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Clinics and Research in Hepatology and Gastroenterology (2013) xxx, xxx—xxx

Available online at

www.sciencedirect.com

ORIGINAL ARTICLE

Co-infection with hepatitis B does not altertreatment response in chronic hepatitis C

Ahmet Uyanikoglua,∗, Filiz Akyuzb, Bulent Baranb, Binnur Pinarbasi Simsekb,Fatih Ermisc, Kadir Demirb, Mine Gulluoglud, Selim Badure,Sabahattin Kaymakoglub

a Harran University, Faculty of Medicine, Department of Gastroenterology, Sanliurfa, Turkeyb Istanbul University, Istanbul Faculty of Medicine, Department of Gastroenterohepatology, Capa 34093, Istanbul, Turkeyc Duzce University, Faculty of Medicine, Department of Gastroenterology, Duzce, Turkeyd Istanbul University, Istanbul Faculty of Medicine, Department of Pathology, Capa 34093, Istanbul, Turkeye Istanbul University, Istanbul Faculty of Medicine, Department of Microbiology, Capa 34093, Istanbul, Turkey

SummaryBackground/Aim: To investigate the clinical features and treatment response in patients withhepatitis B (HBV) and hepatitis C virus (HCV) co-infection receiving anti-HCV therapy.Patients and method: Patients with HBV/HCV co-infection, who were eligible for anti-HCVtherapy, were included in the study. Patients had detectable HBsAg for at least 6 months anddetectable HCV-RNA before the initiation of therapy. Primary end-point was the proportionof patients achieving sustained virological response (SVR). HBV serology and HBV-DNA resultsobtained during the follow-up were assessed to determine HBV clearance or reactivation afteranti-HCV therapy.Results: There were 612 patients in the HCV cohort and 52 (8.5%) of them were HBV/HCVco-infected. Twenty-eight patients (20 male, mean age: 47 ± 12) received anti-HCV treatment

and followed-up for a mean duration of 53 months (12—156). Fifteen patients received peginter-feron/ribavirin combination while the remaining patients received standard interferon/ribavirincombination (n = 6) or standard interferon monotherapy (n = 7). Patients receiving interferonmonotherapy were under chronic hemodialysis therapy. SVR was achieved in 14 (50%) patients

Please cite this article in press as: Uyanikoglu A, et al. Co-infection with hepatitis B does not alter treatment responsein chronic hepatitis C. Clin Res Hepatol Gastroenterol (2013), http://dx.doi.org/10.1016/j.clinre.2013.03.002

∗ Corresponding author. Harran University, Faculty of Medicine, Department of Gastroenterology, Sanliurfa, Turkey.Tel.: +90 5 423 45 55 13.

E-mail addresses: auyanikoglu@hotmail.com (A. Uyanikoglu), filizakyuz@hotmail.com (F. Akyuz), drbulentbaran@gmail.com (B. Baran),binnurcapa@yahoo.com (B.P. Simsek), fatihermis2@hotmail.com (F. Ermis), bkadirdmr@yahoo.com (K. Demir), mggulluoglu@yahoo.com(M. Gulluoglu), selimbadur@hotmail.com (S. Badur), kaymakoglus@hotmail.com (S. Kaymakoglu).

2210-7401/$ – see front matter © 2013 Published by Elsevier Masson SAS.http://dx.doi.org/10.1016/j.clinre.2013.03.002

ARTICLE IN PRESS+ModelCLINRE-424; No. of Pages 6

2 A. Uyanikoglu et al.

at the end of follow-up. The proportion of patients with SVR in three treatment arms werenot significantly different (P = 0.78). Eight of 11 patients with detectable HBV-DNA clearedHBV-DNA during treatment. Seven (25%) patients experienced a rebound in HBV-DNA, and onepatient experienced an acute hepatitis flare which was controlled by tenofovir therapy. Two(7%) patients cleared HBsAg and one of them was seroconverted to anti-HBs.Conclusion: Co-infection with HBV does not have a negative impact on the efficacy of anti-HCVtreatment, but HBV-DNA should be monitored to overcome the risk of HBV exacerbation.© 2013 Published by Elsevier Masson SAS.

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epatitis B (HBV) and hepatitis C viruses (HCV) are the mostrevalent and important hepatotropic viruses globally whichre individually responsible for the development of chroniciver disease. Because of their shared modes of transmis-ion, a significant number of patients are infected with bothiruses in countries where HBV and HCV infection is endemic1—3]. Previous studies have indicated that the progres-ion from chronic hepatitis to cirrhosis and hepatocellulararcinoma is accelerated by HCV and HBV co-infection com-ared to mono-infection of either virus [4,5]. Therefore, theradication or suppression of active infection has utmostmportance to alter the natural course of the liver diseasen co-infection. A unique feature of HBV/HCV co-infection ishat only one of the two has a dominant replication statusn most instances. Previous studies suggested that HBV andCV can inhibit each other while either virus can demon-trate dominant replication [6]. However, recent in vitrovidence suggests that both viruses can replicate in theame hepatocyte without interference [7], which is contraryo findings in earlier studies. Furthermore, a longitudinalollow-up study of HBV/HCV co-infection showed that theeplication pattern in co-infection is variable and dynamic,hich may change in time [8]. Nevertheless, the suppressionf HBV replication by HCV appears to be the most com-on co-infection profile and patients should usually receive

reatment for HCV. In the present study, we aimed to investi-ate the clinical features and treatment response in patientsith HBV/HCV co-infection receiving anti-HCV therapy thatere followed-up and received treatment between January996 and 2009.

aterials and methods

atients

his study is designed as a single centre, retrospectiveohort study in Istanbul University, Istanbul Faculty ofedicine, Department of Gastroenterohepatology. Patientsith HBV/HCV co-infection who were followed-up fromanuary 1996 to May 2009 and eligible for anti-HCV therapyere included in the study. All the patients had detectableepatitis B surface antigen (HBsAg) for at least 6 monthsnd detectable HCV-RNA before the initiation of anti-HCV

Please cite this article in press as: Uyanikoglu A, et al. Co-infein chronic hepatitis C. Clin Res Hepatol Gastroenterol (2013), h

herapy. Demographic characteristics, biochemistry anderological results of included patients were recordedt the time of the treatment initiation. Eligibility for

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nti-HCV therapy was defined as having adequateematopoietic function (white blood cell count > 3000/�L;aemoglobin level >10 g/dL; platelet count >80,000/�L) andompensated liver disease (Child-Pugh stage A). Patients,ho did not receive anti-HCV therapy because of advancedge, decompensated cirrhosis, or any other contraindi-ation, were excluded from the study. Other criteria forxclusion were seropositivity for human immunodeficiencyirus antibody (anti-HIV), pregnancy or breastfeeding andvidence of hepatocellular carcinoma.

linical, laboratory and other investigations

ll the patients had physical examination at baseline, andesults of complete blood count, liver function tests (alanineminotransferase: ALT, aspartate aminotransferase: AST,lkaline phosphatase: ALP, gamma glutamyl transferase:GT), serum albumin and total bilirubin were available.hild-Pugh scores were measured at baseline in cirrhoticatients as previously described [9]. Baseline virologicalarkers, including HBsAg, anti-HBs, hepatitis B ‘‘e’’ antigen

HBeAg), antibody against hepatitis B ‘‘e’’ antigen (anti-Be), antibody against hepatitis D virus (anti-delta) anduman immunodeficiency virus (anti-HIV) were measured bytandard commercial immunoassays. HBV-DNA was quanti-ated by VERSANT HBV 3.0 Assay (bDNA; Bayer Diagnostics,uteaux, France) with a lower detection limit of 400 IU/mL.CV-RNA was measured by different assays in differenteriods. Cobas Amplicor HCV Monitor V2.0 assay (Roche)ith a detection range of 600——500,000 IU/mL was usedefore 2006; Versant HCV-RNA 3.0 assay (Siemens) with aetection range of 615—7,700,000 IU/mL was used from 2006o 2009. HCV genotype was determined using the Inno-Lipaethod (Innogenetics, Zwijnaarde, Belgium). Patients, who

ave no contraindication for a liver biopsy, underwent therocedure and Metavir scoring system [10] was used to assessbrosis stage. In the presence of clinical or histologicalvidence for significant portal hypertension and cirrhosis,pper gastrointestinal endoscopy was performed to evaluateor the presence of esophageal and gastric varices.

reatment and follow-up

atients with HBV/HCV co-infection, who were diagnosedefore 2001, received standard interferon/ribavirin, and

ction with hepatitis B does not alter treatment responsettp://dx.doi.org/10.1016/j.clinre.2013.03.002

atients who were diagnosed after 2001 received pegy-ated interferon/ribavirin combination therapy. In the casef chronic renal insufficiency, patients were initiated with

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Table 1 Baseline demographic, clinical and laboratorycharacteristics of patients.

Characteristics n = 28

Age (years)Mean ± SD 47 ± 12Median (range) 49 (20—64)

Gender, nMale (%) 20 (71)Female (%) 8 (29)

Cirrhosis, n (%) 6 (21)

Baseline ALT (IU/L)Mean ± SD 94 ± 70Median (range) 71 (10—293)

HCV Genotype 1 27 (96)

HCV-RNA, log10 IU/mLMean ± SD 6.01 ± 5.93Median (range) 5.91 (4.83—6.55)

HBeAg positive, n (%) 3 (11)

Detectable HBV-DNA at baseline, n (%) 11 (39)Median HBV-DNA, IU/mL 2713Range 856—274 × 106

Liver histology, METAVIR (n = 17)

Fibrosis stage, median (range) 2 (1—4)Histologic activity, n (%)

A1 7 (41)A2 8 (47)A3 2 (12)

Treatment, n (%)Peg-IFN + Ribavirin 15 (54)Standard IFN + Ribavirin 6 (21)IFN monotherapy 7 (25)

n: number; SD: standard deviation; ALT: alanine aminotrans-

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Hepatitis B and C co-infection

standard interferon monotherapy because of the contraindi-cation for ribavirin. All the patients, except non-responders,received 48 weeks of anti-HCV therapy. Treatment was with-drawn early in patients who were intolerant or who hadpartial or null response during the course of treatment. Allthe patients were routinely assessed at monthly intervalsby the investigators during antiviral treatment and every3—6 months thereafter. HCV-RNA was measured at 4, 12,24 and 48th weeks of treatment and 24 weeks after thecompletion of treatment. HBV serology, including HBsAg,anti-HBs, HBeAg and anti-HBe were available at baseline,after completion of treatment and at the end of follow-up. HBV-DNA levels were obtained at 3 months intervalsduring treatment and every 6 months thereafter. Primaryend-point of the study was the proportion of patients achiev-ing sustained virological response (SVR), which is definedas undetectable HCV-RNA 24 weeks after the completion ofantiviral treatment. Patients with treatment failure werecategorized as relapser, partial and null responders. The def-initions of response were determined according to recentEuropean Association for the Study of the Liver guideline[11]. Secondary end-point was defined as HBsAg loss orseroconversion to anti-HBs at the end of follow-up. In addi-tion, serum HBV-DNA results obtained during and after thetreatment were assessed to determine HBV reactivation forsecondary efficacy analysis. HBV reactivation was definedas an increase in serum HBV-DNA by 1 log above nadirin patients with pretreatment detectable HBV-DNA andappearance of HBV-DNA in patients with pretreatment unde-tectable HBV-DNA.

Statistical analysis

All statistical analyses were performed using IBM SPSSv20 (IBM SPSS Inc., Chicago, IL, USA). Continuous varia-bles are presented as mean ± standard deviation (SD) ormedian (range) while categorical variables were expressedas frequencies (%). The comparisons of continuous variablesamong multiple groups were performed by Kruskal—Wallistest. The differences between categorical variables wereevaluated using Pearson chi-square or Fisher’s exact testwhen necessary. A z test of column proportions with Bon-ferroni adjustment was applied for multiple comparisons incontingency tables larger than 2 × 2. A two-tailed P valueof < 0.05 was considered significant.

Results

Patients

There were 612 patients in the HCV cohort in which 52(8.5%) of them were HBV and HCV co-infected. The patientswho could not receive anti-HCV treatment included eightpatients with decompensated cirrhosis, two patients withsevere thrombocytopenia (<50,000/mm3) due to hyper-splenism, two renal transplant recipients, three patients

Please cite this article in press as: Uyanikoglu A, et al. Co-infein chronic hepatitis C. Clin Res Hepatol Gastroenterol (2013), h

older than 75 years with co-morbid conditions. There werealso two patients with dominant HBV replication whoreceived nucleoside analogue therapy, three patients withanti-delta positivity and four patients were lost to follow-up.

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ferase; HCV: hepatitis C virus; HBeAg: hepatitis B e antigen; IFN:interferon.

A total of 28 patients (20 male, mean age: 47 ± 12 years),ho received anti-HCV treatment, were included into thenalyses. The mean duration of follow-up was 53 monthsrange, 12—156). There were six patients with evi-ence of significant portal hypertension at endoscopy andhree of them had also histological evidence of cirrho-is. Almost all the patients but one were infected withCV genotype 1 and 14 (50%) patients had low viral

oad (HCV-RNA < 800,000 IU/mL) at baseline. The number ofatients with detectable HBV-DNA was 11 (median HBV-DNA713 IU/mL) and three of them had HBeAg+ chronic hepatitis. Liver histology was available in 17 patients with a medianbrosis stage of 2 (range, 1—4). Baseline demographic, clin-

cal, laboratory and histopathological characteristics of 28atients are summarized in Table 1.

ction with hepatitis B does not alter treatment responsettp://dx.doi.org/10.1016/j.clinre.2013.03.002

reatment and primary end-point

ost patients (n = 15) received peginterferon/ribavirinombination therapy while the remaining patients received

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4 A. Uyanikoglu et al.

Table 2 Baseline and response characteristics in treatment subgroups.

Overalln = 28

Peg-IFN + Ribavirinn = 15

StandardIFN + Ribavirinn = 6

IFNmonotherapyn = 7

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Age (years)Mean ± SD 47 ± 12 49 ± 11 54 ± 11 37 ± 12 .039Median (range) 49 (20—64) 52 (30—63) 57 (34—64) 37 (20—59)

Gender, n .12Male (%) 20 (71) 10 (66) 3 (50) 7 (100)Cirrhosis, n (%) 6 (21) 3 (20) 1 (17) 2 (28) .85

Renal failure, n (%) 7 (25) 0 (0) 0 (0) 7 (100) < .001

Baseline ALT (IU/L) .054Mean ± SD 94 ± 70 107 ± 70 100 ± 60 60 ± 75Median (range) 71 (10—293) 74 (34—293) 85 (42—197) 34 (10—228)

HCV-RNA, IU/mLMean ± SD 6.01 ± 5.93 6.08 ± 6.0 6.05 ± 5.84 5.77 ± 5.54 .20Median (range) 5.91 (4.83—6.55) 5.87 (5.08—6.55) 6.03

(5.41—6.37)5.73(4.83—5.99)

Detectable HBV-DNA, n (%) 11 (39) 5 (33) 1 (16.5) 5 (71) .10

Response during therapy, n (%) .18RVR 3 (11) 3 (20) 0 (0) 0 (0)cEVR 11 (39) 6 (60) 2 (33) 3 (42)EVR 2 (7) 0 (0) 0 (0) 2 (29)Partial response 3 (11) 1 (7) 2 (33) 0 (0)Null-response 6 (21) 3 (20) 1 (16.5) 2 (29)Intolerance 3 (11) 2 (13) 1 (16.5) 0 (0)

Primary end-point, n (%) .78SVR 14 (50) 8 (53) 2 (33) 4 (57)Non-response 12 (43) 6 (40) 4 (66) 2 (29)

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tandard interferon/ribavirin combination (n = 6) ortandard interferon monotherapy (n = 7). Among theatients treated with peginterferon/ribavirin combination,ine received peginterferon-alfa 2a. All the patients,ho were treated by interferon monotherapy, were

enal transplant candidates under chronic hemodialysisherapy. Those patients with chronic renal failure wereounger and had lower ALT levels at baseline comparedo patients receiving combination therapy (Table 2). Theistribution of patients according to the type of responseuring treatment was as follows: three patients with rapidirological response (RVR), 11 patients with completearly virological response (cEVR), two patients with EVR,hree patients with partial response, and six patients withull response. Treatment was withdrawn at 4th, 8th and2th weeks in three patients with intolerance to therapy.verall, primary end-point (SVR) was achieved in 14 (50%)atients at the end of follow-up. Patients, who achievedVR during treatment, also had SVR 24 weeks after theompletion of treatment. Ten out of 11 patient with cEVRnd one patient with EVR had SVR. The remaining two

Please cite this article in press as: Uyanikoglu A, et al. Co-infein chronic hepatitis C. Clin Res Hepatol Gastroenterol (2013), h

atients with cEVR and EVR experienced a relapse afterreatment cessation. The proportion of patients with SVRn peginterferon/ribavirin, standard interferon/ribavirinnd interferon monotherapy groups were 8/15 (53%), 2/6

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33%), 4/7 (57%), respectively (P = 0.78). Baseline andn-treatment response characteristics of three subgroupsre summarized in Table 2.

econdary end-point

mong the 11 patients with detectable HBV-DNA, only twoatients had significant HBV replication, which was greaterhan 20,000 IU/mL (4.82 and 8.44 log10 IU/mL) at base-ine. The latter patient was HBeAg+ and required long-termucleos(t)ide analog therapy due to very high viremia,ut the other patient benefited from peginterferon-basedreatment. Eight patients achieved HBV-DNA negativityuring anti-HCV treatment. A decrease in HBV-DNA wasetected in the remaining patients, yet, they did not reachndetectable levels. Seven (25%) patients experienced aebound in HBV-DNA as previously defined after the endf treatment. Four of them (two patients had HBV-DNAegative at baseline) did not require nucleos(t)ide analogherapy and they had insignificant HBV-DNA fluctuations dur-

ction with hepatitis B does not alter treatment responsettp://dx.doi.org/10.1016/j.clinre.2013.03.002

ng the follow-up. The other three patients, in whom aatient experienced an acute hepatitis flare, were initi-ted nucleos(t)ide analog therapy (lamivudine or tenofovir).here were three patients with HBeAg positivity and two

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ARTICLECLINRE-424; No. of Pages 6

Hepatitis B and C co-infection

of them (one received long-term tenofovir treatment) wereseroconverted to anti-HBe during long-term follow-up. Two(7%) patients cleared HBsAg and one of them was sero-converted to anti-HBs. Treated patients did not develophepatocellular carcinoma during the follow-up, but threepatients with decompensated cirrhosis developed hepato-cellular carcinoma and were listed for orthotopic livertransplantation.

Adverse events and safety

A total of nine patients experienced serious adverse eventsduring the treatment. Five patients required ribavirin dosereduction due to anemia (hemoglobin <10 g/dL), and treat-ment was withdrawn in one patient due to severe anemia(hemoglobin < 8.5 g/dL) and major depression. An addi-tional two patients required treatment cessation becauseof adverse events related to interferon therapy, such assevere thrombocytopenia or intolerable fever and fatigue.The remaining two patients were required to skip severaldoses of interferon due to cytopenia or fatigue but theycould remain on therapy after the dose reduction and com-plete the full course of treatment.

Discussion

The present study, which included patients from a ter-tiary referral center in Turkey, shows that standard orpegylated interferon in combination with ribavirin is effec-tive in patients with HBV/HCV co-infection. Our resultsalso demonstrate that standard interferon monotherapy inthe absence of early withdrawal can provide substantialSVR rates among patients with chronic renal failure andHBV/HCV co-infection.

The prevalence of HBV/HCV co-infection is not welldefined due to the lack of large-scale epidemiological stud-ies. In our HCV cohort, the proportion of patients withco-infection was 8.5%, which includes patients who werepositive for HCV-RNA and HBsAg. Previous epidemiologicalstudies showed a prevalence of 15—20% while it should beconsidered that those studies investigated the prevalenceof anti-HCV positivity and did not test for HCV-RNA amongpatients with chronic hepatitis B [12]. Furthermore, the fre-quency of co-infection in our center may overestimate thereal prevalence in Turkey, since it is a tertiary referral centerin which patients with co-infection may significantly accu-mulate.

It has been demonstrated that co-infected patientshave lower levels of HBV-DNA or HCV-RNA compared tomono-infected controls [13]. In our study, one half of thetreated patients had low hepatitis C viremia (< 800,000IU/mL) and most of them had undetectable HBV-DNA,which is in accordance with the previous studies. How-ever, there is substantial evidence that suggests thatHBV/HCV co-infection causes more severe liver damage[14,15] and there is an increased risk of developing hepa-tocellular carcinoma compared to mono-infection of either

Please cite this article in press as: Uyanikoglu A, et al. Co-infein chronic hepatitis C. Clin Res Hepatol Gastroenterol (2013), h

virus [16,17]. The frequency of cirrhotic patients was highin our study (16 patients, 30%) and half of them weredecompensated. Patients with severe thrombocytopeniaand decompensated cirrhosis were not able to receive

PRESS5

nterferon-based treatment and three of them eventuallyeveloped hepatocellular carcinoma during the follow-up.dverse events were prevalent in our study (32%) but treat-ent withdrawal was required only in three patients. Fiveatients experienced anemia but timely dose reduction ofibavirin kept most of the patients on therapy.

It is generally accepted that HCV prevails in HBV/HCVo-infection in most occasions due to the suppression ofBV replication [12]. It is important to determine the dom-

nant replicating virus by quantitative testing before thenitiation of any therapy. In fact, interferon-alfa is thenly treatment option effective on both viral infections;nd most patients require treatment against HCV infec-ion. There were only two patients with pre-treatmentignificant HBV replication and one of them had a veryigh viremia (8.44 log10 IU/mL), who required long-termucleos(t)ide analog therapy. While the other patient bene-ted from peginterferon-based therapy and remain aviremicuring the follow-up. Several uncontrolled and controlledtudies investigated the efficacy of standard or pegylatednterferon as monotherapy or in combination with ribavirinn HBV/HCV co-infection [12]. Most recent studies, whichnvestigated the efficacy of peginterferon/ribavirin combi-ation therapy in co-infection, demonstrated comparableVR rates between HBV/HCV co-infected and HCV mono-nfected patients [18—20]. Those studies also reportedhat around 30% of co-infected patients experienced HBVeactivation during or after treatment, especially patientsho achieve HCV clearance. However, the largest study

ound no difference regarding HBV reactivation betweenatients with HCV clearance and those without. Our resultsonfirm previous reports regarding SVR rate for HCV infec-ion and frequency of HBV reappearance.

In conclusion, our results confirm that co-infection withBV does not have a negative influence on the efficacy ofnti-HCV treatment even in patients with chronic renal fail-re, who receive interferon-alfa monotherapy. Treatment isell tolerated and adverse events are mostly manageable,owever, HBV reactivation during or after treatment is notncommon among co-infected patients. Serial monitoring ofBV-DNA during the follow-up should be the mainstay forhe management of co-infection to prevent clinical hepati-is, even in patients with undetectable serum HBV-DNA ataseline.

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

eferences

[1] Liaw YF. Role of hepatitis C virus in dual and triple hepatitisvirus infection. Hepatology 1995;22:1101—8.

[2] Crespo J, Lozano JL, de la Cruz F, Rodrigo L, Rodriguez M,San Miguel G, et al. Prevalence and significance of hepatitisC viremia in chronic active hepatitis B. Am J Gastroenterol

ction with hepatitis B does not alter treatment responsettp://dx.doi.org/10.1016/j.clinre.2013.03.002

1994;89:1147—51.[3] Liu CJ, Liou JM, Chen DS, Chen PJ. Natural course and treat-

ment of dual hepatitis B virus and hepatitis C virus infections.J Formos Med Assoc 2005;104:783—91.

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[20] Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS, et al.

ARTICLELINRE-424; No. of Pages 6

[4] Sagnelli E, Coppola N, Messina V, Di Caprio D, Marrocco C,Marotta A, et al. HBV superinfection in hepatitis C virus chroniccarriers, viral interaction, and clinical course. Hepatology2002;36:1285—91.

[5] Sun CA, Wu DM, Lin CC, Lu SN, You SL, Wang LY, et al. Inci-dence and cofactors of hepatitis C virus-related hepatocellularcarcinoma: a prospective study of 12,008 men in Taiwan. Am JEpidemiol 2003;157:674—82.

[6] Crockett SD, Keeffe EB. Natural history and treatment ofhepatitis B virus and hepatitis C virus coinfection. Ann ClinMicrobiol Antimicrob 2005;4:13.

[7] Bellecave P, Gouttenoire J, Gajer M, Brass V, Koutsoudakis G,Blum HE, et al. Hepatitis B and C virus coinfection: a novelmodel system reveals the absence of direct viral interference.Hepatology 2009;50:46—55.

[8] Raimondo G, Brunetto MR, Pontisso P, Smedile A, Maina AM,Saitta C, et al. Longitudinal evaluation reveals a complex spec-trum of virological profiles in hepatitis B virus/hepatitis Cvirus-coinfected patients. Hepatology 2006;43:100—7.

[9] Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, WilliamsR. Transection of the oesophagus for bleeding oesophagealvarices. Br J Surg 1973;60:646—9.

10] Bedossa P, The French METAVIR Cooperative Study Group.Intraobserver, interobserver variations in liver biopsy interpre-tation in patients with chronic hepatitis C. The French METAVIRCooperative Study Group. Hepatology 1994;20:15—20.

11] Craxì A, Pawlotsky JM, Wedemeyer H, Bjoro K, Flisiak R, FornsX, et al., EASL. EASL Clinical Practice Guidelines: management

Please cite this article in press as: Uyanikoglu A, et al. Co-infein chronic hepatitis C. Clin Res Hepatol Gastroenterol (2013), h

of hepatitis C virus infection. J Hepatol 2011;55:245—64.12] Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection:

epidemiology, clinical features, viral interactions and treat-ment. J Gastroenterol Hepatol 2008;23:512—20.

PRESSA. Uyanikoglu et al.

13] Liu Z, Hou J. Hepatitis B virus (HBV) and hepatitis C virus (HCV)dual infection. Int J Med Sci 2006;3:57—62.

14] Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, Bost-Bezeaux F, et al. Characteristics of patients with dualinfection by hepatitis B and C viruses. J Hepatol 1998;28:27—33.

15] Sagnelli E, Pasquale G, Coppola N, Scarano F, Marrocco C,Scolastico C, et al. Influence of chronic coinfection with hep-atitis B and C virus on liver histology. Infection 2004;32:144—8.

16] Benvegnu L, Fattovich G, Noventa F, Tremolada F, Chemello L,Cecchetto A, et al. Concurrent hepatitis B and C virus infectionand risk of hepatocellular carcinoma in cirrhosis. A prospectivestudy. Cancer 1994;74:2442—8.

17] Chiaramonte M, Stroffolini T, Vian A, Stazi MA, Floreani A,Lorenzoni U, et al. Rate of incidence of hepatocellular car-cinoma in patients with compensated viral cirrhosis. Cancer1999;85:2132—7.

18] Yu JW, Sun LJ, Zhao YH, Kang P, Gao J, Li SC. Analysis of theefficacy of treatment with peginterferon alpha-2a and ribavirinin patients coinfected with hepatitis B virus and hepatitis Cvirus. Liver Int 2009;29:1485—93.

19] Potthoff A, Wedemeyer H, Boecher WO, Berg T, Zeuzem S,Arnold J, et al. The HEP-NET B/C co-infection trial: a prospec-tive multicenter study to investigate the efficacy of pegylatedinterferon-alpha2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol 2008;49:688—94.

ction with hepatitis B does not alter treatment responsettp://dx.doi.org/10.1016/j.clinre.2013.03.002

Peginterferon alfa-2a plus ribavirin for the treatment of dualchronic infection with hepatitis B and C viruses. Gastroenter-ology 2009;136:496—504, e493.