Hepatology Snapshot:

Current therapeutic approaches for HBV infected patients

Upkar S. Gill1, Patrick T. F. Kennedy1,*
1
Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, UK
*
Corresponding author: Blizard Institute, Barts and The London School of Medicine & Dentistry, 4 Newark Street, London, E1 2AT. E-mail address: p.kennedy@qmul.ac.uk (P. Kennedy)

Subviral particle
CURRENTLY LICENSED ENTRY INHIBITORS SILENCING &
ELIMINATING cccDNA Antigen HBeAg
FUNCTIONAL CURE OF
THERAPIES secretion CHRONIC HEPATITIS B
NTCP

Interferon-alpha Virion
Uncoating
Hepatocyte
siRNA ER and Golgi HBsAg-
Nucleus HBeAg-
HBV DNA-
cccDNA formation Transcription

VIRAL DECLINE
RC DNA cccDNA
VIRAL TARGETS mRNA

SECRETION INHIBITORS Recycling

CD8 APC
HBV T cell
POLYMERASE Translation
INHIBITORS
CpAM
(+) DNA (-) DNA
Polymerase
Virion secretion

RESTORATION
pgRNA
ER and Golgi 5 3
(+) strand Reverse Encapsidation
NOVEL

IMMUNE
synthesis transcription Core proteins

THERAPEUTIC IDEAL OUTCOME

APPROACHES
Hepatocyte
IMMUNE TARGETS

Space of Disse IMMUNE

I CYTOKINES L T CELL THERAPIES
H
MODULATION
LSEC

XX
T reg G IMMUNE STIMULATION NK cell

IMMUNE RECOVERY
Sinusoid
IFN MDSC
TNF NK TLR
IL-2 cells
CD8
Exhausted
TLR T cells APC
CD8
agonists T cell
CD4 B cell
CD8
K THERAPEUTIC T cell
VACCINE recovery
NAs J CHECKPOINT INHIBITORS B cell

PD-1 T cell HBsAg+

HBeAg+
Combination/sequential CTLA-4
APC
HBV DNA++
APC
therapies
Adjuncts for novel
therapies HSC
CHRONIC HEPATITIS B

Keywords: cccDNA; Hepatitis B surface antigen; Nucleos(t)ide analogues; Pegylated interferon; Novel therapeutic agents.
Journal of Hepatology 2017 vol. 67 | 412414
Received 08 March 2017; received in revised form 11 April 2017; accepted 22 April 2017

Chronic Hepatitis B and who to treat?
Chronic hepatitis B (CHB) is traditionally thought to progress through
distinct disease phases; HBeAg positive chronic infection, HBeAg
positive chronic hepatitis, HBeAg negative chronic infection and
HBeAg negative chronic hepatitis (formerly referred to as immune
tolerant, immune clearance, immune control and immune escape
respectively).1,2 Treatment is usually reserved for those patients with
HBeAg positive or negative chronic hepatitis, with evidence of clinical-
ly active disease and the presence of fibrosis.1 Treatment candidacy has
been largely based on biochemical and virological parameters, howev-
er, recent data have demonstrated that the early phase of the disease
may not be as benign as previously believed; thus these patients may
benefit from early treatment.2-4 In addition, it is widely recognised that
antiviral therapy can prevent cirrhosis and reduce the development of
hepatocellular carcinoma (HCC).5 In this article we discuss currently li-
censed therapies, along with novel pipeline therapies for HBV and their
impact on host-viral immunity.
Currently licensed therapies
The definitive treatment goals in CHB are to prevent cirrhosis, hepatic
decompensation and the development of HCC. Current treatments for
HBV include pegylated interferon-alpha (PegIFN) and nucleos(t)ide
analogues (NAs). PegIFN may achieve sustained off-treatment con-
trol, but durable virological response and hepatitis B surface antigen
(HBsAg) loss is limited to a small proportion of patients. Hepatitis B
envelope antigen (HBeAg) seroconversion (in HBeAg positive disease)
with sustained low level HBV DNA and normal alanine aminotrans-
ferase (ALT), (in both HBeAg positive and negative disease), following
therapy cessation are frequently used end-points, indicating response
to PegIFN.6 NAs can suppress HBV DNA to undetectable levels but
HBsAg loss is rarely achieved. NAs directly target virion synthesis
but are ineffective in the eradication of the covalently closed circu-
lar (cccDNA).7 HBsAg loss, representing a functional cure is now the
gold standard treatment endpoint in CHB. However, as this is rarely
achieved with current therapies; intermediate end-points reflecting
viral control (undetectable HBV DNA), cessation of liver inflammation
(normalisation of serum ALT) and HBeAg seroconversion in HBeAg
positive disease are frequently used end-points. Long-term therapy
with NAs is required in most patients, with the inherent risk of sys-
temic toxicity.8 however, emerging data demonstrate the possibility of
safe NA discontinuation in HBeAg negative CHB.9
When used in isolation, these drugs act differentially on the
immune response; NAs positively impact adaptive immunity, and
PegIFN impacts the innate immune response.10,11 Recent studies have
taken advantage of using combination or sequential therapeutic ap-
proaches to potentially achieve better treatment outcomes. Combina-
tion Peg-IFN and NAs have shown marginal improvement in the rates
of HBsAg decline and loss, along with boosting of both adaptive and in-
nate immune responses.12 In addition, PegIFN followed by sequential
NAs demonstrated a superior decline in HBsAg and improved function
of antiviral natural killer (NK) cells.13 Conversely, initial viral suppression
followed by Peg-IFN-add on has shown superiority in rates of HBsAg
loss compared to NA or PegIFN monotherapy.14 Further studies of com-
bination/sequential therapy would be insightful to better define the
immunological effects of these strategies. More recently, the emer-
gence of tenofovir alfenamide (TAF) has demonstrated similar efficacy
to tenofovir (TDF), but a more favourable side-effect profile. This may
lead to its wider employment in specific patient groups, but its supe-
riority over TDF will need to be validated in future long-term clinical
studies.15
Journal of Hepatology 2017 vol. 67 | 412414
JOURNAL OF HEPATOLOGY
Therapeutic approaches in HBV are on the cusp of major change,
however, at present it remains unclear which novel approaches are
likely to be successful and which will fail. In addition, due to the com-
plex nature of HBV, with cccDNA formation and integration into the
host genome, it is uncertain what complete cure will constitute. Cur-
rently licensed therapies, however, are likely to remain a backbone of
HBV management in the short-term, with NAs employed for viral sup-
pression or in combination with novel agents () PegIFN.
Novel pipeline therapies in HBV
Recent progress with in vitro and in vivo models of HBV infection
have reset the therapeutic paradigm for CHB infection. It is clear that
multiple strategies including targeting the viral life cycle and restor-
ing the host immune response are likely to be required in combina-
tion to achieve HBV cure, and it is possible that different therapeutic
approaches may be required for the distinct disease phases in CHB.16
These agents, discussed in the diagram, will most likely be used with
currently licensed therapies.
Viral targets
A) Entry inhibitors
Myrcludex is being tested in clinical trials as an entry inhibitor. It inter-
acts with Na+-taurocholate cotransporting polypeptide (NTCP) aiming
to decrease viral infectivity.17
B) Silencing & Eliminating cccDNA
Targets against cccDNA include antiviral cytokines, blockade of
rcDNA and epigenetic regulation to undergo its degradation. Technolo-
gies such as CRISPR/Cas9 are being utilised to eliminate cccDNA along
with the use of histone deacetylase (HDAC) inhibitors.18,19
C) Secretion inhibitors
These are aimed at preventing the secretion of HBsAg, nucleic acid pol-
ymers have shown promise in inhibiting HBsAg release.20
D) HBV polymerase inhibitors
This group includes the currently used NAs; tenofovir, entecavir, tel-
bivudine, lamivudine and the recently licensed TAF. They inhibit the
reverse transcriptase for hepatitis B polymerase providing viral sup-
pression and are likely to be employed in combination with novel ther-
apeutic approaches.
E) Core allosteric modulators (CpAM)
These agents allow for inhibition of nucleocapsid assembly and ulti-
mately lead to the inability of pgRNA encapsidation resulting to the
arrest of viral rcDNA. Agents such as NVR 3-778, JNJ379 and AT-130 are
currently undergoing clinical trial evaluation.
F) Silencing RNA
Multiple in vitro studies have been conducted using RNA interference
(RNAi) to prevent HBV replication. The in vivo delivery of HBV-specif-
ic small molecules interfering RNA to infected hepatocytes reducing
cccDNA levels is under investigation with molecules such as ALN-HBV
and TKM-HBV.
Immune targets
G) Immune stimulation
Agents for immune stimulation include pattern recognition receptor
(PRR) agonists, the Toll-like receptor TLR7-agonist GS-9620, which has
been shown to induce strong anti-HBV activity.21 Other potential tar-
413
Hepatology Snapshot
gets for immune stimulation include: TLR1/2, retinoic acid inducible
gene I (RIG-I), and stimulator of interferon genes (STING).
H and I) Immune Modulation & Cytokines
Previous work has identified innate cells impacting immune tolerance.
NK cells have been shown to have a regulatory role upon HBV-specific
T cells via the upregulation of a death receptor.22 In addition, myeloid
derived suppressor cells demonstrate dampening of the adaptive im-
mune response.23 Modulation of innate-adaptive interactions could
also hold therapeutic promise. Cytokines such as tumour necrosis fac-
tor (TNF)-, interleukin (IL)-2 and IL-12 have been shown to inhibit
HBV replication in vitro and thus could also be used in therapy.24
J) Check point inhibitors
HBV-specific T cells are exhausted and overexpress inhibitory mole-
cules such as programmed death-ligand 1 (PD-1) and cytotoxic T-lym-
phocyte-associated protein 4 (CTLA-4).25,26 Blockade of these molecules
has shown potential in vitro, with promising data emerging in HBV-re-
lated HCC with the anti-PD1 agent, nivolumab.
K) Therapeutic vaccines
Molecules such as GS-4774 and TG1050 are being investigated in clin-
ical trials. The induction of HBV-specific T cell immunity by improving
the quality of antigen presenting cells may lead to reduced T cell ex-
haustion.
L) T cell therapies
Increasing the number of HBV-specific T cells by autologous infusion
of T cells expressing chimeric antigen receptors (CARs) or by engineer-
ing T cells to overexpress human leukocyte antigen (HLA)-restricted
HBV-specific T cell receptors (TCRs) have been used in human studies
and shown some promise.27,28
2017 European Association for the Study of the Liver. Published by
Elsevier B.V. All rights reserved.
Financial support
USG is a recipient of a Wellcome Trust Clinical Research Fellowship
(Grant No.:107389/Z/15/Z). PTFK is funded by a large project grant
from Barts and The London Charity (Grant No. 723/1795) and an NIHR
Research for patient benefit award (Grant No. PB-PG-0614-34087).
Conflict of interest
The authors declared that they do not have anything to disclose re-
garding funding or conflict of interest with respect to this manuscript.
Authors contributions
Literature review: USG; Drafting of illustration: USG; Drafting of man-
uscript: USG, PTFK; Critical revision of manuscript: USG, PTFK; Ob-
tained funding: USG, PTFK.
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