Drug resistance-associated substitutions identified in HCV genes

Last Updated: 2017-11-24

By Marilynn Larkin

NEW YORK (Reuters Health) - In patients who fail direct-acting antiviral therapy for hepatitis C virus (HCV) infection, resistance-associated substitutions (RASs) vary by HCV genotype and subtype and with different classes of drugs - a finding that might be used to select salvage therapies, researchers suggest.

"Little is known about (genetic) substitutions that mediate resistance of HCV to direct-acting antivirals, due to the small number of patients with treatment failure in approval studies," note Dr. Christoph Sarrazin of the University of Frankfurt, in Germany, and colleagues.

To investigate, the team analyzed samples from patients who had HCV infection with genotypes 1 to 6 for RASs in HCV genes (NS3, NS5A, NS5B) that are targeted by direct-acting antivirals.

They compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with direct-acting antiviral failure to sequences from 2,322 patients infected with HCV genotypes 1-4 who had not been treated with direct-acting antivirals. RASs were considered relevant if they were associated with direct-acting antiviral failure in patients or conferred a greater than two-fold change in susceptibility compared with a reference strain.

As reported in Gastroenterology, online November 3, RASs in NS3 associated with simeprevir or paritaprevir failure included R155K and D168E/V. More specifically, RAS Q80K/R was associated with simeprevir failure in patients with genotype 1a or 4, and Y56H was associated with paritaprevir failure (in combination with D168V) in patients with genotype 1b.

In NS5A, the Y93H RAS was most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection. The L31M RAS was associated with failure of daclatasvir or ledipasvir, but not ombitasvir.

RASs in NS5A were heterogeneous among patients with HCV genotype 1a or 4 infections. In patients with genotype 3, Y93H was associated with resistance to daclatasvir.

Among patients who failed sofosbuvir-containing regimens, L159F was enriched in those with genotype 1b (together with C316N) and genotype 3 infection, whereas the RAS S282T was rarely observed.

Taken together, the findings suggest that "the identified typical treatment-selected resistance patterns for broadly currently used direct-acting antiviral regimens enable the selection of specific treatment options based on the result of resistance analyses," the authors conclude.

Dr. Douglas Dieterich, Director of the Institute of Liver Medicine at the Icahn School of Medicine at Mount Sinai in New York City, told Reuters Health, "This isn't shocking or actually new news. But it is a big, real-world study."

"All those resistance mutations have been previously described," he said by email. "We (do) resistance testing for NS3 and NS5A now and consider it standard practice."

Dr. Ramon Bataller, Chief of Hepatology at the University of Pittsburgh, Pennsylvania, agreed that "this is the most comprehensive study so far aimed at identifying mechanisms of resistance to novel direct-acting antiviral therapy."

"If the results of this study are replicated in future investigations, there is no doubt that in the near future, patients will be tested for most common RASs in order to select the best possible regimen," he told Reuters Health by email.

"However, the percentage of patients non-responding to modern direct-acting antivirals is minimal, so the cost-efficacy of tests assessing the presence of RAS is uncertain," Dr. Bataller concluded.

Dr. Sarrazin did not respond to requests for comment.

SOURCE: http://bit.ly/2zPFz0n

Gastroenterology 2017.