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A Glimpse of the Future?

Potential novel approaches to the treatment of patients with HCV were also discussed during The Liver Meeting 2015.

A DNA-Directed RNA Interference Agent

TT-034 is an RNA interference therapeutic agent composed of a recombinant DNA that is delivered intravenously using an adeno-associated virus capsid for the transduction of hepatocytes. TT-034 uses the transcriptional machinery of the hepatocyte to drive long-term expression of three independent short hairpin RNAs to simultaneously target well-conserved regions of the HCV RNA genome, including the 5'UTR and NS5B. In nonhuman primate studies, clinically relevant doses of TT-034 transduced nearly 100% of hepatocytes and resulted in persistent shRNA expression.

Suhy and colleagues[23] reported the first-in-human, phase 1/2a open-label dose-escalating trial in which a single intravenous infusion of TT-034 was administered to patients with HCV genotype 1. A liver biopsy at 21 days after dosing documented hepatic TT-034 DNA levels, transduction of substantial portions of hepatocytes, and a resultant dose-dependent expression of anti-HCV RNAs.

A GalNAc-Conjugated Oligonucleotide-Targeting MicroRNA-122

MicroRNA-122 (miR-122) plays a crucial role in the HCV life cycle. Binding of miR-122 to the 5'UTR of the HCV genome promotes HCV RNA stability and accumulation, protects the HCV genome from degradation by cellular exonucleases, and prevents induction of an innate immune response against the virus.[24]

van der Ree and colleagues[24] evaluated the safety and efficacy of a single subcutaneous injection of RG-101, a carbohydrate-conjugated oligonucleotide that targets miR-122 in hepatocytes, in patients infected with various HCV genotypes. At weeks 4 and 8, a total of 68% of patients had HCV RNA levels below the limit of quantification. At week 28, a total of 27% still had undetectable HCV RNA levels.

Further validation and experience with these promising novel therapeutic strategies are required. We will then require guidance on when and how to apply these options.

Stemming the Rising Tide of Morbidity and Mortality

Successful treatment of HCV will improve quality of life and reduce mortality for patients at all stages of the disease. Therefore, the American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidance indicates that antiviral treatment is indicated for all patients with HCV unless they have a life expectancy of less than 12 months due to another disease.[25]

Of course, the major impediments to real-life implementation of this strategy are case recognition, access to care, cost, and the resultant restrictions placed on antiviral agents. On November 5, 2015, the Centers for Medicare & Medicaid Services notified state program directors that federal law requires them to cover effective, clinically appropriate, and medically necessary treatments, including clinically appropriate antiviral therapy, for beneficiaries with HCV.[26] Hopefully, the licensure of multiple regimens for HCV will create opportunities for innovative pricing strategies that will increase affordability of new and emerging medications.

Presentations at The Liver Meeting 2015 offered a rationale for widespread screening and access, as well as the promise of pangenotypic "one-size-fits-all" therapeutic options for patients with HCV. This will simplify and hopefully universalize access and effectiveness of care, which will stem the rising tide of morbidity and mortality caused by this virus.


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