Chronic Hepatitis D—What Is Changing?

David Yardeni; Theo Heller; Christopher Koh

J Viral Hepat. 2022;29(4):240-251.

Abstract and Introduction

Abstract

Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.

Introduction

Chronic infection of the liver by the hepatitis D virus (HDV) is considered an incurable disease that is currently without a United States (US) Food and Drug Administration (FDA)–approved therapy.^[1] The combined properties of this defective satellite virus that requires the ever-essential co-infection with the hepatitis B virus (HBV) have managed to prevent significant advancement in therapeutic options for many years. This delay in therapy has unfortunately doomed many patients worldwide to the end points of chronic liver inflammation, which are hepatocellular carcinoma (HCC) and cirrhosis.^[2]

In recent years, several new approaches to HDV therapy have been developed which for the first time bring hope that a long-lasting cure for this virus is within grasp. This review will focus on recent advances in these new approaches that aim to change this unacceptable reality of HDV infection.

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Table 1. A partial list of clinical trials with interferon alpha for hepatitis D
Trial Year/Ref	Trial	Agents and Doses	Study Scheme	Patients	Results
1994³⁸	–	IM IFN-α-2a 3–9 million units three times a week.	3-arm study: A 14 patients receiving 9 million units B 14 patients receiving 3 million units C 14 patients without any treatment For 48 weeks.	A 14 B 14 C 14	At 6 months post-treatment: 6, 2 and 1 patients of arm A, B and C were HDV RNA-negative respectively. Only 3 patients from arm A achieved normal ALT and negative HDV RNA.
2006⁴¹	–	1.5 μg/kg SC PEG-IFN-α-2b once a week.	1.5 μg/kg PEG-IFN-α-2b for 12 months.	14	At the end of treatment, 8 (57%) patients achieved undetected HDV RNA.
2011⁴²	HIDIT-I	SC PEG-IFN-α-2a 180 μg once a week +PO adefovir 10 mg	3-arm study: A PEG-IFN-α-2a 180 μg/week + adefovir 10 mg B PEG-IFN-α-2a 180 μg/week C adefovir 10 mg. For 48 weeks.	A 31 B 29 C 30	At EOT, HDV RNA was negative in 23% (A), 24% (B) and 0% (C). At 6 months off therapy, HDV RNA was negative in 28%(A), 28% (B) and 0% (C).
2019⁴⁵	HIDIT-II	SC PEG-IFN-α-2a 180 μg once a week + PO TDF 300 mg	2-arm study: A PEG-IFN-α-2a 180 μg/week + TDF 300 mg B PEG-IFN-α 2a 180 μg/week + placebo. For 96 weeks.	A 59 B 61	At EOT, HDV RNA was negative in 48% (A) and 33% (B).
2014⁴⁶	–	SC weekly PEG-IFN-α at 180–270 μg	Dose was titrated for each patient. Average dose was 180 μg. Median duration was 140 weeks.	13	At 3 years, 39% achieved negative HDV RNA.

Abbreviations: EOT, end of treatment; PEG-IFN-α, pegylated interferon alpha-2a.

Table 2. Clinical trials with novel therapies for hepatitis D
Trial Year/Ref	Trial	Agents and doses	Study scheme	Patients	Results
Bulevirtide
2016⁵²	MYR201-HBV/HDV	BLV 2 mg SC daily + PEG-IFN-α 180 μg SC weekly	3-arm study: A. BLV 2 mg for 24 weeks followed by PEG-IFN-α for 48 weeks. B. BLV 2 mg + PEG-IFN-α for 24 weeks followed by PEG-IFN-α only for 24 weeks. C. PEG-IFN-α for 48 weeks.	A 8 B 8 C 8	At 24 weeks, A: mean HDV decline was 1.67 log IU/L. 2 patients became HDV-negative. B: mean HDV decline was 2.6 log IU/L. 5 Patients became HDV-negative. C: mean HDV decline was 2.2 log IU/L. 2 Patients became HDV-negative.
2017^{53, 54}	MYR202	BLV 2–10 mg SC daily + TDF 245 mg PO daily	4-arm study: A. BLV 2 mg/day + TDF 245 mg/day for 24 weeks followed by TDF 245 mg/day only for 24 weeks. B. BLV 5 mg/day + TDF 245 mg/day for 24 weeks followed by TDF 245 mg/day only for 24 weeks. C. BLV 10 mg/day + TDF 245 mg/day for 24 weeks followed by TDF 245 mg/day only for 24 weeks. D. TDF 245 mg/day for 48 weeks.	A. 21 B. 21 C. 22 D. 56	At EOT, mean HDV RNA decline for arm: A: 1.75 log IU/ml, B: 1.6 log IU/ml, C: 2.7 log IU/ml, D: 0.18 log IU/ml.
2019⁵⁵	MYR203	BLV 2–10 mg SC daily + PEG-IFN-α 180 μg SC weekly + TDF 300 mg PO daily	4-arm study: A. PEG-IFN-α, B. BLV 2 mg/day + PEG-IFN-α, C. BLV 5 mg/day + PEG-IFN-α, D. BLV 2 mg/day. For 48 weeks	A 15 B 15 C 15 D 15	24 weeks after EOT, HDV RNA was negative in 0% (A), 53% (B), 26% (C) and 0% (D).
2020⁵⁶	MYR203-Extension	BLV 5 mg SC twice daily or 10 mg SC daily + PEG-IFN-α 180 μg SC weekly + TDF 300 mg PO daily	2-arm extension study: E. BLV 10 mg/day + PEG-IFN-α F. BLV 5 mg BID + TDF 300 mg/day For 48 weeks	E. 15 F. 15	At EOT, HDV RNA declined by a median of 6.09 log IU/ml and was undetectable in 86.7% of patients (E). HDV RNA declined by median of 4.58 log10 IU/ml and was undetectable in 40.0% of patients (F)
2021⁵⁷	MYR204	PEG-IFN-α 180 μg SC weekly + BLV 2 mg SC twice daily or 10 mg SC daily	4-arm study: A PEG-IFN-α for 48 weeks. B BLV 2 mg/day + PEG-IFN-α for 48 weeks. Followed by 48 weeks of BLV 2 mg/day C BLV 10 mg/day + PEG-IFN-α for 48 weeks. Followed by 48 weeks of BLV 10 mg/day D BLV 10 mg/day for 96 weeks.	A 25 B 50 C 50 D 50	At week 24 of treatment, ≥2 log IU/ml reduction was achieved in 37.5% (A), 86% (B), 90% (C) and 72% (D). Undetectable HDV RNA was found in 12.5% (A), 24% (B), 34% (C) and 4% (D).
2021⁵⁸	MYR301	BLV 2 mg or 10 mg SC daily	3-arm study: A No treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks. B BLV 2 mg/day for 144 weeks C BLV 10 mg/day for 144 weeks.	A 50 B 50 C 50	At week 24 of treatment, ≥2 log IU/ml reduction was achieved in 0% (A), 55.1% (B) and 68% (C).
Interferon lambda
2019⁶²	LIMIT	PEG-IFN-lambda 120–180 μg/week SC	2-arm study: A SC PEG-IFN-lambda 180 μg/week B SC PEG-IFN-lambda 180 μg/week For 48 weeks	A 14 B 19	At EOT, >2 log IU/ml reduction was achieved in 50% (A), 21% (B). Undetectable HDV RNA was found in 36% (A) and 16% (B).
Lonafarnib
2015⁶⁶	–	PO LNF 100–200 mg twice daily	2-arm study: A LNF 100 mg twice daily. B LNF 200 mg twice daily. For 28 days	A 8 B 6	At EOT, HDV RNA decline of 0.73 log IU/ml (A) and 1.54 log IU/ml (B).
2018⁶⁷	LOWR HDV-1	PO LNF 100–300 mg twice daily, PO LNF 100 mg thrice daily, PO RTV 100 mg once daily, PEG-IFN-α 180 μg SC weekly.	5-arm study: A LNF 200 mg twice daily for 12 weeks. B LNF 300 mg twice daily for 12 weeks. C LNF 100 mg thrice daily for 5 weeks. D LNF 100 mg twice daily + PEG-IFN-α for 8 weeks. E LNF 100 mg twice daily + RTV 100 mg once daily for 8 weeks.	A 3 B 3 C 3 D 3 E 3	At EOT, HDV RNA decline of −0.03 log IU/ml (A), 1.78 log IU/ml (B), 1.31 log IU/ml (C), 2.97 log IU/ml (D) and 3.19 log IU/ml (E).
2017⁶⁸	LOWR HDV-2	PO LNF 25–50 mg twice daily, PO RTV 100 mg twice daily, PEG-IFN-α 180 μg SC weekly.	4-arm study: A LNF 25 mg + RTV 100 mg twice daily. B LNF 50 mg + RTV 100 mg twice daily. C LNF 25 mg + RTV 100 mg twice daily + PEG-IFN-α. D LNF 50 mg + RTV 100 mg twice daily + PEG-IFN-α. For 24 weeks	A.6 B. 8 C. 5 D. 4	At EOT, >2 log IU/ml reduction was achieved in 60% (A), 33% (B), 75% (C) and 100% (D). Undetectable HDV RNA was found in 0% (A), 12.5% (B), 60% (C) and 0% (D).
2017⁶⁹	LOWR HDV-3	PO LNF 50–100 mg twice daily, PO RTV 100 mg once daily, PO ETV 0.5 mg once daily, PO TDF 300 mg once daily.	6-arm study: A LNF 50 mg twice daily + RTV 100 mg + ETV/TDF once daily for 24 weeks. B LNF 75 mg twice daily + RTV 100 mg + ETV/TDF once daily for 24 weeks. C LNF 100 mg twice daily + RTV 100 mg + ETV/TDF once daily for 24 weeks. D Placebo for 12 weeks followed by LNF 50 mg twice daily + RTV 100 mg + ETV/TDF once daily for 12 weeks. E Placebo for 12 weeks followed by LNF 75 mg twice daily + RTV 100 mg + ETV/TDF once daily for 12 weeks. F Placebo for 12 weeks followed by LNF 100 mg twice daily + RTV 100 mg + ETV/TDF once daily for 12 weeks.	A.4 B.4 C.4 D.3 E.3 F.3	At 12 weeks of treatment (nonplacebo), mean HDV RNA decline of 1.6 log IU/ml (A+D), 1.33 log IU/ml (B+E) and 0.83 log IU/ml (C+F).
2017⁷⁰	LOWR HDV-4	PO LNF 50–100 mg twice daily, PO RTV 100 mg twice daily	1-arm, escalating dose study of LNF from 50 to 100 mg twice daily + RTV 100 mg twice up to 18 weeks.	15	At EOT, mean HDV RNA decline was 1.58 log IU/ml. One patient became HDV RNA-negative.
Combination of interferon lambda and lonafarnib
2020⁷¹	LIFT	PO LNF 50 mg twice daily, PO RTV 100 mg twice daily, PEG-IFN-lambda 180 μg/week SC	24 weeks of LNF 50 mg + RTV 100 mg twice daily + PEG-IFN-lambda 180 μg/week SC	26 (4 discontinued at 12 weeks)	At EOT, mean HDV RNA decline of 3.23 log IU/ml. HDV-negative or unquantifiable was found in 50%.
Nucleic acid polymers
2017⁷⁶	REP 301	IV REP 2139 250–500 mg/week, PEG-IFN-α 180 μg SC weekly.	IV REP 2139 500 mg/week for 15 weeks followed by IV REP 2139 250 mg/week + PEG-IFN-α 180 μg SC/week for 15 weeks followed by PEG-IFN-α 180 μg SC/week for 33 weeks.	12	At EOT, >2 log IU/ml reduction was achieved in 83.3%. Undetectable HDV RNA was found in 75%.

Abbreviations: BLV, bulevirtide; EOT, end of treatment; ETV, entecavir; LNF, lonafarnib; PEG-IFN-α, pegylated interferon alpha-2a; RTV, ritonavir; TDF, tenofovir.