Seminar

Hepatitis C

The discovery of a new series of potent hepatitis C virus (HCV) NS5A inhibitors containing biaryl sulfone or sulfate cores is reported. Structure-activity relationship (SAR) studies on inhibitors containing various substitution patterns of the sulfate or sulfone core structure established that m-,m′- substituted biaryl sulfate core-based inhibitors containing an amide moiety (compound 20) or an imidazole moiety (compound 24) showed extremely high potency. Compound 20 demonstrated double-digit pM potencies against both genotype 1b (GT-1b) and 2a (GT-2a). Compound 24 also exhibited double-digit pM potencies against GT-1b and sub nM potencies against GT-2a. Furthermore, compounds 20 and 24 exhibited no cardiotoxicity in an hERG ligand binding assay and showed acceptable plasma stability and no mutagenic potential in the Ames test. In addition, these compounds showed distinctive additive effects in combination treatment with the NS5B targeting drug sofosbuvir (Sovaldi^®). The results of this study showed that the compounds 20 and 24 could be effective HCV inhibitors.

CD81 and CLDN1 interact to form a CD81–CLDN1 co-receptor complex that is crucial in hepatitis C virus (HCV) entry. Variations in the two genes were shown to influence immunological functions; therefore, we hypothesized that polymorphisms in these genes may contribute to HCV susceptibility. A case–control study consisting of 461 patients and 461 controls was conducted to explore the associations between CD81 rs708564 and CLDN1 rs893051 and HCV susceptibility in a Chinese population. We found a decreased HCV risk associated with the CD81 rs708564 TT (odds ratio (OR) = 0.66, 95% CI = 0.44–0.98) genotype. The gene–gene interaction between CD81 and CLDN1 polymorphisms also decreased HCV risk in a joint multiplicative manner (OR for the presence of both CD81 rs708564 TT and CLDN1 rs893051 GG genotypes = 0.59, 95% CI = 0.36–0.97). Furthermore, the CD81 rs708564 TT genotype conferred a more pronounced decrease in HCV susceptibility in combination with lower levels of high-density lipoprotein cholesterol (HDL-C; OR = 0.71, 95% CI = 0.52–0.96), and higher levels of low-density lipoprotein cholesterol (OR = 0.24, 95% CI = 0.09–0.65). We also observed a decreased HCV susceptibility in individuals with higher HDL-C levels who carried the CLDN1 rs893051 G/C genotype. These findings suggest that homozygous CD81 rs708564 TT may be a genetic modifier for avoiding HCV infection whether as a sole single nucleotide polymorphism or combined with the CLDN1 rs893051 GG genotype, and this effect is associated with serum levels of lipoprotein.

Infection with the hepatitis C virus (HVC) is one of the most common viral infections worldwide. Approximately 170 million individuals are infected worldwide. HCV is an important cause of morbidity and mortality. In Mexico, according to the National Health Survey 2000, it is estimated that 70,000 cases exist. We undertook this study to estimate the prevalence of anti-HCV antibodies in patients with association to the risk factors for HCV infection in the lowland (bajio) region.

There were 2803 individuals 15 years of age or older who were treated at the General Hospital Zone #4 who were included in this study. Following informed consent, the participants were given a questionnaire listing the major risk factors for hepatitis C. If they answered positive to any of these identified factors, a blood sample was taken to determine anti-HCV antibodies via ELISA analysis.

Average age in this study was 38.4 ± 13.5 years, and 75.5% were female (n = 2116). Anti-HCV antibodies were isolated in 1.3% of the patients (n = 36). The most commonly identified risk factor among all the participants was a history of previous transfusions (28.8 % of all patients, n = 813 and 41.7%, n = 15 of those with positive HCV antibodies). This was the only statistically significant risk factor identified in this study (p = 0.066).

Mexico is currently considered to have a lower prevalence for HCV in relation to developed countries and other endemic areas. The figures reported are lower than those observed in this study, suggesting that the strategies for detecting HCV in Mexico may be inadequate.