DRUG RESPONSE OF UNTYPABLE HCV ISOLATES TO CURRENT DIRECTLY ACTING ANTIVIRAL (DAA) REGIMEN IN PAKISTAN

Main Article Content

Madiha Khalid
Abdul Rauf
Sadia Mumtaz
Aisha Siddique
Zeeshan Anjum

Keywords

HCV, Untypable isolates, DAAs, Sofosbuvir, Ribavirin, Daclatasvir, Drug response, RVR, SVR, EOT

Abstract

An increased prevalence of diagnostically untypable HCV isolates has been reported for the past few years in Pakistan and the efficacy of DAA-based treatment regimens can be significantly affected by HCV genotypes and subtypes. The Current study aimed to evaluate the drug response of diagnostically untypable isolates to existing DAA based treatment regimens in Pakistan. Drug response was evaluated by an observational study including 192 patients infected with an untypable genotype with 101 patients receiving Sofosbuvir-Daclatasvir (SOF-DCV) and 91 receiving Sofosbuvir-Ribavirin (SOF-RBV) for 12 weeks and by monitoring Rapid virologic response (RVR) at 4 weeks of initiating therapy, end of treatment (EOT) response at 12 weeks and sustained virologic response at 12 weeks (SVR12) after EOT. Overall, SVR12 of untypable genotypes against the current treatment regimen was 83.3% (160/192). The untypable genotype responded significantly well to SOF-DCV as compared to SOF-RBV with an SVR12 rate of 91.0% and 74.7% respectively. The proportion of non-responders to SOF-DCV (6.9%) was significantly less as compared to non-responders to SOF-RBV (19.7%). Also, relapse rates were significantly high in the group treated with SOF-RBV (5.4%) as compared to SOF-DCV (1.9%) (p<0.05). Efficacy of both regimens varied significantly with age (p>0.05) but did not vary with gender. A Pangenotypic SOF-DCV treatment regimen is found as an effective regimen for these circulating untypable genotypes.


 

Abstract 228 | pdf Downloads 115

References

1. World Health Organization. (2021). Accelerating access to Hepatitis C diagnostics and treatment: overcoming barriers in low-and middle-income countries: global progress report 2020. https://www.who.int/publications/i/item/9789240027077 . Accessed on May 2021.
2. Martinez, M.A.; Franco, S. Therapy implications of Hepatitis C virus genetic diversity. Viruses, 2020, 13, 41.
3. Mumtaz, S.; Ahmed, J.; Gul, A.; Tariq, S.A.; Siraj, S.; Sarwar, T. Genetic diversity of Hepatitis C virus genotype 3a based on complete core protein in Peshawar, Pakistan. Jundishapur J. Microbiol. 2020. 13(3), e98942.
4. Shi, G.; Suzuki, T. (2018). Molecular basis of encapsidation of Hepatitis C virus genome. Front. Microbiol. 2018, 9, 396.
5. Li, D.; Huang, Z.; Zhong, J. Hepatitis C virus vaccine development: old challenges and new opportunities. 2015. Natl. Sci. Rev. 2(3), 285-295.
6. Kim, C.W.; Chang, K.M. Hepatitis C virus: virology and life cycle. Clin. Mol. Hepatol. 2013. 19(1), 17.
7. Echeverría, N.; Moratorio, G.; Cristina, J.; Moreno, P. Hepatitis C virus genetic variability and evolution. 2015. World J. Hepatol. 6, 831.
8. Domingo, E.; Sheldon, J.; Perales, C. Viral quasispecies evolution. Microbiol. Mol. Biol. Rev, 2012. 76(2), 159-216.
9. Ribeiro, R.M.; Li, H.; Wang, S.; Stoddard, M.B.; Learn, G.H.; Korber, B.T.; Bhattacharya, T.; Guedj, J.; Parrish, E.H.; Hahn, B.H.; Shaw, G.M. Quantifying the diversification of Hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate. 2012. PLoS Pathog. e1002881.
10. Cuevas, J. M.; González-Candelas, F.; Moya, A.; Sanjuán, R. Effect of ribavirin on the mutation rate and spectrum of Hepatitis C virus in vivo. J. Virol. 2009, 83(11), 5760-5764.
11. Hedskog, C.; Parhy, B.; Chang, S.; Zeuzem, S.; Moreno, C.; Shafran, S.D.; Borgia, S.M.; Asselah, T.; Alric, L.; Abergel, A. and Chen, J.J.; Svarovskaia, E. S. Identification of 19 novel Hepatitis C virus subtypes—further expanding HCV classification. Open Forum Infect. Dis. 2019, 6(3), ofz076.
12. Borgia, S.M.; Hedskog, C.; Parhy, B.; Hyland, R.H.; Stamm, L.M.; Brainard, D.M.; Subramanian, M.G.; McHutchison, J.G.; Mo, H.; Svarovskaia, E.; Shafran, S. D. Identification of a novel Hepatitis C virus genotype from Punjab, India: expanding classification of Hepatitis C virus into 8 genotypes. J. Infect Dis. 2018, 218(11), 1722-1729.
13. Schnell, G.; Krishnan, P.; Tripathi, R.; Beyer, J.; Reisch, T.; Irvin, M.; Dekhtyar, T.; Lu, L.; Ng, T.I.; Xie, W.; Pilot-Matias, T… Collins, C. (2018). Hepatitis C virus genetic diversity by geographic region within genotype 1-6 subtypes among patients treated with glecaprevir and pibrentasvir. PloS one. 2018, 13(10), e0205186.
14. Smith, D. B.; Bukh, J.; Kuiken, C.; Muerhoff, A. S.; Rice, C. M.; Stapleton, J. T.; Simmonds, P. Expanded classification of Hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology.2014, 59(1), 318-327.
15. Sharafi, H.; Alavian, S. M.; Keshvari, M. Efficacy of 24-week pegylated interferon alpha and ribavirin combination therapy in highly selected patients infected with Hepatitis C virus genotype 1. Hepat. Mon. 2015, 15(1).
16. Humphreys, I.S.; von Delft, A.; Brown, A.; Hibbert, L.; Collier, J.D.; Foster, G.R.; Rahman, M.; Christian, A.; Klenerman, P. Barnes, E. HCV genotype-3a T cell immunity: specificity, function and impact of therapy. Gut. 2012, 61(11), 1589-1599.
17. Wasitthankasem, R.; Vongpunsawad, S.; Siripon, N.; Suya, C.; Chulothok, P.; Chaiear, K.; Rujirojindakul, P.; Kanjana, S.; Theamboonlers, A.; Tangkijvanich, P.; Poovorawan, Y. Genotypic distribution of Hepatitis C virus in Thailand and Southeast Asia. PloS one, 2015, 10(5), e0126764
18. Kan, H.; Imamura, M.; Kawakami, Y.; Daijo, K.; Teraoka, Y.; Honda, F.; Nakamura, Y.; Morio, K.; Kobayashi, T.; Nakahara, T.; Nagaoki, Y.; Chayama, K. Emergence of drug resistance‐associated variants and changes in serum lipid profiles in sofosbuvir plus ledipasvir‐treated chronic Hepatitis C patients. J. Med. Virol. 2017, 89(11), 1963-1972.
19. Kanda, T.; Nakamoto, S.; Nakamura, M.; Jiang, X.; Miyamura, T.; Wu, S.; Yokosuka, O. (2014). Direct-acting antiviral agents for the treatment of chronic Hepatitis C virus infection. J. Clin. Transl. Hepatol. 2014, 2(1), 1.
20. Mera, J.; Joshi, K.; Thornton, K.; Box, T.; Scott, J.; Sedillo, M.; Deming, P.; David, C.; Essex, W.; Manch, R.; Kohli, A. Retrospective study demonstrating high rates of sustained virologic response after treatment with direct-acting antivirals among american indian/alaskan natives. Open Forum Infect. Dis. 2019, 6 (7), ofz128.
21. Terrault, N.A.; Dodge, J.L.; Murphy, E.L.; Tavis, J.E.; Kiss, A.; Levin, T.R.; Gish, R.G.; Busch, M.P.; Reingold, A.L.; Alter, M.J. Sexual transmission of Hepatitis C virus among monogamous heterosexual couples: the HCV partners study. Hepatology. 2013, 57(3), 881-889.
22. Feld, J.J.; Jacobson, I.M.; Hézode, C.; Asselah, T.; Ruane, P.J.; Gruener, N.; Abergel, A.; Mangia, A.; Lai, C.L.; Chan, H.L. and Mazzotta, F.; Zeuzem, S. (2015). Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N. Engl. J. Med. 2015, 373(27), 2599-2607.
23. Xie, Z.; Deng, K.; Xia, Y.; Zhang, C.; Xu, M.; Li, F.; Liu, J.; Zhou, Y.; Chen, X.; Chen, X.; Yan, Q.; Guan, Y. Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in Hepatitis C patients: a multi‐center, real‐world study in Guangdong, China. J. Med. Virol. 2022. 94(9), 4459-4469.
24. Hezode, C.; Reau, N.; Svarovskaia, E.S.; Doehle, B.P.; Shanmugam, R.; Dvory-Sobol, H.; Hedskog, C.; McNally, J.; Osinusi, A.; Brainard, D. M. Miller, M. D.; Zeuzem, S. Resistance analysis in patients with genotype 1–6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies. J. Hepatol. 2018. 68(5), 895-903.
25. Wei, L.; Xie, Q.; Hou, J.L.; Tang, H.; Ning, Q.; Cheng, J.; Nan, Y.; Zhang, L.; Li, J.; Jiang, J. and McNabb, B.; Duan, Z. Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study. Hepatol. Int. 2018, 12(2), 126-132.
26. Sarrazin, C.; Dvory-Sobol, H.; Svarovskaia, E.S.; Doehle, B.P.; Pang, P.S.; Chuang, S.M.; Ma, J.; Ding, X.; Afdhal, N.H.; Kowdley, K.V. and Gane, E.J.; ... Mo, H. Prevalence of resistance-associated substitutions in HCV NS5A, NS5B, or NS3 and outcomes of treatment with ledipasvir and sofosbuvir. Gastroenterology, 2016. 151(3), 501-512.
27. Qamar, Z.; Anwar, F.; Ahmad, R.; Haq, I.; Khan, A.M.K.; Hussain, R.; Shahzad, Z.; Ahmad, I.; Malik, M.S.M.; Khan, J. Prevalence of Hepatitis C virus and determination of its genotypes in subjects of Tehsil Daggar District Buner, KP, Pakistan. Clin. Epidemiol. Glob. Health. 2021, 12, 100809.
28. Haqqi, A.; Munir, R.; Khalid, M.; Khurram, M.; Zaid, M.; Ali, M.; Shah, Z.H.; Ahmed, H. Afzal, M. S. Prevalence of Hepatitis C virus genotypes in Pakistan: current scenario and review of literature. Viral Immunol. 2019, 32(9), 402-413.
29. Khan, M. A.; Khan, S. A.; Hamayun, M.; Ali, M.; Idrees, M. Sequence variability of HCV 3a isolates based on core gene in patients from Lahore, Pakistan. Future Virol. 2019. 14(10), 641-653.
30. Wahid, B.; Naeem, N.; Altaf, S.; Ilyas, N. Increasing prevalence of untypable and mixed genotypes of Hepatitis C virus in Pakistan: latest trends in 2018. Viral Immunol. 2019, 32(4), 192-194.
31. Zahid, S.; Andleeb, S.; Anjum, S.; Afzal, S.; Amin, I.; Shahid, M.; Rafique, S. and Idress, M. A Molecular Based Approach to Characterize Untypable HCV Genotype. I.J.P. 2020, 28-135.
32. Zafar, A.; Imran, M.; Zahoor, S.; Shah, Z. H.; Ali, M.; Afzal, M.S. Prevalence and treatment of untypable HCV variants in different districts of Punjab, Pakistan. Viral Immunol. 2018, 31(6), 426-432.
33. Afzal, M. S.; Khan, M. Y.; Ammar, M.; Anjum, S. Diagnostically untypable Hepatitis C virus variants: it is time to resolve the problem. World J. Gastroenterol. 2014, 20(46), 17690.
34. Ali, S.; Ahmad, A.; Khan, R.S.; Khan, S.; Hamayun, M.; Khan, S.A.; Iqbal, A.; Khan, A.A.; Wadood, A.; Ur Rahman, T. Baig, A.H. Genotyping of HCV RNA reveals that 3a is the most prevalent genotype in mardan, Pakistan. Adv. Virol. 2014, 2014, e606201.
35. Waqar, M.; Khan, A.U.; Rehman, H.U.; Idrees, M.; Wasim, M.; Ali, A.; Niaz, Z.; Ismail, Z.; Rehman, M.U.; Tariq, M. and Shah, M.; Murtaza, B. N. Determination of Hepatitis C virus genotypes circulating in different districts of Punjab (Pakistan). Eur. J. Gastroenterol. Hepatol. 2014. 26(1), 59-64.
36. Rauf, A.; Nadeem, M. S.; Riaz, H.; Latif, M. M.; Latif, M. Z.; Nisar, A.; Shakoori, A. R. Tuberculosis and hepatitis infections among the underprivileged orphan children of Northern Pakistan. Pak. J. Zool. 2013. 45(6).
37. Safi, A. Z.; Waheed, Y.; Sadat, J.; Salahuddin, S.; Saeed, U.; Ashraf, M. Molecular study of HCV detection, genotypes and their routes of transmission in North West Frontier Province, Pakistan. Asian. Pac. J. Trop. Biomed. 2012. 2(7), 532-536.
38. Idrees, M.; Lal, A.; Malik, F.A.; Hussain, A.; Rehman, I.; Akbar, H.; Butt, S.; Ali, M.; Ali, L. Occult Hepatitis C virus infection and associated predictive factors: the Pakistan experience. Infect. Genet. Evol. 2011, 11(2), 442-445.

39. Mahmood, H.; Qureshi, H.; Glass, N.; Averhoff, F. Optimizing medicines and treatment regimens for Hepatitis C patients in Pakistan. World Hepatitis Summit. 2017.
40. Waqar, M.; Rehman, H.; Khan, A.U.; Noor, A.A.; Ali, A.; Wasim, M.; Idrees, M.; Ismail, Z.; Niaz, Z.; Akbar, N.; Tariq, M. Frequency Distribution of Hepatitis C virus Genotypes in District Karachi, Pakistan. J. Gastroenterol. Hepatol. Res. 2011, 3(4), 1035-1038.
41. Ahmad, W.; Ijaz, B.; Javed, F.T.; Gull, S.; Kausar, H.; Sarwar, M.T.; Asad, S.; Shahid, I.; Sumrin, A.; Khaliq, S.; Jahan, S. A comparison of four fibrosis indexes in chronic HCV: development of new fibrosis-cirrhosis index (FCI). BMC Gastroenterol. 2011. 11(1), 1-10.
42. Ohno, O.; Mizokami, M.; Wu, R.R.; Saleh, M.G.; Ohba, K.I.; Orito, E.; Mukaide, M.; Williams, R.; Lau, J.Y. New Hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J. Clin. Microbiol. 1997, 35(1), 201-207.
43. Ghani, U.; Rehman, I. U.; Ali, M.; Khan, A.; Ullah, S.; Ali, L.; Butt, S. Phylogenetic Characterization of the 5′ Untranslated Region of Untypable HCV Genotypes Circulating in Pakistan. Intervirology. 2021. 64(1), 16-21.
44. Khan, A.; Nadir, A.; Mushtaq, M.H.; Junaid, K.; Khan, A.M.; Ali, H.; Waqar, F.; Khan, T.A. and Khan, A.A. Molecular epidemiology and genotype distribution of Hepatitis C in Pakistan; a multicenter cross-sectional study. Infect. Genet. Evol. 2020. 84, 104372.
45. Gul, A.; Zahid, N.; Ahmed, J.; Zahir, F.; Khan, I.A.; Ali, I. Molecular characterization of Hepatitis C virus 3a in Peshawar. BMC Infect. Dis. 2016. 16(1), 1-6.
46. Khaliq, S.; Jahan, S.; Pervaiz, A. Sequence variability of HCV Core region: important predictors of HCV induced pathogenesis and viral production. Infect. Genet. Evol. 2011. 11(3), 543-556.
47. Waheed, Y.; Bhatti, A.; Anjum, S.; Ashraf, M. (2014). Sequence comparison and phylogenetic analysis of Hepatitis C virus genotype 3 polymerase. Mol. Med. Rep. 2014. (4), 1266-1270.
48. El-Shamy, A.; Pendleton, M.; Eng, F. J.; Doyle, E. H.; Bashir, A.; Branch, A. D. Impact of HCV core gene quasispecies on hepatocellular carcinoma risk among HALT-C trial patients. Sci. Rep. 2016. 6(1), 1-10
49. Dalgard, O.; Weiland, O.; Noraberg, G.; Karlsen, L.; Heggelund, L.; Färkkilâ, M.; Balslev, U.; Belard, E.; Øvrehus, A.; Skalshøi Kjær, M. and Krarup, H.; Weis, N. Sofosbuvir based treatment of chronic Hepatitis C genotype 3 infections—a Scandinavian real-life study. PLoS One. 2017. 12(7), e0179764.
50. Lawitz, E.; Poordad, F.; Brainard, D.M.; Hyland, R.H.; An, D.; Dvory‐Sobol, H.; Symonds, W.T.; McHutchison, J.G. and Membreno, F.E.; Membreno, F. E. Sofosbuvir with peginterferon‐ribavirin for 12 weeks in previously treated patients with Hepatitis C genotype 2 or 3 and cirrhosis. Hepatology. 2015. 61(3), 769-775.
51. Jacobson, I.M.; Gordon, S.C.; Kowdley, K.V.; Yoshida, E.M.; Rodriguez-Torres, M.; Sulkowski, M.S.; Shiffman, M.L.; Lawitz, E.; Everson, G.; Bennett, M.; Schiff, E.; Nelson, D. R. Sofosbuvir for Hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 2013. 368(20), 1867-1877.
52. Zeuzem, S.; Dusheiko, G.M.; Salupere, R.; Mangia, A.; Flisiak, R.; Hyland, R.H.; Illeperuma, A.; Svarovskaia, E.; Brainard, D.M.; Symonds, W.T.; Subramanian, G.M.; Esteban, R. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N. Engl. J. Med. 2014. 370(21), 1993-2001
53. Yen, H.H.; Chen, Y.Y.; Lai, J.H.; Chen, H.M.; Yao, C.T.; Huang, S.P.; Liu, I.L.; Zeng, Y.H.; Yang, F.C.; Siao, F.Y.; Chen, M.W.; Su, P.Y. Pan-Genotypic Direct-Acting Antiviral Agents for Undetermined or Mixed-Genotype Hepatitis C Infection: A Real-World Multi-Center Effectiveness Analysis. J. Clin. Med. 2022. 11(7), 1853.
54. Ding, Y.J.; Lu, C.K.; Chen, W.M.; Tung, S.Y.; Wei, K.L.; Shen, C.H.; Hsieh, Y.Y.; Yen, C.W.; Chang, K.C.; Chiu, W.N. and Hung, C.H.; … Chang, T. S. Pangenotypic direct‐acting antiviral agents for mixed genotype Hepatitis C infection: A real‐world effectiveness analysis. J. Gastroenterol. Hepatol. 2021. 36(10), 2911-2916.
55. Jamil, Z.; Waheed, Y.; Malik, M.; Durrani, A. A. Effect of Sofosbuvir plus Ribavirin therapy on Hepatitis C patients in Pakistan: a retrospective study. PeerJ. 2018, 6, e4853.
56. Nelson, D.R.; Cooper, J.N.; Lalezari, J.P.; Lawitz, E.; Pockros, P.J.; Gitlin, N.; Freilich, B.F.; Younes, Z.H.; Harlan, W.; Ghalib, R.; Oguchi, G.; ALLY‐3 Study Team. All‐oral 12‐week treatment with daclatasvir plus sofosbuvir in patients with Hepatitis C virus genotype 3 infection: ALLY‐3 phase III study. Hepatology. 2015. 61(4), 1127-1135.
57. Zeuzem, S.; Mizokami, M.; Pianko, S.; Mangia, A.; Han, K.H.; Martin, R.; Svarovskaia, E.; Dvory-Sobol, H.; Doehle, B.; Hedskog, C.; Yun, C.; Sulkowski, M. NS5A resistance-associated substitutions in patients with genotype 1. Hepatitis C virus: prevalence and effect on treatment outcome. J. Hepatol. 2017. 66(5), 910-918.
58. Perales, C.; Chen, Q.; Soria, M. E.; Gregori, J.; Garcia-Cehic, D.; Nieto-Aponte, L.; Castells, L.; Imaz, A.; Llorens-Revull, M.; Domingo, E.; Buti, M.; Quer, J. Baseline Hepatitis C virus resistance-associated substitutions present at frequencies lower than 15% may be clinically significant. Infect. Drug. Resist. 2018, 11, 2207.
59. Di Maio, V.C.; Cento, V.; Aragri, M.; Paolucci, S.; Pollicino, T.; Coppola, N.; Bruzzone, B.; Ghisetti, V.; Zazzi, M.; Brunetto, M. and Bertoli, A.; Vullo, V. (2018). Frequent NS5A and multiclass resistance in almost all HCV genotypes at DAA failures: what are the chances for second-line regimens?. J. Hepatol. 2018, 68(3), 597-600.
60. Dietz, J.; Susser, S.; Vermehren, J.; Peiffer, K.H.; Grammatikos, G.; Berger, A.; Ferenci, P.; Buti, M.; Müllhaupt, B.; Hunyady, B.; Hinrichsen, H.; Fischer, J. Patterns of resistance-associated substitutions in patients with chronic HCV infection following treatment with direct-acting antivirals. Gastroenterology. 2018. 154(4), 976-988.
61. Carver, A. B.; Zuckerman, A. D.; DeClercq, J.; Choi, L.; Chastain, C. A. Incidence and Impact of Persistent Viremia on SVR Rates in Patients Receiving Direct-Acting Antiviral Therapy. Open Forum Infect. Dis. 20207(12), ofaa569.

Most read articles by the same author(s)