<figure><img src="image_1.png" /></figure>

HAL
open science

# Management of chronic HBV-HDV patients chronic HBV-HDV infection: A review on new management options

María Buti, Alexia Gonzalez, Mar Riveiro-Barciela, Marc Bourliere

► To cite this version:

María Buti, Alexia Gonzalez, Mar Riveiro-Barciela, Marc Bourliere. Management of chronic HBV-HDV patients chronic HBV-HDV infection: A review on new management options. United European Gastroenterology Journal, 2023, 12 (2), pp.210-218. 10.1002/ueg2.12494. inserm-04541367

HAL Id: inserm-04541367

https://inserm.hal.science/inserm-04541367

Submitted on 10 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Management of chronic HBV-HDV patients chronic HBV-HDV infection: A review on new management options

María Buti, Alexia Gonzalez, Mar Riveiro-Barciela, Marc Bourliere

► To cite this version:

María Buti, Alexia Gonzalez, Mar Riveiro-Barciela, Marc Bourliere. Management of chronic HBV-HDV patients chronic HBV-HDV infection: A review on new management options. United European Gastroenterology Journal, 2023, 12 (2), pp.210-218. 10.1002/ueg2.12494. inserm-04541367

HAL Id: inserm-04541367

https://inserm.hal.science/inserm-04541367v1

Submitted on 10 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Management of chronic HBV-HDV patients chronic HBV-HDV infection: A review on new management options

María Buti<fnref n="1" />,<fnref n="2" />,<fnref n="3" /> ID | Alexia Gonzalez<fnref n="4" /> | Mar Riveiro-Barciela<fnref n="1" />,<fnref n="2" />,<fnref n="3" /> | Marc Bourliere<fnref n="4" />,<fnref n="5" />

**Correspondence**

María Buti.

Email: mariabutiferret@gmail.com

**Abstract**

Hepatitis D virus was first described by Mario Rizzeto in 1977, and it is considered chronic viral hepatitis with the poorest prognosis. Despite its discovery almost 50 years ago, progress in its diagnosis and treatment has been scarce until recent years. The approval of bulevirtide has shed some light for patients with Chronic Hepatitis D, although important gaps regarding its use in therapy as well as about the epidemiology and diagnosis of the disease need to be addressed.

**KEYWORDS**

Buleviritide, chronic HBV-HDV infection, hepatitis B virus, hepatitis D virus, interferon alpha, lonafarnib

## EPIDEMIOLOGY OF HEPATITIS D VIRUS INFECTION

Hepatitis D virus (HDV) prevalence vary according to geographic regions, with the highest rates of infection found in Mongolia, the Republic of Moldova and countries in Western and Middle Africa.<fnref n="1" />⁻<fnref n="3" /> Hitherto, the real global burden of HDV infections remains elusive. Many factors contribute to this fact. In low-income countries, individuals with chronic HBV infection are frequently not tested for HDV infection, leading to a gap of information in some areas such as central Africa where HDV may affect as much as 26% of the HBsAg population.<fnref n="4" />

Three recent meta-analyses have estimated that the overall prevalence of HDV infection ranges from 0.16%-0.98% among the general population and from 4.5% to 14.57% among HBsAg

carriers.<fnref n="3" />,<fnref n="5" />,⁶ Therefore, a total of 12-72 million individuals could be infected by HDV worldwide.<fnref n="3" />,<fnref n="5" />,⁶

## NATURAL HISTORY OF CHRONIC HEPATITIS D INFECTION

Chronic Hepatitis D (CHD) represents the most severe form of chronic viral hepatitis. The risk of developing cirrhosis, hepatocellular carcinoma (HCC) and decompensated liver disease is 2 to 3 times greater in CHD than in HBV monoinfection.⁷

Several studies have confirmed the poor prognosis of subjects with CHD. A retrospective study in 337 patients with antibodies against the hepatitis D virus (anti-HDV) positivity, 233 with Hepatitis

<footnote n="1">¹Liver Unit, Internal Medicine Department, Hospital Universitari Valld'Hebron, Valld'Hebron Barcelona Hospital Campus, Barcelona, Spain</footnote>

<footnote n="2">²Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain</footnote>

<footnote n="3">³CIBERehd, Instituto Carlos III, Barcelona, Spain</footnote>

<footnote n="4">⁴Liver Unit, Saint Joseph Hopital, Marseille, France</footnote>

<footnote n="5">⁵Aix Marseille University, Inserm, IRD, SESSTIM, Sciences Économiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France</footnote>

<footnote>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.</footnote>
# Management of chronic HBV-HDV patients chronic HBV-HDV infection: A review on new management options

María Buti<fnref n="1" />,<fnref n="2" />,<fnref n="3" /> ID | Alexia Gonzalez<fnref n="4" /> | Mar Riveiro-Barciela<fnref n="1" />,<fnref n="2" />,<fnref n="3" /> | Marc Bourliere<fnref n="4" />,<fnref n="5" />

**Correspondence**

María Buti.

Email: mariabutiferret@gmail.com

**Abstract**

Hepatitis D virus was first described by Mario Rizzeto in 1977, and it is considered chronic viral hepatitis with the poorest prognosis. Despite its discovery almost 50 years ago, progress in its diagnosis and treatment has been scarce until recent years. The approval of bulevirtide has shed some light for patients with Chronic Hepatitis D, although important gaps regarding its use in therapy as well as about the epidemiology and diagnosis of the disease need to be addressed.

**KEYWORDS**

Buleviritide, chronic HBV-HDV infection, hepatitis B virus, hepatitis D virus, interferon alpha, lonafarnib

## EPIDEMIOLOGY OF HEPATITIS D VIRUS INFECTION

Hepatitis D virus (HDV) prevalence vary according to geographic regions, with the highest rates of infection found in Mongolia, the Republic of Moldova and countries in Western and Middle Africa.<fnref n="1" />⁻<fnref n="3" /> Hitherto, the real global burden of HDV infections remains elusive. Many factors contribute to this fact. In low-income countries, individuals with chronic HBV infection are frequently not tested for HDV infection, leading to a gap of information in some areas such as central Africa where HDV may affect as much as 26% of the HBsAg population.<fnref n="4" />

Three recent meta-analyses have estimated that the overall prevalence of HDV infection ranges from 0.16%-0.98% among the general population and from 4.5% to 14.57% among HBsAg

carriers.<fnref n="3" />,<fnref n="5" />,⁶ Therefore, a total of 12-72 million individuals could be infected by HDV worldwide.<fnref n="3" />,<fnref n="5" />,⁶

## NATURAL HISTORY OF CHRONIC HEPATITIS D INFECTION

Chronic Hepatitis D (CHD) represents the most severe form of chronic viral hepatitis. The risk of developing cirrhosis, hepatocellular carcinoma (HCC) and decompensated liver disease is 2 to 3 times greater in CHD than in HBV monoinfection.⁷

Several studies have confirmed the poor prognosis of subjects with CHD. A retrospective study in 337 patients with antibodies against the hepatitis D virus (anti-HDV) positivity, 233 with Hepatitis

<footnote n="1">¹Liver Unit, Internal Medicine Department, Hospital Universitari Valld'Hebron, Valld'Hebron Barcelona Hospital Campus, Barcelona, Spain</footnote>

<footnote n="2">²Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain</footnote>

<footnote n="3">³CIBERehd, Instituto Carlos III, Barcelona, Spain</footnote>

<footnote n="4">⁴Liver Unit, Saint Joseph Hopital, Marseille, France</footnote>

<footnote n="5">⁵Aix Marseille University, Inserm, IRD, SESSTIM, Sciences Économiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France</footnote>

<footnote>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.</footnote>
C Virus RNA detectable, revealed a 3.8-fold higher risk of developing liver-related events and 2.6-fold of HCC than those with undetectable HDV-RNA.⁸ Similar results have been reported in a multicenter Spanish study in 118 anti-HDV-positive individuals, with a higher rate of developing either cirrhosis and/or liver events among those with detectable HDV RNA (31% vs. 0%, *p* = 0.002; and 28% vs. 3%, *p* = 0.019, respectively).⁹

Because of the accelerated development of liver cirrhosis and decompensation, CHD accounts for an important number of HBV liver transplantations. For instances, in a study carried out in Italy, the ratio of HDV to the overall HBsAg transplants was 50.2% in 2010–2019, rate even higher than the observed in previous years at the same centers (38.5% in 2000–2009).¹⁰ Furthermore, age at liver transplantation is lower among CHD patients compared with HBV monoinfected patients.¹¹

Although persistent HDV viremia is the most important risk factor for decompensation and HCC development, it has been suggested that the HDV genotype may also influence disease prognosis, with European HDV-1 and African HDV-5 genotypes associated with a higher risk of developing cirrhosis.¹²

Spontaneous HBsAg loss and seroconversion to anti-HBs have been described, with a rate ranging from 0.25% to 1% for year according to two Italian cohorts including 487 patients.¹³,¹⁴ Importantly, in patients with cirrhosis even after HBsAg loss there is still a risk of developing HCC. This highlights the need to maintain HCC surveillance in patients with liver cirrhosis even after HBsAg is eliminated.

## SCREENING

Screening for hepatitis D involves a combination of laboratory tests and medical history assessment. HBsAg determination is important since hepatitis D can only occur in individuals with HBV infection. The first test for screening HDV is the evaluation of anti-HDV, which can determine whether a person has been exposed to the virus or if they are currently infected. After, testing for serum/plasma HDV RNA is needed to confirm an ongoing HDV infection. Recent 2023 Clinical Practice Guidelines on Hepatitis Delta Virus by the European Association for the Study of the Liver recommends that screening for anti-HDV antibodies should be performed least once in all HBsAg-positive individuals and re-testing for these antibodies should be performed in HBsAg-positive individuals whenever clinically indicated (e.g., in case of aminotransferase flares, or acute decompensation of chronic liver disease) and may be performed yearly in those remaining at risk of infection.¹⁵

This recommendation differs from 2018 American Association for the Study of Liver Diseases guidelines that only recommend anti-HDV testing in those HBsAg-positive who are at risk (people who inject drugs, men who have sex with men, those at risk for sexually transmitted diseases and immigrants from high HDV endemic areas).¹⁶

Testing for HDV RNA still has some issues. Several in-house and commercial reverse transcription-polymerase chain reaction assays are available for the quantitative detection of HDV RNA, but still some harmonization of the different assays optimizing and standardizing HDV RNA detection protocols are needed. For those patients with undetectable HDV RNA, particularly if Alanin aminotransferase (ALT) levels are elevated it is recommended to retest HDV RNA due to the possibility of spontaneous fluctuation on the levels of viremia.¹⁵ Currently there are no other serum markers of HDV replication: Hepatitis D Antigen can only be detected for a short period in the serum of patients with acute HDV infection and IgM anti-HDV antibodies are usually detected in the acute phase of the infection and are associated with disease activity in chronic HDV infection but they are not a direct marker of HDV replication and are not suitable for its monitoring. The best way of increasing screening for HDV is performing reflex testing of anti-HDV antibodies in the new HBsAg positive cases.¹⁷ Even the screening and diagnosis of Hepatitis D can be optimized by doing double reflex testing that means first testing for anti-HDV antibodies and in positive cases for HDV RNA. This is the most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to identify undiagnosed individuals.¹⁸

In patients with CHD, it is also important to test regularly for HBV markers, particularly HBV DNA and HBsAg.

## DIAGNOSIS

For the diagnosis of the presence and degree of liver damage, it is important to determine liver function and fibrosis assessment by non-invasive markers, but specific cut-off values are not well established like in Hepatitis B and C. Liver imaging tests, such as ultrasound, computed tomography scan, or magnetic resonance imaging, can be useful for the diagnosis of liver cirrhosis. Liver biopsy is recommended in certain situations such as when clinical signs or indirect evidence of cirrhosis is absent and if it may contribute to the patient's management.¹⁵

## TREATMENT OF CHRONIC DELTA HEPATITIS

The aim of CHD treatment is to prevent the development of complications of liver disease, such as cirrhosis, decompensation, and HCC, and ultimately death. The ideal endpoint of treatment efficacy is to achieve both HDV RNA undetectability and HBsAg clearance or seroconversion, which would prevent the risk of HDV reactivation. However, this aim was rarely achieved with any HDV treatment.¹⁹,²⁰ Therefore, surrogate endpoints of treatment efficacy have been developed.²¹,²² "Virological response" is defined by > 2 log decline of HDV RNA including HDV RNA undetectability at any time on treatment or off treatment. "Combined response" is defined by > 2 log decline in HDV RNA combined with normal ALT levels". This was
C Virus RNA detectable, revealed a 3.8-fold higher risk of developing liver-related events and 2.6-fold of HCC than those with undetectable HDV-RNA.⁸ Similar results have been reported in a multicenter Spanish study in 118 anti-HDV-positive individuals, with a higher rate of developing either cirrhosis and/or liver events among those with detectable HDV RNA (31% vs. 0%, *p* = 0.002; and 28% vs. 3%, *p* = 0.019, respectively).⁹

Because of the accelerated development of liver cirrhosis and decompensation, CHD accounts for an important number of HBV liver transplantations. For instances, in a study carried out in Italy, the ratio of HDV to the overall HBsAg transplants was 50.2% in 2010–2019, rate even higher than the observed in previous years at the same centers (38.5% in 2000–2009).¹⁰ Furthermore, age at liver transplantation is lower among CHD patients compared with HBV monoinfected patients.¹¹

Although persistent HDV viremia is the most important risk factor for decompensation and HCC development, it has been suggested that the HDV genotype may also influence disease prognosis, with European HDV-1 and African HDV-5 genotypes associated with a higher risk of developing cirrhosis.¹²

Spontaneous HBsAg loss and seroconversion to anti-HBs have been described, with a rate ranging from 0.25% to 1% for year according to two Italian cohorts including 487 patients.¹³,¹⁴ Importantly, in patients with cirrhosis even after HBsAg loss there is still a risk of developing HCC. This highlights the need to maintain HCC surveillance in patients with liver cirrhosis even after HBsAg is eliminated.

## SCREENING

Screening for hepatitis D involves a combination of laboratory tests and medical history assessment. HBsAg determination is important since hepatitis D can only occur in individuals with HBV infection. The first test for screening HDV is the evaluation of anti-HDV, which can determine whether a person has been exposed to the virus or if they are currently infected. After, testing for serum/plasma HDV RNA is needed to confirm an ongoing HDV infection. Recent 2023 Clinical Practice Guidelines on Hepatitis Delta Virus by the European Association for the Study of the Liver recommends that screening for anti-HDV antibodies should be performed least once in all HBsAg-positive individuals and re-testing for these antibodies should be performed in HBsAg-positive individuals whenever clinically indicated (e.g., in case of aminotransferase flares, or acute decompensation of chronic liver disease) and may be performed yearly in those remaining at risk of infection.¹⁵

This recommendation differs from 2018 American Association for the Study of Liver Diseases guidelines that only recommend anti-HDV testing in those HBsAg-positive who are at risk (people who inject drugs, men who have sex with men, those at risk for sexually transmitted diseases and immigrants from high HDV endemic areas).¹⁶

Testing for HDV RNA still has some issues. Several in-house and commercial reverse transcription-polymerase chain reaction assays are available for the quantitative detection of HDV RNA, but still some harmonization of the different assays optimizing and standardizing HDV RNA detection protocols are needed. For those patients with undetectable HDV RNA, particularly if Alanin aminotransferase (ALT) levels are elevated it is recommended to retest HDV RNA due to the possibility of spontaneous fluctuation on the levels of viremia.¹⁵ Currently there are no other serum markers of HDV replication: Hepatitis D Antigen can only be detected for a short period in the serum of patients with acute HDV infection and IgM anti-HDV antibodies are usually detected in the acute phase of the infection and are associated with disease activity in chronic HDV infection but they are not a direct marker of HDV replication and are not suitable for its monitoring. The best way of increasing screening for HDV is performing reflex testing of anti-HDV antibodies in the new HBsAg positive cases.¹⁷ Even the screening and diagnosis of Hepatitis D can be optimized by doing double reflex testing that means first testing for anti-HDV antibodies and in positive cases for HDV RNA. This is the most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to identify undiagnosed individuals.¹⁸

In patients with CHD, it is also important to test regularly for HBV markers, particularly HBV DNA and HBsAg.

## DIAGNOSIS

For the diagnosis of the presence and degree of liver damage, it is important to determine liver function and fibrosis assessment by non-invasive markers, but specific cut-off values are not well established like in Hepatitis B and C. Liver imaging tests, such as ultrasound, computed tomography scan, or magnetic resonance imaging, can be useful for the diagnosis of liver cirrhosis. Liver biopsy is recommended in certain situations such as when clinical signs or indirect evidence of cirrhosis is absent and if it may contribute to the patient's management.¹⁵

## TREATMENT OF CHRONIC DELTA HEPATITIS

The aim of CHD treatment is to prevent the development of complications of liver disease, such as cirrhosis, decompensation, and HCC, and ultimately death. The ideal endpoint of treatment efficacy is to achieve both HDV RNA undetectability and HBsAg clearance or seroconversion, which would prevent the risk of HDV reactivation. However, this aim was rarely achieved with any HDV treatment.¹⁹,²⁰ Therefore, surrogate endpoints of treatment efficacy have been developed.²¹,²² "Virological response" is defined by > 2 log decline of HDV RNA including HDV RNA undetectability at any time on treatment or off treatment. "Combined response" is defined by > 2 log decline in HDV RNA combined with normal ALT levels". This was
based on the long-term clinical results of 9 patients treated with high dose IFN -alfa²³ in the 1990s using an in-house HDV RNA assay of weak sensitivity. Additional confirmatory studies are needed to assess the validity of this "combined response" using HDV RNA assays with excellent sensitivity, specificity, and reproducibility. This "combined response" is currently used to evaluate new treatments.

## INTERFERON ALFA OR PEGYLATED INTERFERON ALFA TREATMENT

For 30 years, CHD treatment was based on the off-label use of Interferon alfa (IFNα) or (peg)-IFNα for their antiviral and immunomodulatory effects.¹⁶,²⁴,²⁵ Treatment was usually given for 48 weeks, sometimes during several years: Viral response defined by HDV RNA undetectable was obtained in 20%-30% of patients 6 months post treatment, with more than 50% late relapse.²⁶ IFNα tolerance is poor, with numerous adverse effects. The use of (peg) IFNα is even more complex in patients with cirrhosis, which explains the frequency of treatment discontinuations or dose reductions. Anti-HBV nucleos(t)ide analogues have no effect on HDV replication, as demonstrated in two prospective studies (HIDIT-1 and 2).²⁷ However, anti-HBV nucleos(t)ide analogue (NUCs) in CHD must be discussed in case of HBV replication persisting or liver cirrhosis. The limited results of (peg)IFNα in CHD patients demonstrate the urgent need for new treatments. Currently, new drugs are under development. They target various steps of the HBV and HDV life cycle and one of them, bulevirtide (BLV), was approved since July 2020 in Europe.

## BULEVIRTIDE-BASED TREATMENT

The first in class of entry inhibitor myrcludexB, also named BLV, inhibits high affinity binding of HBV and HDV to the entry receptor sodium taurocholate co-transporting polypeptide.

In the proof-of-concept phase 1b/IIa study,²⁸ BLV with and without PegIFNα, has showed favorable efficacy and safety profile, that was confirmed in two phase 2 studies: Myr202 that evaluated 3 doses of BLV (2, 5 and 10 mg) for 24 weeks) y and Myr203 that evaluated the combination of PegIFNα and 3 doses of BLV 2, 5 or 10 mg, monotherapy with BLV 2 mg or 10 mg and PegIFNα, all administered for 48 weeks.²⁹,³⁰ The results of these studies have led the European Medicines Agency on 31 July 2020 to grant BLV conditional marketing authorization at a dose of 2 mg daily, alone or in combination with a nucleos(t)ide analogue for the treatment of compensated CHD. Since this authorization, several phase 2 (Myr204) and 3 (Myr301) studies have been undertaken to evaluate the efficacy of long-term BLV treatment for 96 or 144 weeks (Myr301) and of combined BLV plus PegIFNα treatment for 48 weeks followed by 48 weeks of BLV (Myr204). In addition, data from real-life studies on BLV treatment as monotherapy or in combination with PegIFNα have been reported.

## Bulevirtide monotherapy

The main results of clinical trials with BLV monotherapy are summarized in Figure 1. In the phase 2 Myr202 study, a dose-dependent decline of HDV RNA and ALT levels was observed in all BLV arms. However, HDV RNA relapse occurred in 60%-83% of viral responders' patients during follow-up (FU).²⁹ Two treatment arms in the Myr203 study received BLV monotherapy 2 mg or 10 mg for 48 weeks. At the end of treatment, rates of HDV RNA undetectability were 13% versus 47% in the 2 versus 10 mg arm, respectively. After FU, relapse was frequent and only 7% and 33% of the patients remained with HDV RNA undetectability indicating the need for prolonged treatment duration.³⁰

The phase 3 Myr301 study investigated BLV monotherapy.³¹ The interim analysis at week 96 showed similar virological response rates 76% and 82% with HDV RNA undetectability rates of 20% and 36% for the 2 and 10 mg, respectively.³² Rates of response were similar across all patient subgroups including cirrhosis in all treatment arms. A dose-dependent elevation in serum bile acids was observed in both BLV arms. Headache, pruritus, and injection site reactions were reported in 19%, 14% and 23% of cases, respectively, mostly mild to moderate in severity and at a higher frequency in BLV 10 mg dose.³¹ To date study results did not support an efficacy advantage between 10 mg and 2 mg dosage.

The results of real studies with BLV monotherapy are summarized in Figure 1b.³³⁻³⁷ These studies confirm the results of the clinical trials, with an increasing in virological, biochemical and combined response with treatment prolongation up to 96 weeks.³³,³⁸ In the French ATU cohort, patients with cirrhosis and HDV RNA >6.5 log IU/mL at baseline appear more difficult to treat.³⁹ Analysis of virological response on treatment suggests that patients with *a* <1 log reduction in HDV RNA levels at month 6 of treatment have no chance of a virological response at 72 weeks of treatment, suggesting a futility rule to be confirmed in ongoing clinical trials (Myr301).⁴⁰ In addition, increasing the dose of BLV to 10 mg in 15 non virological responders after at least 3 months of treatment did not result in virological benefit at year 1 of therapy.⁴¹ Another potential option suggested by an Austrian study should be to add PegIFNα in patients with no virological response at 24 weeks of monotherapy with BLV based on 8 patients, who showed a decline in HDV RNA levels after adding PegIFNα. These strategies should be evaluated in further studies.³⁵ Data are scarce regarding treatment discontinuation after long-term BLV monotherapy. In the French ATU cohort, stopping treatment after 72 weeks of BLV monotherapy results in (3/5) 60% early relapse, indicating the need for more prolonged treatment³³ and in the Austrian cohort, virological relapse was seen in 4 patients (3 within the first 24 weeks and one after almost 1 year of FU) out of 7 who discontinued therapy including 2 treated with BLV plus PegIFNα, indicating the need for more prolonged treatment.⁴² An Italian CHD patient with compensated cirrhosis treated with BLV for 3 years with more than 2 years of HDV RNA undetectability remained HDV RNA undetectable after 48 weeks of FU despite the persistence of HBsAg. Liver biopsy
based on the long-term clinical results of 9 patients treated with high dose IFN -alfa²³ in the 1990s using an in-house HDV RNA assay of weak sensitivity. Additional confirmatory studies are needed to assess the validity of this "combined response" using HDV RNA assays with excellent sensitivity, specificity, and reproducibility. This "combined response" is currently used to evaluate new treatments.

## INTERFERON ALFA OR PEGYLATED INTERFERON ALFA TREATMENT

For 30 years, CHD treatment was based on the off-label use of Interferon alfa (IFNα) or (peg)-IFNα for their antiviral and immunomodulatory effects.¹⁶,²⁴,²⁵ Treatment was usually given for 48 weeks, sometimes during several years: Viral response defined by HDV RNA undetectable was obtained in 20%-30% of patients 6 months post treatment, with more than 50% late relapse.²⁶ IFNα tolerance is poor, with numerous adverse effects. The use of (peg) IFNα is even more complex in patients with cirrhosis, which explains the frequency of treatment discontinuations or dose reductions. Anti-HBV nucleos(t)ide analogues have no effect on HDV replication, as demonstrated in two prospective studies (HIDIT-1 and 2).²⁷ However, anti-HBV nucleos(t)ide analogue (NUCs) in CHD must be discussed in case of HBV replication persisting or liver cirrhosis. The limited results of (peg)IFNα in CHD patients demonstrate the urgent need for new treatments. Currently, new drugs are under development. They target various steps of the HBV and HDV life cycle and one of them, bulevirtide (BLV), was approved since July 2020 in Europe.

## BULEVIRTIDE-BASED TREATMENT

The first in class of entry inhibitor myrcludexB, also named BLV, inhibits high affinity binding of HBV and HDV to the entry receptor sodium taurocholate co-transporting polypeptide.

In the proof-of-concept phase 1b/IIa study,²⁸ BLV with and without PegIFNα, has showed favorable efficacy and safety profile, that was confirmed in two phase 2 studies: Myr202 that evaluated 3 doses of BLV (2, 5 and 10 mg) for 24 weeks) y and Myr203 that evaluated the combination of PegIFNα and 3 doses of BLV 2, 5 or 10 mg, monotherapy with BLV 2 mg or 10 mg and PegIFNα, all administered for 48 weeks.²⁹,³⁰ The results of these studies have led the European Medicines Agency on 31 July 2020 to grant BLV conditional marketing authorization at a dose of 2 mg daily, alone or in combination with a nucleos(t)ide analogue for the treatment of compensated CHD. Since this authorization, several phase 2 (Myr204) and 3 (Myr301) studies have been undertaken to evaluate the efficacy of long-term BLV treatment for 96 or 144 weeks (Myr301) and of combined BLV plus PegIFNα treatment for 48 weeks followed by 48 weeks of BLV (Myr204). In addition, data from real-life studies on BLV treatment as monotherapy or in combination with PegIFNα have been reported.

## Bulevirtide monotherapy

The main results of clinical trials with BLV monotherapy are summarized in Figure 1. In the phase 2 Myr202 study, a dose-dependent decline of HDV RNA and ALT levels was observed in all BLV arms. However, HDV RNA relapse occurred in 60%-83% of viral responders' patients during follow-up (FU).²⁹ Two treatment arms in the Myr203 study received BLV monotherapy 2 mg or 10 mg for 48 weeks. At the end of treatment, rates of HDV RNA undetectability were 13% versus 47% in the 2 versus 10 mg arm, respectively. After FU, relapse was frequent and only 7% and 33% of the patients remained with HDV RNA undetectability indicating the need for prolonged treatment duration.³⁰

The phase 3 Myr301 study investigated BLV monotherapy.³¹ The interim analysis at week 96 showed similar virological response rates 76% and 82% with HDV RNA undetectability rates of 20% and 36% for the 2 and 10 mg, respectively.³² Rates of response were similar across all patient subgroups including cirrhosis in all treatment arms. A dose-dependent elevation in serum bile acids was observed in both BLV arms. Headache, pruritus, and injection site reactions were reported in 19%, 14% and 23% of cases, respectively, mostly mild to moderate in severity and at a higher frequency in BLV 10 mg dose.³¹ To date study results did not support an efficacy advantage between 10 mg and 2 mg dosage.

The results of real studies with BLV monotherapy are summarized in Figure 1b.³³⁻³⁷ These studies confirm the results of the clinical trials, with an increasing in virological, biochemical and combined response with treatment prolongation up to 96 weeks.³³,³⁸ In the French ATU cohort, patients with cirrhosis and HDV RNA >6.5 log IU/mL at baseline appear more difficult to treat.³⁹ Analysis of virological response on treatment suggests that patients with *a* <1 log reduction in HDV RNA levels at month 6 of treatment have no chance of a virological response at 72 weeks of treatment, suggesting a futility rule to be confirmed in ongoing clinical trials (Myr301).⁴⁰ In addition, increasing the dose of BLV to 10 mg in 15 non virological responders after at least 3 months of treatment did not result in virological benefit at year 1 of therapy.⁴¹ Another potential option suggested by an Austrian study should be to add PegIFNα in patients with no virological response at 24 weeks of monotherapy with BLV based on 8 patients, who showed a decline in HDV RNA levels after adding PegIFNα. These strategies should be evaluated in further studies.³⁵ Data are scarce regarding treatment discontinuation after long-term BLV monotherapy. In the French ATU cohort, stopping treatment after 72 weeks of BLV monotherapy results in (3/5) 60% early relapse, indicating the need for more prolonged treatment³³ and in the Austrian cohort, virological relapse was seen in 4 patients (3 within the first 24 weeks and one after almost 1 year of FU) out of 7 who discontinued therapy including 2 treated with BLV plus PegIFNα, indicating the need for more prolonged treatment.⁴² An Italian CHD patient with compensated cirrhosis treated with BLV for 3 years with more than 2 years of HDV RNA undetectability remained HDV RNA undetectable after 48 weeks of FU despite the persistence of HBsAg. Liver biopsy
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /><figcaption>**FIGURE 1** (a) Virological and combined response rates of bulevirtide (BLV) monotherapy in clinical trials. (b) Virological and combined response rates of BLV monotherapy in real-life.</figcaption></figure>
<figure><img src="image_2.png" /><figcaption>**FIGURE 1** (a) Virological and combined response rates of bulevirtide (BLV) monotherapy in clinical trials. (b) Virological and combined response rates of BLV monotherapy in real-life.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>FIGURE 1 (Continued)</figcaption></figure>

showed significant improvement of fibrosis and HBcAg and HDAg stained negative.⁴³ The safety and efficacy of stopping BLV need to be further studied in larger cohorts.

Off label BLV monotherapy for CHD in 15 patients with decompensated cirrhosis has been recently reported.⁴⁴ 14 patients Child-Pugh B and one Child-Pugh A were treated. Liver function and ascites improved in four patients under BLV treatment. The virologic response was achieved in 66% and biochemical response in 47% of the cases. Controlled trials are urgently needed for confirmation of safety and efficacy in this population.

## Bulevirtide in combination with PegIFNα

The main results of clinical trial studies with PegIFNα plus BLV combination are summarized in Figure 2a. In the phase II (MYR 203), the best response was observed with the combination of PegIFNα + 2 mg BLV with a 4.81log₁₀ decline in HDV RNA at the end of treatment and 4.04log₁₀ decline at week 24 r FU. Hepatitis D virus RNA was undetectable in 60% (9/15) and 53% (8/15) of the patients at the end of treatment and week 24 FU respectively. ALT normalization was observed in 27% (4/15) and 47% (7/15) of patients at the end of treatment and week 24 FU respectively. HBsAg loss or > 1log decline from baseline at week 24 FU was observed, only in patients treated with BLV combined with PegIFNα, in 27% (4/15) or 40%, 7% (1/15) or 13%, 0% or 13% of patients for BLV 2 mg, 5 and 10 mg, respectively.³⁰

In the Phase 2 Myr204 study, the interim analysis at week 24 reported a median -2.68 log IU/mL HDV RNA decline in BLV monotherapy lower than the decline observed with combination therapy -3.78log IU/mL for BLV 2 mg + PegIFNα and -4.11 log IU/mL for BLV10 mg + PegIFNα, while ALT normalization was higher with BLV monotherapy. These results suggest that the BLV plus PegIFNα combination appears to be more virologically potent than BLV monotherapy. Virological efficacy and combined response rates were higher in all BLV ± PegIFNα arms compared to PegIFNα arm.⁴⁵

Real-life studies confirm the results of clinical trials, with faster virological efficacy with the combination than with BLV monotherapy.³³ The results are shown in Figure 2b. In the Agency National Research SIDA and Virakl hepatitis (ANRS) cohort, in multivariate analysis, having been treated with PegIFNα for 12 weeks was associated with virological response (OR 8.4; 95% CI 3.4–20.8, *p* < 0.001).³⁷ As expected, side effects were more frequent during combined treatment, as were PegIFNα discontinuations (10% in the ATU cohort and 14% in the ANRS cohort).

## OTHER THERAPEUTIC OPTIONS UNDER DEVELOPMENT

### Lonafarnib

Lonafarnib (LNF) is an oral farnesyl transferase inhibitor, which blocks assembly and secretion of virions in the cells through the
<figure><img src="image_3.png" /><figcaption>FIGURE 1 (Continued)</figcaption></figure>

showed significant improvement of fibrosis and HBcAg and HDAg stained negative.⁴³ The safety and efficacy of stopping BLV need to be further studied in larger cohorts.

Off label BLV monotherapy for CHD in 15 patients with decompensated cirrhosis has been recently reported.⁴⁴ 14 patients Child-Pugh B and one Child-Pugh A were treated. Liver function and ascites improved in four patients under BLV treatment. The virologic response was achieved in 66% and biochemical response in 47% of the cases. Controlled trials are urgently needed for confirmation of safety and efficacy in this population.

## Bulevirtide in combination with PegIFNα

The main results of clinical trial studies with PegIFNα plus BLV combination are summarized in Figure 2a. In the phase II (MYR 203), the best response was observed with the combination of PegIFNα + 2 mg BLV with a 4.81log₁₀ decline in HDV RNA at the end of treatment and 4.04log₁₀ decline at week 24 r FU. Hepatitis D virus RNA was undetectable in 60% (9/15) and 53% (8/15) of the patients at the end of treatment and week 24 FU respectively. ALT normalization was observed in 27% (4/15) and 47% (7/15) of patients at the end of treatment and week 24 FU respectively. HBsAg loss or > 1log decline from baseline at week 24 FU was observed, only in patients treated with BLV combined with PegIFNα, in 27% (4/15) or 40%, 7% (1/15) or 13%, 0% or 13% of patients for BLV 2 mg, 5 and 10 mg, respectively.³⁰

In the Phase 2 Myr204 study, the interim analysis at week 24 reported a median -2.68 log IU/mL HDV RNA decline in BLV monotherapy lower than the decline observed with combination therapy -3.78log IU/mL for BLV 2 mg + PegIFNα and -4.11 log IU/mL for BLV10 mg + PegIFNα, while ALT normalization was higher with BLV monotherapy. These results suggest that the BLV plus PegIFNα combination appears to be more virologically potent than BLV monotherapy. Virological efficacy and combined response rates were higher in all BLV ± PegIFNα arms compared to PegIFNα arm.⁴⁵

Real-life studies confirm the results of clinical trials, with faster virological efficacy with the combination than with BLV monotherapy.³³ The results are shown in Figure 2b. In the Agency National Research SIDA and Virakl hepatitis (ANRS) cohort, in multivariate analysis, having been treated with PegIFNα for 12 weeks was associated with virological response (OR 8.4; 95% CI 3.4–20.8, *p* < 0.001).³⁷ As expected, side effects were more frequent during combined treatment, as were PegIFNα discontinuations (10% in the ATU cohort and 14% in the ANRS cohort).

## OTHER THERAPEUTIC OPTIONS UNDER DEVELOPMENT

### Lonafarnib

Lonafarnib (LNF) is an oral farnesyl transferase inhibitor, which blocks assembly and secretion of virions in the cells through the
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**FIGURE 2** (a) Virological and combined response rates of bulevirtide (BLV) + PegIFN in clinical trials. (b) Virological and combined response rates of BLV + PegIFN in real-life.</figcaption></figure>

delta antigen prenylation LFN is given booster with tonavir (RTV) to increase LNF levels in the liver and reduce gastrointestinal side effect.⁴⁶ In the phase 2 dose ranging study, the best results were

obtained using either the oral combination of LNF 50 mg twice a day plus ritonavir in patients with low viral load or with the triple combination of LNF 50 mg twice daily plus ritonavir plus weekly
<figure><img src="image_4.png" /><figcaption>**FIGURE 2** (a) Virological and combined response rates of bulevirtide (BLV) + PegIFN in clinical trials. (b) Virological and combined response rates of BLV + PegIFN in real-life.</figcaption></figure>

delta antigen prenylation LFN is given booster with tonavir (RTV) to increase LNF levels in the liver and reduce gastrointestinal side effect.⁴⁶ In the phase 2 dose ranging study, the best results were

obtained using either the oral combination of LNF 50 mg twice a day plus ritonavir in patients with low viral load or with the triple combination of LNF 50 mg twice daily plus ritonavir plus weekly
PegIFNα in a patient with high viral load.⁴⁷ In the phase 3 ran-
domized control study, 407 patients were randomized in four
groups: placebo (n = 52), LNF 50 mg x2/d + RTV 100 mg x2/
d (n = 178), LNF 50 mg x2/d plus RTV 100 mg x2/d plus PegIFNα-
2a weekly (n = 125) and PegIFNα (n = 52) for 48 weeks. The
primary end point “combined response” rates at week 48 were
achieve in 1.9%, 10.1%, 19.2% and 9.6% of the patients in the
placebo, LNF + RTV, LNF + RTV + PegIFNα and PegIFNα arms,
respectively. Virological response rates at week 48 were achieved
in 3.8%, 14.6%, 32% and 36.5% of the patients in placebo,
LNF + RTV, LNF + RTV + PegIFNα and PegIFNα arms respectively.
36.6% of patients had LNF dose modification during treatment. The
combined responses at week 72 were available among 313 patients
and it was achieved in 0%, 15.6%, 29.3% and 15.4% of patients in
the placebo, LNF + RTV, LNF + RTV + PegIFNα and PegIFNα arms
respectively. The histological response with improvement >2 points
in necro-inflammatory activity without worsening fibrosis was
observed in 53% of the LFN/RTV/PegIFNα group (p = 0.014).⁴⁸
Both LNF arms achieved both composite primary endpoint and key
secondary virological endpoints versus placebo. Triple therapy with
PegIFNα seems to give the best results in terms of combined
response. Prolonged FU is necessary to ensure the persistence of
response, which would make it possible to envisage a treatment of
finite duration.

IFN lambda

IFN λ acting on a single site highly expressed on hepatocytes should be better tolerated than PegIFNα. In a phase II study, 33 patients with HDV received 48 weeks 120 µg or 180 µg per week of PegIFNλ. 180 µg per week produced the best response, with a reduction of 2log HDV RNA by 50% at the end of treatment and 36% 6 months after the end of treatment. 36% of patients had undetectable HDV RNA at the end of treatment and 6 months after discontinuation. The combined response virologic and ALT normalization was observed in 14% and 29% of patients at the end of treatment and 6 months after discontinuation respectively. Tolerance appeared to be better than with PegIFNα but, grade 3 bilirubin was elevated in 30% of patients.⁴⁹

In addition, an open-label phase II study investigated the efficacy and safety of the combination of LNF 50 mg twice a day and ritonavir with IFNλ 180 µg/week for 24 weeks in 26 patients with chronic delta hepatitis. Per protocol analysis, a reduction of >2 log HDV RNA was observed in 77% (17/22), undetectable, HDV RNA in 50% of patients at the end of treatment and in 23% (5/22) at week 24 of FU. Hepatis improvement in inflammatory activity was observed in 55% (11/20) of patients with paired biopsies. However, 5 patients had to discontinue treatment due to hyperbilirubinemia⁴ and the appearance of ascites.¹,⁵⁰ A phase 3 study will be crucial to understand the hyperbilirubinemia issue observed in phase 2 studies.

Nucleic acid polymers:

Nucleic acid polymers act by targeting the Host HSP40 chaperone DNA JB12; they block the inhibition of HBV Sub Viral Particle assembly and blocks the envelopment of HDV ribonucleoprotein. Moreover, with continued dosing, they target S-HDAg and L-HDAg and inhibit the replication and morphogenesis of HDV upstream of RNA envelopment. In a phase II study, 12 patients with compensated liver disease received 15 weeks of REP 2139-Ca as an intravenous infusion once weekly, followed by REP 2139 and PegIFN and then PegIFN alone for 33 weeks. At the end of treatment, 6/12 patients were HBsAg negative with HBs seroconversion.⁵¹ After 3.5 years of FU, HBV functional cure was maintained in 4/11 patients, HDV RNA was undetectable in 7/11 and normal ALT in 6/11 patients had a normalization.⁵² Asymptomatic and transient ALT/AST elevations during REP 2139 monotherapy or bitherapy have been reported in 8/12 patients, correlated with the decrease in HBsAg titer, with no sign of liver failure.⁵² A subcutaneous formulation of REP 2139 has been developed and used under an ATU in France in BLV failure patients. 18 NUCS suppress patients received 250 mg REP 2139 and 90 µg PegIFN alfa-2a both weekly (only in case of compensated cirrhosis) for 48 weeks. Among the 6 patients who have more than 24 weeks of treatment, 5 have a virological response of which 3 were HDV RNA undetectable. Two patients have HBs seroconversion and one patient has an HBsAg titer <10 IU/mL.⁵³ Three patients with decompensated cirrhosis were treated with tenofovir disoproxil fumarate plus REP2139 with good tolerability and response, with undetectable HDV RNA in 2 patients (w6 and w20), HBs seroconversion in one patient and reversal of ascites in 2 patients.⁵⁴ Additional phase 2 and 3 studies are urgently needed with REP 2139.

IN SUMMARY

Hepatitis D still needs better available screening and diagnostic tests, particularly for low income countries that allow diagnosis of CHD in early stages. The therapy of CHD is evolving with the introduction of BLV for patients with compensated liver disease. However, many questions remain unanswered, such as the optimal duration of BLV treatment and the potential role of combining BLV with PegIFNα. The ongoing Phase 2 and 3 studies should provide some answers. Besides, other drugs in development such as LNF and REP2139 or even drugs in development for hepatitis B could modify the hepatitis D therapeutic arsenal in the coming years.

CONFLICT OF INTEREST STATEMENT

MB Advisory Board of Gilead. No other COIB of Gilead.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were
created or analyzed in this study.
PegIFNα in a patient with high viral load.⁴⁷ In the phase 3 ran-
domized control study, 407 patients were randomized in four
groups: placebo (n = 52), LNF 50 mg x2/d + RTV 100 mg x2/
d (n = 178), LNF 50 mg x2/d plus RTV 100 mg x2/d plus PegIFNα-
2a weekly (n = 125) and PegIFNα (n = 52) for 48 weeks. The
primary end point “combined response” rates at week 48 were
achieve in 1.9%, 10.1%, 19.2% and 9.6% of the patients in the
placebo, LNF + RTV, LNF + RTV + PegIFNα and PegIFNα arms,
respectively. Virological response rates at week 48 were achieved
in 3.8%, 14.6%, 32% and 36.5% of the patients in placebo,
LNF + RTV, LNF + RTV + PegIFNα and PegIFNα arms respectively.
36.6% of patients had LNF dose modification during treatment. The
combined responses at week 72 were available among 313 patients
and it was achieved in 0%, 15.6%, 29.3% and 15.4% of patients in
the placebo, LNF + RTV, LNF + RTV + PegIFNα and PegIFNα arms
respectively. The histological response with improvement >2 points
in necro-inflammatory activity without worsening fibrosis was
observed in 53% of the LFN/RTV/PegIFNα group (p = 0.014).⁴⁸
Both LNF arms achieved both composite primary endpoint and key
secondary virological endpoints versus placebo. Triple therapy with
PegIFNα seems to give the best results in terms of combined
response. Prolonged FU is necessary to ensure the persistence of
response, which would make it possible to envisage a treatment of
finite duration.

IFN lambda

IFN λ acting on a single site highly expressed on hepatocytes should be better tolerated than PegIFNα. In a phase II study, 33 patients with HDV received 48 weeks 120 µg or 180 µg per week of PegIFNλ. 180 µg per week produced the best response, with a reduction of 2log HDV RNA by 50% at the end of treatment and 36% 6 months after the end of treatment. 36% of patients had undetectable HDV RNA at the end of treatment and 6 months after discontinuation. The combined response virologic and ALT normalization was observed in 14% and 29% of patients at the end of treatment and 6 months after discontinuation respectively. Tolerance appeared to be better than with PegIFNα but, grade 3 bilirubin was elevated in 30% of patients.⁴⁹

In addition, an open-label phase II study investigated the efficacy and safety of the combination of LNF 50 mg twice a day and ritonavir with IFNλ 180 µg/week for 24 weeks in 26 patients with chronic delta hepatitis. Per protocol analysis, a reduction of >2 log HDV RNA was observed in 77% (17/22), undetectable, HDV RNA in 50% of patients at the end of treatment and in 23% (5/22) at week 24 of FU. Hepatis improvement in inflammatory activity was observed in 55% (11/20) of patients with paired biopsies. However, 5 patients had to discontinue treatment due to hyperbilirubinemia⁴ and the appearance of ascites.¹,⁵⁰ A phase 3 study will be crucial to understand the hyperbilirubinemia issue observed in phase 2 studies.

Nucleic acid polymers:

Nucleic acid polymers act by targeting the Host HSP40 chaperone DNA JB12; they block the inhibition of HBV Sub Viral Particle assembly and blocks the envelopment of HDV ribonucleoprotein. Moreover, with continued dosing, they target S-HDAg and L-HDAg and inhibit the replication and morphogenesis of HDV upstream of RNA envelopment. In a phase II study, 12 patients with compensated liver disease received 15 weeks of REP 2139-Ca as an intravenous infusion once weekly, followed by REP 2139 and PegIFN and then PegIFN alone for 33 weeks. At the end of treatment, 6/12 patients were HBsAg negative with HBs seroconversion.⁵¹ After 3.5 years of FU, HBV functional cure was maintained in 4/11 patients, HDV RNA was undetectable in 7/11 and normal ALT in 6/11 patients had a normalization.⁵² Asymptomatic and transient ALT/AST elevations during REP 2139 monotherapy or bitherapy have been reported in 8/12 patients, correlated with the decrease in HBsAg titer, with no sign of liver failure.⁵² A subcutaneous formulation of REP 2139 has been developed and used under an ATU in France in BLV failure patients. 18 NUCS suppress patients received 250 mg REP 2139 and 90 µg PegIFN alfa-2a both weekly (only in case of compensated cirrhosis) for 48 weeks. Among the 6 patients who have more than 24 weeks of treatment, 5 have a virological response of which 3 were HDV RNA undetectable. Two patients have HBs seroconversion and one patient has an HBsAg titer <10 IU/mL.⁵³ Three patients with decompensated cirrhosis were treated with tenofovir disoproxil fumarate plus REP2139 with good tolerability and response, with undetectable HDV RNA in 2 patients (w6 and w20), HBs seroconversion in one patient and reversal of ascites in 2 patients.⁵⁴ Additional phase 2 and 3 studies are urgently needed with REP 2139.

IN SUMMARY

Hepatitis D still needs better available screening and diagnostic tests, particularly for low income countries that allow diagnosis of CHD in early stages. The therapy of CHD is evolving with the introduction of BLV for patients with compensated liver disease. However, many questions remain unanswered, such as the optimal duration of BLV treatment and the potential role of combining BLV with PegIFNα. The ongoing Phase 2 and 3 studies should provide some answers. Besides, other drugs in development such as LNF and REP2139 or even drugs in development for hepatitis B could modify the hepatitis D therapeutic arsenal in the coming years.

CONFLICT OF INTEREST STATEMENT

MB Advisory Board of Gilead. No other COIB of Gilead.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were
created or analyzed in this study.
ORCID

María Buti https://orcid.org/0009-0002-9620-9812

REFERENCES

1. Rizzetto M, Canese MG, Arico S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut. 1977;18(12):997-1003. https://doi.org/10.1136/gut.18.12.997

2. Rizzetto M, Hamid S, Negro F. The changing context of hepatitis D. J Hepatol. 2021;74(5):1200-11. https://doi.org/10.1016/j.jhep.2021.01.014

3. Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73(3):523-32. https://doi.org/10.1016/j.jhep.2020.04.008

4. Stockdale AJ, Chaponda M, Beloukas A, Phillips RO, Matthews PC, Papadimitropoulos A, et al. Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(10):e992-1003. https://doi.org/10.1016/S2214-109X(17)30298-X

5. Chen HY, Shen DT, Ji DZ, Han PC, Zhang WM, Ma JF, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2018;68(3):512-21. https://doi.org/10.1136/gutjnl-2018-316601

6. Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis. 2020;221(10):1677-87. https://doi.org/10.1093/infdis/jiz633

7. Farci P, Niro GA. Clinical features of hepatitis D. Semin Liver Dis. 2012;32(03):228-36. https://doi.org/10.1055/s-0032-1323628

8. Kamal H, Westman G, Falconer K, Duberg AS, Weiland O, Haverinen S, et al. Long-term study of hepatitis delta virus infection at secondary care centers: the impact of viremia on liver-related outcomes. Hepatology. 2020;72(4):1177-90. https://doi.org/10.1002/hep.31214

9. Palom A, Rodríguez-Tajes S, Navascués CA, García-Samaniego J, Riveiro-Barciela M, Lens S, et al. Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia. Aliment Pharmacol Ther. 2020;51(1):158-66. https://doi.org/10.1111/apt.15521

10. Caviglia GP, Martini S, Ciancio A, Niro GA, Olivero A, Fontana R, et al. The hepatitis D virus in Italy. A vanishing infection, not yet a vanished disease. J Adv Res. 2021;33:183-7. https://doi.org/10.1016/j.jare.2021.02.009

11. Kushner T, Da BL, Chan A, Dieterich D, Sigel K, Saberi B. Liver transplantation for hepatitis D virus in the United States: a UNOS study on outcomes in the MELD era. Transpl Direct. 2022;8(1):e1253. https://doi.org/10.1097/txd.00000000000001253

12. Roulot D, Brichler S, Layese R, BenAbdesselam Z, Zoulim F, Thibault V, et al. Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta. J Hepatol. 2020;73(5):1046-62. https://doi.org/10.1016/j.jhep.2020.06.038

13. Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, Olivero A, et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol. 2010;53(3):834-40. https://doi.org/10.1016/j.dld.2008.12.071

14. Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009;136(5):1629-38. https://doi.org/10.1053/j.gastro.2009.01.052

15. Clinical practice guidelines on hepatitis delta virus. J Hepatol 2023.

16. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-99. https://doi.org/10.1002/hep.29800

17. Palom A, Rando-Segura A, Vico J, Pacín B, Vargas E, Barreira-Díaz A, et al. Implementation of anti-HDV reflex testing among HBsAg-positive individuals increases testing for hepatitis D. JHEP Rep. 2022;4(10):100547. https://doi.org/10.1016/j.jhepr.2022.100547

18. Razavi HA, Buti M, Terrault NA, Zeuzem S, Yurdaydin C, Tanaka J, et al. Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries. J Hepatol. 2023;79(2):576-80. https://doi.org/10.1016/j.jhep.2023.02.041

19. Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, et al. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology. 2017;65(2):414-25. https://doi.org/10.1002/hep.28876

20. Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Kabacam G, et al. Interferon treatment duration in patients with chronic delta hepatitis and its effect on the natural course of the disease. J Infect Dis. 2018;217(8):1184-92. https://doi.org/10.1093/infdis/jix656

21. Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O, et al. Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy. J Hepatol. 2019;70(5):1008-15. https://doi.org/10.1016/j.jhep.2018.12.022

22. Ghany MG, Buti M, Lampertico P, Lee HM, Faculty A.-EH.-HTEC. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 AASLD-EASL HBV/HDV treatment endpoints conference. Hepatology. 2023;78(5):1654-73. https://doi.org/10.1097/hep.00000000000000431

23. Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126(7):1740-9. https://doi.org/10.1053/j.gastro.2004.03.017

24. European Association for the Study of the Liver. Electronic address eee, European association for the study of the L. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-98.

25. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98. https://doi.org/10.1007/s12072-015-9675-4

26. Heidrich B, Yurdaydin C, Kabacam G, Ratsch BA, Zachou K, Bremer B, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87-97. https://doi.org/10.1002/hep.27102

27. Wedemeyer H, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis. 2019;19(3):275-86. https://doi.org/10.1016/s1473-3099(18)30663-7

28. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65(3):490-8. https://doi.org/10.1016/j.jhep.2016.04.016

29. Wedemeyer H, Schoneweis K, Bogomolov P, Blank A, Voronkova N, Stepanova T, et al. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 2023;23(1):117-29. https://doi.org/10.1016/s1473-3099(22)00318-8
ORCID

María Buti https://orcid.org/0009-0002-9620-9812

REFERENCES

1. Rizzetto M, Canese MG, Arico S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut. 1977;18(12):997-1003. https://doi.org/10.1136/gut.18.12.997

2. Rizzetto M, Hamid S, Negro F. The changing context of hepatitis D. J Hepatol. 2021;74(5):1200-11. https://doi.org/10.1016/j.jhep.2021.01.014

3. Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73(3):523-32. https://doi.org/10.1016/j.jhep.2020.04.008

4. Stockdale AJ, Chaponda M, Beloukas A, Phillips RO, Matthews PC, Papadimitropoulos A, et al. Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(10):e992-1003. https://doi.org/10.1016/S2214-109X(17)30298-x

5. Chen HY, Shen DT, Ji DZ, Han PC, Zhang WM, Ma JF, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2018;68(3):512-21. https://doi.org/10.1136/gutjnl-2018-316601

6. Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis. 2020;221(10):1677-87. https://doi.org/10.1093/infdis/jiz633

7. Farci P, Niro GA. Clinical features of hepatitis D. Semin Liver Dis. 2012;32(03):228-36. https://doi.org/10.1055/s-0032-1323628

8. Kamal H, Westman G, Falconer K, Duberg AS, Weiland O, Haverinen S, et al. Long-term study of hepatitis delta virus infection at secondary care centers: the impact of viremia on liver-related outcomes. Hepatology. 2020;72(4):1177-90. https://doi.org/10.1002/hep.31214

9. Palom A, Rodríguez-Tajes S, Navascués CA, García-Samaniego J, Riveiro-Barciela M, Lens S, et al. Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia. Aliment Pharmacol Ther. 2020;51(1):158-66. https://doi.org/10.1111/apt.15521

10. Caviglia GP, Martini S, Ciancio A, Niro GA, Olivero A, Fontana R, et al. The hepatitis D virus in Italy. A vanishing infection, not yet a vanished disease. J Adv Res. 2021;33:183-7. https://doi.org/10.1016/j.jare.2021.02.009

11. Kushner T, Da BL, Chan A, Dieterich D, Sigel K, Saberi B. Liver transplantation for hepatitis D virus in the United States: a UNOS study on outcomes in the MELD era. Transpl Direct. 2022;8(1):e1253. https://doi.org/10.1097/txd.00000000000001253

12. Roulot D, Brichler S, Layese R, BenAbdesselam Z, Zoulim F, Thibault V, et al. Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta. J Hepatol. 2020;73(5):1046-62. https://doi.org/10.1016/j.jhep.2020.06.038

13. Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, Olivero A, et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol. 2010;53(3):834-40. https://doi.org/10.1016/j.dld.2008.12.071

14. Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009;136(5):1629-38. https://doi.org/10.1053/j.gastro.2009.01.052

15. Clinical practice guidelines on hepatitis delta virus. J Hepatol 2023.

16. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-99. https://doi.org/10.1002/hep.29800

17. Palom A, Rando-Segura A, Vico J, Pacín B, Vargas E, Barreira-Díaz A, et al. Implementation of anti-HDV reflex testing among HBsAg-positive individuals increases testing for hepatitis D. JHEP Rep. 2022;4(10):100547. https://doi.org/10.1016/j.jhepr.2022.100547

18. Razavi HA, Buti M, Terrault NA, Zeuzem S, Yurdaydin C, Tanaka J, et al. Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries. J Hepatol. 2023;79(2):576-80. https://doi.org/10.1016/j.jhep.2023.02.041

19. Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, et al. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology. 2017;65(2):414-25. https://doi.org/10.1002/hep.28876

20. Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Kabacam G, et al. Interferon treatment duration in patients with chronic delta hepatitis and its effect on the natural course of the disease. J Infect Dis. 2018;217(8):1184-92. https://doi.org/10.1093/infdis/jix656

21. Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O, et al. Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy. J Hepatol. 2019;70(5):1008-15. https://doi.org/10.1016/j.jhep.2018.12.022

22. Ghany MG, Buti M, Lampertico P, Lee HM, Faculty A.-EH.-HTEC. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 AASLD-EASL HBV/HDV treatment endpoints conference. Hepatology. 2023;78(5):1654-73. https://doi.org/10.1097/hep.0000000000000431

23. Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126(7):1740-9. https://doi.org/10.1053/j.gastro.2004.03.017

24. European Association for the Study of the Liver. Electronic address eee, European association for the study of the L. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-98.

25. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98. https://doi.org/10.1007/s12072-015-9675-4

26. Heidrich B, Yurdaydin C, Kabacam G, Ratsch BA, Zachou K, Bremer B, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87-97. https://doi.org/10.1002/hep.27102

27. Wedemeyer H, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis. 2019;19(3):275-86. https://doi.org/10.1016/s1473-3099(18)30663-7

28. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65(3):490-8. https://doi.org/10.1016/j.jhep.2016.04.016

29. Wedemeyer H, Schoneweis K, Bogomolov P, Blank A, Voronkova N, Stepanova T, et al. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 2023;23(1):117-29. https://doi.org/10.1016/s1473-3099(22)00318-8
30. Wedemeyer H, schöneweis K, Bogomolov PO, Chulanov V, Stepanova T, Viacheslav M, et al. 48 weeks of high dose (10mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection (Abstract). J Hepatol. 2020;73:S52-3.

31. Wedemeyer H, Aleman S, Brunetto MR, Blank A, Andreone P, Bogomolov P, et al. A phase 3, randomized trial of bulevirtide in chronic hepatitis D. N Engl J Med. 2023;389(1):22-32. https://doi.org/10.1056/nejmoa2213429

32. Wedemeyer H, Aleman S, Brunetto M, Blank A, Andreone P, Bogomolov P, et al. Efficacy and safety at week 96 of bulevirtide 2mg or 10 mg monotherapy for chronic hepatitis D: results from an interim analysis of a phase 3 randomized study. (Abstract). J Hepatol. 2023;78:S57-8. https://doi.org/10.1016/s0168-8278(23)00522-6

33. De Ledinghen V, Hermabessière P, Metivier S, Bardou-Jacquet E, Hilleret MN, Loustaud-Ratti V, et al. Bulevirtide with or without Peg-Interferon in HDV infected patients in a real-life setting. Two-year results from the French multicenter early access program. Hepatology. 2022;76:S26-8.

34. Dietz-Fricke C, Tacke F, Zollner C, Demir M, Schmidt HH, Schramm C, et al. Treating hepatitis D with bulevirtide - real-world experience from 114 patients. JHEP Rep. 2023;5(4):100686. https://doi.org/10.1016/j.jhepr.2023.100686

35. Jachs M, Schwarz C, Panzer M, Binter T, Aberle SW, Hartl L, et al. Response-guided long-term treatment of chronic hepatitis D patients with bulevirtide-results of a "real world" study. Aliment Pharmacol Ther. 2022;56(1):144-54. https://doi.org/10.1111/apt.16945

36. Degasperi E, Anolli MP, Uceda Renteria SC, Sambarino D, Borghi M, Perbellini R, et al. Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension. J Hepatol. 2022;77(6):1525-31. https://doi.org/10.1016/j.jhep.2022.07.016

37. Zoulim F, Fougerou C, Roulot Marullo D, Metivier S, De Ledinghen V, Ratziu V, et al. Efficacy and safety of treatment with bulevirtidein chronic hepatitis delta: primary results of the reallife ANRS HD EP01 BULEDELTA cohort (abstract). Hepatology. 2022;76:S221-3.

38. Degasperi E, Anolli MP, De Ledinghen V, Metivier S, Jachs M, Reiberger T, et al. Virological and clinical outcomes of patients with HDV-related compensated cirrhosis treated with bulevirtide monotherapy: the retrospective multicenter European study (Save-D). (Abstract). J Hepatol. 2023;78:S107-8. https://doi.org/10.1016/s0168-8278(23)00593-7

39. De Ledinghen V, Metivier S, Bardou-Jacquet E, Hilleret MN, Loustaud-Ratti V, Ganne-Carrie N, et al. Treatment with bulevirtide in chronic HBV/HDV co-infection. Safety and efficacy at month 18 in real-world settings. (Abstract). J Hepatol. 2022;77:S840. https://doi.org/10.1016/s0168-8278(22)01975-4

40. De Ledinghen V, Bardou-Jacquet E, Metivier S, Ganne-Carrie N, Loustaud-Ratti V, Hilleret MN, et al. HDV RNA decline less than 1 log after 6 months of BLV 2mg monotherapy could define poor-response and lead to therapeutic decision. Data from real-life cohort. (Abstract). J Hepatol. 2023;78:S56-7. https://doi.org/10.1016/s0168-8278(23)00520-2

41. De Ledinghen V, Minello Franza A, Ganne-Carrie N, Alric L, Metivier S, Siguier M, et al. Is treatment with bulevirtide 10mg useful in poor responder patients to 2mg? Results from the French multicenter early access program. (Abstract). J Hepatol. 2023;78:S1160-1. https://doi.org/10.1016/s0168-8278(23)03299-3

42. Jachs M, Panzer M, Hartl L, Schwarz M, Balcar L, Camp JV, et al. Long-term follow-up of patients discontinuing bulevirtide treatment upon long-term HDV-RNA suppression. JHEP Rep. 2023;5(8):100751. https://doi.org/10.1016/j.jhepr.2023.100751

43. Anolli MP, Degasperi E, Allweiss L, Sangiovanni A, Maggioni M, Scholtes C, et al. A 3-year course of bulevirtide monotherapy may cure Hdv infection in cirrhotics. J Hepatol. 2023.

44. Dietz-Fricke C, Degasperi E, Lampertico P, Jachs M, Reiberger T, Grottenthaler JM, et al. Off-label bulevirtide monotherapy for chronic hepatitis D virus infection in patients with decompensated liver disease. (Abstract). J Hepatol. 2023;78:S108-9. https://doi.org/10.1016/s0168-8278(23)00594-9

45. Asselah T, Arama SS, Bogomolov P, Bourliere M, Fontaine H, Gherlan GS, et al. Safety and efficacy of bulevirtide monotherapy and in combinaison with Peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data from MYR204 phase 2b study. (Abstract). J Hepatol. 2021;75:S291.

46. Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Karatayli E, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: the LOWR HDV-1 study. Hepatology. 2018;67(4):1224-36. https://doi.org/10.1002/hep.29658

47. Yurdaydin C, Keskin O, Yurdcu E, Caliskan A, Onem S, Karakaya F, et al. A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis. Hepatology. 2022;75(6):1551-65. https://doi.org/10.1002/hep.32259

48. Etzion O, Hamid SS, Asselah T, Gherlan GS, Turcanu A, Petrivna T, et al. Week 48 results of the phase 3 D-LIVR study, a randomized double blind, placebo-controlled trial evaluating the safety and efficacy of lonafarnib-boosted with ritonavir with or without Peginterferon alfa in patients with chronic hepatitis delta. (Abstract). J Hepatol. 2023;78:S10. https://doi.org/10.1016/s0168-8278(23)00451-8

49. Etzion O, Hamid S, Lurie Y, Gane EJ, Yardeni D, Duehren S, et al. Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial. Hepatology. 2023;77(6):2093-103. https://doi.org/10.1097/hep.0000000000000309

50. Koh C, Hercun J, Rahman F, Huang A, Da B, Surana P, et al. A phase 2 study of peginterferon lambda, lonafarnib and ritonavir for 24 weeks: end-of-treatment results from the LIFT HDV study. (Abstract). J Hepatol. 2020;73:S130. https://doi.org/10.1016/s0168-8278(20)30774-1

51. Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, et al. 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 2 trial. Lancet Gastroenterol Hepatol. 2017;2(12):877-89. https://doi.org/10.1016/s2468-1253(17)30288-1

52. Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, Anderson M, et al. Persistent control of hepatitis B virus and hepatitis delta virus infection following REP 2139-Ca and pegylated interferon therapy in chronic hepatitis B virus/hepatitis delta virus coinfection. Hepatol Commun. 2021;5(2):189-202. https://doi.org/10.1002/hep4.1633

53. Bourliere M, Loustaud-Ratti V, Stern C, Benali S, Bardou-Jacquet E, Alric L, et al. Rescue of cirrhotic HBV/HDV infection from bulevirtide failure by subcutaneous REP2139-Mg. (Abstract). J Hepatol. 2023;78:S1150. https://doi.org/10.1016/s0168-8278(23)03284-1

54. Stern C, de Freitas CS, Bazinet M, Mackiewicz V, Brichler S, Gordien E, et al. Safety and efficacy of REP 2139-Mg in association with TDF in chronic hepatitis delta patients with decompensated cirrhosis. (Abstract). J Hepatol. 2023;78:S1160. https://doi.org/10.1016/s0168-8278(23)03298-1

**How to cite this article:** Buti M, Gonzalez A, Riveiro-Barciela M, Bourliere M. Management of chronic HBV-HDV patients chronic HBV-HDV infection: a review on new management options. United European Gastroenterol J. 2024;12(2):210-18. https://doi.org/10.1002/ueg2.12494
30. Wedemeyer H, schöneweis K, Bogomolov PO, Chulanov V, Stepanova T, Viacheslav M, et al. 48 weeks of high dose (10mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection (Abstract). J Hepatol. 2020;73:S52-3.

31. Wedemeyer H, Aleman S, Brunetto MR, Blank A, Andreone P, Bogomolov P, et al. A phase 3, randomized trial of bulevirtide in chronic hepatitis D. N Engl J Med. 2023;389(1):22-32. https://doi.org/10.1056/nejmoa2213429

32. Wedemeyer H, Aleman S, Brunetto M, Blank A, Andreone P, Bogomolov P, et al. Efficacy and safety at week 96 of bulevirtide 2mg or 10 mg monotherapy for chronic hepatitis D: results from an interim analysis of a phase 3 randomized study. (Abstract). J Hepatol. 2023;78:S57-8. https://doi.org/10.1016/s0168-8278(23)00522-6

33. De Ledinghen V, Hermabessière P, Metivier S, Bardou-Jacquet E, Hilleret MN, Loustaud-Ratti V, et al. Bulevirtide with or without Peg-Interferon in HDV infected patients in a real-life setting. Two-year results from the French multicenter early access program. Hepatology. 2022;76:S26-8.

34. Dietz-Fricke C, Tacke F, Zollner C, Demir M, Schmidt HH, Schramm C, et al. Treating hepatitis D with bulevirtide - real-world experience from 114 patients. JHEP Rep. 2023;5(4):100686. https://doi.org/10.1016/j.jhepr.2023.100686

35. Jachs M, Schwarz C, Panzer M, Binter T, Aberle SW, Hartl L, et al. Response-guided long-term treatment of chronic hepatitis D patients with bulevirtide-results of a "real world" study. Aliment Pharmacol Ther. 2022;56(1):144-54. https://doi.org/10.1111/apt.16945

36. Degasperi E, Anolli MP, Uceda Renteria SC, Sambarino D, Borghi M, Perbellini R, et al. Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension. J Hepatol. 2022;77(6):1525-31. https://doi.org/10.1016/j.jhep.2022.07.016

37. Zoulim F, Fougerou C, Roulot Marullo D, Metivier S, De Ledinghen V, Ratziu V, et al. Efficacy and safety of treatment with bulevirtidein chronic hepatitis delta: primary results of the reallife ANRS HD EP01 BULEDELTA cohort (abstract). Hepatology. 2022;76:S221-3.

38. Degasperi E, Anolli MP, De Ledinghen V, Metivier S, Jachs M, Reiberger T, et al. Virological and clinical outcomes of patients with HDV-related compensated cirrhosis treated with bulevirtide monotherapy: the retrospective multicenter European study (Save-D). (Abstract). J Hepatol. 2023;78:S107-8. https://doi.org/10.1016/s0168-8278(23)00593-7

39. De Ledinghen V, Metivier S, Bardou-Jacquet E, Hilleret MN, Loustaud-Ratti V, Ganne-Carrie N, et al. Treatment with bulevirtide in chronic HBV/HDV co-infection. Safety and efficacy at month 18 in real-world settings. (Abstract). J Hepatol. 2022;77:S840. https://doi.org/10.1016/s0168-8278(22)01975-4

40. De Ledinghen V, Bardou-Jacquet E, Metivier S, Ganne-Carrie N, Loustaud-Ratti V, Hilleret MN, et al. HDV RNA decline less than 1 log after 6 months of BLV 2mg monotherapy could define poor-response and lead to therapeutic decision. Data from real-life cohort. (Abstract). J Hepatol. 2023;78:S56-7. https://doi.org/10.1016/s0168-8278(23)00520-2

41. De Ledinghen V, Minello Franza A, Ganne-Carrie N, Alric L, Metivier S, Siguier M, et al. Is treatment with bulevirtide 10mg useful in poor responder patients to 2mg? Results from the French multicenter early access program. (Abstract). J Hepatol. 2023;78:S1160-1. https://doi.org/10.1016/s0168-8278(23)03299-3

42. Jachs M, Panzer M, Hartl L, Schwarz M, Balcar L, Camp JV, et al. Long-term follow-up of patients discontinuing bulevirtide treatment upon long-term HDV-RNA suppression. JHEP Rep. 2023;5(8):100751. https://doi.org/10.1016/j.jhepr.2023.100751

43. Anolli MP, Degasperi E, Allweiss L, Sangiovanni A, Maggioni M, Scholtes C, et al. A 3-year course of bulevirtide monotherapy may cure Hdv infection in cirrhotics. J Hepatol. 2023.

44. Dietz-Fricke C, Degasperi E, Lampertico P, Jachs M, Reiberger T, Grottenthaler JM, et al. Off-label bulevirtide monotherapy for chronic hepatitis D virus infection in patients with decompensated liver disease. (Abstract). J Hepatol. 2023;78:S108-9. https://doi.org/10.1016/s0168-8278(23)00594-9

45. Asselah T, Arama SS, Bogomolov P, Bourliere M, Fontaine H, Gherlan GS, et al. Safety and efficacy of bulevirtide monotherapy and in combinaison with Peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data from MYR204 phase 2b study. (Abstract). J Hepatol. 2021;75:S291.

46. Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Karatayli E, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: the LOWR HDV-1 study. Hepatology. 2018;67(4):1224-36. https://doi.org/10.1002/hep.29658

47. Yurdaydin C, Keskin O, Yurdcu E, Caliskan A, Onem S, Karakaya F, et al. A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis. Hepatology. 2022;75(6):1551-65. https://doi.org/10.1002/hep.32259

48. Etzion O, Hamid SS, Asselah T, Gherlan GS, Turcanu A, Petrivna T, et al. Week 48 results of the phase 3 D-LIVR study, a randomized double blind, placebo-controlled trial evaluating the safety and efficacy of lonafarnib-boosted with ritonavir with or without Peginterferon alfa in patients with chronic hepatitis delta. (Abstract). J Hepatol. 2023;78:S10. https://doi.org/10.1016/s0168-8278(23)00451-8

49. Etzion O, Hamid S, Lurie Y, Gane EJ, Yardeni D, Duehren S, et al. Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial. Hepatology. 2023;77(6):2093-103. https://doi.org/10.1097/hep.0000000000000309

50. Koh C, Hercun J, Rahman F, Huang A, Da B, Surana P, et al. A phase 2 study of peginterferon lambda, lonafarnib and ritonavir for 24 weeks: end-of-treatment results from the LIFT HDV study. (Abstract). J Hepatol. 2020;73:S130. https://doi.org/10.1016/s0168-8278(20)30774-1

51. Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, et al. 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 2 trial. Lancet Gastroenterol Hepatol. 2017;2(12):877-89. https://doi.org/10.1016/s2468-1253(17)30288-1

52. Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, Anderson M, et al. Persistent control of hepatitis B virus and hepatitis delta virus infection following REP 2139-Ca and pegylated interferon therapy in chronic hepatitis B virus/hepatitis delta virus coinfection. Hepatol Commun. 2021;5(2):189-202. https://doi.org/10.1002/hep4.1633

53. Bourliere M, Loustaud-Ratti V, Stern C, Benali S, Bardou-Jacquet E, Alric L, et al. Rescue of cirrhotic HBV/HDV infection from bulevirtide failure by subcutaneous REP2139-Mg. (Abstract). J Hepatol. 2023;78:S1150. https://doi.org/10.1016/s0168-8278(23)03284-1

54. Stern C, de Freitas CS, Bazinet M, Mackiewicz V, Brichler S, Gordien E, et al. Safety and efficacy of REP 2139-Mg in association with TDF in chronic hepatitis delta patients with decompensated cirrhosis. (Abstract). J Hepatol. 2023;78:S1160. https://doi.org/10.1016/s0168-8278(23)03298-1

**How to cite this article:** Buti M, Gonzalez A, Riveiro-Barciela M, Bourliere M. Management of chronic HBV-HDV patients chronic HBV-HDV infection: a review on new management options. United European Gastroenterol J. 2024;12(2):210-18. https://doi.org/10.1002/ueg2.12494