Reviewers Consider the Current State of HCV Host-Targeting Agents

Thomas Baumert, MD

New molecules that target key factors in the life cycle of hepatitis C virus (HCV) are demonstrating potential for treating patients who have failed to respond to, or are unable to receive direct-acting antivirals (DAAs), according to a recent review of early trial developments and future applications of the host-targeting agents (HTAs).

Thomas Baumert, MD, of the Institute for Research on Viral and Hepatic Diseases, University of Strasbourg, France, and colleagues pointed to several limitations of the generally successful DAAs, including limited access for many infected patients, treatment failure in a small subset of patients, potential adverse effects in patients with comorbidity, and the persistent risk of hepatocellular carcinoma (HCC) after achieving sustained virologic response (SVR) in those with advanced fibrosis.

"HTAs provide a broad antiviral activity with very high genetic barrier to drug resistance due to the extremely low mutational rate occurring within host cells," Baumert and colleagues observed.

Reviewers did not respond to requests for comment at the time of publication.

The investigators found that opportunities for developing the novel HTAs have emerged with improved understanding of key factors in the 3 major steps of the viral life cycle: attachment and cell entry, translation and replication, and assembly and release of new infectious virions. Their review identified several candidate HTAs in clinical trials.

Agents that inhibit HCV entry, alone or in combination with other antiviral treatments, represent a particularly attractive strategy for preventing organ infection in liver transplant, or during transplantation of HCV-positive organs, Baumert and colleagues indicate.

The first investigational HTA for this application, ITX-5061, significantly limited viral evolution in patients receiving liver transplant, but allowed escape mutations in long-term in vitro settings and demonstrated only limited efficacy in phase 1 studies. A pair of agents that inhibit HCV entry have moved into phase 2 trials: erlotinib, an epidermal growth factor receptor (EGFR) inhibitor; and silymarin/silibinin, a natural product from milk thistle.

Chloroquin, an antimarlarial drug which was found to affect 2 factors in HCV virus entry, was assessed in a phase 4 clinical study, but viral titers relapsed quickly after stopping the medication. Baumert and colleagues suggested it might still have a role in combination with other treatment. They noted that another investigational agent RG-101, which interferes with viral replication by inhibiting microRNA-122, was also found to allow viral rebound after discontinuation, but is now in a phase 2 study in combination with DAAs.

"Interestingly, combinations of host-targeting HCV entry inhibitors and DAAs are characterized by synergistic antiviral effects," the reviewers noted. "The prophylactic properties of HTAs targeting virus entry could make them a valuable asset in the prevention of graft infection during liver transplant."

Three agents that inhibit HCV RNA replication and have demonstrated clinical efficacy—but with safety limitations—are alisporivir (Debio 025), NIM811, and SCY-635. Alisporivir is of particular interest, Baumert and colleagues noted, as it also inhibits replication of HIV, and so might have a role in cases of co-infection.

Clinical trials of agents that inhibit HCV assembly and release have not yet yielded successful monotherapy candidates. Celgosivir, a glucosidase I inhibitor that demonstrated synergistic effect with interferon-based therapies, was withdrawn after a phase 2 trial determined that it was not efficacious as monotherapy. Pradigastat (LCQ908), a diglyceride acyltransferase inhibitor was also withdrawn after a phase 2 trial demonstrated lack of efficacy as monotherapy.

The reviewers suggested, however, that preclinical data warrant additional studies of their effect in drug combinations.

"Combinations of HTAs and DAAs may even further reduce treatment duration, increase efficacy and thus improve adherence and access to therapy," they opined. "HTAs may also be used for the treatment of patients with advanced disease, to lower HCC risk since this is a limitation of current regimens...(and) are good candidates to prevent HCV infection during liver transplantation or transplantation of HCV-positive organs such as kidneys."

The review, "Host-targeting therapies for hepatitis C virus infection: current developments and future applications," was published online in Therapeutic Advances in Gastroenterology.