Effect of the interleukin-6 C174G gene polymorphism on treatment of acute and chronic hepatitis C in human immunodeficiency virus coinfected patients.
Hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection poses a difficult therapeutic problem. Response to HCV-specific therapy is variable but might be influenced by host genetic factors, including polymorphisms of cytokine genes. Here, we studied whether interleukin-6 (IL-6) C174G gene polymorphism affects the response to antiviral treatment in HCV-infected HIV-positive subjects. We determined IL-6 genotypes in HIV-positive patients with acute (n = 52) and chronic (n = 60) hepatitis C treated with pegylated interferon-alpha. Two hundred ten HCV monoinfected, 197 HIV monoinfected, and 100 healthy individuals were studied as controls. Patients were classified into high and low producers according to IL-6 genotypes. Rates of sustained virological responses (SVRs) were compared between the IL-6 genotypes. Signal transducer and activator of transcription three phosphorylation was analyzed by Western blot in HCV core-transfected human hepatoma cell line (HUH7) cells. Distribution of IL-6 genotypes did not differ significantly between the study groups. SVR was achieved in 63% of HIV/HCV coinfected patients. Carriers of the IL-6 high producer (HP) genotype had significantly higher SVR rates than patients with an IL-6 low producer genotype (70.1% versus 52%; P < 0.002). This effect was seen in both HIV-positive patients with acute (74% versus 33%; P < 0.05) and chronic (66% versus 33%; P < 0.05) hepatitis C. Multivariate analysis confirmed IL-6 HP carriage as an independent positive predictor for SVR (Odd's ratio 6.1; P = 0.004). This effect corresponds to the in vitro observation that in HCV core-transfected HUH7 cells, IL-6 overcomes the HCV core-mediated inhibition of STAT3 activation.


CONCLUSIONS
Response rates to HCV-specific treatment are higher in HCV/HIV-positive patients carrying the IL-6 HP genotype, which might be because of IL-6 mediated STAT3 activation.
Department of Internal Medicine I, University of Bonn, Bonn, Germany. Jacob.Nattermann@ukb.uni-bonn.de
Jacob
J
Nattermann
Martin
M
Vogel
Thomas
T
Berg
Mark
M
Danta
Baumgarten
B
Axel
Christoph
C
Mayr
Raffaele
R
Bruno
Christina
C
Tural
Gerd
G
Klausen
Bonaventura
B
Clotet
Thomas
T
Lutz
Frank
F
Grünhage
Michael
M
Rausch
Hans Dieter
HD
Nischalke
Knud
K
Schewe
Bernhard
B
Bienek
Georg
G
Haerter
Tilman
T
Sauerbruch
Juergen K
JK
Rockstroh
Ulrich
U
Spengler
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications*; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D015850:Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a