Thursday, November 8, 2012

Insulin resistance predicts SVR to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism

Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism

J. A. del Campo1,J. Ampuero1, L. Rojas1,M. Conde2,Á. Rojas1,M. Maraver1,R. Millán1, M. García-Valdecasas1,J. R. García-Lozano2,M. F. González-Escribano2,M. Romero-Gómez1,

* Article first published online: 5 NOV 2012
DOI: 10.1111/apt.12113

Alimentary Pharmacology & Therapeutics

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Our results indicate that insulin resistance, together with fibrosis stage and IL28B polymorphisms, was independently associated with sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R). The outcomes were confined to patients with genotypes 1&4, and not with genotypes 2&3. IL28B genotypes 1&4 have been reported to be strongly related to SVR,[3, 9] but not genotypes 2&3 and, as such, suggests a predictive capacity of this baseline variable in difficult-to-treat subgroups of patients.[10] However, the functionality of the rs12979860 polymorphism remains controversial. This genetic variant does not promote changes in the IL28B protein and the mechanism by which this mutation can modify interferon sensitivity remains unclear.[11] Viral load and viral genotypes are the major viral factors influencing SVR, while fibrosis stage, metabolic disorders and IL28B polymorphisms remain as major host factors related to SVR. Close co-linearity has been reported among several variables e.g. insulin resistance, age, fibrosis stage, steatosis, obesity and GGT levels,[12] while HOMA index has been strongly related to SVR.[2] This association can be of considerable importance as it has been well documented that hepatitis C is closely related to insulin resistance and type 2 diabetes mellitus, the prevalence of which has been shown to be increased in this patient population. Despite our data being based on only 33 subjects with genotypes 2/3 included in the current cohort, our findings are in accord with previous reports from Stättermayer et al.[10] However, there may be insufficient power to find a relationship between these variables and SVR.
The relationship between insulin resistance measured by HOMA and IL28B genotype is subject to debate. Stättermayer et al.[13] reported a strong association between IL28B genotype CC and lower HOMA score in a cohort of 202 patients with chronic hepatitis C genotype 1 or 4, suggesting a link between insulin resistance and genetic variant that could help explain the association between HOMA and SVR. However, our study (and that by Huang et al.[14]) observed no such association between baseline HOMA values and IL28B genotypes. A recent study by Ogawa et al.[6] showed that the distributions of the IL28B rs8099917 polymorphism were not related to HOMA-IR values and, also, the polymorphism was an independent baseline predictor of SVR response to treatment. Despite insulin resistance being associated with fibrosis stage, both variables remained independently associated with SVR. However, Fattovich et al.[15] found that in HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 could independently predict SVR. These authors found that HOMA-IR score was not associated with viral response. On the other hand, our results showed that IL28B polymorphisms were not related to fibrosis stage or HOMA score, which highlights the weakness of the interaction between them and strength of the relationship with SVR. Hepatitis C virus could influence insulin signalling by promoting insulin resistance mediated by IRS-1 and IRS-2 degradation by several pathways, depending on viral genotype.[16] The influence of host genetic factors on this interaction needs to be validated in further studies. For example, hepatitis C virus appears to modify lipid metabolism, according to IL28B genotype. Lower pre-treatment serum low-density lipoprotein cholesterol (LDL-C) levels have been shown to be associated with poor response to peginterferon/ribavirin therapy in patients with chronic hepatitis C.[17, 18] IL28B polymorphisms influence the biological relationships between HCV infection and serum LDL and the clinical value of LDL in predicting response to pegIFN/RBV therapy,[19] the conclusion being that the clinical value of serum LDL in predicting SVR is clear only for those patients heterozygous for IL28B genotype.
Insulin resistance appears not to be predictive of SVR in patients receiving telaprevir-based triple therapy,[20] at least in treatment-naïve and relapser patients. The impact of insulin resistance in more difficult-to-treat patients such as null-responders requires further investigation. Interestingly, our present study demonstrated that viral clearance was associated with improvement in insulin sensitivity, thus supporting the link between viral replication and insulin resistance.
In treatment-naïve genotype 1&4 patients bearing IL28B genotype CC and patients reaching RVR (which could be tested during the lead-in-phase, at least in patients scheduled to receive boceprevir), similar SVR rates were achieved when treated with double or triple therapy.[21] In these groups of patients, adding HOMA-IR could help in clinical decision making. Indeed, nonresponder patients bearing IL28B genotype CC appear to have more advanced disease and higher HOMA-IR index. Despite the association of HOMA-IR with SVR noted in this study being modest, there is a potential use of this index in patients with chronic hepatitis C and favourable genotype CC. In such circumstances, HOMA-IR could help segregate treatment-resistant subgroups of patients who may benefit, instead, from triple therapy. However, these postulations need to be demonstrated and validated in further studies.
In summary, our data indicate that IL28B genotypes, HOMA-IR and fibrosis remain the independent variables predicting SVR in patients treated with peginterferon + ribavirin, particularly in patients with genotypes 1&4. RVR is a major on-treatment variable together with insulin resistance index, while all of the other variables studied (HOMA-IR, IL28B genotype CC, RVR) could be very useful in decision making in the management of hepatitis C infection.

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