Hepatitis D virus: Improving virological knowledge to develop new treatments

Khalfi, Pierre; Majzoub, Karim; Kennedy, Patrick; Asselah, Tarik

doi:10.1016/j.antiviral.2022.105461

Cited by 13 publications

(13 citation statements)

References 182 publications

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“…14 Noteworthy, other antiviral drugs are currently also in development. 22 The majority of patients with HDV infection in our cohort were migrants from Eastern Europe or Sub-Saharan Africa, with only three out of 67 patients who were originally from Western Europe. Interestingly, only six cases had known transmission risk factors (namely IVDU, sex work, MSM and blood transfusions).…”

Section: Discussionmentioning

confidence: 83%

A regular screening for hepatitis delta virus among chronic hepatitis B carriers improves the diagnostic of this infection and of subsequent cirrhosis development

Weichselbaum,

Njimi,

van den Wijngaert

et al. 2024

UEG Journal

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Background and ObjectiveThe prevalence of Hepatitis Delta Virus (HDV) is underestimated and the assessment of fibrosis is recommended for this infection. We tested the diagnostic impact of an annual screening for HDV serology in Hepatitis B Surface Antigen (HBs Ag) chronic carriers and followed the progression of fibrosis in these patients.MethodsBetween January 2014 and October 2021, we annually tested all chronic HBs Ag‐positive patients for HDV antibody (HDV Ab). Each HDV Ab positive patient underwent annually repeated elastometry. Patients with detectable HDV RNA levels (group 1) were compared to those with undetectable HDV RNA (group 2).ResultsWe identified 610 chronic HBs Ag‐positive patients, and repeated screening for HDV Ab was performed in 534 patients. Sixty (11%) patients were HDV Ab positive at baseline and were considered as “coinfected”. Seven cases of HDV superinfection were diagnosed through repeated screening. In co‐infected patients, cirrhosis was initially diagnosed in 12/60 patients and developed in six patients during follow‐up. HDV RNA PCR was performed in 57/67 patients and 27 had detectable levels (group 1). Cumulative incidence of cirrhosis at 7 years was 13.8% (95% CI 0–30) in group 1 and 0 (95% CI 0–0) in group 2 (p = 0.026).ConclusionA systematic screening for HDV in chronic HB Ag carriers revealed a high prevalence of HDV Ab. Repeated serological screening enables the diagnosis of superinfections in asymptomatic patients. Regular assessment of fibrosis using elastometry leads to the identification of incidental cirrhosis in patients with detectable HDV RNA.

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Section: Discussionmentioning

confidence: 83%

A regular screening for hepatitis delta virus among chronic hepatitis B carriers improves the diagnostic of this infection and of subsequent cirrhosis development

Weichselbaum,

Njimi,

van den Wijngaert

et al. 2024

UEG Journal

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“…Moreover, we observed that the CRPQ sequence is neither cleaved nor carboxylmethylated, consistent with its non-canonical sequence (see Figure 4 and Supplemental Figures 2 and 3 ). Prenylation of L-HDAg is required for virion assembly, and the FTI Lonafarnib is currently in Phase 3 clinical trials for use in combination treatments for Hepatitis D infections (Khalfi et al, 2023; Koh et al, 2015; Yardeni et al, 2022). We also determined that the CaaX sequence of human cytomegalovirus protein of unknown function IRL9 (CRIQ) can be farnesylated, cleaved and carboxymethylated.…”

Section: Discussionmentioning

confidence: 99%

A Humanized Yeast System for Evaluating the Protein Prenylation of a Wide Range of Human and Viral CaaX Sequences

Hildebrandt,

Sarkar,

Ravishankar

et al. 2023

Preprint

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The C-terminal CaaX sequence (cysteine-aliphatic-aliphatic-any of several amino acids) is subject to isoprenylation on the conserved cysteine and is estimated to occur in 1-2% of proteins within yeast and human proteomes. Recently, non-canonical CaaX sequences in addition to shorter and longer length CaX and CaaaX sequences have been identified that can be prenylated. Much of the characterization of prenyltransferases has relied on the yeast system because of its genetic tractability and availability of reporter proteins, such as the a-factor mating pheromone, Ras GTPase, and Ydj1 Hsp40 chaperone. To compare the properties of yeast and human prenyltransferases, including the recently expanded target specificity of yeast farnesyltransferase, we have developed yeast strains that express human farnesyltransferase or geranylgeranyltransferase-I in lieu of their yeast counterparts. The humanized yeast strains display robust prenyltransferase activity that functionally replaces yeast prenyltransferase activity in a wide array of tests, including the prenylation of a wide variety of canonical and non-canonical human CaaX sequences, virus encoded CaaX sequences, non-canonical length sequences, and heterologously expressed human proteins HRas and DNAJA2. These results reveal highly overlapping substrate specificity for yeast and human farnesyltransferase, and mostly overlapping substrate specificity for GGTase-I. This yeast system is a valuable tool for further defining the prenylome of humans and other organisms, identifying proteins for which prenylation status has not yet been determined.

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“…Instead, the durable response would be more appropriate (when HDV RNA remains undetectable). 25 On the other hand, there are two different situations for HBsAg elimination, known as HBsAg seroreversion, meaning clearance of circulating HBsAg without developing anti-HBs; and HBsAg seroconversion, referring to development of anti-HBs along with disappearance of circulating HBsAg.…”

Section: End-points For Hdv Therapiesmentioning

confidence: 99%

Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy

Soriano¹,

Moreno-Torres²,

Treviño³

et al. 2023

DDDT

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It has been ten years since the identification of NTCP as the cell surface receptor for HBV and HDV entry into hepatocytes. The search for molecules interfering with the binding of NTCP and HBV/HDV led to design bulevirtide (BLV). This large polypeptide mimics a region of the pre-S1 HBsAg and blocks viral entry by inhibitory competition. BLV was initially tested in cell cultures, animal models and more recently in Phase I–III human trials (called ‘MYRS’). As monotherapy or in combination with peginterferon, BLV is well tolerated and exhibits potent antiviral activity. Plasma viremia significantly declines and/or becomes undetectable in more than 75% of patients treated for >24 weeks. However, serum HBsAg concentrations remain unchanged. No selection of BLV resistance in HBV/HDV has been reported in vivo to date. BLV is administered subcutaneously once daily at doses between 2 and 10 mg. BLV received conditional approval in Europe in 2020 to treat chronic hepatitis delta. The advent of peginterferon lambda or new specific anti-HDV antivirals (lonafarnib, etc.) will open the door for combination therapies with BLV. Since there is no stable reservoir for HDV-RNA within infected hepatocytes, viral clearance might be achieved using antivirals for a minimum timeframe. This is what happens in hepatitis C combining several antivirals, curing nearly all patients treated for 3 months. Clearance of HDV-RNA genomes may occur despite HBV persistence as cccDNA or chromosome integrated HBV-DNA within hepatocytes. This is supported by cases of HDV elimination using BLV despite persistence of serum HBsAg. Another path for HDV cure will derive from achieving HBsAg clearance, the goal of new promising anti-HBV gene therapies (bepirovirsen, etc.). In summary, the advent of BLV has triggered a renovated interest for antiviral therapy in hepatitis delta. We envision combination therapies that will lead to HDV cure in the near future.

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Hepatitis D virus: Improving virological knowledge to develop new treatments

Cited by 13 publications

References 182 publications

A regular screening for hepatitis delta virus among chronic hepatitis B carriers improves the diagnostic of this infection and of subsequent cirrhosis development

A regular screening for hepatitis delta virus among chronic hepatitis B carriers improves the diagnostic of this infection and of subsequent cirrhosis development

A Humanized Yeast System for Evaluating the Protein Prenylation of a Wide Range of Human and Viral CaaX Sequences

Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy

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