Current therapeutic approaches for HBV infected patients
Upkar S. Gill, Patrick T.F. Kennedy'Correspondence information about the author Patrick T.F. KennedyEmail the author Patrick T.F. Kennedy
Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, UK
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DOI: http://dx.doi.org/10.1016/j.jhep.2017.04.015
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Article Outline
Chronic hepatitis B and who to treat?
Currently licensed therapies
Novel pipeline therapies in HBV
Viral targets
A) Entry inhibitors
B) Silencing & eliminating cccDNA
C) Secretion inhibitors
D) HBV polymerase inhibitors
E) Core allosteric modulators (CpAM)
F) Silencing RNA
Immune targets
G) Immune stimulation
H and I) immune modulation & cytokines
J) Check point inhibitors
K) Therapeutic vaccines
L) T cell therapies
Financial support
Conflict of interest
Authors’ contributions
References
Keywords:
cccDNA, Hepatitis B surface antigen, Nucleos(t)ide analogues, Pegylated interferon, Novel therapeutic agents
GoChronic 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], [3], [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.
GoCurrently 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 PegIFNα 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
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.作者: antiHBVren 时间: 2017-12-14 18:04