Distribution of naturally -occurring NS5B resistance-associated substitutions in Egyptian patients with chronic Hepatitis C

Abstract

Background NS5B polymerase inhibitors represent the cornerstone of the present treatment of Hepatitis C virus infection (HCV). Naturally occurring substitution mutations to NS5B inhibitors have been recorded. The current study intended to demonstrate possible natural direct acting antiviral (DAA)—mutations of the HCV NS5B region in HCV patients in Minia governorate, Egypt. Methods Samples were collected from 27 treatment-naïve HCV patients and 8 non-responders. Out of 27 treatment-naïve patients, 17 NS5B sequences (amino acids 221–345) from treatment-naïve patients and one sample of non-responders were successfully amplified. Nucleotide sequences have been aligned, translated into amino acids, and compared to drug resistance mutations reported in the literature. Results NS5B amino acid sequence analysis ensures several novel NS5B mutations existence (more than 40 substitution mutations) that have not been previously documented to be correlated with a resistant phenotype. It was found that K304R (82.4%), E327D and P300T (76.5% each) substitutions were the most distributed in the tested samples, respectively. S282T, the major resistance mutation that induces high sofosbuvir-resistance level in addition to other reported mutations (L320F/C) and (C316Y/N) were not recognized. Q309R mutation is a ribavirin-associated resistance, which was recognized in one strain (5.9%) of genotype 1g sequences. Besides, one substitution mutation (E237G) was identified in the successfully amplified non-responder sample. Conclusion Our study showed various combinations of mutations in the analyzed NS5B genes which could enhance the possibility of therapy failure in patients administered regimens including multiple DAA.

Evaluation of the Safety and Resistance Associated Variants of Sofosbuvir/Daclatasvir Among Egyptian Patients With Hepatitis C Virus: A Prospective Study

“…The most frequent RAVs detected before treatment were R270K, K304R, R231K, P300T, V252A. This is similar to Ahmed et al, 13 study as K304R (82.4%), E327D and P300T (76.5% each) substitutions were the most distributed in the tested samples and one substitution mutation (E237G) was identified in the non-responder sample.…”

Road to elimination of HCV: Clinical challenges in HCV management

“…20 Even though S282T has been shown to confer strong resistance to sofosbuvir, it is rarely detected in patients who have been treated with sofosbuvir. 21,22 One potential explanation suggested by a reviewer is that this variant might overlap a region that forms an RNA hairpin secondary structure, thereby raising the barrier to resistance through stabilizing selection. We speculate that the presence of this variant might be associated with one or more additional compensating mutations, making it unlikely to emerge de novo during sofosbuvir treatment.…”

“…Although a number of RASs, including NS5B L159F, V321I, C316N, M426L, Y448H, Y452H, R465G and V499A, have been detected in treatment‐naïve genotype 1 patients, they tend to confer only a low level of resistance, and so far sofosbuvir resistance is not considered a major concern 20 . Even though S282T has been shown to confer strong resistance to sofosbuvir, it is rarely detected in patients who have been treated with sofosbuvir 21,22 . One potential explanation suggested by a reviewer is that this variant might overlap a region that forms an RNA hairpin secondary structure, thereby raising the barrier to resistance through stabilizing selection.…”

Geometric Deep learning Prioritization and validation of cannabis phytochemicals as anti-HCV non- nucleoside direct-acting inhibitors

“…S282T induces high sofosbuvir-resistance, Q309R is a ribavirin-associated resistance, E237G was identi ed in the successfully ampli ed nonresponder sample 20 .…”