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Background & Aims: Genetic polymorphisms in the sodium taurocholate cotransporting peptide (NTCP encoded by SLC10A1) have been described, but their role in untreated and treated patients with chronic hepatitis delta (CHD) remains unknown. Virological response (VR) to the NTCP inhibitor bulevirtide (BLV) was achieved at week 48 by >70% of patients with CHD, but nearly 15% experienced virological non-response (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in patients with CHD., Methods: BLV-untreated and -treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing., Results: Of the six NTCP polymorphisms studied in 209 untreated patients with CHD, carriers of the rs17556915 TT/CC (n = 142) compared to CT (n = 67) genotype presented with higher median HDV RNA levels (5.39 vs. 4.75 log 10  IU/ml, p = 0.004). Of 209 patients receiving BLV monotherapy at 2 mg/day, 76 were evaluated at week 24 and 40 up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (n = 43) compared to CT (n = 33) carriers (5.38 vs. 4.72 log 10  IU/ml, p = 0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 vs. 17/33, p = 0.565), the former group presented VNR more often than PR (9/11 vs. 9/23, p = 0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment., Conclusions: The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in BLV-untreated and -treated patients with CHD and may contribute to identifying patients with different early virological responses to BLV., Impact and Implications: Although several sodium taurocholate cotransporting polypeptide (NTCP) genetic polymorphisms have been described, no data are available on their potential role in modifying HDV RNA load or treatment response to bulevirtide (BLV) in patients with chronic hepatitis delta (CHD). In this study, we demonstrated that patients with CHD, either treated or untreated, carrying NTCP rs17556915 TT/CC, presented higher baseline HDV RNA levels compared to those with the CT genotype. Higher HDV RNA levels in TT/CC carriers compared to CT carriers were also confirmed in patients with CHD treated with BLV monotherapy up to 96 weeks. Furthermore, carriers of TT/CC, compared to CT genotype, more frequently showed viral non-response (VNR) than partial response (PR) at week 24 of BLV treatment, and 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. This is the first study demonstrating a potential role of NTCP genetic polymorphisms in influencing HDV viral load and early virological response to BLV monotherapy. Since no direct HDV resistance to BLV has been described so far, if confirmed in larger studies, the genetic polymorphisms in NTCP may help identify patients with different patterns of early virological response to BLV., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Recent studies indicate that treatment of chronic hepatitis D virus (HDV) with either pegylated interferon (IFN)λ or pegylated IFNα monotherapy leads to a dramatic decline in HDV RNA. Herein, we investigated the innate antiviral efficacy of IFNλ and IFNα in humanized mice that lack an adaptive immune response. Humanized mice were either co-infected with hepatitis B virus (HBV) and HDV simultaneously, or HDV infection was performed subsequent to HBV infection (i.e., superinfected). After steady viral replication was achieved, mice received either IFNλ (n = 6) or IFNα (n = 7) for 12 (or 13) weeks. Pretreatment median levels of serum HBV DNA (8.8 [IQR:0.2] log IU/ml), HDV RNA (9.8 [0.5] log IU/ml), HBsAg (4.0 [0.4] log IU/ml) and human albumin, hAlb (6.9 [0.1] log ng/mL) were similar between mice treated with IFNα or IFNλ and between those coinfected versus superinfected. Compared to mice treated with IFNλ, mice treated with IFNα had a significantly greater decline in HBV, HDV, and HBsAg levels. In conclusion, IFNα induces stronger inhibition of HBV and HDV than IFNλ in humanized mice that lack an adaptive immune response. Further studies are needed to assess the respective role of the combined innate-and adaptive-immune systems in the treatment of HBV and HDV with IFNα and IFNλ., Competing Interests: Declaration of competing interest Kazuaki Chayama has received honoraria from Bristol-Myers Squibb and MSD K.K., AbbVie, Gilead Science, Dainippon Sumitomo Pharma and Mitsubishi Tanabe Pharma and research funding from Gilead Science, Dainippon Sumitomo Pharma, MSD K.K., AbbVie, Eisai, TORAY, Otsuka Pharma, Chugai Pharma, Takeda Pharma and Roche. Jeffrey Glenn, director, and equity holder of Eiger Biopharmaceuticals. Ohad Etzion has received consulting fees from Eiger Biopharmaceuticals. The other authors declare no conflicts of interest that pertain to this work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24., Methods: In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log 10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA., Results: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV., Conclusions: Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96., Impact and Implications: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96., Gov Identifier: NCT03852719., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear., Methods: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group., Results: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity., Conclusions: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.)., (Copyright © 2024 Massachusetts Medical Society.)

Background & Aims: Bulevirtide (BLV) is a first-in-class entry inhibitor and the only approved treatment for patients chronically infected with HDV in Europe. We aimed to investigate the efficacy of BLV treatment in paired liver biopsies obtained at baseline and after 24 or 48 weeks of treatment., Methods: We performed a combined analysis of 126 paired liver biopsies derived from three clinical trials. In the phase II clinical trial MYR202, patients with chronic hepatitis D were randomised to receive 24 weeks of BLV at 2 mg, 5 mg or 10 mg/day. Patients in MYR203 (phase II) and MYR301 (phase III) received 48 weeks of BLV at 2 mg or 10 mg/day. Tenofovir disoproxil fumarate monotherapy or delayed treatment served as comparators. Virological parameters and infection-related host genes were assessed by qPCR and immunohistochemistry., Results: At week 24, median intrahepatic HDV RNA decline from baseline was 0.9Log 10 with 2 mg (n = 7), 1.1Log 10 with 5 mg (n = 5) and 1.4 Log 10 with 10 mg (n = 7) of BLV. At week 48, median reductions were 2.2Log 10 with 2 mg (n = 27) and 2.7Log 10 with 10 mg (n = 37) of BLV, while HDV RNA levels did not change in the comparator arms. Notably, a drastic decline in the number of hepatitis delta antigen-positive hepatocytes and a concomitant decrease in transcriptional levels of inflammatory chemokines and interferon-stimulated genes was determined in all BLV-treatment arms. Despite the abundance of HBsAg-positive hepatocytes, replication and covalently closed circular DNA levels of the helper virus HBV were low and remained unaffected by BLV treatment., Conclusion: Blocking viral entry diminishes signs of liver inflammation and promotes a strong reduction of HDV infection within the liver, thus suggesting that some patients may achieve HDV cure with long-term treatment., Impact and Implications: Chronic infection with HDV causes the most severe form of viral hepatitis, affecting approximately 12 million people worldwide. The entry inhibitor bulevirtide (BLV) is the only recently approved anti-HDV drug, which has proven efficacious and safe in clinical trials and real-word data. Here, we investigated paired liver biopsies at baseline and after 24 or 48 weeks of treatment from three clinical trials to understand the effect of the drug on viral and host parameters in the liver, the site of viral replication. We found that BLV treatment strongly reduces the number of HDV-infected cells and signs of liver inflammation. This data implies that blocking viral entry ameliorates liver inflammation and that prolonged treatment regimens might lead to HDV cure in some patients. This concept will guide the further development of therapeutic strategies and combination treatments for patients with CHD., Clinical Trial Numbers: NCT03546621, NCT02888106, NCT03852719., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare no conflicts of interest, financial or otherwise for this study., (© 2023 Soriano et al.)

Treatment options for HDV have been limited to interferon alfa-based therapies with its poor efficacy to side effects ratio. Several novel therapies have now advanced into the clinic. As they each have a different mechanism of action, there is the potential for combination therapy. Here we review how studying the HDV life cycle has led to the development of these novel therapies, the key developments leading to, and the details of, the first combination study of novel anti-HDV therapies, and suggest what additional combinations of novel therapies can be anticipated as we enter this exciting new area of HDV treatments.

Co-infection with the hepatitis B virus and hepatitis delta virus (HDV) leads to the most aggressive form of viral hepatitis. Using in vitro infection models, we confirmed that IL-1β, a crucial innate immune molecule for pathogen control, was very potent against HBV from different genotypes. Additionally, we demonstrated for the first time a strong and rapid antiviral effect induced by very low doses of IL-1β against HDV. In parallel, using co-culture assays, we demonstrated that monocytes exposed to HBV, and in particular to HBsAg, during differentiation into pro-inflammatory macrophages secreted less IL-1β. Altogether, our data emphasize the importance of developing combined antiviral strategies that would, for instance, reduce the secretion of HBsAg and stimulate the immune system to produce endogenous IL-1β efficient against both HBV and HDV.

The hepatic bile acid transporter Na + /taurocholate co-transporting polypeptide (NTCP) was identified in 2012 as the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Since then, this carrier has emerged as promising drug target for HBV/HDV virus entry inhibitors, but the synthetic peptide Hepcludex ® of high molecular weight is the only approved HDV entry inhibitor so far. The present study aimed to identify small molecules as novel NTCP inhibitors with anti-viral activity. A ligand-based bioinformatic approach was used to generate and validate appropriate pharmacophore and QSAR (quantitative structure-activity relationship) models. Half-maximal inhibitory concentrations (IC 50 ) for binding inhibition of the HBV/HDV-derived preS1 peptide (as surrogate parameter for virus binding to NTCP) were determined in NTCP-expressing HEK293 cells for 150 compounds of different chemical classes. IC 50 values ranged from 2 µM up to >1000 µM. The generated pharmacophore and QSAR models were used for virtual screening of drug-like chemicals from the ZINC 15 database (~11 million compounds). The 20 best-performing compounds were then experimentally tested for preS1-peptide binding inhibition in NTCP-HEK293 cells. Among them, four compounds were active and revealed experimental IC 50 values for preS1-peptide binding inhibition of 9, 19, 20, and 35 µM, which were comparable to the QSAR-based predictions. All these compounds also significantly inhibited in vitro HDV infection of NTCP-HepG2 cells, without showing any cytotoxicity. The best-performing compound in all assays was ZINC000253533654. In conclusion, the present study demonstrates that virtual compound screening based on NTCP-specific pharmacophore and QSAR models can predict novel active hit compounds for the development of HBV/HDV entry inhibitors.

Identification of Na + /taurocholate co-transporting polypeptide (NTCP) as high-affinity hepatic entry receptor for the Hepatitis B and D viruses (HBV/HDV) opened the field for target-based development of cell-entry inhibitors. However, most of the HBV/HDV entry inhibitors identified so far also interfere with the physiological bile acid transporter function of NTCP. The present study aimed to identify more virus-selective inhibitors of NTCP by screening of 87 propanolamine derivatives from the former development of intestinal bile acid reabsorption inhibitors (BARIs), which interact with the NTCP-homologous intestinal apical sodium-dependent bile acid transporter (ASBT). In NTCP-HEK293 cells, the ability of these compounds to block the HBV/HDV-derived preS1-peptide binding to NTCP (virus receptor function) as well as the taurocholic acid transport via NTCP (bile acid transporter function) were analyzed in parallel. Hits were subsequently validated by performing in vitro HDV infection experiments in NTCP-HepG2 cells. The most potent compounds S985852, A000295231, and S973509 showed in vitro anti-HDV activities with IC 50 values of 15, 40, and 70 µM, respectively, while the taurocholic acid uptake inhibition occurred at much higher IC 50 values of 24, 780, and 490 µM, respectively. In conclusion, repurposing of compounds from the BARI class as novel HBV/HDV entry inhibitors seems possible and even enables certain virus selectivity based on structure-activity relationships.

Chronic HDV infection often is associated with aggressive form of liver disease, compared to chronic HBV mono-infection. However, chronic HDV treatment is challenging because currently there is no approved regimen for affected patients. While standard interferon with/without nucleos(t)ide analogues were reported to be inferior to pegylated interferon (peginterferon) as HDV treatment according to few randomized clinical trials. This meta-analysis will summarize the results of studies on the effectiveness of peginterferon as HDV treatment regimen. An electronic search was performed using PubMed, Cochrane Library, Research Gate, and Medline databases. Studies involving patients who received peginterferon therapy for at least 48 weeks and followed up for 24 weeks post-therapy were included. All analyses were conducted using Review Manager 5.3 designed for Cochrane Reviews. The primary efficacy endpoint was virological response (VR) or HDV-RNA negativity at the end of the follow-up period, whereas secondary efficacy endpoints were biochemical response (BR) or ALT normalization and HBsAg clearance with seroconversion to anti-HBs at the end of follow-up period. Data were abstracted from 13 relevant studies with a total of 475 patients who were treated with peginterferon alpha-2a or -2b. At the end of 24-week post-treatment the pooled VR was achieved in 29% of patients with 95% CI [24%; 34%], BR was reached in 33% of patients [95% CI 27%; 40%] and HBsAg clearance with seroconversion to anti-HBs was achieved in 1% of patients with 95% CI [-0.02; 0.05]. In conclusion, this study showed that peginterferon has limited effectiveness in HDV treatment, since only one-third of chronic HDV patients achieved viral clearance and normalized ALT levels. Morever, HBsAg clearance with seroconversion to anti-HBs has been rarely observed among chronic HDV patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Bulevirtide (Hepcludex ® ), a first-in-class entry inhibitor, is being developed by MYR GmbH for the treatment of chronic hepatitis delta virus (HDV) and chronic hepatitis B virus (HBV) infections. Bulevirtide was recently approved in the European Union (EU) for the treatment of chronic HDV infection in HDV RNA positive adult patients with compensated liver disease. This article summarizes the milestones in the development of bulevirtide leading to this first approval for chronic HDV.

Hepatitis D virus causes chronic hepatitis D. The virus is defective, meaning it requires simultaneous presence of hepatitis B virus within the hepatocytes to complete its viral cycle. Globally, 15 to 20 millions people are estimated to be chronically co-infected by hepatitis B and D viruses. Current therapy remains limited to pegylated interferon alfa, which has an unsatisfactory success rate, several contraindications and many side effects. Drugs directly targeting the hepatitis D virus life cycle are being developed with promising results. These drugs target viral entry into hepatocytes, virion assembly or secretion from infected hepatocytes. This article provides an overview of the newly developed therapies and their efficacy., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Purpose of Review: Limited data exist on the prevalence, determinants, and outcomes of hepatitis delta virus (HDV) infection among HIV/hepatitis B virus (HBV)-coinfected persons. This review provides current evidence on the epidemiology, natural history, and treatment of HDV infection in patients with HIV/HBV coinfection and highlights future research needs., Recent Findings: Cross-sectional studies in Europe, Africa, South America, and Asia show that the prevalence of HDV among HIV/HBV-coinfected patients ranges from 1.2 to 25%. No studies have evaluated the prevalence of HDV infection among HIV/HBV-coinfected patients in the USA. HDV infection increases the risk of hepatic decompensation and hepatocellular carcinoma among HIV/HBV-coinfected patients. HDV treatment remains limited to pegylated interferon-alpha, which results in sustained virologic response in fewer than 25%. Data on the epidemiology, natural history, and treatment of HDV among HIV/HBV-coinfected persons remain limited. More research is needed to address these knowledge gaps in order to better manage HDV coinfection in HIV/HBV-coinfected patients.

Background: Therapy of chronic hepatitis D (CHD) is still based on interferon alpha (IFNα), introduced in clinical practice 30 years ago: results are modest and better therapies are an urgent medical need., Aims: This article provides a critical overview of the new therapies under investigation for CHD., Sources: Review of the recently published medical literature., Content: New therapeutic efforts aim to deprive the hepatitis D virus (HDV) of functions provided to its life cycle by the hepatitis B Virus (HBV) or by the host. Three therapeutic strategies are in evaluation: a) Myrcludex B, a myristolated lipopeptide of the pre-S1 domain of the HBsAg that blocks the entry of the HDV into hepatocyes and controls infection by preventing the spreading of the virus to liver cells not infected by the HBV; b) Lonafarnib, an inhibitor of a host farnesyl-transferase that hinders morphogenesis of the HDV by preventing the farnesylation of the large HD-antigen, necessary for virion assembly; c) REP 2139, a nucleic acid polymer that prevents export of the mature HDV by the presumed inhibition of the synthesis of subviral HBsAg particles with which the virion is coated. Myrcludex B and Lonafarnib increase therapeutic efficacy in combination with Peg-IFNα. In a pilot study, REP 2139 in combination with Peg-IFNα induced the clearance of serum HDV RNA and of the HBsAg in about half of 12 treated patients., Implications: Long-term therapies with either Myrcludex B or Lonafarnib in combination with Peg-IFNα are required to achieve clinical control of CHD. However, with prolonged therapies tolerance becomes a problem; studies are on the way to determine whether Peg-IFN lambda may be better tolerated that Peg-IFNα. The promising preliminary data of REP 2139 in combination with Peg-IFNα await confirmation of the original pilot study., (Copyright © 2020. Published by Elsevier Ltd.)

Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) for its assembly and release. Current HBV treatments are only marginally effective against HDV because they fail to inhibit HBsAg production/secretion. However, monotherapy with the nucleic acid polymer REP 2139-Ca is accompanied by rapid declines in both HBsAg and HDV RNA. We used mathematical modeling to estimate HDV-HBsAg-host parameters and to elucidate the mode of action and efficacy of REP 2139-Ca against HDV in 12 treatment-naive HBV/HDV co-infected patients. The model accurately reproduced the observed decline of HBsAg and HDV, which was simultaneous. Median serum HBsAg half-life (t 1/2 ) was estimated as 1.3 [0.9-1.8] days corresponding to a pretreatment production and clearance of ~10 8 [10 7.7 -10 8.3 ] IU/day. The HDV-infected cell loss was estimated to be 0.052 [0.035-0.074] days -1 corresponding to an infected cell t 1/2  = 13.3 days. The efficacy of blocking HBsAg and HDV production were 98.2 [94.5-99.9]% and 99.7 [96.0-99.8]%, respectively. In conclusion, both HBsAg production and HDV replication are effectively inhibited by REP 2139-Ca. Modeling HBsAg kinetics during REP 2139-Ca monotherapy indicates a short HBsAg half-life (1.3 days) suggesting a rapid turnover of HBsAg in HBV/HDV co-infection.

Aims: Little data have been published so far on the epidemiological aspects of hepatitis D virus (HDV) infection in immigrant populations and even poorer is the information on the virological, phylogenetic, and clinical aspects of this infection in these populations. This review article, aimed primarily at physicians caring for immigrants, summarizes the information available on HDV infection and analyzes data on this topic concerning the immigrant populations., Methods and Results: The prevalence of HDV infection in HBsAg-positive immigrants varies according to the country of origin. For example, in immigrants from sub-Saharan Africa, this prevalence is higher in those born in Equatorial Guinea (24.4%) than those from other African countries (10.3%). The epidemiological impact of HDV infection linked to migratory flows is a function of the different endemicity between countries of origin and countries in which a new existence has been established. This impact is high when immigrants from areas endemic to HDV infection (eg, Equatorial Guinea) settle in areas of low endemicity (eg, Germany or England, with a prevalence of around 4%), while the impact is lesser or nonexistent if the migratory flows are directed toward countries with intermediate endemicity (eg, Italy and Greece, with a prevalence of around 10%)., Conclusion: This impact of immigration on HDV epidemiology can be strong when HDV endemicity is high in the country of origin and low in the host country and slight when immigrants move to high or medium endemic countries., (© 2019 Wiley Periodicals, Inc.)

Background: Cytotoxic and immunosuppressive therapies for cancer treatment may allow hepatitis reactivation. Hepatitis due to viral hepatitis reactivation is detected in 14%-25% of hepatitis B surface antigen (HBsAg)-positive cancer patients undergoing anticancer treatments. Drug toxicity may be confused with hepatitis reactivation, which may cause a delay in diagnosis., Case Report: A 60-year-old man with metastatic renal cell carcinoma was treated with sunitinib. Sixteen months after sunitinib inception, liver enzymes were elevated and viral hepatitis reactivation was detected as hepatitis delta virus infection in the HBsAg-positive patient., Conclusion: Cancer patients should be screened for viral hepatitis prior to immunosuppressive therapy or chemotherapy.

Short-term administration of the entry inhibitor myrcludex-B (MyrB) has been shown to be safe and effective in phase II studies in patients coinfected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). However, its effectiveness and safety are unknown during long-term and high-dose treatment of patients with compensated cirrhosis in real-life settings. Herein, we describe the first 3 European patients with HDV-related compensated cirrhosis who were treated with MyrB 10 mg/day for 48 weeks as a compassionate therapy. Liver function tests, bile acids, and virological markers were monitored every 4 weeks. HBV/HDV-specific T cell quantity (up to 48 and 36 weeks) and HBV RNA levels were also assessed in 2 cases. During MyrB treatment, HDV RNA levels progressively declined from 4.4 and 5.6 logs IU/ml to undetectability in 2 cases, and from 6.8 log copies/ml to 500 copies/ml for the other patient. Alanine aminotransferase normalised after 20, 12 and 28 weeks, respectively. A significant improvement in features of portal hypertension, liver function tests and alpha-fetoprotein levels were documented in 2 cases. In the male patient with histological and clinical stigmata of autoimmune hepatitis, IgG and immunoglobulins rapidly normalised. No significant changes in HBV surface antigen levels and circulating HBV/HDV-specific T cells were demonstrated; HBV DNA and HBV RNA levels remained undetectable throughout the study period. MyrB was well tolerated; patients remained fully asymptomatic despite a significant increase of bile acids. In conclusion, this report shows excellent safety and effectiveness of a 48-week course of MyrB 10 mg/day, combined with tenofovir disoproxil fumarate, for the treatment of HDV-related compensated cirrhosis., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic infection with the human Hepatitis B virus (HBV) is a major global health problem. Hepatitis D virus (HDV) is a satellite of HBV that uses HBV envelope proteins for cell egress and entry. Using infection systems encoding the HBV/HDV receptor human sodium taurocholate co-transporting polypeptide (NTCP), we screened 1181 FDA-approved drugs applying markers for interference for HBV and HDV infection. As one primary hit we identified Acitretin, a retinoid, as an inhibitor of HBV replication and HDV release. Based on this, other retinoic acid receptor (RAR) agonists with different specificities were found to interfere with HBV replication, verifying that the retinoic acid receptor pathway regulates replication. Of the eight agonists investigated, RARα-specific agonist Am80 (tamibarotene) was most active. Am80 reduced secretion of HBeAg and HBsAg with IC 50 s < 10 nM in differentiated HepaRG-NTCP cells. Similar effects were observed in primary human hepatocytes. In HepG2-NTCP cells, profound Am80-mediated inhibition required prolonged treatment of up to 35 days. Am80 treatment of cells with an established HBV cccDNA pool resulted in a reduction of secreted HBsAg and HBeAg, which correlated with reduced intracellular viral RNA levels, but not cccDNA copy numbers. The effect lasted for >12 days after removal of the drug. HBV genotypes B, D, and E were equally inhibited. By contrast, Am80 did not affect HBV replication in transfected cells or HepG2.2.15 cells, which carry an integrated HBV genome. In conclusion, our results indicate a persistent inhibition of HBV transcription by Am80, which might be used for drug repositioning., (Copyright © 2019. Published by Elsevier B.V.)

Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics., (Published by Elsevier Inc.)

Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs., (© 2019 John Wiley & Sons Ltd.)

Hepatitis delta virus (HDV) depends on the helper function of hepatitis B virus (HBV), which provides the envelope proteins for progeny virus secretion. Current infection-competent cell culture models do not support assembly and secretion of HDV. By stably transducing HepG2 cells with genes encoding the NTCP-receptor and the HBV envelope proteins we produce a cell line (HepNB2.7) that allows continuous secretion of infectious progeny HDV following primary infection. Evaluation of antiviral drugs shows that the entry inhibitor Myrcludex B (IC 50 : 1.4 nM) and interferon-α (IC 50 : 28 IU/ml, but max. 60-80% inhibition) interfere with primary infection. Lonafarnib inhibits virus secretion (IC 50 : 36 nM) but leads to a substantial intracellular accumulation of large hepatitis delta antigen and replicative intermediates, accompanied by the induction of innate immune responses. This work provides a cell line that supports the complete HDV replication cycle and presents a convenient tool for antiviral drug evaluation.

Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts, and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually infected humanized mice. Treatment with ARB-1740, a clinical stage HBV-targeting siRNA agent delivered using lipid nanoparticle (LNP) technology, effectively reduced HBV viremia by 2.3 log 10 and serum HBsAg by 2.6 log 10 , leading to 1.6 log 10 reduction of HDV viremia. In contrast, HDV-targeting siRNA inhibited HDV in both blood and liver compartments without affecting HBV and PEGylated interferon-alpha reduced HBV viremia by 2.0 log 10 but had no effect on HDV viremia under these study conditions. These results illustrate the inhibitory effects of siRNAs against these two viral infections and suggest that ARB-1740 may be of therapeutic benefit for hepatitis delta patients, a subpopulation with high unmet medical need.

Nucleic acid polymers (NAPs) are broad spectrum antiviral agents whose antiviral activity in hepatitis B virus (HBV) infection is derived from their ability to block the release of the hepatitis B virus surface antigen (HBsAg). This pharmacological activity blocks replenishment of HBsAg in the circulation, allowing host mediated clearance. This effect has important clinical significance as the clearance of circulating HBsAg dramatically potentiates the ability of immunotherapies to restore functional control of HBV infection which persists after antiviral therapy is removed. These effects are reproducible in preclinical evaluations and in several clinical trials that have evaluated the activity of the lead NAP, REP 2139, in monotherapy and in combination with immunotherapy in hepatitis B e antigen (HBeAg) negative and HBeAg positive HBV infection and also in HBeAg negative HBV/hepatitis D virus (HDV) coinfection. These antiviral effects of REP 2139 are achieved in the absence of any direct immunostimulatory effect in the liver and also without any discernible direct interaction with viral components. The search for the host protein interaction with NAPs that drives their antiviral effects is ongoing, and the interaction targeted by REP 2139 within infected cells has not yet been elucidated. This article provides an updated review of available data on the effects of REP 2139 in HBV and HDV infection and the ability of REP 2139-based combination therapy to achieve functional control of HBV and HDV infection in patients.

Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection., (Copyright: © 2019 Permanyer.)

Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatitis D virus (HDV) is a hepatotropic subviral infectious agent, obligate satellite of the Hepatitis B virus (HBV) and is highly related to viroids. HDV affects around 5% of the 257 million chronic HBV-carriers worldwide, leading to the most severe form of chronic viral hepatitis. Interferon alpha is the only approved treatment for chronic hepatitis D, albeit with low response rates (around 20%-30%). New antiviral strategies are currently under study. Due to the high viral evolution rates (10 -3 to 10 -4 substitutions/site/year) HDV forms an extremely complex viral population (quasispecies) that can be studied by Next-Generation Sequencing. Therefore, although specific viral resistance in HDV infection has not been reported, it cannot be completely discarded., (Copyright © 2018 Elsevier B.V. All rights reserved.)

An estimated 240 million people worldwide are chronically infected with the hepatitis B virus (HBV). Despite readily available vaccination, HBV infections remain highly prevalent. As established HBV infections constitute a strong risk factor for developing hepatocellular carcinoma their treatment is a major task for the health system. Unfortunately, HBV is not curable with today's medicine. Approximately 15 million HBV patients have developed a hepatitis delta (HDV) infection on top of their HBV infection. The patients superinfected with this satellite virus suffer from a more severe disease development. The knowledge of the viruses, their classifications, clinical implications, treatment options and efforts to increase the drug variety are compiled in this review. The current standard therapies include nucleosidic reverse transcriptase inhibitors and interferon. As the known treatments fail to cure HBV and HDV, targeted treatment is highly warranted. The focus of this review is set on the drugs currently under clinical investigation. Furthermore, strategies for the development of targeted treatment, and compounds with novel mode of action are described., (Copyright © 2018. Published by Elsevier B.V.)

Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and natural killer cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small-animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis and immune responses and for testing novel HDV therapeutics., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Worldwide, hepatitis B virus (HBV) infection is among the 30 leading causes of death, despite effective vaccination and therapeutic options. Chronic hepatitis delta (coinfection with hepatitis D virus) leads to a rapid disease progression., Aims: Based on current international guidelines and studies, an overview about present and future therapeutic options for chronic hepatitis B and delta is provided., Results: Therapy with nucleoside or nucleotide analogues leads to nearly complete HBV DNA suppression, which is associated with regression of liver fibrosis and a lower risk for the development of hepatocellular carcinoma. Therapy of chronic hepatitis delta with pegylated interferon alfa achieves only low response rates with high risk for virological relapse. Various therapeutic approaches are currently being investigated in preclinical and clinical studies and have led to a significant reduction of hepatitis B surface antigen (HBsAg) and HDV RNA., Conclusion: Current therapies of chronic HBV infection can effectively reduce subsequent complications. New therapeutic approaches promise functional cure (HBsAg loss) of HBV infection and effective treatment options for patients with chronic hepatitis delta.

While chronic infection with the human hepatitis B virus (HBV) and hepatitis delta virus (HDV) inflict major health burdens worldwide, current therapies cannot cure patients. One possible novel approach is blocking virus entry to prevent the establishment of infection in naïve hepatocytes. As HBV and HDV use identical viral envelope proteins and the same entry mechanisms, such a strategy would target both viruses. Entry inhibitors (e.g. neutralizing antibodies) have been relegated to the limited role of prophylaxis. However, recent clinical data and infection studies show that new viral entry inhibitors could play a major role in eliminating intrahepatic HBV/HDV genomes. We highlight the consequences on viral persistence after preventing virus entry and the therapeutic benefits entry inhibitors could achieve., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In a proof-of-concept (POC) study, the oral prenylation inhibitor, lonafarnib (LNF), decreased hepatitis D virus (HDV) RNA during 4 weeks of treatment. Here, we explored optimal LNF regimens. Fifteen patients (five groups; 3 per group) completed dosing as follows: (1) LNF 200 mg twice-daily (BID; 12 weeks); (2) LNF 300 mg BID (12 weeks); (3) LNF 100 mg thrice-daily (5 weeks); (4) LNF 100 mg BID + pegylated interferon alfa (PEG-IFNα) 180 μg once-weekly (QW; 8 weeks); and (5) LNF 100 mg BID + ritonavir (RTV) 100 mg once-daily (QD; 8 weeks). Tolerability and efficacy were assessed. Higher LNF monotherapy doses had greater decreases in HDV viral load than achieved in the original POC study. However, this was associated with increased gastrointestinal adverse events. Addition of RTV 100 mg QD to a LNF 100 mg BID regimen yielded better antiviral responses than LNF 300 mg BID monotherapy and with less side effects. A similar improvement was observed with LNF 100 mg BID + PEG-IFNα 180 μg QW. Two of 6 patients who received 12 weeks of LNF experienced transient posttreatment alanine aminotransferase (ALT) increases resulting in HDV-RNA negativity and ALT normalization., Conclusion: The cytochrome P450 3A4 inhibitor, RTV, allows a lower LNF dose to be used while achieving higher levels of postabsorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG-IFNα achieved more substantial and rapid HDV-RNA reduction, compared to historical responses with PEG-IFNα alone. Twelve weeks of LNF can result in posttreatment HDV-RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. (Hepatology 2018;67:1224-1236)., (© 2017 by the American Association for the Study of Liver Diseases.)

Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture. One of such compound, NPD8716, a coumarin derivative, interacted with NTCP and inhibited HBV infection without causing cytotoxicity. Consistent with its NTCP interaction capacity, this compound was shown to block viral attachment to host hepatocytes. NPD8716 also prevented the infection with hepatitis D virus, but not hepatitis C virus, in agreement with NPD8716 specifically inhibiting NTCP-mediated infection. Analysis of derivative compounds showed that the anti-HBV activity of compounds was apparently correlated with the affinity to NTCP and the capacity to impair NTCP-mediated bile acid uptake. These results are the first to show that the chemical array technology represents a powerful platform to identify novel viral entry inhibitors.

New therapeutic strategies to treat chronic hepatitis D are directed to deprive the hepatitis D virus (HDV) of functions necessary to complete its life cycle that are provided by the hepatitis B virus (HBV) and by the host. Current options are (1) the block by the synthetic peptide Myrcludex B of HBV surface antigen (HBsAg) entry into cells through the inhibition of the sodium taurocholate cotransporting receptor; (2) the inhibition with lonafarnib of the farnesylation of the large HD antigen, required for virion assembly; (3) the presumed reduction by the nucleic acid polymer REP 2139 of the release of the HBsAg and subviral HBV particles necessary for HD virion morphogenesis. Lonafarnib and Myrcludex in monotherapy reduced serum HDV-RNA but did not reduce the HBsAg and HD viremia rebounded after therapy; they may provide additional efficacy to pegylated interferon alpha (Peg IFN-α) therapy. Treatment with REP-2139 in combination with Peg IFN-α induced a sustained clearance both of the HDV-RNA and HBsAg in 5 of 12 patients, providing the best interim results so far obtained in the therapy of chronic hepatitis D., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

In this study, an in vitro infection model for the hepatitis delta virus (HDV) was used to evaluate the antiviral effects of phosphorothioate nucleic acid polymers (NAPs) and investigate their mechanism of action. The results show that NAPs inhibit HDV infection at concentrations less than 4 μM in cultures of differentiated human hepatoma cells. NAPs were shown to be active at viral entry but inactive postentry on HDV RNA replication. Inhibition was independent of the NAP nucleotide sequence but dependent on both size and amphipathicity of the polymer. NAP antiviral activity was effective against HDV virions bearing the main hepatitis B virus (HBV) immune escape substitutions (D144A and G145R) and was pangenomic with regard to HBV envelope proteins. Furthermore, similar to immobilized heparin, immobilized NAPs could bind HDV particles, suggesting that entry inhibition was due, at least in part, to preventing attachment of the virus to cell surface glycosaminoglycans. The results document NAPs as a novel class of antiviral compounds that can prevent HDV propagation. IMPORTANCE HDV infection causes the most severe form of viral hepatitis in humans and one of the most difficult to cure. Currently, treatments are limited to long-term administration of interferon at high doses, which provide only partial efficacy. There is thus an urgent need for innovative approaches to identify new antiviral against HDV. The significance of our study is in demonstrating that nucleic acid polymers (NAPs) are active against HDV by targeting the envelope of HDV virions. In an in vitro infection assay, NAP activity was recorded at concentrations less than 4 μM in the absence of cell toxicity. Furthermore, the fact that NAPs could block HDV at viral entry suggests their potential to control the spread of HDV in a chronically HBV-infected liver. In addition, NAP anti-HDV activity was pangenomic with regard to HBV envelope proteins and not circumvented by HBsAg substitutions associated with HBV immune escape., (Copyright © 2018 American Society for Microbiology.)

Background: Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be coadministered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro., Methods: Inhibition of P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates. Inhibition of cytochrome P450 enzymes (CYPs) was assessed with commercially available kits. mRNA induction of drug transporting and metabolizing enzymes was measured in LS180 cells after 4 days of treatment by quantitative real-time PCR. Pregnane X receptor (PXR) activation was assessed using a reporter-gene assay., Results: Whereas activities of P-gp and BCRP were not influenced by myrcludex B, OATP1B1 and OATP1B3 were specifically inhibited with a 50% inhibitory concentration (IC 50 ) of 0.5 and 8.7 µM, respectively. Myrcludex B weakly inhibited all CYPs tested at concentrations ≥10 µM except CYP2D6, which was not inhibited at concentrations up to 2 µM. Myrcludex B had no influence on mRNA expression of CYP1A1, CYP3A4, UGT1A3, ABCB1, ABCC2 and ABCG2, and on PXR activity., Conclusions: Our in vitro study suggests that myrcludex B is not at major risk of acting as a perpetrator drug. A potential inhibition of the uptake transporters OATP1B1 and OATP1B3 and a previous clinical finding of potential CYP3A inhibition, requires further evaluation and should be carefully addressed in future trials.

Hepatitis B virus (HBV) infection is a major global health problem. Currently-available therapies are ineffective in curing chronic HBV infection. HBV and its satellite hepatitis D virus (HDV) infect hepatocytes via binding of the preS1 domain of its large envelope protein to sodium taurocholate cotransporting polypeptide (NTCP). Here, we developed novel human monoclonal antibodies that block the engagement of preS1 with NTCP and neutralize HBV and HDV with high potency. One antibody, 2H5-A14, functions at picomolar level and exhibited neutralization-activity-mediated prophylactic effects. It also acts therapeutically by eliciting antibody-Fc-dependent immunological effector functions that impose durable suppression of viral infection in HBV-infected mice, resulting in reductions in the levels of the small envelope antigen and viral DNA, with no emergence of escape mutants. Our results illustrate a novel antibody-Fc-dependent approach for HBV treatment and suggest 2H5-A14 as a novel clinical candidate for HBV prevention and treatment of chronic HBV infection.

Introduction: Treatment of chronic hepatitis D still relies on Interferon. To improve efficacy, new therapeutic strategies are in development which aim to deprive the Hepatitis D Virus (HDV) of functions of the Hepatitis B Virus and of the host required for its life-cycle. Areas covered: The therapeutic options are; 1) The inhibition of the farnesylation of the large HD-protein permissive of virion assembly with Lonafarnib, 2) The blocking of HBsAg entry into cells with Myrcludex B via the inhibition of the Sodium Taurocholate Cotransporting Receptor, to prevent the spreading of HDV to uninfected hepatocytes, 3) The reduction of subviral HBsAg particles by REP 2139, leading to diminished virion morphogenesis . Expert opinion: Lonafarnib and Myrcludex reduced serum HVD-RNA; neither diminished serum HBsAg. NAP REP-2139 diminished both HDV-RNA and HBsAg in serum; a full report is awaited. In combination with Peg-Interferon, these new drugs may provide additional efficacy.

The hepatitis viruses represent a major public health problem worldwide. Procedures for characterization of the genomic composition of their populations, accurate diagnosis, identification of multiple infections, and information on inhibitor-escape mutants for treatment decisions are needed. Deep sequencing methodologies are extremely useful for these viruses since they replicate as complex and dynamic quasispecies swarms whose complexity and mutant composition are biologically relevant traits. Population complexity is a major challenge for disease prevention and control, but also an opportunity to distinguish among related but phenotypically distinct variants that might anticipate disease progression and treatment outcome. Detailed characterization of mutant spectra should permit choosing better treatment options, given the increasing number of new antiviral inhibitors available. In the present review we briefly summarize our experience on the use of deep sequencing for the management of hepatitis virus infections, particularly for hepatitis B and C viruses, and outline some possible new applications of deep sequencing for these important human pathogens., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis and is associated with a higher risk of cirrhosis, liver decompensation and liver cancer. Interferon alpha is the only agent that has demonstrated efficacy to date, although response rates are low and it is associated with significant side effects. A better understanding of the relevant molecular virology has resulted in the identification of new candidate targets. Future therapeutic options are rapidly evolving as several new agents have entered clinical development, including the entry inhibitor myrcludex-B, the nucleic acid polymer REP2139-Ca inhibiting HBV surface antigen secretion, the farnesyltransferase inhibitor lonafarnib that targets virus assembly, and a better tolerated interferon-interferon lambda., (Copyright © 2017. Published by Elsevier B.V.)

Hepatitis delta virus (HDV) is a minimalistic satellite virus of hepatitis B virus (HBV). HBV/HDV co-infection, i.e. "hepatitis D", is the most severe form of viral hepatitis. No effective therapy for HDV infection is available partly due to the fact that HDV is a highly host-dependent virus devoid of any potentially drugable enzyme encoded in its small genome. In this study we present a semi-automated method to evaluate HDV infection and replication under the influence of different drugs. We utilized a Huh-7/hNTCP cell culture based system in a 96-well plate format, an automated microscope and image acquisition as well as analysis with the CellProfiler software to quantify the impact of these drugs on HDV infection. For validation, three groups of potential anti-HDV agents were evaluated: To target ribozyme activity of HDV RNA, we screened ribozyme inhibitors but only observed marked toxicity. Testing innate antiviral mediators showed that interferons alpha-2a and beta-1a had a specific inhibitory effect on HDV infection. Finally, we screened a library of 160 human kinase inhibitors covering all parts of the human kinome. Overall, only inhibitors targeting the tyrosine kinase-like group had significant average anti-HDV activity. Looking at individual substances, kenpaullone, a GSK-3β and Cdk inhibitor, had the highest selective index of 3.44. Thus, we provide a potentially useful tool to screen for substances with anti-HDV activity and novel insights into interactions between HDV replication and the human kinome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We analyzed changes in hepatitis B virus and hepatitis delta virus (HDV) viral loads (VL) during tenofovir-containing antiretroviral therapy among patients with a replicating HDV infection in the Swiss HIV Cohort Study. Only 28.6% experienced a ≥2.0 log reduction in HDV RNA, and 14.3% had undetectable HDV VL within 5 years., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction of direct-acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral-targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell-based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP-mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan-genotypic anti-HBV activity and was also effective against a clinically relevant nucleoside analog-resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more-potent anti-HBV activity over PAC., Conclusion: PAC and its analogs represent a new class of anti-HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well-tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2017;65:1104-1116)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background & Aims: The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function., Methods: We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed., Results: We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC 50 . Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate., Conclusions: This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects., Lay Summary: In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)