Treatment of Hepatitis C: Don’t Put All Your Eggs in One Basket!

5
References 1. Friedman LS. The risk of surgery in patients with liver disease. Hepatology 1999;29:1617–1623. 2. Garrison NR, Cryer HM, Howard DA, Polk HC. Clarification of risk factors for abdominal operations in patients with hepatic cirrho- sis. Ann Surg 1984;199:648 – 655. 3. Mansour A, Watson W, Shayani V, Pickleman J. Abdominal oper- ations in patients with cirrhosis: still a major surgical challenge. Surgery 1997;122:730 –735. 4. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing tran- sjugular intrahepatic portosystemic shunts. Hepatology 2000; 31:864 – 871. 5. Northup PG, Wanamaker RC, Lee VD, Adams RB, Berg CL. Model for End-Stage Liver Disease (MELD) predicts nontransplant sur- gical mortality in patients with cirrhosis. Ann Surg 2005;242: 244 –251. 6. Perkins L, Jeffries M, Patel T. Utility of preoperative scores for predicting morbidity after cholecystectomy in patients with cirrho- sis. Clin Gastroenterol Hepatol 2004;2:1123–1128. 7. Farnsworth N, Fagan SP, Berger DH, Awad SS. Child-Turcotte- Pugh versus MELD score as a predictor of outcome after elective and emergent surgery in cirrhotic patients. Am J Surg 2004;188: 580 –583. 8. Befeler AS, Palmer DE, Hoffman M, Longo W, Solomon H, Di Bisceglie AM. The safety of intra-abdominal surgery in patients with cirrhosis: Model of End-stage Liver Disease score is superior to Child-Turcotte-Pugh classification in predicting outcome. Arch Surg 2005;140:650 – 654. 9. Suman A, Barnes DS, Zein NN, Levinthal GN, Connor JT, Carey WD. Predicting outcome after cardiac surgery in patients with cirrhosis: a comparison of Child-Pugh and MELD scores. Clin Gastroenterol Hepatol 2004;2:719 –723. 10. Teh SH, Christein J, Donohue J, Que F, Kendrick M, Farnell M, Cha S, Kamath P, Kim R, Nagorney DM. Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: Model of End-Stage Liver Disease (MELD) score predicts perioperative mortality. J Gastrointest Surg 2005;9:1207–1215. 11. Cucchetti A, Ercolani G, Vivarelli M, Cescon M, Ravaioli M, La Barba G, Zanelloi M, Grazi GL, Pinna AD. Impact of Model for End-Stage Liver Disease (MELD) score on prognosis after hepa- tectomy for hepatocellular carcinoma on cirrhosis. Liver Transpl 2006;12:966 –971. 12. Schroeder RA, Marroquin CE, Bute BP, Khuri S, Henderson WG, Kuo PC. Predictive indices of morbidity and mortality after liver resection. Ann Surg 2006;243:373–379. 13. Teh SW, Nagorney DM, Stevens SR, et al. Risk factors for mor- tality after surgery in patients with cirrhosis. Gastroenterology 2007;132:1261–1269. Address requests for reprints to: Address correspondence to: Law- rence S. Friedman, MD, Department of Medicine, Newton-Wellesley Hospital, 2014 Washington Street, Newton, Massachusetts 02462. e-mail: [email protected]. © 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.03.016 Treatment of Hepatitis C: Don’t Put All Your Eggs in One Basket! See “SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon -2b for genotype 1 non-responders,” by Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta S, Hussain M, Shah A, Cutler D, Zhang J, Zeuzem S, on page 1270. T he current standard of care for chronic hepatitis C is the combination of pegylated interferon (IFN)- and ribavirin, with the aim of eradicating the infection. 1 This is an ambitious goal, so it is not surprising that treatment sometimes fails: indeed, the infection fails to clear during therapy in approximately 20% of patients infected with hepatitis C virus (HCV) genotypes 2 and 3 and nearly half the patients infected with HCV genotypes 1 or 4. 2– 4 There are currently no approved alternatives for these patients. With 170 million infected individuals worldwide and a high prevalence of HCV infection in industrialized countries (which can afford long and ex- pensive therapeutic strategies), the pharmaceutical indus- try is engaged in an active drug discovery program with the goal of capturing part of what is a very promising market. Several dozen anti-HCV drugs are currently in development, but few have entered clinical trials. Among the many new avenues being explored, orally administered antiviral drugs that specifically inhibit a step of the HCV lifecycle (so-called specifically targeted antiviral therapies for hepatitis C [STAT-C]), have come under the spotlight for several reasons. First, the HCV lifecycle offers an almost infinite number of potential targets for specific intervention. Every single HCV protein or enzyme offers several potential targets for molecules belonging to different drug families. Second, in vitro models are giving exciting results before these drugs enter clinical development. Third, the antiviral mecha- nisms of these drugs are easy to explain and understand. Finally, the publication a couple of years ago of the results of a proof-of-concept clinical trial in which a specific inhibitor of HCV nonstructural protein 3 (NS3) serine protease inhibitor was shown to reduce HCV rep- lication by several log 10 international units per milliliter (IU/mL) in patients infected with HCV genotype 1 and, to a lesser extent, genotypes 2 and 3, 5,6 convinced many specialists in this field that these drugs were able to work miracles and that hepatitis C could well become history within a few years. Two articles, one published a few months ago 7 and one in the present issue of GASTROENTEROLOGY, 8 report excit- ing results on the capacity of specific HCV NS3 serine protease inhibitors to reduce HCV genotype 1 replica- tion. Reesink et al 7 showed that VX-950, a peptidomi- April 2007 EDITORIALS 1611

Transcript of Treatment of Hepatitis C: Don’t Put All Your Eggs in One Basket!

References

1. Friedman LS. The risk of surgery in patients with liver disease.Hepatology 1999;29:1617–1623.

2. Garrison NR, Cryer HM, Howard DA, Polk HC. Clarification of riskfactors for abdominal operations in patients with hepatic cirrho-sis. Ann Surg 1984;199:648–655.

3. Mansour A, Watson W, Shayani V, Pickleman J. Abdominal oper-ations in patients with cirrhosis: still a major surgical challenge.Surgery 1997;122:730–735.

4. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter BorgPC. A model to predict poor survival in patients undergoing tran-sjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864–871.

5. Northup PG, Wanamaker RC, Lee VD, Adams RB, Berg CL. Modelfor End-Stage Liver Disease (MELD) predicts nontransplant sur-gical mortality in patients with cirrhosis. Ann Surg 2005;242:244–251.

6. Perkins L, Jeffries M, Patel T. Utility of preoperative scores forpredicting morbidity after cholecystectomy in patients with cirrho-sis. Clin Gastroenterol Hepatol 2004;2:1123–1128.

7. Farnsworth N, Fagan SP, Berger DH, Awad SS. Child-Turcotte-Pugh versus MELD score as a predictor of outcome after electiveand emergent surgery in cirrhotic patients. Am J Surg 2004;188:580–583.

8. Befeler AS, Palmer DE, Hoffman M, Longo W, Solomon H, DiBisceglie AM. The safety of intra-abdominal surgery in patientswith cirrhosis: Model of End-stage Liver Disease score is superiorto Child-Turcotte-Pugh classification in predicting outcome. ArchSurg 2005;140:650–654.

9. Suman A, Barnes DS, Zein NN, Levinthal GN, Connor JT, CareyWD. Predicting outcome after cardiac surgery in patients withcirrhosis: a comparison of Child-Pugh and MELD scores. ClinGastroenterol Hepatol 2004;2:719–723.

10. Teh SH, Christein J, Donohue J, Que F, Kendrick M, Farnell M,Cha S, Kamath P, Kim R, Nagorney DM. Hepatic resection ofhepatocellular carcinoma in patients with cirrhosis: Model ofEnd-Stage Liver Disease (MELD) score predicts perioperativemortality. J Gastrointest Surg 2005;9:1207–1215.

11. Cucchetti A, Ercolani G, Vivarelli M, Cescon M, Ravaioli M, LaBarba G, Zanelloi M, Grazi GL, Pinna AD. Impact of Model forEnd-Stage Liver Disease (MELD) score on prognosis after hepa-tectomy for hepatocellular carcinoma on cirrhosis. Liver Transpl2006;12:966–971.

12. Schroeder RA, Marroquin CE, Bute BP, Khuri S, Henderson WG,Kuo PC. Predictive indices of morbidity and mortality after liverresection. Ann Surg 2006;243:373–379.

13. Teh SW, Nagorney DM, Stevens SR, et al. Risk factors for mor-tality after surgery in patients with cirrhosis. Gastroenterology2007;132:1261–1269.

Address requests for reprints to: Address correspondence to: Law-rence S. Friedman, MD, Department of Medicine, Newton-WellesleyHospital, 2014 Washington Street, Newton, Massachusetts 02462.e-mail: [email protected].

© 2007 by the AGA Institute0016-5085/07/$32.00

doi:10.1053/j.gastro.2007.03.016

Treatment of Hepatitis C: Don’t Put All Your Eggs in One Basket!

See “SCH 503034, a novel hepatitis C virus proteaseinhibitor, plus pegylated interferon �-2b for genotype1 non-responders,” by Sarrazin C, Rouzier R, WagnerF, Forestier N, Larrey D, Gupta S, Hussain M, Shah A,Cutler D, Zhang J, Zeuzem S, on page 1270.

The current standard of care for chronic hepatitis C isthe combination of pegylated interferon (IFN)-�

and ribavirin, with the aim of eradicating the infection.1

This is an ambitious goal, so it is not surprising thattreatment sometimes fails: indeed, the infection fails toclear during therapy in approximately 20% of patientsinfected with hepatitis C virus (HCV) genotypes 2 and 3and nearly half the patients infected with HCV genotypes1 or 4.2– 4 There are currently no approved alternatives forthese patients. With �170 million infected individualsworldwide and a high prevalence of HCV infection inindustrialized countries (which can afford long and ex-pensive therapeutic strategies), the pharmaceutical indus-try is engaged in an active drug discovery program withthe goal of capturing part of what is a very promisingmarket. Several dozen anti-HCV drugs are currently indevelopment, but few have entered clinical trials.

Among the many new avenues being explored, orallyadministered antiviral drugs that specifically inhibit a

step of the HCV lifecycle (so-called specifically targetedantiviral therapies for hepatitis C [STAT-C]), have comeunder the spotlight for several reasons. First, the HCVlifecycle offers an almost infinite number of potentialtargets for specific intervention. Every single HCV proteinor enzyme offers several potential targets for moleculesbelonging to different drug families. Second, in vitromodels are giving exciting results before these drugsenter clinical development. Third, the antiviral mecha-nisms of these drugs are easy to explain and understand.Finally, the publication a couple of years ago of theresults of a proof-of-concept clinical trial in which aspecific inhibitor of HCV nonstructural protein 3 (NS3)serine protease inhibitor was shown to reduce HCV rep-lication by several log10 international units per milliliter(IU/mL) in patients infected with HCV genotype 1 and,to a lesser extent, genotypes 2 and 3,5,6 convinced manyspecialists in this field that these drugs were able to workmiracles and that hepatitis C could well become historywithin a few years.

Two articles, one published a few months ago7 and onein the present issue of GASTROENTEROLOGY,8 report excit-ing results on the capacity of specific HCV NS3 serineprotease inhibitors to reduce HCV genotype 1 replica-tion. Reesink et al7 showed that VX-950, a peptidomi-

April 2007 EDITORIALS 1611

metic inhibitor of NS3 protease that should now becalled telaprevir (Vertex Pharmaceuticals, Cambridge,MA), is able to reduce HCV genotype 1 replication by3.5– 4.8 logs in a dose-dependent manner within 3– 4 daysof administration, both in treatment-naive patients andin patients whose infection was not cured by a previouscourse of pegylated IFN-�–ribavirin therapy. The phar-macokinetic study showed that the initial rapid declinewas related to maximal exposure to the drug, whereas thesecond phase was due to the drug’s trough concentra-tions. The decline in HCV RNA was always associatedwith a fall in alanine aminotransferase activity. Therewere no serious adverse events and no treatment inter-ruptions or discontinuations because of adverse eventsduring 2 weeks of telaprevir administration.7

In the second study, published in the present issue ofthis journal, Sarrazin et al8 report the antiviral propertiesof another peptidomimetic NS3 serine protease inhibi-tor, SCH 503034 (Schering-Plough Corporation, Ken-ilworth, NJ), used alone or in combination with pegylatedIFN-�-2b in patients who had previously failed to re-spond to pegylated IFN-�-2b alone or in combinationwith ribavirin. One week of SCH 503034 monotherapyinduced an average HCV RNA load reduction of about1.0 and 1.6 Log10 IU/mL at doses of 200 mg and 400 mg3 times a day, respectively. On average, SCH 503034appeared to exert a dose-dependent, strictly additive an-tiviral effect to that of pegylated IFN-�-2b in this heter-ogeneous population of IFN nonresponders. IndividualHCV RNA levels fluctuated over the week, reflecting theknown pharmacokinetics of pegylated IFN-�-2b, withgradual extinction of the antiviral effect before the fol-lowing injection. These fluctuations were not abrogatedby adding SCH 503034. SCH 503034 monotherapy waswell tolerated, and the side effects that occurred in pa-tients treated with the combination were ascribed topegylated IFN-�.8

These results will undoubtedly fire the enthusiasm ofpatients and physicians desperately awaiting new, effec-tive therapies. The optimistic view is indeed that STAT-Cinhibitors now exist, and that they can potently inhibitHCV replication, are well tolerated (in monotherapy, overa few days), and exert at least an additive antiviral effectwhen combined with pegylated IFN-�. The more realisticview is that, although encouraging, these results raiseserious issues as to the antiviral potency of these drugs,their tolerability, and the crucial problem of viral resis-tance.

Antiviral potency. Several classes of STAT-Cdrugs are being developed. Telaprevir and SCH 503034act as competitive inhibitors of the NS3 serine proteaseactive site.7,8 Other drug families target different func-tional regions of the NS3 protein.9 Beside NS3 serineprotease inhibitors, inhibitors of the HCV RNA-depen-dent RNA polymerase (RdRp) are in preclinical and earlyclinical development. They belong either to the nucleo-

side/nucleotide analogs, which target the RdRp catalyticsite,10 or to a number of nonnucleoside inhibitor familiesof molecules that target different allosteric sites at thesurface of the enzyme.11 Inhibitors of the HCV internalribosome entry site (IRES; inhibitors of polyproteintranslation) are being evaluated. Drugs targeting theearly steps of the HCV lifecycle or HCV proteins withunclear functions, such as NS5A, are also under study.Many other targets may at least theoretically be envisagedin the future.12 These molecules usually enter develop-ment as soon as they show some degree of antiviralefficacy in one of the existing in vitro models. However, invitro antiviral activity does not always translate into an-tiviral efficacy in vivo. There are several examples of drugsthat were highly potent in vitro but failed when admin-istered to patients, such as ribozymes or antisense oligo-nucleotides targeting the HCV IRES, or JTK-003 (AkrosPharmaceuticals, Princeton, NJ) and R803 (Rigel Pharma-ceuticals, South San Francisco, CA), nonnucleoside in-hibitors of HCV RdRp.12,13 Unfortunately, studies withnegative results are rarely published, although they couldteach us a lot. There are several possible reasons for thesein vitro/in vivo discrepancies, including the use of poorlyrelevant preclinical models, misinterpretation of preclin-ical data, poor pharmacokinetics, poor delivery of a po-tentially potent drug to its target site, or the fact that thetarget is not physically accessible in infected cells in vivo.Other drugs displayed somewhat disappointing in vivoefficacy when administered alone. Although the 2 drugswere not formally compared in a randomized controlledtrial, the studies by Reesink et al7 and by Sarrazin et al8

suggest that SCH 503034 at the dose of 400 mg 3 timesa day is a less potent antiviral drug than telaprevir givenat a dose of 750 mg every 8 hours. Valopicitabine (NM283, Idenix Pharmaceuticals, Cambridge, MA), a nucleo-side inhibitor of HCV RdRp initially tested on the modelof bovine viral diarrhea virus (a virus close to HCV),reduces HCV replication by �1 log10 IU/mL on averagewhen given alone at the dose of 800 mg/d.14 It is tempt-ing to increase the administered dose to achieve betterantiviral efficacy. For instance, R1626 (Roche, Basel, Swit-zerland), another nucleoside analog, reduces viral repli-cation by up to 3.7 log10 IU/mL on average, but at thevery high dose of 4500 mg twice a day.15 This approach,however, has limitations: high doses are often associatedwith adverse effects and they do not always improveantiviral efficacy; this is apparently the case of HCV 796(Wyeth Pharmaceuticals, Madison, NJ), a nonnucleosideinhibitor of HCV RdRp, which induces a 1.5 log10 IU/mLdecline in HCV RNA, with no difference, on average,between 500, 1000, or 1500 mg twice a day.16

Tolerability. Since the death of several patientswith chronic hepatitis B in a clinical trial of fialuridine, anucleoside analog, in the early 1990s,17 small-moleculeviral inhibitors have been under close scrutiny for poten-tial toxicity. The clinical development of BILN 2061

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(Boehringer-Ingelheim, Ingelheim, Germany), a potentHCV NS3 serine protease inhibitor and the first drug ofthis type to be administered to infected patients, has beensuspended because of myocardial toxicity in animals.5,6

The development of an enormous number of potentiallyactive HCV drug candidates was stopped before they weregiven to patients owing to concerns raised by preclinicaltoxicity studies in vitro and in animal models. Valopicit-abine induced frequent gastrointestinal symptoms, lead-ing the manufacturer to reduce the doses used in ongo-ing clinical trials. R1626 has been shown to induce adose-dependent reduction of blood cell counts and he-moglobin levels after 2 weeks of administration at highdoses,15 and the outcome of these effects is unknown iftherapy is prolonged or if ribavirin is used in combina-tion. Apparent safety during short-term administrationdoes not guarantee that no serious adverse effects willoccur when the drug is given for several weeks or months.Reesink et al7 observed no serious adverse events during14 days of telaprevir administration. However, a recentcommercial press release from Vertex Pharmaceuticals(December 13, 2006) states that, in the PROVE 1 study, aphase IIb 12-week clinical trial of the triple combinationof pegylated IFN-�, ribavirin, and telaprevir in treatment-naive patients, 3% of the patients discontinued telaprevirbecause of rash (rash was the most common reason fortreatment discontinuation). Drug– drug interactions mayalso be a problem when HCV inhibitors are used incombination with pegylated IFN, with or without ribavi-rin. In addition, although synergy or additive efficacymay be expected, antagonism can also occur, especiallybetween ribavirin, a guanosine analog, and other nucle-oside/nucleotide analogs.18 Here again, in vitro studiesmay give clues as to likely adverse effects but they cannotreplace in vivo studies.

Resistance. Another study to be published in theMay issue of GASTROENTEROLOGY19 provides a detailedmolecular analysis of HCV resistance to telaprevir over 2weeks of administration of different treatment schedulesused in the clinical trial reported by Reesink et al.7 Theauthors carefully describe the dynamics of HCV quasi-species populations during therapy. They show that re-lapse related to selection of resistant variants mainlyoccurred in patients with lower exposure to the drug.Telaprevir had to be administered every 8 hours precisely,at a dose of 750 mg, to induce a sustained biphasicdecline in viral replication. A higher dose administeredevery 12 hours, or a lower dose administered every 8hours, was associated with frequent relapses or with alack of second-phase viral decline. Both these phenomenacould be due to selection of telaprevir-resistant variants.The principal mutations were V36M/A, T54A, R155K/Tand A156S/T/V, and some patients harbored double-mutant populations. Interestingly, however, the most re-sistant virus (A156V/T) was also the least fit in vivo. Theother variants that were intrinsically less resistant to

telaprevir had better replication fitness and predomi-nated in the patients in whom high-level replicationresumed upon telaprevir administration. After treatmentcessation, resistant variants were slowly replaced by thewild-type, sensitive virus.19 Resistance selection withSTAT-C is not surprising: HCV bears all the characteris-tics required for the generation of mutant viruses, includ-ing rapid viral kinetics, large population sizes, and aquasispecies distribution of viral populations.20 In addi-tion, antiviral drugs are, by definition, drugs that selectfor resistance.21 The most surprising finding in the studyby Sarrazin et al.19 is the frequency and timing of theemergence of resistance: indeed, it occurred during thefirst week of administration in 21 of 28 treated patients.These results, together with the recent observations thatvalopicitabine can select for the RdRp S282T substitu-tion after several weeks of administration, and that HCV796 selects for the RdRp C316Y substitution in the vastmajority of treated patients after only 3 days of admin-istration (Villano S, et al, presented at the 1st Interna-tional Workshop on Hepatitis C Resistance and NewCompounds, Boston, Massachusetts, October 25–26,2006), suggest that resistant variants are preexisting, fit,and ready to be selected by any specific HCV inhibitor.These findings disqualify HCV inhibitor monotherapyand raise major ethical issues as to whether naive ornonresponder patients should now be included in trialsof STAT-C monotherapy, as there is a risk that they willbe disqualified from future trials and therapies with drugcombinations.

The 3 studies published in GASTROENTEROLOGY7,8,19 canbe interpreted in different ways. Some will consider that,at last, new potent inhibitors of HCV replication areavailable and that they will change the landscape of HCVtherapy forever. Others will focus on the many caveats ofthese studies and on the most appropriate midterm pa-tient management strategy. At this point, it is clear thatspecific HCV inhibitors should not be used alone. Com-bination therapy with oral antiviral drugs requires com-pany portfolios to contain more than one such drug.Appropriate preclinical drug– drug interaction studieshave to be performed before clinical trials are initiated.This may take several years. In the meantime, new strat-egies are needed to improve the results of current HCVtherapy. The conservative approach aimed at optimizingpegylated IFN-ribavirin therapy should not be neglected.Preliminary results have shown that increasing the doseand/or the number of injections of pegylated IFN in-creases the response rate, and this is being further ex-plored in ongoing trials. Likewise, increasing the dose ofribavirin has been shown to significantly improve thecure rate, and the adverse effects of ribavirin can now bepartly controlled by using erythropoietin.22–24 Other trialsare addressing the best way of tailoring the duration oftreatment to the early virologic response (the HCV RNAdecline at week 4 or even week 2) to shorten therapy in rapid

April 2007 EDITORIALS 1613

responders and to prolong therapy in slow responders whomay relapse if treatment is withdrawn too early.25–28 An-other option is to enhance pegylated IFN-ribavirin efficacyby adding STAT-C drugs with an additive or synergisticantiviral effect. Such combinations have the advantage oftheoretically preventing the onset of resistance to the inhib-itor, through the antiviral effect of IFN-�. This may indeedhappen in good IFN responders, although it is unclearwhether IFN inhibition is sufficient to avoid the emergenceof resistance. In addition, patients with little or no responseto IFN will in effect be receiving inhibitor monotherapy.Preliminary data are encouraging: valopicitabine and SCH503034 appear to have a dose-dependent additive effectwhen combined with pegylated IFN-�,8,14 and HCV RNAbecame undetectable (�10 IU/mL) in 12 patients receivingthe triple combination of pegylated IFN-�, ribavirin, andtelaprevir.29 Ongoing trials will show how well double andtriple combinations are tolerated, and whether the re-sponses persist when the STAT-C drug or the combinationis withdrawn.

Novel oral antiviral approaches are exciting and fash-ionable. The spectacular antiviral efficacy of some ofthese drugs should not, however, be allowed to mask thespecific new problems they raise. Although adjunction ofan oral HCV inhibitor may give interesting results, otheroptions are already available for the treatment of chronichepatitis C, including optimization of the current pegy-lated IFN-�–ribavirin combination. All these optionsshould be explored, as they may benefit patients in thenear future. So there is not one, but several potentialfutures for hepatitis C therapy. Let’s keep our mindsopen and not put all our eggs in one basket, even if thebasket looks adequate for the job.

JEAN–MICHEL PAWLOTSKYFrench National Reference Center for ViralHepatitis B, C and DeltaDepartment of VirologyHôpital Henri MondorUniversité Paris 12; andINSERM U841Créteil, France

References

1. National Institutes of Health Consensus Development Confer-ence Statement: Management of hepatitis C: 2002-June 10–12,2002. Hepatology 2002;36:S3–20.

2. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, GoncalesFL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, LinA, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronichepatitis C virus infection. N Engl J Med 2002;347:975–982.

3. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Mar-cellin P, Ramadori G, Bodenheimer H Jr, Bernstein D, Rizzetto M,Zeuzem S, Pockros PJ, Lin A, Ackrill AM. Peginterferon-alpha2aand ribavirin combination therapy in chronic hepatitis C: a ran-domized study of treatment duration and ribavirin dose. AnnIntern Med 2004;140:346–355.

4. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M,Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Pegin-terferon alfa-2b plus ribavirin compared with interferon alfa-2bplus ribavirin for initial treatment of chronic hepatitis C: a ran-domised trial. Lancet 2001;358:958–965.

5. Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, SentjensRE, Calleja JL, Forns X, Erhardt A, Cronlein J, Chaves RL, Yong CL,Nehmiz G, Steinmann GG. Short-term antiviral efficacy of BILN2061, a hepatitis C virus serine protease inhibitor, in hepatitis Cgenotype 1 patients. Gastroenterology 2004;127:1347–1355.

6. Reiser M, Hinrichsen H, Benhamou Y, Reesink HW, WedemeyerH, Avendano C, Riba N, Yong CL, Nehmiz G, Steinmann GG.Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 inpatients with chronic genotype 2 and 3 hepatitis C. Hepatology2005;41:832–835.

7. Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, vande Wetering de Rooij J, McNair L, Purdy S, Kauffman R, Alam J,Jansen PL. Rapid decline of viral RNA in hepatitis C patientstreated with VX-950: a phase Ib, placebo-controlled, randomizedstudy. Gastroenterology 2006;131:997–1002.

8. Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta S,Hussain M, Shah A, Cutler D, Zhang J, Zeuzem S. SCH 503034,a novel hepatitis C virus protease inhibitor, plus pegylated inter-feron a-2b for genotype 1 non-responders. Gastroenterology2007;132:1270–1278.

9. Pawlotsky JM, McHutchison JG. Hepatitis C. Development of newdrugs and clinical trials: promises and pitfalls. Summary of anAASLD hepatitis single topic conference, Chicago, IL, February27–March 1, 2003. Hepatology 2004;39:554–567.

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11. Koch U, Narjes F. Allosteric inhibition of the hepatitis C virusNS5B RNA dependent RNA polymerase. Infect Disord Drug Tar-gets 2006;6:31–41.

12. McHutchison JG, Bartenschlager R, Patel K, Pawlotsky JM. Theface of future hepatitis C antiviral drug development: recentbiological and virologic advances and their translation to drugdevelopment and clinical practice. J Hepatol 2006;44:411–421.

13. Georgopapadakou N. Discontinued drugs in 2005: anti-infec-tives. Expert Opin Investig Drugs 2007;16:1–10.

14. Afdhal NH, O’Brien C, Godofsky E, Rodriguez-Torres M, PappasSC, Pockros P, Lawitz E, Bzowej N, Rustgi V, Sulkowski M,Sherman KE, Jacobson I, Chao G, Knox S, Pietropaolo K, BrownN. Valopicitabine (NM283), alone or with peg-interferon, com-pared to peg-interferon/ribavirin (PEGIFN/RBV) retreatment inhepatitis C patients with prior non-response to PEGIFN/RBV:week 24 results. J Hepatol 2006;44(Suppl 2):S19.

15. Roberts S, Cooksley G, Dore G, Robson R, Shaw D, Berns H,Brandl M, Fettner S, Hill G, Ipe D, Klumpp K, Mannino M, O’MaraE, Tu Y, Washington C. Results of a phase 1b, multiple dosestudy of R1626, a novel nucleoside analogue targeting HCVpolymerase in chronic HCV genotype 1 patients. Hepatology2006;44(Suppl 1):692A.

16. Chandra P, Raible D, Harper D, Speth J, Villano S, Bichier G.Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in patients with chronic hepatitis C virus: preliminary resultsfrom a randomized, double-blind, placebo-controlled, ascendingmultiple dose study. Gastroenterology 2006;130(Suppl 2):A748.

17. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM,Park Y, Savarese B, Kleiner D, Tsokos M, Luciano C, Pruett T,Stotka JL, Strauss SE, Hoofnagle JH. Hepatic failure and lacticacidosis due to fialuridine (FIAU), an investigational nucleosideanalogue for chronic hepatitis B. N Engl J Med 1995;333:1099–1105.

18. Coelmont L, Paeshuyse J, Windisch MP, De Clercq E, Barten-schlager R, Neyts J. Ribavirin antagonizes the in vitro anti-hepa-titis C virus activity of 2’-C-methylcytidine, the active component

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of valopicitabine. Antimicrob Agents Chemother 2006;50:3444–3446.

19. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M,Wincheringer D, Zhou Y, Chu HM, Lin C, Weegink C, Reesink H,Zeuzem S, Kwong AD. Dynamic HCV genotypic and phenotypicchanges in patients treated with the protease inhibitor telaprevir(VX-950). Gastroenterology 2007;132:(In Press)

20. Pawlotsky JM. Hepatitis C virus population dynamics during in-fection. Curr Top Microbiol Immunol 2006;299:261–284.

21. Richman DD. The impact of drug resistance on the effectivenessof chemotherapy for chronic hepatitis B. Hepatology 2000;32:866–867.

22. Darling JM, Fried MW. Optimizing treatment regimens in hepatitisC. Clin Liver Dis 2006;10:835–850.

23. Del Rio RA, Post AB, Singer ME. Cost-effectiveness of hemato-logic growth factors for anemia occurring during hepatitis C com-bination therapy. Hepatology 2006;44:1598–1606.

24. Thevenot T, Cadranel JF, Di Martino V, Pariente A, Causse X,Renou C, Hagege H, Denis J, Lunel-Fabiani F. A national Frenchsurvey on the use of growth factors as adjuvant treatment ofchronic hepatitis C. Hepatology 2007;45:377–3383.

25. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M,Vinelli F, Scotto G, Bacca D, Annese M, Romano M, Zechini F,Sogari F, Spirito F, Andriulli A. Peginterferon alfa-2b and ribavirinfor 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med2005;352:2609–2617.

26. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J,Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J. Efficacy of

24 weeks treatment with peginterferon alfa-2b plus ribavirin inpatients with chronic hepatitis C infected with genotype 1 and lowpretreatment viremia. J Hepatol 2006;44:97–103.

27. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR,Hadziyannis SJ, Ferenci P, Ackrill AM, Willems B. Early identifica-tion of HCV genotype 1 patients responding to 24 weeks pegin-terferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43:954–960.

28. Berg T, von Wagner M, Nasser S, Sarrazin C, Heintges T, GerlachT, Buggisch P, Goeser T, Rasenack J, Pape GR, Schmidt WE,Kallinowski B, Klinker H, Spengler U, Martus P, Alshuth U,Zeuzem S. Extended treatment duration for hepatitis C virus type1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plusribavirin. Gastroenterology 2006;130:1086–1097.

29. Rodriguez-Torres M, Lawitz E, Muir AJ, Keane J, Kieffer TL, McNairL, McHutchison J. Current status of subjects receiving peginter-feron alfa-2a (PEG-IFN) and ribavirin (RBV) follow-on therapy after28-day treatment with the hepatitis C protease inhibitor telaprevir(VX-950), PEG-IFN and RBV. Hepatology 2006;44 (suppl 2):532A.

Address requests for reprints to: Prof. Jean-Michel Pawlotsky, MD,PhD, Department of Virology, Hôpital Henri Mondor, 51 avenue duMaréchal de Lattre de Tassigny, 94010 Créteil, France. e-mail: [email protected].

© 2007 by the AGA Institute0016-5085/07/$32.00

doi:10.1053/j.gastro.2007.03.014

Got Guts? Need Nerve!

See “Enteric glia regulate intestinal barrierfunction and inflammation via release of s-nitrosoglutathione,” by Savidge T, Newman P,Pothoulakis C, Ruhl A, Neunlist M, BourreilleA, Hurst R, Sofroniew MV, on page 1344.

Studies of inflammatory bowel disease (IBD) patho-genesis have primarily focused on the mucosal im-

mune system and, more recently, the epithelium. Studiesof experimental IBD also suggest a potential role forenteric glia in disease pathogenesis.1,2 Together with neu-rons, glia are intrinsic components of the enteric nervoussystem. Within the mucosa, the enteric glia, which encasenerve fibers, form a dense mesh surrounding the crypt basesand experimental ablation of these enteric glia results insevere hemorrhagic enteritis.1,2 New data reported in thisissue of GASTROENTEROLOGY suggest that disruption of in-testinal epithelial barrier function may be one mechanismby which glial ablation causes enteritis (Figure 1).3

Disruption of the intestinal epithelial barrier, whichcan be measured as increased permeability, is common ingastrointestinal disease and was reported in Crohn’s dis-

ease (CD) �25 years ago.4 These increases in permeabilitymight simply be due to mucosal ulceration, but are alsopresent in patients with inactive CD, in which ulcerationis not present. In addition, the presence of increasedpermeability during clinical remission is associated withgreater rates of relapse to active CD.5,6 Correlative dataalso suggest that barrier defects may be related to initialCD pathogenesis; a subset of healthy first-degree relativesof CD patients are known to have increased permeabil-ity.7 Although anecdotal, the report of CD in a previouslyhealthy first-degree relative with increased permeabilityfurther supports the idea that barrier loss may be acontributing factor in IBD development.8 There are alsoemerging data that immune-mediated barrier defects areprevalent in diarrhea-predominant irritable bowel syn-drome (IBS).9,10 Together with increased appreciation ofpermeability defects in animal models over the past de-cade,11,12 these observations have fueled interest in the roleof intestinal permeability in disease. Many believe that im-proved understanding of the mechanisms of barrier loss hasgreat potential to define pathogenesis of IBD, and IBS, andmay drive development of novel treatments.

Inflammatory activity and cytokine stimulation may beresponsible for some cases in which increased intestinal

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