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Management of hepatitis C virus genotype 4: Recommendations of An International Expert Panel

Open AccessPublished:December 09, 2010DOI:https://doi.org/10.1016/j.jhep.2010.11.016
      HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections.

      Introduction

      Hepatitis C virus (HCV), a member of the Flavivirida family of RNA viruses, is characterized by a high spontaneous mutation rate with an estimated frequency of 1.4–1.9 × 10−3 mutations per nucleotide per year [
      • Ogata N.
      • Alter H.J.
      • Miller R.H.
      • Purcell R.H.
      Nucleotide sequence and mutation rate of the H strain of hepatitis C virus.
      ,
      • Simmonds P.
      • Alberti A.
      • Alter H.J.
      • Bonino F.
      • Bradley D.W.
      • Brechot C.
      • et al.
      A proposed system for the nomenclature of hepatitis C viral genotypes.
      ]. As a result, HCV exists as a heterogeneous group of viruses sharing approximately 70% homology. On the basis of nucleotide sequence homology, HCV has been classified into no fewer than six major genotypes and a series of subtypes [
      • Kuiken C.
      • Simmonds P.
      Nomenclature and numbering of the hepatitis C virus.
      ]. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy [
      • Hnatyszyn H.J.
      Chronic hepatitis C and genotyping: the clinical significance of determining HCV genotypes.
      ]. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries [

      World Health Organization. Hepatitis C. Geneva, Switzerland: World Health Organization, 2000 WHO fact sheet 164. Available at http://www.who.int/mediacentre/factsheets/fs164/en/print.html. Accessed 1 August 2010.

      ,
      • Nguyen M.H.
      • Keeffe E.B.
      Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6.
      ]. HCV-4 is considered a major cause of chronic liver disease and cirrhosis, which leads to liver failure and is the root cause of hepatocellular carcinoma. Because of these complications, extended cirrhosis during chronic infection is a primary cause of liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections.

      Epidemiology

      Approximately 34 million people are chronically infected with HCV-4. The Iinfection is common in the Middle East and Africa, where it accounts for more than 80% of all hepatitis C cases [

      World Health Organization. Hepatitis C. Geneva, Switzerland: World Health Organization, 2000 WHO fact sheet 164. Available at http://www.who.int/mediacentre/factsheets/fs164/en/print.html. Accessed 1 August 2010.

      ,
      • Nguyen M.H.
      • Keeffe E.B.
      Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6.
      ,

      Egyptian Ministry of Health. Egyptian Ministry of Health Annual Report: 2007. Available at http://www.mohp.gov. eg/Main.asp (accessed 6 July 2010).

      ,
      • Abdel-Aziz F.
      • Habib M.
      • Mohamed M.K.
      • Abdel-Hamid M.
      • Gamil F.
      • Madkour S.
      • et al.
      Hepatitis C virus (HCV) infection in a community in the Nile Delta: population description and HCV prevalence.
      ]. The risk factors for HCV-4 transmission are determined by the geographical distribution of this genotype.
      Egypt has the highest prevalence of HCV worldwide (15%) and the highest prevalence of HCV-4, which is responsible for 90% of infections, with a predominance of subtype 4a (55%) [

      World Health Organization. Hepatitis C. Geneva, Switzerland: World Health Organization, 2000 WHO fact sheet 164. Available at http://www.who.int/mediacentre/factsheets/fs164/en/print.html. Accessed 1 August 2010.

      ,
      • Nguyen M.H.
      • Keeffe E.B.
      Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6.
      ,

      Egyptian Ministry of Health. Egyptian Ministry of Health Annual Report: 2007. Available at http://www.mohp.gov. eg/Main.asp (accessed 6 July 2010).

      ,
      • Abdel-Aziz F.
      • Habib M.
      • Mohamed M.K.
      • Abdel-Hamid M.
      • Gamil F.
      • Madkour S.
      • et al.
      Hepatitis C virus (HCV) infection in a community in the Nile Delta: population description and HCV prevalence.
      ,
      • Elkady A.
      • Tanaka Y.
      • Kurbanov F.
      • Sugauchi F.
      • Sugiyama M.
      • Khan A.
      • et al.
      Genetic variability of hepatitis C virus in South Egypt and its possible clinical implication.
      ]. Epidemiological and molecular evolutionary analysis on Egyptian genotype 4a isolates suggest the origin of the HCV-4 epidemic arises from the antischistosomal campaign, which was administered parenterally, and only stopped in the mid-1960s [
      • Frank C.
      • Mohamed M.K.
      • Strickland G.T.
      • Lavanchy D.
      • Arthur R.R.
      • Magder L.S.
      • et al.
      The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt.
      ,
      • Tanaka Y.
      • Agha S.
      • Saudy N.
      • Kurbanov F.
      • Orito E.
      • Kato T.
      • et al.
      Exponential spread of hepatitis C virus genotype 4a in Egypt.
      ]. However, other risk factors, mostly related to prevailing social and cultural conditions, are responsible for maintaining the high rates of HCV-4 transmission even after the treatment campaign was stopped. Currently, the major route of transmission appears to be health-related procedures with inadequately sterilized instruments. Procedures performed by non-medical professionals and traditional healers have been identified as important risk factors for HCV transmission in Egypt [
      • Stoszek S.K.
      • Abdel-Hamid M.
      • Narooz S.
      • El Daly M.
      • Saleh D.A.
      • Mikhail N.
      • et al.
      Prevalence of and risk factors for hepatitis C in rural pregnant Egyptian women.
      ,
      • El Katsha S.
      • Labeeb S.
      • Watts S.
      • Younis A.
      Informal health providers and the transmission of hepatitis C virus: pilot study in two Egyptian villages.
      ,
      • Talaat M.
      • Kandeel A.
      • El-Shoubary W.
      • Bodenschatz C.
      • Khairy I.
      • Oun S.
      • et al.
      Occupational exposure to needlestick injuries and hepatitis B vaccination coverage among health care workers in Egypt.
      ]. Intrafamilial and sexual transmissions also play a role in the high prevalence of HCV-4 in this country [
      • Magder L.S.
      • Fix A.D.
      • Mikhail N.N.
      • Mohamed M.K.
      • Abdel-Hamid M.
      • Abdel-Aziz F.
      • et al.
      Estimation of the risk of transmission of hepatitis C between spouses in Egypt based on seroprevalence data.
      ,
      • Mohamed M.K.
      • Abdel-Hamid M.
      • Mikhail N.N.
      • Abdel-Aziz F.
      • Medhat A.
      • Magder L.S.
      • et al.
      Intrafamilial transmission of hepatitis C in Egypt.
      ].
      The prevalence of HCV in Saudi Arabia is 1–3%, [
      • Al-Faleh F.Z.
      Changing pattern of hepatitis viral infection in Saudi Arabia in the last two decades.
      ] with a predominance of genotype 4 (62%). Unlike the predominance of subtype 4a in Egypt, subtypes 4c/4d are the most prevalent subtypes among Saudis, followed by subtypes 4h, 4e, and 4a, suggesting that the origin and transmission of HCV-4 is different from that in Egypt [
      • Al-Faleh F.Z.
      Changing pattern of hepatitis viral infection in Saudi Arabia in the last two decades.
      ]. Similarly, studies from other parts of the Middle East also suggest a high prevalence of HCV-4. For example, 36–46% of HCV-infected Lebanese patients have HCV-4 [
      • Sharara A.I.
      • Ramia S.
      • Ramlawi F.
      • Fares J.E.
      • Klayme S.
      • Naman R.
      Genotypes of hepatitis C virus (HCV) among Lebanese patients: comparison of data with that from other middle Eastern countries.
      ], 59% of Syrian patients [
      • Antaki N.
      • Haddad M.
      • Kebbewar K.
      • Abdelwahab J.
      • Hamed O.
      • Aaraj R.
      • et al.
      The unexpected discovery of a focus of hepatitis C virus genotype 5 in a Syrian province.
      ] and 27% of HCV-infected Jordanian patients on dialysis have HCV-4 [
      • Bdour S.
      Hepatitis C virus infection in Jordanian hemodialysis units: serological diagnosis and genotyping.
      ].
      HCV-4 is also endemic throughout Central and West African countries such as the Congo, Liberia, and Uganda (where it accounts for 100% of HCV infections), as well as Gabon, Tanzania, and Cameroon (97%, 50%, and 36% of HCV infections, respectively) [
      • Njouom R.
      • Nerrienet E.
      • Dubois M.
      • Lachenal G.
      • Rousset D.
      • Vessie‘re A.
      • et al.
      The hepatitis C virus epidemic in Cameroon: genetic evidence for rapid transmission between 1920 and 1960.
      ,
      • Xu L.-Z.
      • Larzul D.
      • Delaporte E.
      • Br´echot C.
      • Kremsdorf D.
      Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon).
      ,
      • Ndjomou J.
      • Pybus O.G.
      • Matz B.
      Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon.
      ,
      • Wansbrough-Jones M.H.
      • Frimpong E.
      • Cant B.
      • Harris K.
      • Evans M.R.
      • Teo C.G.
      Prevalence and genotype of hepatitis C virus infection in pregnant women and blood donors in Ghana.
      ,
      • Kamal S.
      • Nasser I.
      Hepatitis C genotype 4: what we know and what we don’t yet know.
      ]. Scarification, circumcision practices, and sexual transmission may contribute to the persistence and propagation of HCV transmission in these countries [
      • Njouom R.
      • Nerrienet E.
      • Dubois M.
      • Lachenal G.
      • Rousset D.
      • Vessie‘re A.
      • et al.
      The hepatitis C virus epidemic in Cameroon: genetic evidence for rapid transmission between 1920 and 1960.
      ,
      • Kamal S.
      • Nasser I.
      Hepatitis C genotype 4: what we know and what we don’t yet know.
      ].
      Recently, HCV-4 has become increasingly prevalent in some southern European countries on the Mediterranean Sea, particularly Italy, France, Greece, and Spain, where prevalence rates of 10–24% have been reported in some areas [
      • Esteban J.I.
      • Sauleda S.
      • Quer J.
      The changing epidemiology of hepatitis C virus infection in Europe.
      ,
      • Katsoulidou A.
      • Sypsa V.
      • Tassopoulos N.C.
      • Boletis J.
      • Karafoulidou A.
      • Ketikoglou I.
      • et al.
      Molecular epidemiology of hepatitis C virus (HCV) in Greece. temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates.
      ,
      • Payan C.
      • Roudot-Thoraval F.
      • Marcellin P.
      • Bled N.
      • Duverlie G.
      • Fouchard-Hubert I.
      • et al.
      Changing of hepatitis C virus genotype patterns in France at the beginning of the third millennium: the GEMHEP Geno CII Study.
      ,
      • Ansaldi F.
      • Bruzzone B.
      • Salamaso S.
      • Rota M.C.
      • Durando P.
      • Gasparini R.
      • et al.
      Different seroprelavence and molecular epidemiology pattern of hepatitis C virus infection in Italy.
      ,
      • Fernandez-Arcas N.
      • Lopez-Siles J.
      • Trapero S.
      • Ferraro A.
      • Ibanez A.
      • Orihuela F.
      • et al.
      High prevalence of hepatitis C virus subtypes 4c and 4d in Malaga (Spain): phylogenetic and epidemiological analyses.
      ,
      • Franco S.
      • Tural C.
      • Clotet B.
      • Martı´nez M.A.
      Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1.
      ]. HCV-4 infection is frequent among intravenous drug users (IVDUs) (European and non-European), HCV/HIV-coinfected patients, and immigrants from North and sub-Saharan Africa [
      • Esteban J.I.
      • Sauleda S.
      • Quer J.
      The changing epidemiology of hepatitis C virus infection in Europe.
      ,
      • Katsoulidou A.
      • Sypsa V.
      • Tassopoulos N.C.
      • Boletis J.
      • Karafoulidou A.
      • Ketikoglou I.
      • et al.
      Molecular epidemiology of hepatitis C virus (HCV) in Greece. temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates.
      ,
      • Payan C.
      • Roudot-Thoraval F.
      • Marcellin P.
      • Bled N.
      • Duverlie G.
      • Fouchard-Hubert I.
      • et al.
      Changing of hepatitis C virus genotype patterns in France at the beginning of the third millennium: the GEMHEP Geno CII Study.
      ,
      • Ansaldi F.
      • Bruzzone B.
      • Salamaso S.
      • Rota M.C.
      • Durando P.
      • Gasparini R.
      • et al.
      Different seroprelavence and molecular epidemiology pattern of hepatitis C virus infection in Italy.
      ,
      • Fernandez-Arcas N.
      • Lopez-Siles J.
      • Trapero S.
      • Ferraro A.
      • Ibanez A.
      • Orihuela F.
      • et al.
      High prevalence of hepatitis C virus subtypes 4c and 4d in Malaga (Spain): phylogenetic and epidemiological analyses.
      ,
      • Franco S.
      • Tural C.
      • Clotet B.
      • Martı´nez M.A.
      Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1.
      ]. HCV-4 was probably introduced into Europe through immigration and the movement of IVDUs across European borders [
      • Franco S.
      • Tural C.
      • Clotet B.
      • Martı´nez M.A.
      Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1.
      ].
      HCV-4 infections are uncommon in the United States, Canada, South America, and Asia. The prevalence of HCV-4 in the United States is about 1% [
      • Nainan O.V.
      • Alter M.J.
      • Kruszon-Moran D.
      • Gao F.X.
      • Xia G.
      • McQuillan G.
      • et al.
      Hepatitis C genotypes and viral concentrations in participants of general population survey in the United States.
      ]. Most HCV-4 cases reported from the United States were clustered among IVDUs or immigrants from countries where subtype HCV-4 is known to be most prevalent or among individuals who acquired the infection in these countries [
      • Nainan O.V.
      • Alter M.J.
      • Kruszon-Moran D.
      • Gao F.X.
      • Xia G.
      • McQuillan G.
      • et al.
      Hepatitis C genotypes and viral concentrations in participants of general population survey in the United States.
      ,
      • Zein N.
      • Rakela J.
      • Krawitt E.
      • Reddy K.R.
      • Tominaga T.
      • Persing D.H.
      Hepatitis C virus genotypes in the United States: epidemiology, pathogenicity, and response to interferon therapy.
      ]. There are no reliable data on the prevalence of HCV-4 either in Australia or in South East Asia. However, HCV-4 appears to be rare in these regions.

      Natural history

      There are few data on the natural history of HCV-4. It is likely that the course of genotype 4 infection is similar to that of other genotypes [
      • Kamal S.
      • Nasser I.
      Hepatitis C genotype 4: what we know and what we don’t yet know.
      ,
      • Antaki N.
      • Craxì A.
      • Kamal S.M.
      • Moucari M.
      • Van der Merwe S.
      • Haffar S.
      • et al.
      The neglected hepatitis C virus genotype 4, 5 and 6: an international consensus report.
      ].
      HCV-4 represents more than 30% of the annually reported acute hepatitis cases in Egypt [
      • Zakaria S.
      • Fouad R.
      • Shaker O.
      • Zaki S.
      • Hashem A.
      • El-Kamary S.S.
      • et al.
      Changing patterns of acute viral hepatitis at a major urban referral center in Egypt.
      ]. Very few studies address the outcome of acute HCV-4 infection. Indeed, prospective studies have shown 20–50% rates of spontaneous resolution in acute HCV-4 infections [
      • Micallef J.M.
      • Kaldor J.M.
      • Dore G.J.
      Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.
      ,
      • Kamal S.M.
      • Moustafa K.N.
      • Chen J.
      • Fehr J.
      • Abdel Moneim A.
      • Khalifa K.E.
      • et al.
      Duration of peginterferon therapy in acute hepatitis C: a randomised trial.
      ,
      • Kamal S.M.
      • Rasenack J.W.
      • Bianchi L.
      • Al Tawil A.
      • El Sayed Khalifa K.
      • Peter T.
      • et al.
      Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4 (+) T-cell and cytokine response.
      ]; whereas those rates are reduced in patients with a coinfection with HIV or Schistosoma mansoni, as frequently occurs in Egyptians [
      • Antaki N.
      • Craxì A.
      • Kamal S.M.
      • Moucari M.
      • Van der Merwe S.
      • Haffar S.
      • et al.
      The neglected hepatitis C virus genotype 4, 5 and 6: an international consensus report.
      ,
      • Kamal S.M.
      • Moustafa K.N.
      • Chen J.
      • Fehr J.
      • Abdel Moneim A.
      • Khalifa K.E.
      • et al.
      Duration of peginterferon therapy in acute hepatitis C: a randomised trial.
      ]. The presence of schistosomiasis is a negative predictor of outcome, being associated with accelerated progression of hepatic fibrosis among HCV-4 patients. In fact, the fibrosis progression rate of 0.1 ± 0.06 fibrosis units/year observed in HCV-4 patients (similar to that of patients infected with other genotypes) increased up to 0.6 ± 0.13 in patients with associated schistosomiasis [
      • Roulot D.
      • Bourcier V.
      • Grando V.
      • Deny P.
      • Baazia Y.
      • Fontaine H.
      • et al.
      Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.
      ,
      • Moucari R.
      • Ripault M.P.
      • Martinot-Peignoux M.
      • Voitot H.
      • Cardoso A.C.
      • Stern C.
      • et al.
      Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.
      ,
      • Gambotti L.
      • Batisse D.
      • Colin-de-Verdiere N.
      • Delaroque-Astagneau E.
      • Desenclos J.C.
      • Dominguez S.
      • et al.
      Acute Hepatitis C collaborating Group. Acute Hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001–2004.
      ,
      • Kamal S.M.
      • Graham C.S.
      • He Q.
      • Bianchi L.
      • Tawil A.A.
      • Rasenack J.W.
      • et al.
      Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis.
      ,
      • Kamal S.M.
      • Turner B.
      • He Q.
      • Rasenack J.
      • Bianchi L.
      • Al Tawil A.
      • et al.
      Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum marker of fibrosis.
      ]. An Egyptian origin was independently associated with severe fibrosis in two French studies, however the higher fibrosis scores in these studies might be attributed to concomitant schistosomiasis in these Egyptian patients rather than ethnicity or HCV subtype [
      • Roulot D.
      • Bourcier V.
      • Grando V.
      • Deny P.
      • Baazia Y.
      • Fontaine H.
      • et al.
      Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.
      ,
      • Moucari R.
      • Ripault M.P.
      • Martinot-Peignoux M.
      • Voitot H.
      • Cardoso A.C.
      • Stern C.
      • et al.
      Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.
      ]. Insulin resistance was also found to be correlated independently with severity of fibrosis [
      • Moucari R.
      • Ripault M.P.
      • Martinot-Peignoux M.
      • Voitot H.
      • Cardoso A.C.
      • Stern C.
      • et al.
      Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.
      ]. The known association between hepatocellular carcinoma (HCC) and HCV needs to be weighed against other potential risk factors for HCC like schistosomiasis and exposure to aflatoxins or pesticides [
      • Abdel-Hamid M.
      • El-Daly M.
      • Molnegren V.
      • El-Kafrawy S.
      • Abdel-Latif S.
      • Esmat G.
      • et al.
      Genetic diversity in hepatitis C virus in Egypt and possible association with hepatocellular carcinoma.
      ,
      • Abdel-Wahab M.
      • Mostafa M.
      • Sabry M.
      • el-Farrash M.
      • Yousef T.
      Aflatoxins as a risk factor for hepatocellular carcinoma in Egypt, Mansoura Gastroenterology Center study.
      ,
      • Anwar W.A.
      • Khaled H.M.
      • Amra H.A.
      • El-Nezami H.
      • Loffredo C.A.
      Changing pattern of hepatocellular carcinoma (HCC) and its risk factors in Egypt: possibilities for prevention.
      ,
      • Ezzat S.
      • Abdel-Hamid M.
      • Eissa S.A.
      • Mokthar N.
      • Labib N.A.
      • El-Ghorory L.
      • et al.
      Associations of pesticides, HCV, HBV, and hepatocellular carcinoma in Egypt.
      ].

      Utility of liver biopsy and noninvasive fibrosis tests

      The biopsy is assessed for grade and stage of the liver injury, but also provides information on other histological features that might have a bearing on liver disease progression [
      • Kleiner D.E.
      The liver biopsy in chronic hepatitis C: a view from the other side of the microscope.
      ]. The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis [
      • Asselah T.
      • Rubbia-Brandt L.
      • Marcellin P.
      • Negro F.
      Steatosis in chronic hepatitis C: why does it really matter?.
      ,
      • Khattab M.A.
      • Abdel-Fattah M.E.
      • Eslam M.
      • Abdelaleem A.
      • Abdelaleem R.A.
      • Shatat M.
      • et al.
      Hepatic Steatosis in Genotype 4 Chronic Hepatitis C Patients: Implication for Therapy.
      ] and excess of hepatocellular iron [
      • Olynyk J.K.
      • Reddy K.R.
      • Di Bisceglie A.M.
      • Jeffers L.J.
      • Parker T.I.
      • Radick J.L.
      • et al.
      Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C.
      ]. The pathological findings in chronic HCV-4 are in general similar to other types of viral hepatitis C. However, certain features may be prominent in this genotype, one of which is the presence of moderate to severe steatosis [
      • Khattab M.A.
      • Abdel-Fattah M.E.
      • Eslam M.
      • Abdelaleem A.
      • Abdelaleem R.A.
      • Shatat M.
      • et al.
      Hepatic Steatosis in Genotype 4 Chronic Hepatitis C Patients: Implication for Therapy.
      ,
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manesis E.K.
      • Chrysanthos N.
      • Kafiri G.
      • Petraki K.
      • et al.
      Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors.
      ,
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ] with no associated sinusoidal fibrosis [
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ]. Host and viral factors contribute to the development of steatosis in hepatitis C, but their relative importance varies with genotype [
      • Sestre T.
      • Nkuize M.
      • Moucari R.
      • Van Gossum M.
      • Reynders M.
      • Scheen R.
      • et al.
      Metabolic disorders associated with chronic hepatitis C: impact of genotype and ethnicity.
      ,
      • Lonardo A.
      • Loria P.
      • Adinolfi L.E.
      • Carulli N.
      • Ruggiero G.
      Hepatitis C and steatosis: a reappraisal.
      ,
      • Negro F.
      • Sanyal A.J.
      Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data.
      ]. Hepatic steatosis in patients infected with HCV-4 is mainly associated with metabolic factors and follows the same pattern as those infected with genotype 1 [
      • Khattab M.A.
      • Abdel-Fattah M.E.
      • Eslam M.
      • Abdelaleem A.
      • Abdelaleem R.A.
      • Shatat M.
      • et al.
      Hepatic Steatosis in Genotype 4 Chronic Hepatitis C Patients: Implication for Therapy.
      ,
      • Sestre T.
      • Nkuize M.
      • Moucari R.
      • Van Gossum M.
      • Reynders M.
      • Scheen R.
      • et al.
      Metabolic disorders associated with chronic hepatitis C: impact of genotype and ethnicity.
      ]. Steatosis, in particular moderate-to-severe steatosis was detected in similar proportions of patients with genotype 1 and 4 [
      • Khattab M.A.
      • Abdel-Fattah M.E.
      • Eslam M.
      • Abdelaleem A.
      • Abdelaleem R.A.
      • Shatat M.
      • et al.
      Hepatic Steatosis in Genotype 4 Chronic Hepatitis C Patients: Implication for Therapy.
      ,
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manesis E.K.
      • Chrysanthos N.
      • Kafiri G.
      • Petraki K.
      • et al.
      Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors.
      ,
      • Sestre T.
      • Nkuize M.
      • Moucari R.
      • Van Gossum M.
      • Reynders M.
      • Scheen R.
      • et al.
      Metabolic disorders associated with chronic hepatitis C: impact of genotype and ethnicity.
      ]. Several studies have shown that steatosis in chronic HCV-4 is macrovesicular [
      • Khattab M.A.
      • Abdel-Fattah M.E.
      • Eslam M.
      • Abdelaleem A.
      • Abdelaleem R.A.
      • Shatat M.
      • et al.
      Hepatic Steatosis in Genotype 4 Chronic Hepatitis C Patients: Implication for Therapy.
      ,
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manesis E.K.
      • Chrysanthos N.
      • Kafiri G.
      • Petraki K.
      • et al.
      Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors.
      ,
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ] and is seen without any prominent zonal preference [
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ]. More detailed studies are needed to determine if there is a characteristic histological pattern that might distinguish chronic HCV-4. Efforts are ongoing to seek alternative means focusing on noninvasive blood marker panels. In a recent study, the combination of hyaluronic acid, YKL-40, platelet count and serum aminotransferases provided information about the amount of hepatic inflammation and steatosis in Egyptian patients and achieved this cost-effectively [
      • Esmat G.
      • Metwally M.
      • Zalata K.R.
      • Gadalla S.
      • Abdel-Hamid M.
      • Abouzied A.
      • et al.
      Evaluation of serum biomarkers of fibrosis and injury in Egyptian patients with chronic hepatitis C.
      ].

      Hepatocellular carcinoma

      HCC is a major cause of cancer death worldwide [
      • El-Serag H.B.
      Hepatocellular carcinoma: an epidemiologic view.
      ], with evidence that its incidence has sharply increased in many countries as a consequence of the accumulation of patients with chronic liver disease caused by viral hepatitis or alcohol abuse [
      • El-Serag H.B.
      Hepatocellular carcinoma: an epidemiologic view.
      ,
      • Colombo M.
      Screening and diagnosis of hepatocellular carcinoma.
      ]. The incidence of HCC in Egypt is also increasing [
      • El-Zayadi A.R.
      • Badran H.M.
      • Barakat E.M.
      • Attia Mel D.
      • Shawky S.
      • Mohamed M.K.
      • et al.
      Hepatocellular carcinoma in Egypt: a single center study over a decade.
      ,
      • Hassan M.M.
      • Zaghloul A.S.
      • El-Serag H.B.
      • Soliman O.
      • Patt Y.Z.
      • Chappell C.L.
      • et al.
      The role of hepatitis C in hepatocellular carcinoma: a case control study among Egyptian patients.
      ,
      • Strickland G.T.
      • Elhefni H.
      • Salman T.
      • Waked I.
      • Abdel-Hamid M.
      • Mikhail N.N.
      • et al.
      Role of hepatitis C infection in chronic liver disease in Egypt.
      ] and is now the second most frequent cause of cancer and cancer mortality among men [

      Freedman LS, Edwards BK, Ries LAG, Young JL, eds. Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the middle east cancer consortium (MECC) compared with US SEER. National Cancer Institute. Bethesda, MD: NIH Pub. No. 06-5873, 2006.

      ]. Hospital based studies have reported an increase in the relative frequency of all liver-related cancers in Egypt (>95% as HCC), from ∼4.0% in 1993 to 7.3% in 2003 [
      • El-Zayadi A.R.
      • Badran H.M.
      • Barakat E.M.
      • Attia Mel D.
      • Shawky S.
      • Mohamed M.K.
      • et al.
      Hepatocellular carcinoma in Egypt: a single center study over a decade.
      ,
      • Hassan M.M.
      • Zaghloul A.S.
      • El-Serag H.B.
      • Soliman O.
      • Patt Y.Z.
      • Chappell C.L.
      • et al.
      The role of hepatitis C in hepatocellular carcinoma: a case control study among Egyptian patients.
      ,
      • Strickland G.T.
      • Elhefni H.
      • Salman T.
      • Waked I.
      • Abdel-Hamid M.
      • Mikhail N.N.
      • et al.
      Role of hepatitis C infection in chronic liver disease in Egypt.
      ].
      Data from the National Cancer Registry of Egypt, the National Cancer Institute and the Middle East Cancer Consortium recently reported that the incidence rate among males was 7 times greater than the next highest rate (among Israeli Jews) and more than 3 times that reported in the United States Surveillance Epidemiology and End Results summary [

      Freedman LS, Edwards BK, Ries LAG, Young JL, eds. Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the middle east cancer consortium (MECC) compared with US SEER. National Cancer Institute. Bethesda, MD: NIH Pub. No. 06-5873, 2006.

      ,

      National Cancer Registry of Egypt. Magnitude of hepatocellular carcinoma in Egypt. Available at: http://www.nci.edu.eg. Accessed 6 August 2010.

      ].
      A possible association has been suggested between HCV-4 and HCC based on the similarity of distribution of HCC and HCV-4 in Egypt [

      Freedman LS, Edwards BK, Ries LAG, Young JL, eds. Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the middle east cancer consortium (MECC) compared with US SEER. National Cancer Institute. Bethesda, MD: NIH Pub. No. 06-5873, 2006.

      ,

      National Cancer Registry of Egypt. Magnitude of hepatocellular carcinoma in Egypt. Available at: http://www.nci.edu.eg. Accessed 6 August 2010.

      ,
      • Bhattacherjee V.
      • Prescott L.E.
      • Pike I.
      • Rodgers B.
      • Bell H.
      • El-Zayadi A.R.
      • et al.
      Use of NS-4 peptides to identify type specific antibody to hepatitis C virus genotypes 1, 2, 3, 4, 5 and 6.
      ,
      • Angelico M.
      • Renganathan E.
      • Gandin C.
      • Fathy M.
      • Profili M.C.
      • Refai W.
      • et al.
      Chronic liver disease in the Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections.
      ,
      • Kamal S.
      • Madwar M.
      • Bianchi L.
      • Tawil A.E.
      • Fawzy R.
      • Peters T.
      • et al.
      Clinical, virological and histopathological features: long-term follow-up in patients with chronic hepatitis C co-infected with S. mansoni.
      ,
      • Lehman E.M.
      • Wilson M.L.
      Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis.
      ]. A recent meta-analysis showed that more than 84% of Egyptian patients with HCC are positive for HCV-4 [
      • Lehman E.M.
      • Wilson M.L.
      Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis.
      ].
      A significant association seems to exist not only with the most prevalent subtype 4a, but also with subtype 4o [
      • Abdel-Hamid M.
      • El-Daly M.
      • Molnegren V.
      • El-Kafrawy S.
      • Abdel-Latif S.
      • Esmat G.
      • et al.
      Genetic diversity in hepatitis C virus in Egypt and possible association with hepatocellular carcinoma.
      ] even though this association has not been confirmed by others [
      • Ryu S.H.
      • Fan X.
      • Xu Y.
      • Elbaz T.
      • Zekri A.R.
      • Abdelaziz A.O.
      • et al.
      Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt.
      ]. Other factors related to HCC development may play a role, such as coinfection with schistosomiasis which is known to increase risk of HCC [
      • Hnatyszyn H.J.
      Chronic hepatitis C and genotyping: the clinical significance of determining HCV genotypes.
      ,
      • Angelico M.
      • Renganathan E.
      • Gandin C.
      • Fathy M.
      • Profili M.C.
      • Refai W.
      • et al.
      Chronic liver disease in the Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections.
      ], exposure to pesticides [
      • Ezzat S.
      • Abdel-Hamid M.
      • Eissa S.A.
      • Mokthar N.
      • Labib N.A.
      • El-Ghorory L.
      • et al.
      Associations of pesticides, HCV, HBV, and hepatocellular carcinoma in Egypt.
      ], and dietary aflatoxins [
      • Hifnawy M.S.
      • Mangoud A.M.
      • Eissa M.H.
      • Nor Edin E.
      • Mostafa Y.
      • Abouel-Magd Y.
      • et al.
      The role of aflatoxin-contaminated food materials and HCV in developing hepatocellular carcinoma in Al-Sharkia Governorate, Egypt.
      ].

      Evolution of treatment

      Combination therapy with pegylated interferon alpha and ribavirin represents the current standard of care in chronic HCV-4. Interferon (IFN) based therapies were introduced in chronic hepatitis C in the 1980s and have improved dramatically over the subsequent years. With conventional IFN-α monotherapy the SVR rates were very poor, similar to those achieved in HCV genotype 1 infection, ranging between 5% and 25% [
      • Zylberberg H.
      • Chaix M.L.
      • Brechot C.
      Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha.
      ,
      • El-Zayadi A.
      • Simmonds P.
      • Dabbous H.
      • Prescott L.
      • Selim O.
      • Ahdy A.
      Response to interferon-alpha of Egyptian patients infected with hepatitis C virus genotype 4.
      ]. However, with the addition of ribavirin to conventional IFN-α, SVR rates increased to 25–42% [
      • Hasan F.
      • Asker H.
      • Al-Khaldi J.
      • Siddique I.
      • Al-Ajmi M.
      • Owaid S.
      • et al.
      Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4.
      ,
      • Shobokshi O.A.
      • Serebour F.E.
      • Skakni L.
      • Al Khalifa M.
      Combination therapy of peginterferon alfa-2a and ribavirin significantly enhance sustained virological and biochemical response rate in chronic hepatitis C genotype 4 patients in Saudi Arabia.
      ], about intermediate between those achieved in HCV-1 and HCV-2 or HCV-3. With the introduction of pegylated IFN compounds in combination with ribavirin, the efficacy of treatment in HCV-4 further improved significantly. In various studies from European and Middle Eastern countries, SVR rates ranging from 43% to 70% were reported [
      • Roulot D.
      • Bourcier V.
      • Grando V.
      • Deny P.
      • Baazia Y.
      • Fontaine H.
      • et al.
      Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.
      ,
      • Moucari R.
      • Ripault M.P.
      • Martinot-Peignoux M.
      • Voitot H.
      • Cardoso A.C.
      • Stern C.
      • et al.
      Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.
      ,
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ,
      • Esmat G.
      • Abouzied A.M.
      • Abdel-Aziz F.
      • Strickland T.
      Subjects with chronic hepatitis C and genotype 4 have a similarly effective response to standard or pegylated interferon in combination with ribavirin.
      ,
      • Al Ali J.
      • Owayed S.
      • Al-Qabandi W.
      • Husain K.
      • Hasan F.
      Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents.
      ,
      • Khattab M.
      • Eslam M.
      • Sharwae M.A.
      • Shatat M.
      • Ali A.
      • Hamdy L.
      Insulin resistance predicts rapid virologic response to Peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients.
      ,
      • Khattab M.
      • Emad M.
      • Abdelaleem A.
      • Eslam M.
      • Atef R.
      • Shaker Y.
      • et al.
      Pioglitazone improves virological response to peginterferon alpha-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance.
      ,
      • El Makhzangy H.
      • Esmat G.
      • Said M.
      • Elraziky M.
      • Shouman S.
      • Refai R.
      • et al.
      Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4.
      ,
      • Dahlan Y.
      • Ather H.M.
      • Al-ahmadi M.
      • Batwa F.
      • Al-hamoudi W.
      Sustained virological response in a predominantly hepatitis C virus genotype 4 infected population.
      ,
      • Elefsiniotis I.S.
      • Vezali E.
      • Mihas C.
      • Saroglou G.
      Predictive value of complete and partial early virological response on sustained virological response rates of genotype-4 chronic hepatitis C patients treated with PEG-interferon plus ribavirin.
      ,
      • Varghese R.
      • Al-Khaldi J.
      • Asker H.
      • Fadili A.A.
      • Al Ali J.
      • Hassan F.A.
      Treatment of chronic hepatitis C genotype 4 with peginterferon alpha-2a plus ribavirin.
      ,
      • Rossignol J.F.
      • Elfert A.
      • El-Gohary Y.
      • Keeffe E.B.
      Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin.
      ,
      • Ferenci P.
      • Laferl H.
      • Scherzer T.M.
      • Gschwantler M.
      • Maieron A.
      • Brunner H.
      • et al.
      Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.
      ,

      Derbala MF, El Dweik NZ, Al Kaabi SR, Al-Marri AD, Pasic F, Bener AB, et al. Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: ribavirin therapy. J Viral Hepat. 2008 May 15.

      ,
      • Derbala M.F.
      • Al Kaabi S.R.
      • El Dweik N.Z.
      • Pasic F.
      • Butt M.T.
      • Yakoob R.
      • et al.
      Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.
      ,
      • El Zayadi A.R.
      • Attia M.
      • Barakat E.M.
      • Badran H.M.
      • Hamdy H.
      • El-Tawil A.
      • et al.
      Response of hepatitis C genotype-4 naive patients to 24 weeks of peg-interferon-a2b/ribavirin or induction-dose interferon a2b/ribavirin/ amantadine: a non-randomized controlled study.
      ,
      • Kamal S.M.
      • El Tawil A.A.
      • Nakano T.
      • He Q.
      • Rasenack J.
      • Hakam S.A.
      • et al.
      Peginterferon alpha-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response.
      ,
      • Thakeb F.A.I.
      • Omar M.M.
      • El Awadi M.M.
      • Isshak S.Y.
      Randomized controlled trial of peginterferon alpha-2a plus ribavirin for chronic hepatitis C virus genotype 4 among Egyptian patients.
      ,
      • Diago M.
      • Hassanein T.
      • Rodes J.
      • Ackrill A.M.
      • Sedarati F.
      Optimized virologic response in hepatitis C virus genotype 4 with peginterferon alpha2a and ribavirin.
      ,
      • Alfaleh F.Z.
      • Hadad Q.
      • Khuroo M.S.
      • Aljumah A.
      • Algamedi A.
      • Alashgar H.
      • et al.
      Peginterferon a-2b plus ribavirin compared with interferona-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.
      ] (Table 1). These results are indeed higher than those (42–46%) achieved in genotype 1 patients but still lower than those (76–82%) reported in chronic hepatitis C genotype 2 and 3.
      Table 1Summary of studies of PEG-IFN-α in patients with chronic HCV-4.
      Abbreviations: Wk: week, d: day, x: for treatment duration, HOMA-IR: homeostasis model assessment index NA: no available data, EVR, early virologic response; RVR: rapid virologic response, ETR: end of treatment response, PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response.
      Studies looking at predictive factors on HCV-4 patients are relatively scarce. Negative predictive factors at baseline include high viral load, presence of cirrhosis and steatosis, insulin resistance, IL-28B polymorphism TT, and HIV coinfection [
      • Esmat G.
      • Abouzied A.M.
      • Abdel-Aziz F.
      • Strickland T.
      Subjects with chronic hepatitis C and genotype 4 have a similarly effective response to standard or pegylated interferon in combination with ribavirin.
      ,
      • Derbala M.F.
      • Al Kaabi S.R.
      • El Dweik N.Z.
      • Pasic F.
      • Butt M.T.
      • Yakoob R.
      • et al.
      Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.
      ,
      • Hasan F.
      • Asker H.
      • Al-Khaldi J.
      • Siddique I.
      • Al-Ajmi M.
      • Owaid S.
      • et al.
      Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4.
      ,
      • Alfaleh F.Z.
      • Hadad Q.
      • Khuroo M.S.
      • Aljumah A.
      • Algamedi A.
      • Alashgar H.
      • et al.
      Peginterferon a-2b plus ribavirin compared with interferona-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.
      ,
      • Martín-Carbonero L.
      • Puoti M.
      • García-Samaniego J.
      • De Luca A.
      • Losada E.
      • Quinzan G.
      • et al.
      Response to pegylated interferon plus ribavirin in HIV infected patients with chronic hepatitis C due to genotype 4.
      ,
      • Rallón N.I.
      • Naggie S.
      • Benito J.M.
      • Medrano J.
      • Restrepo C.
      • Goldstein D.
      • et al.
      Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
      ]; these factors are associated with a lower SVR. A rather unexpected finding of the therapeutic trials in HCV-4 has been that under the same treatment regimen, patients from Egypt and the Middle East experienced higher SVR rates than patients from Europe or Africa. In a French retrospective study, conducted in 242 HCV-4 patients from various geographical areas (40% Egyptians, 35% Europeans, and 24% Africans) the respective SVR rates were 54.9%, 40.3%, and 32.4%. Egyptian origin and the absence of severe fibrosis were found to be independently associated with SVR [
      • Roulot D.
      • Bourcier V.
      • Grando V.
      • Deny P.
      • Baazia Y.
      • Fontaine H.
      • et al.
      Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.
      ]. It remains unclear whether the difference in SVR is related to ethnicity, HCV-G4 subtype, the mode of transmission or IL-28B genotype [
      • Rallón N.I.
      • Naggie S.
      • Benito J.M.
      • Medrano J.
      • Restrepo C.
      • Goldstein D.
      • et al.
      Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
      ].
      Similar results have recently been reported in a prospective study of HCV-4 patients from Europe, France, and Africa with respective SVR rates of 63%, 51%, and 39% and an overall SVR percentage of 54%. Despite the presence of severe fibrosis in a large proportion of the Egyptian patients, Egyptian origin was again independently associated with SVR (p = 0.001); OR: 5.87 (95% CI: 2.75–12.55) (p = 0.001). SVR was also independently associated with insulin resistance measured by the homeostasis model assessment index (HOMA-IR)<2 (p = 0.001) and by non-severe fibrosis (p = 0.001) [
      • Moucari R.
      • Ripault M.P.
      • Martinot-Peignoux M.
      • Voitot H.
      • Cardoso A.C.
      • Stern C.
      • et al.
      Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.
      ]. Moreover, in another trial from Egypt, HOMA-IR was found to be a predictor not only of SVR but also of rapid virologic response (RVR) (p= 0.002 and 0.0041; respectively) [
      • Khattab M.
      • Eslam M.
      • Sharwae M.A.
      • Shatat M.
      • Ali A.
      • Hamdy L.
      Insulin resistance predicts rapid virologic response to Peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients.
      ]. The use of insulin-sensitizing agents such as pioglitazone in conjunction with HCV-4 treatment increases both SVR and RVR rates [
      • Khattab M.
      • Emad M.
      • Abdelaleem A.
      • Eslam M.
      • Atef R.
      • Shaker Y.
      • et al.
      Pioglitazone improves virological response to peginterferon alpha-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance.
      ]. HCV kinetics under therapy has been found to be extremely useful to predict SVR [
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ,
      • Kamal S.M.
      • El Tawil A.A.
      • Nakano T.
      • He Q.
      • Rasenack J.
      • Hakam S.A.
      • et al.
      Peginterferon alpha-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response.
      ]. Other factors during treatment are patients’ compliance and no dosage reductions or dose fulfilled with 80/80/80 [
      • Kamal S.M.
      Hepatitis C genotype 4: increasing options and improving outcomes.
      ].

      IL28B polymorphism

      A genome wide association study in patients infected with HCV-1 revealed a single nucleotide polymorphism (SNP)-rs12979860 in the IL-28B region on chromosome 19 (19q13.13), associated with a more than twofold increased rate of SVR [

      Stättermayer AF, Stauber R, Hofer H, Rutter K, Beinhardt S, Scherzer TM, et al. Impact of the IL28B-genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2010 [Epub ahead of print].

      ]. In a multivariate analysis of HCV-4 patients, baseline viral load, fibrosis and the IL28 (rs8099917 T/T allele) (OR: 0.124, 95% CI: 0.030–0.505) were significantly associated with SVR [

      Stättermayer AF, Stauber R, Hofer H, Rutter K, Beinhardt S, Scherzer TM, et al. Impact of the IL28B-genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2010 [Epub ahead of print].

      ]. The strongest predictor for the final outcome was RVR (OR: 26.00; 95% CI: 7.148–94.545, p<0.0001). If RVR was included into the multivariate model, only the RVR and the fibrosis score remained significant. Thus, determination of IL28B polymorphism may not be useful to select patients with HCV-4 for abbreviated treatment schedules. However these data need further confirmation.

      Duration of treatment

      The duration of treatment is based on HCV genotype in current guidelines [
      • Dienstag J.L.
      • McHutchison J.G.
      American Gastroenterological Association technical review on the management of hepatitis C.
      ,

      APASL Consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. APASL Hepatitis C Working Party, et al. J Gastroenterol Hepatol 2007;22L615-33.

      ]. Forty-eight-week regimens are recommended for patients infected with HCV-1 and 4. This recommendation is based on the results of large randomized, international, phase III trials of peginterferon alfa-2 combined with ribavirin [
      • Hadziyannis S.J.
      • Sette Jr, H.
      • Morgan T.R.
      • Balan V.
      • Diago M.
      • Marcellin P.
      • et al.
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
      ,
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • Smith C.
      • Marinos G.
      • Gonçales Jr, F.L.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      ,
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • Rustgi V.K.
      • Shiffman M.
      • Reindollar R.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
      ]. Unfortunately these studies included very few patients with HCV-4.
      Measurement of the virological response at 4 and 12 weeks of therapy is a simple and reliable tool that allows the treatment regimen to be tailored to the individual. Patients who become HCV-RNA negative (<50 IU/ml by qualitative PCR assay) or have a ⩾2 log10 drop in serum HCV RNA level by quantitative PCR assay after 12 weeks of therapy are defined as having an early virological response (EVR). Failure to achieve an EVR can predict which patients are unlikely to have a successful outcome with combination therapy. Those who are HCV-RNA negative after 4 weeks of treatment are defined as having a RVR. In contrast to EVR, RVR predicts which patients are most likely to have a successful outcome with combination therapy.
      The probability of SVR increases with the speed of viral load decline. For example, a higher proportion of patients with HCV-1 who become HCV-RNA negative after 4 weeks of treatment will achieve an SVR than those who become HCV-RNA negative after 12 weeks of treatment [
      • Ferenci P.
      • Fried M.W.
      • Shiffman M.L.
      • Smith C.I.
      • Marinos G.
      • Gonçales Jr, F.L.
      • et al.
      Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.
      ]. SVR rates were much lower in patients who did not clear HCV RNA during the first 12 weeks of treatment. A completely negative test for HCV RNA at week 12 (complete EVR) is a better predictor of an SVR after 48 weeks of combination therapy than a partial EVR (⩾2 log10 drop in serum HCV RNA at week 12). Those who achieved an RVR had an SVR rate of 91%, those who achieved a complete EVR had an SVR rate of 75%, and among the 22% of patients with a partial EVR and virus negative by week 24 only 27% achieved an SVR [
      • Ferenci P.
      • Fried M.W.
      • Shiffman M.L.
      • Smith C.I.
      • Marinos G.
      • Gonçales Jr, F.L.
      • et al.
      Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.
      ].

      Response-guided therapy

      There are only two randomized controlled trials in patients with HCV-4 reporting viral response at week 4 (Table 2). Patients with HCV-4 who achieve an RVR are potential candidates for abbreviated 24-week treatment regimens; provided that no other predictors of poor response (Fig. 1). [
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ,
      • Ferenci P.
      • Laferl H.
      • Scherzer T.M.
      • Gschwantler M.
      • Maieron A.
      • Brunner H.
      • et al.
      Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.
      ]. Response rates are similar to those treated for 48 weeks [
      • El Zayadi A.R.
      • Attia M.
      • Barakat E.M.
      • Badran H.M.
      • Hamdy H.
      • El-Tawil A.
      • et al.
      Response of hepatitis C genotype-4 naive patients to 24 weeks of peg-interferon-a2b/ribavirin or induction-dose interferon a2b/ribavirin/ amantadine: a non-randomized controlled study.
      ]. The prospect of shorter treatment for these patients is appealing because the overall tolerability is likely to be better and the costs lower with an abbreviated treatment regimen; conversely, slow responders who do not achieve HCV RNA negativity by week 4 or 12 are potential candidates for prolonging treatment up to 72-weeks. Only one randomized study examined prolonged 72-week regimens in HCV4 patients [
      • Ferenci P.
      • Laferl H.
      • Scherzer T.M.
      • Andreas Maieron A.
      • Hofer H.
      • Stauber R.
      • et al.
      Peginterferon α-2a/ribavirin for 72 weeks reduces relapse among Hepatitis C type 1 and 4 patients with early virologic responses.
      ] but the number of patients was too small to draw any conclusions.
      Table 2Outcome by virological response at weeks 4 and 12 in genotype four patients treated for 48 weeks with peginterferon alfa-2 plus ribavirin.
      Abbreviations: EVR = early virological response (HCV RNA < 50 IU/ml or 2 log drop in viral load); RVR = rapid virological response (HCV RNA < 50 IU/ml); SVR = sustained virological response (HCV RNA < 50 IU/ml); Patients were treated for 24 weeks; ∗∗Patients were treated for 48 weeks or longer.
      Fig. 1 presents a proposed algorithm for treating patients with chronic HCV-4 based on the kinetics of viral response (response-guided therapy). In conclusion, measurement of RVR and complete/partial EVR is a simple and reliable tool that allows clinicians to estimate the likelihood of an SVR and to individualize the duration of treatment. Unfortunately, in contrast to patients with HCV-1 the concept of response-guided therapy has not been validated in patents with HCV-4. In the current absence of any firm data on HCV-4 patients, we suggest that similar response-guided approaches used in HCV-1 patients may be considered. Thus those with an RVR are highly likely to achieve SVR and are candidates for abbreviated, 24-week regimens. Patients with a complete EVR at week 12 have a high probability of achieving an SVR with a 48-week regimen. Patients with a partial (slow) EVR (no RVR and detectable HCV RNA but >2 log10 drop at week 12 and virus negative at week 24) may be considered for treatment prolongation to 72 weeks, if they can tolerate this.
      Figure thumbnail gr1
      Fig. 1A proposed algorithm for treating patients with chronic HCV-4 based on the kinetics of viral response (response-guided therapy). RVR, rapid viral response.

      Treatment in special populations

      Cirrhosis

      Treatment of compensated cirrhosis is a relevant issue since sustained HCV clearance is associated with a better survival, reduced HCC occurrence and absence of decompensation [
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • Bollani S.
      • Benvegnù L.
      • Mazzella G.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      ]. However, severity of liver fibrosis and HCV genotype are the two major determinants of SVR. The published data on the efficacy of Peg-IFN and ribavirin in cirrhotic patients infected by HCV-4 are limited (Table 3) [
      • Roulot D.
      • Bourcier V.
      • Grando V.
      • Deny P.
      • Baazia Y.
      • Fontaine H.
      • et al.
      Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.
      ,
      • Kamal S.M.
      • El Kamary S.S.
      • Shardell M.D.
      • Hashem M.
      • Ahmed I.N.
      • Muhammadi M.
      • et al.
      Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
      ,
      • El Makhzangy H.
      • Esmat G.
      • Said M.
      • Elraziky M.
      • Shouman S.
      • Refai R.
      • et al.
      Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4.
      ,
      • Ferenci P.
      • Laferl H.
      • Scherzer T.M.
      • Gschwantler M.
      • Maieron A.
      • Brunner H.
      • et al.
      Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.
      ,
      • Derbala M.F.
      • Al Kaabi S.R.
      • El Dweik N.Z.
      • Pasic F.
      • Butt M.T.
      • Yakoob R.
      • et al.
      Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.
      ,
      • Hasan F.
      • Asker H.
      • Al-Khaldi J.
      • Siddique I.
      • Al-Ajmi M.
      • Owaid S.
      • et al.
      Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4.
      ,
      • Derbala M.
      • Amer A.
      • Bener A.
      • Lopez A.C.
      • Omar M.
      • El Ghannam M.
      Pegylated interferon-alpha 2b-ribavirin combination in Egyptian patients with genotype 4 chronic hepatitis.
      ,
      • Males S.
      • Gad R.R.
      • Esmat G.
      • Abobakr H.
      • Anwar M.
      • Rekacewicz C.
      • et al.
      Serum alpha-fetoprotein level predicts treatment outcome in chronic hepatitis C.
      ,
      • Gad R.R.
      • Males S.
      • El Makhzangy H.
      • Shouman S.
      • Hasan A.
      • Attala M.
      • et al.
      Predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C.
      ,
      • Giannini E.G.
      • Basso M.
      • Savarino V.
      • Picciotto A.
      Predictive value of on-treatment response during full-dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension.
      ]. Overall the cumulative response rate is about 30% of treated patients, but this figure includes also incomplete cirrhosis, or F3, that probably overestimates the real treatment efficacy in cirrhotic patients.
      Table 3Summary of studies on combined therapy in HCV-4 patients with incomplete (F3) or complete (F4) cirrhosis.
      Abbreviations: Wk: week, d: day, n = number, PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response.

      HIV coinfection

      It has been reported that the prevalence of HCV-4 among HIV-infected individuals is at least 15% of all anti-HCV positive subjects [
      • Ramos B.
      • Núñez M.
      • Toro C.
      • Sheldon J.
      • García-Samaniego J.
      • Ríos P.
      • et al.
      Changes in the distribution of hepatitis C virus (HCV) genotypes over time in Spain according to HIV serostatus: implications for HCV therapy in HCV/HIV-coinfected patients.
      ]. Data derived from two trials showed that among 75 HIV-infected patients with HCV-4 treated with Peg-IFN alfa-2a plus ribavirin, only 21 (28.0%) achieved SVR [
      • Martín-Carbonero L.
      • Puoti M.
      • García-Samaniego J.
      • De Luca A.
      • Losada E.
      • Quinzan G.
      • et al.
      Response to pegylated interferon plus ribavirin in HIV infected patients with chronic hepatitis C due to genotype 4.
      ]. The major factor of low rate of response was related to premature treatment discontinuation due to severe adverse effects.

      Hemodialysis

      The prevalence of HCV infection in patients with end stage renal disease is highly variable ranging from 3% to 80% between different countries and centers [
      • Fabrizi F.
      • Poordad F.
      • Martin P.
      Hepatitis C infection and the patient with end-stage renal disease.
      ]. HCV-4 infected subjects have a shorter graft survival after kidney transplantation due to increased risk of severe infection and liver disease deterioration. As a consequence, the current recommendation is to give antiviral therapy before transplantation with the aim to eradicate the infection. However the use of Peg-IFN and ribavirin in dialysis patients is hampered by fairly frequent side-effects [
      • Bruchfeld A.
      • Lindahl K.
      • Reichard O.
      • Carlsson T.
      • Schvarcz R.
      Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.
      ]. Two recent meta-analyses have shown that the overall SVR after Peg-IFN with or without ribavirin was 40%, including 33% for genotype 1 [
      • Casanovas Taltavull T.
      • Baliellas Comellas C.
      • Cruzado Garrit J.M.
      Results of hepatitis C virus treatment in patients on hemodialysis: data from published meta-analyses in 2008.
      ]. No data on efficacy of combined therapy in patients infected by genotype 4 are available so far.

      Children/adolescents

      Combination therapy with Peg-IFN-alpha and ribavirin treatment is effective in children with chronic hepatitis C [
      • Wirth S.
      • Pieper-Boustani H.
      • Lang T.
      • Ballauff A.
      • Kullmer U.
      • Gerner P.
      • et al.
      Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C.
      ,
      • Jara P.
      • Hierro L.
      • de la Vega A.
      • Díaz C.
      • Camarena C.
      • Frauca E.
      • et al.
      Efficacy and safety of peginterferon-alpha2b and ribavirin combination therapy in children with chronic hepatitis C infection.
      ] with SVR rates across different genotypes comparable to adults. One study reported the results of Peg-IFN plus ribavirin treatment in 12 adolescents infected by genotype 4 [
      • Al Ali J.
      • Owayed S.
      • Al-Qabandi W.
      • Husain K.
      • Hasan F.
      Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents.
      ]. Nine patients (75%) achieved SVR suggesting that combination therapy is effective in this clinical context.

      Acute hepatitis C

      Scant data are available about the optimal treatment regimen in acute HCV-4 and demonstrated a high SVR with IFN-based therapies compared with no treatment [
      • Kamal S.M.
      • Moustafa K.N.
      • Chen J.
      • Fehr J.
      • Abdel Moneim A.
      • Khalifa K.E.
      • et al.
      Duration of peginterferon therapy in acute hepatitis C: a randomised trial.
      ,
      • Kamal S.M.
      • Ismail A.
      • Graham C.S.
      • He Q.
      • Rasenack J.W.
      • Peters T.
      • et al.
      ,
      • Kamal S.M.
      • Fouly A.E.
      • Kamel R.R.
      • Hockenjos B.
      • Al Tawil A.
      • Khalifa K.E.
      • et al.
      Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response.
      ]. The available clinical trails showed that acute hepatitis patients infected with HCV-4 have higher rates of SVR compared with HCV-1 infections. In one study [
      • Nomura H.
      • Sou S.
      • Tanimoto H.
      • Nagahama T.
      • Kimura Y.
      • Hayashi J.
      • et al.
      Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.
      ], an SVR was achieved in 60% and 88% of genotype 1 patients and in 93% and 100% of HCV-4 patients after 12 and 24 weeks of treatment, respectively [
      • Kamal S.M.
      • Moustafa K.N.
      • Chen J.
      • Fehr J.
      • Abdel Moneim A.
      • Khalifa K.E.
      • et al.
      Duration of peginterferon therapy in acute hepatitis C: a randomised trial.
      ].

      Thalassamia major

      Few data are available on the treatment of HCV-4 in patients with thalassamia. Current literature is lacking sufficient evidence about the use of PEG-IFN as monotherapy or in combination with ribavirin in thalassamic patients. Inati et al. evaluated in a randomized study [
      • Inati A.
      • Taher A.
      • Ghorra S.
      • Koussa S.
      • Taha M.
      • Aoun E.
      • et al.
      Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection.
      ] the safety and efficacy of PEG-IFN-α with or without ribavirin therapy in 20 patients with thalassamia and HCV-4. An SVR was achieved in (30% and 62.5%; p= 0.19) in the monotherapy and combination groups, respectively. They reported an increase in the transfusion requirements by 34% in the combination group (p= 0.08). In another study, Kamal et al. [

      Kamal S, Fouly A, Mohamed S, et al. Peginterferon alfa-2b therapy with and without ribavirin in patients with thalassemia: a randomized study. Presented at the 41st Annual Meeting of the European Association for the Study of the Liver, 26–30 April 2006, Austria Center, Vienna, Austria, abstract 585.

      ] reported that the overall SVR rates were (46% and 64%) with PEG-IFN alfa-2b vs. PEG-IFN alfa-2b plus ribavirin combination therapy, respectively. However, the reported adverse events were more frequent with combination therapy than with PEG-IFN alfa-2b alone.

      Liver transplantation

      End-stage liver disease secondary to HCV infection is the major indication for orthotopic liver transplantation (OLT) worldwide [
      • Terrault N.
      • Berenguer M.
      Treating Hepatitis C infection in liver transplant recipients.
      ]. The percentage of HCV-4 patients among recipients of OLT varies depending on the geographic location from around 29% in Saudi Arabia [
      • Al Sebayel M.
      • Khalaf H.
      • Al Sofayan M.
      • Al Saghier M.
      • Abdo A.
      • Al Bahili H.
      • et al.
      Experience with 122 consecutive liver transplant procedures at King Faisal Specialist Hospital and Research Center.
      ] to more than 90% in Egypt, [
      • Yosry A.
      • Esmat G.
      • El Serafy M.
      • Omar A.
      • Doss W.
      • Said M.
      • et al.
      Outcome of Living donor liver transplantation for Egyptian patients with hepatitis C (Genotype 4)-related cirrhosis.
      ] while it represents a relatively uncommon indication in the western world [
      • Wali M.H.
      • Heydtmann M.
      • Harrison R.F.
      • Gunson B.K.
      • Mutimer D.J.
      Outcome of liver transplantation for patients infected by hepatitis C including those infected by genotype 4.
      ,
      • Zekry A.
      • Whiting P.
      • Crawford D.
      • Angus P.
      • Jeffrey G.
      • Padbury R.
      • et al.
      Liver transplantation for HCV associated liver cirrhosis: Predictors of outcomes in a population with significant genotype 3 and 4 distribution.
      ].
      The natural history of HCV-4 re-infection after liver transplantation is inadequately described in the literature. Re-infection of the graft with HCV is universal after liver transplantation regardless of the genotype, leading to an accelerated course of liver injury in many cases [
      • Berenguer M.
      • Prieto M.
      • Rayon J.
      • Mora J.
      • Pastror M.
      • Ortiz V.
      • et al.
      Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation.
      ]. Most studies conducted worldwide have investigated disease recurrence in HCV genotypes 1, 2, and 3 [
      • Terrault N.
      • Berenguer M.
      Treating Hepatitis C infection in liver transplant recipients.
      ]. However, there are few reports on post-OLT recurrence of HCV-4.
      Four studies have been reported from liver transplant centers in Europe and Australia. Gane et al. reported on 14 patients with recurrent HCV-4 post-OLT and found that about 50% of these patients have progressive liver disease [
      • Gane E.
      • Portmann B.
      • Naoumov N.
      • Smith H.
      • Underhill Jm.
      • Donaldson O.
      • et al.
      Long term outcome of hepatitis C infection after liver transplantation.
      ]. They also found that patients infected with genotypes 1b and 4 had the worst outcomes, while genotype 2 and 3 patients had less severe disease recurrence. Similarly, an analysis of 182 patients transplanted for HCV in Australia and New Zealand (16 of whom had HCV-4) found that among the many factors studied in univariate and multivariate analyses, genotype 4 was associated with an increased risk for re-transplantation and death [
      • Zekry A.
      • Whiting P.
      • Crawford D.
      • Angus P.
      • Jeffrey G.
      • Padbury R.
      • et al.
      Liver transplantation for HCV associated liver cirrhosis: Predictors of outcomes in a population with significant genotype 3 and 4 distribution.
      ]. By contrast, a study from another Australian center, including patients with HCV-4, showed that genotype 1b, but not 4, was associated with higher recurrence rates after transplantation [
      • Sugo H.
      • Balderson G.A.
      • Crawford D.H.
      • Fawcett J.
      • Lynch S.V.
      • Strong R.W.
      • et al.
      The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation.
      ]. In a more detailed study from the UK, 32 of 128 patients who underwent OLT for hepatitis C were infected with HCV-4 [
      • Wali M.H.
      • Heydtmann M.
      • Harrison R.F.
      • Gunson B.K.
      • Mutimer D.J.
      Outcome of liver transplantation for patients infected by hepatitis C including those infected by genotype 4.
      ]. A statistically significant greater fibrosis progression rate was observed in HCV-4 patients compared to non-genotype-4, although their rates of survival were similar. The authors attributed the difference between these two groups to the significantly older donor age in the HCV-4 group and the ethnic background of these patients (predominantly Egyptian). On the other hand, studies from the Middle East show a more favorable outcome of HCV-4 patients. In a study from Saudi Arabia on biopsy proven recurrence HCV post-OLT there were no significant differences between genotype 1 and 4 patients in terms of epidemiological, clinical, and histological factors as well as outcome (patients and graft survival) [
      • Mudawi H.
      • Helmy A.
      • Khalaf H.
      • Al Bahili H.
      • Al Shiek Y.
      • Medhat Y.
      • et al.
      Recurrence of hepatitis C virus genotype-4 infection following liver transplantation.
      ]. Among many epidemiologic, laboratory, virologic factors included in that analysis, the only factor predictive of an advanced histological score was the HCV RNA level at the time of biopsy.
      In Egyptian studies of living-related liver transplantation of HCV-4 patients a similar good outcome was observed. HCV clinical recurrence was observed in 31% of patients and was mostly mild, as 91% of patients had fibrosis scores less than F2 [
      • Yosry A.
      • Abdel-Rahman M.
      • Esmat G.
      • El Serafy M.
      • Omar A.
      • Doss W.
      • et al.
      Recurrence of Hepatitis C virus (Genotype 4) infection after living-donor liver transplant in Egyptian patients.
      ]. After 36 months of follow-up, 91% of patients were alive with good graft function. Similar to the study from Saudi Arabia, recurrent HCV was associated with pre-transplant and post-transplant viral load and to the presence of antibodies to hepatitis B core antigen.
      Published studies on the response rates and outcome of antiviral therapy in patients with HCV-4 post-OLT are lacking. In an abstract from Saudi Arabia, 25 patients infected with HCV-4 were treated with PEG-IFN alfa-2a at a dose of 180 μg/week plus ribavirin 800 mg/day, (dose was adjusted as tolerated range 400–1200 mg) [

      Al Hamoudi W, Mohamed H, Kamel Y, Abaalkail F, Al Masri N, Khalaf H, et al. Pegylated Interferon alfa-2a and ribavirin for the treatment of genotype-4 recurrent hepatitis C after liver transplantation. Hepatol Int. 2010;4:S25.

      ]. Fourteen patients (56%) achieved sustained virological response (SVR). The results of this study suggest that the post-transplant treatment outcome in HCV-4 is probably better then genotype 1 and less favorable than genotypes 2 and 3. This response pattern among the different genotypes parallels the response pattern in the immunocompetent population.
      More studies are warranted to further understand HCV4 and OLT and to establish effective strategies for limiting the progression of liver disease post-OLT in HCV-4 patients.

      Novel treatments

      In spite of the improvement of chronic hepatitis C treatment over the last two decades, treatment with PEG-IFN and ribavirin is still associated with frequent and sometimes severe side effects and many patients cannot be treated because of contraindications [
      • Manns M.P.
      • Wedemeyer H.
      • Cornberg M.
      Treating viral hepatitis C: efficacy, side effects, and complications.
      ]. A major step forward in the therapy of HCV infection is expected by the approval of new direct inhibitors of HCV replication. Several compounds, mainly inhibitors of the HCV NS3/4A protease and NS5B polymerase, are currently in phase II and III trials and the first HCV protease inhibitors will hopefully be licensed in 2011–2012. [
      • Mederacke I.
      • Wedemeyer H.
      • Manns M.P.
      Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection.
      ,
      • Manns M.P.
      • Foster G.R.
      • Rockstroh J.K.
      • Zeuzem S.
      • Zoulim F.
      • Houghton M.
      The way forward in HCV treatment – finding the right path.
      ]. The large majority of the new antiviral drugs are currently developed only for HCV-1 infection. The most advanced compounds in clinical development are two protease inhibitors: telaprevir (VX950) and boceprevir (SCH503034). Telaprevir has shown an improvement of SVR rates in treatment naive HCV-1 patients to almost 70% and up to 40% in previously unresponsive patients [
      • McHutchison J.G.
      • Everson G.T.
      • Gordon S.C.
      • Jacobson I.M.
      • Sulkowski M.
      • Kauffman R.
      • et al.
      Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.
      ,
      • McHutchison J.G.
      • Manns M.P.
      • Muir A.J.
      • Terrault N.A.
      • Jacobson I.M.
      • Afdhal N.H.
      • et al.
      Telaprevir for previously treated chronic HCV infection.
      ]. In a proof of concept study, telaprevir has also shown activity against HCV-4 during 15 days monotherapy or combination with Peg-IFN and RBV compared to Peg-IFN, RBV and placebo [
      • McHutchison J.G.
      • Manns M.P.
      • Muir A.J.
      • Terrault N.A.
      • Jacobson I.M.
      • Afdhal N.H.
      • et al.
      Telaprevir for previously treated chronic HCV infection.
      ]. Boceprevir is effective in HCV-1 patients [
      • Benhamou Y.
      • Moussalli J.
      • Ratziu V.
      • Lebray P.
      • Gysen V.
      • de Backer K.
      • et al.
      ], however, preclinical data suggests, that boceprevir might not be effective in HCV-4 with the currently used dosages [
      • Seiwert S.D.
      • Andrews S.W.
      • Jiang Y.
      • Serebryany V.
      • Tan H.
      • Kossen K.
      • et al.
      Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).
      ], and data on boceprevir in HCV-4 patients haves not been published. R7128 is another nucleoside analog polymerase inhibitor that has demonstrated potent antiviral activity. In a recent interim analysis at week 12; the combination of R7128 (1500 mg twice daily) plus Peg-IFN α-2a and ribavirin in treatment-naive patients with HCV-1 and 4; R7 128 has show high rates of early viral response with promising safety profiles and low rates of resistance or breakthrough [

      Jensen DM, Wedemeyer H, Herring RW, Ferenci P, Ma MM, Zeuzem S, et al. High rates of early viral response, promising safety profile and lack of resistance related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12interim analysis from the PROPEL study. AASLD 2010.

      ].
      Further data haves been published for two other compounds with different mode of actions, nitazoxanide (NTZ) and Debio 025. NTZ, a synthetic antiprotozoal agent, is licensed in the United States for the treatment of infections with Cryptosporidium parvum and Giardia lamblia. Antiviral properties of this compound were discovered when patients with acquired immune deficiency syndrome (AIDS) coinfected with hepatitis B and C were treated for cryptosporidiosis. As a potential mechanism of action, NTZ activates the protein kinase activated by double-stranded RNA (PKR), a key kinase that regulates the cell’s innate antiviral response [
      • Elazar M.
      • Liu M.
      • McKenna S.A.
      • Liu P.
      • Gehrig E.A.
      • Puglisi J.D.
      • et al.
      The anti-hepatitis C agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2alpha via protein kinase activated by double-stranded RNA activation.
      ]. These observations could explain the clinical antiviral effect of NTZ. In this context, two clinical studies are of interest. A pilot trial explored NTZ monotherapy in Egyptian hepatitis C patients infected with HCV-4. HCV-RNA became undetectable in seven out of 23 patients who all had a rather low viral load before treatment (⩽400,000 IU/ml). Interestingly, four patients achieved SVR after 24 weeks of NTZ treatment [
      • Rossignol J.F.
      • Kabil S.M.
      • El Gohary Y.
      • Elfert A.
      • Keeffe E.B.
      Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4.
      ]. A recent study by Rossignol et al. explored the combination of NTZ and standard PEG-IFN/RBV combination therapy in Egyptian HCV-4 infected patients [
      • Rallón N.I.
      • Naggie S.
      • Benito J.M.
      • Medrano J.
      • Restrepo C.
      • Goldstein D.
      • et al.
      Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
      ]. The trial was conducted in two Egyptian centers and included 96 treatment-naïve patients – all were infected with HCV-4. Patients were randomized in one of three arms, a control arm with Peg-IFN alfa-2a and ribavirin for 48 weeks (n = 40), and two arms with a 12 week lead-in monotherapy with NTZ followed by a 36 week course of NTZ in combination with pegylated interferon with (n = 28) or without ribavirin (n = 28). SVR rates in the control arm were only 50%, which is relatively low as compared to most other previous HCV-4 trials [
      • Khuroo M.S.
      • Khuroo M.S.
      • Dahab S.T.
      Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4.
      ]. Importantly, 79% of the patients receiving triple therapy with NTZ and PEG-IFN/RBV achieved a SVR that reached statistical significance although patients in the triple therapy arm were treated for only 36 weeks with PEG-IFN. Of note, patients receiving NTZ and PEG-IFN without RBV also showed a surprisingly high SVR of 61%. Although these data are promising, several issues need to be considered, for example the rather small overall number of patients with only five of the 96 patients having advanced fibrosis or cirrhosis (Ishak S F4-6) [
      • Mederacke I.
      • Wedemeyer H.
      Nitazoxanide for the treatment of chronic hepatitis C New opportunities but new challenges?.
      ]. In addition, there were some differences in patient characteristics between the study arms as the body mass index (BMI) was significantly lower in patients who received PEG-IFN, RBV, and NTZ as compared to the control group. This also could have contributed to the better response in the triple therapy arm although the BMI was not an independent factor associated with SVR. Nevertheless, it is quite obvious that further studies are needed to investigate NTZ in genotype 4 patients. The antiviral efficacy of NTZ was confirmed during the 12 week lead-in phase when NTZ was administered alone. NTZ induced a modest but significant HCV-RNA decline of −0.27 log10, which is in line with the previous monotherapy study [
      • Rallón N.I.
      • Naggie S.
      • Benito J.M.
      • Medrano J.
      • Restrepo C.
      • Goldstein D.
      • et al.
      Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
      ]. However, only two out of 53 patients treated with NTZ monotherapy had a decline of more than 1 log10 and just one patient achieved a complete response (HCV-RNA negative) after 12 weeks, which is in contrast to a previous trial where six out of 23 patients (26%) were HCV-RNA-negative after 12 weeks [
      • Mederacke I.
      • Wedemeyer H.
      Nitazoxanide for the treatment of chronic hepatitis C New opportunities but new challenges?.
      ]. Thus, it is very unlikely that NTZ monotherapy will play any role in future treatment of chronic hepatitis C.
      The cyclophilin inhibitior Debio 025 inhibits HCV replication by inhibiting endogenous cyclophilin and interaction with the NS5B polymerase, but without immunosuppressive activity. For treatment-naïve HCV-1 monoinfected patients a reduction of HCV-RNA of up to 4.75 log10 after 29 days of combination therapy with Debio 025, PEG-IFN alfa-2a, and ribavirin was shown [
      • Flisiak R.
      • Feinman S.V.
      • Jablkowski M.
      • Horban A.
      • Kryczka W.
      • Pawlowska M.
      • et al.
      The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients.
      ]. Two HCV-4 patients were treated underin this study, one of them ose in a Debio 025 monotherapy arm. With a dose of 1000 mg per day the mean viral load reduction after 29 days was 2.2 ± 2.4 log10 for the 12 patients in that arm (11 patients with genotype 1, one with HCV-4). Importantly, the one genotype-4 patient also had a viral load decline of >2 log10 [
      • Flisiak R.
      • Feinman S.V.
      • Jablkowski M.
      • Horban A.
      • Kryczka W.
      • Pawlowska M.
      • et al.
      The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients.
      ]. Finally, silibinin, for which the mechanism of action is not yet entirely resolved, administered intravenously (20 mg/kg/day) for 7 days, led to a mean decline of the HCV-RNA concentration by 3 log10 IU/ml. So far, mainly genotype 1 and single patients with genotype 2, 3, and 4 infections have been investigated and no data on differences of antiviral activities for the different HCV genotypes are available [
      • Ferenci P.
      • Scherzer T.M.
      • Kerschner H.
      • Rutter K.
      • Beinhardt S.
      • Hofer H.
      • et al.
      Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.
      ]. Recently, Beinhardt et al. reported a case that the use of silibinin IV are associated with prevention of graft re-infection in a patient infected with mixed genotype 1a/4. [

      Beinhardt S, Rasoul-Rockenschaub S, Matthias Scherzer T, Ferenci P. Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in patient with chronic hepatitis C. J Hepatol. 2010; in press.

      ].
      The available data on NTZ is are promising, but has need to be confirmed in larger studies. Other new compounds have been shown to suppress viral load in HCV-4 patients in proof-of-concept studies. Further larger trials on the combination of new compounds with PEG-IFN and RBV are needed to explore the beneficial effect in terms of SVR improvement in patients with HCV-4.

      Conclusions

      In recent years the study of HCV kinetics under therapy has been found to be extremely useful to guide the appropriate duration of therapy, motivate the patient and improve the cost/effectiveness of treatment. By the application of the RVR, as well as of the complete (cEVR) and partial early responses (pEVR), the duration of therapy can be individualized between 24 and 48 weeks. In this context it has become clear that in HCV genotype 4 – similar to genotype 1, 2, and 3 – a response guided duration of combination therapy is becoming the current standard of care.
      Figure thumbnail fx4
      Figure thumbnail fx5

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Acknowledgements

      The authors thanks Dr. Ingmar Mederacke, from Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, Roberta D’Ambrosio and Dr. Massimo Lavarone from First Division of Gastroenterology, Department of Medicine, Università degli Studi di Milano, Milan, Italy, Guillaume Geri from Service de Médecine Interne II, AP-HP, Hôpital Pitié-Salpêtrière; Université Pierre et Marie Curie-Paris 6, Paris, F-75013 France and Alessio Aghemo from First Division of Gastroenterology, Department of Medicine, Università degli Studi di Milano, Milan, Italy, for their assistance in the preparation of this manuscript.

      References

        • Ogata N.
        • Alter H.J.
        • Miller R.H.
        • Purcell R.H.
        Nucleotide sequence and mutation rate of the H strain of hepatitis C virus.
        Proc Natl Acad Sci USA. 1991; 88: 3392-3396
        • Simmonds P.
        • Alberti A.
        • Alter H.J.
        • Bonino F.
        • Bradley D.W.
        • Brechot C.
        • et al.
        A proposed system for the nomenclature of hepatitis C viral genotypes.
        Hepatology. 1994; 19: 1321-1324
        • Kuiken C.
        • Simmonds P.
        Nomenclature and numbering of the hepatitis C virus.
        Methods Mol Biol. 2009; 510: 33-53
        • Hnatyszyn H.J.
        Chronic hepatitis C and genotyping: the clinical significance of determining HCV genotypes.
        Antiviral Ther. 2005; 10: 1-11
      1. World Health Organization. Hepatitis C. Geneva, Switzerland: World Health Organization, 2000 WHO fact sheet 164. Available at http://www.who.int/mediacentre/factsheets/fs164/en/print.html. Accessed 1 August 2010.

        • Nguyen M.H.
        • Keeffe E.B.
        Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6.
        Clin Gastroenterol Hepatol. 2005; 3: S97-S101
      2. Egyptian Ministry of Health. Egyptian Ministry of Health Annual Report: 2007. Available at http://www.mohp.gov. eg/Main.asp (accessed 6 July 2010).

        • Abdel-Aziz F.
        • Habib M.
        • Mohamed M.K.
        • Abdel-Hamid M.
        • Gamil F.
        • Madkour S.
        • et al.
        Hepatitis C virus (HCV) infection in a community in the Nile Delta: population description and HCV prevalence.
        Hepatology. 2000; 32: 111-115
        • Elkady A.
        • Tanaka Y.
        • Kurbanov F.
        • Sugauchi F.
        • Sugiyama M.
        • Khan A.
        • et al.
        Genetic variability of hepatitis C virus in South Egypt and its possible clinical implication.
        J Med Virol. 2009; 81: 1015-1023
        • Frank C.
        • Mohamed M.K.
        • Strickland G.T.
        • Lavanchy D.
        • Arthur R.R.
        • Magder L.S.
        • et al.
        The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt.
        Lancet. 2000; 355: 887-912
        • Tanaka Y.
        • Agha S.
        • Saudy N.
        • Kurbanov F.
        • Orito E.
        • Kato T.
        • et al.
        Exponential spread of hepatitis C virus genotype 4a in Egypt.
        J Mol Evol. 2004; 58: 191-195
        • Stoszek S.K.
        • Abdel-Hamid M.
        • Narooz S.
        • El Daly M.
        • Saleh D.A.
        • Mikhail N.
        • et al.
        Prevalence of and risk factors for hepatitis C in rural pregnant Egyptian women.
        Trans R Soc Trop Med Hyg. 2006; 100: 102-107
        • El Katsha S.
        • Labeeb S.
        • Watts S.
        • Younis A.
        Informal health providers and the transmission of hepatitis C virus: pilot study in two Egyptian villages.
        East Mediterr Health J. 2006; 12: 758-767
        • Talaat M.
        • Kandeel A.
        • El-Shoubary W.
        • Bodenschatz C.
        • Khairy I.
        • Oun S.
        • et al.
        Occupational exposure to needlestick injuries and hepatitis B vaccination coverage among health care workers in Egypt.
        Am J Infect Control. 2003; 31: 469-474
        • Magder L.S.
        • Fix A.D.
        • Mikhail N.N.
        • Mohamed M.K.
        • Abdel-Hamid M.
        • Abdel-Aziz F.
        • et al.
        Estimation of the risk of transmission of hepatitis C between spouses in Egypt based on seroprevalence data.
        Int J Epidemiol. 2005; 34: 160-165
        • Mohamed M.K.
        • Abdel-Hamid M.
        • Mikhail N.N.
        • Abdel-Aziz F.
        • Medhat A.
        • Magder L.S.
        • et al.
        Intrafamilial transmission of hepatitis C in Egypt.
        Hepatology. 2005; 42: 683-687
        • Al-Faleh F.Z.
        Changing pattern of hepatitis viral infection in Saudi Arabia in the last two decades.
        Ann Saudi Med. 2003; 23: 367-371
        • Sharara A.I.
        • Ramia S.
        • Ramlawi F.
        • Fares J.E.
        • Klayme S.
        • Naman R.
        Genotypes of hepatitis C virus (HCV) among Lebanese patients: comparison of data with that from other middle Eastern countries.
        Epidemiol Infect. 2007; 135: 427-432
        • Antaki N.
        • Haddad M.
        • Kebbewar K.
        • Abdelwahab J.
        • Hamed O.
        • Aaraj R.
        • et al.
        The unexpected discovery of a focus of hepatitis C virus genotype 5 in a Syrian province.
        Epidemiol Infect. 2008; 17: 1-6
        • Bdour S.
        Hepatitis C virus infection in Jordanian hemodialysis units: serological diagnosis and genotyping.
        J Med Microbiol. 2002; 51: 700-704
        • Njouom R.
        • Nerrienet E.
        • Dubois M.
        • Lachenal G.
        • Rousset D.
        • Vessie‘re A.
        • et al.
        The hepatitis C virus epidemic in Cameroon: genetic evidence for rapid transmission between 1920 and 1960.
        Infect Genet Evol. 2007; 7: 361-367
        • Xu L.-Z.
        • Larzul D.
        • Delaporte E.
        • Br´echot C.
        • Kremsdorf D.
        Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon).
        J Gen Virol. 1994; 75: 2393-2398
        • Ndjomou J.
        • Pybus O.G.
        • Matz B.
        Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon.
        J Gen Virol. 2003; 84: 2333-2341
        • Wansbrough-Jones M.H.
        • Frimpong E.
        • Cant B.
        • Harris K.
        • Evans M.R.
        • Teo C.G.
        Prevalence and genotype of hepatitis C virus infection in pregnant women and blood donors in Ghana.
        Trans R Soc Tropical Med Hyg. 1998; 92: 496-499
        • Kamal S.
        • Nasser I.
        Hepatitis C genotype 4: what we know and what we don’t yet know.
        Hepatology. 2008; 47: 1371-1383
        • Esteban J.I.
        • Sauleda S.
        • Quer J.
        The changing epidemiology of hepatitis C virus infection in Europe.
        J Hepatol. 2008; 48: 148-162
        • Katsoulidou A.
        • Sypsa V.
        • Tassopoulos N.C.
        • Boletis J.
        • Karafoulidou A.
        • Ketikoglou I.
        • et al.
        Molecular epidemiology of hepatitis C virus (HCV) in Greece. temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates.
        J Viral Hepat. 2006; 13: 19-27
        • Payan C.
        • Roudot-Thoraval F.
        • Marcellin P.
        • Bled N.
        • Duverlie G.
        • Fouchard-Hubert I.
        • et al.
        Changing of hepatitis C virus genotype patterns in France at the beginning of the third millennium: the GEMHEP Geno CII Study.
        J Viral Hepat. 2005; 12: 405-413
        • Ansaldi F.
        • Bruzzone B.
        • Salamaso S.
        • Rota M.C.
        • Durando P.
        • Gasparini R.
        • et al.
        Different seroprelavence and molecular epidemiology pattern of hepatitis C virus infection in Italy.
        J Med Virol. 2005; 76: 327-332
        • Fernandez-Arcas N.
        • Lopez-Siles J.
        • Trapero S.
        • Ferraro A.
        • Ibanez A.
        • Orihuela F.
        • et al.
        High prevalence of hepatitis C virus subtypes 4c and 4d in Malaga (Spain): phylogenetic and epidemiological analyses.
        J Med Virol. 2006; 78: 1429-1435
        • Franco S.
        • Tural C.
        • Clotet B.
        • Martı´nez M.A.
        Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1.
        Virus Res. 2007; 123: 161-169
        • Nainan O.V.
        • Alter M.J.
        • Kruszon-Moran D.
        • Gao F.X.
        • Xia G.
        • McQuillan G.
        • et al.
        Hepatitis C genotypes and viral concentrations in participants of general population survey in the United States.
        Gastroenterology. 2006; 131: 478-484
        • Zein N.
        • Rakela J.
        • Krawitt E.
        • Reddy K.R.
        • Tominaga T.
        • Persing D.H.
        Hepatitis C virus genotypes in the United States: epidemiology, pathogenicity, and response to interferon therapy.
        Ann Int Med. 1996; 125: 634-639
        • Antaki N.
        • Craxì A.
        • Kamal S.M.
        • Moucari M.
        • Van der Merwe S.
        • Haffar S.
        • et al.
        The neglected hepatitis C virus genotype 4, 5 and 6: an international consensus report.
        Liver Int. 2010; 30: 342-355
        • Zakaria S.
        • Fouad R.
        • Shaker O.
        • Zaki S.
        • Hashem A.
        • El-Kamary S.S.
        • et al.
        Changing patterns of acute viral hepatitis at a major urban referral center in Egypt.
        Clin Infect Dis. 2007; 44: e30-e36
        • Micallef J.M.
        • Kaldor J.M.
        • Dore G.J.
        Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.
        J Viral Hepat. 2006; 13: 34-41
        • Kamal S.M.
        • Moustafa K.N.
        • Chen J.
        • Fehr J.
        • Abdel Moneim A.
        • Khalifa K.E.
        • et al.
        Duration of peginterferon therapy in acute hepatitis C: a randomised trial.
        Hepatology. 2006; 43: 923-931
        • Kamal S.M.
        • Rasenack J.W.
        • Bianchi L.
        • Al Tawil A.
        • El Sayed Khalifa K.
        • Peter T.
        • et al.
        Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4 (+) T-cell and cytokine response.
        Gastroenterology. 2001; 121: 646-656
        • Roulot D.
        • Bourcier V.
        • Grando V.
        • Deny P.
        • Baazia Y.
        • Fontaine H.
        • et al.
        Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection.
        J Viral Hepat. 2007; 14: 460-467
        • Moucari R.
        • Ripault M.P.
        • Martinot-Peignoux M.
        • Voitot H.
        • Cardoso A.C.
        • Stern C.
        • et al.
        Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.
        Gut. 2009; 59: 418
        • Gambotti L.
        • Batisse D.
        • Colin-de-Verdiere N.
        • Delaroque-Astagneau E.
        • Desenclos J.C.
        • Dominguez S.
        • et al.
        Acute Hepatitis C collaborating Group. Acute Hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001–2004.
        Euro Surveill. 2005; 10: 115-117
        • Kamal S.M.
        • Graham C.S.
        • He Q.
        • Bianchi L.
        • Tawil A.A.
        • Rasenack J.W.
        • et al.
        Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis.
        J Infect Dis. 2004; 189: 1140-1150
        • Kamal S.M.
        • Turner B.
        • He Q.
        • Rasenack J.
        • Bianchi L.
        • Al Tawil A.
        • et al.
        Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum marker of fibrosis.
        Hepatology. 2006; 43: 771-779
        • Abdel-Hamid M.
        • El-Daly M.
        • Molnegren V.
        • El-Kafrawy S.
        • Abdel-Latif S.
        • Esmat G.
        • et al.
        Genetic diversity in hepatitis C virus in Egypt and possible association with hepatocellular carcinoma.
        J Gen Virol. 2007; 88: 1526-1531
        • Abdel-Wahab M.
        • Mostafa M.
        • Sabry M.
        • el-Farrash M.
        • Yousef T.
        Aflatoxins as a risk factor for hepatocellular carcinoma in Egypt, Mansoura Gastroenterology Center study.
        Hepatogastroenterology. 2008; 55: 1754-1759
        • Anwar W.A.
        • Khaled H.M.
        • Amra H.A.
        • El-Nezami H.
        • Loffredo C.A.
        Changing pattern of hepatocellular carcinoma (HCC) and its risk factors in Egypt: possibilities for prevention.
        Mutat Res. 2008; 659: 176-184
        • Ezzat S.
        • Abdel-Hamid M.
        • Eissa S.A.
        • Mokthar N.
        • Labib N.A.
        • El-Ghorory L.
        • et al.
        Associations of pesticides, HCV, HBV, and hepatocellular carcinoma in Egypt.
        Int J Hyg Environ Health. 2005; 208: 329-339
        • Kleiner D.E.
        The liver biopsy in chronic hepatitis C: a view from the other side of the microscope.
        Semin Liver Dis. 2005; 25: 52-64
        • Asselah T.
        • Rubbia-Brandt L.
        • Marcellin P.
        • Negro F.
        Steatosis in chronic hepatitis C: why does it really matter?.
        Gut. 2006; 55: 123-130
        • Khattab M.A.
        • Abdel-Fattah M.E.
        • Eslam M.
        • Abdelaleem A.
        • Abdelaleem R.A.
        • Shatat M.
        • et al.
        Hepatic Steatosis in Genotype 4 Chronic Hepatitis C Patients: Implication for Therapy.
        J Clin Gastroenterol. 2010; 44: 707-712
        • Olynyk J.K.
        • Reddy K.R.
        • Di Bisceglie A.M.
        • Jeffers L.J.
        • Parker T.I.
        • Radick J.L.
        • et al.
        Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C.
        Gastroenterology. 1995; 108: 1104-1109
        • Tsochatzis E.
        • Papatheodoridis G.V.
        • Manesis E.K.
        • Chrysanthos N.
        • Kafiri G.
        • Petraki K.
        • et al.
        Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors.
        Am J Gastroenterol. 2007; 102: 634-641
        • Kamal S.M.
        • El Kamary S.S.
        • Shardell M.D.
        • Hashem M.
        • Ahmed I.N.
        • Muhammadi M.
        • et al.
        Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response.
        Hepatology. 2007; 46: 1732-1740
        • Sestre T.
        • Nkuize M.
        • Moucari R.
        • Van Gossum M.
        • Reynders M.
        • Scheen R.
        • et al.
        Metabolic disorders associated with chronic hepatitis C: impact of genotype and ethnicity.
        Liver Int. 2010; 30: 1131-1136
        • Lonardo A.
        • Loria P.
        • Adinolfi L.E.
        • Carulli N.
        • Ruggiero G.
        Hepatitis C and steatosis: a reappraisal.
        J Viral Hepat. 2006; 13: 73-80
        • Negro F.
        • Sanyal A.J.
        Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data.
        Liver Int. 2009; 29: 26-37
        • Esmat G.
        • Metwally M.
        • Zalata K.R.
        • Gadalla S.
        • Abdel-Hamid M.
        • Abouzied A.
        • et al.
        Evaluation of serum biomarkers of fibrosis and injury in Egyptian patients with chronic hepatitis C.
        J Hepatol. 2007; 46: 620-627
        • El-Serag H.B.
        Hepatocellular carcinoma: an epidemiologic view.
        J Clin Gastroenterol. 2002; 35: S72-S78
        • Colombo M.
        Screening and diagnosis of hepatocellular carcinoma.
        Liver Int. 2009; 29: 143-147
        • El-Zayadi A.R.
        • Badran H.M.
        • Barakat E.M.
        • Attia Mel D.
        • Shawky S.
        • Mohamed M.K.
        • et al.
        Hepatocellular carcinoma in Egypt: a single center study over a decade.
        World J Gastroenterol. 2005; 11: 5193-5198
        • Hassan M.M.
        • Zaghloul A.S.
        • El-Serag H.B.
        • Soliman O.
        • Patt Y.Z.
        • Chappell C.L.
        • et al.
        The role of hepatitis C in hepatocellular carcinoma: a case control study among Egyptian patients.
        J Clin Gastroenterol. 2001; 33: 123-126
        • Strickland G.T.
        • Elhefni H.
        • Salman T.
        • Waked I.
        • Abdel-Hamid M.
        • Mikhail N.N.
        • et al.
        Role of hepatitis C infection in chronic liver disease in Egypt.
        Am J Trop Med Hyg. 2002; 67: 436-442
      3. Freedman LS, Edwards BK, Ries LAG, Young JL, eds. Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the middle east cancer consortium (MECC) compared with US SEER. National Cancer Institute. Bethesda, MD: NIH Pub. No. 06-5873, 2006.

      4. National Cancer Registry of Egypt. Magnitude of hepatocellular carcinoma in Egypt. Available at: http://www.nci.edu.eg. Accessed 6 August 2010.

        • Bhattacherjee V.
        • Prescott L.E.
        • Pike I.
        • Rodgers B.
        • Bell H.
        • El-Zayadi A.R.
        • et al.
        Use of NS-4 peptides to identify type specific antibody to hepatitis C virus genotypes 1, 2, 3, 4, 5 and 6.
        J Gen Virol. 1995; 76: 1737-1748
        • Angelico M.
        • Renganathan E.
        • Gandin C.
        • Fathy M.
        • Profili M.C.
        • Refai W.
        • et al.
        Chronic liver disease in the Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections.
        J Hepatol. 1997; 26: 236-243
        • Kamal S.
        • Madwar M.
        • Bianchi L.
        • Tawil A.E.
        • Fawzy R.
        • Peters T.
        • et al.
        Clinical, virological and histopathological features: long-term follow-up in patients with chronic hepatitis C co-infected with S. mansoni.
        Liver. 2000; 20: 281-289
        • Lehman E.M.
        • Wilson M.L.
        Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis.
        Int J Cancer. 2009; 124: 690-697
        • Ryu S.H.
        • Fan X.
        • Xu Y.
        • Elbaz T.
        • Zekri A.R.
        • Abdelaziz A.O.
        • 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
        • Hifnawy M.S.
        • Mangoud A.M.
        • Eissa M.H.
        • Nor Edin E.
        • Mostafa Y.
        • Abouel-Magd Y.
        • et al.
        The role of aflatoxin-contaminated food materials and HCV in developing hepatocellular carcinoma in Al-Sharkia Governorate, Egypt.
        J Egypt Soc Parasitol. 2004; 34: 479-488
        • Zylberberg H.
        • Chaix M.L.
        • Brechot C.
        Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha.
        Ann Intern Med. 2000; 132: 845-846
        • El-Zayadi A.
        • Simmonds P.
        • Dabbous H.
        • Prescott L.
        • Selim O.
        • Ahdy A.
        Response to interferon-alpha of Egyptian patients infected with hepatitis C virus genotype 4.
        J Viral Hepat. 1996; 3: 261-264
        • Hasan F.
        • Asker H.
        • Al-Khaldi J.
        • Siddique I.
        • Al-Ajmi M.
        • Owaid S.
        • et al.
        Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4.
        Am J Gastroenterol. 2004; 99: 1733-1737
        • Shobokshi O.A.
        • Serebour F.E.
        • Skakni L.
        • Al Khalifa M.
        Combination therapy of peginterferon alfa-2a and ribavirin significantly enhance sustained virological and biochemical response rate in chronic hepatitis C genotype 4 patients in Saudi Arabia.
        Hepatology. 2003; 38 ([Abstract]): 996A
        • Esmat G.
        • Abouzied A.M.
        • Abdel-Aziz F.
        • Strickland T.
        Subjects with chronic hepatitis C and genotype 4 have a similarly effective response to standard or pegylated interferon in combination with ribavirin.
        Hepatology. 2003; 38 ([Abstract]): 324A
        • Al Ali J.
        • Owayed S.
        • Al-Qabandi W.
        • Husain K.
        • Hasan F.
        Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents.
        Ann Hepatol. 2010; 9: 156-160
        • Khattab M.
        • Eslam M.
        • Sharwae M.A.
        • Shatat M.
        • Ali A.
        • Hamdy L.
        Insulin resistance predicts rapid virologic response to Peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients.
        Am J Gastroenterol. 2010; 105: 1970-1977
        • Khattab M.
        • Emad M.
        • Abdelaleem A.
        • Eslam M.
        • Atef R.
        • Shaker Y.
        • et al.
        Pioglitazone improves virological response to peginterferon alpha-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance.
        Liver Int. 2010; 30: 447-454
        • El Makhzangy H.
        • Esmat G.
        • Said M.
        • Elraziky M.
        • Shouman S.
        • Refai R.
        • et al.
        Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4.
        J Med Virol. 2009; 81: 1576-1583
        • Dahlan Y.
        • Ather H.M.
        • Al-ahmadi M.
        • Batwa F.
        • Al-hamoudi W.
        Sustained virological response in a predominantly hepatitis C virus genotype 4 infected population.
        World J Gastroenterol. 2009; 15: 4429-4433
        • Elefsiniotis I.S.
        • Vezali E.
        • Mihas C.
        • Saroglou G.
        Predictive value of complete and partial early virological response on sustained virological response rates of genotype-4 chronic hepatitis C patients treated with PEG-interferon plus ribavirin.
        Intervirology. 2009; 52: 247-251
        • Varghese R.
        • Al-Khaldi J.
        • Asker H.
        • Fadili A.A.
        • Al Ali J.
        • Hassan F.A.
        Treatment of chronic hepatitis C genotype 4 with peginterferon alpha-2a plus ribavirin.
        Hepatogastroenterology. 2009; 56: 218-222
        • Rossignol J.F.
        • Elfert A.
        • El-Gohary Y.
        • Keeffe E.B.
        Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin.
        Gastroenterology. 2009; 136: 856-862
        • Ferenci P.
        • Laferl H.
        • Scherzer T.M.
        • Gschwantler M.
        • Maieron A.
        • Brunner H.
        • et al.
        Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.
        Gastroenterology. 2008; 135: 451-458
      5. Derbala MF, El Dweik NZ, Al Kaabi SR, Al-Marri AD, Pasic F, Bener AB, et al. Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: ribavirin therapy. J Viral Hepat. 2008 May 15.

        • Derbala M.F.
        • Al Kaabi S.R.
        • El Dweik N.Z.
        • Pasic F.
        • Butt M.T.
        • Yakoob R.
        • et al.
        Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.
        World J Gastroenterol. 2006; 12: 5692-5698
        • El Zayadi A.R.
        • Attia M.
        • Barakat E.M.
        • Badran H.M.
        • Hamdy H.
        • El-Tawil A.
        • et al.
        Response of hepatitis C genotype-4 naive patients to 24 weeks of peg-interferon-a2b/ribavirin or induction-dose interferon a2b/ribavirin/ amantadine: a non-randomized controlled study.
        Am J Gastroenterol. 2005; 100: 2447-2452
        • Kamal S.M.
        • El Tawil A.A.
        • Nakano T.
        • He Q.
        • Rasenack J.
        • Hakam S.A.
        • et al.
        Peginterferon alpha-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response.
        Gut. 2005; 54: 858-866
        • Thakeb F.A.I.
        • Omar M.M.
        • El Awadi M.M.
        • Isshak S.Y.
        Randomized controlled trial of peginterferon alpha-2a plus ribavirin for chronic hepatitis C virus genotype 4 among Egyptian patients.
        Hepatology. 2003; 38 ([Abstract]): 252A
        • Diago M.
        • Hassanein T.
        • Rodes J.
        • Ackrill A.M.
        • Sedarati F.
        Optimized virologic response in hepatitis C virus genotype 4 with peginterferon alpha2a and ribavirin.
        Ann Intern Med. 2004; 140: 72-73
        • Alfaleh F.Z.
        • Hadad Q.
        • Khuroo M.S.
        • Aljumah A.
        • Algamedi A.
        • Alashgar H.
        • et al.
        Peginterferon a-2b plus ribavirin compared with interferona-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.
        Liver Int. 2004; 24: 568-574
        • Martín-Carbonero L.
        • Puoti M.
        • García-Samaniego J.
        • De Luca A.
        • Losada E.
        • Quinzan G.
        • et al.
        Response to pegylated interferon plus ribavirin in HIV infected patients with chronic hepatitis C due to genotype 4.
        J Viral Hepat. 2008; 15: 710-715
        • Rallón N.I.
        • Naggie S.
        • Benito J.M.
        • Medrano J.
        • Restrepo C.
        • Goldstein D.
        • et al.
        Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
        AIDS. 2010; 24: F23-F29
        • Kamal S.M.
        Hepatitis C genotype 4: increasing options and improving outcomes.
        Liver Int. 2009; 29: 39-48
      6. Stättermayer AF, Stauber R, Hofer H, Rutter K, Beinhardt S, Scherzer TM, et al. Impact of the IL28B-genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2010 [Epub ahead of print].

        • Dienstag J.L.
        • McHutchison J.G.
        American Gastroenterological Association technical review on the management of hepatitis C.
        Gastroenterology. 2006; 130: 231-264
      7. APASL Consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. APASL Hepatitis C Working Party, et al. J Gastroenterol Hepatol 2007;22L615-33.

        • Hadziyannis S.J.
        • Sette Jr, H.
        • Morgan T.R.
        • Balan V.
        • Diago M.
        • Marcellin P.
        • et al.
        Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
        Ann Intern Med. 2004; 140: 346-355
        • Fried M.W.
        • Shiffman M.L.
        • Reddy K.R.
        • Smith C.
        • Marinos G.
        • Gonçales Jr, F.L.
        • et al.
        Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
        N Engl J Med. 2002; 347: 975-982
        • Manns M.P.
        • McHutchison J.G.
        • Gordon S.C.
        • Rustgi V.K.
        • Shiffman M.
        • Reindollar R.
        • et al.
        Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
        Lancet. 2001; 358: 958-965
        • Ferenci P.
        • Fried M.W.
        • Shiffman M.L.
        • Smith C.I.
        • Marinos G.
        • Gonçales Jr, F.L.
        • et al.
        Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.
        J Hepatol. 2005; 43: 425-433
        • Ferenci P.
        • Laferl H.
        • Scherzer T.M.
        • Andreas Maieron A.
        • Hofer H.
        • Stauber R.
        • et al.
        Peginterferon α-2a/ribavirin for 72 weeks reduces relapse among Hepatitis C type 1 and 4 patients with early virologic responses.
        Gastroenterology. 2010; 138: 503-512
        • Bruno S.
        • Stroffolini T.
        • Colombo M.
        • Bollani S.
        • Benvegnù L.
        • Mazzella G.
        • et al.
        Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
        Hepatology. 2007; 45: 579-587
        • Derbala M.
        • Amer A.
        • Bener A.
        • Lopez A.C.
        • Omar M.
        • El Ghannam M.
        Pegylated interferon-alpha 2b-ribavirin combination in Egyptian patients with genotype 4 chronic hepatitis.
        J Viral Hepat. 2005; 12: 380-385
        • Males S.
        • Gad R.R.
        • Esmat G.
        • Abobakr H.
        • Anwar M.
        • Rekacewicz C.
        • et al.
        Serum alpha-fetoprotein level predicts treatment outcome in chronic hepatitis C.
        Antivir Ther. 2007; 12: 797-803
        • Gad R.R.
        • Males S.
        • El Makhzangy H.
        • Shouman S.
        • Hasan A.
        • Attala M.
        • et al.
        Predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C.
        Liver Int. 2008; 28: 1112-1119
        • Giannini E.G.
        • Basso M.
        • Savarino V.
        • Picciotto A.
        Predictive value of on-treatment response during full-dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension.
        J Intern Med. 2009; 266: 537-546
        • Ramos B.
        • Núñez M.
        • Toro C.
        • Sheldon J.
        • García-Samaniego J.
        • Ríos P.
        • et al.
        Changes in the distribution of hepatitis C virus (HCV) genotypes over time in Spain according to HIV serostatus: implications for HCV therapy in HCV/HIV-coinfected patients.
        J Infect. 2007; 54: 173-179
        • Fabrizi F.
        • Poordad F.
        • Martin P.
        Hepatitis C infection and the patient with end-stage renal disease.
        Hepatology. 2002; 36: 3-10
        • Bruchfeld A.
        • Lindahl K.
        • Reichard O.
        • Carlsson T.
        • Schvarcz R.
        Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.
        J Viral Hepat. 2006; 13: 316-321
        • Casanovas Taltavull T.
        • Baliellas Comellas C.
        • Cruzado Garrit J.M.
        Results of hepatitis C virus treatment in patients on hemodialysis: data from published meta-analyses in 2008.
        Transplant Proc. 2009; 41: 2082-2084
        • Wirth S.
        • Pieper-Boustani H.
        • Lang T.
        • Ballauff A.
        • Kullmer U.
        • Gerner P.
        • et al.
        Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C.
        Hepatology. 2005; 41: 1013-1018
        • Jara P.
        • Hierro L.
        • de la Vega A.
        • Díaz C.
        • Camarena C.
        • Frauca E.
        • et al.
        Efficacy and safety of peginterferon-alpha2b and ribavirin combination therapy in children with chronic hepatitis C infection.
        Pediatr Infect Dis J. 2008; 27: 142-148
        • Kamal S.M.
        • Ismail A.
        • Graham C.S.
        • He Q.
        • Rasenack J.W.
        • Peters T.
        • et al.
        Hepatology. 2004; 39: 1721
        • Kamal S.M.
        • Fouly A.E.
        • Kamel R.R.
        • Hockenjos B.
        • Al Tawil A.
        • Khalifa K.E.
        • et al.
        Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response.
        Gastroenterology. 2006; 130: 632-638
        • Nomura H.
        • Sou S.
        • Tanimoto H.
        • Nagahama T.
        • Kimura Y.
        • Hayashi J.
        • et al.
        Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.
        Hepatology. 2004; 39: 1213-1219
        • Inati A.
        • Taher A.
        • Ghorra S.
        • Koussa S.
        • Taha M.
        • Aoun E.
        • et al.
        Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection.
        Br J Haematol. 2005; 130: 644-646
      8. Kamal S, Fouly A, Mohamed S, et al. Peginterferon alfa-2b therapy with and without ribavirin in patients with thalassemia: a randomized study. Presented at the 41st Annual Meeting of the European Association for the Study of the Liver, 26–30 April 2006, Austria Center, Vienna, Austria, abstract 585.

        • Terrault N.
        • Berenguer M.
        Treating Hepatitis C infection in liver transplant recipients.
        Liver Transpl. 2006; 12: 1192-1204
        • Al Sebayel M.
        • Khalaf H.
        • Al Sofayan M.
        • Al Saghier M.
        • Abdo A.
        • Al Bahili H.
        • et al.
        Experience with 122 consecutive liver transplant procedures at King Faisal Specialist Hospital and Research Center.
        Ann Saudi Med. 2007; 27: 1-6
        • Yosry A.
        • Esmat G.
        • El Serafy M.
        • Omar A.
        • Doss W.
        • Said M.
        • et al.
        Outcome of Living donor liver transplantation for Egyptian patients with hepatitis C (Genotype 4)-related cirrhosis.
        Transplant Proc. 2008; 40: 1481-1484
        • Wali M.H.
        • Heydtmann M.
        • Harrison R.F.
        • Gunson B.K.
        • Mutimer D.J.
        Outcome of liver transplantation for patients infected by hepatitis C including those infected by genotype 4.
        Liver Transpl. 2003; 9: 796-804
        • Zekry A.
        • Whiting P.
        • Crawford D.
        • Angus P.
        • Jeffrey G.
        • Padbury R.
        • et al.
        Liver transplantation for HCV associated liver cirrhosis: Predictors of outcomes in a population with significant genotype 3 and 4 distribution.
        Liver Transpl. 2003; 9: 339-347
        • Berenguer M.
        • Prieto M.
        • Rayon J.
        • Mora J.
        • Pastror M.
        • Ortiz V.
        • et al.
        Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation.
        Hepatology. 2000; 32: 852-858
        • Gane E.
        • Portmann B.
        • Naoumov N.
        • Smith H.
        • Underhill Jm.
        • Donaldson O.
        • et al.
        Long term outcome of hepatitis C infection after liver transplantation.
        N Engl J Med. 1996; 20: 773-779
        • Sugo H.
        • Balderson G.A.
        • Crawford D.H.
        • Fawcett J.
        • Lynch S.V.
        • Strong R.W.
        • et al.
        The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation.
        Surg Today. 2003; 33: 421-425
        • Mudawi H.
        • Helmy A.
        • Khalaf H.
        • Al Bahili H.
        • Al Shiek Y.
        • Medhat Y.
        • et al.
        Recurrence of hepatitis C virus genotype-4 infection following liver transplantation.
        Annals of Saudi Med. 2009; 29: 91-97
        • Yosry A.
        • Abdel-Rahman M.
        • Esmat G.
        • El Serafy M.
        • Omar A.
        • Doss W.
        • et al.
        Recurrence of Hepatitis C virus (Genotype 4) infection after living-donor liver transplant in Egyptian patients.
        Exp Clin Transplant. 2009; 7: 157-163
      9. Al Hamoudi W, Mohamed H, Kamel Y, Abaalkail F, Al Masri N, Khalaf H, et al. Pegylated Interferon alfa-2a and ribavirin for the treatment of genotype-4 recurrent hepatitis C after liver transplantation. Hepatol Int. 2010;4:S25.

        • Manns M.P.
        • Wedemeyer H.
        • Cornberg M.
        Treating viral hepatitis C: efficacy, side effects, and complications.
        Gut. 2006; 55: 1350-1359
        • Mederacke I.
        • Wedemeyer H.
        • Manns M.P.
        Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection.
        Curr Opin Investig Drugs. 2009; 10: 181-189
        • Manns M.P.
        • Foster G.R.
        • Rockstroh J.K.
        • Zeuzem S.
        • Zoulim F.
        • Houghton M.
        The way forward in HCV treatment – finding the right path.
        Nat Rev Drug Discov. 2007; 6: 991-1000
        • McHutchison J.G.
        • Everson G.T.
        • Gordon S.C.
        • Jacobson I.M.
        • Sulkowski M.
        • Kauffman R.
        • et al.
        Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.
        N Engl J Med. 2009; 360: 1827-1838
        • McHutchison J.G.
        • Manns M.P.
        • Muir A.J.
        • Terrault N.A.
        • Jacobson I.M.
        • Afdhal N.H.
        • et al.
        Telaprevir for previously treated chronic HCV infection.
        N Engl J Med. 2010; 362: 1292-1303
        • Benhamou Y.
        • Moussalli J.
        • Ratziu V.
        • Lebray P.
        • Gysen V.
        • de Backer K.
        • et al.
        J Hepatol. 2009; 50: S6
        • Seiwert S.D.
        • Andrews S.W.
        • Jiang Y.
        • Serebryany V.
        • Tan H.
        • Kossen K.
        • et al.
        Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).
        Antimicrob Agents Chemother. 2008; 52: 4432-4441
      10. Jensen DM, Wedemeyer H, Herring RW, Ferenci P, Ma MM, Zeuzem S, et al. High rates of early viral response, promising safety profile and lack of resistance related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12interim analysis from the PROPEL study. AASLD 2010.

        • Elazar M.
        • Liu M.
        • McKenna S.A.
        • Liu P.
        • Gehrig E.A.
        • Puglisi J.D.
        • et al.
        The anti-hepatitis C agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2alpha via protein kinase activated by double-stranded RNA activation.
        Gastroenterology. 2009; 137: 1827-1835
        • Rossignol J.F.
        • Kabil S.M.
        • El Gohary Y.
        • Elfert A.
        • Keeffe E.B.
        Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4.
        Aliment Pharmacol Ther. 2008; 28: 574-580
        • Khuroo M.S.
        • Khuroo M.S.
        • Dahab S.T.
        Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4.
        Aliment Pharmacol Ther. 2004; 20: 931-938
        • Mederacke I.
        • Wedemeyer H.
        Nitazoxanide for the treatment of chronic hepatitis C New opportunities but new challenges?.
        Ann Hepatol. 2009; 8: 166-168
        • Flisiak R.
        • Feinman S.V.
        • Jablkowski M.
        • Horban A.
        • Kryczka W.
        • Pawlowska M.
        • et al.
        The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients.
        Hepatology. 2009; 49: 1460-1468
        • Ferenci P.
        • Scherzer T.M.
        • Kerschner H.
        • Rutter K.
        • Beinhardt S.
        • Hofer H.
        • et al.
        Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.
        Gastroenterology. 2008; 135: 1561-1567
      11. Beinhardt S, Rasoul-Rockenschaub S, Matthias Scherzer T, Ferenci P. Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in patient with chronic hepatitis C. J Hepatol. 2010; in press.