Retreatment of Hepatitis C Virus-Infected Patients with Direct-Acting Antiviral Failures

Abstract

The treatment of chronic hepatitis C virus (HCV) infection has considerably evolved with the development of safe and well-tolerated combinations of direct-acting antiviral (DAA) drugs yielding high rates of infection cure. However, some patients fail to achieve a sustained virological response while receiving the most recent DAA combinations. Several waves of treatment failures have occurred concomitantly to the use of different drug combinations. The outcome of their retreatment strongly depends on the DAA(s) received and the retreatment regimen(s) available. This article discusses virological failure rates with the successive waves of HCV combination regimens, the reasons for failure, the role of HCV resistance, and current retreatment options. The triple combination of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks is the first-line retreatment strategy in patients previously exposed to DAAs. Difficult-to-retreat patients may benefit from the combination of sofosbuvir plus glecaprevir/pibrentasvir and/or the addition of ribavirin and/or longer retreatment duration.

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

“…therapies with direct-acting antivirals (DAAs) against essential viral proteins NS3/4A, NS5A, and NS5B have significantly improved treatment options and outcomes (2)(3)(4)(5) with cure rates of ϳ95% for treatment-naive patients (6)(7)(8)(9)(10)(11)(12). However, even the most recent DAA combinations, still in 2019, fail to cure some patients (4,5,13,14). Especially for DAA-experienced patients, baseline polymorphisms among diverse genotypes and preexisting resistance-associated substitutions (RASs) negatively impact treatment outcomes (3-5, 14, 15).…”

“…Especially for DAA-experienced patients, baseline polymorphisms among diverse genotypes and preexisting resistance-associated substitutions (RASs) negatively impact treatment outcomes (3-5, 14, 15). Treatment failure is highly associated with RASs in the therapeutic target (4,5,(14)(15)(16)(17)(18)(19). With the WHO goal to increase treatment from 13% (2016) to 80% (2030) of the 71 million infected globally (1,20), even a small failure rate will result in many HCV-infected patients failing therapy due to drug resistance (3, 14-19, 21, 22).…”

Factors Influencing the Prevalence of Resistance-Associated Substitutions in NS5A Protein in Treatment-Naive Patients with Chronic Hepatitis C

“…At the same time, the M28V polymorphism in the Russian strains of HCV genotype 1a was found to be unexpectedly frequent (57.9%). This particular RAS is associated with resistance of HCV 1a to ombitasvir and, to lesser extent, to ledipasvir, velpatasvir, and pibrentasvir [7,19,33,34]. The usual incidence of M28V polymorphism in treatment-naïve HCV 1a patients is 4-8% [8,9].…”

Quasispecies dynamics in disease prevention and control

“…Selection of resistant mutants has been described for virtually any chemical type of antiviral agent directed to any step of the infectious cycle of DNA or RNA viruses, including important pathogens, such as herpesviruses, picornaviruses, IV, HBV, and hepatitis C virus (HCV). Several reviews and articles have covered the theoretical basis of drug resistance, and consequences for treatment management [as examples see (Domingo et al, 2001b) and previous versions in Progress in Drug Research (Richman, 1994(Richman, , 1996Ribeiro and Bonhoeffer, 2000;Domingo et al, 2001aDomingo et al, , 2012Menendez-Arias, 2013;Perales, 2018;Mokaya et al, 2018;Nitta et al, 2019;Pawlotsky, 2019), and the articles in the Current Opinion of Virology volume edited by L. Menendez-Arias and D. Richman (Menendez-Arias and Richman, 2014)]. Therefore, the general mechanisms that confer adaptability to viruses are very effective in finding drug-escape pathways through molecular mechanisms that are summarized in Section 8.5.…”