Clinical Investigation| Volume 355, ISSUE 5, P456-466, May 2018

Effectiveness of Sofosbuvir, Ribavirin and PEG-IFNα-2a in the Treatment of Naïve Egyptian Patients With Chronic Hepatitis C Virus Genotype 4



      Egypt is one of the largest epidemic areas of hepatitis C virus (HCV) in the world. Its prevalent genotype is 4 with a majority of subtype 4a. In 2013, the Food and Drug Administration approved a new direct-acting antiviral drug (sofosbuvir) to treat patients with chronic HCV infection. In Egypt, the patients are already being treated with sofosbuvir in conjunction with ribavirin and pegylated interferon alfa-2a (PEG-IFNα-2a) for 12 weeks since 2015. The present study was planned to explain the efficacy of this treatment regimen against the HCV genotype 4a in Egyptian patients and its pretreatment predictive factors of virological response.


      In this population-based study, serum samples were biochemically analyzed and the HCV RNA levels were quantified. The direct sequencing and bioinformatics analysis were utilized to investigate the mutation of the core protein.


      The sustained virological response (SVR) and non-SVR were 72% and 16% respectively, but the nonvirological response was only 12% following the treatment regimen. The multivariable analysis recognized viral (level of viremia and substitution of aa70) and host-related factors (age, alanine aminotransferase and aspartate aminotransferase levels) affecting the virological response in patients infected with high viral load of HCV 4a.


      Overall, these results concluded that sofosbuvir with ribavirin and PEG-IFNα-2a are highly efficient in HCV-4a Egyptian patients where a high SVR was achieved (72%). In addition to this, there is a significant association between core protein mutations and treatment outcome predominantly at amino acid position 70 (Arg or Gln).

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        • Chevaliez S.
        • Pawlotsky J.M.
        Hepatitis C virus serologic and virological tests and clinical diagnosis of HCV-related liver disease.
        Int J Med Sci. 2006; 3: 35-40
        • Houghton M.
        • Selby M.
        • Weiner A.
        • et al.
        Hepatitis C virus: structure, protein products and processing of the polyprotein. In hepatitis C virus.
        Curr Stud Hematol Blood Transfus. 1994; 61: 1-11
        • Moradpour D.
        • Evans M.J.
        • Gosert R.
        • et al.
        Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes.
        J Virol. 2004; 78: 7400-7409
        • Tellinghuisen T.L.
        • Foss K.L.
        • Treadaway J.
        Regulation of hepatitis C virion production via phosphorylation of the NS5A protein.
        PLoS Pathog. 2008; 4: e1000032
        • Rumi M.G.
        • Aghemo A.
        • Prati G.M.
        • et al.
        Randomized study of peginterferon-alpha2a plus Ribavirin vs peginterferon-alpha2b plus Ribavirin in chronic hepatitis C.
        Gastroenterology. 2010; 138: 108-115
        • Khattab M.A.
        • Ferenci P.
        • Hadziyannis S.J.
        • et al.
        Management of hepatitis C virus genotype 4: recommendations of an international expert panel.
        J Hepatol. 2011; 54: 1250-1262
        • Strader D.B.
        • Wright T.
        • Thomas D.L.
        • et al.
        Diagnosis, management, and treatment of hepatitis C.
        J Hepatol. 2004; 39: 1147-1171
        • Fried M.W.
        • Shiffman M.L.
        • Reddy K.R.
        • et al.
        Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
        N Engl J Med. 2002; 347: 975-982
        • Haydon G.H.
        • Jarvis L.M.
        • Blair C.S.
        • et al.
        Clinical significance of intrahepatic hepatitis C virus levels in patients with chronic HCV infection.
        Gut. 1998; 42: 570-575
        • Hajarizadeh B.
        • Grebely J.
        • Dore G.J.
        Epidemiology and natural history of HCV infection.
        Nat Rev Gastroenterol Hepatol. 2013; 10: 553-562
      1. FDA Approves Sovaldi for Chronic Hepatitis C. [Last accessed on 2012 Dec 6]. Available from:

        • Zeng Q.L.
        • Zhang J.Y.
        • Zhang Z.
        • et al.
        Sofosbuvir and ABT-450: terminator of hepatitis C virus?.
        World J Gastroenterol. 2013; 19: 3199-3206
        • Soriano V.
        • Vispo E.
        • Mendoza C.D.
        • et al.
        Hepatitis C therapy with HCV NS5B polymerase inhibitors.
        Expert Opin Pharmacother. 2013; 14: 1161-1170
        • Bhatia H.K.
        • Singh H.
        • Grewal N.
        • et al.
        Sofosbuvir: a novel treatment option for chronic hepatitis C infection.
        J Pharmacolpharmacother. 2014; 5: 278-284
        • Akuta N.
        • Suzuki F.
        • Sezaki H.
        • et al.
        Predictive factors of virological non-response to interferon–ribavirin combination therapy for patients infected with hepatitis C virus of genotype1b and high viral load.
        J Med Virol. 2006; l78: 83-90
        • Akuta N.
        • Suzuki F.
        • Hirakawa M.
        • et al.
        Association of amino acid substitution patternin core protein of hepatitis C virus genotype2a high viral load and virological response to interferon-ribavirin combination therapy.
        Intervirology. 2009; 52: 301-309
        • Hashimoto Y.
        • Ochi H.
        • Abe H.
        • et al.
        Prediction of response to peginterferon-alfa-2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b.
        J Med Virol. 2011; 83: 981-988
        • Lole K.S.
        • Jha J.A.
        • Shrotri S.P.
        • et al.
        Comparison of hepatitis C virus genotyping by 5′ noncoding region- and core-based reverse transcriptase PCR assay with sequencing and use of the assay for determining subtype distribution in India.
        J Clin Microbiol. 2003; 41: 5240-5244
        • Hall T.A.
        Bio3Edit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT.
        Nucl Acid Symp Ser. 1999; 41: 95-98
        • Tamura K.
        • Stechner G.
        • Petersun D.
        • et al.
        MEGA6: molecular evolutionary genetics analysis version 6.0.
        Mol Biol Evol. 2013; 30: 2725-2729
        • Chamberlain R.W.
        • Adams N.
        • Saeed A.A.
        • et al.
        Complete nucleotide sequence of a type 4 hepatitis C virus variant, the predominant genotype in the Middle East.
        J Gen Virol. 1997; 78: 1341-1347
        • Bukh J.
        • Purcell R.H.
        • Miller R.H.
        Sequence analysis of the core gene of 14 hepatitis C virus genotypes.
        Proc Natl Acad Sci USA. 1994; 91: 8239-8243
        • Alhamlan F.S.
        • Al-Ahdal M.N.
        • Khalaf N.Z.
        • et al.
        Genetic variability of the core protein in hepatitis C virus genotype 4 in Saudi Arabian patients and its implication on pegylated interferon and ribavirin therapy.
        J Transl Med. 2014; 12: 91
      2. SAS. Version 90 SAS Institute Inc Cary NC. 2012.

        • Alter M.J.
        Epidemiology of hepatitis C virus infection.
        World J Gastroenterol. 2007; 13: 2436-2441
        • Lavanchy D.
        Evolving epidemiology of hepatitis C virus.
        Clin Microbiol Infect. 2011; 17: 107-115
        • Kamal S.M.
        • Nasser I.A.
        Hepatitis C genotype 4: what we know and what we don′t yet know.
        J Hepatol. 2008; 47: 1371-1383
        • Lawitz E.
        • Mangia A.
        • Wyles D.
        • et al.
        Sofosbuvir for previously untreated chronic hepatitis C infection.
        N Engl J Med. 2013; 368: 1878-1887
        • Alessandra M.
        • Valeria P.
        Overall efficacy and safety results of sofosbuvir-based therapies in Phase II and III studies.
        Dig Liver Dis. 2014; 46: S179-S185
        • Elsharkawy A.
        • Fouad R.
        • El Akel W.
        • et al.
        Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt.
        Aliment Pharmacol Ther. 2017; 45: 681-687
        • Nagaty A.
        • Abd El-Wahab E.W.
        Real-life results of sofosbuvir based therapy in chronic hepatitis C -naïve and -experienced patients in Egypt.
        PLoS One. 2017; 12: e0184654
        • Ray S.C.
        • Arthur R.R.
        • Carella A.
        • et al.
        Genetic epidemiology of hepatitis C virus throughout Egypt.
        J Infect Dis. 2000; 182: 698-707
        • Genovese D.
        • Dettori S.
        • Argentini C.
        • et al.
        Molecular epidemiology of hepatitis C virus genotype 4 isolates in Egypt and analysis of the variability of envelope proteins E1 and E2 in patients with chronic hepatitis.
        J Clin Microbiol. 2005; 43: 1902-1909
        • Abdel-Hamid M.
        • El-Daly M.
        • Molnegren V.
        • et al.
        Genetic diversity in hepatitis C virus in Egypt and possible association with hepatocellular carcinoma.
        J Gen Virol. 2007; 88: 1526-1531
        • Ryu S.H.
        • Fan X.
        • Xu Y.
        • et al.
        Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt.
        J Med Virol. 2009; 81: 844-847
        • Youssef A.
        • Yano Y.
        • Utsumi T.
        • et al.
        Molecular epidemiological study of hepatitis viruses in Ismailia, Egypt.
        Intervirology. 2009; 52: 123-131
        • Kowdley K.V.
        • Lawitz E.
        • Crespo I.
        • et al.
        Sofosbuvir with pegylated interferon Alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.
        Lancet. 2013; 15: 2100-2107
        • Reddy K.R.
        • Hoofnagle J.H.
        • Tong M.J.
        • et al.
        Racial differences in responses to therapy with interferon in chronic hepatitis C Consensus Interferon Study Group.
        J Hepatol. 1999; 30: 787-793
        • Akuta N.
        • Suzuki F.
        • Kawamura Y.
        • et al.
        Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels.
        J Hepatol. 2007; 46: 403-410
        • Schaefer E.A.
        • Chung R.T.
        The impact of human gene polymorphisms on HCV infection and disease outcome.
        Semin Liver Dis. 2011; 31: 375-386
        • Mangia A.
        • Santoro R.
        • Minerva N.
        • et al.
        Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3.
        N Engl J Med. 2005; 352: 2609-2617
        • Toyoda H.
        • Kumada T.
        • Kiriyama S.
        • et al.
        Eight-week regimen of antiviral combination therapy with peginterferon and ribavirin for patients with chronic hepatitis C with hepatitis C virus genotype 2 and a rapid virological response.
        Liver Int. 2009; 29: 120-125
        • Kountouras J.
        • Zavos C.
        • Chatzopoulos D.
        Apoptosis in hepatitis C.
        J Viral Hepat. 2003; 10: 335-342
        • Lin W.
        • Kim S.S.
        • Yeung E.
        • et al.
        Hepatitis C virus core protein blocks interferon signaling byinteraction with the STAT1 SH2 domain.
        J Virol. 2006; 80: 9226-9235
        • Akuta N.
        • Suzuki F.
        • Sezaki H.
        • et al.
        Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non virological response to interferon-ribavirin combination therapy.
        Intervirology. 2005; 48: 372-380
        • El-Shamy A.
        • Shoji I.
        • Ryang S.K.
        • et al.
        NS5A sequence heterogeneity of hepatitis C virus genotype 4a predicts clinical outcome of pegylated-interferon–ribavirin therapy in Egyptian patients.
        J Clin Microbiol. 2012; 50: 3886-3892
        • Funaoka Y.
        • Sakamoto N.
        • Itsui Y.G.
        • et al.
        Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91.
        J Virol. 2011; 85: 5986-5994