Fibrosis severity and progression
According to the reported evidence, the interplay between HCV and metabolic disorders induces liver disease complications; first of all, it accelerates the progression of fibrosis. A close relationship between IR and liver fibrosis has been shown in many studies. Hui et al. [
8] reported that, in 260 patients with chronic hepatitis C, the HOMA-IR score, but not steatosis, was associated with the severity of fibrosis and accelerated the rate of progression. Therefore, regardless of the viral genotype and severity of liver damage, serum insulin concentrations and HOMA-IR index scores increase with the severity of hepatic fibrosis. Petta et al. found that in HCV genotype 1 patients, HOMA-IR scores >2.7 and platelet levels <200 × 10
3/μl were the diagnostic criteria for severe fibrosis (F3 and F4) [
51]. The association between IR and hepatic fibrosis exists independently of the exclusion of cirrhotic patients from the analysis or of the adjustment for other factors associated with fibrosis, including steatosis [
52]. This suggests that insulin is a driving force behind accelerated fibrosis progression in patients chronically infected with HCV [
53]. Hyperinsulinemia and hyperglycemia directly stimulate hepatic stellate cells, leading to activation of connective tissue growth factor and subsequent accumulation of extracellular matrix [
54,
55]. In addition, leptin and TNF-α could be the molecules responsible for accelerated fibrosis. Patients diagnosed with IR frequently show hyperleptinemia and increased serum TNF-α levels; both of these are also able to activate hepatic stellate cells, leading to increased fibrogenesis [
56,
57].
The hypothesis of an association between steatosis and fibrosis progression in HCV-infected patients needs to be confirmed. Indeed, while several studies claimed that there is an association between steatosis and fibrosis progression, very few evaluated the association with a proper methodological approach. Thus, only longitudinal studies investigating paired biopsies might guarantee sound results on this association. Of interest, in the Maid study, a large multicenter cohort study involving HCV patients infected with multiple genotypes from different countries around the world, it was demonstrated that while the main predictor of fibrosis in patients with genotype 1 is the presence of diabetes, in HCV-3 a higher grade of inflammatory activity is independently associated with fibrosis progression [
58].
HCC development
In patients with diabetes, HCV is an independent factor for the development of HCC, even after adjusting for the confounding variables of age and gender [
59,
60]. It is well recognized that in males a HOMA-IR score >3 is an independent predictor of HCC [
61,
62]. The molecular mechanisms underlying the link between IR and HCC remain unclear and include the mitogenic role of insulin and its stimulating property on cell proliferation [
63]. Additional hypotheses are based on the binding of insulin with insulin-like growth factor (IGF)-1 receptor, resulting in the activation of tyrosine kinase and a cascade of downstream intracellular responses [
63]. The question is now whether the coexistence of HCV increases the risk of cancer in patients with metabolic syndrome. Strikingly, insulin resistance and obesity are associated with a higher risk of adenocarcinoma, including colon cancer [
63]. The long duration of chronic HCV diseases hampers designing effective studies. Therefore, it is not surprising that a number of small studies evaluating the association among HCV, diabetes and HCC reached contrasting results on this debated aspect. In paired biopsies of patients with HCV who did or did not develop cancer, Kumar et al. [
64] failed to show an association with diabetes. In contrast, a study performed by Pekow [
65] on explanted livers of patients with cancer demonstrated an association between a more severe liver steatosis and the presence of cancer. A promoting role of HCV has been shown in a large European multicenter study conducted by Veldt et al. [
66]. In this study, the coexistence of diabetes increased the frequency of liver cancer in comparison to HCV infection alone [
66]. In contrast, in a study on 82,000 veterans with HCV infection and a comparable number of non-HCV-infected patients, despite a lower frequency of hypercholesterolemia, hypertrygliceridemia, hyperlypemia and hypertension in HCV-infected patients, a significant increase in the risk of liver cancer in the presence of a higher degree of steatosis was demonstrated [
59].
Atherosclerosis development
A further question on the interactions between HCV and metabolic disorders is related to the possible increased risk of cardiovascular morbidity and mortality in patients with chronic hepatitis C. The results so far accumulated on this topic are contradictory. In a large European survey, the risk of arterial damage observed in patients with HBV was comparable to that of patients with HCV infection [
67]. However, recently, exploring surrogate markers of cardiovascular mortality, evidence of intima-media thickness (IMT) and carotid plaques was investigated [
68]. In the Reveal HCV cohort, a 1.5 risk of cardiovascular-related deaths was registered in Taiwan [
69]. The association was significantly higher in patients with active HCV RNA replication [
64]. Petta et al. [
70] evaluated the prevalence of carotid atherosclerosis compared with a control population in order to assess the potential association among atherosclerosis, host and viral factors, and liver histological features. Out of 174 consecutive G1 CHC patients, 73 (41.9 %) showed carotid plaques at a rate significantly higher than that of control subjects (22.9 %) (
p < 0.001). Similarly, HCV-1 chronic hepatitis C patients had a greater IMT compared with control patients (1.04 ± 0.21 vs. 0.90 ± 0.16;
p < 0.001). Multivariate logistic regression analysis showed that older age [odds ratio (OR) 1.047, 95 % confidence interval (CI): 1.014–1.082,
p = 0.005] and severe hepatic fibrosis (OR 2.177, 95 % CI:1.043–4.542,
p = 0.03) were independently linked to the presence of carotid plaques.
Reduced response to interferon treatment
The treatment of metabolic disorders in HCV-infected patients coincides with the treatment of HCV. However, among the clinical consequences of HCV-induced IR, there is an impaired response to antiviral treatment [
71]. Although not unanimously accepted, rates of response to antiviral treatment, including pegylated interferon and ribavirin, are inversely associated with HOMA-IR index scores [
72]. An increased HOMA-IR index score is associated with reductions in 24-h virological response, early virological response (EVR) and sustained virological response (SVR) to antiviral therapy [
73]. The relevance of IR in antiviral therapy based on the combination of pegylated interferon and ribavirin has been reported, regardless of the HCV genotype [
74,
75].
An increase of HCV RNA levels and reduced rates of SVR, irrespectively of other response predictors, have indeed been registered in HCV-infected patients.
Several studies evaluated the negative effect of IR on SVR. The first evidence was reported by Romero-Gomez et al. [
76] in patients with HCV-1 infection. A French meta-analysis recently showed that the rate of SVR is significantly reduced by the severity of IR in patients with HCV infection overall and in patients with genotype 1 in particular [
77]. However, the study showed an inverse correlation between the severity of IR and SVR in both HCV patients overall and patients with HCV-1 in particular [
77]. The impact of HOMA-IR in patients with genotype 2 and 3, in case of dual treatment with pegylated interferon and ribavirin, was recently explored by Poustchi et al. [
78]. In these patients, a six-fold risk of non-response in case of a HOMA-IR value higher than 2 was observed.
Many authors have been trying to increase insulin sensitivity with the aim of increasing SVR. In particular, antidiabetic drugs such as metformin and thiazolidinediones have been used to improve insulin sensitivity. In a multicenter study, treatment non-responders were re-treated with pegylated interferon-α, ribavirin and pioglitazone. An early termination of this study was required as none of the patients showed a virological response at week 12 despite the improvement in insulin sensitivity [
79]. Another analysis in naïve non-diabetic patients who received a lead-in regimen of pioglitazone monotherapy for 4 weeks, followed by pioglitazone added to standard therapy with pegylated interferon-α and ribavirin, revealed that, despite an increase in rapid virologic response, no significant effect on SVR can be appreciated. [
80]. Treatment with metformin or thiazolidinediones, in addition to antiviral therapy, will probably be less important in the future, when more potent antivirals, such as the combination of different direct inhibitors of HCV enzymes, will be used in clinical practice. Currently, the uselessness of insulin sensitizers to reduce the severity of IR before starting an antiviral treatment plays against the idea that insulin resistance per se reduces SVR.
According to the knowledge accumulated so far, the only way to obtain an increase in the rates of SVR in these patients may be to advise weight loss before starting antiviral treatment [
81]. As shown in patients without concomitant viral hepatic infections, only exercise ensures both fat deposit and liver enzyme decreases.
IR can be influenced by lifestyle changes. It is known that weight loss can improve different clinical features of metabolic syndrome, including insulin sensitivity, irrespectively of the pathogenesis. Moreover, a study on 19 subjects showed that weight loss may also improve fibrosis in CHC patients [
82]. Aerobic exercise improves HOMA-IR values and decreases body fat in patients with chronic hepatitis C.
As anticipated, with the use of triple combination treatment including protease inhibitors, the role of IR showed a minor impact. Strikingly, danoprevir response is not reduced by insulin resistance status [
83]. As demonstrated by Serfaty et al. [
84] in naïve HCV-1 patients receiving triple treatment with pegylated interferon, ribavirin and telaprevir, HOMA-IR values were not predictive of virological response, while sustained virological response appeared to be associated with improved HOMA-IR scores. These results suggest that metabolic factors and insulin resistance do not have a significant effect on telaprevir-based treatment efficacy.
These data led us to expect that a pre-treatment evaluation of HOMA-IR, encouraged by the previously reported meta-analysis results, may be less relevant in the future workup of patients undergoing triple treatment regimens.
In our experience, higher body mass index and severe liver damage have been associated with higher rates of relapse in patients with HCV-2 and 3 receiving short treatments [
85]. Therefore, lifestyle changes are urgently recommended in patients such as those with genotype 2 dealing with dual treatment in the immediate future. The forthcoming analyses of data obtained in the Fission study with all oral interferon-free regimens combining sofosbuvir with ribavirin in patients infected with HCV-2 and 3 may shed further light on the future role of both HOMA-IR and dieting in patients infected with these genotypes.