Induction Pegylated Interferon Alfa-2a and High Dose Ribavirin Do Not Increase SVR in Heavy Patients With HCV Genotype 1 and High Viral Loads

Reddy, K. Rajender; Shiffman, Mitchell L.; Rodrı́guez-Torres, Maribel; Cheinquer, Hugo; Abdurakhmanov, Dzhamal; Бакулин, И. Г.; Morozov, Viacheslav; Silva, Giovanni Faria; Geyvandova, Natalia; Stanciu, C; Rabbia, Michael; McKenna, Michael; Thommes, James; Harrison, Stephen A.

doi:10.1053/j.gastro.2010.08.051

Cited by 28 publications

(20 citation statements)

References 26 publications

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“…In this study, we showed that RBV antiviral activity is blocked due to an induced autophagy response in HCV-infected cell cultures. These results based on cell culture experiments are consistent with clinical findings, where it has been observed that individuals with high viral titers are more resistant to combination therapy with IFN-␣ and RBV (34). The mechanism of impaired RBV antiviral activity in persistently HCV-infected cells is related to the reduced expression of ENT1, an RBV transporter, and the reduced uptake of RBV is in agreement with the results of other research reported previously (14)(15)(16)(17).…”

Section: Discussionsupporting

confidence: 82%

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Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Panigrahi

Chandra

Ferraris

et al. 2015

J Virol

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Ribavirin (RBV) continues to be an important component of interferon-free hepatitis C treatment regimens, as RBV alone does not inhibit hepatitis C virus (HCV) replication effectively; the reason for this ineffectiveness has not been established. In this study, we investigated the RBV resistance mechanism using a persistently HCV-infected cell culture system. The antiviral activity of RBV against HCV was progressively impaired in the persistently infected culture, whereas interferon lambda 1 (IFN-1), a type III IFN, showed a strong antiviral response and induced viral clearance. We found that HCV replication in persistently infected cultures induces an autophagy response that impairs RBV uptake by preventing the expression of equilibrative nucleoside transporter 1 (ENT1). The Huh-7.5 cell line treated with an autophagy inducer, Torin 1, downregulated membrane expression of ENT1 and terminated RBV uptake. In contrast, the autophagy inhibitors hydroxychloroquine (HCQ), 3-methyladenine (3-MA), and bafilomycin A1 (BafA1) prevented ENT1 degradation and enhanced RBV antiviral activity. The HCV-induced autophagy response, as well as treatment with Torin 1, degrades clathrin heavy chain expression in a hepatoma cell line. Reduced expression of the clathrin heavy chain by HCV prevents ENT1 recycling to the plasma membrane and forces ENT1 to the lysosome for degradation. This study provides a potential mechanism for the impairment of RBV antiviral activity in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy for improving RBV antiviral activity against HCV infection. IMPORTANCEThe results from this work will allow a review of the competing theories of antiviral therapy development in the field of HCV virology. Ribavirin (RBV) remains an important component of interferon-free hepatitis C treatment regimens. The reason why RBV alone does not inhibit HCV replication effectively has not been established. This study provides a potential mechanism for why RBV antiviral activity is impaired in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy to increase RBV antiviral activity against HCV infection. Therefore, it is anticipated that this work would generate a great deal of interest, not only among virologists but also among the general public. H epatitis C virus (HCV) is estimated to infect Ͼ185 million people worldwide (1). Infection by HCV leads to a high likelihood of chronic liver disease, which often progresses to liver cirrhosis and hepatocellular carcinoma; HCV is therefore a major public health problem. Interferon alpha (IFN-␣) and ribavirin (RBV) (a guanosine analogue) have been used as standard therapy for chronic HCV infection for over a decade, with a sustained virologic response rate of 50% for genotype 1a virus. In 2011, two HCV-specific direct-acting antivirals (DAAs) targeting to NS3 protease (telaprevir and boceprevir) received FDA appro...

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Section: Discussionsupporting

confidence: 82%

“…Ribavirin monotherapy is not very effective (33,34); however, RBV in combination with IFN-␣ shows a significant improvement in the HCV treatment response. The results from recent clinical trials suggest that RBV may remain an essential component of HCV treatment in combination with new DAAs to prevent relapse (4).…”

Section: Discussionmentioning

confidence: 99%

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Panigrahi

Chandra

Ferraris

et al. 2015

J Virol

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“…Many previous studies have shown that higher body mass index (BMI) and weight are associated with reduced response (23)(24)(25). However, early viral kinetics and SVR were not associated with BMI when weight-adjusted dosing of RBV was used (26,27). Our study suggests that the relationship of weight to response is not a linear relationship, and that the adjustment should be by the factor of (weight/typical weight) 3/4 .…”

Section: Discussionmentioning

confidence: 53%

“…Previous attempts to determine the role of drug concentrations for interferon-based compounds in the treatment of HCV have generally met with limited success (28)(29)(30). Reasons for previous lack of predictive insights from others' data might be due to limited precision of pharmacokinetic parameter estimates, use of a single-time-point drug concentration, the type of viral kinetic measurements utilized, or the statistical methods to determine the relationship (26,27). Second, our sample size was only 42, which could throw the generalizability of our study into question.…”

Section: Discussionmentioning

confidence: 99%

Pegylated Interferon Fractal Pharmacokinetics: Individualized Dosing for Hepatitis C Virus Infection

Jain

Pasipanodya

Alder

et al. 2013

Antimicrob Agents Chemother

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Despite recent advances in hepatitis C virus (HCV) therapeutics, the combination of pegylated interferon and ribavirin (PEGIFN/RBV) remains the cornerstone of treatment. Optimization and individualization of PEGIFN dosing could improve outcomes. Week one PEGIFN serum concentrations in 42 HCV genotype 1-infected patients treated with conventional PEGIFN/ RBV were analyzed using multicompartmental pharmacokinetic models. For each patient, pharmacokinetic parameter estimates, weight, age, interleukin-28B (IL-28B) single-nucleotide polymorphism, CD4 count, baseline HCV RNA, gender, race, and HIV status were examined using classification and regression tree analysis to identify factors predictive of sustained viral response (SVR). Survival analysis was performed to compare the time to undetectable viral load in patients with and without the highest scoring predictor. PEGIFN concentrations varied at least 87-fold. Pharmacokinetics were best described by a two-compartment model with an 8.4-h absorption lag. Patient weight correlated with PEGIFN systemic clearance based on fractal geometry relationships. SVR was achieved in 36% of patients; a PEGIFN cumulative 1-week area under the curve (AUC) of <0.79 mg · h/liter scored highest in predicting poor response, followed by a weight of >93.7 kg. Patients with a PEGIFN AUC of >0.79 mg · h/liter achieved undetectable viral load more rapidly than those with a lower AUC (hazard ratio, 1.63; 95% confidence interval, 1.21 to 2.04). PEGIFN exhibits wide pharmacokinetic variability, mainly driven by patient weight, so that the standard dose may not reach levels needed to achieve SVR. Optimizing dose to patient weight and PEGIFN AUC in the first week offers a solution to improve SVR and to potentially shorten duration of therapy.

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“…Only a few randomized controlled trials (RCTs) have examined the relationship between drug dose reduction and antiviral effect with Peg-IFN plus ribavirin combination therapy [1][2][3][20][21][22][23], and the findings are controversial. Manns et al [1] reported that the SVR rate was significantly lower in patients given 0.5 lg/kg/week of Peg-IFN than in those given 1.5 lg/kg/week of Peg-IFN (34 vs. 42%, p \ 0.05).…”

Section: Introductionmentioning

confidence: 99%

Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin

et al. 2011

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Induction Pegylated Interferon Alfa-2a and High Dose Ribavirin Do Not Increase SVR in Heavy Patients With HCV Genotype 1 and High Viral Loads

Cited by 28 publications

References 26 publications

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Pegylated Interferon Fractal Pharmacokinetics: Individualized Dosing for Hepatitis C Virus Infection

Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin

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