Interferon and Ribavirin vs Interferon Alone in the Re-treatment of Chronic Hepatitis C Previously Nonresponsive to Interferon

Cummings, Kristin J.; Lee, Shing M.; West, Emily S.; Cid‐Ruzafa, Javier; Fein, Steven G.; Aoki, Yutaka; Sulkowski, Mark S.; Goodman, Steven N.

doi:10.1001/jama.285.2.193

Cited by 155 publications

(107 citation statements)

References 34 publications

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“…The remaining three reviews assessed study quality using scales, with each using a different scale. The total quality scale scores were presented in the Cummings and San Miguel reviews, 78,80 whereas quality subscale scores (including a bias subscale) as well as a total quality score were presented in the AHRQ review. Table 16 presents a summary of results from the four reviews that performed statistical metaanalyses pertaining specifically to the comparison of IFN + RBV versus IFN retreatment in previous non-responders to IFN monotherapy.…”

Section: Results Of Previous Systematic Reviews Of Retreatmentmentioning

confidence: 99%

Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation

Shepherd

Brodin²,

Cave³

et al. 2004

Health Technol Assess

191

133

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Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is £2 per monograph and for the rest of the world £3 per monograph.You can order HTA monographs from our Despatch Agents:-fax (with credit card or official purchase order) -post (with credit card or official purchase order or cheque) -phone during office hours (credit card only).Additionally the HTA website allows you either to pay securely by credit card or to print out your order and then post or fax it. NHS libraries can subscribe free of charge. Public libraries can subscribe at a very reduced cost of £100 for each volume (normally comprising 30-40 titles). The commercial subscription rate is £300 per volume. Please see our website for details. Subscriptions can only be purchased for the current or forthcoming volume. Contact details are as follows: Payment methods Paying by chequeIf you pay by cheque, the cheque must be in pounds sterling, made payable to Direct Mail Works Ltd and drawn on a bank with a UK address. Paying by credit cardThe following cards are accepted by phone, fax, post or via the website ordering pages: Delta, Eurocard, Mastercard, Solo, Switch and Visa. We advise against sending credit card details in a plain email. Paying by official purchase orderYou can post or fax these, but they must be from public bodies (i.e. NHS or universities) within the UK. We cannot at present accept purchase orders from commercial companies or from outside the UK. How do I get a copy of HTA on CD?Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact Direct Mail Works (see contact details above) by email, post, fax or phone. HTA on CD is currently free of charge worldwide.The website also provides information about the HTA Programme and lists the membership of the various committees. HTA Declared competing interests of authors:John Gabbay is Director of the NCCHTA, but is not directly involved in setting research agendas. He is also a member of the editorial board for Health Technology Assessment, although was not involved in the editorial process for this report. JG is a member of the consumer involvement steering group at the NCCHTA and also is a member of INVOLVE, which promotes public involvement in the NHS, public health and social care research. Published October 2004This report should be referenced as follows: NHS R&D HTA ProgrammeT he research findings from the NHS R&D Health Technology Assessment (HTA) Programme directly influence key decision-making bodies such as the National Institute for Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the 'National Knowledge Service' that is being developed to improve the evidence of clinical practice throughout the NHS.The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness...

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Section: Results Of Previous Systematic Reviews Of Retreatmentmentioning

confidence: 99%

Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation

Shepherd

Brodin²,

Cave³

et al. 2004

Health Technol Assess

191

133

View full text Add to dashboard Cite

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“…A medically relevant aspect of NTP use by the HCV RdRp is the incorporation of ribavirin, which is used in combination with interferon to treat HCV infection (10)(11)(12)20). Ribavirin is incorporated in place of purine triphosphates and may result in an increased error rate in the newly synthesized RNAs, leading to a loss of virus infectivity (9,19).…”

Section: Resultsmentioning

confidence: 99%

De Novo Initiation Pocket Mutations Have Multiple Effects on Hepatitis C Virus RNA-Dependent RNA Polymerase Activities

Ranjith-Kumar

Sarisky

Gutshall

et al. 2004

J Virol

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The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has several distinct biochemical activities, including initiation of RNA synthesis by a de novo mechanism, extension from a primed template, nontemplated nucleotide addition, and synthesis of a recombinant RNA product from two or more noncovalently linked templates (template switch). All of these activities require specific interaction with nucleoside triphosphates (NTPs). Based on the structure of the HCV RdRp bound to NTP (S. Bressanelli, L. Tomei, F. A. Rey, and R. DeFrancesco, J. Virol. 76:3482-3492, 2002), we mutated the amino acid residues that contact the putative initiation GTP and examined the effects on the various activities. Although all mutations retained the ability for primer extension, alanine substitution at R48, R158, R386, R394, or D225 decreased de novo initiation, and two or more mutations abolished de novo initiation. While the prototype enzyme had a K m for GTP of 3.5 M, all of the mutations except one had K m s that were three-to sevenfold higher. These results demonstrate that the affected residues are functionally required to interact with the initiation nucleotide. Unexpectedly, many of the mutations also affected the addition of nontemplated nucleotide, indicating that residues in the initiating NTP (NTPi)-binding pocket are required for nontemplated nucleotide additions. Interestingly, mutations in D225 are dramatically affected in template switch, indicating that this residue of the NTPi pocket also interacts with components in the elongation complex. We also examined the interaction of ribavirin triphosphate with the NTPi-binding site.Hepatitis C Virus (HCV), a member of the flaviviridae family of positive-strand RNA viruses, infects up to 3% of the world's population (1). A prime target for antiviral treatment in HCV is the NS5B protein, the RNA-dependent RNA polymerase (RdRp) responsible for viral RNA synthesis. The RdRp is one of the subunits expected to participate in HCV replication and is responsible for the initiation and elongation of viral RNA synthesis. Initiation of RNA synthesis in infected cells likely starts de novo; that is, by use of a 1-nucleotide (nt) primer (3,14). This mode of RNA synthesis requires a specialized site in the RdRp, called the I site, that specifically recognizes the initiating nucleoside triphosphate (designated NTPi, with GTP being preferred by the recombinant HCV RdRp) (14,23,25). A second NTP-binding pocket, the I ϩ 1 site, binds a nucleotide for phosphoryl transfer as dictated by the template base (14). Cocrystal structures of the HCV RdRp and nucleotides have been reported previously (3, 21), identifying a number of residues at D225, R48, R158, R386, R394, and S367 that interact with specific moieties of the initiation GTP (Fig. 1A). In this structure, it is not known whether the GTP binds to the I site or the I ϩ 1 site. NTPi binding to the I site is base specific, while binding of the second NTP to the I ϩ 1 site should be directed by the template (25). Because the RdRp-GTP st...

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“…Directly acting antiviral agents (DAAs)-some currently in use and others under development-offer great promise for control of HCV either as a substitute for or complement of the standard-of-care (SOC) therapy based on treatment using a combination of pegylated alpha interferon (IFN-␣) and ribavirin (30)(31)(32)(33)(34)(35)(36). Combinations that include the polymerase inhibitor sofosbuvir have produced sustained viral responses that in some cases have been higher than 90% in clinical trials (37)(38)(39)(40), but the possible impact of resistance mutations is not known; sofosbuvir resistance substitution S282T in NS5B is present in the sequence of HCV reference isolate ED43 of genotype 4a and L159F is present in the mutant spectrum of HCV quasispecies following treatment of HCV p100 with ribavirin (I. Gallego, E. Domingo, and C. Perales, unpublished results).…”

mentioning

confidence: 99%

Increased Replicative Fitness Can Lead to Decreased Drug Sensitivity of Hepatitis C Virus

Sheldon

Beach

Moreno

et al. 2014

J Virol

123

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Passage of hepatitis C virus (HCV) in human hepatoma cells resulted in populations that displayed partial resistance to alpha interferon (IFN-␣), telaprevir, daclatasvir, cyclosporine, and ribavirin, despite no prior exposure to these drugs. Mutant spectrum analyses and kinetics of virus production in the absence and presence of drugs indicate that resistance is not due to the presence of drug resistance mutations in the mutant spectrum of the initial or passaged populations but to increased replicative fitness acquired during passage. Fitness increases did not alter host factors that lead to shutoff of general host cell protein synthesis and preferential translation of HCV RNA. The results imply that viral replicative fitness is a mechanism of multidrug resistance in HCV. IMPORTANCEViral drug resistance is usually attributed to the presence of amino acid substitutions in the protein targeted by the drug. In the present study with HCV, we show that high viral replicative fitness can confer a general drug resistance phenotype to the virus. The results exclude the possibility that genomes with drug resistance mutations are responsible for the observed phenotype. The fact that replicative fitness can be a determinant of multidrug resistance may explain why the virus is less sensitive to drug treatments in prolonged chronic HCV infections that favor increases in replicative fitness. Selection of viral mutants resistant to antiviral agents is a major problem for the successful treatment of viral diseases. In the case of RNA viruses, high mutation rates during genome replication provide viral populations with an ample reservoir of phenotypic variants, including mutants that can escape selective constraints. Resistance to a single drug that targets a viral protein develops at a rate that depends on the genetic barrier (number and types of mutations needed to acquire resistance) and the phenotypic barrier (fitness cost) imposed by the resistance mutations (1-16). When drug resistance mutations do not entail a significant fitness cost-either because the mutations per se do not critically affect viral functions or because compensatory mutations are acquired-they may reach detectable levels despite no prior exposure of the viral population to the drug (1, 16-27).Control of hepatitis C virus (HCV) infections is hampered by the complexity of HCV quasispecies replicating in the liver (16,28,29). Directly acting antiviral agents (DAAs)-some currently in use and others under development-offer great promise for control of HCV either as a substitute for or complement of the standard-of-care (SOC) therapy based on treatment using a combination of pegylated alpha interferon (IFN-␣) and ribavirin (30)(31)(32)(33)(34)(35)(36). Combinations that include the polymerase inhibitor sofosbuvir have produced sustained viral responses that in some cases have been higher than 90% in clinical trials (37-40), but the possible impact of resistance mutations is not known; sofosbuvir resistance substitution S282T in NS5B is present in the ...

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Interferon and Ribavirin vs Interferon Alone in the Re-treatment of Chronic Hepatitis C Previously Nonresponsive to Interferon

Abstract: For chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options.

Cited by 155 publications

References 34 publications

Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation

Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation

De Novo Initiation Pocket Mutations Have Multiple Effects on Hepatitis C Virus RNA-Dependent RNA Polymerase Activities

Increased Replicative Fitness Can Lead to Decreased Drug Sensitivity of Hepatitis C Virus

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