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See the retraction notice E3S Web of Conferences 538, 00001 (2024), https://doi.org/10.1051/e3sconf/202453800001

Background: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB)., Aims: Here, we report the studies' final 8-year results., Methods: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping., Results: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFR CG ) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFR CG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF., Conclusion: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance., Clinicaltrials: gov numbers NCT01940341 and NCT01940471., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: The results from 2 phase 3 studies, through 2 years, in chronic hepatitis B infection showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. We report updated results through 5 years., Methods: Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B infection with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, and serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses., Results: Of 1,298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA <29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median estimated glomerular filtration rate (by using Cockcroft-Gault) declined <2.5 mL/min, and mean declines of <1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF., Discussion: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles., Aim: To evaluate how these changes affect cardiovascular risk., Methods: This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs., Results: Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events., Conclusion: Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Bulevirtide (BLV) is a small lipopeptide agent that specifically binds to the sodium taurocholate cotransporting polypeptide (NTCP) bile salt transporter and HBV/HDV receptor on the surface of human hepatocytes and inhibits HDV and HBV entry. As a satellite virus of HBV, HDV virions are formed after assembly of HDV RNA with the HBV envelope proteins (HBsAg). Because both viruses exist as eight different genotypes, this creates a potential for high diversity in the HBV/HDV combinations. To investigate the sensitivity of various combinations of HBV/HDV genotypes to BLV, clinical and laboratory strains were assessed., Methods: For the laboratory strains, the different envelopes from HBV genotypes A through H were combined with HDV genotypes 1-8 in cotransfection assays. Clinical plasma isolates were obtained from clinical studies and academic collaborations to maximise the diversity of HBV/HDV genotypes tested., Results: The mean BLV EC 50 against HDV laboratory strains ranged from 0.44 to 0.64 nM. Regardless of HBV and HDV genotypes, the clinical isolates showed similar sensitivities to BLV with mean values that ranged from 0.2 to 0.73 nM., Conclusions: These data support the use of BLV in patients infected with any HBV/HDV genotypes., Impact and Implications: This study describes the potent activity of BLV against multiple laboratory strains spanning all HBV/HDV A-H/1-8 genotype combinations and the most diverse collection of HDV clinical samples tested to date, including HBV/HDV genotype combinations less frequently observed in the clinic. Overall, all isolates and laboratory strains displayed similar in vitro nanomolar sensitivity to BLV. This broad-spectrum antiviral activity of BLV has direct implications on potential simplified treatment for any patient infected with HDV, regardless of genotype, and supports the new 2023 EASL Clinical Practice Guidelines on HDV that recommend antiviral treatment for all patients with CHD., Competing Interests: DA and JH report no conflicts of interest. RMat, YL, SX, SC, RM, SM, TAe, BH, TY, LM, DH, AS, RMar, DM, CR, EM, CM, and HM are employees and stockholders of Gilead Sciences. Tas and PL are consultants for Gilead Sciences. SU is a co-applicant and co-inventor on patents protecting Hepcludex (bulevirtide/Hepcludex) and consultant for Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Interstitial lung disease (ILD) has been recognized as an extrahepatic manifestation ofprimary biliary cholangitis (PBC), althoughlimited data are available on its prevalence and clinical significance. Therefore, we evaluated the occurrence and clinical features of ILD in a cohort of PBC patients. Ninety-three individuals without concomitant rheumatic diseases were enrolled in our prospective cohort study. All patients underwent chest high-resolution computed tomography (HRCT). Liver-related and lung-related survival wereassessed. A lung-related outcome was defined as death from ILD complications; a liver-related outcome was defined as liver transplantation or death from liver cirrhosis complications. HRCT findings suggestive ofILD were detected in 38 patients (40.9%). A sarcoid-like pattern of PBC-associated ILD was the most frequent, followed by subclinical ILD and organizing pneumonia. Patients with ILD were less likely to have liver cirrhosis and liver-related symptoms and presented with higher serum immunoglobulin M(IgM) and M2 subtype antimitochondrial antibodies (AMA-M2) positivity rates. In a multivariate analysis, the absence of liver disease symptoms at the disease presentation (OR 11.509; 95% CI 1.210-109.421; p = 0.033), the presence of hepatic non-necrotizing epithelioid cell granulomas (OR 17.754; 95% CI 1.805-174.631; p = 0.014), higher serum IgM (OR 1.535; 95% CI 1.067-2.208; p = 0.020) and higher blood leukocyte count (OR 2.356; 95% CI 1.170-4.747; p = 0.016) were independent risk factors associated with ILD in PBC. More than a third of patients with ILD showed no respiratory symptoms, and only one ILD-related death occurred during a follow-up of 29.0 months (IQR 11.5; 38.0). Patients with ILD had better liver transplant-free survival.ILD in PBC had a benign course and was associated with a lower liver disease severity. PBC-associated ILD should be included in a list of differential diagnoses of ILD.

Objectives: Due to limited hepatitis C virus (HCV) sequence availability from patients in Russia, the relationship between subtypes and baseline resistance-associated substitutions (RAS) to direct antiretroviral treatment outcome is not fully understood., Methods: Deep sequencing of HCV NS3, NS5A, and NS5B sequences was performed on plasma HCV samples from 412 direct-acting antiviral (DAA)-naïve patients from Russia. Phylogenetic analysis was performed to investigate sequence similarities between HCV strains from Russia, Asia, Europe, and North America. Pretreatment HCV RAS was assessed with a 15% cutoff., Results: HCV genotype GT1b and GT3a sequences in Russia were related to strains in Europe and Asia. The prevalence of GT1a and GT2a was low in Russia. In GT1b, the prevalence of NS5A Y93H was lower in Russia (6%) compared with Asia (15%). The prevalence of NS5B L159F was similar between Russia and Europe (26-39%). GT3a RAS prevalence was similar between Russia and Asia, Europe, and North America. The 2k/1b recombinant strain in Russia was related to strains from Europe. A higher prevalence of the NS5A RAS L31M (10%) was observed in 2k/1b sequences compared to GT1b (1-6%)., Conclusions: The prevalence of RASs and the phylogenetic analysis showed similarities in HCV strains between Russia, Europe, and North America. This information may be useful for HCV regimens in Russia., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The hepatitis C virus-positive (HCV+) mixed cryoglobulinaemia (MC) is associated with haematological alterations such as monoclonal B-cell lymphocytosis or non-Hodgkin lymphomas (NHLs). Antiviral therapy for MC, based on interferon and ribavirin, has been shown to be able to eliminate the viral replication as well as the B-cell monoclonal alterations. Many studies have reported the efficacy of direct-acting antivirals (DAAs) in the treatment of HCV+ MC. However, some authors noticed the persistence of haematological diseases despite HCV eradication. To verify the effects of DAAs on B-cell proliferation, we evaluated 67 patients with HCV+ MC. Six patients had an overt NHL and 30% had monoclonal B-lymphocytosis. In 20% of the patients, the mutation L265P of the myeloid differentiation factor 88 (MYD88) gene was detected in peripheral blood. All patients had negative HCV viraemia at week 12; one had a breakthrough, while two cases relapsed. A complete clinical response of vasculitis was seen in 60% of the patients. Among the six patients with NHL, one showed a complete response, whereas in the others there were no changes in the number and size of the nodes. Among the patients carrying a clonal population in peripheral blood, only 22% became negative. These data indicate that DAAs are not able to eliminate the clonal alterations induced by HCV in a large proportion of cases., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: In both Russia and Sweden, the dominant hepatitis C virus (HCV) is genotype 1, but around one-third of patients have genotype 3 infection. For such countries, HCV genotype testing is recommended prior to therapy. An effective pangenotypic therapy may potentially eliminate the need for genotyping. In this study, we evaluated the efficacy and safety of sofosbuvir/velpatasvir for 12 weeks in patients from Russia and Sweden., Methods: In an open-label, single-arm phase-3 study, patients could have HCV genotype 1-6 infection and were treatment-naïve or interferon treatment-experienced. All patients received sofosbuvir/velpatasvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12)., Results: Of 122 patients screened, 119 were enrolled and treated. Overall, half (50%) were male, 18% had cirrhosis, and 24% had failed prior interferon-based therapy. In total, 66% of patients were infected with HCV genotype 1 (59% 1b and 7% 1a), 6% with genotype 2, and 29% with genotype 3. The overall SVR12 rate was 99% (118/119, 95% confidence interval 95-100%). One treatment-experienced patient infected with HCV genotype 3 experienced virologic relapse after completing treatment. The most common adverse events were headache (16%) and fatigue (7%). Serious adverse events were observed in four patients, but none were related to treatment. No patients discontinued treatment due to adverse events., Conclusion: Sofosbuvir/velpatasvir as a pangenotypic treatment for 12 weeks was highly effective in patients from Russia and Sweden infected with HCV genotypes 1, 2, or 3. Sofosbuvir/velpatasvir was safe and well-tolerated. Clinical trial number: ClinicalTrials.gov NCT02722837.