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Natural Polymorphisms Conferring Resistance to HCV Protease and Polymerase Inhibitors in Treatment-Naïve HIV/HCV Co-Infected Patients in China.

Zhou K, Liang Z, Wang C, Hu F, Ning C, Lan Y, Tang X, Tucker JD, Cai W - PLoS ONE (2016)

Bottom Line: Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance.Overall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance.Further phenotypic studies and clinical research are needed.

View Article: PubMed Central - PubMed

Affiliation: Guangzhou Eighth People's Hospital, 627 Dongfeng Dong Road, Guangzhou, Guangdong 510060, China.

ABSTRACT

Background: The advent of direct-acting agents (DAAs) has improved treatment of HCV in HIV co-infection, but may be limited by primary drug resistance. This study reports the prevalence of natural polymorphisms conferring resistance to NS3/4A protease inhibitors and NS5B polymerase inhibitors in treatment-naïve HIV/HCV co-infected individuals in China.

Methods: Population based NS3/4A sequencing was completed for 778 treatment-naïve HIV/HCV co-infected patients from twelve provinces. NS3 sequences were amplified by nested PCR using in-house primers for genotypes 1-6. NS5B sequencing was completed for genotyping in 350 sequences. Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance.

Results: Overall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance. Variants were found in 3.6% (7/193) of genotype 1, 100% (23/23) of genotype 2, 100% (237/237) of genotype 3 and 92% (299/325) of genotype 6 sequences. The Q80K variant was present in 98.4% of genotype 6a sequences. High-level RAVs were rare, occurring in only 0.8% of patients. 93% (64/69) patients with genotype 1b also carried the C316N variant associated with NS5B low-level resistance.

Conclusions: The low frequency of high-level RAVs associated with primary HCV DAA resistance among all genotypes in HIV/HCV co-infected patients is encouraging. Further phenotypic studies and clinical research are needed.

No MeSH data available.


Related in: MedlinePlus

Phylogenetic tree.Neighbor-joining tree representing the relationship of all sequences with reference sequences. Solid circle (●) marks different subtype identified reference. Bootstrap analysis was performed with 1000 replicates and only bootstrap values ≥70% are shown at the corresponding nodes. Reference sequences: Genotype 1a (AF511950, NC004102, M67463); 1b (AY587016, D11355, EF032892); 2a (AY746460, D00944, AB047639); 3a (NC009824, AF046866, X76918); 3b (D49374); 6a (DQ480513, AY859526, Y12083); 6u (EU408332, EU408331, EU408330); 6n (EU246937, EU246938, AY878652).
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pone.0157438.g001: Phylogenetic tree.Neighbor-joining tree representing the relationship of all sequences with reference sequences. Solid circle (●) marks different subtype identified reference. Bootstrap analysis was performed with 1000 replicates and only bootstrap values ≥70% are shown at the corresponding nodes. Reference sequences: Genotype 1a (AF511950, NC004102, M67463); 1b (AY587016, D11355, EF032892); 2a (AY746460, D00944, AB047639); 3a (NC009824, AF046866, X76918); 3b (D49374); 6a (DQ480513, AY859526, Y12083); 6u (EU408332, EU408331, EU408330); 6n (EU246937, EU246938, AY878652).

Mentions: HCV genotype and subtype were determined by RT-PCR and sequencing of the HCV core region. A subset of patients was sequenced using both HCV core and NS5B regions. Consensus sequences of the forward and reverse strands were used. Sequences obtained were compared against the Los Alamos HCV database [16]; reference sequences can be found in S1 Table. Genotype and subtype were then confirmed by phylogenetic tree reconstruction (see Fig 1) in MEGA v5.05 [17] using the neighbor joining method with the Kimura-2 parameter model. A gamma parameter of 0.5 was used to model differences in substitution rates among base sites. Branch support was assessed by bootstrap analysis with 1000 replicates.


Natural Polymorphisms Conferring Resistance to HCV Protease and Polymerase Inhibitors in Treatment-Naïve HIV/HCV Co-Infected Patients in China.

Zhou K, Liang Z, Wang C, Hu F, Ning C, Lan Y, Tang X, Tucker JD, Cai W - PLoS ONE (2016)

Phylogenetic tree.Neighbor-joining tree representing the relationship of all sequences with reference sequences. Solid circle (●) marks different subtype identified reference. Bootstrap analysis was performed with 1000 replicates and only bootstrap values ≥70% are shown at the corresponding nodes. Reference sequences: Genotype 1a (AF511950, NC004102, M67463); 1b (AY587016, D11355, EF032892); 2a (AY746460, D00944, AB047639); 3a (NC009824, AF046866, X76918); 3b (D49374); 6a (DQ480513, AY859526, Y12083); 6u (EU408332, EU408331, EU408330); 6n (EU246937, EU246938, AY878652).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920402&req=5

pone.0157438.g001: Phylogenetic tree.Neighbor-joining tree representing the relationship of all sequences with reference sequences. Solid circle (●) marks different subtype identified reference. Bootstrap analysis was performed with 1000 replicates and only bootstrap values ≥70% are shown at the corresponding nodes. Reference sequences: Genotype 1a (AF511950, NC004102, M67463); 1b (AY587016, D11355, EF032892); 2a (AY746460, D00944, AB047639); 3a (NC009824, AF046866, X76918); 3b (D49374); 6a (DQ480513, AY859526, Y12083); 6u (EU408332, EU408331, EU408330); 6n (EU246937, EU246938, AY878652).
Mentions: HCV genotype and subtype were determined by RT-PCR and sequencing of the HCV core region. A subset of patients was sequenced using both HCV core and NS5B regions. Consensus sequences of the forward and reverse strands were used. Sequences obtained were compared against the Los Alamos HCV database [16]; reference sequences can be found in S1 Table. Genotype and subtype were then confirmed by phylogenetic tree reconstruction (see Fig 1) in MEGA v5.05 [17] using the neighbor joining method with the Kimura-2 parameter model. A gamma parameter of 0.5 was used to model differences in substitution rates among base sites. Branch support was assessed by bootstrap analysis with 1000 replicates.

Bottom Line: Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance.Overall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance.Further phenotypic studies and clinical research are needed.

View Article: PubMed Central - PubMed

Affiliation: Guangzhou Eighth People's Hospital, 627 Dongfeng Dong Road, Guangzhou, Guangdong 510060, China.

ABSTRACT

Background: The advent of direct-acting agents (DAAs) has improved treatment of HCV in HIV co-infection, but may be limited by primary drug resistance. This study reports the prevalence of natural polymorphisms conferring resistance to NS3/4A protease inhibitors and NS5B polymerase inhibitors in treatment-naïve HIV/HCV co-infected individuals in China.

Methods: Population based NS3/4A sequencing was completed for 778 treatment-naïve HIV/HCV co-infected patients from twelve provinces. NS3 sequences were amplified by nested PCR using in-house primers for genotypes 1-6. NS5B sequencing was completed for genotyping in 350 sequences. Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance.

Results: Overall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance. Variants were found in 3.6% (7/193) of genotype 1, 100% (23/23) of genotype 2, 100% (237/237) of genotype 3 and 92% (299/325) of genotype 6 sequences. The Q80K variant was present in 98.4% of genotype 6a sequences. High-level RAVs were rare, occurring in only 0.8% of patients. 93% (64/69) patients with genotype 1b also carried the C316N variant associated with NS5B low-level resistance.

Conclusions: The low frequency of high-level RAVs associated with primary HCV DAA resistance among all genotypes in HIV/HCV co-infected patients is encouraging. Further phenotypic studies and clinical research are needed.

No MeSH data available.


Related in: MedlinePlus