Treatment failure with DAA therapy: Importance of resistance

Abstract

Viral resistance is a major reason for virological failure in patients being treated with direct-acting antivirals (DAAs) for chronic HCV infection. However, the importance of viral resistance mainly depends on the DAA regimen and HCV genotype. For first-line therapy with glecaprevir/pibrentasvir (G/P) or velpatasvir/sofosbuvir (VEL/SOF) no general baseline resistance analysis is required because of the high antiviral activity and high barrier to resistance. If available, resistance testing may help to optimise therapy in certain subgroups of patients with HCV genotype 3 and other rare HCV geno/subtypes. Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is the first choice for the second-line treatment of patients following a previous DAA failure, with rates of viral eradication above 90% irrespective of the presence of resistance-associated substitutions (RASs). However, in resource-limited settings, only firstgeneration DAAs may be available for second-line therapy. Here, RASs selected during initial antiviral therapy should be considered if testing is available and rescue treatment should include a switch to a regimen with a new DAA class to optimise treatment response. Patients with HCV genotype 3 are overrepresented in the group who experience DAA treatment failure. Limited data are available for thirdline therapies, but promising results have been achieved with G/P plus SOF or VOX/VEL/SOF with or without ribavirin for 12 to 24 weeks; these regimens should be administered irrespective of a patient's RAS profile.

Effectiveness and Safety of Pangenotypic Regimens in the Most Difficult to Treat Population of Genotype 3 HCV Infected Cirrhotics

“…The choice of a therapeutic regimen in all patients was based on the treating physician’s decision regarding recommendations and regulations. However, according to the most recent EASL guidelines, if resistance testing is available and performed, only DAA-experienced patients with the NS5A Y93H RAS at baseline should be treated with SOF/VEL plus RBV, whereas those without should receive SOF/VEL alone, so we assumed that this factor did not affect efficacy reported in our analysis, no NS5A-experienced patient was treated with SOL/VEL [ 11 , 39 ]. Noteworthy, the other regimen prescribed in GT3 infected patients with the presence of Y93H RAS is the combination of SOF/VEL and protease inhibitor voxilaprevir is not recommended in decompensated cirrhotics; moreover, it was not available in Poland within a reimbursed therapeutic program in the analyzed period.…”

The Role of RASs /RVs in the Current Management of HCV

“…Voxilaprevir/velpatasvir/sofosbuvir as multiple targeted rescue therapy is the first choice for patients who fail DAA therapy with rates of SVR above 90%, irrespective of the presence of RAS [ 77 ]. Despite the high efficacy of the fixed triple combination, treatment failure has been observed in patients with genotypes 1a and 3 and cirrhosis [ 78 ].…”

SHARED: An International Collaboration to Unravel Hepatitis C Resistance

“…Baseline NS5A RAS also reduced the efficacy of elbasvir-grazoprevir and ledipasvir-sofosbuvir in GT1a patients, requiring extended treatment duration [6]. The negative effects of specific baseline NS5A RAS on SVR were further manifested in GT3 patients with cirrhosis treated with ledipasvir-sofosbuvir, daclatasvir-sofosbuvir, velpatasvir-sofosbuvir, or glecaprevirpibrentasvir [6,7]. Ongoing viral replication in the face of sub-optimal drug pressure during DAA treatment results in an enrichment of the pre-existing RAS or accumulation Viruses 2021, 13, 1580 2 of 11 of additional RAS, which reduce drug susceptibility or enhance viral replicative fitness.…”