Ribavirin Improves Early Responses to Peginterferon Through Improved Interferon Signaling

Feld, Jordan J.; Lutchman, Glen; Heller, Theo; Hara, Koji; Pfeiffer, Julie K.; Leff, Richard D.; Meek, Claudia; Rivera, María M.; Ko, Myung Kwan; Koh, Christopher; Rotman, Yaron; Ghany, Marc G.; Haynes-Williams, Vanessa; Neumann, Avidan U.; Liang, T. Jake; Hoofnagle, Jay H.

doi:10.1053/j.gastro.2010.03.037

Cited by 93 publications

(87 citation statements)

References 29 publications

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“…For example, IFN-α produced by pDCs was necessary In this clinical trial in which patients were randomized to weight-based or low-dose RBV, treatment with low-dose RBV was not associated with an increased risk of treatment relapse in a bivariable model of treatment outcome, a conclusion limited by the small sample size of the clinical study (8). Because RBV is known to sensitize the host to the effect of IFN and reduce hepatic transaminases (17,(36)(37)(38), it is possible that the IFN signature described herein could be partially attributed to interindividual differences in responsiveness to RBV. To explore this possibility, our present findings should be assessed in future IFN-and RBVfree DAA clinical trials.…”

Section: The Journal Of Clinical Investigationmentioning

confidence: 99%

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Meissner¹,

Wu²,

Osinusi³

et al. 2014

J. Clin. Invest.

189

192

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BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS.We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS.On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION.These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180. FUNDING. Intramural Programs of the National Institute of Allergy and Infectious The Journal of Clinical Investigation C l i n i C a l M e d i C i n e3 3 5 3 jci.orgVolume 124 Number 8 August 2014We next evaluated on-treatment serum protein levels of select chemokines and cytokines and observed similar expression at baseline and during treatment comparing patients who achieved SVR versus those who relapsed (Supplemental Table 3). Serum levels of the IFN-inducible cytokine IP-10, the protein product of the CXCL10 gene that was downregulated in liver (Figure 2A), correlated significantly with baseline viral load ( Figure 3A). Expression decreased rapidly on-treatment, regardless of treatment outcome, and increased with relapse ( Figure 3B). Viral kinetic and IP-10 decline were significantly correlated ( Figure 3C and Table 1). IL-10 and IFN-γ decreased modestly during treatment, while expression of most other proteins did not change, including TGF-β1 and TIMP1, which are associated with hepatic fibrosis (Supplemental Table 3 and ref. 25).To assess whether a similar pattern of gene expression changes could be observed in the periphery, we performed microarray mRNA analysis in PBMCs collected before treatment, early in treatment (day 6-11), and at EOT (week 24) and identified a significant decrease of IFN signaling during treatment (Supplemental Figure 2 and Supplemental Table 4). qRT-PCR analysis in PBMCs confirmed rapid and sustained downregulation of I...

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Section: The Journal Of Clinical Investigationmentioning

confidence: 99%

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Meissner¹,

Wu²,

Osinusi³

et al. 2014

J. Clin. Invest.

189

192

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“…However, none of these mechanisms has been convincingly shown to be responsible for its efficacy when combined with IFN (42). Nonetheless, RBV was recently shown to improve early responses to IFN (43), thus supporting its role in enhancing IFN signaling (44,132) and emphasizing the leading role of IFN in combination therapy.…”

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confidence: 99%

Coevolution of the Hepatitis C Virus Polyprotein Sites in Patients on Combined Pegylated Interferon and Ribavirin Therapy

Lara

Xia

Purdy

et al. 2011

J Virol

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Genotype-specific sensitivity of the hepatitis C virus (HCV) to interferon-ribavirin (IFN-RBV) combination therapy and reduced HCV response to IFN-RBV as infection progresses from acute to chronic infection suggest that HCV genetic factors and intrahost HCV evolution play important roles in therapy outcomes. HCV polyprotein sequences (n ‫؍‬ 40) from 10 patients with unsustainable response (UR) (breakthrough and relapse) and 10 patients with no response (NR) following therapy were identified through the Virahep-C study. Bayesian networks (BNs) were constructed to relate interrelationships among HCV polymorphic sites to UR/NR outcomes. All models showed an extensive interdependence of HCV sites and strong connections (P < 0.003) to therapy response. Although all HCV proteins contributed to the networks, the topological properties of sites differed among proteins. E2 and NS5A together contributed ϳ40% of all sites and ϳ62% of all links to the polyprotein BN. The NS5A BN and E2 BN predicted UR/NR outcomes with 85% and 97.5% accuracy, respectively, in 10-fold cross-validation experiments. The NS5A model constructed using physicochemical properties of only five sites was shown to predict the UR/NR outcomes with 83.3% accuracy for 6 UR and 12 NR cases of the HALT-C study. Thus, HCV adaptation to IFN-RBV is a complex trait encoded in the interrelationships among many sites along the entire HCV polyprotein. E2 and NS5A generate broad epistatic connectivity across the HCV polyprotein and essentially shape intrahost HCV evolution toward the IFN-RBV resistance. Both proteins can be used to accurately predict the outcomes of IFN-RBV therapy.Hepatitis C virus (HCV) is the major etiologic agent of blood-borne non-A, non-B hepatitis (25). Chronic HCV infection is an established risk factor for the development of liver diseases, such as fibrosis, cirrhosis, and hepatocellular carcinoma (33,124,125). Approximately 70% to 80% of HCVinfected patients fail to clear the virus and progress to chronicity (89a). At present, there are no preventive vaccines against HCV. The current, accepted therapeutic approach to treating chronic hepatitis C infection involves a 24-or 48-week course of pegylated alpha interferon (IFN-␣) combined with ribavirin (RBV) (i.e. IFN-RBV therapy) (48, 52). Because only 50% to 70% of chronically infected patients develop a sustained virologic response (SVR) to this treatment (48,52,55,80) and because patient intolerance to such therapy is common (61, 68, 120), the development and application of other therapeutic approaches using antiviral compounds that act against HCV more efficaciously and yet generate lower rates of adverse effects are major clinical management and public health objectives. Therapeutic failure presents in two forms: (i) complete resistance to treatment (no response [NR]) and (ii) unsustainable response (UR), which is characterized by an increase in HCV load observed during therapy after an initial period of decline in viral load (breakthrough) or observed after cessation of therapy (relapse)...

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“…Lack of an early virological response (EVR; Ն2-log decline in HCV RNA by week 12) is generally an indicator of those who will not respond to therapy (22). Additionally, several viral and host factors are associated with a positive treatment response, such as low baseline viral loads, female gender, lack of comorbidities such as HIV coinfection, low initial IFN-stimulated-gene (ISG) expression, and specific alleles of the IL-28B gene (15,21,22).…”

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confidence: 99%

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Ibarra

Jain

Pfeiffer

2011

J Virol

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Many individuals infected with hepatitis C virus (HCV) develop a chronic infection, and of those who are treated with pegylated interferon and ribavirin (RBV), many do not respond. While the nucleoside analog RBV improves treatment outcome, and will likely be an important component of therapy with next-generation viral inhibitors, RBV's mechanism is controversial. Most of RBV's proposed mechanisms require RBV import into cells. Therefore, we explored whether host-based RBV resistance develops through reduced cellular uptake, akin to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on HCV replication in cultured hepatoma Huh7.5 liver cells and whether RBV resistance develops in HCV patients. When Huh7.5 cells were exposed to RBV, resistance developed through reduced RBV uptake via the ENT1 nucleoside transporter and antiviral efficacy was reduced. The uptake defect in RBV-resistant cells was specific to RBV, since transport of another ENT1 substrate, cytidine, was unaffected. Importantly, RBV uptake significantly declined in HCV patient peripheral blood mononuclear cells (PBMCs) following 4 weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance and suggest that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance.

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Ribavirin Improves Early Responses to Peginterferon Through Improved Interferon Signaling

Cited by 93 publications

References 29 publications

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Coevolution of the Hepatitis C Virus Polyprotein Sites in Patients on Combined Pegylated Interferon and Ribavirin Therapy

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

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