Natural history of chronic hepatitis C

Seeff, Leonard B.

doi:10.1053/jhep.2002.36806

Cited by 790 publications

(600 citation statements)

References 95 publications

(126 reference statements)

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“…Following exposure and an acute, usually asymptomatic infection, only 20% of individuals clear the virus, while up to 80% develop a chronic infection. Over an extended period of decades, infected patients are at high risk of developing severe liver disease which may include steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (3). In fact, HCV is the leading cause of liver transplantation in the United States (4,5).…”

mentioning

confidence: 99%

Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread

Barretto

Sáinz

Hussain

et al. 2014

J Virol

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Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, "cellfree" entry of infectious extracellular virions that have been released by infected cells and direct "cell-to-cell" transmission. Here, we examined host cell requirements for HCV spread and found that the cholesterol uptake receptor NPC1L1, which we recently identified as being an antiviral target involved in HCV cell-free entry/spread, is also required for the cell-to-cell spread. In contrast, the very low density lipoprotein (VLDL) pathway, which is required for the secretion of cell-free infectious virus and thus has been identified as an antiviral target for blocking cell-free virus secretion/spread, is not required for cell-to-cell spread. Noting that HCV cell-free and cell-to-cell spread share some common factors but not others, we tested the therapeutic implications of these observations and demonstrate that inhibitors that target cell factors required for both forms of HCV spread exhibit synergy when used in combination with interferon (a representative inhibitor of intracellular HCV production), while inhibitors that block only cell-free spread do not. This provides insight into the mechanistic basis of synergy between interferon and HCV entry inhibitors and highlights the broader, previously unappreciated impact blocking HCV cell-to-cell spread can have on the efficacy of HCV combination therapies. IMPORTANCEHCV can spread to naive cells using distinct mechanisms: "cell-free" entry of extracellular virus and direct "cell-to-cell" transmission. Herein, we identify the host cell HCV entry factor NPC1L1 as also being required for HCV cell-to-cell spread, while showing that the VLDL pathway, which is required for the secretion of cell-free infectious virus, is not required for cell-to-cell spread. While both these host factors are considered viable antiviral targets, we demonstrate that only inhibitors that block factors required for both forms of HCV entry/spread (i.e., NPC1L1) exhibit synergy when used in combination with interferon, while inhibitors that block factors required only for cell-free spread (i.e., VLDL pathway components) do not. Thus, this study advances our understanding of HCV cell-to-cell spread, provides mechanistic insight into the basis of drug synergy, and highlights inhibition of HCV spread as a previously unappreciated consideration in HCV therapy design.

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mentioning

confidence: 99%

Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread

Barretto

Sáinz

Hussain

et al. 2014

J Virol

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“…Around 50%-80% of persons with acute hepatitis C will develop CHC infection, and 5%-25% of them reportedly progress to cirrhosis after 20-25 years [78] . Persons with cirrhosis are at risk for developing end-stage liver disease as well as HCC [79] .…”

Section: Treatmentmentioning

confidence: 99%

Hepatitis C virus: Virology, diagnosis and treatment

2015

WJH

161

114

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More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these antiviral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection. Core tip: Understanding the general properties of hepatitis C virus (HCV) viral RNA and proteins facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. To 2014, in addition to pegylated interferon and ribavirin, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration to treat HCV infections. The majority of HCV infections can be cured by these anti-viral treatments. An efficient prophylactic vaccine will be the next challenge in the fight against HCV infection. REVIEWSubmit a

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“…Exclusion criteria included: decompensated liver disease, hemoglobin < 13 g·dL -1 for men and <12 g·dL -1 for women, white blood cell count of <3000/mm 3 , neutrophil count of <1500/mm 3 , or platelet count of <100,000/ mm 3 . Patients who had had hepatitis B surface antigen (HBsAg), autoimmune hepatitis, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, aalcoholic liver disease, and drug induced liver disease, active Schistosomiasis, or hepatic tumors were excluded.…”

Section: Selection Of Patientsmentioning

confidence: 99%

“…About 85% of those exposed to HCV become chronically infected and only 15% clear the virus. Chronic hepatitis and liver cirrhosis have been documented in 70% and 20%, respectively, of those chronically infected [2,3]. Egypt has an overall HCV antibody prevalence around 15% in the general population [4][5][6][7] and genotype 4 has been identified in about 90% of HCV isolates [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%