Correction of insulin resistance in chronic hepatitis C patients not responding to the standard of care: More questions than answers
Authors: Francesco Negro
Journal: Journal of Hepatology (2009)

We read with interest the comment by Serfaty and collaborators on our previous paper, and congratulate them for the successful outcome of this interesting case. We fully agree that our approach may have been inadequate and concur that, based on this case report and on other recent data [1Elgouhari H.M. Cesario K.B. Lopez R. Zein N.N. Pioglitazone improves early virologic kinetic response to PEG IFN/RBV combination therapy in hepatitis C genotype 1 naive pts.Hepatology. 2008; 48: 383AAbstract Full Text Full Text PDF Scopus (16) Google Scholar, 2Conjeevaram H. Burant C.F. McKenna B. Harsh D. Kang H. Das A.K. et al.A randomized, double-blind, placebo-controlled study of PPAR-gamma agonist pioglitazone given in combination with peginterferon and ribavirin in patients with genotype-1 chronic hepatitis C.Hepatology. 2008; 48: 384AGoogle Scholar, 3Romero-Gomez M. Diago M. Andrade R.J. Calleja J.L. Salmeron J. Fernández-Rodriguez M. et al.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.Hepatology. 2008; 48: 95AGoogle Scholar], the pharmacological correction of the level of insulin resistance prior to retreatment with antivirals should be more aggressive, and possibly precede the administration of the interferon-alpha/ribavirin combination, until a HOMA score associated with a higher rate of sustained virological response has been reached [4Romero-Gomez M. Del Mar Viloria M. Andrade R.J. Salmeron J. Diago M. Fernandez-Rodriguez C.M. et al.Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients.Gastroenterology. 2005; 128: 636-641Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar, 5Poustchi H. Negro F. Hui J. Cua I.H.Y. Rubbia-Brandt L. Kench J. et al.Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3.J Hepatol. 2008; 48: 28-34Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. It is noteworthy that the patient described by Serfaty and colleagues was infected by the genotype 3a of HCV. In in vitro models [[6]Pazienza V. Clément S. Conzelmann S. Pugnale P. Foti M. Mangia A. et al.The hepatitis C virus core protein of genotypes 3a and 1b down-regulates IRS-1 via genotype-specific mechanisms.Hepatology. 2007; 45: 1164-1171Crossref PubMed Scopus (201) Google Scholar], the mechanism of virally-associated insulin resistance has been reported to be HCV genotype-specific, the genotype 3a being partly associated with the downregulation of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment of transfected cells with a PPAR-γ agonist (rosiglitazone) partially reverted the suppression of the insulin signaling associated with the expression of the HCV core protein [[6]Pazienza V. Clément S. Conzelmann S. Pugnale P. Foti M. Mangia A. et al.The hepatitis C virus core protein of genotypes 3a and 1b down-regulates IRS-1 via genotype-specific mechanisms.Hepatology. 2007; 45: 1164-1171Crossref PubMed Scopus (201) Google Scholar]. Thus, it is possible that the insulin sensitizing therapy should be tailored according to the infecting HCV genotype. In the INSPIRED-HCV trial, only one patient was infected with genotype 3a. This patient had extensive fibrosis and a mild steatosis affecting 20% of hepatocytes, but no overweight or arterial hypertension. Quite oddly, upon retreatment, her HOMA-IR score underwent a surge from 2.65 to 11, while serum HCV RNA level remained unmodified. We fear that this paradoxical increase may have been the consequence of a pharmacological interaction between interferon-alpha and two additional drugs, i.e. duloxetine and zopiclone, which have been occasionally associated with glucose metabolism derangements [[6]Pazienza V. Clément S. Conzelmann S. Pugnale P. Foti M. Mangia A. et al.The hepatitis C virus core protein of genotypes 3a and 1b down-regulates IRS-1 via genotype-specific mechanisms.Hepatology. 2007; 45: 1164-1171Crossref PubMed Scopus (201) Google Scholar]. We remain convinced that correcting insulin resistance is a rational option in chronic hepatitis C patients failing to respond to combination therapy. However, the modalities of this correction have to be fully explored. The sequential administration of higher doses of insulin sensitizers seems a reasonable approach, but the likely genotype specificity of the mechanisms underlying the insulin resistant state and the risk of pharmacological interactions should both be taken in consideration before designing clinical trials. Finally, one should not forget that the most effective way of correcting glucose metabolism disturbances consists in lifestyle interventions [[7]Goldberg R.B. Temprosa M. Haffner S. Orchard T.J. Ratner R.E. et al.The effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: the Diabetes Prevention Program Randomized Trial.Diab Care. 2009; (The Diabetes Prevention Program Research Group,) ([Epub ahead of print])Google Scholar], such as diet modifications and increased physical activity, and that there is no excuse why chronic hepatitis C patients should be spared such interventions.