Naturally occurring resistance mutations within the core and NS5B regions in hepatitis C genotypes, particularly genotype 5a, in South Africa

Abstract

Approximately 1 million South Africans are infected with Hepatitis C virus (HCV). The standard of care (SOC) in South Africa is combination therapy (pegylated interferon and ribavirin). HCV genotypes and/or mutations in the core/ non-structural regions have been associated with response to therapy and/or disease progression. This study examines mutations in the core (29-280 amino acids, including ~90 E1 amino acids) and NS5B (241-306 amino acids) regions on pre-treatment isolates from patients attending Johannesburg hospitals or asymptomatic South African blood donors. Diversity within known CD4+ and CD8+ T-cell epitopes was also explored. Samples grouped into subtypes 1a (N=10) 1b (N=12), 3a(N=5), 4a (N=3) and 5a(N=61). Two mutations, associated with interferon resistance-R70Q and T110N-were present in 29 genotype 5a core sequences. No resistance mutation to NS5B nucleotide inhibitors, sofosbuvir was found. Six putative CD8+ and one CD4+ T-cell epitope sequence in the core region showed binding scores of <300 IC 50 nM to HLA alleles frequently observed in the South African population. No known CD8+ and CD4+ T-cell epitopes were mapped in the NS5B region. The analysis begs the question whether those infected with genotype 5a will benefit better on interferon-free combination therapies. This study provides new insight into one of the lesser studied HCV genotypes and compares the diversity seen in a large pre-treatment cohort with other subtypes. KeywordsHepatitis C, genotype 5, interferon, mutations, therapy Highlights  We examined mutational changes of hepatitis C in the core/E1 and NS5B genes. Phylogenetic analyses were performed using Bayesian inferences. Diversity within known CD4+ and CD8+ T-cell epitopes was also explored. Mutations, associated with interferon resistance, were present in genotype 5a samples at baseline. 2

Molecular characterization of hepatitis C virus in liver disease patients in Botswana: a retrospective cross-sectional study

“…From the analysis with the GenBank genotype 5 sequences, it was interesting to note that 81% of the references contained the R70Q mutation compared to 16% with the wildtype amino acid. In a study conducted in South Africa, the R70Q mutation was observed in 90% of genotype 5a blood donors [33]. Whether the impact of this mutation in genotype 1 strains is the same in genotype 5 remains unclear.…”

“…Whether the impact of this mutation in genotype 1 strains is the same in genotype 5 remains unclear. Presence of this mutation in only genotype 5 isolates could either be due to transmission of a mutated strain or a naturally occurring drug resistant mutation to the SOC [33]. However, the latter assumption cannot be confirmed since there are no data on duration of treatment.…”

Systematic review: cost‐effectiveness of direct‐acting antivirals for treatment of hepatitis C genotypes 2‐6

“…HCV Genotype 4, however, resembles genotype 1 in both clinical and economic aspects. As for genotype 5, only one study from South Africa, where genotype 5 is the predominant infection, found that treatment with SOF‐LDV was cost‐effective at the listed price and would be cost‐saving at lower prices available in Egypt and elsewhere …”

Characterization of partial NS5B region among hepatitis C virus genotype 6 subtypes isolated from Thai blood donors

“…It has been reported that amino acid mutations in other regions of NS5B are associated with resistance to NS5B polymerase inhibitors. These amino acid residues include S96, S365, S368, M414, L419, M423, Y448, I482, V494, P495, V499, G554, and D559 [Aissa et al, ; Prabdial‐Sing et al, ; Sarrazin, ]. To achieve the high efficacy for drug treatment, it may be important to investigate amino acid mutations of the entire NS5B region.…”