Free accessResearch articleFirst published online 2009-8
Insulin resistance impairs sustained virological response rate to pegylated interferon plus ribavirin in HIV–hepatitis C virus-coinfected patients: HOMAVIC-ANRS HC02 Study
The aim of this study was to assess the effect of insulin resistance (IR) on the response to hepatitis C virus (HCV) therapy in HIV-HCV-coinfected patients.
Methods
A total of 238 HIV-HCV-coinfected patients (74% male, mean ±sd age 40 ±5 years, mean alcohol intake <50 g/day and 38% HCV genotype 2 or 3), treated by standard or pegylated interferon-α2b plus ribavirin during 48 weeks were studied. Liver biopsies were assessed before treatment. Patients were considered to have IR when the homeostasis model assessment of IR (HOMA-IR) was ≥2.5. Multiple logistic regression with stepwise selection was used to estimate independent factors associated with sustained virological response (SVR).
Results
IR was present in 32% and significant liver fibrosis (Metavir≥F2) in 74% of patients. Patients with SVR (96/238 [40%]) were more likely to be infected with HCV genotype 2 or 3 (54% versus 27%; P<0.0001), and had more severe liver fibrosis (≥F3; 45% versus 30%; P=0.03). By multivariate analysis, a HOMA-IR>2.5 had a negative effect on the SVR (odds ratio 0.49 [95% confdence interval 0.26-0.92]; P=0.05).
Conclusions
A high HOMA-IR level is frequently found in HIV-HCV-coinfected patients and is associated with a reduced SVR rate. Improving insulin sensitivity might be a useful adjunct to HCV therapy in HIV-HCV-coinfected patients.
References
1.
CammaC., BrunoS., Di MarcoV.Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C.Hepatology2006; 43: 64–71.
2.
MirandolaS., RealdonS., IqbalJ.Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis.Gastroenterology2006; 130: 1661–1669.
3.
OkudaM., LiK., BeardM.R.Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology2002; 122: 366–375.
4.
Romero-GomezM., Del Mar ViloriaM., AndradeR.J.Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients.Gastroenterology2005; 128: 636–641.
5.
ConjeevaramH.S., KleinerD.E., EverhartJ.E.Race, insulin resistance and hepatic steatosis in chronic hepatitis C.Hepatology2007; 45: 80–87.
6.
SulkowskiM.S., ThomasD.L.Hepatitis C in the HIV-infected person.Ann Intern Med2003; 138: 197–207.
7.
ShermanK., RoustrerS., ChungR., RajicicN.Hepatitis C: prevalence in HIV-infected patients across sectional analysis of the US ACTG.Antivir Ther2000; 5 Suppl 1: 64–65.
8.
BenhamouY., BochetM., Di MartinoV.Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group.Hepatology1999; 30: 1054–1058.
9.
PuotiM., BonaciniM., SpinettiA.Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus.J Infect Dis2001; 183: 134–137.
10.
de TorresM., PoynardT.Risk factors for liver fibrosis progression in patients with chronic hepatitis C.Ann Hepatol2003; 2: 5–11.
11.
KramerJ.R., GiordanoT.P., SouchekJ., RichardsonP., HwangL.Y., El-SeragH.B.The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in US veterans with hepatitis C.Am J Gastroenterol2005; 100: 56–63.
12.
BenhamouY., Di MartinoV., BochetM.Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy.Hepatology2001; 34: 283–287.
13.
SterlingR.K., ContosM.J., SanyalA.J.The clinical spectrum of hepatitis C virus in HIV coinfection.J Acquir Immune Defic Syndr2003; 32: 30–37.
14.
Martin-CarboneroL., SorianoV., ValenciaE., Garcia-SamaniegoJ., LopezM., Gonzalez-LahozJ.Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients.AIDS Res Hum Retroviruses2001; 17: 1467–1471.
15.
PuotiM., SpinettiA., GhezziA.Mortality for liver disease in patients with HIV infection: a cohort study.J Acquir Immune Defic Syndr2000; 24: 211–217.
16.
Martin-CarboneroL., BenhamouY., PuotiM.Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study.Clin Infect Dis2004; 38: 128–133.
17.
CacoubP., GeffrayL., RosenthalE., PerronneC., VeyssierP., RaguinG.Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997.Clin Infect Dis2001; 32: 1207–1214.
18.
BicaI., McGovernB., DharR.Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection.Clin Infect Dis2001; 32: 492–497.
19.
SelikR.M., ByersR.H.Jr., DworkinM.S.Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987-1999.J Acquir Immune Defic Syndr2002; 29: 378–387.
20.
RosenthalE., PoireeM., PradierC.Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study).AIDS2003; 17: 1803–1809.
21.
RosenthalE., PialouxG., BernardN.Liver-related mortality in human-immunodeficiency-virus-infected patients between 1995 and 2003 in the French GERMIVIC Joint Study Group Network (MORTAVIC 2003 Study).J Viral Hepat2007; 14: 183–188.
22.
ChungR.T., AndersenJ., VolberdingP.Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med2004; 351: 451–459.
23.
TorrianiF.J., Rodriguez-TorresM., RockstrohJ.K.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.N Engl J Med2004; 351: 438–450.
24.
CarratF., Bani-SadrF., PolS.Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial.JAMA2004; 292: 2839–2848.
25.
LagunoM., MurillasJ., BlancoJ.L.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients.AIDS2004; 18: F27–F36.
26.
The French METAVIR Cooperative Study Group.Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C.Hepatology1994; 20: 15–20.
27.
MatthewsD.R., HoskerJ.P., RudenskiA.S., NaylorB.A., TreacherD.F., TurnerR.C.Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia1985; 28: 412–419.
28.
OzdemirA., YalinbasB., SelametU.The effect of hepatitis C virus infection on insulin resistance in chronic haemodialysis patients.Yonsei Med J2007; 48: 274–280.
29.
MasuoK., KatsuyaT., OgiharaT., TuckM.L.Acute hyperinsulinemia reduces plasma leptin levels in insulin-sensitive Japanese men.Am J Hypertens2005; 18: 235–243.
30.
MannsM.P., McHutchisonJ.G., GordonS.C.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet2001; 358: 958–965.
31.
Bani-SadrF., GoderelI., MorandP.High hepatitis C virus viral load in HIV/hepatitis C virus-co-infected patients: a different influence of protease inhibitor and non-protease inhibitor-based HAART?AIDS2007; 21: 1645–1648.
32.
LokA.S., EverhartJ.E., ChungR.T.Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial.Clin Gastroenterol Hepatol2007; 5: 245–254.
33.
DaiC.Y., HuangJ.F., HsiehM.Y.Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients.J Hepatol2009; 50: 712–718.
34.
HarrisonS.A.Steatosis and chronic hepatitis C infection: mechanisms and significance.Clin Gastroenterol Hepatol2005; 3: S92–S96.
35.
RyanP., ResinoS., MirallesP.Insulin resistance impairs sustained virologic response to interferon plus ribavirin in HIV/HCV co-infected patients.16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, QC, Canada. Abstract Q-162.
36.
MerchanteN., de los Santos-GilI., MerinoD.Insulin resistance is not a relevant predictor of sustained virological response to pegylated interferon plus ribavirin in HIV/HCV co-infected patients.J Hepatol2009; 50: 684–692.
37.
NastaP., GattiF., PuotiM.Insulin resistance impairs rapid virologic response in HIV/hepatitis C virus coinfected patients on peginterferon-alfa-2a.AIDS2008; 22: 857–861.
38.
RyanP., BerenguerJ., MichelaudD.Insulin resistance is associated with advanced liver fibrosis and high body mass index in HIV/HCV-coinfected patients.J Acquir Immune Defic Syndr2009; 50: 109–110.
39.
BugianesiE., MarchesiniG., GentilcoreE.Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis.Hepatology2006; 44: 1648–1655.
40.
ChitturiS., AbeygunasekeraS., FarrellG.C.NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome.Hepatology2002; 35: 373–379.
41.
MoucariR., AsselahT., Cazals-HatemD.Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis.Gastroenterology2008; 134: 416–423.
42.
PoustchiH., NegroF., HuiJ.Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3.J Hepatol2008; 48: 28–34.
43.
Bani-SadrF., CarratF., BedossaP.Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors.AIDS2006; 20: 525–531.
44.
MiraJ.A., Torre-CisnerosJ., MerinoD.Efficacy of pegylated intereron plus ribavirin in HIV/HCV coinfection outside of well circumscribed clinical trials: the Andalusian multicenter study.13th Conference on Retroviruses and Opportunistic Infections, 5–8 February 2006, Denver, CO, USA. Abstract 861.
45.
D'SouzaR., SabinC.A., FosterG.R.Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy.Am J Gastroenterol2005; 100: 1509–1515.
46.
CammaC., PettaS.Insulin resistance in HCV mono-infected and in HIV/HCV co-infected patients: looking to the future.J Hepatol2009; 50: 648–651.
47.
ShireN., RaoM., AndersenJ.Improving non-invasive discrimination of fibrosis in HIV/HCV-co-infected patients.14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los Angeles, CA, USA. Abstract 914.
48.
OverbeckK., GenneD., GolayA., NegroF.Pioglitazone in chronic hepatitis C not responding to pegylated interferon-alpha and ribavirin.J Hepatol2008; 49: 295–298.
49.
BasuR., ShahP., BasuA.Comparison of the effects of pioglitazone and metformin on hepatic and extra-hepatic insulin action in people with type 2 diabetes.Diabetes2008; 57: 24–31.
50.
ShawR.J., LamiaK.A., VasquezD.The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.Science2005; 310: 1642–1646.
51.
ElgouhariH.M., CesarioK., LopezR., ZeinN.Pioglitazone improves early virologic kinectic response to PEG IFN/RBV combination therapy in hepatitis C genotype 1 naive patients.Hepatology2008; 48: 383A.
52.
Romero GomezM., DiagoM., AndradeR.Metformin with peginterferon alfa-2a and ribavirin in the treatment of naive genotype 1 chronic hepatitis C patients with insulin resistance (TRIC-1): final results of a randomized and double-blinded trial.Hepatology2008; 48: 380A.
