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• W2016458526 abstract "The medical management of patients with gastrointestinal diseases is advancing rapidly. At a recent symposium held during Digestive Disease Week in Chicago in May of 2005, specific attention was given to the future prospects for medical management of 3 common gastrointestinal disease areas: antisecretory therapy, chronic hepatitis C, and inflammatory bowel disease. Antisecretory approaches include drug combinations including a proton pump inhibitor, potassium competitive acid blockers, and antigastrin agents. The latter two classes are still experimental, but the former combinations have potential to enhance the highly effective agents currently available. The focus of treatment advances in chronic hepatitis C in the immediate future is the discovery of more effective treatment regimens for nonresponders to prior therapy, who are becoming the largest group of patients seeking treatment of hepatitis C. The combination of peginterferon with ribavirin results in 6%–15% sustained virologic response rates in patients who were prior nonresponders to standard interferon plus ribavirin. Newer strategies to eradicate hepatitis C virus infection using different interferons, such as interferon alfacon-1 or higher doses of peginterferon, or long-term maintenance peginterferon, are undergoing study and show promise based on data from preliminary studies. Several immunomodulators have promise in inflammatory bowel disease, although the risk-benefit ratio and costs of therapy require evaluation. Nevertheless, the success of new biologics such as anti-TNFα agents augurs well for effective future therapies. The medical management of patients with gastrointestinal diseases is advancing rapidly. At a recent symposium held during Digestive Disease Week in Chicago in May of 2005, specific attention was given to the future prospects for medical management of 3 common gastrointestinal disease areas: antisecretory therapy, chronic hepatitis C, and inflammatory bowel disease. Antisecretory approaches include drug combinations including a proton pump inhibitor, potassium competitive acid blockers, and antigastrin agents. The latter two classes are still experimental, but the former combinations have potential to enhance the highly effective agents currently available. The focus of treatment advances in chronic hepatitis C in the immediate future is the discovery of more effective treatment regimens for nonresponders to prior therapy, who are becoming the largest group of patients seeking treatment of hepatitis C. The combination of peginterferon with ribavirin results in 6%–15% sustained virologic response rates in patients who were prior nonresponders to standard interferon plus ribavirin. Newer strategies to eradicate hepatitis C virus infection using different interferons, such as interferon alfacon-1 or higher doses of peginterferon, or long-term maintenance peginterferon, are undergoing study and show promise based on data from preliminary studies. Several immunomodulators have promise in inflammatory bowel disease, although the risk-benefit ratio and costs of therapy require evaluation. Nevertheless, the success of new biologics such as anti-TNFα agents augurs well for effective future therapies. The medical management of patients with gastrointestinal disease states is advancing rapidly. At a recent symposium held during Digestive Disease Week in Chicago in May of 2005, specific attention was given to the future prospects for medical management of 3 common gastrointestinal disease areas: antisecretory therapy, chronic hepatitis C, and inflammatory bowel disease. This article consists of an abbreviated review of the information presented covering each of these 3 clinical areas with particular attention to promising agents that may become available to expand the therapeutic armamentarium for gastroenterologists in the future.New Drugs for Acid SuppressionNew drugs for acid inhibition are being developed to overcome the limitations of currently available proton pump inhibitors (PPIs) (Table 1). The first limitation is the long time these drugs take to reach their peak effect. The currently available PPIs may take 3–5 days of treatment to achieve maximal acid inhibition at therapeutic doses and the degree of acid control is inadequate for many patients who continue to use supplemental acid suppressants such as antacids and H2-receptor antagonists.1Tytgat G.N. Shortcomings of the first-generation proton pump inhibitors.Eur J Gastroenterol Hepatol. 2001; 13: S29-S33PubMed Google Scholar Second, PPI treatment frequently does not provide complete acid inhibition throughout the day and night, even when the drugs are administered at twice the recommended daily dose.2Hatlebakk J.G. Katz P.O. Kuo B. et al.Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily.Aliment Pharmacol Ther. 1998; 12: 1235-1240Crossref PubMed Scopus (167) Google Scholar, 3Katz P.O. Hatlebakk J.G. Castell D.O. Gastric acidity and acid breakthrough with twice-daily omeprazole or lansoprazole.Aliment Pharmacol Ther. 2000; 14: 709-714Crossref PubMed Scopus (84) Google Scholar Nocturnal acid breakthrough is common in patients on PPI therapy and may cause symptoms in some patients. Therefore, efficacy over the entire 24-hour period would be an important attribute for new acid inhibitors. Third, there is substantial interpatient variability in the inhibition of gastric acid secretion with the PPIs. PPIs are metabolized by hepatic cytochrome P450 enzymes, mainly cytochrome P450-2C19. A proportion of individuals (3% of Caucasians and approximately 15% of east Asians) show mutations in the cytochrome P450-2C19 gene, resulting in a decreased clearance of the PPIs in these so-called poor metabolizers.4Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole.Clin Pharmacokinet. 1996; 31: 9-28Crossref PubMed Scopus (353) Google Scholar This creates a variability in drug effect and unpredictable responses to therapy in some patients.Table 1New Drugs for Acid SuppressionNovel drug categoriesExamplesCurrent development statusPPIs IlaprazoleTenatoprazole Phase IIPhase IIPotassium-competitive acid blockers AZD0865RevaprazanSoraprazanCS-526 Development terminatedPhase IIPhase IIPhase IHistamine H3 agonistsR-α-methylhistaminePreclinicalAntigastrin agents Antigastrin vaccineItriglumide Phase IPhase I Open table in a new tab New Developments in the Class of Proton Pump InhibitorsPPIs are substituted benzimidazoles; after absorption, they have a relatively short half-life of 90–120 minutes. During this time, they accumulate in the acidic space of the actively secreting parietal cell (Figure 1) where they are transformed into the active sulphenamide. This forms noncompetitive covalent (and by definition, irreversible) disulphide bonds with key cysteine residues of the H+, K+–adenosine triphosphatase.5Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Scopus (355) Google Scholar Because of the irreversible nature of this binding, a proportion of the H+, K+–adenosine triphosphatase pumps will stay inhibited after each dose. As repeated daily administration continues, a steady state of inhibition is established typically after 4 days. All known PPIs form a disulfide bond with cysteine 813 that is accessible from the luminal surface.Two new PPI agents currently are under development: ilaprazole (IY-81149) and tenatoprazole.6Kim E.J. Lee R.K. Lee S.M. et al.General pharmacology of IY-81149, a new proton pump inhibitor.Arzneimittelforschung. 2001; 51: 51-59PubMed Google Scholar, 7Tenatoprazole. Benatoprazole, TU 199.Drugs R D. 2002; 3 (Anonymous): 276-277Crossref PubMed Scopus (5) Google Scholar In a rat reflux esophagitis model, ilaprazole was a more potent inhibitor of acid output than omeprazole. Human data are awaited. In contrast to current PPIs, which are all substituted benzimidazoles, tenatoprazole (TU-199) is a new chemical entity, characterized by an imidazopyridine backbone that likely is responsible for its substantially prolonged plasma half-life (7 h). Pharmacokinetic studies suggest that tenatoprazole may have a relatively longer plasma half-life (approximately 5–7 hours, depending on dose) compared with existing PPIs (ie, approximately 1–2 h).8Domalga F. Ficheux H. Pharmacokinetics of tenatoprazole, a novel proton pump inhibitor, in healthy male Caucasian volunteers.Gastroenterology. 2003; 124 (abstr): S1608Google Scholar The increased plasma half-life may translate into more sustained acid control. In 18 healthy volunteers, a 40-mg dose of tenatoprazole resulted in a higher mean intragastric pH than 40 mg of esomeprazole (4.6 ± .9 vs 4.2 ± .8), which was significantly better in maintaining intragastric pH at night and reduced the duration of nocturnal acid breakthrough.9Galmiche J.P. Bruley Des Varannes S. Ducrotté P. et al.Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life effects on intragastric pH and comparison with esomeprazole in healthy volunteers.Aliment Pharmacol Ther. 2004; 19: 655-662Crossref PubMed Scopus (76) Google Scholar The same group confirmed the better nocturnal acid control in 24 healthy volunteers treated with the same medications over 2 days.10Galmiche J.P. Sacher-Huvelin S. Bruley des Varannes S. et al.A comparative study of the early effects of tenatoprazole 40 mg and esomeprazole 40 mg on intragastric pH in healthy volunteers.Aliment Pharmacol Ther. 2005; 21: 575-582Crossref PubMed Scopus (35) Google Scholar It is unclear whether these differences persist when these drugs are given for longer periods of time, or whether this difference in nocturnal pH is significant clinically. There is no information about effects of the new agents on gastric volume, which is an important determinant of whether gastric content will reflux.Drug Combinations With a Proton Pump InhibitorNovel formulations of PPIs with other compounds may combine the advantages of 2 compounds with differing characteristics. Immediate-release omeprazole consists of a combination of omeprazole powder (without an enteric coating) and sodium bicarbonate. PPIs are destroyed by gastric acid and generally are administered as enteric-coated tablets or as enteric-coated granules contained in a capsule. With the formulation of immediate-release omeprazole, an antacid (sodium bicarbonate) is administered to neutralize gastric acid and allow the omeprazole to pass into the intestine without being damaged by acid in the stomach. An important benefit of this compound is the immediate effect of the antacid, which neutralizes intragastric pH rapidly. Repeated once-daily (bedtime) dosing for 8 days with immediate-release omeprazole suspension produced significantly better nocturnal gastric pH values than repeated once-daily (before dinner) or twice-daily (before breakfast and bedtime) dosing with pantoprazole in 1 study.11Castell D. Bagin R. Goldlust B. et al.Comparison of the effects of immediate-release omeprazole powder for oral suspension and pantoprazole delayed-release tablets on nocturnal acid breakthrough in patients with symptomatic gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2005; 21: 1467-1474Crossref PubMed Scopus (62) Google ScholarAnother study in critical care units showed that intragastric pH was controlled better with immediate-release omeprazole administered twice daily compared with cimetidine administered intravenously. However, bleeding rates were not statistically different.12Conrad S.A. Gabrielli A. Margolis B. et al.Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients.Crit Care Med. 2005; 33: 760-765Crossref PubMed Scopus (130) Google Scholar An important disadvantage of immediate-release omeprazole is the sodium load (1680 mg of sodium bicarbonate [20 mEq] or 460 mg of sodium), which is about 20% of the recommended daily sodium intake. Most Americans exceed the current recommended dietary sodium intake.13Available at: http://www.cnpp.usda.gov/FENR/V11N4/fenrv11n4p49.PDF. Accessed: July 23, 2005.Google Scholar Another approach is to combine the speed of H2 receptor antagonists for rapid control of intragastric pH with PPIs that have greater potency. New drug formulations allow coating of a PPI with a rapidly disintegrating H2 receptor antagonist that can be taken as a single tablet,14Available at: www.orexo.com. Accessed: July 23, 2005.Google Scholar without a significant sodium load.Potassium-Competitive Acid BlockersPotassium-competitive acid inhibitors are a new class of drugs that act by inhibiting K+ entry into the parietal cell in exchange for H+, without forming a covalent disulfide bond with cysteine 813 (Figure 2). After the first of these drugs, SCH28080, caused hepatotoxicity,15Beil W. Hackbarth I. Sewing K.F. Mechanism of gastric antisecretory effect of SCH 28080.Br J Pharmacol. 1986; 88: 19-23Crossref PubMed Scopus (82) Google Scholar newer agents are currently in development, including revaprazan (YH1885), soraprazan (BY359), AZD0865, and CS-526. Each binds ionically to the proton pump at or near the potassium-binding site in a K+-competitive manner, thereby blocking acid secretion through a direct reversible mechanism.16Pope A.J. Sachs G. Reversible inhibitors of the gastric (H+/K+)-ATPase as both potential therapeutic agents and probes of pump function.Biochem Soc Trans. 1992; 20: 566-572PubMed Google Scholar, 17Wurst W. Hartmann M. Current status of acid pump antagonists (reversible PPIs).Yale J Biol Med. 1996; 69: 233-243PubMed Google Scholar This results in a very rapid onset of effect, with almost complete acid inhibition within 30–40 minutes of administration.18Sachs G. Moo Shin J. Vagin O. et al.Current trends in the treatment of upper gastrointestinal disease.Best Pract Res Clin Gastroenterol. 2002; 16: 835-849Abstract Full Text PDF PubMed Scopus (20) Google ScholarFigure 2Postulated mechanism of action of potassium-competitive acid blockers. Note that transformation to a sulphenamide is not required. Concentration in the cell is greater than with conventional PPIs and the binding is ionic and reversible.View Large Image Figure ViewerDownload (PPT)Some specific information is available on each of these compounds.Revaprazan (Yuhan Corporation, Seoul, Korea) has linear pharmacokinetics, good oral bioavailability, achieves maximal plasma concentrations at 1.3–2.5 hours after administration, with a plasma half-life of 2.2–2.4 hours in single-dose studies.19Han K.S. Kim Y.G. Yoo J.K. et al.Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intravenous and oral administrations to rats and dogs hepatic first-pass effect in rats.Biopharm Drug Dispos. 1998; 19: 493-500Crossref PubMed Scopus (32) Google Scholar, 20Yu K.S. Bae K.S. Shon J.H. et al.Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers.J Clin Pharmacol. 2004; 44: 73-82Crossref PubMed Scopus (59) Google Scholar According to its manufacturer, Soraprazan (Altana AG, Konstanz, Germany) has met its proof of efficacy and safety targets in phase II studies but data on this drug have not been published.21Available at: http://www.altana.com/files/publikationen/finanzen/praesentationen/20031009_sal-oppenheim_69.pdf. Accessed: July 23, 2005.Google ScholarIn humans, AZD0865 is absorbed rapidly, reaches peak plasma concentrations within 1 hour,22Nilsson C. Albrektson E. Rydholm H. et al.Tolerability, pharmacokinetics and effects on gastric acid secretion after single oral doses of the potassium-competitive acid blocker ASD0865 in healthy male subjects.Gastroenterology. 2005; 138: A-528Google Scholar peak inhibition of acid secretion (>95%) within the first hour of dosing, and this was sustained for 14 hours.The major potential advantages of these drugs are as follows. (1) The rapid onset of effect. A peak effect within 1 hour is an important advantage over currently available agents and may have important clinical implications for on-demand therapy and in the management of patients with gastrointestinal bleeding. (2) A linear relationship with the orally administered dose, which implies that drug dosage may be tailored to provide optimal acid control to suit individual patients.Major unanswered questions are whether these agents provide adequate acid control over the entire 24-hour period or if a second dose will need to be administered 12 hours after the initial dose and their safety over current PPIs. The development of AZ0865 was halted recently because it failed to show clinical superiority over esomeprazole.Histamine H3 AgonistsH3 receptors are located in the central nervous system and in the stomach and play a role in regulating gastric acid secretion and maintaining gastric mucosal integrity. Histamine H3 receptors are located presynaptically on brain histaminergic neurons. In the gastrointestinal tract, they are on cholinergic neurons in the myenteric plexus, in endocrine cells of the gastric mucosa, and, in some species, on parietal cells.23Coruzzi G. Poli E. Morini G. et al.The histamine H3 receptor.in: Gaginella T.S. Guglietta A. Molecular targets for drug development GI diseases. Humana Press, Totowa, NJ2000: 239-267Crossref Google Scholar Histamine H3 receptor agonists (eg, (R)-α-methylhistamine) and antagonists (eg, thioperamide) have been evaluated for their effects on acid secretion. In dogs, a dose-dependent inhibition of pentagastrin-stimulated acid output has been observed with R-α-methylhistamine.24Soldani G. Garbarg M. Intorre L. et al.Modulation of pentagastrin-induced histamine release by histamine H3 receptors in the dog.Scand J Gastroenterol. 1996; 31: 631-638Crossref PubMed Scopus (24) Google Scholar This drug has poor ability to cross membranes and is inactivated rapidly in vivo, and further development of this class will be necessary before human use can be envisaged.Antigastrin AgentsThe biological effects of cholecystokinin (CCK) are mediated by 2 specific G protein–coupled receptor subtypes, termed CCK1 and CCK2. CCK2 antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.25Lehmann F. Hildebrand P. Beglinger C. New molecular targets for treatment of peptic ulcer disease.Drugs. 2003; 63: 1785-1797Crossref PubMed Scopus (31) Google Scholar Current developmental products include Z-360, a CCK2 antagonist in phase I trials, and itriglumide, which has undergone phase 1 trials, and decreased gastrin-mediated acid secretion in phase 2 studies.26Available at: http://www.rotta.com/pages/canali/r&d/profili/2945.asp. Accessed: July 23, 2005.Google ScholarThere also is ongoing research to develop an antigastrin vaccine that would neutralize the gastrin-17 hormone. Anti–gastrin-17 vaccine is an immunoconjugate consisting of the 9 NH2-terminal amino acids of human gastrin-17 linked to a large carrier protein—diphtheria toxoid. After administration, it stimulates the production of high-affinity, gastrin-17–neutralizing antibodies. Animal data suggest that this antigastrin vaccine may have a future role as an acid-reducing agent.27Smith A.M. Morris T. Justin T. et al.Gastrimmune-induced antigastrin-17 antibodies inhibit acid secretion in a rat fistula model.Aliment Pharmacol Ther. 2001; 15: 1981-1988Crossref PubMed Scopus (11) Google Scholar, 28Justin T. Watson S. Michaeli D. et al.Gastric acid suppression using anti-gastrin 17 antibodies produced by a gastrin immunogen, Gastrimmune, in an in vivo pig model.Gastroenterology. 1995; 108: A125Abstract Full Text PDF PubMed Google Scholar No human data are available.Management of Nonresponders to Prior Treatment of Chronic Hepatitis CChronic hepatitis C virus (HCV) infection affects up to 4 million persons in the United States.29Alter M.J. Kruszon-Moran D. Nainan O.V. et al.The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.N Engl J Med. 1999; 341: 556-562Crossref PubMed Scopus (2431) Google Scholar Treatment of chronic hepatitis C has evolved over the past decade. The sustained virologic response (SVR) rate 6 months after completion of therapy improved from 10% or less with interferon monotherapy in the early 1990s, to approximately 40% with combination interferon plus ribavirin in the late 1990s,30Zaman A. Fennerty M.B. Keeffe E.B. Systematic review peginterferon vs. standard interferon in the treatment of chronic hepatitis C.Aliment Pharmacol Ther. 2003; 18: 661-670Crossref PubMed Scopus (22) Google Scholar and currently to 54%–63% with peginterferon alfa-2a or alfa-2b with ribavirin.31Manns M.P. McHutchinson J.G. Gordon S.C. et al.Peginterferon-alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomized trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar, 32Fried M.W. Shiffman M.L. Reddy K.R. et al.Combination of peginterferon alfa-2a (40 kd) plus ribavirin in patients with chronic hepatitis C virus infection.N Eng J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 33Hadziyannis S.J. Sette Jr, H. Morgan T.R. et al.Peginterferon-alfa 2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2740) Google Scholar Thus, nonresponse or relapse after therapy with peginterferon plus ribavirin now occurs in just less than half of all patients in the United States. Somewhat higher rates of response are reported in other continents where the predominant viral genotype differs from the type that is prevalent in the United States.Candidates for Re-treatmentThe goal of re-treatment, as in initial treatment, is to achieve an SVR. Re-treatment with the same regimen is not likely to result in an SVR, unless the initial drug dosage, particularly ribavirin in the first half of therapy, or duration of treatment was inadequate. An important factor to consider when evaluating a patient for possible re-treatment with peginterferon and ribavirin is the type of response achieved during previous therapy (Figure 3). Patients who relapsed, or were nonresponders but had a partial virologic response, are more likely to achieve an SVR with re-treatment than patients who had either no or minimal reduction of viral load.34Shiffman M.L. Retreatment of patients with chronic hepatitis C.Hepatology. 2002; 36: S128-S134Crossref PubMed Google Scholar Re-treatment strategies using incremental therapy can achieve modest success (Table 2). If eradication of virus is not possible, using maintenance therapy is a reasonable alternative strategy in principle to attempt to achieve the alternative goal of preventing the clinical consequences of chronic hepatitis C—cirrhosis, hepatocellular carcinoma, or death. However, this assumption is unproven and undergoing current study.Figure 3Chronic hepatitis C: possible treatment outcomes after therapy. An early virologic response is defined as greater than a 2-log reduction in HCV RNA level at week 12.View Large Image Figure ViewerDownload (PPT)Table 2Efficacy of Re-treatment in Patients Failing Prior TherapyRe-treatment regimenSVRPrior therapy nonresponders Interferon monotherapyInterferon and ribavirin13%–15% Interferon monotherapyPeginterferon and ribavirin16%–28% Interferon and ribavirinPeginterferon and ribavirin6%–15%Prior therapy relapsers Interferon monotherapyInterferon and ribavirin47% Interferon and ribavirinPeginterferon and ribavirin32%–50% Open table in a new tab The same factors that have been associated with a poor response to initial therapy also predict a poor response with re-treatment (Table 3).35Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C who responds less well?.Ann Intern Med. 2004; 140: 370-381PubMed Google Scholar Some factors potentially are correctable: patient noncompliance or excessive dose reduction by the treating physician. Other factors such as genotype, HCV RNA level, degree of fibrosis, race, and age cannot be changed and decrease the overall chance of success with re-treatment.Table 3Factors Predicting Poor Response to Re-treatmentViral characteristics Genotype 1 High HCV RNA levelHost factors Older age Advanced hepatic fibrosis African American race Obesity Hepatic steatosisAspects of prior therapy Null nonresponse (rather than relapse or partial nonresponse) Poor adherence to treatment Alcohol abuse during therapy Open table in a new tab Re-treatment of NonrespondersRe-treatment of interferon nonresponders with combination interferon plus ribavirin will achieve an SVR in 13%–15% of these individuals (Table 2).36Cheng S.J. Bonis P.A. Lau J. et al.Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy a meta-analysis of controlled and uncontrolled trials.Hepatology. 2001; 33: 231-240Crossref PubMed Scopus (124) Google Scholar, 37Cummings K.J. Lee S.M. Wen E.S. et al.Interferon and ribavirin vs. interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon.JAMA. 2001; 285: 193-199Crossref PubMed Scopus (163) Google Scholar, 38San Miguel R. Guillen F. Cabases J.M. et al.Combination therapy with interferon alfa-2a/b and ribavirin in patients with chronic hepatitis C previously non-responsive to interferon.Aliment Pharmacol Ther. 2002; 16: 1611-1621Crossref PubMed Scopus (17) Google Scholar The current approach to nonresponders to interferon monotherapy or interferon plus ribavirin is to use combination peginterferon and ribavirin (Table 4). In a trial of 604 interferon or interferon plus ribavirin nonresponders, called the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial, patients with stages 3 or 4 fibrosis were treated with peginterferon alfa-2a plus ribavirin for 48 weeks.39Shiffman M.L. Di Bisceglie A.M. Lindsay K.L. et al.Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.Gastroenterology. 2004; 126: 1015-1023Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Overall, 18% of patients had an SVR, with a higher rate in previous interferon nonresponders (28%) compared with interferon plus ribavirin nonresponders (12%). The SVR rate also varied based on a number of pretreatment parameters including genotype (65% in genotype non-1 and 14% in genotype 1), HCV RNA level, absence vs presence of cirrhosis race, age, and presence vs absence of an early virologic response.Table 4Studies of Re-treatment of Prior HCV NonrespondersPrior therapyReferenceRe-treatment regimenSVRInterferon monotherapy36Cheng S.J. Bonis P.A. Lau J. et al.Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy a meta-analysis of controlled and uncontrolled trials.Hepatology. 2001; 33: 231-240Crossref PubMed Scopus (124) Google Scholar, 37Cummings K.J. Lee S.M. Wen E.S. et al.Interferon and ribavirin vs. interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon.JAMA. 2001; 285: 193-199Crossref PubMed Scopus (163) Google Scholar, 38San Miguel R. Guillen F. Cabases J.M. et al.Combination therapy with interferon alfa-2a/b and ribavirin in patients with chronic hepatitis C previously non-responsive to interferon.Aliment Pharmacol Ther. 2002; 16: 1611-1621Crossref PubMed Scopus (17) Google ScholarInterferon plus ribavirin (meta-analysis)13%–15%Interferon monotherapy39Shiffman M.L. Di Bisceglie A.M. Lindsay K.L. et al.Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.Gastroenterology. 2004; 126: 1015-1023Abstract Full Text Full Text PDF PubMed Scopus (468) Google ScholarPeginterferon alfa-2a plus ribavirin28%Interferon monotherapy40Jacobsen I.M. Ahmed F. Russo M.W. et al.Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: a trial in prior nonresponders to interferon monotherapy or combination therapy and in combination therapy relapsers: final results.Gastroenterology. 2003; 124 (abstr): A-714Google ScholarPeginterferon alfa-2b plus ribavirin27%aPeginterferon alfa-2b 1.0 μg/kg/wk plus ribavirin 1000–1200 mg/day., 16%bPeginterferon alfa-2b 1.5 μg/kg/wk plus ribavirin 800 mg/day.Interferon plus ribavirin39Shiffman M.L. Di Bisceglie A.M. Lindsay K.L. et al.Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment.Gastroenterology. 2004; 126: 1015-1023Abstract Full Text Full Text PDF PubMed Scopus (468) Google ScholarPeginterferon alfa-2a plus ribavirin12%Interferon plus ribavirin40Jacobsen I.M. Ahmed F. Russo M.W. et al.Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: a trial in prior nonresponders to interferon monotherapy or combination therapy and in combination therapy relapsers: final results.Gastroenterology. 2003; 124 (abstr): A-714Google ScholarPeginterferon alfa-2b plus ribavirin6%aPeginterferon alfa-2b 1.0 μg/kg/wk plus ribavirin 1000–1200 mg/day.cGenotype 1 nonresponders., 11%bPeginterferon alfa-2b 1.5 μg/kg/wk plus ribavirin 800 mg/day. cGenotype 1 nonresponders.Interferon plus ribavirin41Poynard" @default.
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