Generic placeholder image

Reviews on Recent Clinical Trials

Author(s): Riccardo Scotto, Antonio Riccardo Buonomo*, Nicola Schiano Moriello, Alberto Enrico Maraolo, Emanuela Zappulo, Biagio Pinchera, Ivan Gentile and Guglielmo Borgia

DOI: 10.2174/1574887114666190306154650

DownloadDownload PDF Flyer Cite As
Real-World Efficacy and Safety of Pangenotypic Direct-Acting Antivirals Against Hepatitis C Virus Infection

Page: [173 - 182] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Advances in the development of Direct-Acting Antivirals (DAAs), particularly pangenotypic drugs, have led to a high rate of hepatitis C virus (HCV) eradication. Notably, real- world studies have confirmed the efficacy and safety of pangenotypic DAA combinations reported in registration trials. The aim of this study was to review the treatment recommendations, and the efficacy and safety data of anti-HCV pangenotypic drugs reported in registration clinical trials and in recent real-life cohort studies.

Methods: We reviewed the efficacy and safety data of pangenotypic anti-HCV drug combinations reported in original articles and in online conference abstracts.

Results: Current pangenotypic drug combinations resulted in very high rates of sustained virologic response and few adverse reactions in real-life settings. SVR12 rates in real-life studies ranged from 90-100% depending on the pangenotypic combination, the HCV genotype and the stage of liver disease. Most adverse reactions reported in real-life settings were mild in intensity and rarely led to treatment discontinuation. These results are in accordance with those of clinical trials.

Conclusion: Pangenotypic DAAs result in very high rates of sustained virologic responses and are well tolerated. However, they are contraindicated in patients with decompensated cirrhosis or advanced chronic kidney disease who failed previous DDA-based treatment. Further research is required to customize treatment to “unpackage” current DAA combinations and to develop generic drugs against HCV.

Keywords: Direct-acting antivirals, glecaprevir, HCV, pangenotypic drugs, pibrentasvir, real-world, sofosbuvir, velpatasvir, voxilaprevir.

Graphical Abstract

[1]
Gentile I, Scotto R, Zappulo E, et al. Investigational direct-acting antivirals in hepatitis C treatment: The latest drugs in clinical development. Expert Opin Investig Drugs 2016; 25: 557-72.
[2]
Westerhoff M, Ahn J. Chronic Hepatitis C and direct acting antivirals. Surg Pathol Clin 2018; 11: 287-96.
[3]
Gentile I, Buonomo AR, Borgia G. Ombitasvir: A potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 2014; 12: 1033-43.
[4]
Asselah T, Marcellin P. Interferon free therapy with direct acting antivirals for HCV. Liver Int 2013; 33(Suppl. 1): 93-104.
[5]
Gentile I, Borgia F, Buonomo AR, et al. ABT-450: A novel protease inhibitor for the treatment of hepatitis C virus infection. Curr Med Chem 2014; 21: 3261-70.
[6]
Gentile I, Buonomo AR, Zappulo E, et al. Asunaprevir, a protease inhibitor for the treatment of hepatitis C infection. Ther Clin Risk Manag 2014; 10: 493-504.
[7]
Ansaldi F, Orsi A, Sticchi L, et al. Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 2014; 20: 9633-52.
[8]
Buonomo AR, Scotto R, Pinchera B, et al. Epidemiology and risk factors for hepatitis C virus genotypes in a high prevalence region in Italy. New Microbiol 2018; 41: 26-9.
[9]
Chhatwal J, Wang X, Ayer T, et al. Hepatitis C Disease Burden in the United States in the era of oral direct-acting antivirals. Hepatology (Baltimore, Md) 2016; 64: 1442-50.
[10]
Lanini S, Easterbrook PJ, Zumla A, et al. Hepatitis C: Global epidemiology and strategies for control. Clin Microbiol Infect 2016; 22: 833-8.
[11]
Gentile I, Coppola N, Buonomo AR, et al. Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus. Expert Opin Investig Drugs 2014; 23: 1211-23.
[12]
Gentile I, Borgia G. Ledipasvir/Sofosbuvir administration achieves very high rate of viral clearance in patients with HCV genotype 1 infection without cirrhosis, regardless of ribavirin co-administration or length of treatment. Evid Based Med 2014; 19: 223-4.
[13]
Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014; 147: 359-65.e1.
[14]
Buggisch P, Vermehren J, Mauss S, et al. Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C. J Hepatol 2018; 68(4): 663-71.
[15]
Curry MP, Tapper EB, Bacon B, et al. Effectiveness of 8- or 12-weeks of ledipasvir and sofosbuvir in real-world treatment-naive, genotype 1 hepatitis C infected patients. Aliment Pharmacol Ther 2017; 46: 540-8.
[16]
Gentile I, Scotto R, Coppola C, et al. Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort). Hepatol Int 2019; 13: 66-7.
[17]
Mensa FJ, Lovell S, Pilot-Matias T, et al. Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C virus infection. Future Microbiol 2019; 14: 89-110.
[18]
Hubbard H, Lawitz E. Glecaprevir + pibrentasvir (ABT493 + ABT-530) for the treatment of Hepatitis C. Expert Rev Gastroenterol Hepatol 2018; 12: 9-17.
[19]
Bourliere M, Pietri O, Castellani P, et al. Sofosbuvir, velpatasvir and voxilaprevir: A new triple combination for hepatitis C virus treatment. One pill fits all? Is it the end of the road? Therap Adv Gastroenterol 2018; 11: 1756284818812358.
[20]
Voaklander R, Jacobson IM. Sofosbuvir, velpatasvir and voxilaprevir combination for the treatment of hepatitis C. Expert Rev Gastroenterol Hepatol 2017; 11: 789-95.
[21]
Borgia G, Maraolo AE, Buonomo AR, et al. The therapeutic potential of new investigational hepatitis C virus translation inhibitors. Expert Opin Investig Drugs 2016; 25: 1209-14.
[22]
Greig SL. Sofosbuvir/Velpatasvir: A review in chronic Hepatitis C. Drugs 2016; 76: 1567-78.
[23]
American Association for the Study of Liver Diseases. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available from: https: //www.hcvguidelines.org/ [Accessed Dec 18, 2018]..
[24]
European Association for the Study of the Liver. Recommendations on Treatment of Hepatitis C 2018. Available at: http: //www.easl.eu/research/our-contributions/clinical-practice-guidelines/detail/easl-recommendations-on-treatment-of-hepatitis-c-2018 [Accessed Dec 18, 2018].
[25]
Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015; 373: 2599-607.
[26]
Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med 2015; 373: 2608-17.
[27]
Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015; 373: 2618-28.
[28]
Stamm LM, Brainard DM, McHutchison JG. Sofosbuvir/ velpatasvir for patients with chronic genotype 3 HCV infection with compensated cirrhosis: Response to EASL recommendations on treatment of Hepatitis C 2018. J Hepatol 2019; 70(3): 561-2.
[29]
European Association for the Study of the Liver Reply to: “Sofosbuvir/velpatasvir for patients with chronic genotype 3 HCV infection with compensated cirrhosis: Response to EASL recommendations on treatment of Hepatitis C 2018”: EASL Recommendations on Treatment of Hepatitis C 2018: Precision on the treatment of patients with genotype 3a infection and compensated cirrhosis. J Hepatol 2019; 70(3): 562-4.
[30]
Landis CS, Sulkowski MS, Reau N, et al. Safety and efficacy of velpatasvir and sofosbuvir-based regimens for the treatment of HCV genotype 1–6: Results of the HCV-TARGET study. Hepatology 2017; 66: 587A.
[31]
Buggisch P, Atanasov P, Wursthorn K, et al. Real-world effectiveness and cost per svr of sofosbuvir/velpatasvir chronic Hepatitis C treatment. Hepatology (Baltimore, Md) 2017; 66: 856A.
[32]
Boyle A, Marra F, Peters E, et al. PS-034 - 8 weeks sofosbuvir/velpatasvir in genotype 3 patients with significant fibrosis: Highly effective amongst an OST cohort. J Hepatol 2018; 68: S20.
[33]
Ferret MB, Pineda J, Panero JLC, et al. PS-035 - Safety and efficacy of Sofosbuvir/Velpatasvir with and without Ribavirin in genotype 3HCV-infected patients with cirrhosis. J Hepatol 2018; 68: S20-1.
[34]
Nguyen E, Trinh S, Trinh H, et al. THU-346 - Sustained virologic response rates (SVR-12) for chronic hepatitis C genotype 6 patients treated with Ledipasvir/Sofosbuvir or Sofosbuvir/Velpatasvir. J Hepatol 2018; 68: S284-5.
[35]
Hu C, Yuan G, Liu J, et al. Sofosbuvir-based therapies for patients with Hepatitis C virus infection: Real-world experience in China. Can J Gastroenterol Hepatol 2018; 2018: 3908767.
[36]
Belperio PS, Shahoumian TA, Loomis TP, et al. Real-world effectiveness of daclatasvir plus sofosbuvir and velpatasvir/sofosbuvir in hepatitis C genotype 2 and 3. J Hepatol 2019; 70: 15-23.
[37]
Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): A single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017; 17: 1062-8.
[38]
Rockstroh JK, Lacombe K, Viani RM, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients coinfected with Hepatitis C Virus and human immunodeficiency virus Type 1: The EXPEDITION-2 Study. Clin Infect Dis 2018; 67: 1010-7.
[39]
Zeuzem S, Foster GR, Wang S, et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med 2018; 378: 354-69.
[40]
Asselah T, Kowdley KV, Zadeikis N, et al. Efficacy of Glecaprevir/pibrentasvir for 8 or 12 weeks in patients with Hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol 2018; 16: 417-26.
[41]
Foster GR, Gane E, Asatryan A, et al. GS-007 - ENDURANCE-3: Safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3-infected patients without cirrhosis. J Hepatol 2017; 66: S33.
[42]
Flamm SL, Kort J, Marx S, et al. Effectiveness of 8‐Week Glecaprevir/Pibrentasvir (G/P) for treatment naïve, non‐cirrhotic patients with HCV infection in the trio health network. Hepatology 2017; 1: 1.
[43]
Berg T, Naumann U, Stoehr A, et al. GS-007 - First real-world data on safety and effectiveness of glecaprevir/pibrentasvir for the treatment of patients with chronic hepatitis C virus infection: Data from the German Hepatitis C-Registry. J Hepatol 2018; 68: S37.
[44]
Belperio PS, Shahoumian T, Loomis T, et al. Real‐world effectiveness of Glecaprevir/Pibrentasvir in 1,941 patients with Hepatitis C genotypes 1 through 4. Hepatology 2017; 66: 1.
[45]
D’Ambrosio R, Pasulo L, Puoti M, et al. Real-life effectiveness and safety of Glecaprevir/Pibrentasvir in 723 patients with chronic hepatitis C. J Hepatol 2018; 68(Suppl. 1): S65.
[46]
Osawa M, Imamura M, Teraoka Y, et al. Real-world efficacy of glecaprevir plus pibrentasvir for chronic hepatitis C patient with previous direct-acting antiviral therapy failures. J Gastroenterol 2019; 54(3): 291-6.
[47]
Akuta N, Sezaki H, Suzuki F, et al. Favorable efficacy of glecaprevir plus pibrentasvir as salvage therapy for HCV failures to prior direct-acting antivirals regimens. J Med Virol 2019; 91: 102-6.
[48]
Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology 2017; 153: 113-22.
[49]
Bourliere M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV Infection. N Engl J Med 2017; 376: 2134-46.
[50]
Pearlman BL, Hinds A, Perrys M. Sofosbuvir/Velpatasvir/ Voxilaprevir (SOF/VEL/VOX) for prior treatment failures with Glecaprevir/Pibrentasvir (G/P) in chronic Hepatitis C infection. Hepatology 2017; 66: 1.
[51]
Hezode C, Guyader D, Nguyen-Khac E, et al. Sofosbuvir + Velpatasvir + Voxilaprevir in Daa failure patients with cirrhosis. Final Results of the French Compassionate Use Program. Hepatology 2017; 66.
[52]
Vermehren J, Dietz J, Pieffer KH, et al. Resistance analysis in direct acting antiviral‐experienced patients with chronic Hepatitis C virus infection treated with Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) ‐ results from the frankfurt resistance database. Hepatology 2017; 66.
[53]
Bacon BR, Curry MP, Flamm SL, et al. Sofosbuvir/Velpatasvir/ Voxilaprevir (SOF/VEL/VOX) in care of chronic hepatitis c patients; Clinical practice experience from the trio network. Hepatology 2017; 66.
[54]
Gentile I, Maraolo AE, Buonomo AR, et al. The discovery of sofosbuvir: A revolution for therapy of chronic hepatitis C. Expert Opin Drug Discov 2015; 10: 1363-77.
[55]
Lim TS, Ahn SH. Use of sofosbuvir in chronic kidney disease: Is it necessary? Clin Mol Hepatol 2017; 23: 308-10.
[56]
Gentile I, Borgia F, Zappulo E, et al. Efficacy and safety of sofosbuvir in treatment of chronic Hepatitis C: the dawn of the a new era. Rev Recent Clin Trials 2014; 9: 1-7.
[57]
Mendizabal M, Reddy KR. Chronic hepatitis C and chronic kidney disease: Advances, limitations and unchartered territories. J Viral Hepat 2017; 24: 442-53.