The Risk of Long-term Morbidity and Mortality in Patients With Chronic Hepatitis C

McCombs, Jeffrey S.; Matsuda, T.; Tonnu-Mihara, Ivy; Saab, Sammy; Hines, P.; L’Italien, G.; Juday, Timothy; Yuan, Yong

doi:10.1001/jamainternmed.2013.12505

Cited by 111 publications

(51 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1, 3, and 4). 4 NS3 and other nonstructural proteins (NS4A, NS4B, NS5A, and NS5B) comprising the replication complexes (RC) were targeted to the DRM for HCV RNA replication (27,28). RC are likely enclosed by membrane invaginations called membranous web (69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

“…Globally, nearly 200 million people are infected with this virus, which causes severe morbidity and mortality due to its persistent replication in the liver (3,4). HCV encodes a single open reading frame that is processed by host and viral proteases into three structural proteins, including Core and two envelope proteins (E1 and E2), and seven nonstructural proteins, including p7, NS2 and NS3-5B (NS3, NS4A, NS4B, NS5A, and NS5B) (5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Detergent-Resistant Membrane Association of NS2 and E2 during Hepatitis C Virus Replication

Shanmugam

Saravanabalaji

2015

J Virol

View full text Add to dashboard Cite

Previously, we demonstrated that the efficiency of hepatitis C virus (HCV) E2-p7 processing regulates p7-dependent NS2 localization to putative virus assembly sites near lipid droplets (LD). In this study, we have employed subcellular fractionations and membrane flotation assays to demonstrate that NS2 associates with detergent-resistant membranes (DRM) in a p7-dependent manner. However, p7 likely plays an indirect role in this process, since only the background level of p7 was detectable in the DRM fractions. Our data also suggest that the p7-NS2 precursor is not involved in NS2 recruitment to the DRM, despite its apparent targeting to this location. Deletion of NS2 specifically inhibited E2 localization to the DRM, indicating that NS2 regulates this process. Treatment of cells with methyl-␤-cyclodextrin (M␤CD) significantly reduced the DRM association of Core, NS2, and E2 and reduced infectious HCV production. Since disruption of the DRM localization of NS2 and E2, either due to p7 and NS2 defects, respectively, or by M␤CD treatment, inhibited infectious HCV production, these proteins' associations with the DRM likely play an important role during HCV assembly. Interestingly, we detected the HCV replication-dependent accumulation of ApoE in the DRM fractions. Taking into consideration the facts that ApoE was shown to be a major determinant for infectious HCV particle production at the postenvelopment step and that the HCV Core protein strongly associates with the DRM, recruitment of E2 and ApoE to the DRM may allow the efficient coordination of Core particle envelopment and postenvelopment events at the DRM to generate infectious HCV production. IMPORTANCEThe biochemical nature of HCV assembly sites is currently unknown. In this study, we investigated the correlation between NS2 and E2 localization to the detergent-resistant membranes (DRM) and HCV particle assembly. We determined that although NS2's DRM localization is dependent on p7, p7 was not targeted to these membranes. We then showed that NS2 regulates E2 localization to the DRM, consistent with its role in recruiting E2 to the virus assembly sites. We also showed that short-term treatment with the cholesterol-extracting agent methyl-␤-cyclodextrin (M␤CD) not only disrupted the DRM localization of Core, NS2, and E2 but also specifically inhibited intracellular virus assembly without affecting HCV RNA replication. Thus, our data support the role of the DRM as a platform for particle assembly process. H epatitis C virus (HCV) is a small, enveloped, positive-strand RNA virus belonging to the Flaviviridae family (1, 2). Globally, nearly 200 million people are infected with this virus, which causes severe morbidity and mortality due to its persistent replication in the liver (3, 4). HCV encodes a single open reading frame that is processed by host and viral proteases into three structural proteins, including Core and two envelope proteins (E1 and E2), and seven nonstructural proteins, including p7, NS2 and NS3-5B (NS3, NS4A, NS4B, NS5A, and NS5B) (5)...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Detergent-Resistant Membrane Association of NS2 and E2 during Hepatitis C Virus Replication

Shanmugam

Saravanabalaji

2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Recent studies investigating long-term clinical endpoints have found that for patients with all stages of fibrosis, SVR is associated with marked reductions in all-cause mortality 25 , progression of fibrosis 26 , need for liver transplantation 10 , extrahepatic complications 27 , and hepatocarcinogenesis.…”

Section: Risk Reduction Of Hcc In Individuals Achieving Svr Withmentioning

confidence: 99%

Impact of hepatitis C virus eradication on hepatocellular carcinogenesis

Chung

2015

Cancer

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in the world. Infection with the hepatitis C virus (HCV) represents one of the most common risk factors for HCC development and cases of HCV-related complications have been rising over the last two decades. Though the standard of HCV therapy has been interferon (IFN)-based for many years, the therapeutic revolution spurred by the development of direct-acting antivirals (DAAs) promises to usher in a new era in which chronic hepatitis C becomes a rare disease. Based on long term follow-up in persons experiencing IFN-based sustained virologic responses (SVR), we can expect that rates of HCV-associated HCC will decrease significantly after the widespread adoption of DAAs, but there remains a persistent risk for HCC even among some patients with advanced fibrosis who have achieved SVR. As such, individuals treated for HCV with advanced fibrosis should continue to be screened regularly for HCC post-SVR. Furthermore, as the population of patients with SVR grows, it will become imperative to accurately identify those individuals at high-risk for developing HCC, appropriately allocate resources for screening, and consider cost-effective chemopreventive strategies. Risk factors include pre-existing advanced fibrosis/cirrhosis, older age, diabetes mellitus, and ethanol use. Additionally, laboratory biomarkers and genetic signatures are currently being identified that not only predict the likelihood of HCC development in SVR patients but may also serve as dynamic indicators of therapeutic response.

show abstract

“…Hepatitis C virus (HCV) genotype 3 is the second most prevalent genotype worldwide,1 and associated with several features, such as accelerated progression of fibrosis and a greater risk of steatosis and hepatocellular carcinoma (HCC),2, 3, 4 that significantly increase liver‐related hospitalization and death relative to other genotypes 5. Thus, there is an urgent need for safe and effective treatment of genotype 3 infection.…”

Section: Introductionmentioning

confidence: 99%

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme

Hézode

Lebray

Lédinghen

et al. 2017

Liver International

View full text Add to dashboard Cite

Background & AimsOptimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real‐world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization.MethodsPatients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post‐liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post‐treatment week 12 (SVR12; modified intention‐to‐treat). Safety was assessed by spontaneous adverse event reporting.ResultsThe efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6‐92.5%), 98% (43/44) without cirrhosis (95% CI 88.2‐99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5‐90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5‐89.6%]). Among 516 GT3‐infected patients with safety data, 5 discontinued for adverse events and 11 died.ConclusionsDaclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real‐world cohort of GT3‐infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.

show abstract

The Risk of Long-term Morbidity and Mortality in Patients With Chronic Hepatitis C

Cited by 111 publications

References 34 publications

Detergent-Resistant Membrane Association of NS2 and E2 during Hepatitis C Virus Replication

Detergent-Resistant Membrane Association of NS2 and E2 during Hepatitis C Virus Replication

Impact of hepatitis C virus eradication on hepatocellular carcinogenesis

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme

Contact Info

Product

Resources

About