We conducted a case-control study to investigate the efficacy of interferon-alpha (IFN-α) and ribavirin combination therapy for patients with chronic hepatitis C and B virus (HCV/HBV) coinfection and to elucidate the interaction of these two viruses.
Methods
Forty-two chronic HCV/HBV-coinfected patients (29 IFN-naive, 13 IFN-relapsed) and 84 HCV-monoinfected controls, matched for age, sex and previous history of IFN-α therapy, were enrolled. All patients were treated with IFN-α-2b 6 MU three-times weekly plus ribavirin 1000–1200 mg daily for 24 weeks. Serum HCV RNA and HBV DNA were determined every 24 weeks for 72 weeks.
Results
The rate of HCV sustained virological response (SVR) was comparable among IFN-naive and IFN-relapsed HCV/HBV-coinfected patients and IFN-naive and IFN-relapsed HCV-monoinfected patients (69.0%, 69.2%, 67.2% and 57.7%, respectively; intention-to-treat analysis). HCV genotype 1b, high pretreatment HCV RNA levels and liver fibrosis were significantly associated with a lower HCV SVR. Of 16 baseline HBV viraemic patients, five (31.3%) achieved HBV SVR, which correlated negatively to HCV genotype non-1b and HCV SVR. Only one (6.3%) had simultaneous seroclearance of HCV and HBV. Antibodies to HBV surface antigen seroconversion developed in five (11.9%) patients during long-term follow-up. HCV responders had significantly higher rates of HBV DNA resurgence than HCV non-responders during and after treatment. Reciprocal viral interference was noted between HCV and HBV after IFN-α/ribavirin therapy.
Conclusions
IFN-α/ribavirin combination therapy is effective for HCV/HBV-coinfected patients in eradicating HCV infection and might promote HBV seroclearance, and there is a mutual viral response and reciprocal viral interaction between HBV and HCV.
References
1.
ChuangW.L., ChangW.Y., LuS.N., SuW.P., LinZ.Y., ChenS.C., HsiehM.Y., WangL.Y., YouS.L., & ChenC.J.The role of hepatitis B and C viruses in hepatocellular carcinoma in a hepatitis B endemic area: a case-control study.Cancer1992; 69: 2052–2054.
2.
LauerG.M., & WalkerB.D.Hepatitis C virus infection.New England Journal of Medicine2001; 345: 41–52.
3.
LiawY.F., ChenY.C., SheenI.S., ChienR.N., YehC.T., & ChuC.M.Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection.Gastroenterology2004; 126: 1024–1029.
4.
KaklamaniE., TrichopoulosD., TzonouA., ZavitsanosX., KoumantakiY., HatzakisA., HsiehC.C., & HatziyannisS.Hepatitis B and C viruses and their interaction in the origin of hepatocellular carcinoma.Journal of the American Medical Association1991; 265: 1974–1976.
5.
LiawY.F.Role of hepatitis C virus in dual and triple hepatitis virus infection.Hepatology1995; 22: 1101–1108.
6.
MannsM.P.Current state of interferon therapy in the treatment of chronic hepatitis B.Seminars in Liver Disease2002; 22 (Suppl 1): 7–13.
7.
YuM.L., ChuangW.L., DaiC.Y., ChenS.C., LinZ.Y., HsiehM.Y., WangL.Y., & ChangW.Y.Clinical evaluation of the automated COBAS AMPLICOR HCV MONITOR test version 2.0 for quantifying serum hepatitis C virus RNA and comparison to the Quantiplex HCV version 2.0 test.Journal of Clinical Microbiology2000; 38: 2933–2939.
8.
LiawY.F., ChienR.N., LinS.M., YehC.T., TsaiS.L., SheenI.S., & ChuC.M.Response of patients with dual hepatitis B virus and C virus infection to interferon therapy.Journal of Interferon & Cytokine Research1997; 17: 449–452.
9.
WeltmanM.D., BrotodihardjoA., CreweE.B., FarrellG.C., BilousM., GriersonJ.M., & LiddleC.Coinfection with hepatitis B and C or B, C, and delta viruses results in severe chronic liver disease and responds poorly to interferon alpha treatment.Journal of Viral Hepatitis1995; 2: 39–45.
10.
PontissoP., GerottoM., BenvegnuL., ChemelloL., & AlbertiA.Coinfection by hepatitis B virus and hepatitis C virus.Antiviral Therapy1998; 3: 137–142.
11.
VillaE., GrottolaA., ButtafocoP., ColantoniA., BagniA., FerrettiI., CremoniniC., BertaniH., & ManentiF.High doses of alpha-interferon are required in chronic hepatitis due to coinfection with hepatitis B virus and hepatitis C virus: long term results of a prospective randomized trial.American Journal of Gastroenterology2001; 96: 2973–2977.
12.
StraderD.B.Understudied populations with hepatitis C.Hepatology2002; 36: S226–236.
13.
DavisG.L., Esteban-MurR., RustgiV., HoefsJ., GordonS.C., TrepoC., ShiffmanM.L., ZeuzemS., CraxiA., LingM.H., & AlbrechtJ.Recombinant interferon alfa-2b alone or in combination with ribavirin for retreatment of interferon relapse in chronic hepatitis C.New England Journal of Medicine1998; 339: 1493–1499.
14.
McHutchisonJ.G., GordonS.C., SchiffE.R., ShiffmanM.L., LeeW.M., RustgiV.K., GoodmanZ.D., LingM.H., CortS., & AlbrechtJ.K.Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis interventional therapy group.New England Journal of Medicine1998; 339: 1485–1492.
15.
EASL International Consensus Conference on Hepatitis C.Paris, 26–28, February 1999, Consensus Statement. European Association for the Study of the Liver.Journal of Hepatology1999; 30: 956–961.
16.
ChuangW.L., DaiC.Y., ChenS.C., LeeL.P., LinZ.Y., HsiehM.Y., WangL.Y., YuM.L., & ChangW.Y.Randomized trial of three different regimens for 24 weeks for re-treatment of chronic hepatitis C patients who failed to respond to interferon-alpha monotherapy in Taiwan.Liver International2004; 24: 595–602.
17.
CotonatT., QuirogaJ.A., Lopez-AlcorochoJ.M., ClouetR., PardoM., ManzarbeitiaF., & CarrenoV.Pilot study of combination therapy with ribavirin and interferon alfa for the retreatment of chronic hepatitis B e antibody-positive patients.Hepatology2000; 31: 502–506.
18.
LiuC.J., ChenP.J., LaiM.Y., KaoJ.H., JengY.M., & ChenD.S.Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients.Hepatology2003; 37: 568–576.
19.
SagnelliE., CoppolaN., MessinaV., Di CaprioD., MarroccoC., MarottaA., OnofrioM., ScolasticoC., & FilippiniP.HBV superinfection in hepatitis C virus chronic carriers, viral interaction, and clinical course.Hepatology2002; 36: 1285–1291.
20.
SagnelliE., CoppolaN., ScolasticoC., FilippiniP., SantantonioT., StroffoliniT., & PiccininoF.Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis.Hepatology2000; 32: 1106–1110.
21.
KnodellR.G., IshakK.G., BlackW.C., ChenT.S., CraigR., KaplowitzN., KiernanT.W., & WollmanJ.Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis.Hepatology1981; 1: 431–435.
22.
OkamotoH., TokitaH., SakamotoM., HorikitaM., KojimaM., IizukaH., & MishiroS.Characterization of the genomic sequence of type V (or 3a) hepatitis C virus isolates and PCR primers for specific detection.Journal of General Virology1993; 74: 2385–2390.
23.
ZeuzemS.Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well?Annals of Internal Medicine2004; 140: 370–381.
24.
MannsM.P., McHutchisonJ.G., GordonS.C., RustgiV.K., ShiffmanM., ReindollarR., GoodmanZ.D., KouryK., LingM., & AlbrechtJ.K.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.Lancet2001; 358: 958–965.
25.
FriedM.W., ShiffmanM.L., ReddyK.R., SmithC., MarinosG., GoncalesF.L.Jr., HaussingerD., DiagoM., CarosiG., DhumeauxD., CraxiA., LinA., HoffmanJ., & YuJ.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.New England Journal of Medicine2002; 347: 975–982.
26.
HadziyannisS.J., SetteH.Jr., MorganT.R., BalanV., DiagoM., MarcellinP., RamadoriG., BodenheimerH.Jr., BernsteinD., RizzettoM., ZeuzemS., PockrosP.J., LinA., & AckrillA.M.; PEGASYS international study group. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Annals of Internal Medicine2004; 140: 346–355.
27.
Di BisceglieA.M., & HoofnagleJ.H.Optimal therapy of hepatitis C.Hepatology2002; 36 (Suppl 1): 121–127.
28.
YuenM.F., HuiC.K., ChengC.C., WuC.H., LaiY.P., & LaiC.L.Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.Hepatology2001; 34: 139–145.
29.
VillaE., GrottolaA., TrandeP., SeiumY., RebecchiA.M., DuganiA., & ManentiF.Reactivation of hepatitis B virus infection induced by interferon (IFN) in HBsAg-positive, anti-HCV-positive patients.Lancet1993; 341: 1413.
30.
ShihC.M., LoS.J., MiyamuraT., ChenS.Y., & LeeY.H.Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells.Journal of Virology1993; 67: 5823–5832.
31.
SchuttlerC.G., FiedlerN., SchmidtK., ReppR., GerlichW.H., & SchaeferS.Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein.Journal of Hepatology2002; 37: 855–862.
32.
LimS.G., WaiC.T., RajnakovaA., KajijiT., & GuanR.Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B.Gut2002; 51: 597–599.
33.
YalcinK., DegertekinH., YildizF., & KilincN.A severe hepatitis flare in an HBV-HCV coinfected patient during combination therapy with A-interferon and ribavirin.Journal of Gastroenterology2003; 38: 796–800.
