Efficacy of adding metformin to pegylated interferon and ribavirin in treatment naive patients with chronic hepatitis C: a randomized double-blind controlled trial

Evidence indicates that insulin resistance results in poor sustained viral response [SVR] in patients with chronic hepatitis C [CHC]. Metformin is an oral hypoglycemic agent which improves insulin resistance. We sought to determine if the addition of metformin to the treatment regimen could improve SVR in treatment-naïve CHC patients in a randomized, double-blind, placebo-controlled trial. We randomized 140 consecutive CHC patients to receive either metformin 500 mg three times a day or placebo in addition to pegylated interferon [PEG-IFN] and ribavirin [RBV]. Only treatment-naïve subjects aged between 15 and 65 years of age were included. SVR was defined as no detectable HCV RNA six months after the end of treatment. Subjects who received at least one dose of PEG-IFN were included in the final analysis. The SVR rate in the metformin group was 75% versus 79% in controls [intention-to-treat] which was not significantly different. Also, the difference between the placebo and metformin group was not significant in subsets of different genotypes or those with homeostasis model assessment of insulin resistance [HOMA-IR] levels greater than 2 or body mass index greater than 25. The most common complaint was gastrointestinal discomfort [13% in metformin group versus 4% in controls; p=0.002] that lead to discontinuation of metformin in 8 participants. Although triple therapy with metformin, PEG-IFN and RBV is relatively well tolerated, the addition of metformin did not significantly improve viral response in CHC patients.

Expansion of CD4+CD25+FoxP3+ regulatory T cells in chronic hepatitis C virus infection

Regulatory T cells [Tregs] have been involved in impaired immunity and may have a pivotal role in persistence of viral infections. To develop a simple and reliable in-house three color flow cytometery of peripheral blood to understand the role of HCV infection in the increase of Tregs. The level of naturally occurring CD4+ CD25+ FoxP3+ regulatory T cells [nTregs] in 20 chronically infected with hepatitis C virus [HCV] patients was compared to those of 15 healthy individuals by flowcytometry. In a different approach we performed permeabilization and intracellular staining before surface staining which allows the preservation of the surface molecules in the combined detection process and results in the normal frequency of nTregs in blood. Using the optimized method, it was shown that a significantly higher proportion of nTregs in the total CD4+ T cell population was seen in the peripheral blood of chronic HCV patients [0.83 +/- 0.21%, p=0.05] as compared to controls [0.26 +/- 0.1, p=0.05]. Conclusions: In accordance with other studies, we showed that HCV infection induces a dramatic increase in Tregs, which might contribute to the immune response failure during HCV infection