Direct-acting antivirals and management of hepatitis C: updates on treatment guidelines

Abstract

Hepatitis C virus (HCV) remains a major global health burden, causing significant morbidity, mortality, and economic costs. Direct-acting antivirals (DAAs) have become the primary treatment for patients with hepatitis C. Since the first approval in 2011, more effective agents have entered the market. Different guidelines for hepatitis treatment are implemented worldwide. The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend using DAAs in combination to achieve better outcomes and reduce resistance. The guidelines include regimens for treatment-naive and -experienced patients. They also include treatment recommendations for cirrhotic patients and unique populations. With mass screening, treatment over the last few years, and possible vaccination, eradication is attainable.

Keywords

hepatitis C virus (HCV) / direct-acting antiviral (DAA) / NS3/4A protease inhibitors / NS5A inhibitors / NS5B polymerase inhibitors / treatment guidelines / Egypt

References

[1] Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood—borne non—A, non—B viral hepatitis genome. Science. 1989; 244: 359-62.

[2] Global hepatitis report 2026 [Internet]. WHO; c2026 [cited 2026 May 10]. Available from: https://www.who.int/publications/i/item/9789240122383

[3] Fasano M, Ieva F, Ciarallo M, Caccianotti B, Santantonio TA. Acute Hepatitis C: Current Status and Future Perspectives. Viruses. 2024; 16: 1739.

[4] Fiehn F, Beisel C, Binder M. Hepatitis C virus and hepatocellular carcinoma: carcinogenesis in the era of direct—acting antivirals. Curr Opin Virol. 2024; 67: 101423.

[5] Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023; 79: 516—37.

[6] Abosheaishaa H, Abdelghany A, Abdelhalim O, Mohamed I, Morsi S, Youssef M, et al. The Egyptian journey from having the highest prevalence of hepatitis C virus to being the first to achieve “gold tier” in conquering the disease. Proc (Bayl Univ Med Cent). 2024; 37: 877—83.

[7] Stroffolini T, Stroffolini G. Prevalence and Modes of Transmission of Hepatitis C Virus Infection: A Historical Worldwide Review. Viruses. 2024; 16: 1115.

[8] Fabris P, Fleming VM, Giordani MT, Barnes E. Acute hepatitis C: clinical aspects, diagnosis, and outcome of acute HCV infection. Curr Pharm Des. 2008; 14: 1661—5.

[9] Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology. 1997; 26: 15S-20S.

[10] Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet. 2008; 372: 321-32.

[11] Lee JJ, Lin MY, Yang YH, Lu SN, Chen HC, Hwang SJ. Association of hepatitis C and B virus infection with CKD in an endemic area in Taiwan: a cross—sectional study. Am J Kidney Dis. 2010; 56: 23-31.

[12] Liu CH, Kao JH. Acute hepatitis C virus infection: clinical update and remaining challenges. Clin Mol Hepatol. 2023; 29: 623—42.

[13] Benjaram S, Kapur S, McKay A, Almujarkesh MK, Carter KS, Picardal A, et al. Hepatitis C—Everything a Primary Care Physician Needs to Know About Diagnosis, Management, and Follow—Up. J Clin Med. 2025; 14: 4801.

[14] Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepatitis C. Best Pract Res Clin Gastroenterol. 2012; 26: 401—12.

[15] Cho YK, Kim YN, Song BC. Predictors of spontaneous viral clearance and outcomes of acute hepatitis C infection. Clin Mol Hepatol. 2014; 20: 368-75.

[16] Song BC, Cho YK, Jwa H, Choi EK, Kim HU, Song HJ, et al. Erratum. Clin Mol Hepatol. 2015; 21: 104.

[17] Yeung LT, To T, King SM, Roberts EA. Spontaneous clearance of childhood hepatitis C virus infection. J Viral Hepat. 2007; 14: 797-805.

[18] Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006; 13: 34-41.

[19] Bakr I, Rekacewicz C, El Hosseiny M, Ismail S, El Daly M, El—Kafrawy S, et al. Higher clearance of hepatitis C virus infection in females compared with males. Gut. 2006; 55: 1183-7.

[20] Moorman AC, Xing J, Ko S, Rupp LB, Xu F, Gordon SC, et al. ; CHeCS Investigators. Late diagnosis of hepatitis C virus infection in the Chronic Hepatitis Cohort Study (CHeCS): Missed opportunities for intervention. Hepatology. 2015; 61: 1479-84.

[21] Bulteel N, Partha Sarathy P, Forrest E, Stanley AJ, Innes H, Mills PR, et al. Factors associated with spontaneous clearance of chronic hepatitis C virus infection. J Hepatol. 2016; 65: 266-72.

[22] Watanabe H, Saito T, Shinzawa H, Okumoto K, Hattori E, Adachi T, et al. Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: a population—based cohort study. J Med Virol. 2003; 71: 56-61.

[23] Scott JD, McMahon BJ, Bruden D, Sullivan D, Homan C, Christensen C, et al. High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives. Clin Infect Dis. 2006; 42: 945-52.

[24] Lee YH, Ji JD, Yeon JE, Byun KS, Lee CH, Song GG. Cryoglobulinaemia and rheumatic manifestations in patients with hepatitis C virus infection. Ann Rheum Dis. 1998; 57: 728—31.

[25] Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud—Ratti V, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d'Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l'Hepatite C. Medicine (Baltimore). 2000; 79: 47-56.

[26] Adinolfi LE, Restivo L, Zampino R, Guerrera B, Lonardo A, Ruggiero L, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV—related steatosis. Atherosclerosis. 2012; 221: 496-502.

[27] Petta S, Torres D, Fazio G, Cammà C, Cabibi D, Di Marco V, et al. Carotid atherosclerosis and chronic hepatitis C: a prospective study of risk associations. Hepatology. 2012; 55: 1317-23.

[28] Butt AA, Wang X, Fried LF. HCV infection and the incidence of CKD. Am J Kidney Dis. 2011; 57: 396-402.

[29] Serfaty L, Capeau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int. 2009; 29 Suppl 2: 13-25.

[30] Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu L, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999; 29: 328—33.

[31] Golden J, O'Dwyer AM, Conroy RM. Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors. Gen Hosp Psychiatry. 2005; 27: 431—8.

[32] Boukaira S, Madihi S, Bouafi H, Rchiad Z, Belkadi B, Benani A. Hepatitis C in North Africa: A Comprehensive Review of Epidemiology, Genotypic Diversity, and Hepatocellular Carcinoma. Adv Virol. 2025; 2025: 9927410.

[33] Feinstone SM, Kapikian AZ, Purcell RH, Alter HJ, Holland PV. Transfusion—associated hepatitis not due to viral hepatitis type A or B. N Engl J Med. 1975; 292: 767—70.

[34] Houghton M. Hepatitis C Virus: 30 Years after Its Discovery. Cold Spring Harb Perspect Med. 2019; 9: a037069.

[35] Mbisa JL, Lapp Z, Bibby DF, Phillips LT, Manso CF, Packer S, et al. Identification of 2 Novel Subtypes of Hepatitis C Virus Genotype 8 and a Potential New Genotype Successfully Treated With Direct Acting Antivirals. J Infect Dis. 2024; 230: e1254—62.

[36] Toma D, Anghel L, Patraș D, Ciubară A. Hepatitis C Virus: Epidemiological Challenges and Global Strategies for Elimination. Viruses. 2025; 17: 1069.

[37] Brzdęk M, Dobrowolska K, Flisiak R, Zarębska—Michaluk D. Genotype 4 hepatitis C virus—a review of a diverse genotype. Adv Med Sci. 2023; 68: 54-9.

[38] Dubuisson J. Hepatitis C virus proteins. World J Gastroenterol. 2007; 13: 2406—15.

[39] Gu M, Rice CM. Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function. Curr Opin Virol. 2013; 3: 129—36.

[40] Basyte—Bacevice V, Kupcinskas J. Evolution and Revolution of Hepatitis C Management: From Non—A, Non—B Hepatitis Toward Global Elimination. Dig Dis. 2020;[Epub ahead of print].

[41] Gordon SC, Muir AJ, Lim JK, Pearlman B, Argo CK, Ramani A, et al. ; HCV—TARGET study group. Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV—TARGET. J Hepatol. 2015; 62: 286-93.

[42] González—Colominas E, Broquetas T, Retamero A, García—Retortillo M, Cañete N, Coll S, et al. Drug—drug interactions of telaprevir and boceprevir in HCV—monoinfected and HIV/HCV—coinfected patients can modify the adherence. Liver Int. 2015; 35: 1557-65.

[43] Gohil K. Pharmaceutical Approval Update. P T. 2015; 40: 649-89.

[44] Fellner C. Pharmaceutical Approval Update. P T. 2016; 41: 162—3.

[45] Kaufman MB. Pharmaceutical Approval Update. P T. 2016; 41: 617-39.

[46] Kaufman MB. Pharmaceutical Approval Update. P T. 2017; 42: 673-83.

[47] Binay UD, Karakeçili F, Aygen B, Kılınç Toker A, Çelik İ, Demirtürk N, et al. Evaluation of Treatment Response in Chronic Hepatitis C Patients Receiving Sofosbuvir/Velpatasvir/Voxilaprevir: A Multicenter Real—World Experience from Türkiye. Viruses. 2025; 17: 931.

[48] Stinco M, Rubino C, Bartolini E, Nuti F, Paolella G, Nebbia G, et al. Effectiveness and Safety of Glecaprevir/Pibrentasvir in Italian Children and Adolescents With Chronic Hepatitis C: A Real—Word, Multicenter Study. Liver Int. 2025; 45: e16180.

[49] Updated Recommendations on Treatment of Adolescents and Children with Chronic HCV Infection, and HCV Simplified Service Delivery and Diagnostics [Internet]. Geneva: World Health Organization; 2022.

[50] Moradpour D, Penin F. Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol. 2013; 369: 113-42.

[51] Manns MP, Buti M, Gane E, Pawlotsky JM, Razavi H, Terrault N, et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017; 3: 17006.

[52] Horner SM, Gale M Jr. Regulation of hepatic innate immunity by hepatitis C virus. Nat Med. 2013; 19: 879-88.

[53] Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms. 2024; 12: 1035.

[54] Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, et al. Cardif is an adaptor protein in the RIG—I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005; 437: 1167—72.

[55] Ahmed A, Felmlee DJ. Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals. Viruses. 2015; 7: 6716—29.

[56] Gitto S, Gamal N, Andreone P. NS5A inhibitors for the treatment of hepatitis C infection. J Viral Hepat. 2017; 24: 180—6.

[57] Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol. 2017; 9: 1305-14.

[58] Pawlotsky JM. NS5A inhibitors in the treatment of hepatitis C. J Hepatol. 2013; 59: 375-82.

[59] Kaul A, Stauffer S, Berger C, Pertel T, Schmitt J, Kallis S, et al. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog. 2009; 5: e1000546.

[60] Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA. Direct Acting Anti—hepatitis C Virus Drugs: Clinical Pharmacology and Future Direction. J Transl Int Med. 2017; 5: 8-17.

[61] Gao Y, Kong F, Li G, Li C, Zheng S, Lin J, et al. Coblopasvir and sofosbuvir for treatment of chronic hepatitis C virus infection in China: A single—arm, open—label, phase 3 trial. Liver Int. 2020; 40: 2685-93.

[62] Cheong MWL, Piedagnel JM, Khor SK. Ravidasvir: equitable access through an alternative drug development pathway. Lancet Glob Health. 2021; 9: e1496—7.

[63] Zhou Z, Zhang J, Zhou E, Ren C, Wang J, Wang Y. Small molecule NS5B RdRp non—nucleoside inhibitors for the treatment of HCV infection: A medicinal chemistry perspective. Eur J Med Chem. 2022; 240: 114595.

[64] Zhao F, Liu N, Zhan P, Jiang X, Liu X. Discovery of HCV NS5B thumb site I inhibitors: core—refining from benzimidazole to indole scaffold. Eur J Med Chem. 2015; 94: 218-28.

[65] Labonté P, Axelrod V, Agarwal A, Aulabaugh A, Amin A, Mak P. Modulation of hepatitis C virus RNA—dependent RNA polymerase activity by structure—based site—directed mutagenesis. J Biol Chem. 2002; 277: 38838-46.

[66] Hundt J, Li Z, Liu Q. Post—translational modifications of hepatitis C viral proteins and their biological significance. World J Gastroenterol. 2013; 19: 8929-39.

[67] Neufeldt CJ, Joyce MA, Van Buuren N, Levin A, Kirkegaard K, Gale M Jr, et al. The Hepatitis C Virus—Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites. PLoS Pathog. 2016; 12: e1005428.

[68] Caillet—Saguy C, Lim SP, Shi PY, Lescar J, Bressanelli S. Polymerases of hepatitis C viruses and flaviviruses: structural and mechanistic insights and drug development. Antiviral Res. 2014; 105: 8-16.

[69] Lohmann V. Hepatitis C virus RNA replication. Curr Top Microbiol Immunol. 2013; 369: 167-98.

[70] Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol. 2007; 5: 453-63.

[71] Appel N, Schaller T, Penin F, Bartenschlager R. From structure to function: new insights into hepatitis C virus RNA replication. J Biol Chem. 2006; 281: 9833—6.

[72] Blackard JT, Ma G, Limketkai BN, Welge JA, Dryer PD, Martin CM, et al. Variability of the polymerase gene (NS5B) in hepatitis C virus—infected women. J Clin Microbiol. 2010; 48: 4256—9.

[73] Bhatia HK, Singh H, Grewal N, Natt NK. Sofosbuvir: A novel treatment option for chronic hepatitis C infection. J Pharmacol Pharmacother. 2014; 5: 278-84.

[74] Potisopon S, Ferron F, Fattorini V, Selisko B, Canard B. Substrate selectivity of Dengue and Zika virus NS5 polymerase towards 2'—modified nucleotide analogues. Antiviral Res. 2017; 140: 25-36.

[75] Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, et al. Discovery of a β—d—2'—deoxy—2'—α—fluoro—2'—β—C—methyluridine nucleotide prodrug (PSI—7977) for the treatment of hepatitis C virus. J Med Chem. 2010; 53: 7202—18.

[76] Keating GM, Vaidya A. Sofosbuvir: first global approval. Drugs. 2014; 74: 273-82.

[77] Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. ; ION—1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014; 370: 1889-98.

[78] Shi Y, Moody J. Most Likely to Succeed: Long—Run Returns to Adolescent Popularity. Soc Curr. 2017; 4: 13-33.

[79] Abdurakhmanov E, Øie Solbak S, Danielson UH. Biophysical Mode—of—Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase. Viruses. 2017; 9: 151.

[80] Nakamura F, Takeda H, Ueda Y, Takai A, Takahashi K, Eso Y, et al. Mutational spectrum of hepatitis C virus in patients with chronic hepatitis C determined by single molecule real—time sequencing. Sci Rep. 2022; 12: 7083.

[81] Malandris K, Kalopitas G, Theocharidou E, Germanidis G. The Role of RASs/RVs in the Current Management of HCV. Viruses. 2021; 13: 2096.

[82] Liu Z, Mao X, Wu J, Yu K, Yang Q, Suo C, et al. World—wide Prevalence of Substitutions in HCV Genome Associated With Resistance to Direct—Acting Antiviral Agents. Clin Gastroenterol Hepatol. 2021; 19: 1906-14.e25.

[83] Matthew AN, Leidner F, Newton A, Petropoulos CJ, Huang W, Ali A, et al. Molecular Mechanism of Resistance in a Clinically Significant Double—Mutant Variant of HCV NS3/4A Protease. Structure. 2018; 26: 1360-72.e5.

[84] Dultz G, Srikakulam SK, Konetschnik M, Shimakami T, Doncheva NT, Dietz J, et al. Epistatic interactions promote persistence of NS3—Q80K in HCV infection by compensating for protein folding instability. J Biol Chem. 2021; 297: 101031.

[85] Chui CK, Dong WW, Joy JB, Poon AF, Dong WY, Mo T, et al. Development and Validation of Two Screening Assays for the Hepatitis C Virus NS3 Q80K Polymorphism Associated with Reduced Response to Combination Treatment Regimens Containing Simeprevir. J Clin Microbiol. 2015; 53: 2942—50.

[86] Jennings TA, Chen Y, Sikora D, Harrison MK, Sikora B, Huang L, et al. RNA unwinding activity of the hepatitis C virus NS3 helicase is modulated by the NS5B polymerase. Biochemistry. 2008; 47: 1126—35.

[87] Mani N, Yuzhakov A, Yuzhakov O, Coll JT, Black J, Saxena K, et al. Nonstructural protein 5A (NS5A) and human replication protein A increase the processivity of hepatitis C virus NS5B polymerase activity in vitro. J Virol. 2015; 89: 165-80.

[88] Nguyen D, Smith D, Vaughan—Jackson A, Magri A; STOP—HCV Consortium; Barnes E, Simmonds P. Efficacy of NS5A inhibitors against unusual and potentially difficult—to—treat HCV subtypes commonly found in sub—Saharan Africa and South East Asia. J Hepatol. 2020; 73: 794—9.

[89] Pérez AB, Chueca N, García F. Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long? Germs. 2017; 7: 40-4.

[90] Smith—Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits. BMC Infect Dis. 2015; 15: 19.

[91] Rich NE, Singal AG. Direct—Acting Antiviral Therapy and Hepatocellular Carcinoma. Clin Liver Dis (Hoboken). 2021; 17: 414-7.

[92] Singal AG, Rich NE, Mehta N, Branch AD, Pillai A, Hoteit M, et al. Direct—Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma. Gastroenterology. 2019; 157: 1253-63.e2.

[93] van Velsen LM, Krassenburg LAP, Hirode G, Agarwal K, Foster GR, Cargill Z, et al. Association Between Sustained Virological Response and Adverse Liver—Related Events in Patients With Decompensated Hepatitis C Virus Cirrhosis. Clin Gastroenterol Hepatol. 2026; 24: 1877-87.

[94] Yoshida EM, Sulkowski MS, Gane EJ, Herring RW Jr, Ratziu V, Ding X, et al. Concordance of sustained virological response 4, 12, and 24 weeks post—treatment with sofosbuvir—containing regimens for hepatitis C virus. Hepatology. 2015; 61: 41-5.

[95] McDonell C, Assaf R, McKinney J, Glidden D, Luetkemeyer A, Ayala B, et al. Assessment of RNA at SVR4 and Treatment Completion as Alternative Measures of Hepatitis C Cure for People Who Inject Drugs. Open Forum Infect Dis. 2025; 13: ofaf737.

[96] Gane E, de Ledinghen V, Dylla DE, Rizzardini G, Shiffman ML, Barclay ST, et al. Positive predictive value of sustained virologic response 4 weeks posttreatment for achieving sustained virologic response 12 weeks posttreatment in patients receiving glecaprevir/pibrentasvir in Phase 2 and 3 clinical trials. J Viral Hepat. 2021; 28: 1635—42.

[97] Milošević I, Filipović A, Beronja B, Mitrović N, Ružić M, Simić J, et al. Optimizing Hepatitis C Treatment Monitoring: Is Sustained Virologic Response at 4 Weeks Becoming the New Standard? Microorganisms. 2024; 12: 2050.

[98] Bhattacharya D, Aronsohn A, Price J, Lo Re V, AASLD—IDSA HCV Guidance Panel. Hepatitis C Guidance 2023 Update: AASLD—IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis. 2023;[Epub ahead of print].

[99] European Association for the Study of the Liver; Clinical Practice Guidelines Panel: Chair:; EASL Governing Board representative:; Panel members:. EASL recommendations on treatment of hepatitis C: Final update of the series^☆. J Hepatol. 2020; 73: 1170-218.

[100] Dai CY, Chuang WL, Yu ML. EASL recommendations on treatment of hepatitis C: Final update of the series — Some issues. J Hepatol. 2021; 74: 473—4.

[101] Asselah T, Kowdley KV, Zadeikis N, Wang S, Hassanein T, Horsmans Y, 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.

[102] Kwo PY, Poordad F, Asatryan A, Wang S, Wyles DL, Hassanein T, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1—6 without cirrhosis. J Hepatol. 2017; 67: 263-71.

[103] Wyles D, Poordad F, Wang S, Alric L, Felizarta F, Kwo PY, et al. Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial. Hepatology. 2018; 67: 514—23.

[104] Zeuzem S, Foster GR, Wang S, Asatryan A, Gane E, Feld JJ, et al. Glecaprevir—Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection. N Engl J Med. 2018; 378: 354-69.

[105] Forns X, Lee SS, Valdes J, Lens S, Ghalib R, Aguilar H, 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.

[106] Benson CA, Andersen JW, Macatangay BJC, Mailliard RB, Rinaldo CR Jr, Read S, et al. Safety and Immunogenicity of Zoster Vaccine Live in Human Immunodeficiency Virus—Infected Adults With CD4+ Cell Counts >200 Cells/mL Virologically Suppressed on Antiretroviral Therapy. Clin Infect Dis. 2018; 67: 1712—9.

[107] Brown RS Jr, Buti M, Rodrigues L, Chulanov V, Chuang WL, Aguilar H, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment—naïve patients with chronic HCV genotypes 1—6 and compensated cirrhosis: The EXPEDITION—8 trial. J Hepatol. 2020; 72: 441-9.

[108] Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, et al. ; ASTRAL—1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015; 373: 2599-607.

[109] Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S, et al. ; ASTRAL—2 Investigators; ASTRAL—3 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015; 373: 2608—17.

[110] European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol. 2017; 66: 153-94.

[111] AASLD—IDSA HCV Guidance Panel. Hepatitis C Guidance 2018 Update: AASLD—IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis. 2018; 67: 1477-92.

[112] Mangia A, Milligan S, Khalili M, Fagiuoli S, Shafran SD, Carrat F, et al. Global real—world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts. Liver Int. 2020; 40: 1841-52.

[113] Buggisch P, Wursthorn K, Stoehr A, Atanasov PK, Supiot R, Lee J, et al. Real—world effectiveness and safety of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir hepatitis C treatment in a single centre in Germany. PLoS One. 2019; 14: e0214795.

[114] Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. ; ION—3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014; 370: 1879—88.

[115] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. ; ION—2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014; 370: 1483-93.

[116] Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. ; ION—4 Investigators. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV—1. N Engl J Med. 2015; 373: 705—13.

[117] Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof—of—concept, single—centre, open—label phase 2a cohort study. Lancet Infect Dis. 2015; 15: 1049-54.

[118] Esteban R, Flamm S, Buti M, Turnes J, Ni L, Hernández C, et al. Concomitant use of proton pump inhibitors and Sofosbuvir/Velpatasvir: evidence from randomized clinical trials and real—world data. Dig Liver Dis. 2024; 56: S37—8.

[119] German P, Mathias A, Brainard DM, Kearney BP. Drug—Drug Interaction Profile of the Fixed—Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir. Clin Pharmacokinet. 2018; 57: 1369-83.

[120] Goble SR, Nyembo P, Rodin H, Konstantinides G, Powell J, Noska AJ. Statin Utilization Among Individuals Infected With Hepatitis C Virus: A Retrospective Cohort Study. Cureus. 2023; 15: e36049.

[121] Torre P, Festa M, Sarcina T, Masarone M, Persico M. Elimination of HCV Infection: Recent Epidemiological Findings, Barriers, and Strategies for the Coming Years. Viruses. 2024; 16: 1792.

[122] Zou Z, Cao Y, Zhang Y, Hu Y, Wang Q, Su S, et al. Progressing towards global hepatitis C elimination: a systematic review and meta—analysis of care cascades in key populations. Lancet Reg Health West Pac. 2026; 67: 101803.

[123] Waheed Y, Siddiq M, Jamil Z, Najmi MH. Hepatitis elimination by 2030: Progress and challenges. World J Gastroenterol. 2018; 24: 4959-61.

[124] Marshall AD, Willing AR, Kairouz A, Cunningham EB, Wheeler A, O'Brien N, et al. ; Global HCV and HIV Treatment Restrictions Group. Direct—acting antiviral therapies for hepatitis C infection: global registration, reimbursement, and restrictions. Lancet Gastroenterol Hepatol. 2024; 9: 366-82.

[125] Calvaruso V, Petta S, Craxì A. Is global elimination of HCV realistic? Liver Int. 2018; 38 Suppl 1: 40-6.

[126] GLOBAL HEPATITIS REPORT 2017 [Internet]. [cited 2026 May 10]. Available from: https://iris.who.int/server/api/core/bitstreams/c89b995d—7136—4c5c—a3a0—6b697eccab51/content

[127] El—Zanaty FH, Way A. Egypt demographic and health survey, 2005. Cairo, Egypt: Ministry of Health and Population, National Population Council, El—Zanaty and Associates, and ORC Macro; 2006.

[128] Omran D, Alboraie M, Zayed RA, Wifi MN, Naguib M, Eltabbakh M, et al. Towards hepatitis C virus elimination: Egyptian experience, achievements and limitations. World J Gastroenterol. 2018; 24: 4330—40.

[129] Hassanin A, Kamel S, Waked I, Fort M. Egypt's Ambitious Strategy to Eliminate Hepatitis C Virus: A Case Study. Glob Health Sci Pract. 2021; 9: 187-200.

[130] Derbala M, Amer A, Bener A, Lopez AC, Omar M, El Ghannam M. Pegylated interferon—alpha 2b—ribavirin combination in Egyptian patients with genotype 4 chronic hepatitis. J Viral Hepat. 2005; 12: 380-5.

[131] Gomaa A, Gomaa M, Allam N, Waked I. Hepatitis C Elimination in Egypt: Story of Success. Pathogens. 2024; 13: 681.

[132] Seifert LL, Perumpail RB, Ahmed A. Update on hepatitis C: Direct—acting antivirals. World J Hepatol. 2015; 7: 2829-33.

[133] Elgharably A, Gomaa AI, Crossey MM, Norsworthy PJ, Waked I, Taylor—Robinson SD. Hepatitis C in Egypt — past, present, and future. Int J Gen Med. 2016; 10: 1-6.

[134] Pepe GM, Kaefer TN, Goode JKR. Impact of pharmacist identification of medication—related problems in a nontraditional long—term care pharmacy. J Am Pharm Assoc (2003). 2018; 58: S51-4.

[135] Doss W, Shiha G, Hassany M, Soliman R, Fouad R, Khairy M, et al. Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4. J Hepatol. 2015; 63: 581—5.

[136] Elsharkawy A, Fouad R, El Akel W, El Raziky M, Hassany M, Shiha G, et al. Sofosbuvir—based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt. Aliment Pharmacol Ther. 2017; 45: 681-7.

[137] Ahmed OA, Elsebaey MA, Fouad MHA, Elashry H, Elshafie AI, Elhadidy AA, et al. Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Infect Drug Resist. 2018; 11: 441-5.

[138] El—Khayat HR, Fouad YM, Maher M, El—Amin H, Muhammed H. Efficacy and safety of sofosbuvir plus simeprevir therapy in Egyptian patients with chronic hepatitis C: a real—world experience. Gut. 2017; 66: 2008—12.

[139] El—Khayat H, Fouad Y, Mohamed HI, El—Amin H, Kamal EM, Maher M, et al. Sofosbuvir plus daclatasvir with or without ribavirin in 551 patients with hepatitis C—related cirrhosis, genotype 4. Aliment Pharmacol Ther. 2018; 47: 674—9.

[140] El Kassas M, Omran D, Elsaeed K, Alboraie M, Elakel W, El Tahan A, et al. Spur—of—the—Moment Modification in National Treatment Policies Leads to a Surprising HCV Viral Suppression in All Treated Patients: Real—Life Egyptian Experience. J Interferon Cytokine Res. 2018; 38: 81-5.

[141] Omar H, El Akel W, Elbaz T, El Kassas M, Elsaeed K, El Shazly H, et al. Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real—world results from 18 378 patients in Egypt. Aliment Pharmacol Ther. 2018; 47: 421—31.

[142] Elsharkawy A, El—Raziky M, El—Akel W, El—Saeed K, Eletreby R, Hassany M, et al. Planning and prioritizing direct—acting antivirals treatment for HCV patients in countries with limited resources: Lessons from the Egyptian experience. J Hepatol. 2018; 68: 691—8.

[143] Rose C. Am I Part of the Cure or Am I Part of the Disease? Keeping Coronavirus Out When a Doctor Comes Home. N Engl J Med. 2020; 382: 1684—5.

[144] Skinner S, Nader E, Stauffer E, Robert M, Boisson C, Cibiel A, et al. Differential impacts of trail and ultra—trail running on cytokine profiles: An observational study. Clin Hemorheol Microcirc. 2021; 78: 301—10.

[145] WHO welcomes Egypt’s support to 14 African countries in their fight against hepatitis C [Internet]. WHO; c2026 [cited 2026 May 10]. Available from: https://www.emro.who.int/media/news/who—welcomes—egypts—support—to—14—african—countries—in—their—fight—against—hepatitis—c.html

[146] Cox AL. Challenges and Promise of a Hepatitis C Virus Vaccine. Cold Spring Harb Perspect Med. 2020; 10: a036947.

[147] Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C Virus Vaccine: Challenges and Prospects. Vaccines (Basel). 2020; 8: 90.

[148] Law JL, Chen C, Wong J, Hockman D, Santer DM, Frey SE, et al. A hepatitis C virus (HCV) vaccine comprising envelope glycoproteins gpE1/gpE2 derived from a single isolate elicits broad cross—genotype neutralizing antibodies in humans. PLoS One. 2013; 8: e59776.

[149] Stamataki Z, Coates S, Abrignani S, Houghton M, McKeating JA. Immunization of human volunteers with hepatitis C virus envelope glycoproteins elicits antibodies that cross—neutralize heterologous virus strains. J Infect Dis. 2011; 204: 811—3.

[150] Barnes E, Folgori A, Capone S, Swadling L, Aston S, Kurioka A, et al. Novel adenovirus—based vaccines induce broad and sustained T cell responses to HCV in man. Sci Transl Med. 2012; 4: 115ra1.

[151] Page K, Melia MT, Veenhuis RT, Winter M, Rousseau KE, Massaccesi G, et al. Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection. N Engl J Med. 2021; 384: 541-9.

[152] Topi S, Gaxhja E, Charitos IA, Colella M, Santacroce L. Hepatitis C Virus: History and Current Knowledge. Gastroenterol Insights. 2024; 15: 676-707.

[153] Colella M, Charitos IA, Ballini A, Cafiero C, Topi S, Palmirotta R, et al. Microbiota revolution: How gut microbes regulate our lives. World J Gastroenterol. 2023; 29: 4368—83.

[154] Good SS, Luo S, Lin K, Vo A, Agrawal NGB, Sommadossi JP. Bemnifosbuvir and ruzasvir in combination exhibit potent synergistic antiviral activity in vitro while maintaining a favorable nonclinical safety profile in vivo. Antiviral Res. 2025; 237: 106137.

[155] Zhou XJ, Morelli G, Montrond M, Lynch S, Pietropaolo K, Belanger B, et al. Clinical Evaluation of Potential Interaction Between Bemnifosbuvir and Ruzasvir With an Assessment of Food Effect: Results of a Phase 1 Study in Healthy Participants. Clin Pharmacol Drug Dev. 2025; 14: 461-71.

[156] Andrieux—Meyer I, Tan SS, Thanprasertsuk S, Salvadori N, Menétrey C, Simon F, et al. Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM—C—1): interim analysis of a two—stage, open—label, multicentre, single arm, phase 2/3 trial. Lancet Gastroenterol Hepatol. 2021; 6: 448-58.

[157] Correction to Lancet Gastroenterol Hepatol 2021; 6: 448—58. Lancet Gastroenterol Hepatol. 2022; 7: 704.

[158] Abu Hassan MR, Muhamad NA, Mohammed NS, Mohd Suan MA, Zulkifli Supramaniam DN, Jogulu SR, et al. ; EASE Trial Group. A Multicenter, open—label, randomized, non—inferiority trial of 8 versus 12 weeks of sofosbuvir/ravidasvir treatment in non—cirrhotic patients with chronic hepatitis C virus infection (EASE trial). Int J Infect Dis. 2026; 169: 108788.