SUMMARY BackgroundMost studies evaluating chronic hepatitis C virus (HCV) natural history have taken the development of cirrhosis as an end-point.

Chronic hepatitis C infection represents a significant and growing health problem worldwide. Patients with genotype 1 hepatitis C respond poorly to the current standard of care, pegylated interferon and ribavirin, which is frequently associated with unpleasant side effects. Consequently new agents with improved efficacy and tolerability are needed. The efficacy and safety of the direct-acting antiviral agent telaprevir in the treatment of genotype 1 hepatitis C infection have been demonstrated in a number of clinical trials. The addition of telaprevir to standard therapy considerably improves response rates and allows responseguided shortening of treatment duration in a substantial number of treatment-naïve patients. Side effects associated with telaprevir therapy include rash, anaemia, gastrointestinal disturbance and anorectal discomfort. Telaprevir-resistant variants have been identified in patients who have failed telaprevir-containing therapy, and whether selection of these variants will compromise future therapeutic options is currently unknown. The efficacy and safety of telaprevir in the treatment of the most challenging patients, including those with recurrent hepatitis C following liver transplantation and those co-infected with HIV, remains to be established.

SB 9200 is a novel, first-in-class oral modulator of innate immunity that is believed to act via the activation of the RIG-I and NOD2 pathways. SB 9200 has broad-spectrum antiviral activity against RNA viruses including hepatitis C virus (HCV), norovirus, respiratory syncytial virus and influenza and has demonstrated activity against hepatitis B virus (HBV) in vitro and in vivo. In phase I clinical trials in chronically infected HCV patients, SB 9200 has been shown to reduce HCV RNA by up to 1.9 log10. Here, we demonstrate the antiviral activity of SB 9200 against a HCV replicon system and patient derived virus. Using the HCV capture-fusion assay, we show that SB 9200 is active against diverse HCV genotypes and is also effective against HCV derived from patients who relapse following direct-acting antiviral treatment, including viruses containing known NS5A resistance-associated sequences. These data confirm the broad antiviral activity of SB 9200 and indicate that it may have clinical utility in HCV patients who have failed to respond to current antiviral regimens.

Background & AimsSofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England’s National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure.MethodsWe collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon.ResultsWe identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system.ConclusionsA common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.

Endothelin-1 is a potent vasoconstrictor and a therapeutic target in pulmonary arterial hypertension. Endothelial cells are the physiological source of endothelin-1 but in vitro data from our group shows that interferons (IFNα, IFNβ or IFNγ) induce endothelin-1 in pulmonary vascular smooth muscle cells. IFNs are integral to innate immunity and their antiviral and immunomodulatory capability has been harnessed therapeutically; for example, IFNα plays a critical role in the treatment of chronic hepatitis C infection. However, in some patients, IFN causes pneumonitis and possibly irreversible pulmonary arterial hypertension. In this study, we found that of 16 patients undergoing a six-month course of IFNα therapy, two demonstrated considerably increased serum levels of endothelin-1. We propose that IFN therapy results in elevated levels of endothelin-1 in some patients and when clinically significant levels are reached, pulmonary side effects could ensue. This hypothesis can be easily tested in IFN-treated patients by measuring serum endothelin-1 levels and cardiopulmonary physiological parameters.