Treatment of chronic hepatitis C with direct-acting antivirals: The role of resistance

Abstract

The use of direct-acting antivirals (DAAs) to treat chronic hepatitis C has resulted in a significant increase in rates of sustained viral response (around 90%-95%) as compared with the standard treatment of peginterferon/ribavirin. Despite this, however, the rates of therapeutic failure in daily clinical practice range from 10%-15%. Most of these cases are due to the presence of resistant viral variants, resulting from mutations produced by substitutions of amino acids in the viral target protein that reduce viral sensitivity to DAAs, thus limiting the efficacy of these drugs. The high genetic diversity of hepatitis C virus has resulted in the existence of resistance-associated variants (RAVs), sometimes even before starting treatment with DAAs, though generally at low levels. These pre-existing RAVs do not appear to impact on the sustained viral response, whereas those that appear after DAA therapy could well be determinant in virological failure with future treatments. As well as the presence of RAVs, virological failure to treatment with DAAs is generally associated with other factors related with a poor response, such as the degree of fibrosis, the response to previous therapy, the viral load or the viral genotype. Nonetheless, viral breakthrough and relapse can still occur in the absence of detectable RAVs and after the use of highly effective DAAs, so that the true clinical impact of the presence of RAVs in therapeutic failure remains to be determined.

State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization

“…The efficacy of treatment containing DAAs is very high in terms of sustained virological response (SVR); nonetheless 10–15% of therapeutic failure is observed in clinical practice, mainly associated with the selection of DAAs-resistant viral variants, resulting from mutations produced by amino acid substitutions in the target virus protein that reduce viral sensitivity to DAAs [84]. Resistance-associated variants (RAVs) may be present, despite being usually at low levels even before the beginning of DAAs treatment due to the great genetic variability of HCV [84].…”

“…Resistance-associated variants (RAVs) may be present, despite being usually at low levels even before the beginning of DAAs treatment due to the great genetic variability of HCV [84]. Moreover, genotype 3 virus consistently demonstrates lower SVR rates to DAAs, despite higher SVR rates in other forms of the virus [85].…”

Sofosbuvir and daclatasvir combination therapy for current hepatitis C virus genotype 4 achieves SVR: a case report of HCV genotype 4 from the Amazon

“…These drug combinations are well tolerated and have been reported to increase sustained virological response (SVR) rates to approximately 90% [5][6][7] .…”

Letter: should direct‐acting antiviral drugs be used concomitantly with chemotherapeutic drugs in hepatitis C virus‐infected patients with cancer?

“…Compared with the standard treatment of peginterferon/ribavirin, the use of DAAs to treat chronic hepatitis C has resulted in a significant increase in more than 90% sustained viral response. 1 However, the feasibility of concomitant use of DAAs and chemotherapy in hepatitis C virus-infected patients with cancer is not well illustrated. Therefore, Economides and coworkers 2 performed a small prospective study for the first time to examine the safety and clinically significant drug-drug interactions observed in patients who received simultaneous treatment with DAAs and chemotherapy.…”

“…In their reply letter, Jiang et al, 1 reported that we included a heterogeneous group of cancer patients receiving concomitant treatment for various reasons. Whereas eight of our patients experienced adverse events (AEs) that were serious (grade 3 or grade 4), only two of the patients experienced grade 4 AEs.…”