The next decade will be a crucial period in the public health response to hepatitis C virus (HCV) infection. The rapid development of direct-acting antiviral (DAA) therapy for HCV infection has ...brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon provide near-optimal efficacy with well-tolerated short-duration, all-oral regimens. As the zenith in HCV therapeutic development approaches, there remain several key obstacles to the broad implementation of interferon-free DAA regimens. The extent of HCV screening and disease assessment, global and national public health prioritization, and drug pricing will determine the potential impact on disease burden derived from introduction of these exciting new HCV therapies. Public health partnerships and advocacy will be crucial to remove barriers to enhanced HCV treatment access.
Direct-acting antiviral (DAA) regimens are safe and effective at eradicating hepatitis C virus (HCV) infection. Unfortunately, DAAs remain expensive, so treatment of all HCV-infected patients would ...substantially affect health care costs. It is therefore important to continue to assess the hepatic and extrahepatic benefits of a DAA-induced sustained virologic response (SVR). A DAA-induced SVR reduces a patient’s risk of cirrhosis and hepatocellular carcinoma and extrahepatic manifestations of HCV infection; there are also data to indicate that an SVR can reduce mortality. SVR is a relevant clinical end point, but further analyses are required to confirm its importance among diverse HCV-infected populations and to document the public health benefits of HCV elimination at the population level. We review the evidence for the benefits associated with SVRs in different clinical settings and challenges to data collection.
Summary
Background Non‐alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing ...agents such as metformin may be beneficial for NASH.
Aim To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH.
Methods Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three‐point improvement in the histological NASH activity index.
Results Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement.
Conclusion Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss.
Since the identification of the hepatitis C virus, great strides have been made in the development of an antiviral therapy. As a crucial mediator of the innate antiviral immune response, ...interferon-alpha (IFN-alpha) was a natural choice for treatment. Whereas treatment with IFN-alpha alone achieved only modest success, the addition of the broad-spectrum antiviral agent ribavirin greatly improved responses. However, half of the infected individuals with chronic disease do not achieve sustained clearance of hepatitis C virus. To optimize current therapeutic strategies and to develop new therapies, a better understanding of the mechanism of action of IFN and ribavirin will be essential.
The treatment of HCV infection has evolved at an extremely rapid pace over the past few years. The development of direct-acting antiviral agents, which potently inhibit different stages in the viral ...life cycle, has led to the replacement of interferon with well-tolerated oral therapies with cure rates of >90% in most patient populations. Understanding the mechanisms of action of the various agents as well as related issues, including the molecular basis for resistance, helps to guide drug development and clinical use. In this Review, we provide a mechanistic description of NS3/4A protease inhibitors, nucleotide and non-nucleotide inhibitors of the NS5B viral polymerase and inhibitors of the NS5A protein, followed by a summary of clinical data from studies of each drug class alone and in combination. Remaining challenges in drug development efforts are also discussed.
Summary
Background
Treatment of hepatitis B virus (HBV) infection with current therapy suppresses HBV DNA, but loss of hepatitis B surface antigen (HBsAg; functional cure), is rare. Multiple ...compounds are under investigation.
Aims
To describe the pharmacology, including drug interactions, efficacy, safety and mechanisms of action of investigational compounds for HBV infection.
Methods
Descriptive review using PubMed and Google to identify literature/conference papers on investigational compounds (≥Phase 2) with data on efficacy and safety in HBV‐infected patients.
Results
Bulevirtide, JNJ‐56136379, ABI‐H0731, REP‐2139, and inarigivir decrease HBV DNA/RNA, with greater potency than current nucleos(t)ide analogues. REP‐2139 (25%‐75% of patients, 20‐48 weeks treatment) and inarigivir (26% of patients, 12‐24 weeks treatment) induce HBsAg loss. ARO‐HBV reduced (>1.5 log10 UI/mL) HBsAg in 85% of patients (12 weeks treatment). There are some safety concerns with investigational agents (e.g., increased bile acids with bulevirtide, and liver enzyme flares with REP‐2139) which will require a risk benefit assessment compared with current therapies. Single and multidose pharmacokinetic data are available for bulevirtide, JNJ‐56136379, ABI‐H0731; no such data are available for REP‐2139, ARO‐HBV, inarigivir. Initial drug interaction assessments have been performed with bulevirtide and inarigivir (only in vitro).
Conclusions
There are promising investigational therapies for HBV infection. Increasing the potential for HBsAg loss may result in more patients achieving functional cure. However, many knowledge gaps remain such as pharmacokinetics in those with HBV, cirrhosis and renal impairment but also the interaction potential between investigational therapies, risk‐benefit profiles, and potential for drug interactions with medications used to treat comorbidities associated with aging.
Despite remarkable therapeutic advances, hepatitis C virus (HCV) infection continues to be a major global problem. While the development of highly effective direct-acting antivirals has ensured that ...almost all those who are treated achieve viral cure, progress toward HCV elimination globally has stalled due to challenges upstream of treatment in the cascade of care, namely diagnosis and linkage to care. The major challenge continues to be the relative complexity of HCV diagnosis with the current requirement for a confirmatory HCV RNA test after an initial antibody-positive result. In this review, challenges with the current paradigm are highlighted with a focus on new technologies, as well as simple strategies using existing tools, which may simplify diagnosis and improve linkage to care and treatment. To achieve HCV elimination, improvements in the HCV diagnostics field to allow for a simple single-step diagnosis are required.
Redox-active self-assembled monolayers (SAMs) provide an excellent platform for investigating electron transfer kinetics. Using a well-defined bridge, a redox center can be positioned at a fixed ...distance from the electrode and electron transfer kinetics probed using a variety of electrochemical techniques. Cyclic voltammetry, AC voltammetry, electrochemical impedance spectroscopy, and chronoamperometry are most commonly used to determine the rate of electron transfer of redox-activated SAMs. A variety of redox species have been attached to SAMs, and include transition metal complexes (e.g., ferrocene, ruthenium pentaammine, osmium bisbipyridine, metal clusters) and organic molecules (e.g., galvinol, C
60). SAMs offer an ideal environment to study the outer-sphere interactions of redox species. The composition and integrity of the monolayer and the electrode material influence the electron transfer kinetics and can be investigated using electrochemical methods. Theoretical models have been developed for investigating SAM structure. This review discusses methods and monolayer compositions for electrochemical measurements of redox-active SAMs.
Interferons induced early after SARS-CoV-2 infection are crucial for shaping immunity and preventing severe COVID-19. We previously demonstrated that injection of pegylated interferon-lambda ...accelerated viral clearance in COVID-19 patients (NCT04354259). To determine if the viral decline is mediated by enhanced immunity, we assess in vivo responses to interferon-lambda by single cell RNA sequencing and measure SARS-CoV-2-specific T cell and antibody responses between placebo and interferon-lambda-treated patients. Here we show that interferon-lambda treatment induces interferon stimulated genes in peripheral immune cells expressing IFNLR1, including plasmacytoid dendritic cells and B cells. Interferon-lambda does not affect SARS-CoV-2-specific antibody levels or the magnitude of virus-specific T cells. However, we identify delayed T cell responses in older adults, suggesting that interferon-lambda can overcome delays in adaptive immunity to accelerate viral clearance in high-risk patients. Altogether, interferon-lambda offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral adaptive immunity.
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