Therapy of Chronic Hepatitis D: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Infectious Diseases
Contributor:
Giorgio Maria Saracco

Peg-IFN is the only therapy for chronic hepatitis D (CHD) recommended by professional societies (not approved by Drug Regulatory Agencies); it has limited efficacy, and valid treatment of CHD has so far remained an unmet medical need

  • chronic hepatitis D
  • bulevertide
  • lonafarnib
  • interferon

1. Introduction

Peg-IFN is the only therapy for chronic hepatitis D (CHD) recommended by professional societies (not approved by Drug Regulatory Agencies); it has limited efficacy, and valid treatment of CHD has so far remained an unmet medical need [1].
The therapy for HDV infection is challenging due to the unique virology of the HDV [2]. The virus has a circular RNA genome of about 1700 nucleotides, which is too small to code for the complex viral polymerase and protease proteins that drive the autonomous replication process of ordinary viruses. It relies on the synthetic machinery of the infected hepatocyte for replication, which duplicates the viral genome through DNA-dependent RNA polymerases subverted to copy the viral RNA [3]; the corollary is that HDV cannot be targeted by conventional antivirals that are active against virus-coded proteins. Though the HBV infection required by HDV to become infectious could theoretically offer a target, treatment of HBV with ETV or TDF is of no avail, as the HDV requires from the partner virus only the HBsAg necessary to coat its virion and is not in need of its replicative machinery [4].
A second problem is the high potential infectivity of HDV on the background of a pre-existing HBV infection; end-titration experiments in HBsAg-susceptible chimpanzees have shown that an HDV-containing serum could transmit infection up to a 10−11 dilution [5]. Therefore, the persistence of HBsAg in patients who obtained an SVR may enable the late rescue of HDV still present in the liver at low levels but undetectable in serum with currently available HDV-RNA assays.
This raises the issue of how to determine the end point of therapy in CHD. Though the only robust end point is the clearance of the HBsAg, this is seldom achieved with current therapies. Therefore, in all CDH studies, the cardinal criterion of efficacy has been the clearance of HDV-RNA from serum, the so-called sustained viral response (SVR); in CHD, however, SVR is not an absolute end point of therapy, but rather the best that can be presumed in clinical practice [6]. Based on a small study showing an association of HDV decline with survival benefit [6], a ≥2-log reduction in serum HDV-RNA from baseline was proposed as initial treatment efficacy in clinical trials for CHD [7]. Subsequent studies used this log reduction as a therapeutic end point, making it difficult to interpret the results and especially the comparison with studies that adopted viral clearance as their primary treatment end point [8].
Current therapeutic efforts are directed to deprive the HDV of HBsAg functions critical to its life cycle [4]. Three therapeutic strategies are currently being evaluated. As the HBsAg enters hepatocytes through the NTCP expressed on the cell membrane [9], drugs that interfere with the NTCP may prevent access of the HDV into the cells. As the assembly of HDV virions requires the farnesylation by the host of the large HD antigen of the virus [10], interference with this cellular process may lead to the disruption of viral assembly [11]. As the HDV needs to encapsidate in the HBsAg coat for discharge into the blood, nucleic acid polymers (NAPs) that appear to prevent the synthesis of subviral HBsAg particles may prevent the export of the HD virion to the blood [12].

2. Nucleic Acid Polymers

The NAP REP 2139-Ca given to 12 CHD patients for 15 weeks as monotherapy, followed by add-on Peg-IFN for 15 weeks and then Peg-IFN monotherapy for another 33 weeks, led at the end of therapy to undetectable HDV-RNA in 7 patients and the loss of HBsAg in 4 patients [13]. These results were maintained after a 3.5 year follow-up [14]. These preliminary data of REP 2139/Peg IFN in a small series are promising, but further studies are needed to confirm the impressive response rates.

3. The Farnesyl-Transferase Inhibitor Lonafarnib

In a pilot study, the farnesylation inhibitor Lonafarnib (LNF), given orally, decreased serum HDV-RNA levels, but was aggravated by gastrointestinal side effects [11]. Subsequent studies have used LNF in combination with the cytochrome P450 3A4 inhibitor Ritonavir to permit a lower dose of LNF while preserving its antiviral activity. In the LOWR-2 study [15], HDV-RNA became undetectable in 5 of 13 patients given LNF 50 mg bid with Ritonavir 100 mg bid for 24 weeks. In the LIFT-HDV study, serum HDV-RNA became undetectable at the end of treatment in 11 of 26 patients, given LNF and Ritonavir together with Peg-IFN lambda at weekly doses of 180 µg for 24 weeks [16]; IFN lambda is credited to have fewer side effects than IFN alfa. In the ongoing phase 3 D-LIVR study, LNF plus Ritonavir is combined with Peg-IFN lambda for 48 weeks. In light of the need for long-term therapies, the side effects of LNF, though mitigated by Ritonavir, might remain a concern, particularly when added to those of Peg-IFN.

4. Bulevertide

Bulevertide (BLV), formerly Myrcludex B, a myristolated synthetic lipopeptide corresponding to the preS1 sequence of the HBsAg [17], is used to block the engagement of the HBsAg of the HDV with the NTCP in order to prevent the de-novo infection of yet uninfected liver cells, with the aim to eliminate all HDV-infected hepatocytes and recolonize the liver with regenerating HDV-free cells. It is administered daily by the subcutaneous route and is generally well-tolerated despite a dose-dependent bile acid increase. On 31 July 2020, the European Medicines Agency has afforded a conditional marketing authorization to BLV under the trade name Hepcludex, with a recommended dose of 2 mg daily [18].
Preliminary data were reported in abstract form in the study MYR 202 and MYR 203. In MYR 202 trial [19], HDV RNA decreased by ≥2 Log or became undetectable by the end of therapy in 46–77% of the 90 patients given TDF for 12 weeks followed by BLV 2, 5 or 10 mg plus TDF for 24 weeks, and then by TDF alone for 24 weeks; the best response was seen in the group given BLV at a 10 mg dose. However, only 7–10% of patients maintained the HDV RNA response in the follow-up.
In the MYR 203 study [20][21], 90 patients were entered in six groups of 15 patients each and treated for 48 weeks. After 24 weeks of post-therapy follow-up, HDV-RNA was undetectable in 8 (53%), 4 (27%), and 1 (7%) of the patients given the combination of Peg-IFN and 2, 5, or 10 mg BLV, respectively; HDV-RNA was undetectable in 1 (7%) of the patients given 2 mg BLV monotherapy, in 3 (33%) of those given 10 mg BLV and TDF, and in none of the patients given Peg-IFN alone. ALT remained normal in 7and 5 of the 15 patients treated with the two combinations, and in 3 patients given 2 mg of BLV. The HBsAg became undetectable in 4 of the 15 patients treated with the combination using 2 mg of BLV.
These encouraging results have led to the design and implementation of two long-term studies that are ongoing, one of finite therapy with Peg-IFN and BLV (MYR-204 Phase 2b Study) and one of chronic therapy with BLV alone (MYR-301 Phase 3); data at the 24 weeks interim have been reported for both studies. In the MYR-204, 25, 50, 50, and 50 patients are treated with Peg-IFN alone, BLV 2mg + Peg-IFN, BLV 10 mg + Peg-IFN, and BLV 10 mg, respectively; undetectable HDV-RNA is the primary end-point [22]. At week 24 of therapy, serum HDV-RNA was undetectable in 13, 24, 34, and 4 patients, respectively, and ALT had normalized in 13%, 30%, 24%, and 64%, respectively. In the MYR-301, 49 patients were treated with BLV 2 mg, 50 patients with BLV 10 mg, and 51 were left untreated; the primary endpoint is the combination of HDV-RNA undetectable or decreased by ≥2 log IU/mL from baseline with ALT normalization [23]. This was achieved in 6%, 53%, 38%, and 6% of the patients, respectively.
Interim data are also available from patients recruited in a compassionate study of BLV in France [24]. Seventy-seven patients treated with BLV 2 mg alone and sixty-eight treated with BLV 2 mg in combination with Peg-IFN have been considered in a per-protocol analysis at month 12 of therapy; 39% of the first and 85% of the second had HDV-RNA undetectable and serum ALT had normalized in 48.8% of the first and 36.4% of the second. These results are outstanding but require confirmation in a properly designed prospective randomized study in patients with homogeneous demographic and clinical features using a common standardized procedure to detect HDV-RNA.
In conclusion, BLV and LNF in combination with Peg-IFN provide a synergistic therapeutic effect and appear to represent the best therapy for CHD patients that can tolerate Peg-IFN.
In patients who cannot tolerate Peg-IFN, long-term BLV monotherapy may provide an alternative. Though less active against the HDV than the combinations, it has driven good biochemical responses and has been generally well tolerated; BLV monotherapy would seem the only viable option for the many HDV cirrhotics who are at risk with Peg-IFN.
Prolonged treatments raise the concern of the safety of LNF, especially in association with the poorly tolerated Peg-IFN alfa. Peg-IFN lambda might provide an alternative, as it is credited with fewer side effects than Peg-IFN alfa.
This entry is adapted from 10.3390/biomedicines10030534

References

  1. Niro, G.A.; Rosina, F.; Rizzetto, M. Treatment of hepatitis D. J. Viral. Hepat. 2005, 12, 2–9.
  2. Taylor, J.M. Virology of hepatitis D virus. Semin. Liver Dis. 2012, 32, 195–200.
  3. Lai, M.M. RNA replication without RNA-dependent RNA polymerase: Surprises from hepatitis delta virus. J. Virol. 2005, 79, 7951–7958.
  4. Rizzetto, M. Targeting Hepatitis D. Semin Liver Dis. 2018, 38, 66–72.
  5. Ponzetto, A.; Hoyer, B.H.; Popper, H.; Engle, R.; Purcell, R.H.; Gerin, J.L. Titration of the infectivity of hepatitis D virus in chimpanzees. J. Infect. Dis. 1987, 155, 72–78.
  6. Farci, P.; Roskams, T.; Chessa, L.; Peddis, G.; Mazzoleni, A.P.; Scioscia, R.; Serra, G.; Lai, M.E.; Loy, M.; Caruso, L. Long-term benefit of interferon a therapy of chronic hepatitis D: Regression of advanced hepatic fibrosis. Gastroenterology 2004, 126, 1740–1749.
  7. Yurdaydin, C.; Abbas, Z.; Buti, M.; Cornberg, M.; Esteban, R.; Etzion, O.; Gane, E.J.; Gish, R.G.; Glenn, J.S.; Hamid, S.; et al. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy. J. Hepatol. 2019, 70, 1008–1015.
  8. Lok, A.; Negro, F.; Asselah, T.; Farci, P.; Rizzetto, M. Endpoints and New Options for Treatment of Chronic Hepatitis D. Hepatology 2021, 74, 3479–3485.
  9. Urban, S.; Bartenschlager, R.; Kubitz, R.; Zoulim, F. Strategies to Inhibit Entry of HBV and HDV Into Hepatocytes. Gastroenterology 2014, 147, 48–64.
  10. Bordier, B.B.; Marion, P.L.; Ohashi, K.; Kay, M.A.; Greenberg, H.B.; Casey, J.L.; Glenn, J.S. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J. Virol. 2002, 76, 10465–10472.
  11. Koh, C.; Canini, L.; Dahari, H.; Zhao, X.; Uprichard, S.L.; Haynes-Williams, V.; A Winters, M.; Subramanya, G.; Cooper, S.L.; Pinto, P.; et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: A proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect. Dis. 2015, 15, 1167–1174.
  12. Vaillant, A. Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection. Antivir. Res. 2016, 133, 32–40.
  13. Bazinet, M.; Pantea, V.; Cebotarescu, V.; Cojuhari, L.; Jimbei, P.; Albrecht, J. 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, 877–889.
  14. Bazinet, M.; Pântea, V.; Cebotarescu, V.; Cojuhari, L.; Jimbei, P.; Anderson, M.; Gersch, J.; Holzmayer, V.; Elsner, C.; Krawczyk, A.; 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. 2020, 5, 189–202.
  15. Yurdaydin, C.; Idilman, R.; Keskin, O.; Kakan, ç.; Karakaya, F.M.; Çaliskan, A. A phase 2 dose-optimization study of lonafarnib with ritonavir for the treatment of chronic delta hepatitis—Analysis from the LOWR HDV-2 study using the Robogene real-time qPCR HDV RNA assay. J. Viral Hepat. 2018, 25, 10.
  16. Koh, C.; Hercun, J.; Rahman, F.; Huang, A.; Da, B.; Surana, P. A Phase 2 Study of Peginterferon Lambda, Lonafarnib and Ritonavir for 24 Weeks: End-of-Treatment Results from the LIFT HDV Study; Oral late breaker L08. 30 October 2020. Available online: https://assets.website-files.com/5f3d77cd56d46907a50fb8d9/5f9d9c2057efc43f55b78db7_2020%20TLMdX%20Late-breaking%20Abstracts-%20Oct%2030.pdf (accessed on 31 October 2021).
  17. Blank, A.; Markert, C.; Hohmann, N. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J. Hepatol. 2016, 65, 483–489.
  18. European Medicines Agency. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/hepcludex (accessed on 15 April 2021).
  19. Wedemeyer, H.; Bogomolov, P.; Blank, A.; Allweiss, L.; Dandri-Petersen, M.; Bremer, B.; Voronkova, N.; Schöneweis, K.; Pathil, A.; Burhenne, J.; et al. Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with tenofovir in patients with chronic HBV/HDV co-infection. J. Hepatol. 2018, 68, S3.
  20. Wedemeyer, H.; Schoeneweis, K.; Bogomolov, P.O.; Voronka, V.; Chulanov, V.; Stepanova, T. Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in combination with PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection. J. Hepatol. 2019, 70, E81.
  21. Wedemeyer, H.; Schöneweis, K.; Pavel, O.; Bogomolov, P.O.; Chulanov, V.; Stepanova, T. 48 weeks of high dose (10 mg) bulevirtide as mono-therapy or with peginterferon alfa-2a in patients with chronic HBV/HDV coinfection. J. Hepatol. 2020, 73, S52.
  22. Asselah, T. Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR204 phase 2b study. In Proceedings of the International Liver Congress, Online, 23–26 June 2021; Volume 75.
  23. Wedemeyer, H. Bulevirtide monotherapy at low and high dose in patients with chronic hepatitis delta: 24 weeks interim data of the phase 3 MYR301 study. In Proceedings of the International Liver Congress, Online, 23–26 June 2021; Volume 75.
  24. De Ledinghen, V. Safety and efficacy of 2mg bulevertide in patients with chronic HBV/HDV infection, First real world results. In Proceedings of the International Liver Congress, Online, 23–26 June 2021; Volume 74.
More
©Text is available under the terms and conditions of the Creative Commons-Attribution ShareAlike (CC BY-SA) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback