Hepatitis C Viral RNA Genotype 3 NS5A Drug Resistance

NS5A inhibitors are antiviral drugs. They are classified as direct acting agents (DAAs) and work by inhibiting the HCV NS5A protein.^1,2

In genotype 3 treatment-naïve patients without cirrhosis, Mavyret® (glecaprevir/pibrentasvir) for 8 weeks, or Epclusa® (sofosbuvir/velpatasvir) for 12 weeks, may be used. Cirrhotic patients may require the addition of ribavirin to a sofosbuvir/velpatasvir regimen or a Vosevi® (sofosbuvir/velpatasvir/voxilapravir) regimen if they harbor the NS5A Y93H mutation at baseline.

Refer to the applicable FDA-approved package inserts for intended use, indications for use, dosing, warnings and other relevant clinical information.^3-6

Quest Diagnostics uses reverse transcription polymerase chain reaction (PCR) and DNA sequencing of HCV genotype 3 NS5A codons 1 to 150. This method detects NS5A inhibitor resistance-associated variants (RAVs), in particular the Y93H mutation, which occurs in <10% of patients with HCV genotype 3.^7,8

NS5A RAVs are associated with a lower sustained virologic response (SVR) in patients with HCV genotype 3 who are being treated with velpatasvir and sofosbuvir for 12 weeks.

In a phase 3 clinical trial, the SVR rate was 88% for patients with any NS5A RAVs at baseline, 84% for patients with Y93H at baseline, and 97% for patients without baseline RAVs.⁹  In the POLARIS-1 trial of VOSEVI®, of the 4 genotype 3a virologic failures, 2 individuals had Y93H at failure, 1 had E92K and 1 had A30K.⁵

The AASLD and IDSA guidelines currently recommend NS5A drug resistance testing for treatment-naïve cirrhotic patients or treatment-experienced non-cirrhotic patients being considered for 12 weeks of sofosbuvir/velpatasvir treatment. If the NS5A Y93H mutation is present, the addition of ribavirin is recommended, or another regimen should be considered.⁶

For specimens being submitted for NS5A resistance testing, the recommended HCV RNA level is at least 1,000 IU/mL. The assay may fail at lower viral loads.