Elsevier

Journal of Hepatology

Volume 71, Issue 4, October 2019, Pages 834-839
Journal of Hepatology

Case Report
Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: A case report of 3 patients

https://doi.org/10.1016/j.jhep.2019.07.003Get rights and content

Summary

Short-term administration of the entry inhibitor myrcludex-B (MyrB) has been shown to be safe and effective in phase II studies in patients coinfected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). However, its effectiveness and safety are unknown during long-term and high-dose treatment of patients with compensated cirrhosis in real-life settings. Herein, we describe the first 3 European patients with HDV-related compensated cirrhosis who were treated with MyrB 10 mg/day for 48 weeks as a compassionate therapy. Liver function tests, bile acids, and virological markers were monitored every 4 weeks. HBV/HDV-specific T cell quantity (up to 48 and 36 weeks) and HBV RNA levels were also assessed in 2 cases. During MyrB treatment, HDV RNA levels progressively declined from 4.4 and 5.6 logs IU/ml to undetectability in 2 cases, and from 6.8 log copies/ml to 500 copies/ml for the other patient. Alanine aminotransferase normalised after 20, 12 and 28 weeks, respectively. A significant improvement in features of portal hypertension, liver function tests and alpha-fetoprotein levels were documented in 2 cases. In the male patient with histological and clinical stigmata of autoimmune hepatitis, IgG and immunoglobulins rapidly normalised. No significant changes in HBV surface antigen levels and circulating HBV/HDV-specific T cells were demonstrated; HBV DNA and HBV RNA levels remained undetectable throughout the study period. MyrB was well tolerated; patients remained fully asymptomatic despite a significant increase of bile acids. In conclusion, this report shows excellent safety and effectiveness of a 48-week course of MyrB 10 mg/day, combined with tenofovir disoproxil fumarate, for the treatment of HDV-related compensated cirrhosis.

Introduction

Hepatitis delta virus (HDV) is a defective RNA virus, discovered in 1977, that requires the presence of hepatitis B virus (HBV) surface antigen (HBsAg) to envelop its viral ribonucleoprotein complex to become infectious. Approximately 15–20 million individuals worldwide have evidence of chronic HDV-induced hepatitis that typically shows a more rapid progression to cirrhosis (4% per year) and provokes more complications than HBV-monoinfection. The only off-label therapy available so far, pegylated-interferon (Peg-IFN), is endowed with significant side effects and only suppresses HDV replication in a minority of patients.1 However, the therapeutic landscape of HDV therapy is changing rapidly as promising new compounds, given as monotherapies or in combination with Peg-IFN, are now under investigation in phase I and II clinical trials.2 Among these new strategies, the peptidic entry inhibitor MyrB, targeting the commonly used receptor for HBV and HDV (sodium taurocholate co-transporting polypeptide, NTCP) has interesting properties. In phase II studies, patients treated with MyrB monotherapy at 2 or 5 mg/day for up to 48 weeks experienced a significant reduction in serum levels of HDV RNA coupled with alanine aminotransferase (ALT) normalisation.[3], [4] When combined with Peg-IFN for 48 weeks, the virological suppression rates further improved (50% vs. 13% of Peg-IFN monotherapy arm), and HBsAg loss occurred in 13% of the patients in the combination arms (vs. 0/15 patients in the Peg-IFN monotherapy arm).5 MyrB was safe and well tolerated despite the significant increase of total bile acids,6 which correlates with an inhibition of the major conjugated bile salt transporter NTCP. Therefore, administration of MyrB may represent a new therapeutic opportunity for patients with HDV, especially for those with an urgent need for treatment, such as cirrhotics or patients in whom IFN is contraindicated due to disease severity or previous non response.7 Of note, no data are available on high-dose MyrB therapy given for more than 24 weeks.

Therefore, this is the first report aimed at describing the safety and effectiveness of MyrB 10 mg/day administered for 48 weeks in the first 3 European patients with compensated cirrhosis treated outside clinical trials. Following the Ethical Committee approval for MyrB compassionate use for the 2 Italian patients and the written informed consent for the Austrian patient, MyrB was added to the ongoing tenofovir disoproxil fumarate (TDF) therapy.

MyrB was self-administered as 2 subcutaneous injections every 24 hours (2 vials of 5 mg each). Liver function tests, total bile acids and virological HDV and HBV markers were monitored every 4 weeks. HDV RNA was quantified by RoboGene® (Aj-Roboscreen, Jena, Germany; lower limit of detection [LLOD] 6 IU/ml) or by in-house reverse-transcription PCR (RT-PCR) (lower limit of quantification [LLOQ] 100 copies/ml). HBV DNA was quantified by Abbott RealTime HBV (Abbott Diagnostics, Rome, Italy; LLOQ 10 IU/ml) or by Roche Cobas® (AmpliPrep/TaqMan System®, LLOQ 20 IU/ml). HBV genotype was determined by INNO-LiPA HBV genotyping (Fujirebio Europe NV, Ghent, Belgium), while HDV genotype was assessed by sanger sequencing and analyses of the hepatitis delta antigen region: HDV RNA was transcribed using primers random hexamers and SuperScript III First-Strand Synthesis System for RT-PCR Kit (Invitrogen, California, USA). First PCR and Nested PCR were performed using primers synthesised by metabion international AG (Metabion GmbH, Germany) and TaKaRa Ex Taq Hot Start Version Kit (TAKARA BIO INC, Kusatsu, Japan). Auto-antibodies and immunoglobulins were assessed every 6 months, liver stiffness by Fibroscan® every 3–6 months, abdominal ultrasound every 6 months.

In 2 of the cases, additional analyses were performed. HBV RNA was tested after every 12 weeks of treatment using a specific real-time PCR technique: to achieve high sensitivity, 200 µl of serum were used for nucleic acid extraction (LLOD 160 copies/ml). In peripheral blood mononuclear cells collected and cryopreserved every 4 weeks, HBV/HDV-specific T cell quantity and function were analysed by direct ex vivo IFN-y ELISPOT methods using overlapping peptides (15 mers/overlap of 10AA), covering both HBV and HDV proteomes.10 The positivity of spot forming units are determined when the values were above the threshold (which is 3-fold higher than the negative control wells).

Patients provided written informed consent for additional sera sample storage and analysis.

Section snippets

Case 1

A 69-year-old, female, Caucasian HBV e antigen (HBeAg)-negative patient with HDV-related compensated cirrhosis (Child-Pugh Score A5) complicated by portal hypertension (splenomegaly and thrombocytopenia), was evaluated for MyrB treatment in January 2018 since interferon therapy was contraindicated because of age, platelet count and previous non response. She had genotype D for HBV and genotype 1 for HDV.

She had been treated with Peg-IFN alpha 135 μg/week for 18 months in 2011, with

Case 2

A 51-year-old, male, Caucasian HBeAg-negative patient with HDV-compensated cirrhosis (Child-Pugh Score A5), complicated by splenomegaly, thrombocytopenia and small oesophageal varices, was evaluated for MyrB therapy in May 2018. He had genotype D for HBV and genotype 1 for HDV.

The patient was known to have HBV/HDV coinfection since June 2010, when a liver biopsy revealed moderate to severe HDV-related hepatitis (Grading 9, Staging 6, according to Ishak score) with a significant plasma cellular

Case 3

A 58-year-old female, from Uzbekistan, was referred in 2012 for HBV/HDV coinfection. She was known to be HBsAg positive since 1988. A liver biopsy was never performed but based on the ultrasound findings she was suggested to have compensated cirrhosis. She was HBeAg negative, HBV DNA was 4,850 IU/ml, HDV RNA 6.2 log copies/ml. She started TDF 245 mg/day, and 3 months later she received Peg-IFN alpha 180 µg/week that was however discontinued because of an increase of ALT levels and a significant

Discussion

This case report demonstrated the effectiveness and safety of 48-week administration of MyrB 10 mg/day in 3 patients with HDV-related compensated cirrhosis. To our knowledge, these are the first cases ever treated with this strategy. Patients showed a fast normalisation of aminotransferases, and a profound reduction of HDV serum RNA levels with clinically relevant improvements of liver function in the context of an excellent safety profile. Responses were maintained during the study period.

Financial support

Grant from “Ricerca Corrente RC2019/105-01”, Italian Ministry of Health, and by a Singapore Translational Research (STaR) Investigator Award MOH-000019 (MOH-StaR17Nov-0001) to AB.

Conflict of interest

Peter Ferenci: advisor and speaker bureau for Gilead Sciences, GSK, MSD, Abbvie; Florian van Bömmel: research grants from Gilead Sciences Inc., MYR Pharma and Roche Diagnostics, speaker and advisor for Gilead Sciences, Roche, Janssen, Abbvie, MSD and BMS; Antonio Bertoletti advisor for Gilead, Spring-Bank, Vir, Simcere. He is also Scientific Founder of LION TCR pte.; Pietro Lampertico: advisor and speaker bureau for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie, Janssen, Arrowhead, Alnylam,

Authors’ contributions

AL, PF and PL were involved in patient’s care and drafting of the manuscript. AL, MB, RP were involved in data collection. ET, SG, LP, LL, DP were involved in PBMC extraction and cryopreservation. CT and AB performed T cell analysis. HH, SU, LG, FC, GL and FvB performed molecular and virological analysis. AL, AB, PF and PL were involved in manuscript editing. All authors approved the final version of the manuscript.

Declarations

The uses of myrcludex-B were approved by the local Ethics Committee on a 6-month basis for the Italian patients.

Acknowledgement

We thank Dr. Alexander Alexandrov from MYR Pharma for the free supply of myrcludex-B.

References (10)

There are more references available in the full text version of this article.

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