Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Howe, Anita Y.M.; Rodrigo, Chaturaka; Cunningham, Evan B; Douglas, Mark W.; Dietz, Julia; Grebely, Jason; Popping, Stephanie; Sfalcin, Javier Alejandro; Parczewski, Miłosz; Sarrazin, Christoph; Salazar, Adolfo de; Fuentes, Ana; Sayan, Murat; Quer, Josep; Kjellin, Midori; Kileng, Hege; Mor, Orna; Lennerstrand, Johan; Fourati, Slim; Maio, V.C. Di; Chulanov, Vladimir; Pawlotsky, Jean‐Michel; Harrigan, P. Richard; Ceccherini‐Silberstein, Francesca; García, Féderico; Martinello, Marianne; Matthews, Gail; Fernando, Fay Fabián; Esteban, Juan Ignacio; Müllhaupt, Beat; Wiesch, Julian Schulze zur; Buggisch, Peter; Neumann‐Haefelin, Christoph; Berg, Thomas; Berg, Christoph P.; Schattenberg, Jörn M.; Moreno, Christophe; Stauber, Rudolf; Lloyd, Andrew R.; Dore, Gregory J.; Applegate, Tanya; Ignacio, Juan; García-Cehic, Damir; Gregori, Josep; Rodríguez‐Frías, Francisco; Rando, Ariadna; Angélico, M.; Andreoni, Massimo; Babudieri, Sergio; Bertoli, Ada; Cento, Valeria; Coppola, Nicola; Craxı̀, Antonio; Paolucci, Stefania; Parruti, Giustino; Pasquazzi, C.; Perno, Carlo Federico; Teti, Elisabetta; Vironet, C.; Lannergård, Anders; Duberg, Ann‐Sofi; Aleman, Soo; Gutteberg, Tore Jarl; Soulier, Alexandre; Gourgeon, Aurélie; Chevaliez, Stéphane; Pol, Stanislas; Carrat, Fabrice; Salmon, Dominique; Kaiser, Rolf; Knopes, Elena; Gómes, Perpétua; Kneght, Rob de; Rijnders, Bart; Poljak, Mario; Lunar, Maja M.; Usubillaga, Rafael; Séguin, Carole; Tay, Enoch; Wilson, Caroline; Wang, Dao Sen; George, Jacob; Kok, Jen; Pérez, Ana Belén Macho; Chueca, Natalia; García-Deltoro, Miguel; Martínez-Sapiña, Ana; Lara-Pérez, María Magdalena; García‐Bujalance, Silvia; Aldámiz‐Echevarría, Teresa; Vera-Méndez, Francisco Jesús; Pineda, Juan A; Casado, Marta; Pascasio, J.M.; Salmerón, Javier; Alados-Arboledas, Juan Carlos; Poyato, Antonio; Téllez, Francisco Ayuga; Rivero‐Juárez, Antonio; Merino, Dolores; Vivancos-Gallego, María Jesús; Rosales-Zábal, José Miguel; Ocete, María Dolores; Simón, Miguel Ángel; Rincón, Pilar; Reus, Sergi; Iglesia, Alberto de la; García-Arata, Isabel; Jiménez, Fernando; Hernández-Quero, José; Galera, Carlos; Balghata, Mohamed Omar; Primo, J; Masía, Mar; Espinosa, Núria; Delgado, Marcial; von-Wichmann, Miguel Ángel; Collado, Antonio; Santos, Jesús; Mínguez, Carlos; Díaz‐Flores, Felicitas; Fernández, Elisa; Bernal, Enrique; Juan, José de; Antón, J.; Vélez, Mónica; Aguilera, Antonio; Navarro, Daniel; Arenas, Juan; Fernández, Clotilde; Espinosa, María Dolores; Rios, María; Alonso, Roberto; Hidalgo, Carmen; Hernández, Rosario; Téllez, María J.; Rodríguez, Francisco Javier; Antequera, Pedro; Delgado, Cristina; Martin, Patrícia; Crespo, Javier; Becerril, Berta; Pérez, Óscar; Garcı́a-Herola, Antonio; Montero, J.L.; Freyre, Carolina; Grau, Concepción; Cabezas, Joaquín; Jiménez, Miguel; Rodrı́guez, Manuel; Quílez, Cristina; Pardo, Maria Rodriguez; Muñoz-Medina, Leopoldo; Figueruela, Blanca

doi:10.1016/j.jhepr.2022.100462

Cited by 22 publications

(8 citation statements)

References 25 publications

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“…In clinical trials, the majority of people who fail first-line DAA treatment develop RASs in the virus [ 8 , 9 ]. We have confirmed this previously in the real world, using data from Australia and the international SHARED consortium [ 10 , 11 ]. In our large cohorts, although the background prevalence of NS5A RASs in untreated patients is approximately 30%, in patients who fail treatment this increases to 70%–80% [ 10–12 ].…”

supporting

confidence: 84%

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia

Wang,

Phu,

McKee

et al. 2024

Open Forum Infectious Diseases

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Background Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) which reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens and treatment outcome. Results Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens which included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n=140), sofosbuvir/velpatasvir 75.0% (n=52), elbasvir/grazoprevir 81.6% (n=38), and glecaprevir/pibrentasvir 84.6% (n=13). NS5A RASs were present in 71.0% (n=210) of patients who achieved SVR and in 66.7% (n=30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions In our cohort the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

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supporting

confidence: 84%

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia

Wang,

Phu,

McKee

et al. 2024

Open Forum Infectious Diseases

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“…Considering the high conservation per genotype that renders the HCV core reliable for genotyping/subtyping [ 25 ], this finding could be particularly alarming as it implies the emergence of novel viral isolates that might be associated with potential DAA resistance, since this isolate was amplified from treatment-failure patient, although such resistance is usually associated with the polymorphism with drug-targeted genes, i.e. NS3 and NS5 [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Glycylglycine promotes the solubility and antigenic utility of recombinant HCV structural proteins in a point-of-care immunoassay for detection of active viremia

Shawky,

Tabll,

Elshenawy

et al. 2024

Microb Cell Fact

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Background Although E. coli is generally a well-opted platform for the overproduction of recombinant antigens as heterologous proteins, the optimization of expression conditions to maximize the yield of functional proteins remains empirical. Herein, we developed an optimized E. coli (BL21)-based system for the overproduction of soluble immunoreactive HCV core/envelope proteins that were utilized to establish a novel immunoassay for discrimination of active HCV infection. Methods The core/E1-E2 genes were amplified and expressed in E. coli BL21 (DE3) in the absence/presence of glycylglycine. The antigenic performance of soluble proteins was assessed against 63 HCV-seronegative (Ab−) sera that included normal and interferent sera (HBV and/or chronic renal failure), and 383 HCV-seropositive (Ab+) samples that included viremic (chronic/relapsers) and recovered patients’ sera. The color intensity (OD450) and S/Co values were estimated. Results The integration of 0.1–0.4M glycylglycine in the growth media significantly enhanced the solubility/yield of recombinant core and envelope proteins by ~ 225 and 242 fold, respectively. This was reflected in their immunoreactivity and antigenic performance in the developed immunoassay, where the soluble core/E1/E2 antigen mixture showed 100% accuracy in identifying HCV viremic sera with a viral RNA load as low as 3800 IU/mL, without cross-reactivity against normal/interferent HCV-Ab−sera. The ideal S/Co threshold predicting active viremia (> 2.75) showed an AUC value of 0.9362 (95% CI: 0.9132 to 0.9593), with 87.64, 91.23% sensitivity and specificity, and 94.14, 82.11% positive and negative predictive values, respectively. The different panels of samples assayed with our EIA showed a good concordance with the viral loads and also significant correlations with the golden standards of HCV diagnosis in viremic patients. The performance of the EIA was not affected by the immunocompromised conditions or HBV co-infection. Conclusion The applicability of the proposed platform would extend beyond the reported approach, where glycylglycine, low inducer concentration and post-induction temperature, combined with the moderately-strong constitutive promoter enables the stable production of soluble/active proteins, even those with reported toxicity. Also, the newly developed immunoassay provides a cost-effective point-of-care diagnostic tool for active HCV viremia that could be useful in resource-limited settings.

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“… 8 , 9 Previous work has shown that GT4 subtypes present NS5A resistance‐associated substitutions (RAS), leading to low cure rates after treatment with first‐generation DAAs (sofosbuvir combined with ledipasvir or daclatasvir). 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

“…8,9 Previous work has shown that GT4 subtypes present NS5A resistance-associated substitutions (RAS), leading to low cure rates after treatment with first-generation DAAs (sofosbuvir combined with ledipasvir or daclatasvir). 10,11 Furthermore, wider implementation of HCV programs reveal the diversity of population affected by HCV, linked with varying risk factors. In a similar way to Human Immunodeficiency virus (HIV), stigma is a greater burden for some HCV subpopulations, such as people who use drugs (PWUD).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C treatment program in Maputo, Mozambique, the challenge of genotypes and key populations: A 5‐year retrospective analysis of routine programmatic data

Loarec¹,

Gutierrez²,

Muvale

et al. 2023

Health Science Reports

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Background and Aims Hepatitis C (HCV) programs face challenges, especially linked to key populations to achieve World Health Organization (WHO) goals of eliminating hepatitis. Médecins Sans Frontières and Mozambique's Ministry of Health first implemented HCV treatment in Maputo, in 2016 and harm reduction activities in 2017. Methods We retrospectively analyzed routine data of patients enrolled between December 2016 and July 2021. Genotyping was systematically requested up to 2018 and subsequently in cases of treatment failure. Sustainable virological response was assessed 12 weeks after the end of treatment by sofosbuvir‐daclatasvir or sofosbuvir‐velpatasvir. Results Two hundred and two patients were enrolled, with 159 (78.71%) males (median age: 41 years [interquartile range (IQR): 37.10, 47.00]). Risk factors included drug use (142/202; 70.29%). One hundred and eleven genotyping results indicated genotype 1 predominant (87/111; 78.37%). Sixteen patients presented genotype 4, with various subtypes. The people who used drugs and HIV coinfected patients were found more likely to present a genotype 1. Intention‐to‐treat analysis showed 68.99% (89/129) cure rate among the patients initiated and per‐protocol analysis, 88.12% (89/101) cure rate. Nineteen patients received treatment integrated with opioid substitution therapy, with a 100% cure rate versus 59.37% (38/64) for initiated ones without substitution therapy ( p < 0.001). Among the resistance testing performed, NS5A resistance‐associated substitutions were found in seven patients among the nine tested patients and NS5B ones in one patient. Conclusion We found varied genotypes, including some identified as difficult‐to‐treat subtypes. People who used drugs were more likely to present genotype 1. In addition, opioid substitution therapy was key for these patients to achieve cure. Access to second‐generation direct‐acting antivirals (DAAs) and integration of HCV care with harm reduction are crucial to program effectiveness.

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Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Cited by 22 publications

References 25 publications

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia

Glycylglycine promotes the solubility and antigenic utility of recombinant HCV structural proteins in a point-of-care immunoassay for detection of active viremia

Hepatitis C treatment program in Maputo, Mozambique, the challenge of genotypes and key populations: A 5‐year retrospective analysis of routine programmatic data

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