Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation

Abstract

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a Scavenger Receptor B-I (SR-BI) antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV infected patients undergoing liver transplantation. The first 13 “control” patients did not receive drug. The subsequent 10 patients received ITX5061 150 mg immediately pre- and post-transplant, and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing. ITX5061 was well tolerated with measurable plasma concentrations during therapy. Whilst the median HCV RNA reduction was greater in ITX treated patients at all time points in the first week after transplantation there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype 1 infected patients treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, p=0.004). Ultradeep pyrosequencing revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. Conclusions ITX5061 reduces plasma HCV RNA post transplant notably in genotype 1 infected patients and slows viral evolution. Following liver transplantation the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies.

Daytime variation in hepatitis C virus replication kinetics following liver transplant

“…We 12 and others 13, 14 have previously reported a rapid decrease in HCV RNA within the first 16 hours following surgery due to clearance of virus in the periphery by the reticular endothelial system of the new liver. To assess the influence of transplant time on viral clearance and allograft infection kinetics we calculated the area over the infection curve for control and treated subjects between 0–16 h and 24–168 h after transplantation ( Figure 3C, D).…”

“…The data presented were obtained from subjects enrolled in an open-label phase 1b study to assess the effect of ITX5061 in patients undergoing liver transplantation at a single centre (Queen Elizabeth Hospital Birmingham, Birmingham, UK), described previously 12 . All patients gave informed written consent and ethical approval was given by the UK National Research Ethics Service (reference 10/H0301/36) 12 .…”

“…In almost every case HCV infects the newly transplanted organ or donor allograft, providing an unprecedented window to study the early stages of HCV infection. We had the opportunity to study the relationship between the time of liver transplantation and HCV replication dynamics in subjects enrolled in a clinical trial to assess the safety and efficacy of an entry inhibitor targeting scavenger receptor BI (SR-BI) 12 . We noted differences in viral infection of the allograft in control subjects that associated with the time of liver transplant, suggesting a role for circadian processes to regulate HCV entry into the liver.…”

The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control

“…Monoclonal antibodies that block CD81 or SR-BI protected against subsequent HCV challenge with different genotypes in human liver chimeric mice [200][201][202]. The anti-SR-BI entry inhibitor ITX5061 has been tested in the clinic [203,204], and showed some evidence of reducing HCV RNA titers and viral evolution in patients undergoing liver transplantation [203]. An antibody against Claudin-1 can control HCV in human liver chimeric mice [205].…”

Strategies to Preclude Hepatitis C Virus Entry

“…The anti-HCV effect of ITX 5061 was found additive to synergistic in combination with several standard-of-care therapeutics, and the resistant mutant was defined on the viral glycoprotein E2 [123]. A latest phase 1b clinical trial [124] revealed that the ITX 5061-treated patients, especially the genotype 1-infected patients, had a significant reduction in HCV RNA through the first week after liver transplantation and viral evolution were restricted; however, the viral RNA levels became comparable in both ITX 5061-treated and untreated patients, suggesting the need to incorporate other antiviral agents using different modes of actions to eliminate HCV infection. Aspirin, alternatively, inhibited HCV entry by downregulating CLDN1 [125].…”