Virological characterization of treatment failures and retreatment outcomes in patients infected with “unusual” HCV genotype 1 subtypes

Abstract

Background and Aims: Suboptimal rates of sustained virological response have been reported in patients infected with an “unusual,” non-1a/1b HCV genotype 1 subtype. The objectives of this study were to assess the proportion of non-1a/1b genotype 1 subtypes in a population of HCV-infected patients who failed to achieve sustained virological response after first-line direct-acting antiviral treatment, to virologically characterize their failures and to assess their outcomes on retreatment. Approach and Results: Samples addressed between January 2015 and December 2021 to the French National Reference Center for Viral Hepatitis B, C, and D were prospectively analyzed by means of Sanger and deep sequencing. Among 640 failures, 47 (7.3%) occurred in patients infected with an “unusual” genotype 1 subtype. Samples were available in 43 of them; 92.5% of these patients were born in Africa. Our results show the presence at baseline and at treatment failure of NS3 protease and/or NS5A polymorphisms conferring inherent reduced susceptibility to direct-acting antivirals in these patients, together with the presence at failure of additional resistance-associated substitutions not naturally present as dominant species, but jointly selected by first-line therapy. Conclusions: Patients infected with “unusual” HCV genotype 1 subtypes are over-represented among direct-acting antiviral treatment failures. Most of them were born and likely infected in sub-Saharan Africa. “Unusual” HCV genotype 1 subtypes naturally carry polymorphisms that confer reduced susceptibility to the drugs currently used to cure hepatitis C, in particular the NS5A inhibitors. Retreatment with sofosbuvir plus an NS3 protease and an NS5A inhibitor is generally efficacious.

‘Unusual’ HCV genotype subtypes: origin, distribution, sensitivity to direct-acting antiviral drugs and behaviour on antiviral treatment and retreatment

“…15 Between January 2015 and December 2021, we analysed samples collected at the time of relapse in 640 patients who failed to achieve SVR after receiving an NS5A inhibitorcontaining regimen at the French National Reference Center for Viral Hepatitis B, C and D. Of these, 47 patients (7.3%) were infected with an unusual genotype 1 subtype, the vast majority of whom were born in Africa. 21 This prevalence is much higher than that of unusual genotype 1 subtypes in the French population of patients infected with HCV, which was estimated at 0.8% in a nationwide multicentre study, 47 confirming that these patients are more likely to fail to achieve SVR on DAA therapy than those infected with other viral subtypes. Treatment failure occurred with sofosbuvir/ledipasvir in 74.4% of cases, other earlier generation combinations in 14.0% of cases, sofosbuvir/ velpatasvir in 4.7% of cases and glecaprevir/pibrentasvir in 7.0% of cases.…”

“…Treatment failure occurred with sofosbuvir/ledipasvir in 74.4% of cases, other earlier generation combinations in 14.0% of cases, sofosbuvir/ velpatasvir in 4.7% of cases and glecaprevir/pibrentasvir in 7.0% of cases. 21 In a German study using the European Resistance Database, which includes samples from patients in several Western and Central European countries, the prevalence of unusual HCV subtypes was 1.6% (75 of 4,653) in DAA-naïve patients and 4.4% (60 of 1,376) in patients who failed to achieve SVR after DAA-based therapy. 95 Six patients infected with genotype 1 (1c, n=1; 1e, n=2; 1l, n=1; unassigned 1, n=2) failed DAA therapy, including ombitasvir/paritaprevir/ritonavir plus dasabuvir in one case, grazoprevir/elbasvir in one case and sofosbuvir/ledipasvir in four cases.…”

Therapeutic preparedness: DAA-resistant HCV variants in vitro and in vivo

“…In this subgroup, RASs were characterized by different sequencing approaches, and the outcome of retreatment was analyzed. [7] Unusual GT1 and GT4 subtypes are rarely found in European or North American patients but are common in patients of African origin; unusual GT1 subtypes are particularly prevalent in sub-Saharan Africa. In addition, high numbers of baseline NS5A RASs as well as reduced SVR rates, were observed, especially when first-generation DAAs were used for treatment.…”

“…In patients with baseline samples available, unfortunately only 6 of 43 DAA treatments did not select additional RASs; therefore, the detected RASs can be considered naturally inherent in unusual subtypes. Interestingly, all patients achieved SVR after retreatment with optimal second-generation regimens, such as GLE/PIB or a triple DAA combination, such as VOX-/VEL/SOF, [7] with data available for 26 individuals.…”

“…In a French cohort who failed to first-line DAA treatment, 47 patients (7%) were infected with unusual GT1 subtypes, mainly patients of African origin. In this subgroup, RASs were characterized by different sequencing approaches, and the outcome of retreatment was analyzed 7 . Unusual GT1 and GT4 subtypes are rarely found in European or North American patients but are common in patients of African origin; unusual GT1 subtypes are particularly prevalent in sub-Saharan Africa.…”