Global prevalence of pre-existing HCV variants resistant to direct-acting antiviral agents (DAAs): mining the GenBank HCV genome data

Abstract

Direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) proteins open a whole new era for anti-HCV therapy, but DAA resistance associated variants (RAVs) could jeopardize the effectiveness of DAAs. We reported the global prevalence of DAA RAVs using published GenBank data. 58.7% of sequences (854/1455) harbored at least one dominant resistance variant and the highest RAV frequency occurred in Asia (74.1%), followed by Africa (71.9%), America (53.5%) and Europe (51.4%). The highest RAV frequency was observed in genotype (GT) 6 sequences (99%), followed by GT2 (87.9%), GT4 (85.5%), GT1a (56%), GT3 (50.0%) and GT1b (34.3%). Furthermore, 40.0% and 29.6% of sequences were detected RAVs of non-structural (NS) 5A inhibitors and NS3 protease inhibitors, respectively. However, RAVs to NS5B nucleo(t)ide inhibitor (NI) and NI-based combinations were uncommon (<4% of sequences). As expected, combinations of multiple RAVs to the IFN-free regimens recommended by current guidelines were rarely detected (0.2%-2.0%). Our results showed that the overall global prevalence of DAA RAVs was high irrespective of geography or genotype. However, the NI-based multi-DAA regimens had a low RAV prevalence, suggesting that these regimens are the most promising strategies for cure of the long-term HCV infection.

Figure 1. Illustration of GenBank database HCV genome searching and screening strategy.

Figure 2. The prevalence of total and clinically relevant DAA resistance associated variants to different DAAs (A) and regions (B).

Figure 3. The geographic prevalence of total and clinically relevant DAA resistance associated variants.

Oceania was not assessed due to the low number of available samples (four sequences). *p < 0.05.

Figure 4

The prevalence of resistance associated variants in various genotypes (GTs). Frequency of all RAVs for different DAAs (A) and regions (B). Frequency of clinically relevant RAVs for different DAAs (C) and regions (D).

Figure 5. The prevalence of resistance associated variants to IFN-free regimens in total

(A) and among various genotypes (B). GT, genotype; SMV, Simeprevir; SOF, Sofosbuvir; DCV, Daclatasvir; LDV, Ledipasvir; 3D, Paritaprevir and Ombitasvir plus Dasabuvir.

Figure 6. Resistance associated variants for NS3 protease inhibitors, NS5A inhibitors and NS5B polymerase inhibitors.

Variants are color-coded based on genotype: 1a, red; 1b, blue; 2, yellow; 3, green; 4, brown; 6, grey. Clinically relevant RAVs are highlighted in bold, in vitro RAVs are identified by italics. Note: X, amino acid deletion.