Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial

Abstract

Background & aims: Hepatitis C virus (HCV) infection is associated with an increased prevalence of diabetes and insulin resistance (IR); whether this is a causal relationship has not been established.

Methods: We performed a longitudinal study within the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial to evaluate whether suppression of hepatitis C is associated with improvement in IR. Participants had advanced hepatic fibrosis and carried non-3 HCV genotypes (n = 96). Patients underwent 24 weeks of pegylated interferon and ribavirin therapy and were categorized into HCV clearance groups at week 20 on the basis of HCV RNA levels; null responders had <1 log(10) decline (n = 38), partial responders had >or=1 log(10) decline (n = 37) but detectable HCV RNA, and complete responders had no detectable HCV RNA (n = 21). The primary outcome was change (week 20 minus week 0) in IR by using the homeostasis model assessment (HOMA2-IR).

Results: Adjusting only for baseline HOMA2-IR, mean HOMA2-IR differences were -2.23 (complete responders), -0.90 (partial responders), and +0.18 (null responders) (P = .036). The observed differences in mean HOMA2-IR scores were ordered in a linear fashion across response groups (P = .01). The association between HCV clearance and improvement in HOMA2-IR could not be accounted for by adiponectin or tumor necrosis factor-alpha and was independent of potential confounders including age, gender, ethnicity, body mass index, duration of infection, medications used, and fibrosis.

Conclusions: HCV suppression correlates with improvement in IR. These data provide further support for a role of HCV in the development of insulin resistance.

Figure 1

Side-by-side quartile box and whisker plots of difference in HOMA2-IR by HCV clearance categories. Box plots represent median (center line in boxes), means (open circles), 25^th to 75^th percentiles (box ends) and 5^th to 95^th percentiles (whisker ends) of HOMA2-IR difference scores, n=96. Mean HOMA2-IR differences are −2.23 (CR), −0.90 (PR), and +0.18 (NR), (p =0.036), adjusted for natural log of baseline HOMA2-IR. HOMA2-IR difference scores were ordered in a linear fashion across response groups and this linear trend was statistically significant (F(1,92)=6.8, p=0.01).

Figure 2

Plot of change in Adiponectin (X-axis) versus change in HOMA2-IR (Y-axis) (week 20 – week 0). A trend towards decreasing HOMA2-IR with increasing adiponectin level is noted (R²= − 0.14) but this did not achieve statistical significance (p= 0.19).