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Acta Pharmaceutica Sinica. B Jan 2016Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA)... (Review)
Review
Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir (Sovaldi), simeprevir (Olysio), and fixed combination medicines Harvoni and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the "cure HCV" goal has become a reality. Concerns remain about drug resistance mutations and the high cost of these drugs. The investigation of new HCV drugs is progressing rapidly; fixed dose combination medicines in phase III clinical trials include Viekirax, asunaprevir+daclatasvir+beclabuvir, grazoprevir+elbasvir and others.
PubMed: 26904396
DOI: 10.1016/j.apsb.2015.09.008 -
Cell Research Dec 2023Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including...
Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.
Topics: Humans; Biological Transport; Cryoelectron Microscopy; Liver; Liver-Specific Organic Anion Transporter 1; Organic Anion Transporters; Thyroid Hormones
PubMed: 37674011
DOI: 10.1038/s41422-023-00870-8 -
Visceral Medicine Apr 2016Treatment of chronic hepatitis C infection is most urgent in patients with severe liver fibrosis and cirrhosis because of the high risk of decompensation, hepatocellular... (Review)
Review
BACKGROUND
Treatment of chronic hepatitis C infection is most urgent in patients with severe liver fibrosis and cirrhosis because of the high risk of decompensation, hepatocellular carcinoma, and consecutively death. The development and approval of several direct-acting antiviral drugs (DAA) in the past years has revolutionized antiviral therapy especially for patients with liver cirrhosis.
METHODS
This review will focus on recent data from clinical trials and recommendations for the therapy of hepatitis C-infected patients with compensated cirrhosis.
RESULTS
Clinical data for cirrhotic patients mainly exist for a combination of the nucleotide analog sofosbuvir with either a protease inhibitor (simeprevir) or an NS5A inhibitor (daclatasvir, ledipasvir) or a three-DAA combination consisting of an NS3 protease inhibitor, an NS5A inhibitor, and a non-nucleoside NS5B inhibitor (paritaprevir/ritonavir, ombitasvir, and dasabuvir). Rates of sustained virologic response in patients with compensated cirrhosis are comparable to patients without cirrhosis; however, the addition of ribavirin and/or longer treatment durations are especially recommended when other negative predictors are present, such as prior treatment failure, features of advanced cirrhosis, or the presence of baseline resistance.
CONCLUSION
Nowadays, a highly active, short, and safe interferon-free treatment regimen is available for almost all patients.
PubMed: 27413726
DOI: 10.1159/000445330 -
BMJ (Clinical Research Ed.) Jul 2014Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of... (Review)
Review
Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.
Topics: Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Uridine Monophosphate; Viral Nonstructural Proteins
PubMed: 25002352
DOI: 10.1136/bmj.g3308 -
BMJ Clinical Evidence Jun 2015About 60% to 85% of people infected with hepatitis C virus will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population. (Review)
Review
INTRODUCTION
About 60% to 85% of people infected with hepatitis C virus will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.
METHODS AND OUTCOMES
We conducted a systematic overview and aimed to answer the following clinical questions: What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection without cirrhosis? What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection with cirrhosis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this review).
RESULTS
After deduplication and removal of conference abstracts, 30 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 11 studies and the further review of 19 full publications. Of the 19 full articles evaluated, two systematic reviews and one RCT were added. We performed a GRADE evaluation for two PICO combinations.
CONCLUSIONS
In this systematic overview, we categorised the efficacy for 12 different intervention/comparison combinations, based on information relating to the effectiveness and safety of sofosbuvir (with or without ribavirin), sofosbuvir (with or without ribavirin) plus ledipasvir, and sofosbuvir (with or without ribavirin) plus simeprevir, all in people with and without cirrhosis.
Topics: Antiviral Agents; Hepatitis C, Chronic; Humans; Treatment Outcome
PubMed: 26107930
DOI: No ID Found