod), on the function of innate and unconventional T cells.
Studies first show that DCs are significantly altered in patients with CHB. A
marked reduction in the expression of co-stimulatory molecules CD80/CD86 is
also observed, along with weakened TLR activity and metabolic disturbances.
PEG-IFN-α appears
capable of partially restoring these functions, unlike NUCs alone, which remain
largely ineffective in this regard.
Monocytes show overexpression of PD-L1 and IL-10, as well as a weakened TLR
response. PEG-IFN-α
shifts their transcriptional profile toward an IFN-α-type response, whereas TDF or ETV treatments
show little reparative effect on these alterations.
Myeloid-derived suppressor cells, whose expansion inhibits T cell responses,
decrease in frequency under PEG-IFN-α, suggesting a key role in restoring antiviral immunity.
NK cells show highly variable responses depending on the treatment. Under NUCs,
activation markers are heterogeneously modulated. In contrast, PEG-IFN-α stimulates CD56bright NK cells,
inducing increased TRAIL, HLA-DR, and IFN-γ—signs of enhanced activation.
Finally, unconventional T cells are globally reduced in number and functionally
exhausted, with high expression of PD-1 and Tim-3. Some treatments,
particularly TLR8 agonists such as selgantolimod and PEG-IFN, show partial
restoration of their cytotoxic activity.
Reactivating immunity—toward a cure?
CHB is associated with profound immune alteration, marked by inhibited
cytotoxic functions, overexpression of inhibitory receptors, and ineffective T
cell responses. This immune dysfunction is a major barrier to achieving
functional cure. In this context, this review aims to provide a mechanistic
framework based on solid clinical data to guide the development of
immunomodulatory strategies in combination with classical antiviral treatments.
The results highlight the limitations of NUCs, which alone provide only partial
and inconsistent immune restoration. In contrast, PEG-IFN-α appears more effective in
reactivating key immune functions. New approaches—TLR agonists—offer promising
perspectives for reactivating immunity and increasing the likelihood of durable
virological control.
However, several limitations still hinder optimization of therapeutic
approaches, underscoring the need for further studies. These should prioritize
the exploration of combination strategies integrating antivirals and
immunomodulators. Moreover, individualized patient selection, guided by
immunological biomarkers, appears essential to maximize the chances of
achieving functional HBV cure.
Read next: Hepatitis: when the virus writes its own rules
About the author – Ana EspinoPhD in Immunology, specialized in Virology
