Abstract
Background and AimsHaving a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear.MethodsThis study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC).ResultsPatients with BMI ≥30 kg/m2 showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140).ConclusionsReduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.
Highlights
Hepatitis C virus (HCV) is the foremost cause of parenterally transmitted hepatitis [1,2], and chronic infection is associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma [3,4]
It has been hypothesized that high body mass index (BMI) induces: (i) the metabolic syndrome leading to insulin resistance, hepatic steatosis, and higher baseline viral load [13], (ii) altered cytokine signaling as manifested by elevated levels of leptin, adiponectin, and resistin [14], and (iii) reduced bioavailability of interferon-a [15]
A strong association was noted between liver histopathology and body mass index (BMI) as well as Homeostatic model assessment-insulin resistance (HOMA-IR) with patients having higher BMI having higher HOMA-IR, indicative of insulin resistance and more pronounced steatosis and fibrosis (Figure 1)
Summary
Hepatitis C virus (HCV) is the foremost cause of parenterally transmitted hepatitis [1,2], and chronic infection is associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma [3,4]. Treatment with pegylated interferon-a and ribavirin yields sustained viral response (SVR) rates of 50–80% [5,6,7], with higher SVR rates seen in patients infected with HCV of genotypes 2 and 3. It has been hypothesized that high BMI induces: (i) the metabolic syndrome leading to insulin resistance, hepatic steatosis, and higher baseline viral load [13], (ii) altered cytokine signaling as manifested by elevated levels of leptin, adiponectin, and resistin [14], and (iii) reduced bioavailability of interferon-a [15]. Having a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear
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