Introduction and nomenclature for ‘cure’
|Sterilising ‘cure’||Idealistic functional ‘cure’||Realistic functional ‘cure’||Attainable partial functional ‘cure’|
|Clinical scenario||Never infected||Recovery after acute HBV||Chronic HBV with HBsAg loss||Inactive carrier off treatment|
|Serum HBV DNA||Not detected||Not detected||Not detected||Low level or not detected|
|Hepatic cccDNA, transcription||Not detected|
|Integrated HBV DNA||Not detected||Detected?||Detected||Detected|
|Liver disease||None||None||Inactive, fibrosis regress over time||Inactive|
|Risk of HCC||Not increased||Not increased||Declines with time||Risk lower vs. active hepatitis|
Endpoint definitions for HBV therapy and surrogates for HBV functional cure
HBsAg loss as a surrogate for HBV functional cure
Decline in HBsAg levels as predictor for HBsAg loss in early phase trials
Reliability of current HBsAg assays to assess HBV functional cure
Serum HBV RNA as a measure of cccDNA and HBV transcription
Serum HBcrAg as a measure of cccDNA and HBV translation
- Maasoumy B.
- Wiegand S.B.
- Jaroszewicz J.
- Bremer B.
- Lehmann P.
- Deterding K.
- et al.
- Maasoumy B.
- Wiegand S.B.
- Jaroszewicz J.
- Bremer B.
- Lehmann P.
- Deterding K.
- et al.
Current therapies for chronic HBV and HDV infection
New therapies and mode of action
|Compound||Phase of development||Comments / Data|
|HBV entry inhibitors|
|NTCP inhibitor, Myrcludex B (Myr Pharmaceuticals)||Phase III (Hepatitis D)|
Phase I/II (Hepatitis B)
|Strong effect on serum HDV RNA levels, induced ALT normalisation under monotherapy.|
|Cyclosporine analogues||Preclinical||Several cyclosporine derivatives inhibited HBV infection with a sub-micromolar IC50 with no inhibition of bile acid uptake.|
|Targeting cccDNA (Destabiliser, epigenetic regulators, endonucleases)|
|cccDNA destabiliser, ccc_R08 (Roche)||Preclinical||First-in-class orally available HBV cccDNA destabiliser achieved sustained HBsAg and HBV DNA suppression in a mouse model.|
|Targeted endonuclease, CRISPR/CAS9||Preclinical||Cleavage of cccDNA by Cas9 showed reduction in both cccDNA and other parameters of viral gene expression and replication in vitro|
|CRV431 (ContraVir)||Phase I||Cyclophilin inhibitor that prevents Cyclophilin A-HBx complex formation and HBV replication.|
|Nitazoxanide (Romark)||Phase II||First-in-class thiazolide originally developed as antiprotozoal agent. Inhibits HBV transcription from cccDNA by targeting the HBx–DDB1 interaction.|
A pilot trial showed antiviral efficacy.
|Inhibition of gene expression / gene silencing|
|Antisense oligonucleotides and locked nucleic acids|
|GSK3389404 (GlaxoSmith Kline)||Phase II||Methoxyethyl antisense oligonucleotide conjugated to N-acetylgalactosamine moieties. Acceptable safety and pharmacokinetic profile in phase I.|
A randomized, double-blind, placebo-controlled, first-time-in-human study to assess the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of GSK3389404 in healthy subjects.
Clin Pharmacol Drug Dev. 2019; 8: 790-801
|Locked nucleic acid platform-based single-stranded oligonucleotides (Roche)||Preclinical||Liver-targeted single-stranded oligonucleotide therapeutics based on the locked nucleic acid platform. Rapid and long-lasting reduction of HBsAg in a mouse model.|
|ARC-520 (Arrowhead)||Development discontinued||Decrease in HBsAg level in HBeAg-positive but not in HBeAg-negative patients.|
|JNJ-3989 (Janssen) formerly ARO-HBV-1001 (Arrowhead)||Phase I/II||HBsAg reduction in HBeAg-positive and HBeAg-negative patients. Majority of patients achieved HBsAg <100 IU/ml.|
|AB-729 (Arbutus)||Preclinical||Activity in vitro and strong HBsAg reduction in mice.|
|ALN-HBV (Alnylam)||Preclinical||Profound and durable HBsAg silencing in vitro and in vivo.|
|Targeting the viral RNA post-transcriptional regulatory element|
|Dihydroquinolizinone compounds||Preclinical||Specific blockage of the production of HBV DNA and viral antigens.|
Preclinical antiviral drug combination studies utilizing novel orally bioavailable investigational agents for chronic hepatitis B infection: AB-506, a next generation HBV capsid inhibitor, and AB-452, a HBV RNA destabilizer.
J Hepatol. 2018; 68: S17
|Core protein (Capsid) assembly modulators (CpAMs)|
|NVR 3-778 (Novira, Janssen Pharmaceutica)||Development discontinued||First in-class CpAM showed reduction of HBV DNA and HBV RNA, greater effect in combination with PEG-IFN.|
|ABI-H0731 (Assembly Bioscience)||Phase IIa||CpAMs showed high antiviral efficacy in phase I and IIa studies with >2 log decline of HBV DNA. HBV RNA decline is stronger with CpAM (ABI-H0731) compared to NA therapy.|
|RO7049389 (Roche)||Phase II|
|JNJ-56136379 (Janssen)||Phase II|
|AB-506 (Arbutus)||Phase I|
|ABI-H2158 (Assembly Bioscience)||Phase I|
|GLS4JHS (Jilin University)||Phase I/II|
|GLP-26 (Emory University)||Preclinical|
|ABI-H3733 (Assembly Bioscience)||Preclinical|
|HBsAg release inhibitors|
|Nucleic acid polymers (REP compound series) (Replicor)||Phase II||Small studies with REP compounds (i.v. application) in combination with TDF and PEG-IFN in HBV monoinfected and HBV/HDV co-infected patients show strong HBsAg decline.|
Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase II trial.
Lancet Gastroenterol Hepatol. 2017; 2: 877-889
HBV entry inhibitors
Targeting cccDNA and its transcriptional activity
Inhibition of gene expression
- Han K.
- Cremer J.
- Elston R.
- Oliver S.
- Baptiste-Brown S.
- Chen S.
- et al.
Nucleocapsid assembly and pgRNA packaging
- Bazinet M.
- Pantea V.
- Cebotarescu V.
- Cojuhari L.
- Jimbei P.
- Albrecht J.
- et al.
|Compound||Phase of development||Comments / Data|
|Targeting cell intrinsic and Innate Immune responses|
TLR 7 agonist
|Phase I||Combination with the CpAM RO7049389 achieved sustained HBV DNA suppression and HBsAg loss in a mouse model.|
|Vesatolimod, GS-9620 (Gilead)|
TLR 7 agonist
|Phase II||Dose-dependent pharmacodynamic induction of ISG15 and host NK and HBV-specific T cell responses but no HBsAg reduction in patients.|
Lack of effect for cccDNA in vitro.
TLR 7 agonist
|Preclinical||Antiviral efficacy (HBV DNA, HBsAg, liver HBV DNA, HBV RNA) in a mouse model.|
TLR 8 agonist
|Phase I||Induced IL-12 and IL-RA1 in humans. Short duration did not result in HBsAg decline.|
TLR 9 agonist
|Phase I||Increased IL-1β, IL-6, IL-8 and IFN-γ and reductions in IL-10 levels.|
|Inarigivir soproxil (Spring Bank)|
|Phase II||Dual mode of action: RIG-I Agonist and interference with the interaction of the viral polymerase and pgRNA. The ACHIEVE trial showed dose-dependent antiviral response on HBV DNA and HBV RNA.|
|Targeting adaptive immune responses|
Nivolumab (Opdivo, Bristol-Myers Squibb)
|Phase I||Single dose of Nivolumab (with or without GS4774) showed HBsAg reduction >0.5 log in some patients.|
Non-replicative adenovirus serotype 5 encoding 3 HBV proteins (Therapeutic Vaccine)
|Phase I||Induction of T cell responses in mouse models and reduction of viral parameters.|
Dose-related immunogenicity in patients but so far only preliminary data on clinical effects.
Adjuvanted ChAd and MVA vectored therapeutic HBV vaccines
|Phase I||Robust T cell and anti-HBs response in mice.|
Prime-boost vaccination strategies using chimpanzee-adeno and MVA viral vectored vaccines encoding multiple HBV antigens (CPmutS) and class II invariant chain molecular adjuvants induces robust T-cell and anti-HBs antibody response in mice.
J Hepatol. 2019; 70: E459-E460
HBV Peptide therapeutic vaccine with TLR9 adjuvant IC31
|Phase I||Human T cell responses against HBV markedly increased over baseline compared to placebo but no effect on HBsAg.|
Electroporation of DNA vaccine
|Phase I||No clinical data (NCT03463369).|
DNA plasmids encoding HBsAg and HBcAg) plus INO-9112 (DNA plasmid encoding human interleukin 12)
|Phase I||Activated and expanded CD8+ killer T cells (www.inovio.com).|
|GS-4774 (Globeimmune, Gilead)|
Heat-inactivated, yeast-based, T cell vaccine
|development discontinued||No significant reductions in serum HBsAg in phase II.|
|Genetically engineered T cells / Monoclonal or bispecific antibodies||Preclinical||Reductions in HBsAg and HBV DNA in mouse models.|
Stimulation of pathogen recognition receptors
Stimulator of interferon genes agonists
Engineered HBV-specific T cells
Clinical trials aimed at HBV functional cure
Assessment of safety and indications for stopping trials of new HBV therapies
|Compound||Phase of development||Comments / Data|
|Entry (NTCP) inhibitor:|
Myrcludex B (Myr Pharmaceuticals)
|Phase III (in progress)|
|Phase III (in progress)|
Pegylated interferon-lambda (Eiger)
|Nucleic acid polymers:|
(REP compound series)(Replicor)
|Antiviral flare||Virus-induced flare||Drug-induced flare|
|Timing of flare||Variable depending on mechanism of drug||May be early if due to lack of efficacy, and variable if due to antiviral drug resistance||Any time during treatment|
|Course of flare||Usually self-limiting within weeks||Progressive if not recognised and remedied||Static or progressive|
|Association with HBV DNA||After HBV DNA decline||Preceded by HBV DNA increase||Unrelated|
|Alkaline phosphatase level||Normal||Normal||Normal or elevated|
|Bilirubin level||Usually normal||May be elevated||Normal or elevated|
|Liver biopsy||Not needed||Not needed||May be needed for diagnosis|
|Baseline ALT value||Elevation during treatment|
|1 to less than 2x ULN||>5x from baseline and >10x ULN|
|2 to less than 5x ULN||>3x from baseline|
|Greater or equal to 5x ULN||>2x from baseline|
Design of phase II and III trials
Design of trials of combination therapies for chronic HBV
Discussion on endpoints, trial design, and desired response rates
Primary endpoint for phase II clinical trials
Primary endpoint and desired response rate for phase III clinical trials
Criteria for approval of diagnostic assays for new HBV markers used to determine efficacy endpoints
Prerequisites for testing a new therapy in combination with other (new or existing) therapies
Target patient population for new HBV therapies
Primary endpoint for clinical trials of new HDV treatment
Conflicts of interest
‡EASL-AASLD HBV Treatment Endpoints Conference Faculty
- •Thomas Berg (Section of Hepatology, Clinic of Gastroenterology, University Hospital Leipzig, Leipzig, Germany)
- •Maurizia R. Brunetto (Department of Clinical and Experimental Medicine, University of Pisa and Hepatology Unit, University Hospital of Pisa, Italy)
- •Stephanie Buchholz (Federal Institute for Drugs and Medical Devices, BfArM, Bonn, Germany)∗∗∗∗This article represents the opinion of the author and does not represent the official policy or views of the EMA/CHMP or the Federal Institute for Drugs and Medical Devices (BfArM).
- •Maria Buti (Liver Unit, Hospital Universitario Valle Hebron. Barcelona 08021)
- •Henry LY Chan (Department of Medicine and Therapeutics, The Chinese University of Hong Kong)
- •Kyong-Mi Chang (Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine; Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA)
- •Maura Dandri (I. Department of Medicine, University Medical center Hamburg-Eppendorf, Hamburg and German Center for Infection Research (DZIF), Germany
- •Geoffrey Dusheiko (Kings College Hospital and University College London Medical School, London, UK)
- •Jordan J. Feld (Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada)
- •Carlo Ferrari (Unit of Infectious Diseases and Hepatology, Department of Medicine and Surgery, University of Parma, Italy)
- •Marc Ghany (Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
- •Harry L.A. Janssen (Toronto General Hospital, University of Toronto, Canada)
- •Patrick Kennedy (Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK)
- •Pietro Lampertico (CRC “A. M. and A. Migliavacca” Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy)
- •Jake Liang (Liver Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA)
- •Stephen Locarnini (Victorian Infectious Diseases Laboratories, Melbourne, Australia)
- •Mala K. Maini (Division of Infection and Immunity, University College London, UK)
- •Poonam Mishra∗(Division of Antiviral Products, Center for Drug Evaluation and Research, US Food and Drug Administration, USA)∗This article reflects the views of the author and should not be construed to represent US Food and Drug Administration views, guidance or policies.
- •George Papatheodoridis (Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens, Greece)
- •Jörg Petersen (IFI Institute at the Asklepios Klinik St Georg Hamburg, University of Hamburg, Hamburg, Germany)
- •Silke Schlottmann∗(Food and Drug Administration, USA)
- •Su Wang (Saint Barnabas Medical Center, RWJ Barnabas Health, USA, and World Hepatitis Alliance, UK and Hepatitis B Foundation, USA)
- •Heiner Wedemeyer (Essen University Hospital, University of Duisburg-Essen, Germany)
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