Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D.

Background & Aims: Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown.

Quality-of-life scores improve after 96 weeks of PEG-IFNa-2a treatment of hepatitis D: An analysis of the HIDIT-II trial.

Background & Aims: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient-reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta.

Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis delta: Results from the HIDIT-II study.

The role of low levels of HDV-RNA during and after interferon therapy of hepatitis D is unknown. We re-analysed HDV RNA in 372 samples collected in the HIDIT-2 trial (Wedemeyer et al, Lancet Infectious Diseases 2019) with the Robogene assay (RA; Jena Analytics). Data were compared with the previously reported in-house assay (IA).

A transient early HBV-DNA increase during PEG-IFNα therapy of hepatitis D indicates loss of infected cells and is associated with HDV-RNA and HBsAg reduction.

HBV-DNA levels are low or even undetectable in the majority HDV-infected patients. The impact of PEG-IFNα on HBV-DNA kinetics in HDV-infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV-RNA-positive patients were randomized to receive PEG-IFNα-2a plus tenofovir-disoproxil-fumarate (PEG-IFNα/TDF, n = 59) or placebo (PEG-IFNα/PBO; n = 61) for 96 weeks.

Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study.

Background: Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis.

Methods: We analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis.

Optimisation of the use of APRI and FIB-4 to rule out cirrhosis in patients with chronic hepatitis B: results from the SONIC-B study.

Background: Ruling out the presence of cirrhosis is important for the management of chronic hepatitis B. We aimed to study and optimise the performance of two non-invasive indices for ruling out cirrhosis: the aspartate aminotransferase-platelet ratio index (APRI) and fibrosis score based on four factors (FIB-4).

Methods: We applied established cutoffs to rule in (APRI >2·00; FIB-4 >3·25) or rule out (APRI <1·00; FIB-4 <1·45) cirrhosis to data from eight global randomised trials that required baseline biopsy, and identified new cutoffs aiming for a sensitivity for detection of cirrhosis greater than 90% and a negative predictive value (NPV) of greater than 95% in the same dataset.

Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial.

Background: Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25-30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown.

Simultaneous hepatic and portal vein ligation induces rapid liver hypertrophy: A study in pigs.

Background: Liver hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection ("ALPPS procedure"). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection.

Methods: A pig model of portal vein occlusion was compared with the novel model of simultaneous portal and hepatic vein occlusion, where major hepatic veins draining the portal vein-deprived lobe were identified with intraoperative ultrasonography and ligated using pledgeted transparenchymal sutures.

Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies.

Background: Hepatitis C virus (HCV) direct-acting antiviral therapy is effective among people receiving opioid substitution therapy (OST), but studies are limited by small numbers of nongenotype 1 (GT1) patients. The aim of this study was to evaluate the treatment completion, adherence, SVR12, and safety of sofosbuvir-based therapies in HCV patients receiving and not receiving OST.

Methods: Ten phase 3 studies of sofosbuvir-based regimens included ION (ledipasvir/sofosbuvir ± ribavirin for 8, 12, or 24 weeks in GT1), ASTRAL (sofosbuvir/velpatasvir for 12 weeks in GT1-6), and POLARIS (sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir in GT1-6).

Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies.

Background & Aims: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1-6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir.

Methods: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1-3, ASTRAL-5 and POLARIS-2-3 studies.

Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1-6 and compensated cirrhosis or advanced fibrosis.

Background & Aims: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis.

Methods: This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

Background: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

Methods: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks.

Global epidemiology of HCV subtypes and resistance-associated substitutions evaluated by sequencing-based subtype analyses.

Background & Aims: HCV genotype, subtype, and presence of resistance-associated substitutions (RASs) are key determinants for the selection of direct-acting antiviral (DAA) treatment regimens. However, current HCV genotyping assays have limitations in differentiating between HCV subtypes, and RAS prevalence is largely undefined. The aim of this study was to investigate HCV epidemiology in 12,615 patient samples from 28 different countries across five geographic regions.

Sofosbuvir and ribavirin for genotype 2 HCV infected patients with cirrhosis: A real life experience.

Background & Aims: Sofosbuvir (SOF) and weight-based ribarivin (RBV) represented until recently the standard of care in hepatitis C virus (HCV) genotype (GT)2 patients. In registration studies 12-16weeks duration were associated with a 90% sustained virological response at 12weeks (SVR12). Real life cohorts showed lower SVR12 rates.

Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer.

Background: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.

Methods: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed.

Sofosbuvir and Velpatasvir Combination Improves Patient-reported Outcomes for Patients With HCV Infection, Without or With Compensated or Decompensated Cirrhosis.

Background & Aims: The combination of sofosbuvir and velpatasvir is used to treat patients with hepatitis C virus (HCV) infection of different genotypes. We compared the effects of this treatment regimen, with and without ribavirin, on outcomes reported by patients (patient-reported outcomes [PROs]) with HCV infection, with or without cirrhosis.

Methods: We performed a post hoc analysis of data collected from phase 3 clinical trials (ASTRAL-1, -2, -3, and -4) of 1701 patients infected with HCV of different genotypes treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks (n = 87), sofosbuvir with ribavirin for 12 or 24 weeks (n = 401), and ribavirin-free sofosbuvir and velpatasvir for 12 or 24 weeks (n = 1213).

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.

Background: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials.

Efficacy and Safety of Sofosbuvir/Velpatasvir in Patients With Chronic Hepatitis C Virus Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ASTRAL Trials.

In this analysis of the ASTRAL trials (non-opioid substitution therapy [OST], n = 984; OST, n = 51) evaluating the once-daily, pan-genotypic regimen of sofosbuvir/velpatasvir for hepatitis C virus infection, OST did not impact completion, adherence, sustained virologic response (SVR12), or safety. SVR12 was 96% (95% confidence interval, 87%, >99%) in those receiving OST.

Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: Results from ASTRAL-1 placebo-controlled trial.

Background & Aims: The new pan-genotypic regimen [sofosbuvir (SOF) and velpatasvir (VEL)] for hepatitis C virus (HCV) has been associated with high efficacy. The aim of this study was to assess patient-reported outcomes (PROs) of this regimen.

Methods: The PRO data (CLDQ-HCV, SF-36, FACIT-F, WPAI) came from the ASTRAL-1 study, a multicenter multinational blinded placebo-controlled phase 3 clinical trial of a fixed dose combination of SOF 400mg and VEL 100mg for patients with genotype 1, 2, 4, 5, and 6 compared to placebo for 12weeks.

On-treatment HCV RNA in patients with varying degrees of fibrosis and cirrhosis in the SOLAR-1 trial.

Background: In the Phase II SOLAR-1 study, 12 or 24 weeks of ledipasvir/sofosbuvir and ribavirin yielded high sustained virological response rates at 12 weeks (SVR12) in patients with chronic HCV infection and advanced liver disease, including untransplanted patients with decompensated cirrhosis and liver transplant recipients with all stages of liver disease.

Methods: We performed a post hoc analysis using data from this study to investigate associations between baseline characteristics and early on-treatment HCV RNA, and to determine the utility of early virological response (week 2 and 4) to predict SVR12. Serum HCV RNA was quantified using the Roche COBAS Ampliprep/Cobas TaqMan HCV Test, Version 2.

Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection.

Background: A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need.

Methods: We conducted a phase 3, double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks.

Evolution of hepatitis C virus quasispecies during repeated treatment with the NS3/4A protease inhibitor telaprevir.

In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.

Background: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials.

Methods: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only).

Anti-HDV IgM as a marker of disease activity in hepatitis delta.

Background: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.

Sofosbuvir and ribavirin in HCV genotypes 2 and 3.

Background: In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection.

Methods: We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks.