The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C

Abstract

The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 μm; P=0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 μm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P=0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P=0.002) but marginal in HCV-1 (38.7%vs 27.8%; P=0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P=0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.

A preliminary investigation on single nucleotide polymorphism rs2287622 of bile salt export pump gene in patients with chronic hepatitis C virus infection in Hunan, China

“…Europeans researches suggested that the polymorphism of BSEP V444A might be associated with the HCV infection development, liver fibrosis progression and long-term treatment response [8–11]. The few studies needed to be further supported by researches on extended population.…”

“…Since 2011, several European researches have underscored associations between a certain SNP, V444A (HGVS name: NM_003742.2: c.1331 T > C; ref SNP: rs2287622) in exon 13 of the hepatobiliary bile salt export pump (BSEP) gene, and the risk of HCV infection, progression of liver fibrosis and even the virological response during anti-HCV therapy [8–11]. But their findings need to be validated by investigation on extended population, especially on population of different races.…”

Role of Membrane Transport in Hepatotoxicity and Pathogenesis of Drug-Induced Cholestasis

“…An association of the c.1331C allele with acquired cholestasis was confirmed in patient cohorts with DIC (140) and cholestasis of pregnancy (143,144). Interestingly, the same polymorphism correlates with progression to cirrhosis in hepatitis C genotype 2 and 3 patients (145) and shows an association with a lower sustained viral response for hepatitis C genotype 2 and 3 (146). The underlying mechanism could be a positive correlation between intracellular bile salt levels and hepatitis virus C replication (101).…”

Nuclear Receptor Variants in Liver Disease

“…Viral replication efficiency has been linked to variations in cellular bile salt concentrations using the HCV replicon system [61]. Of note, variants of the human bile salt that export pump ABCB11 might be associated with sustained virological response [62] and progression towards liver cirrhosis [63]. In vitro experiments using HCV replicon-harboring cells have shown that the impact of bile salts on HCV replication might be through the action of FXR rather than a direct effect of bile salts themselves [64].…”