Sodium taurocholate cotransporting polypeptide (NTCP) polymorphisms may influence HDV RNA load and early response to bulevirtide.

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 log10 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 log10 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.

Blocking viral entry with bulevirtide reduces the number of HDV-infected hepatocytes in human liver biopsies.

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 0.9Log10 with 2 mg (n = 7), 1.1Log10 with 5 mg (n = 5) and 1.4 Log10 with 10 mg (n = 7) of BLV. At week 48, median reductions were 2.2Log10 with 2 mg (n = 27) and 2.7Log10 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.

Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase III randomized trial.

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 log10 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.

Patient-reported outcomes in chronic hepatitis delta: An exploratory analysis of the Phase III MYR301 trial of bulevirtide.

BACKGROUND & AIMS: Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD. METHODS: In an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS). RESULTS: Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale. CONCLUSION: PROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD. IMPACT AND IMPLICATIONS: Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03852719.

A 3-Year Course Of Bulevirtide Monotherapy May Cure Hdv Infection In Cirrhotics.

Bulevirtide has been recently conditionally approved by the European Medicines Agency for the treatment of Chronic Hepatitis Delta, but the ideal duration of therapy is unknown. Here we describe the first case of cure of Hepatitis Delta following 3 years of Bulevirtide monotherapy in a patient with compensated cirrhosis and esophageal varices. During the 72-week off-Bulevirtide follow-up, virological and biochemical responses were maintained. In the off-therapy liver biopsy, intrahepatic HDV RNA and Hepatitis D antigen were undetectable, <1% hepatocytes were Hepatitis B surface antigen positive while hepatitis B core antigen was negative. Grading and staging improved compared to pre-treatment biopsy.

No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta.

BACKGROUND & AIMS: Bulevirtide (BLV) is a HDV/HBV entry inhibitor that is associated with virologic response (responders, HDV-RNA undetectable or ≥2 log10 IU/ml decrease from baseline) in >50% of patients after a 24-week treatment. However, some patients only achieve a <1 log10 IU/ml decline in HDV-RNA after the 24-week treatment (non-responders). Here, we report a viral resistance analysis in participants receiving BLV monotherapy who were non-responders or experienced virologic breakthrough (VB, i.e., two consecutive increases in HDV-RNA of ≥1 log10 IU/ml from nadir or two consecutive HDV-RNA detectable results if previously undetectable) from the phase II MYR202 and phase III MYR301 study. METHODS: Deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, were performed for the participant with VB (n = 1) and non-responders (n = 20) at baseline (BL) and Week 24 (WK24). RESULTS: No amino acid exchanges associated with reduced susceptibility to BLV within the BLV-corresponding region or within HDAg were identified in isolates from any of the 21 participants at BL or at WK24. Although variants (HBV n = 1; HDV n = 13) were detected at BL in some non-responders or in the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was detected in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log10 IU/ml), and responders regardless of the presence of HBV and/or HDV polymorphisms. CONCLUSIONS: No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment. IMPACT AND IMPLICATIONS: This is the first study investigating the development of resistance in patients treated with BLV. Excluding resistance to BLV as an explanation for an insufficient decrease in HDV-RNA levels during BLV therapy is an important finding for patients, clinicians, and researchers. It demonstrates that BLV has a high barrier to resistance, indicating it is safe and suitable for long-term treatment, although long-term surveillance for resistance should be performed. Our results hint at other still unknown mechanisms as an explanation for the persistence of serum HDV-RNA during inhibition of viral entry. CLINICAL TRIAL NUMBERS: NCT03546621 and NCT03852719.

"Real world" efficacy of bulevirtide in HBV/HDV-related cirrhosis including people living with HIV: Results from the compassionate use programme at INMI Spallanzani in Rome, Italy.

OBJECTIVES: We describe the preliminary results of bulevirtide compassionate use in patients with hepatitis B and delta virus (HBV/HDV)-related cirrhosis and clinically significant portal hypertension, including those living with HIV. METHODS: We conducted a prospective observational study of consecutive patients. Clinical evaluation, liver function tests, bile acid levels, HDV-RNA, HBV-DNA, hepatitis B surface antigen, and liver and spleen stiffness were assessed at baseline and after treatment months 1, 2, 3, 4, 6, 9, and 12. HIV-RNA and CD4+/CD8+ count were assessed in people living with HIV. The first drug injection was administered under nurse supervision, and counselling was provided and adherence reviewed at each visit. RESULTS: In total, 13 patients (61.5% migrants) were enrolled. The median treatment duration was 11 months. At month 6, mean alanine aminotransferase (ALT) levels fell by 64.5% and mean liver and spleen stiffness decreased by 8.6 and 0.9 kPa, respectively. The mean baseline HDV-RNA was 3.34 log IU/mL and 5.10 log IU/mL in people without and with HIV (n = 5) (p = 0.28), respectively. A similar mean decline was observed in both groups: -2.06 log IU/mL and -1.93 log IU/mL, respectively (p = 0.87). A combined response (undetectable HDV RNA or ≥ -2 log IU/mL decline vs. baseline, with ALT normalization) was achieved in 66% of subjects without and in 60% of patients with HIV. Patients with HIV showed persistently undetectable HIV-RNA and a progressive increase in CD4+/CD8+ cells during treatment. No patient discontinued bulevirtide because of adverse effects. CONCLUSIONS: Preliminary results suggest that bulevirtide is feasible and well-tolerated in populations with difficult-to-treat conditions, such as those with HIV/HBV/HDV co-infection and migrants, when special attention is given to patient education. HDV-RNA decline during treatment was similar in people living with and without HIV.

Kinetics and predictive value of HBcrAg, HBV RNA and anti-HBc during bulevirtide treatment of chronic HDV-infected patients.

The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real-life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti-HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93-4.78) vs. 3.4 logU/ml (IQR 2-4.68), p=0.002). A similar trend was shown for anti-HBc between BL and 6M. Levels of HBcrAg or anti-HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti-HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes.

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA.

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+-taurocholate co-transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p = .0029) and evidence of portal hypertension (p = .0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = -0.577; p = .0078; rho = -0.635, p = .0026; rho = -0.577, p = .0077; rho = -0.519, p = .0191; rho = -0.564, p = .0119 and rho = -0.393, p = .087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV-induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed.

Bulevirtide-based treatment strategies for chronic hepatitis delta: A review.

Chronic hepatitis Delta (CHD) is a rare and severe form of chronic viral hepatitis. Until recently, the only therapeutic approach has been the off-label use of a 48 weeks course of PegInterferon alpha (PegIFNα), that was characterized by suboptimal efficacy and burdened by significant side effects that limited treatment applicability in patients with advanced liver disease. In July 2020, European Medicines Agency (EMA) conditionally approved the entry inhibitor Bulevirtde (BLV) at the dose of 2 mg/day for the treatment of adult patients with compensated CHD. Efficacy and safety of BLV in CHD have been evaluated in clinical trials either as monotherapy or in combination with PegIFNα. These results were confirmed by real-life studies, which also evaluated long-term BLV monotherapy in patients with advanced compensated cirrhosis. Notwithstanding these promising results there are still several issues to be addressed, such as the optimal duration of the treatment, the rates of off-therapy responses, as well as the long-term clinical benefits. This review summarizes updated and current literature data about clinical trials and real-life studies with BLV monotherapy and/or in combination with PegIFNα.

Beyond bulevirtide: Alternative therapeutic options for the management of hepatitis delta virus.

Hepatitis delta virus (HDV) is a small RNA virus which needs Hepatitis B Surface Antigen for its envelope, for entry into hepatocytes and secretion. HDV chronic infection affects around 12 million people worldwide. HDV infection is believed to be the most severe form of viral hepatitis, with a high risk of developing cirrhosis and hepatocellular carcinoma. Pegylated interferons has been used and recommended by guidelines, although not approved, with low efficacy and poor tolerability. Bulevirtide (entry inhibitor) has been recently conditionally approved by the European Medicines Agency. These treatments have many advantages, but they have also limitations since there are non-responders to these previous therapies. There is an urgent need to develop new drugs. In this article, we review antiviral treatments under development for HDV chronic infection (except bulevirtide reviewed in a specific article), including those in the HBV cure programme, outlining their respective mechanisms-of-action.

Treatment of hepatitis delta and HIV infection.

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15-25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct-acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow-up, we propose that HIV-HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta.

Bulevirtide for patients with compensated chronic hepatitis delta: A review.

Chronic hepatitis delta (CHD) affects approximately 10-20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end-stage liver disease, hepatocellular carcinoma). In the last 30 years, the only treatment option for CHD has been represented by the off-label administration of Interferon (or Pegylated Interferon)-alpha: antiviral treatment, however, resulted in suboptimal (20-30%) virological response and was burdened by several side effects, de facto contraindicating Interferon (IFN) administration in patients with more advanced liver disease. Recently, Bulevirtide (BLV), a first-in-class HBV-HDV entry inhibitor blocking Na+ -taurocholate co-transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real-life reports. In July 2020, BLV has granted conditional approval by EMA for treatment of compensated CHD, at the dose of 2 mg/day by self-administered subcutaneous injections. In Phase II and Phase III trials, BLV was evaluated at different doses (2 vs. 10 mg/day) for 24 or 48 weeks, either in monotherapy or in combination with PegIFN. Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%-83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%-78% ALT normalization. Combination therapy with PegIFN provided synergistic effects. These results were replicated in real-life studies and confirmed also in patients with advanced cirrhosis and clinically significant portal hypertension. BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids.

Emerging drugs for hepatitis D.

INTRODUCTION: Chronic hepatitis delta (CHD) is the most severe form of chronic viral hepatitis. Until recently, its treatment consisted of pegylated interferon alfa (pegIFN) use. AREAS COVERED: Current and new drugs for treating CHD. Virus entry inhibitor bulevirtide has received conditional approval by the European Medicines Agency. Prenylation inhibitor lonafarnib and pegIFN lambda are in phase 3 and nucleic acid polymers in phase 2 of drug development. EXPERT OPINION: Bulevirtide appears to be safe. Its antiviral efficacy increases with treatment duration. Combining bulevirtide with pegIFN has the highest antiviral efficacy short-term. The prenylation inhibitor lonafarnib prevents hepatitis D virus assembly. It is associated with dose-dependent gastrointestinal toxicity and is better used with ritonavir which increases liver lonafarnib concentrations. Lonafarnib also possesses immune modulatory properties which explains some post-treatment beneficial flare cases. Combining lonafarnib/ritonavir with pegIFN has superior antiviral efficacy. Nucleic acid polymers are amphipathic oligonucleotides whose effect appears to be a consequence of phosphorothioate modification of internucleotide linkages. These compounds led to HBsAg clearance in a sizable proportion of patients. PegIFN lambda is associated with less IFN typical side effects. In a phase 2 study it led to 6 months off treatment viral response in one third of patients.

Comparative effectiveness of seven interventions for chronic hepatitis D: a systematic review and network meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the effectiveness of seven major interventions [Bulevirtide (BLV), Interferon (IFN), Nucleoside analogs (NAs), BLV + IFN, BLV + NAs, IFN + NAs, and Placebo] to treat chronic hepatitis D. METHODS: We followed PRISMA-NMA guidelines, searched databases (Cochrane Library, PubMed, EMBASE, and Web Of Science) for eligible randomized controlled trials (RCTs), and applied STATA17.0 software to execute the meta-analysis. RESULTS: We included 14 randomized controlled trials (814 patients) comparing seven different interventions. The results of the network meta-analysis showed that: ① Sustained virological response (after 24 weeks of follow-up): Four intervention groups (BLV + IFN, IFN alone, IFN + NAs, and NAs alone) were effective (relative risk (RR) = 13.30, 95% confidence interval (Cl) [1.68,105.32], RR = 12.13, 95% Cl [1.46,101.04], RR = 5.05, 95% Cl [1.68,15.19], RR = 5.03, 95% Cl [1.66,15.20]), with no statistically significant differences between the four groups. The top three in probability rankings were: BLV + NAs, BLV + IFN, and BLV alone (surface under the cumulative ranking curve (SUCRA) = 86.8%, 80.3%, and 48.4%; ② Sustained biochemical response (after 24 weeks of follow-up): BLV + IFN and IFN were superior to BLV (RR = 14.71, 95% Cl [1.14,189.07], RR = 16.67, 95% Cl [1.39,199.52]). The top three were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 86.9%,81.2%, and 64.3%). ③ Histological response: NAs were superior to BLV (RR = 2.08, 95% Cl [1.10,3.93]), whereas the difference between other treatment regimens was not statistically significant, and the top three in the probability ranking were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 75.6%, 75.6%, and 61.8%). CONCLUSIONS: IFN, IFN + BLV, and IFN + NAs were effective in clearing HDV RNA and normalizing alanine aminotransferase levels; however, IFN and IFN + NAs had a high rate of viral relapse at 24 weeks post-treatment follow-up. There was no additional benefit of adding NAs to IFN therapy for chronic hepatitis D; however, the combination of IFN + BLV significantly improved short-term HDV RNA clearance, which showed strong synergistic effects. The seven regimens included in the study did not contribute significantly to liver histological improvement. Therefore, the IFN + BLV combination has the most potential as a treatment option to improve the long-term prognosis or even cure chronic hepatitis D. TRIAL REGISTRATION: This systematic evaluation and meta-analysis was registered with PROSPERO under the registration number: CRD42022314544.).

Safety and effectiveness of up to 3 years' bulevirtide monotherapy in patients with HDV-related cirrhosis.

The entry inhibitor bulevirtide (BLV) received conditional approval from the EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult-to-treat patients with HDV-related cirrhosis is presently unknown. Herein, we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to 3 years on a compassionate use program. Patients were also monitored for HBcrAg and HBV RNA levels, and HDV- and HBV-specific T-cell markers. In the patient who stopped BLV at week 48, after achieving a virological and biochemical response, the initial virological and biochemical rebound was followed by alanine aminotransferase normalization coupled with low HDV RNA and HBsAg levels. In the 2 patients treated continuously for 3 years, virological and biochemical responses were maintained throughout the treatment period even after dose reduction. In a patient with advanced compensated cirrhosis, liver function tests significantly improved, esophageal varices disappeared, and histological/laboratory features of autoimmune hepatitis resolved. Overall, no safety issues were recorded, as bile salt increase was asymptomatic. While serum HBV RNA levels remained undetectable in all patients, HBV core-related antigen levels showed a progressive, yet modest decline during long-term BLV treatment. No HDV-specific interferon-γ-producing T cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment. In conclusion, this report shows that continuous administration of BLV monotherapy for 3 years leads to excellent virological and clinical responses in patients with HDV-related cirrhosis who had contraindications to interferon-based therapies.

Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension.

BACKGROUND & AIMS: Bulevirtide (BLV) has recently been conditionally approved for the treatment of chronic hepatitis delta (CHD) in Europe, but its effectiveness and safety in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) are unknown. METHODS: Consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2 mg/day were enrolled in this single-center study. Clinical/virological characteristics were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. HDV RNA was quantified by Robogene 2.0 (lower limit of detection 6 IU/ml). RESULTS: Eighteen Caucasian patients with compensated cirrhosis and CSPH under nucleos(t)ide analogue treatment were enrolled: median (IQR) age was 48 (29-77) years, and 67% were male. Median (IQR) platelet count was 70 (37-227) x103/µl, liver stiffness measurement (LSM) 16.4 (7.8-57.8) kPa, alanine aminotransferase (ALT) 106 (32-222) U/L, HBsAg 3.7 (2.5-4.3) log IU/ml, HDV RNA 4.9 (3.3-6.6) log IU/ml. During 48 weeks of BLV monotherapy, HDV RNA declined by 3.1 (0.2-4.3) log IU/ml (p <0.001 vs. baseline), becoming undetectable in 5 patients (23%). A virological response was observed in 14 (78%) patients while a non-response was observed in 2 (11%). ALT decreased to 35 (15-86) U/L (p <0.001 vs. baseline), normalizing in 83% of patients. A combined response was observed in 67% of patients. Aspartate aminotransferase and gamma-glutamyltransferase levels significantly improved. Concerning liver function parameters, albumin values significantly increased and bilirubin remained stable. LSM significantly improved in patients with virological response, while platelet count was unchanged. None of the patients developed decompensating events or hepatocellular carcinoma. BLV was well tolerated, no patient discontinued treatment and the increase in bile acids was fully asymptomatic. CONCLUSIONS: A 48-week course of BLV 2 mg/day monotherapy is safe and effective even for difficult-to treat patients with HDV-related compensated cirrhosis and CSPH. LAY SUMMARY: Hepatitis delta virus (HDV) is associated with the most severe form of viral hepatitis. A new treatment for HDV called bulevirtide has recently received conditional approval for patients with chronic HDV infection. However, its safety and effectiveness in patients with more advanced liver disease is not known. Herein, we show that it is safe and effective in patients with HDV-related cirrhosis and clinically significant portal hypertension.

Bulevirtide with or without pegIFNα for patients with compensated chronic hepatitis delta: From clinical trials to real-world studies.

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, characterised by the greatest increase in risk of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Pegylated-interferon-α (pegIFNα), the only off-label therapeutic option, has been available for the last 30 years but is associated with suboptimal response rates and poor tolerability. Among the new treatment strategies under clinical evaluation, the entry inhibitor bulevirtide (BLV) is the only one that has received conditional approval from the European Medicines Agency (EMA); approval was granted in July 2020 for the treatment of adult patients with compensated CHD at a dose of 2 mg daily. Phase II studies and the week 24 interim analysis of a phase III study demonstrated the efficacy and safety of this treatment as a monotherapy or combined with pegIFNα. This favourable profile has been confirmed by recent real-world studies performed in Europe. As a long-term monotherapy, BLV has been successfully used to treat patients with advanced compensated cirrhosis. These encouraging yet preliminary findings must be viewed with caution as many critical issues related to this new antiviral strategy are still poorly understood, as summarised in this review. While waiting for new anti-HBV and anti-HDV drugs to become available for combination studies, BLV treatment is currently the only available anti-HDV therapeutic option that might improve the long-term prognosis of difficult-to-manage patients with CHD.

Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide-An Exploratory Phase I Clinical Trial.

Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges−Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans.

Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation.

The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.