Assessing the validity of surrogate endpoints in the context of a controversy about the measurement of effectiveness of hepatitis C virus treatment

2018 ◽  
Vol 23 (2) ◽  
pp. 50-53 ◽  
Author(s):  
Claudia C Dobler ◽  
Rebecca L Morgan ◽  
Yngve Falck-Ytter ◽  
Victor M Montori ◽  
M Hassan Murad
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Low Density Lipoprotein ◽  
Sustained Viral Response ◽  
Density Lipoprotein ◽  
Surrogate Endpoint ◽  
Glycated Haemoglobin ◽  
Surrogate Endpoints ◽  
Indirect Measures ◽  
Based Medicine

Surrogate endpoints are often used in clinical trials, as they allow for indirect measures of outcomes (eg, shorter trials with less participants). Improvements in surrogate endpoints (eg, reduction in low density lipoprotein cholesterol, normalisation of glycated haemoglobin) achieved with an intervention are, however, not always associated with improvements in patient-important outcomes. The common tendency in evidence-based medicine is to view results based on surrogate endpoints as less certain than results based on long term, final patient-important outcomes and rate them as ‘lower quality evidence’. However, careful appraisal of the validity of a surrogate endpoint as a measure of the final, patient-important outcome is more useful than an automatic judgement. In this guide, we use a contemporary and currently highly debated example of the surrogate endpoint ‘sustained viral response’ (ie, viral eradication considered to represent successful treatment) in patients treated for chronic hepatitis C virus. We demonstrate how the validity of a surrogate endpoint can be critically appraised to assess the quality of the evidence (ie, the certainty in estimates) and the implications for decision-making.

scholarly journals Hepatitis C virus entry into the hepatocyte

2011 ◽  
Vol 6 (6) ◽  
pp. 933-945 ◽  
Author(s):  
Sandrine Belouzard ◽  
Laurence Cocquerel ◽  
Jean Dubuisson
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Current Knowledge ◽  
Virus Entry ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Surface Proteins ◽  
Enveloped Virus ◽  
Early Endosomes

AbstractHepatitis C virus (HCV) is a small enveloped virus with a positive stranded RNA genome belonging to the Flaviviridae family. The virion has the unique ability of forming a complex with lipoproteins, which is known as the lipoviroparticle. Lipoprotein components as well as the envelope proteins, E1 and E2, play a key role in virus entry into the hepatocyte. HCV entry is a complex multistep process involving sequential interactions with several cell surface proteins. The virus relies on glycosaminoglycans and possibly the low-density lipoprotein receptors to attach to cells. Furthermore, four specific entry factors are involved in the following steps which lead to virus internalization and fusion in early endosomes. These molecules are the scavenger receptor SRB1, tetraspanin CD81 and two tight junction proteins, Claudin-1 and Occludin. Although they are essential to HCV entry, the precise role of these molecules is not completely understood. Finally, hepatocytes are highly polarized cells and which likely affects the entry process. Our current knowledge on HCV entry is summarized in this review.

scholarly journals Infectivity of Hepatitis C Virus Is Influenced by Association with Apolipoprotein E Isoforms

2010 ◽  
Vol 84 (22) ◽  
pp. 12048-12057 ◽  
Author(s):  
Takayuki Hishiki ◽  
Yuko Shimizu ◽  
Reiri Tobita ◽  
Kazuo Sugiyama ◽  
Kazuya Ogawa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Apolipoprotein E ◽  
Culture Medium ◽  
Low Density Lipoprotein ◽  
Ectopic Expression ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Virus Production ◽  
Low Density

ABSTRACT Hepatitis C virus (HCV) is a causative agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV in circulating blood associates with lipoproteins such as very low density lipoprotein (VLDL) and low-density lipoprotein (LDL). Although these associations suggest that lipoproteins are important for HCV infectivity, the roles of lipoproteins in HCV production and infectivity are not fully understood. To clarify the roles of lipoprotein in the HCV life cycle, we analyzed the effect of apolipoprotein E (ApoE), a component of lipoprotein, on virus production and infectivity. The production of infectious HCV was significantly reduced by the knockdown of ApoE. When an ApoE mutant that fails to be secreted into the culture medium was used, the amount of infectious HCV in the culture medium was dramatically reduced; the infectious HCV accumulated inside these cells, suggesting that infectious HCV must associate with ApoE prior to virus release. We performed rescue experiments in which ApoE isoforms were ectopically expressed in cells depleted of endogenous ApoE. The ectopic expression of the ApoE2 isoform, which has low affinity for the LDL receptor (LDLR), resulted in poor recovery of infectious HCV, whereas the expression of other isoforms, ApoE3 and ApoE4, rescued the production of infectious virus, raising it to an almost normal level. Furthermore, we found that the infectivity of HCV required both the LDLR and scavenger receptor class B, member I (SR-BI), ligands for ApoE. These findings indicate that ApoE is an essential apolipoprotein for HCV infectivity.

scholarly journals Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA-Containing Particles

2002 ◽  
Vol 76 (14) ◽  
pp. 6919-6928 ◽  
Author(s):  
P. André ◽  
F. Komurian-Pradel ◽  
S. Deforges ◽  
M. Perret ◽  
J. L. Berland ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Apolipoprotein B ◽  
Core Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hcv Rna ◽  
Low Density ◽  
Density Fractions

ABSTRACT The presence of hepatitis C virus (HCV) RNA-containing particles in the low-density fractions of plasma has been associated with high infectivity. However, the nature of circulating HCV particles and their association with immunoglobulins or lipoproteins as well as the characterization of cell entry have all been subject to conflicting reports. For a better analysis of HCV RNA-containing particles, we quantified HCV RNA in the low-density fractions of plasma corresponding to the very-low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) fractions from untreated chronically HCV-infected patients. HCV RNA was always found in at least one of these fractions and represented 8 to 95% of the total plasma HCV RNA. Surprisingly, immunoglobulins G and M were also found in the low-density fractions and could be used to purify the HCV RNA-containing particles (lipo-viro-particles [LVP]). Purified LVP were rich in triglycerides; contained at least apolipoprotein B, HCV RNA, and core protein; and appeared as large spherical particles with a diameter of more than 100 nm and with internal structures. Delipidation of these particles resulted in capsid-like structures recognized by anti-HCV core protein antibody. Purified LVP efficiently bind and enter hepatocyte cell lines, while serum or whole-density fractions do not. Binding of these particles was competed out by VLDL and LDL from noninfected donors and was blocked by anti-apolipoprotein B and E antibodies, whereas upregulation of the LDL receptor increased their internalization. These results suggest that the infectivity of LVP is mediated by endogenous proteins rather than by viral components providing a mechanism of escape from the humoral immune response.

scholarly journals Chronic Hepatitis C Association with Diabetes Mellitus and Cardiovascular Risk in the Era of DAA Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Sylvia Drazilova ◽  
Jakub Gazda ◽  
Martin Janicko ◽  
Peter Jarcuska
Keyword(s):  
Diabetes Mellitus ◽  
Chronic Hepatitis ◽  
Cardiovascular Risk ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Low Density Lipoprotein ◽  
Sustained Viral Response ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Infected People

Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. Sustained viral response (SVR) achievement led to decreasing incidence and prevalence of T2DM during the interferon era of HCV treatment. Currently, direct-acting antiviral drugs (DAA) are the gold standard for treating HCV infection, while yielding SVR in nearly all patients. In chronic HCV patients with T2DM (prediabetes most likely too), DAA therapy is associated with both better fasting glucose and glycated hemoglobin (HbA1C) controls; thus reducing pharmacotherapy in a certain part of patients is possible. Papers mentioned in the review confirmed DAA role in both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase. This alteration was accompanied by an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides (TG) verified by most of the studies. However, the clinical significance of lipoprotein alterations caused by DAA therapy has not been explained yet. Moreover, DAA treatment of chronic hepatitis C improves hypertension control and atherosclerotic plaques. It is very likely that DAA therapeutic regimens will decrease both T2DM prevalence and cardiovascular risk in chronic hepatitis C patients; further research, however, is needed.

scholarly journals Hepatitis C virus utilizes VLDLR as a novel entry pathway

2015 ◽  
Vol 113 (1) ◽  
pp. 188-193 ◽  
Author(s):  
Saneyuki Ujino ◽  
Hironori Nishitsuji ◽  
Takayuki Hishiki ◽  
Kazuo Sugiyama ◽  
Hiroshi Takaku ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Host Factors ◽  
Entry Pathway ◽  
Hypoxic Conditions ◽  
Cellular Factors ◽  
Density Lipoprotein Receptor

Various host factors are involved in the cellular entry of hepatitis C virus (HCV). In addition to the factors previously reported, we discovered that the very-low-density lipoprotein receptor (VLDLR) mediates HCV entry independent of CD81. Culturing Huh7.5 cells under hypoxic conditions significantly increased HCV entry as a result of the expression of VLDLR, which was not expressed under normoxic conditions in this cell line. Ectopic VLDLR expression conferred susceptibility to HCV entry of CD81-deficient Huh7.5 cells. Additionally, VLDLR-mediated HCV entry was not affected by the knockdown of cellular factors known to act as HCV receptors or HCV entry factors. Because VLDLR is expressed in primary human hepatocytes, our results suggest that VLDLR functions in vivo as an HCV receptor independent of canonical CD81-mediated HCV entry.

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