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Liver disease in the UK stands out as the one glaring exception to the vast improvements made during the past 30 years in health and life expectancy for chronic disorders such as stroke, heart disease, and many cancers. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost five-times.

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1-6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus <65 years. Of the 2369 patients enrolled, 328 (14%) were aged ≥65 years. Among patients aged ≥65 years, 42% and 34% had GT1 and GT2, respectively; 40% were treatment-experienced and 20% had compensated cirrhosis. Glecaprevir/pibrentasvir treatment resulted in SVR12 rates of 97.9% (95% CI, 96.3-99.4; n/N = 321/328) for patients aged ≥65 years and 97.3% (95% CI, 96.6-98.0; n/N = 1986/2041) for patients aged <65 years. The rates were not significantly different between the two age groups (P = 0.555). DAA-related AEs leading to treatment discontinuation, or serious AEs were similarly rare (<0.5%) for patients ≥65 and <65 years old. Glecaprevir/pibrentasvir is an efficacious and well-tolerated treatment option for patients aged ≥65 years with chronic HCV infection.

Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782. Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1–38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. Janssen Infectious Diseases–Diagnostics.

ObjectivesTo estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer.MethodsWe employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England.ResultsDeclines in urgent referrals (median=−70.4%) and chemotherapy attendances (median=−41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=−44.5%) and chemotherapy attendances (median=−31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity.ConclusionsDramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are 'primed' with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNα-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNα only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNγ and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNα priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB.

•Hepatitis C virus (HCV) is a blood-borne virus that affects at least 50 million people globally.•Most people exposed to HCV develop chronic infection and are at risk of liver cirrhosis that develops over decades of infection and may lead to hepatocellular carcinoma.•Chronic HCV infection is associated with a variety of non-specific symptoms including fatigue and concentration difficulties.•HCV treatment with virtually side effect free oral drugs cures the infection in >95% of infected people.•Hepatitis C infection is common in marginalised communities (migrants, people who are homeless and people who use drugs) but with appropriate support, all can be effectively treated. Hepatitis C virus (HCV) remains a significant global health challenge, affecting an estimated 50 million people. In most cases, infection becomes chronic, with long-term risks including liver cirrhosis and hepatocellular carcinoma. Beyond hepatic complications, many individuals experience non-specific symptoms such as fatigue and cognitive impairment, which can significantly impact daily functioning. The introduction of direct-acting antivirals has transformed HCV management, offering cure rates above 95% with minimal side effects. However, HCV continues to disproportionately affect marginalised groups, including people who inject drugs, migrants, and those experiencing homelessness. With targeted support and inclusive care pathways, these populations can be effectively treated. In this review, we examine the latest developments in HCV care, including current treatment protocols, emerging clinical trial data, and future directions – particularly the pursuit of a preventative vaccine. Achieving HCV elimination will require not only continued therapeutic innovation, but also a commitment to equality and equity in healthcare delivery.

Chronic infection with hepatitis C virus (HCV) is a major healthcare problem, affecting an estimated 170 million people worldwide. Interferon-alpha has formed the basis of treatment regimens since the identification of HCV, either alone or in conjunction with the nucleoside analogue ribavirin. The relatively recent introduction of pegylated forms of interferon-alpha, with greater stability and in vivo activity, has substantially improved sustained virological response (SVR) rates compared with unmodified interferon-alpha, with SVR rates of 35-66% when used in conjunction with ribavirin in randomized controlled trials. Two pegylated interferon (peginterferon)-alpha molecules are commercially available for the treatment of chronic hepatitis C, and these differ in the size and nature of the covalently attached polyethylene glycol (PEG) moiety, with resulting differences in pharmacokinetics and in dosing regimens. Peginterferon-alpha-2b has a linear 12 kDa PEG chain covalently attached primarily to histidine-34 of interferon-alpha-2b via an unstable urethane bond that is subject to hydrolysis once injected, releasing native interferon-alpha-2b. The branched, 40 kDa PEG chain of peginterferon-alpha-2a is covalently attached via stable amide bonds to lysine residues of interferon-alpha-2a, and circulates as an intact molecule. Consequently, peginterferon-alpha-2a has a very restricted volume of distribution, longer half-life and reduced clearance compared with native interferon-alpha-2a, and can be given once weekly independently of bodyweight. Peginterferon-alpha-2b has a shorter half-life in serum than peginterferon-alpha-2a and requires bodyweight-based dosing. The majority of head-to-head randomized controlled trials, including the large, randomized IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial (n = 3070), demonstrated similar SVR rates for peginterferon-alpha-2a and peginterferon-alpha-2b (41% vs 39% in IDEAL), in combination with ribavirin; however, two randomized controlled trials (n = 431 and 320) demonstrated a statistically significant benefit for peginterferon-alpha-2a (66% vs 54%, and 69% vs 54%). Furthermore, two large retrospective studies and one prospective observational study in real-life settings have shown a significant benefit for peginterferon-alpha-2a versus peginterferon-alpha-2b, although SVR rates were generally lower than those seen in controlled trials. The use of interferon-alpha with or without ribavirin is frequently associated with a range of adverse effects, including influenza-like symptoms, haematological changes and neuropsychiatric disturbances, and this is true also of the peginterferons, with similar levels of adverse events, dose reduction and discontinuation from treatment. Peginterferon-alpha-2a and peginterferon-alpha-2b appear from comparative studies to be similarly tolerated, with few differences of clinical significance noted. Peginterferon plus ribavirin, as the standard of care for patients with chronic hepatitis C, may in the future form the basis of improved treatment regimens that include new, targeted anti-HCV agents to increase SVR rates even further.

Chris Spencer, Eleanor Barnes and colleagues use human genotyping arrays and whole-genome viral sequencing to perform a systematic genome-to-genome study of 542 individuals chronically infected with hepatitis C virus (HCV). They show that both HLA alleles and genes encoding factors of the innate immune system drive viral genome polymorphism and that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific polymorphism encoded in the HCV polyprotein. Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.

Chronic infection with hepatitis C virus (HCV) is a major healthcare problem, affecting an estimated 170 million people worldwide. Interferon-α has formed the basis of treatment regimens since the identification of HCV, either alone or in conjunction with the nucleoside analogue ribavirin. The relatively recent introduction of pegylated forms of interferon-α, with greater stability and in vivo activity, has substantially improved sustained virological response (SVR) rates compared with unmodified interferon-α, with SVR rates of 35–66% when used in conjunction with ribavirin in randomized controlled trials. Two pegylated interferon (peginterferon)-α molecules are commercially available for the treatment of chronic hepatitis C, and these differ in the size and nature of the covalently attached polyethylene glycol (PEG) moiety, with resulting differences in pharmacokinetics and in dosing regimens. Peg-interferon-α-2b has a linear 12 kDa PEG chain covalently attached primarily to histidine-34 of interferon-α-2b via an unstable urethane bond that is subject to hydrolysis once injected, releasing native interferon-α-2b. The branched, 40 kDa PEG chain of peginterferon-α-2a is covalently attached via stable amide bonds to lysine residues of interferon-α-2a, and circulates as an intact molecule. Consequently, peginterferon-α-2a has a very restricted volume of distribution, longer half-life and reduced clearance compared with native interferon-α-2a, and can be given once weekly independently of bodyweight. Peginterferon-α-2b has a shorter half-life in serum than peginterferon-α-2a and requires bodyweight-based dosing. The majority of head-to-head randomized controlled trials, including the large, randomized IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial (n = 3070), demonstrated similar SVR rates for peginterferon-α-2a and peginterferon-α-2b (41% vs 39% in IDEAL), in combination with ribavirin; however, two randomized controlled trials (n = 431 and 320) demonstrated a statistically significant benefit for peginterferon-α-2a (66% vs 54%, and 69% vs 54%). Furthermore, two large retrospective studies and one prospective observational study in real-life settings have shown a significant benefit for peginter-feron-α-2a versus peginterferon-α-2b, although SVR rates were generally lower than those seen in controlled trials. The use of interferon-α with or without ribavirin is frequently associated with a range of adverse effects, including influenza-like symptoms, haematological changes and neuropsychiatric disturbances, and this is true also of the peginterferons, with similar levels of adverse events, dose reduction and discontinuation from treatment. Peginterferon-α-2a and peginterferon-α-2b appear from comparative studies to be similarly tolerated, with few differences of clinical significance noted. Peginterferon plus ribavirin, as the standard of care for patients with chronic hepatitis C, may in the future form the basis of improved treatment regimens that include new, targeted anti-HCV agents to increase SVR rates even further.