Current therapeutic approaches for HBV infected patients

Hepatology Snapshot:

Current therapeutic approaches for HBV infected patients Upkar S. Gill1, Patrick T. F. Kennedy1,* Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, UK Blizard Institute, Barts and The London School of Medicine & Dentistry, 4 Newark Street, London, E1 2AT

1 *

CURRENTLY LICENSED THERAPIES

ENTRY INHIBITORS

Subviral particle

SILENCING &

Antigen secretion

ELIMINATING cccDNA

FUNCTIONAL CURE OF CHRONIC HEPATITIS B

HBeAg

NTCP Virion

Hepatocyte

Uncoating

siRNA

Nucleus

VIRAL TARGETS

cccDNA formation

Transcription

cccDNA

RC DNA

mRNA

Recycling

SECRETION INHIBITORS

HBsAgHBeAgHBV DNA-

ER and Golgi

VIRAL DECLINE

Interferon-alpha

HBV POLYMERASE INHIBITORS

CD8 T cell

CpAM (+) DNA

(-) DNA

Polymerase

ER and Golgi

NOVEL THERAPEUTIC APPROACHES

IMMUNE RESTORATION

Virion secretion

pgRNA Encapsidation

Reverse transcription

(+) strand synthesis

5’

3’

Core proteins

IDEAL OUTCOME Hepatocyte Space of Disse LSEC Sinusoid

I T reg

L

CYTOKINES

G IFNγ TNFα IL-2

T CELL THERAPIES

IMMUNE STIMULATION

B cell

J

NA’s

K

CHECKPOINT INHIBITORS

Adjuncts for novel therapies

CTLA-4

HSC

Keywords: cccDNA; Hepatitis B surface antigen; Nucleos(t)ide analogues; Pegylated interferon; Novel therapeutic agents. Received 08 March 2017; received in revised form 11 April 2017; accepted 22 April 2017

THERAPEUTIC VACCINE

B cell

CD8 T cell recovery

T cell

PD-1

Combination/sequential therapies

XX

MDSC

CD8 T cells

TLR agonists CD4

IMMUNE MODULATION NK cell

TLR

NK cells

H

APC APC

IMMUNE RECOVERY

IMMUNE TARGETS

APC

Translation

Exhausted CD8 T cell

APC

HBsAg+ HBeAg+ HBV DNA++

CHRONIC HEPATITIS B

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Hepatology Snapshot 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 clinically active disease and the presence of fibrosis.1 Treatment candidacy has been largely based on biochemical and virological parameters, however, 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 licensed 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 (PegIFNα) and nucleos(t)ide analogues (NAs). PegIFNα may achieve sustained off-treatment control, 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 aminotransferase (ALT), (in both HBeAg positive and negative disease), following therapy cessation are frequently used end-points, indicating response to PegIFNα.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 circular (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 systemic 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 PegIFNα impacts the innate immune response.10,11 Recent studies have taken advantage of using combination or sequential therapeutic approaches to potentially achieve better treatment outcomes. Combination Peg-IFNα and NAs have shown marginal improvement in the rates of HBsAg decline and loss, along with boosting of both adaptive and innate immune responses.12 In addition, PegIFNα 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-IFNα-add on has shown superiority in rates of HBsAg loss compared to NA or PegIFNα monotherapy.14 Further studies of combination/sequential therapy would be insightful to better define the immunological effects of these strategies. More recently, the emergence 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 superiority over TDF will need to be validated in future long-term clinical studies.15

2

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 complex nature of HBV, with cccDNA formation and integration into the host genome, it is uncertain what complete cure will constitute. Currently licensed therapies, however, are likely to remain a backbone of HBV management in the short-term, with NAs employed for viral suppression or in combination with novel agents (±) PegIFNα. 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 restoring the host immune response are likely to be required in combination 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 interacts 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. Technologies 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 polymers have shown promise in inhibiting HBsAg release.20 D) HBV polymerase inhibitors This group includes the currently used NAs; tenofovir, entecavir, telbivudine, lamivudine and the recently licensed TAF. They inhibit the reverse transcriptase for hepatitis B polymerase providing viral suppression and are likely to be employed in combination with novel therapeutic approaches. E) Core allosteric modulators (CpAM) These agents allow for inhibition of nucleocapsid assembly and ultimately 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-specific 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-

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JOURNAL OF HEPATOLOGY 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 immune response.23 Modulation of innate-adaptive interactions could also hold therapeutic promise. Cytokines such as tumour necrosis factor (TNF)-α, 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 molecules such as programmed death-ligand 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).25,26 Blockade of these molecules has shown potential in vitro, with promising data emerging in HBV-related HCC with the anti-PD1 agent, nivolumab. K) Therapeutic vaccines Molecules such as GS-4774 and TG1050 are being investigated in clinical trials. The induction of HBV-specific T cell immunity by improving the quality of antigen presenting cells may lead to reduced T cell exhaustion. 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 engineering 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 regarding funding or conflict of interest with respect to this manuscript. Authors’ contributions Literature review: USG; Drafting of illustration: USG; Drafting of manuscript: USG, PTFK; Critical revision of manuscript: USG, PTFK; Obtained funding: USG, PTFK.

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