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A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C

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A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C
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   A National French Survey on the Use of GrowthFactors as Adjuvant Treatment of Chronic Hepatitis C Thierry Th´ evenot, 1  Jean-Franc¸ois Cadranel, 2  Vincent Di Martino, 1  Alexandre Pariente, 3  Xavier Causse, 4 Christophe Renou, 5 Herv ´ e Hagege, 6  Jacques Denis, 7 and Franc¸oise Lunel-Fabiani 8  We conducted a national retrospective survey on hospital practitioners to evaluate themagnitude of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) pre-scriptions in patients treated for chronic hepatitis C. Four hundred seventy-one question-nairesweresent,and274practitioners(58.2%)responded.Forty-sixpercentofpractitionersused EPO, and 31% used G-CSF. The total number of HCV-infected patients receivingantiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% receivedEPO and G-CSF, respectively. EPO-   was the main EPO molecule prescribed at a mediandose of 30,000 IU/wk (range: 2,000-80,000). The indications for prescribing EPO variedgreatly, including “fragile patients” (34%), “low” Hb level (8-11 g/dL) (19%), “rapid de-cline” in Hb level (2-5 g/dL during the first month of therapy) (12%), and symptomaticanemicpatients(7%).G-CSFwasmainlyprescribedfora“low”levelofneutrophilsrangingfrom 400 to 750 neutrophils/mm 3 . In multivariate analysis, independent predictors of EPOand G-CSF prescription were age of practitioner less than 45 years (EPO: OR   1.96,  P   0.03;G-CSF:OR   2.27, P   0.004),practiceinuniversityhospital(EPO:OR   5.89, P  < 0.0001; G-CSF: OR   2.39,  P   0.003), and the high number of CHC treated/year (EPO:OR   6.18, P  < 0.0001;G-CSF:OR   2.58, P   0.002). Conclusion :Oursurveyrevealsanimportant rate of EPO and G-CSF prescriptions but with considerable disparity in thescheduleofinjections,themoleculesused,andabovealltheindications.Thesuitableroleof EPOandG-CSFascomplementstoHCVtherapyurgentlyneedstobeclarified. (H EPATOLOGY  2007;45:377-383.) H epatitis C virus infection is a major cause of morbidity and mortality, affecting 170 millionpeopleworldwide 1,2 andatotalof368,000peo-ple in France in 2004, of whom 221,000 were RNA pos-itive. 3 Persistent infection over many years is associated with an increased risk of complications including cirrho-sis, hepatic decompensation, and hepatocellular carci-noma.ThecurrentandmoreeffectivetreatmentforHCV infection consists of a combination of pegylated inter-feron with ribavirin, providing a sustained virological re-sponse rate of 40% to 45% in patients with HCV genotype 1 and of 80% in patients with HCV genotypes2 or 3 in randomized controlled trials. 4,5 However, thesustained viral response rate decreases dramatically whenadherence to treatment is not optimal. 6 Patients may notcomply with the treatment regularly because of the mul-tiple side effects encountered, especially a dose-limiting hemolytic anemia with ribavirin that often results in early  withdrawal. Neutropenia is another concern, but to a lesser extent. Adverse hematological events may requiretreatmentdisruptionorresultina10%to20%reductionin virological response. 4,5,7 Because the primary goal of   Abbreviations: ANGH, Association Nationale des He ´pato-Gastroente ´rologues desHoˆpitauxge ´ne ´rauxdeFrance;EPO,erythropoietin;G-CSF,granulocytecolony-stimulating factor; HGF, hematopoietic growth factors; PEG-IFN, pegylated inter- feron; QoL, quality of life.From the   1 Service d’He ´patologie et de Soins Intensifs Digestifs, Hoˆpital Univer-sitaire Jean Minjoz, the   2  Service d’He ´pato-Gastroente ´rologie et de Diabe ´tologie, HoˆpitalLaennec,the   3 Serviced’He ´pato-Gastroente ´rologie,HoˆpitalMitterrand,the  4  Service d’He ´pato-Gastroente ´rologie, Centre Hospitalier Re ´gional d’Orle ´ans, the  5  Service d’He ´pato-Gastroente ´rologie, Hoˆpital d’Hye `res,  6  Service d’He ´pato-Gastro-ente ´rologie, Centre Hospitalier Intercommunal de Cre ´teil, the   7  Service d’He ´pato-Gastroente ´rologie, Hoˆpital Louise Michel, and the   8  Laboratoire de Bacte ´riologie-Virologie et Hygie `ne Hospitalie `re, Hoˆpital Universitaire d’Angers, France.Received August 16, 2006; accepted October 22, 2006.This study was conducted on behalf of the: Association Nationale des He ´pato-Gastroente ´rologues des Hoˆpitaux ge ´ne ´raux (National Association of General Hos-  pitalHepatogastroenterologists)ANGHandtheAssociationFranc ¸aisedel’EtudeduFoie (French Association for the study of the Liver) AFEF. Address reprint requests to: Thierry The ´venot, Service d’He ´patologie et de Soins Intensifs Digestifs, Hoˆpital Jean Minjoz, 25000 Besanc ¸on, France. E-mail:tthevenot@chu-besancon.fr; fax: (33)-3-81-66-88-18.Copyright © 2007 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.21517 Potential conflict of interest: Nothing to report. 377  HCV therapy is to achieve a sustained viral response andultimately to avoid long-term complications of HCV in-fection,itseemsimportanttomaximizetherapeuticcom-pliance. Evolving experience and recent clinical trialsindicate that the use of hematopoietic growth factors(HGF), namely the granulocyte colony–stimulating fac-tor(G-CSF)anderythropoietin(EPO),inadditiontothetreatment of HCV infection, may allow maintenance of the optimal dose and duration of ribavirin or pegylatedinterferon (PEG-IFN) while improving the quality of life. 8-10 Currently, no official guidelines exist for treating antiviraltherapy–associatedanemiaandneutropenia,andmany issues remain unresolved. Nevertheless, differentcommercialized HGF seem to be prescribed more andmoreinFrance,althoughtherenodataareavailableaboutthe real burden of these prescriptions. Our study aims toevaluate the magnitude of HGF prescriptions in Franceand to specify the schedules of these prescriptions. Materials and Methods Study Design.  This was a retrospective study con-ducted by practitioners belonging to general or university hospitals. In November 2005, a first anonymous ques-tionnaire was sent to 296 department heads of generalhospitals belonging to the “Association Nationale desHe´pato-Gastroente´rologues des Hoˆpitaux ge´ne´raux deFrance” (ANGH) covering 95 out of the 100 metropoli-tanandoverseasadministrativedivisions(“departments”)that make up France. The addresses of the ANGH’smembers were taken from the 2005 yearbook. Fourmonths later, the same questionnaire was mailed again tothe department heads of those general hospitals who hadnot answered. This survey was then extended to the uni-versity hospitals, and 175 questionnaires were sent tohepatogastroenterologists practicing in these settings.There was no follow-up letter for university hospitals. Alloftheassistantsofeachdepartmentheadwereencouragedto fill out the questionnaire. Survey and Data Record.  The single-page question-nairewasmailedwithacoverletterdescribingthepurposeof the survey and its confidential nature. The following data were recorded: age, sex, department area and/ortown, specialized area of medicine (hepato-gastroenterol-ogist, internist, or infectious diseases specialist), numberof HCV-positive patients treated in the previous 12months, and number of patients treated with EPO or with G-CSF during that period. Regarding HGF pre-scriptions,weaskedpractitionersthefollowingquestions:(1) what molecule, dose, and number of injections per week were prescribed for the 3 available erythropoieticagents [epoetin alfa (Eprex), epoetin beta (Neorecor-mon),anddarbepoetinalfa(Aranesp)]andthe3availableG-CSF[filgrastim(Neupogen),lenograstim(Granocyte),andpegfilgrastim(Neulasta)]?(2)IfyoudidnotuseEPO(orG-CSF),doyouprefertodecreasetheribavirindoseto600 mg/day when hemoglobin (Hb) level is less than 10g/dL and to stop ribavirin below an Hb level less than 8.5g/dL according to manufacturer’s recommendations? (3)If you did not use EPO (or G-CSF), do you prefer toadapt antiviral therapy to the patients’ clinical tolerance?Finally, we also inquired about the adverse effects ob-served with these molecules. Statistical Analysis.  Responses were collected by 2investigators (T.T. for general hospitals and F.L.B. foruniversity hospitals), and data were analyzed by a thirdinvestigator (V.D.M.) with the NCSS package for Win-dows (Hintze J, 2004, Kaysiville, UT). Quantitative vari-ables were expressed as means  SE or as medians (95%confidenceintervals,CI)incaseofabnormaldistribution.The relationship between physician characteristics andHGF prescription was assessed using a chi-square or Stu-dent t test for univariate analyses. Multivariate analyses were performed using logistic regression analysis on thebasis of univariate analyses results and absence of colin-earity.A  P  valuelessthan0.05wasconsideredstatistically significant. Results Study Population.  Of 471 questionnaires sent, wecollected 274 responses (58.2%), including 205 of 296responses (69.3%) from ANGH members and 69 of 175responses (39.4%) from university hospitals. Nearly 75%ofallresponsescamefromgeneralhospitals.ANGHprac-titioners from 84 departments (88.4%) responded. Only  ANGH practitioners from 13 hospitals representing 10metropolitan and one overseas ‘departments’ did not re-spond despite a follow-up letter.The total number of HCV-infected patients receiving antiviral therapy per year as declared by the responding practitioners was estimated at 6,630 patients. Table 1showsthecharacteristicsofrespondingpractitionersfrom  Table 1. Characteristics of Practitioners Parameter OverallUniversity HospitalsGeneralHospitals  P   Value Age (years) 47  8 45  8 48  8 0.013Sex (% males) 76% 56.7% 83.1%   0.0001Hepatogastroenterologists (%) 96% 98.6% 95.1% NSNumber of cases of hepatitis C treated/year   30 cases/year (%) 25.9% 56.5% 15.6%   10  6  50 cases/year (%) 9.8% 26.1% 4.4%   10  6 P   value indicates difference between university and general hospitals. 378 THE´VENOT ET AL. HEPATOLOGY, February 2007  general hospitals and university hospitals. In general hos-pitals, practitioners were older (48    8 versus 45    8years, P   0.013),predominantlymale(83%versus57%, P   0.0001) and declared a lower number of HCV-in-fected patients treated per year. Considering the wholepopulation of practitioners, 90% and 74% said that they had treated fewer than 50 and 30 cases of CHC respec-tively over the previous 12 months. EPO Prescription.  Overall, 136 practitioners(49.6%) used HGF: 52 only EPO, 74 both EPO andG-CSF, and 10 only G-CSF. There were 126 (46%) whoprescribed EPO (EPO-  , 20%; darbepoetin-  , 30%;EPO-  , 38%; and not determined in 12%). The numberof EPO-treated patients was 581 (8.8% of the HCV-infectedpopulationreceivingantiviraltherapy).Itrangedfrom 1 to 30 (median, 3 patients) per practitioner. Only 21.4% of practitioners prescribed EPO for more than 5patients; most (78%) work in university hospitals. Tocompare the dose administered by each practitioner, weassumed that 200 IU EPO was equivalent to 1  g darbe-poetin-  ,andweusedthemeanvaluebetweenthelowestand the highest declared doses. The median dose was30,000IU/week(range,2,000-80,000IU/wk)with1to3injections/week. The reported indications for prescribing EPO varied greatly among practitioners. They could becategorizedaccordingtopatientstatusasfollows:“fragile”patients,patientswitharapiddeclineofHblevel,patients with a “low” Hb level, and patients with symptomaticanemia. The “fragile patients” represented 34% of themainindicationsofEPOprescription.ItconcernedHIV-HCV-coinfected patients, hemodialyzed patients, or pa-tients with end-stage renal disease, liver transplantrecipients, and patients with cirrhosis. The patients withso-called “low” Hb level represented the second indica-tion of EPO prescription (19%), but the threshold of “low” Hb level extended from 8 to 11 g/dL. A rapiddecline in Hb level concerned 12% of EPO prescription.This decline in Hb level was widely scattered from 2 to 5points during the first month of therapy. Symptomaticanemic patients (7%) were the last indication. In univar-iate analysis (Table 2), practitioner characteristics associ-ated with EPO prescription were as follows: practice inuniversity hospital (84% versus 33%,  P   0.0001), ageyounger than 45 years (59% versus 41%,  P     0.005),femalegender(61%versus42.5%,P  0.009),andmorethan 30 chronic hepatitis C treated/year (82% versus33.5%, P   0.0001).Inmultivariateanalysis(Table2),3independent predictors of EPO prescription were as-sessed:ageyoungerthan45years(OR   1.93, P   0.03),practice in university hospital (OR   5.89,  P   0.0001),and high number of CHC treated/year (OR   6.18,  P   0.0001). G-CSF Prescription.  G-CSF was prescribed by 84(31%) practitioners, 74 of whom used both EPO andG-CSF. The number of G-CSF–treated patients was 268(4% of the HCV-infected population receiving antiviraltherapy). One to 20 patients (median, 2 patients) weretreated by each of these practitioners. Only 10.8% of practitioners prescribed G-CSF for more than 5 patients;most (67%) work in university hospitals. When only onemolecule of G-CSF was used (84.5%), it was filgrastim in43 cases (61%), lenograstim in 21 cases (30%), and peg-filgrastim in seven cases (9%). The G-CSF molecule wasnot mentioned in 7% of additional cases. Several mole-cules of G-CSF were used in 8.5%. The schedule of lenograstim administration was either 1 or 2 injectionsperweek.Seventy-fourpercentofpractitionersprescribedhigh doses of lenograstim (Granocyte 34), whereas theothers used Granocyte 13. Concerning pegfilgrastim, theprescription schedule was undetermined in three cases,and the medication was administered at 6 mg/2 weeks in2 cases and at 6 mg/3 weeks in the remaining two cases.Filgrastimwasthemostprescribedmolecule(n  43)ata mean dose of 43 millions  20 (range, 15-90) IU/week.Most practitioners prescribed filgrastim once weekly (73%), and a minority (9%) used a thrice-weekly sched-ule. The reported indication for prescribing G-CSF wasmainlya“low”levelofneutrophils(65%),butthethresh-old of prescription ranged from 400 to 750 neutrophils/mm 3 . The other indications were related to patientcondition: patients with cirrhosis, HIV-HCV-coinfectedpatients, hemodialyzed patients, and liver transplant re-  Table 2. Multivariate Analysis of Factors Associated with EPO Prescription Parameter Univariate Analyses Logistic Regression Analysis% EPOPrescription  P   OR 95% CI OR  P   Value University hospitals (vs. general hospitals) 84.1 vs. 33.2   0.0001 5.89 2.64-13.12   0.0001Hepatogastroenterologists (vs. others) 46.2 vs. 36.4 NS 0.83 0.20-3.35 NSAge  45 years (vs.  45 years) 58.8 vs. 41 0.005 1.93 1.05-3.57 0.035Female gender of practitioner (vs. male gender) 61.3 vs. 42.5 0.009 1.07 0.51-2.27 NS  30 cases (vs.  30 cases) of hepatitis C treated/year 81.7 vs. 33.5   0.0001 6.18 2.79-13.67   0.0001Use of G-CSF (vs. non use) 88.1 vs. 27   10  5 – – – HEPATOLOGY, Vol. 45, No. 2, 2007 THE´VENOT ET AL. 379  cipients, or aimed to preserve a good anti-viral response,especially in patients with a high fibrosis score (F2 orgreater according to the Metavir scoring system). In uni-variate analysis (Table 3), practitioner characteristics as-sociated with G-CSF prescription were as follows:practice in university hospital (63% versus 20%,  P    0.0001), age younger than 45 years (41% versus 27%, P   0.018), female sex (43.5 % versus 28 %,  P   0.023),high number of chronic hepatitis C treated/year (  30/year) (60% versus 21%,  P   0.0001). The use of EPO was also more frequent for practitioners using G-CSF(59% versus 7%,  P   0.0001). In multivariate analysis(Table 3), the 3 independent predictors of G-CSF pre-scription were: age younger than 45 years (OR   2.27, P   0.004), practice in university hospital (OR   2.40, P     0.003), and high number of chronic hepatitis Ctreated per year (OR   2.59,  P   0.002). ReportedSideEffects.  Side effects of EPO or G-CSF were reported by only 13% of practitioners. For EPO, 13adverseeventswerereported:“allergy”withpruritus(n  5), headache (n  2), arterial hypertension (n  2), purered-cellaplasia(n  2),andmyalgia(n  2).ForG-CSF,only eight side effects were observed: arthralgia (n  2)and bone pain (n  6). Discussion ThemainresultprovidedbythecurrentstudywasthatEPO and G-CSF were widely used by 46% and 31% of practitioners,respectively,andfor8.8%and4%ofHCV-infected patients, respectively. Encouraging patient com-pliance to antiviral therapy and limiting dose disruptionsor decreases provoked by side effects may be useful inachieving viral clearance. To maximize sustained viral re-sponserateinHCV-positivepatientsreceivingtreatment,it appears critical to maintain ribavirin dose, especially during the first 12 weeks, 11 and adequate doses and dura-tion of PEG-IFN. 6 Toward this, HGF may be a promis-ing approach to counteract adverse effects of bothribavirin and interferon, including ribavirin-induced he-molysis and PEG-IFN–related neutropenia, which haveresultedintheneedfordosereductionordiscontinuationof therapy in up to 30% of patients. 12 This “optimizedtherapy” could be of particular interest in “difficult-to-treat” patients, including HIV- and HCV-coinfected pa-tients, patients with end-stage renal disease, livertransplant recipients, and patients with cirrhosis. 13 De-spite growing evidence suggesting that EPO and G-CSFmay preserve HCV-combination therapy, there is no li-cense to date for their prescription in the setting of chronic hepatitis C. Indeed, health authorities are still waiting for randomized controlled trials showing thatHGF actually increases the rates of sustained viral re-sponse. Moreover, numerous issues such as optimal dos-age,timeofinitiation,durationoftherapy,andefficacyof this strategy are still unresolved. We present herein the first survey providing a reliablepicture assessing the clinical use of HGF as an adjuvanttherapy of chronic hepatitis C in a representative panel of French practitioners treating more than 6,500 HCV-in-fectedpatientsduringthepastyear.Indeed,thequestion-naire was anonymous, and the responding practitioners were informed of the scientific nature of this study con-ducted on behalf of 2 scientific societies (i.e., AFEF and ANGH) totally independent of the firms commercializ-ing EPO and G-CSF. The 60% response rate closely cor-relates with the percentages (49%-94%) noted in otherFrench epidemiological surveys on viral hepatitis. 14-17 TheprofileofapractitionerprescribingEPOorGCSF was typically a young female doctor from a university hospital in charge of a large number of HCV-infectedpatients.Despitethewide-scaleuseofthesedrugsandthereproducibleprofileofpractitionersprescribingthem,theresponses reflected considerable disparity in terms of thecircumstances of prescription, the molecules used, andthe schedules followed. For instance, the administereddose of EPO varied from 2,000 to 80,000 IU/week, withone to three injections/week similarly in general or uni-versity hospitals. Surprisingly, most practitioners usedEPO-   as the main molecule, whereas trials in chronichepatitis C have preferred EPO-  . 8,9,18-23 Few studies  Table 3. Multivariate Analysis of Factors Associated with G-CSF Prescription Parameter Univariate Analyses Logistic Regression Analysis% GCSF prescription  P   OR 95% CI OR  P   Value University hospitals (vs. general hospitals) 63.2 vs. 20   0.0001 2.40 1.33-4.34 0.004Hepatogastroenterologists (vs. others) 31 vs. 27.3 NS 0.66 0.15-2.84 NSAge  45 yrs (vs.  45 yrs) 40.7 vs. 26.6 0.018 2.27 1.29-3.95 0.004Female gender of practitioner (vs. male gender) 43.5 vs. 28.1 0.023 1.32 0.69-2.49 NS  30 cases (vs.  30 cases) of hepatitis C treated/year 60 vs. 20.7   0.0001 2.59 1.40-4.78 0.002Use of EPO (vs. non use) 59.2 vs. 6.8   0.0001 – – – 380 THE´VENOT ET AL. HEPATOLOGY, February 2007  used EPO-  21,24 or darbepoetin-  . 25,26 Regarding EPOindications, large variations of the Hb threshold (8-11g/dL) or the magnitude of Hb decline (1-5 points) wereobserved during the first month of therapy. These resultsclearly show the lack of harmonization for EPO prescrip-tion in most trials, especially those related to treating recurrent hepatitis C after liver transplantation whereEPO was started at a Hb level between 8 and 10g/dL. 22,23,26,27  As expected, multivariate analysis demonstrated thatthestrongestindependentpredictorsofEPOprescription were associated with the experience of “difficult-to-treat”HCV-positivepatients(i.e.,practiceinuniversityhospitaland high number of HCV-infected patients treated peryear). The third independent predictor was a practitionerage of younger than 45 years. Such “young” practitioners were probably more receptive to innovative treatments. Adverse events related to EPO were rare. However, purered-cell aplasia was reported for 2 patients treated withepoetin-  . This uncommon disorder, associated with thepresence of anti-EPO antibodies, has no well-identifiedcausative factors. 30 It has been described in hemodialyzedpatients receiving subcutaneous injections of epoetin-  ,and it has been reported in only one HCV-infected pa-tient treated with peginterferon  -2a, ribavirin, and epo-etin-  . 31 Moreover, it was remarkable to discover thesecases 3 years after the reported peak of incidence in 2001-2002,whenimprovementsinstorage,handling,EPOad-ministration, and the monitoring of treated patients weresupposed to prevent such disorders. 32  Although there were not enough data to check the diagnosis of pure red-cell aplasia, we think that our two reported cases werevalid because two cases of pure red-cell aplasia in FrenchHCV-infected patients occurred within the same periodas reported by one of the manufacturers (Roche, personalcommunication). One of the 2 reported cases by theRoche laboratory was doubtful. Although a great disparity was reported in the dosesadministered and prescription indications of G-CSF, it was prescribed less frequently than EPO and mainly in-volved filgrastim, in concordance with studies employing G-CSF as an adjuvant therapy in chronic hepatitisC. 21,23,26-29 The prescription of G-CSF covered a smallerproportion of practitioners (31% versus 46%) and only 4% of HCV-infected patients undergoing antiviral ther-apy. Two reasons may explain this finding. First, ribavi-rin-induced anemia is more common than IFN-inducedneutropenia. In patients receiving PEG-IFN and ribavi-rin, an Hb drop of 3 g/dL or more occurred in 49% of cases whereas 34% of patients became anemic according to the WHO definition of anemia (Hb  11 g/dl). 33 Inthe pivotal trials, neutropenia accounting for dose reduc-tions of PEG-interferon occurred in only 20% of pa-tients. 4,5 Secondly, practitioners were probably lessresponsive to neutropenia than to anemia. Anemia is in-deed more often symptomatic than neutropenia. Never-theless, the use of G-CSF has revolutionized the field of dose-intensive chemotherapy by reducing neutropenia-related complications. 34,35  As regards chronic hepatitis C,no official guidelines have been set for the use of G-CSF,probably because of the absence of firm data resulting inan increased sustained viral response or reduced infec-tions.Thereareconflictingresultsonneutropeniaasarisk factorforinfectionsduringantiviraltherapy.Threeretro-spectivestudiesdidnotidentifysuchariskfactor 36-38 ;themore recent one demonstrated that infections did notcorrelate with the nadir of neutrophil count (  1,000 or  750/mm 3 ) or with the magnitude of its decrease frombaseline. 37 Conversely, Puoti et al. 39 reported that acuterespiratory infections were associated with neutropenia and that pegylated interferon increased the risk of non-respiratory infections independent of neutropenia. 39 Moreover, neutropenic HCV-infected patients with end-stage liver disease, liver transplant recipients, or HIV in-fection are more susceptible to bacterial infections. Thelatter conditions warrant further trials to clarify how and when G-CSF should be used.HGF are not yet an official adjuvant therapy forchronic hepatitis C. Recent studies indicate that EPOmakes it possible to maintain ribavirin dosage and im-prove quality of life during combination therapy, 8-10 as inthe case of reported patients with cancer. 40 Moreover,EPOwasshowntoenhanceplateletreactivityandplateletcounts in patients with alcoholic cirrhosis, an interesting feature during antiviral therapy in thrombopenic HCV-positive patients with cirrhosis. 41 For all these reasons,EPO will likely play a greater role in the treatment of HCV infection.Finally, our French survey reveals an important rate of HGF prescriptions but with considerable disparity in theschedule of injections, the molecule used, and above allregardingtheindications.Weareawarethatthisstudyhasseveral limitations. First, it does not provide an accurateestimation of the dose and duration of HGF actually re-ceivedbythepatientsbecauseitisbasedonself-reportsby practitionersandcannotavoidrecallbiases.Second,somepractitioners could have been reluctant to declare thatthey transgressed official recommendations by prescrib-ing HGF. These drugs are costly, but when compared with standard care, the use of EPO has recently beenshown to be cost-effective in managing HCV by increas-ingtherapeuticcompliance,improvingqualityoflife,andavoiding complications of chronic liver disease. 42  Whileawaiting new innovating molecules causing fewer hema- HEPATOLOGY, Vol. 45, No. 2, 2007 THE´VENOT ET AL. 381
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