Induction Therapy with Natural Interferon-Beta and a Protease Inhibitor Restores Innate-Immune Responses and Suppresses Chronic Hepatitis C Infection
Main Article Content
Abstract
Background: Persistent hepatitis C virus (HCV) infection results from inefficient innate and adaptive immune responses and exhausted virus-specific T-cell responses. Host cytokines and innate immune responses play important roles in controlling HCV infection. Innate immune responses modulate adaptive immune responses. These responses have recently been shown to have roles in antiviral therapy for chronic HCV infection. My previous study has indicated that viral clearance early in the course of therapy is associated with the restoration of innate and adaptive immune responses, and thus has potential as a novel therapeutic strategy for chronic hepatitis C (CHC).
Methods: The efficacy and safety of induction therapy (IT) with natural (n)-interferon (IFN)-beta followed by pegylated-IFN-alpha and ribavirin (PR) alone (group A, n = 30) were compared with those of IT with a protease inhibitor (PI) (Simeprevir or Vaniprevir) plus PR (group B, n = 13) in patients with CHC with genotype 1b and high viral load.
Results: During IT with n-IFN-beta, the virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4; 30% and 16% (p = 0.6989) at week 12; and 47% and 20% (p = 0.0887) at week 24. During and after treatment with PR alone, or PI plus PR, the virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4: 53% and 91% (p = 0.006745) at week 8; 57% and 91% (p = 0.001126) at week 12; 57% and 100% (p = 0.001845) at the end of the treatment; and 57% and 80% (p = 0.005166) after treatment cessation.
Conclusion: IT with PI plus PR restored the innate immune response, was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in patients with intractable CHC. Thus, IT with PI plus PR is beneficial for patients with intractable CHC. Steps for augmenting immune responses must be identified.
Article Details
How to Cite
KISHIDA, Yutaka.
Induction Therapy with Natural Interferon-Beta and a Protease Inhibitor Restores Innate-Immune Responses and Suppresses Chronic Hepatitis C Infection.
Medical Research Archives, [S.l.], v. 11, n. 1, jan. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3488>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i1.3488.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. World Health Organization (WHO). Global Hepatitis Report 2017. World Health Organization; 2017. [Accessed December 9,2021] https://www.who.int/publications/i/item/global-hepatitis-report-2017.
2. Yutaka Kishida. Immunological aspects controlling hepatitis C virus infection. Research Trends; Current Topics in Virology. 2019;16:75-93.
3. Major EM, Dahari H, Mihalik K, Puig M, Rice CM, Neuman AU, Feinstone SM. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in Chimpanzees. Hepatology. 2004;39:1709-1720. DOI: 10.1002/hep.20239
4. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA. 2005; 102: 17717-17722. DOI: 10.1073/pnas.0508531102
5. Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, Carney DS, Wang T, Ishida H, Yoneyama M, Fujita T, Saito T, Lee WM, Hagedorn CH, Lau DT, Weinman SA, Lemon SM, Gale M Jr. Viral and therapeutic control of IFN-beta promoter stimulator and during hepatitis C virus infection. Proc Natl Acad Sci USA. 2006; 103 (15): 6001-6006. doi: 10.1073/pnas.0601523103.
6. Platanias LC, Shahab US and Colamonics OR. Tyrosine phosphorylation of the alpha and beta Subunit of the Type 1 interferon Receptor. J Biol Chem. 1994; 269 (27): 17761-17764.
7. Domarski P, Nadeu OW, Platanias LC, Fish E, Kellum M, Pitha P, Colamonici OR. Differential use of the betaL subunit of the type 1 inteferon (IFN) receptor determines signaling specificity for IFN-alpha 2 and beta. J Biol Chem. 1998; 273: 3144-3147. doi: 10.1074/jbc.273.6.3144.
8. Da Silvia AJ, Brickelmaier M, Majeau GM, Lukashin AV, Peyman J, Whitety A, Hochman PS. Comparison of gene expression patterns induced by treatment of human umbilical vein endothelial cells with IFN-alpha 2b vs IFN-beta 1a understanding the functional relationship between distinct type 1 interferons that act through a common receptor. J interferon Cytokine Research. 2002; 22: 173-188. DOI: 10.1089/107999002753536149
9. Olagenier D and Hiscott J. Interferon (IFN)-beta has different signaling and biological activities from IFN-alpha, and achieves a higher rate of viral clearance than IFN-alpha. Hepatology. 2014; 59:1225-1228.
10. Yutaka Kishida, Yoshimichi Haruna, Masahumi Naitoh, Kazuhiro Katayama, Toru Kashiwagu. Multiple Cytokine Profiling of the Therapeutic Responses to Ribavirin and Pegylated Interferon-alpha2 Using “Induction” Approach With Natural Interferon-bet in Difficult-to-Treat Chronic Hepatitis C. Journal of Interferon and Cytokine Research. 2009; 29 (6): 353-368.
11. Yutaka Kishida, Naohiko Imaizumi, Hirihisa Tanimura, Toru Kashiwagi. Restoration of innate and adaptive immune responses by HCV viral inhibition with an induction approach using natural IFN-beta in chronic hepatitis C. Clinical and Developmental Immunology. 2012; Article ID 582716: 1-15.
doi: 10.1155/2012/582716
12. Yutaka Kishida, Naohiko Imaizumi, Hirohisa Tanimura, Shinichiro Kashiwamura, Toru Kashiwagi. Treatment of Chronic Hepatitis C with Viral-Suppression linked to Restoration of Innate-Immune Responses with Induction-Therapy with n-IFN-beta followed by Simprevir. MOJ Immunology. 2015; 2(2): 1-7.
13. Liang Y, Cao X, Ding Q, Zhao, He Z, Zhong J. Hepatitis C virus NS4B induces the degradation of TRIF to inhibit TLR3-mediated interferon signaling pathway. PLoS Pathog. 2018; 14 (5), e1007075. doi: 10.1371/journal. Ppat. 1007075.
14. Itakura J, Kurosaki M, Higuchi M, Takada H, Nakakuki N, Itakura Y, Tamaki N, Yasui Y, Suzuki S, Tsuchiya K, Nakanishi H, Takahashi Y, Maekawa S, Enomoto N, Izumi N. Resistance-associated NS5A variants of hepatitis C Virus are susceptible to interferon-based therapy. PLos One. 2015; 10(9). Doi: 10.1371/journal.pone.0138060
15. Itakura J, Kurosaki M, Kakizaki S, Amano K, Nakayama N, Inoue J, Endo T, Marusawa H, Hasebe C, Joko K, Wada S, Akahane T, Koushima Y, Ogawa C, Kanto T, Mizokami M, Izumi N. Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C. JHEP Rep. 2020; 2 (5): 100138. doi: 10.1016/j-jhepr. 2020.100138.
16. Gozlan Y, Bucris E, Shirazi R, Rakovsky A, Ben-Ari Z, Davidov Y, Veizman E, Saadi T, Braun M, Cohen-Naftaly M, Shlomai A, Shibolet O, Zigmond E, Katchman H, Menachem Y, Safadi R, Galun E, Zuckerman E, Nimer A, Hazzan R, Maor Y, Saif AB, Etzion O, Lurie Y, Mendelson E, Mor O.. High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: real-life data. Antiviral Ther. 2019; 24 (3): 221-228. doi: 10.3851/MP3301.
17. Ceccherin-Silberstein F, Cento V, Di Mario VC, Perno CF, Craxi A. Viral resistance in HCV infection. Curr. Opin. Virol. 2018; 32: 115-127. doi: 10.1016/j.coviro.2018.10.005.
18. Yutaka Kishida, Naohiko Imaizumi, Hirohisa Tanimura, Shinichiro Kashiwamura, Toru Kashiwagi. A Protease Inhibitor with Induction Therapy with Natural Interferon-beta in Patients with HCV Genotype 1b Infection. International Journal of Molecular Sciences. 2016; 17 (3): 350. 1-12. doi: 10.3390/ijms17030350
19. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Cooregidor A, DeJesus E, Pearlman B, Rabinovitz M, Gitlin N, Lin JK, Pockros PJ, Scott JD, Fevery B, Lambrecht T, Ouwerkerk-Mahadevan S, Callewaert K, Symonds WT, Picchio G, Lindsay K, Beumont M, Jacobson IM. Simeprevir plus sofosbuvir with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naïve patients: the COSMOS randomized study. Lancet. 2014; 384: 1756-1765.
DOI: 10.1016/S0140-6736(14)61036-9
20. Sulkowski MS, Gardiner DF, Roriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinesrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; A1444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014; 370: 211-221. DOI: 10.1056/NEJMoa1306218
21. Poordad F, Hezode C, Trinh R, Kowdley K, Zeuzem S, Agarwal K, Shiffman ML, Wedemeyer H, Berg T, Yoshida EM, Forms X, Lovell SS, Silva-Tillmann BD, Collins CA, Campbell AL, Podsadecki T, Bernstein B. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014; 370: 1973-1982. DOI: 10.1056/NEJMoa1402869
22. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein D, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M, Rustgi V, Chojkier M, Herring R, Bisceglie AM, Pockros PJ, Subramanian GM, An D, Svarovskaia E, Hyland RH, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Pound D, Fried MW; ION-3 investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014; 370: 1879-1888. DOI: 10.1056/NEJMoa1402355
23. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P; ION-2 investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014; 370: 1483-1493. DOI: 10.1056/NEJMoa1316366
24. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster G, Brau N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P; ION-1 investigators. Ledipasvir and Sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014; 370: 1889-1898. DOI: 10.1056/NEJMoa1402454
25. Pawlotsky JM. Hepatitis C Treatment: The data flood goes on-An update from the liver meeting 2014. Gastroenterology. 2015; 148: 15 468-479. DOI: 10.1053/j.gastro.2015.01.002
26. Uemura H, Uchida Y, Kouyama J, Niki K, Tsuji S, Sugawara K, Nakao M, Motoya D, Nakayama N, Imai Y, Tomiya T, Mochida S. NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaplevir and pibrentasvir. J Gastroenterology. 2019; 54 (5): 459-470. doi: 10.1007/s00535-018-01543-9.
27. Chayama K and Hayes CN. HCV drug resistance challenges in Japan: The role of pre-existing variants and emerging resistant strains in direct acting antiviral therapy. Viruses. 2015; 7: 5328-42. Doi: 10.10.3390/v7102876.
28. Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T, Dekhtya T, Irvin M, Xie W, Fu B, Burroughs M, Redman R, Kumada H, Chayama K, Collins C, Pilot-Matias T. Integrated resistance analysis of CERTAIN-1 and CERTAIN-2 studies in hepatitis C virus-Infected patients receiving Glecaprevir and Pibrentasvir. Antimicrob Agents Chemother. 2018; 62 (2): e02217-17. doi: 10.1128/AAC.02217-17.
2. Yutaka Kishida. Immunological aspects controlling hepatitis C virus infection. Research Trends; Current Topics in Virology. 2019;16:75-93.
3. Major EM, Dahari H, Mihalik K, Puig M, Rice CM, Neuman AU, Feinstone SM. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in Chimpanzees. Hepatology. 2004;39:1709-1720. DOI: 10.1002/hep.20239
4. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA. 2005; 102: 17717-17722. DOI: 10.1073/pnas.0508531102
5. Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, Carney DS, Wang T, Ishida H, Yoneyama M, Fujita T, Saito T, Lee WM, Hagedorn CH, Lau DT, Weinman SA, Lemon SM, Gale M Jr. Viral and therapeutic control of IFN-beta promoter stimulator and during hepatitis C virus infection. Proc Natl Acad Sci USA. 2006; 103 (15): 6001-6006. doi: 10.1073/pnas.0601523103.
6. Platanias LC, Shahab US and Colamonics OR. Tyrosine phosphorylation of the alpha and beta Subunit of the Type 1 interferon Receptor. J Biol Chem. 1994; 269 (27): 17761-17764.
7. Domarski P, Nadeu OW, Platanias LC, Fish E, Kellum M, Pitha P, Colamonici OR. Differential use of the betaL subunit of the type 1 inteferon (IFN) receptor determines signaling specificity for IFN-alpha 2 and beta. J Biol Chem. 1998; 273: 3144-3147. doi: 10.1074/jbc.273.6.3144.
8. Da Silvia AJ, Brickelmaier M, Majeau GM, Lukashin AV, Peyman J, Whitety A, Hochman PS. Comparison of gene expression patterns induced by treatment of human umbilical vein endothelial cells with IFN-alpha 2b vs IFN-beta 1a understanding the functional relationship between distinct type 1 interferons that act through a common receptor. J interferon Cytokine Research. 2002; 22: 173-188. DOI: 10.1089/107999002753536149
9. Olagenier D and Hiscott J. Interferon (IFN)-beta has different signaling and biological activities from IFN-alpha, and achieves a higher rate of viral clearance than IFN-alpha. Hepatology. 2014; 59:1225-1228.
10. Yutaka Kishida, Yoshimichi Haruna, Masahumi Naitoh, Kazuhiro Katayama, Toru Kashiwagu. Multiple Cytokine Profiling of the Therapeutic Responses to Ribavirin and Pegylated Interferon-alpha2 Using “Induction” Approach With Natural Interferon-bet in Difficult-to-Treat Chronic Hepatitis C. Journal of Interferon and Cytokine Research. 2009; 29 (6): 353-368.
11. Yutaka Kishida, Naohiko Imaizumi, Hirihisa Tanimura, Toru Kashiwagi. Restoration of innate and adaptive immune responses by HCV viral inhibition with an induction approach using natural IFN-beta in chronic hepatitis C. Clinical and Developmental Immunology. 2012; Article ID 582716: 1-15.
doi: 10.1155/2012/582716
12. Yutaka Kishida, Naohiko Imaizumi, Hirohisa Tanimura, Shinichiro Kashiwamura, Toru Kashiwagi. Treatment of Chronic Hepatitis C with Viral-Suppression linked to Restoration of Innate-Immune Responses with Induction-Therapy with n-IFN-beta followed by Simprevir. MOJ Immunology. 2015; 2(2): 1-7.
13. Liang Y, Cao X, Ding Q, Zhao, He Z, Zhong J. Hepatitis C virus NS4B induces the degradation of TRIF to inhibit TLR3-mediated interferon signaling pathway. PLoS Pathog. 2018; 14 (5), e1007075. doi: 10.1371/journal. Ppat. 1007075.
14. Itakura J, Kurosaki M, Higuchi M, Takada H, Nakakuki N, Itakura Y, Tamaki N, Yasui Y, Suzuki S, Tsuchiya K, Nakanishi H, Takahashi Y, Maekawa S, Enomoto N, Izumi N. Resistance-associated NS5A variants of hepatitis C Virus are susceptible to interferon-based therapy. PLos One. 2015; 10(9). Doi: 10.1371/journal.pone.0138060
15. Itakura J, Kurosaki M, Kakizaki S, Amano K, Nakayama N, Inoue J, Endo T, Marusawa H, Hasebe C, Joko K, Wada S, Akahane T, Koushima Y, Ogawa C, Kanto T, Mizokami M, Izumi N. Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C. JHEP Rep. 2020; 2 (5): 100138. doi: 10.1016/j-jhepr. 2020.100138.
16. Gozlan Y, Bucris E, Shirazi R, Rakovsky A, Ben-Ari Z, Davidov Y, Veizman E, Saadi T, Braun M, Cohen-Naftaly M, Shlomai A, Shibolet O, Zigmond E, Katchman H, Menachem Y, Safadi R, Galun E, Zuckerman E, Nimer A, Hazzan R, Maor Y, Saif AB, Etzion O, Lurie Y, Mendelson E, Mor O.. High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: real-life data. Antiviral Ther. 2019; 24 (3): 221-228. doi: 10.3851/MP3301.
17. Ceccherin-Silberstein F, Cento V, Di Mario VC, Perno CF, Craxi A. Viral resistance in HCV infection. Curr. Opin. Virol. 2018; 32: 115-127. doi: 10.1016/j.coviro.2018.10.005.
18. Yutaka Kishida, Naohiko Imaizumi, Hirohisa Tanimura, Shinichiro Kashiwamura, Toru Kashiwagi. A Protease Inhibitor with Induction Therapy with Natural Interferon-beta in Patients with HCV Genotype 1b Infection. International Journal of Molecular Sciences. 2016; 17 (3): 350. 1-12. doi: 10.3390/ijms17030350
19. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Cooregidor A, DeJesus E, Pearlman B, Rabinovitz M, Gitlin N, Lin JK, Pockros PJ, Scott JD, Fevery B, Lambrecht T, Ouwerkerk-Mahadevan S, Callewaert K, Symonds WT, Picchio G, Lindsay K, Beumont M, Jacobson IM. Simeprevir plus sofosbuvir with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naïve patients: the COSMOS randomized study. Lancet. 2014; 384: 1756-1765.
DOI: 10.1016/S0140-6736(14)61036-9
20. Sulkowski MS, Gardiner DF, Roriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinesrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; A1444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014; 370: 211-221. DOI: 10.1056/NEJMoa1306218
21. Poordad F, Hezode C, Trinh R, Kowdley K, Zeuzem S, Agarwal K, Shiffman ML, Wedemeyer H, Berg T, Yoshida EM, Forms X, Lovell SS, Silva-Tillmann BD, Collins CA, Campbell AL, Podsadecki T, Bernstein B. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014; 370: 1973-1982. DOI: 10.1056/NEJMoa1402869
22. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein D, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M, Rustgi V, Chojkier M, Herring R, Bisceglie AM, Pockros PJ, Subramanian GM, An D, Svarovskaia E, Hyland RH, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Pound D, Fried MW; ION-3 investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014; 370: 1879-1888. DOI: 10.1056/NEJMoa1402355
23. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P; ION-2 investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014; 370: 1483-1493. DOI: 10.1056/NEJMoa1316366
24. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster G, Brau N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P; ION-1 investigators. Ledipasvir and Sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014; 370: 1889-1898. DOI: 10.1056/NEJMoa1402454
25. Pawlotsky JM. Hepatitis C Treatment: The data flood goes on-An update from the liver meeting 2014. Gastroenterology. 2015; 148: 15 468-479. DOI: 10.1053/j.gastro.2015.01.002
26. Uemura H, Uchida Y, Kouyama J, Niki K, Tsuji S, Sugawara K, Nakao M, Motoya D, Nakayama N, Imai Y, Tomiya T, Mochida S. NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaplevir and pibrentasvir. J Gastroenterology. 2019; 54 (5): 459-470. doi: 10.1007/s00535-018-01543-9.
27. Chayama K and Hayes CN. HCV drug resistance challenges in Japan: The role of pre-existing variants and emerging resistant strains in direct acting antiviral therapy. Viruses. 2015; 7: 5328-42. Doi: 10.10.3390/v7102876.
28. Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T, Dekhtya T, Irvin M, Xie W, Fu B, Burroughs M, Redman R, Kumada H, Chayama K, Collins C, Pilot-Matias T. Integrated resistance analysis of CERTAIN-1 and CERTAIN-2 studies in hepatitis C virus-Infected patients receiving Glecaprevir and Pibrentasvir. Antimicrob Agents Chemother. 2018; 62 (2): e02217-17. doi: 10.1128/AAC.02217-17.