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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

Comparison of crystal structures of NS3 protease with and without the Q80K variant complexing with TMC-435350 (Simeprevir).Similar changes in structure are seen in both genotype 1a and genotype 6a. NS3 protease is shown as light blue ribbon. Yellow structure represents simeprevir (TMC-435350). Residues pictured are as follows: gray (Q80), blue (R155) and red (D168).
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pone.0157438.g002: Comparison of crystal structures of NS3 protease with and without the Q80K variant complexing with TMC-435350 (Simeprevir).Similar changes in structure are seen in both genotype 1a and genotype 6a. NS3 protease is shown as light blue ribbon. Yellow structure represents simeprevir (TMC-435350). Residues pictured are as follows: gray (Q80), blue (R155) and red (D168).

Mentions: We report the presence of the Q80K variant, associated with decreased response to simeprevir in genotype 1a patients, in the majority of individuals with genotype 6a. Endemic to Southeast Asia, genotype 6a is the second most common genotype behind genotype 1b in Southern China [33]. Liu et al. reported similar findings with variant Q80K present in 95% of mono-infected HCV patients in their patients with genotype 6a [32]. The importance of this RAV, seen in 48.1% of genotype 1a patients in North America [34], lies in its influence on clinical response to simeprevir in patients with genotype 1a. Response to simeprevir in patients with the Q80K variant was not statistically significant compared to placebo in the QUEST-1/QUEST-2 trials [35]. A pooled 58.3% of patients with the Q80K variant attained sustained virologic response with simeprevir compared to 83.6% without [35]. The effect of Q80K, however, does not appear to be class-specific given equivalent response to macrocyclic PI faldaprevir [36]. The theory behind decreased efficacy of simeprevir in the presence of Q80K is related to the direct contact between Q80K and R155, which participates in the formation of a salt bridge with residue D168. The disruption of this R155-D168 salt bridge by the Q80K variant leads to a weakened interaction between the protease and the inhibitor and subsequently decreased susceptibility [37]. Our modeling of the Q80K variant in genotype 6a reveals the same structural changes that occur in genotype 1a (Fig 2), which suggests that genotype 6a patients may also have decreased response to simeprevir. However, a phase IIa open-label study on simeprevir monotherapy demonstrated potent antiviral activity against a small cohort of genotype 6 patients, although pretreatment Q80K was present in only one patient [25]. The same study found potent antiviral activity in genotype 4 patients, corroborated by preliminary results from a Phase III trial in genotype 4 patients demonstrating excellent response to simeprevir in combination with peg-interferon and ribavirin, although with higher SVR rates seen in treatment-naïve and relapsed patients than non-responders [38]. These findings lend credence to studying the use of simeprevir in genotype 6 as well. The recent creation of a hepatitis C replicon encoding a genotype-6a NS3 protease should also facilitate phenotypic resistance testing and clarify impact of the Q80K variant [39].


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)

Comparison of crystal structures of NS3 protease with and without the Q80K variant complexing with TMC-435350 (Simeprevir).Similar changes in structure are seen in both genotype 1a and genotype 6a. NS3 protease is shown as light blue ribbon. Yellow structure represents simeprevir (TMC-435350). Residues pictured are as follows: gray (Q80), blue (R155) and red (D168).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0157438.g002: Comparison of crystal structures of NS3 protease with and without the Q80K variant complexing with TMC-435350 (Simeprevir).Similar changes in structure are seen in both genotype 1a and genotype 6a. NS3 protease is shown as light blue ribbon. Yellow structure represents simeprevir (TMC-435350). Residues pictured are as follows: gray (Q80), blue (R155) and red (D168).
Mentions: We report the presence of the Q80K variant, associated with decreased response to simeprevir in genotype 1a patients, in the majority of individuals with genotype 6a. Endemic to Southeast Asia, genotype 6a is the second most common genotype behind genotype 1b in Southern China [33]. Liu et al. reported similar findings with variant Q80K present in 95% of mono-infected HCV patients in their patients with genotype 6a [32]. The importance of this RAV, seen in 48.1% of genotype 1a patients in North America [34], lies in its influence on clinical response to simeprevir in patients with genotype 1a. Response to simeprevir in patients with the Q80K variant was not statistically significant compared to placebo in the QUEST-1/QUEST-2 trials [35]. A pooled 58.3% of patients with the Q80K variant attained sustained virologic response with simeprevir compared to 83.6% without [35]. The effect of Q80K, however, does not appear to be class-specific given equivalent response to macrocyclic PI faldaprevir [36]. The theory behind decreased efficacy of simeprevir in the presence of Q80K is related to the direct contact between Q80K and R155, which participates in the formation of a salt bridge with residue D168. The disruption of this R155-D168 salt bridge by the Q80K variant leads to a weakened interaction between the protease and the inhibitor and subsequently decreased susceptibility [37]. Our modeling of the Q80K variant in genotype 6a reveals the same structural changes that occur in genotype 1a (Fig 2), which suggests that genotype 6a patients may also have decreased response to simeprevir. However, a phase IIa open-label study on simeprevir monotherapy demonstrated potent antiviral activity against a small cohort of genotype 6 patients, although pretreatment Q80K was present in only one patient [25]. The same study found potent antiviral activity in genotype 4 patients, corroborated by preliminary results from a Phase III trial in genotype 4 patients demonstrating excellent response to simeprevir in combination with peg-interferon and ribavirin, although with higher SVR rates seen in treatment-naïve and relapsed patients than non-responders [38]. These findings lend credence to studying the use of simeprevir in genotype 6 as well. The recent creation of a hepatitis C replicon encoding a genotype-6a NS3 protease should also facilitate phenotypic resistance testing and clarify impact of the Q80K variant [39].

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