Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors

Smith, David A.; Magrì, Andrea; Bonsall, David; Ip, Camilla L. C.; Trebes, Amy; Brown, Aaron; Piazza, P; Bowden, Rory; Nguyen, Dung; Ansari, M Azim; Simmonds, Peter; Barnes, Eleanor

doi:10.1002/hep.29837

Cited by 75 publications

(95 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we accounted for genotype, viral load, and various comorbidities in the multivariable model, further studies are required to evaluate the difference in the SVR between LDV/SOF and VEL/SOF while accounting for patient characteristics. There is also a need for evaluations of baseline mutations in genotype 3, which make VEL less effective in certain subtypes of genotype 3 . Similarly, we found SVR rates were significantly different between 8 weeks and 12 weeks of treatment after adjusting for viral load and genotype in the overall analysis and the analysis restricted to LDV/SOF; others have reported no difference in SVR with 8 weeks versus 12 weeks of LDV/SOF .…”

Section: Discussionsupporting

confidence: 61%

Effectiveness of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in People Who Inject Drugs and/or Those in Opioid Agonist Therapy

et al. 2019

View full text Add to dashboard Cite

We evaluated the effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in treating hepatitis C virus (HCV) genotype 1 and SOF/velpatasvir (SOF/VEL) for all genotypes among people who inject drugs (PWID) and those not injecting drugs and who were on or off opioid agonist therapy (OAT). Study participants comprised a population‐based cohort in British Columbia, Canada. The British Columbia Hepatitis Testers Cohort includes data on individuals tested for HCV from 1990 to 2016 that are integrated with medical visits, hospitalization, and prescription drug data. We classified study participants as off OAT/recent injection drug use (off‐OAT/RIDU), off OAT/past IDU (off‐OAT/PIDU), off OAT/no IDU (off‐OAT/NIDU), on OAT/IDU (on‐OAT/IDU), and on OAT/no IDU (on‐OAT/NIDU). We assessed sustained virologic response (SVR) 10 weeks after HCV treatment among study groups treated with LDV/SOF or SOF/VEL until January 13, 2018. Analysis included 5,283 eligible participants: 390 off‐OAT/RIDU, 598 off‐OAT/PIDU, 3,515 off‐OAT/NIDU, 609 on‐OAT/IDU, and 171 on‐OAT/NIDU. The majority were male patients (64%‐74%) and aged ≥50 years (58%‐85%). The SVRs for off‐OAT/RIDU, off‐OAT/PIDU, off‐OAT/NIDU, on‐OAT/IDU, and on‐OAT/NIDU were 91% (355/390), 95% (570/598), 96% (3,360/3,515), 93% (567/609), and 95% (163/171), respectively. Among those with no SVR, 14 individuals died while on treatment or before SVR assessment, including 4 from illicit drug overdose. In the overall multivariable model, off‐OAT/RIDU, on‐OAT/IDU, male sex, cirrhosis, treatment duration <8 weeks, treatment duration 8 weeks, and treatment with SOF/VEL were associated with not achieving SVR. Conclusion: In this large real‐world cohort, PWID and/or those on OAT achieved high SVRs, although slightly lower than people not injecting drugs. This finding also highlights the need for additional measures to prevent loss to follow‐up and overdose‐related deaths among PWID.

show abstract

Section: Discussionsupporting

confidence: 61%

Effectiveness of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in People Who Inject Drugs and/or Those in Opioid Agonist Therapy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…). Genotype 3a is difficult to treat with DAAs, due to its relatively low sensititivy to several PIs and NS5A inhibitors . Our work suggests that an additional reason might be its greater propensity to develop resistance to PIs and sofosbuvir (this study and Ramirez et al).…”

Section: Discussionmentioning

confidence: 51%

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Jensen¹,

Fahnøe²,

Pham³

et al. 2019

Hepatology

View full text Add to dashboard Cite

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.

show abstract

“…The recent rollout of direct-acting antiviral (DAA) drugs against HCV, which can cure infection in more than 90% of cases and have considerably less toxicity than previous drug treatment regimens (2), has been a major breakthrough. However, treatment success varies among viral strains, host genotype, and disease status (3,4). In addition, DAAs remain out of reach for many individuals, especially if they are unaware of their infection and/or are living in resource-poor countries with high HCV burdens.…”

Section: Introductionmentioning

confidence: 99%

High resolution evolutionary analysis of within-host hepatitis C virus infection

Raghwani

et al. 2018

Preprint

View full text Add to dashboard Cite

Despite the breakthroughs in the treatment of HCV infection in recent years, we have a limited understanding of how virus diversity generated within individuals impacts the evolution and spread of HCV variants at the population scale. Addressing this gap will be important for building models for molecular epidemiology, which can identify main sources of disease transmission and evaluate the risks of drug-resistance mutations emerging and disseminating in a population. Here, we have undertaken a high-resolution analysis of HCV within-host evolution from four individuals co-infected with HIV. Specifically, we used longread, deep-sequenced data of the full-length HCV envelope glycoprotein, longitudinally sampled from acute to chronic HCV infection to investigate the underlying viral evolutionary dynamics. In three individuals we found strong statistical support for population structure maintaining within-host HCV genetic diversity. Furthermore, we found significant variation in rates of molecular evolution among different regions of the HCV envelope region, both within and between individuals. Lastly, we report the first estimate of the within-host population genetic rate of recombination for HCV (0.28 x 10 -7 recombinations per site per day; interquartile range: 0.13-1.05 x 10 -7 ), which is two orders of magnitude lower than that estimated for HIV-1, and four orders of magnitude lower than the nucleotide substitution rate of the HCV envelope gene. Together, these observations indicate that population structure and strong genetic linkage shapes within-host HCV evolutionary dynamics. These results will guide the future investigation of potential HCV drug resistance adaptation during infection, and at the population scale.

show abstract

Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors

Cited by 75 publications

References 41 publications

Effectiveness of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in People Who Inject Drugs and/or Those in Opioid Agonist Therapy

Effectiveness of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in People Who Inject Drugs and/or Those in Opioid Agonist Therapy

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

High resolution evolutionary analysis of within-host hepatitis C virus infection

Contact Info

Product

Resources

About