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Eliminating hepatitis C within low-income countries – The need to cure genotypes 4, 5, 6

Published:December 08, 2017DOI:https://doi.org/10.1016/j.jhep.2017.11.037

      Summary

      Around 70 to 100 million people are chronically infected with HCV worldwide. HCV antiviral drug development has revolutionised the treatment of HCV, with several direct-acting antiviral agents offering patients the chance of cure after only 8–12 weeks of treatment. Drug development was initially focussed on HCV genotype 1 (GT1) infection, since this was the most prevalent worldwide, although clinical trials included all genotypes prevalent in the US and Europe. Because the earliest in vitro assays utilised the GT1b and 2 replicons, the initial classes of direct-acting antivirals (protease inhibitors, non-nucleotide polymerase inhibitors) were GT1-specific, albeit they had an effect on other less prevalent genotypes. Epidemiological data has shown the regional importance of other HCV genotypes. More than 50% of all HCV infections around the globe are not with GT1. The prevalence of HCV genotype 4 (GT4), 5 (GT5), and 6 (GT6) is increasing in North America and Europe due to migration from the Middle East, Africa and South-East Asia. With the successful development of the multi and pan-genotypic non-structural protein 5A inhibitors, second generation protease inhibitors and nucleotide non-structural protein 5B inhibitors comes a unique opportunity to achieve global HCV elimination. The goal of this review is to summarise the available information pertaining to GT4, GT5 and GT6, with a specific focus on direct-acting antiviral agents.

      Keywords

      Open research questions

      There are still several open research questions which should be addressed by future studies:
      • Although the numbers of patients infected with HCV genotype 4 (GT4), 5 (GT5) and 6 (GT6) recruited into phase II and III clinical trials has been small, the sustained virological response (SVR) rates achieved suggest that infections with these uncommon genotypes is easier to treat with DAAs than the more common HCV GT1 and GT3. Future studies should be designed to determine whether treatment can be shortened in HCV GT4, GT5 and GT6 non-cirrhotic treatment-naïve patients – i.e. reduce sofosbuvir-ledipasvir to eight weeks, glecaprevir-pibrentasvir to less than eight weeks.
      • Studies of resistance-associated substitutions which pertain to HCV GT4, GT5 and GT6 and GT4 subtypes are needed.
      • Further studies must elucidate the modes of transmission of HCV GT5 and identify measures to eliminate HCV GT5 in south west African countries.
      • The impact of generic drugs on relapse rates, and their impact in low-income countries should be monitored.
      • Global trends in new HCV infections must be identified.

      HCV genotype 4-5-6 epidemiology

      HCV genotype 4

      Epidemiology: among the 70 to 100 million HCV-infected subjects worldwide, HCV GT4 accounts for around 15% of those infected; HCV GT5 and GT6 account for less than 5% worldwide.
      Among the 70 to 100 million HCV-infected subjects worldwide, HCV GT4 accounts for around 15% of those infected.

      WHO global hepatitis report 2017 (available : www.who.int/hepatitis/publications/global-hepatitis-report2017).

      • Messina J.P.
      • Humphreys I.
      • Flaxman A.
      • Brown A.
      • Cooke G.S.
      • Pybus O.G.
      • et al.
      Global distribution and prevalence of hepatitis C virus genotypes.
      • Abdel-Razek W.
      • Waked I.
      Optimal therapy in genotype 4 chronic hepatitis C: finally cured?.
      HCV GT4 is most prevalent in the Middle East and sub-Saharan African regions, and accounts for most new infections in that region.
      • Messina J.P.
      • Humphreys I.
      • Flaxman A.
      • Brown A.
      • Cooke G.S.
      • Pybus O.G.
      • et al.
      Global distribution and prevalence of hepatitis C virus genotypes.
      • Abdel-Razek W.
      • Waked I.
      Optimal therapy in genotype 4 chronic hepatitis C: finally cured?.
      In Egypt, where the prevalence of HCV is the highest in the world, the reuse of glass syringes during parenteral campaigns to control the endemic of schistosomiasis in the 1950–70s is widely held to be responsible for a large number of iatrogenic transmissions.
      • 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.
      Epidemiologic studies report an increase in the HCV GT4 infected population in Southern Europe and worldwide as a result of large-scale migration.
      • Asselah T.
      • Perumalswami P.V.
      • Dieterich D.
      Is screening baby boomers for HCV enough? A call to screen for hepatitis C virus in persons from countries of high endemicity.

      HCV genotype 5

      HCV GT5 accounts for about 1.4 million cases of HCV infection worldwide; with more than 80% of cases occurring in southern and eastern sub-Saharan Africa.
      • Messina J.P.
      • Humphreys I.
      • Flaxman A.
      • Brown A.
      • Cooke G.S.
      • Pybus O.G.
      • et al.
      Global distribution and prevalence of hepatitis C virus genotypes.
      GT5 was first reported in South Africa.
      • Smuts H.E.
      • Kannemeyer J.
      Genotyping of hepatitis C virus in South Africa.
      An analysis of blood donors and the general population in South Africa showed that overall GT5 was a prevalent genotype and accounted for 54% of HCV infections in Black South Africans.
      • Prabdial-Sing N.
      • Chirwa T.
      • Thaver J.
      • Smuts H.
      • Vermeulen M.
      • Suchard M.
      • et al.
      Hepatitis C genotype distribution in patient and blood donor samples in South Africa for the period 2008–2012.
      HCV GT5 has also been reported in some regions of Belgium, France, Spain, Greece, the Netherlands, Luxembourg and Syria.
      • van Doorn L.J.
      • Kleter G.E.
      • Stuyver L.
      • Maertens G.
      • Brouwer J.T.
      • Schalm S.W.
      • et al.
      Sequence analysis of hepatitis C virus genotypes 1 to 5 reveals multiple novel subtypes in the Benelux countries.
      • Henquell C.
      • Cartau C.
      • Abergel A.
      • Laurichesse H.
      • Regagnon C.
      • De Champs C.
      • et al.
      High prevalence of hepatitis C virus type 5 in central France evidenced by a prospective study from 1996 to 2002.
      • Martinot-Peignoux M.
      • Roudot-Thoraval F.
      • Mendel I.
      • Coste J.
      • Izopet J.
      • Duverlie G.
      • et al.
      Hepatitis C virus genotypes in France: relationship with epidemiology, pathogenicity and response to interferon therapy. The GEMHEP.
      • Legrand-Abravanel F.
      • Sandres-Sauné K.
      • Barange K.
      • Alric L.
      • Moreau J.
      • Desmorat P.
      • et al.
      Hepatitis C virus genotype 5: epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin.
      • Abergel A.
      • Ughetto S.
      • Dubost S.
      • Bonny C.
      • Aublet-Cuvelier B.
      • Delarocque-Astagneau E.
      • et al.
      The epidemiology and virology of hepatitis C virus genotype 5 in central France.
      • Karatapanis S.
      • Tsoplou P.
      • Papastergiou V.
      • Vasiageorgi A.
      • Stampori M.
      • Saitis I.
      • et al.
      Hepatitis C virus genotyping in Greece: unexpected high prevalence of genotype 5a in a Greek island.
      These unusual pockets of GT5 infection in Europe are among individuals who have not travelled. Modes of transmission among these patients are known in most cases.
      • 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.
      • Jover R.
      • Pérez-Serra J.
      • de Vera F.
      • Alamo J.M.
      • Muñoz C.
      • Yago C.
      • et al.
      Infection by genotype 5a of HCV in a district of southeast Spain.

      HCV genotype 6

      HCV GT6 represents about 1% of HCV infection worldwide and is found mainly in Southeast Asia and Southern China.
      • Wantuck J.M.
      • Ahmed A.
      • Nguyen M.H.
      Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6.
      GT6 accounts for 20–50% of HCV infections in Indochina (Laos), Cambodia, Thailand, Vietnam and Myanmar.
      • Thong V.D.
      • Akkarathamrongsin S.
      • Poovorawan K.
      • Tangkijvanich P.
      • Poovorawan Y.
      Hepatitis C virus genotype 6: virology, epidemiology, genetic variation and clinical implication.
      A map representing HCV GT4, GT5, and GT6 distribution worldwide is provided (Fig. 1).
      Figure thumbnail gr1
      Fig. 1HCV GT4, GT5, and GT6 distribution worldwide. HCV GT4, GT5, and GT6 infect an estimated 30 million people worldwide and account for approximately 20% of global HCV infections.

      HCV genotype 4-5-6 diversity

      There is high genetic diversity of GT4, with at least 17 subtypes of GT4 reported.
      • Zhou N.
      • Hernandez D.
      • Ueland J.
      • Yang X.Y.
      • Yu F.
      • Sims K.
      • et al.
      NS5A Sequence heterogeneity and mechanisms of daclatasvir resistance in hepatitis C virus genotype 4 infection.
      The prevalence of these subtypes varies geographically. While GT4a predominates in Egypt, GT4d in the Middle East, non-4a and non-4d subtypes are the most commonly reported in sub-Saharian Africa. Numerous subtypes of GT4 have been reported in several countries in Africa. There is a more heterogeneous distribution of GT4 subtypes in Europe, probably reflecting the diverse country of origin of the infected individuals.
      • Asselah T.
      • Bourliere M.
      Hepatitis C virus current and evolving treatments for genotype 4.
      HCV GT5 is highly conserved, with only one subtype, 5a, identified until now,
      • Messina J.P.
      • Humphreys I.
      • Flaxman A.
      • Brown A.
      • Cooke G.S.
      • Pybus O.G.
      • et al.
      Global distribution and prevalence of hepatitis C virus genotypes.
      • Smith D.B.
      • Bukh J.
      • Kuiken C.
      • Muerhoff A.S.
      • Rice C.M.
      • Stapleton J.T.
      • et al.
      Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource.
      while GT6 is genetically diverse, with 23 subtypes described.
      • Thong V.D.
      • Akkarathamrongsin S.
      • Poovorawan K.
      • Tangkijvanich P.
      • Poovorawan Y.
      Hepatitis C virus genotype 6: virology, epidemiology, genetic variation and clinical implication.
      Moreover, several HCV GT4 and GT6 subtypes have not been cloned, limiting in vitro testing for direct-antiviral agents (DAAs).
      Viral diversity: there is a high genetic diversity for GT4 and GT6, with at least 17 subtypes of GT4 reported, and 23 subtypes described for GT6. GT5 is highly conserved with only one subtype (GT5a).

      HCV genotype 4-5-6 natural history

      HCV GT4

      We have to point out that data on GT4, GT5 and GT6 were not derived from typical studies of natural history, but rather from mainly cross-sectional or retrospective analyses. The association between HCV genotype and disease progression is unclear and controversial. If there is a role for genotype, it appears to be minor. In the era of interferon-based therapy, genotype was clinically relevant to predict treatment response and to select the duration of treatment.
      • Estrabaud E.
      • Vidaud M.
      • Marcellin P.
      • Asselah T.
      Genomics and HCV infection: progression of fibrosis and treatment response.
      In the future, with pan-genotypic DAAs, the need for genotyping and subtyping might lose its importance.
      A study to understand the natural history (and response to treatment) was performed in a large single centre cohort of 164 patients with HCV GT4 infection, from three different ethnic groups with 70 (43%) Egyptians, 53 (32%) Europeans, and 37 (23%) sub-Saharan Africans.
      • Asselah T.
      • De Muynck S.
      • Broët P.
      • Masliah-Planchon J.
      • Blanluet M.
      • Bièche I.
      • et al.
      IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.
      More than 50% had significant fibrosis by liver biopsy. The genotype distributions for the single nucleotide polymorphism rs12979860 were significantly different between the three ethnic groups (p <0.0002). Frequencies of the C allele were 61.4%, 54.7%, and 31.0% for patients of Egyptian, European and sub-Saharan African origin, respectively. Univariate analysis showed no relationship with fibrosis and either age at therapy, gender, obesity (body mass index), baseline viral load or viral genotype (4a vs. other subtypes). Moreover, no significant relationship between IL28B rs12979860 and fibrosis stage was observed. In contrast, a significant relationship was observed between fibrosis and alcohol consumption (a higher consumption linked to fibrosis) and ethnicity (lower rate of fibrosis for sub-Saharan African patients).
      • Asselah T.
      • De Muynck S.
      • Broët P.
      • Masliah-Planchon J.
      • Blanluet M.
      • Bièche I.
      • et al.
      IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.
      In a multivariate analysis, these two factors showed a significant effect providing additional, non-redundant information on fibrosis progression.
      Genotypes and natural history: the association between HCV genotype and disease progression is unclear and controversial. If there is a role for genotype, it appears to be minor.

      HCV genotype 5

      Due to their relatively low prevalence, the natural history and results of treatment of GT5 and GT6 are less well known. In some regions, patients infected with GT5 are generally older, have higher viral loads, and have cirrhosis more frequently than patients infected with other genotypes.
      • Bonny C.
      • Fontaine H.
      • Poynard T.
      • Hézode C.
      • Larrey D.
      • Marcellin P.
      • et al.
      Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study.

      HCV genotype 6

      HCV GT6 long-term infection appears to be associated with the similar risk of cirrhosis and liver-related complications as HCV GT1 infection.
      • Seto W.K.
      • Lai C.L.
      • Fung J.
      • Hung I.
      • Yuen J.
      • Young J.
      • et al.
      Natural history of chronic hepatitis C: genotype 1 vs. genotype 6.
      The effects of environmental factors known to be found in South East Asia, which are associated with hepatocarcinogenesis in patients with chronic HBV infection (aflatoxin, alcohol, smoking) are not well studied in chronic HCV.

      Historical treatment: pegylated interferon plus ribavirin

      HCV genotype 4

      HCV GT4 has been considered ‘‘difficult to treat’’ with pegylated interferon (PegIFN) and ribavirin (RBV) treatment, with sustained virological response (SVR) rates around 50%.
      • Asselah T.
      • Bourliere M.
      Hepatitis C virus current and evolving treatments for genotype 4.
      The SVR rates reported in the real-life Prophesys study with PegIFN and RBV therapy for 48 weeks were low for patients with GT4 infection (SVR at 24 weeks [SVR24] in 41% of 317 patients).
      • Marcellin P.
      • Cheinquer H.
      • Curescu M.
      • Dusheiko G.M.
      • Ferenci P.
      • Horban A.
      • et al.
      High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials.
      Among patients with HCV GT4 infections who achieved rapid virological response (n = 30), when treated with PegIFN-RBV for 24 weeks, 80% achieved SVR.
      • 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.
      A major predictor of response to PegIFN-RBV therapy in patients with HCV GT4 was the IL28B genotype.
      • Asselah T.
      • De Muynck S.
      • Broët P.
      • Masliah-Planchon J.
      • Blanluet M.
      • Bièche I.
      • et al.
      IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.
      SVR rates for IL28B rs12979860 CC patients ranged from more than 80% to around 30% for TT patients. Egyptian patients infected with HCV GT4, treated with PegIFN-RBV in Europe, responded better than French/European or African patients infected with the same genotype. A better overall response was observed in patients infected with the HCV GT4 subtype 4a, which was the predominant subtype among patients infected in Egypt compared to patients from sub-Saharan Africa who were infected with diverse subtypes. In France, the patient population infected with HCV GT4 is diverse (sub-Saharan Africans, Caucasians, Egyptians). The distribution of IL28B polymorphism in different ethnicities appears to be the explanation for this difference in terms of SVR.
      • Asselah T.
      • De Muynck S.
      • Broët P.
      • Masliah-Planchon J.
      • Blanluet M.
      • Bièche I.
      • et al.
      IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.
      A simple scoring system has been proposed to identify patients infected with GT4 who have a high probability of achieving an SVR with dual PegIFN alfa-2a plus RBV therapy.
      • Asselah T.
      • Esmat G.
      • Sanai F.M.
      • Goulis I.
      • Messinger D.
      • Bakalos G.
      • et al.
      Simple predictive model for identifying patients with chronic hepatitis C and hepatitis C virus genotype 4 infection with a high probability of sustained virologic response with peginterferon alfa-2a/ribavirin: pooled analysis of data from two large.

      HCV genotype 5

      In the real-life Prophesys study, SVR rates of 67% were reported for patients with HCV GT5 treated with PegIFN and RBV therapy for 48 weeks (however, the sample size was small: 10 of 15 [67%] patients with HCV GT5 reached SVR24).
      • Marcellin P.
      • Cheinquer H.
      • Curescu M.
      • Dusheiko G.M.
      • Ferenci P.
      • Horban A.
      • et al.
      High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials.
      A meta-analysis of ten studies including a total of 423 patients, confirmed similar SVR rates.
      • Devaki P.
      • Jencks D.
      • Yee B.E.
      • Nguyen M.H.
      Sustained virologic response to standard interferon or pegylated interferon and ribavirin in patients with hepatitis C virus genotype 5: systematic review and meta-analysis of ten studies and 423 patients.

      Genotype 6

      In the real-life Prophesys study, SVR rates of 80% were reported for patients with HCV GT5 treated with PegIFN and RBV therapy for 48 weeks (however, the sample size was very small; 8 of 10 [80%] patients with HCV GT6 reached SVR24).
      • Marcellin P.
      • Cheinquer H.
      • Curescu M.
      • Dusheiko G.M.
      • Ferenci P.
      • Horban A.
      • et al.
      High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials.
      A meta-analysis of 13 studies with 641 patients, confirmed similar SVR rates.
      • Nguyen N.H.
      • McCormack S.A.
      • Yee B.E.
      • Devaki P.
      • Jencks D.
      • Chao D.T.
      • et al.
      Meta-analysis of patients with hepatitis C virus genotype 6: 48 weeks with pegylated interferon and ribavirin is superior to 24 weeks.

      Direct-acting antivirals: mechanisms of action

      HCV, identified in 1989, is an enveloped virus with a 9.6 kb single-stranded RNA genome, belonging to the genus Hepacivirus, a member of the Flaviviridae family.
      • Choo Q.L.
      • Kuo G.
      • Weiner A.J.
      • Overby L.R.
      • Bradley D.W.
      • Houghton M.
      Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.
      The development of a subgenomic HCV RNA replicon capable of replication in the human hepatoma cell line, HuH7, has been a major advance.
      • Lohmann V.
      • Korner F.
      • Koch J.
      • Herian U.
      • Theilmann L.
      • Bartenschlager R.
      Replication of sub-genomic hepatitis C virus RNAs in a hepatoma cell line.
      • Blight K.J.
      • Kolykhalov A.A.
      • Rice C.M.
      Efficient initiation of HCV RNA replication in cell culture.
      Replicon-based systems improved our understanding of HCV replication, and enabled evaluation of potential DAAs for efficacy and resistance. The HCV replication cycle starts with virion attachment to its specific receptor. The HCV RNA genome serves as a template for viral replication and as viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. Subsequently, viral assembly occurs.
      In 2002, the proof-of-concept for the first DAA (a protease inhibitor) was reported.
      • Lamarre D.
      • Anderson P.C.
      • Bailey M.
      • Beaulieu P.
      • Bolger G.
      • Bonneau P.
      • et al.
      An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.
      • Zeuzem S.
      • Soriano V.
      • Asselah T.
      • Bronowicki J.P.
      • Lohse A.W.
      • Müllhaupt B.
      • et al.
      Faldaprevir and deleobuvir for HCV genotype 1 infection.
      All the HCV enzymes (non-structural protein 2/3 and non-structural protein 3/4A [NS3/4A] proteases, non-structural protein 3 [NS3] helicase and non-structural protein 5B [NS5B] RNA-dependent RNA polymerase) are essential for HCV replication, and are therefore potential drug discovery targets. In addition, DAAs targeting non-structural protein 5A (NS5A) have been developed
      • Gao M.
      • Nettles R.E.
      • Belema M.
      • Snyder L.B.
      • Nguyen V.N.
      • Fridell R.A.
      • et al.
      Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
      over the last fifteen years.
      DAAs with different viral targets (NS3 protease inhibitors, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the RNA-dependent RNA polymerase and NS5A inhibitors) have been developed
      • Schinazi R.
      • Halfon P.
      • Marcellin P.
      • Asselah T.
      HCV direct-acting antiviral agents: The best interferon-free combinations.
      in combination and lead to higher efficacy, reduced risk of resistance and shorter treatment duration (Fig. 2A).
      Recent development of pan-genotypic DAA regimens, provide safe and effective treatment for patients infected with GT4, GT5 or GT6.
      Figure thumbnail gr2
      Fig. 2Mode of action of direct-acting antivirals (DAAs) and developmental milestones of approved DAAs. (A) DAA with different viral targets (NS3 protease inhibitors, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the RNA-dependent RNA polymerase and NS5A inhibitors) have been developed in combination and leads to high efficacy, reduced risk of resistance and shorten treatment duration. (B) Development milestones of approved DAAs. DAA, direct-acting antiviral; DCV, daclatasvir; DSV, dasabuvir; EBV, elbasvir; GLE, glecaprevir; GRZ, grazoprevir; GT, genotype; LDV, ledipasvir; NS, non-structural protein; OMV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.

      Protease inhibitors

      The NS3 serine protease, located in the N-terminal region of NS3, associates with the non-structural protein 4A cofactor to cleave four specific sites on the HCV polyprotein. This enzyme has been characterised biochemically and its structure has been established.
      • Kim J.L.
      • Morgenstern K.A.
      • Lin C.
      • Fox T.
      • Dwyer M.D.
      • Landro J.A.
      • et al.
      Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.
      • Yao N.
      • Hesson T.
      • Cable M.
      • Hong Z.
      • Kwong A.D.
      • Le H.V.
      • et al.
      Structure of the hepatitis C virus RNA helicase domain.
      The serine protease activity of NS3 is an interesting target for drugs that could effectively block viral replication. The NS3/4A protease inhibitors can be divided into two classes: macrocyclic inhibitors and linear tetra-peptide a-ketoamide derivatives.
      In 2003, a macrocyclic protease inhibitor (BILN 2061; faldaprevir) that blocks HCV replication in the replicon model demonstrated efficacy in humans.
      • Lamarre D.
      • Anderson P.C.
      • Bailey M.
      • Beaulieu P.
      • Bolger G.
      • Bonneau P.
      • et al.
      An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.
      • Zeuzem S.
      • Soriano V.
      • Asselah T.
      • Bronowicki J.P.
      • Lohse A.W.
      • Müllhaupt B.
      • et al.
      Faldaprevir and deleobuvir for HCV genotype 1 infection.
      The main weaknesses of the first-generation PIs (boceprevir, teleprevir, and simeprevir) were their low genetic barrier to resistance and the fact that their effectiveness was limited to patients with GT1 infections
      • Halfon P.
      • Locarnini S.
      Hepatitis C virus resistance to protease inhibitors.
      The genetic barrier to resistance is defined as the number of amino acid substitutions required to confer full resistance to a drug. Usually, DAA with a low genetic barrier to resistance require only one or two amino acid substitutions for high resistance. DAA with a high barrier to resistance usually require three or more amino acid substitutions in the same region to confer loss of activity. Second generation PIs have a higher barrier to resistance, better potency against multiple genotypes, more convenient dosing schedules and improved safety and tolerability. In combination with DAAs with different mechanisms of action, these new PIs appear to achieve greater SVR rates than the first-generation PIs.

      Polymerase inhibitors

      Nucleoside polymerase inhibitors in their 5′-triphosphate form interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. There are two different classes of NS5B RNA polymerase inhibitors: nucleoside inhibitors (NI) and non-nucleoside inhibitors (NNI).
      NI mimic the natural substrates of the polymerase and are therefore incorporated into the RNA chain, leading to direct chain termination.
      • Koch U.
      • Narjes F.
      Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
      NI require bioconversion to an active triphosphate form in the hepatocyte. Since the active site of NS5B is highly conserved, NI are usually pan-genotypic. However, single amino acid substitutions in every position of the active site may result in loss of function of the NI, but resistance to nucleoside analogue inhibitors is rare since these substitutions reduce fitness.
      In contrast, allosteric NNI bind to several discrete sites outside of the HCV polymerase active site, which results in conformational protein change before the elongation complex is formed.
      • Koch U.
      • Narjes F.
      Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
      NS5B is structurally organised in a characteristic ‘right-hand motif’, containing finger, palm and thumb domains, and offers four main NNI-binding sites (benzimidazole [thumb 1], thiophene [thumb 2], benzothiadiazine [palm 1] and benzofuran [palm 2]). Resistance is more frequent with NNI than NI treatment. Moreover, mutations at NNI-binding sites do not necessarily lead to impaired function of the enzyme.

      NS5A inhibitors

      The NS5A is a membrane-associated phosphoprotein present in basally phosphorylated (p56) and hyperphosphorylated (p58) form.
      • Gao M.
      • Nettles R.E.
      • Belema M.
      • Snyder L.B.
      • Nguyen V.N.
      • Fridell R.A.
      • et al.
      Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
      • Gish R.G.
      • Meanwell N.A.
      The NS5A replication complex inhibitors: Difference makers?.
      It has been reported that only p58-defective mutants could be complemented in trans, and NS5A is involved in HCV virion production, suggesting that different forms of NS5A exert multiple functions at various steps of the viral replication cycle.
      • Gao M.
      • Nettles R.E.
      • Belema M.
      • Snyder L.B.
      • Nguyen V.N.
      • Fridell R.A.
      • et al.
      Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
      • Gish R.G.
      • Meanwell N.A.
      The NS5A replication complex inhibitors: Difference makers?.
      The N terminus of NS5A (domain I) has been crystallised in alternative dimeric forms and contains both zinc-and RNA-binding domains, properties that have been demonstrated in vitro. NS5A has been shown to interact with a number of host proteins and plays a role in interferon resistance in vivo.
      • Gao M.
      • Nettles R.E.
      • Belema M.
      • Snyder L.B.
      • Nguyen V.N.
      • Fridell R.A.
      • et al.
      Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
      • Gish R.G.
      • Meanwell N.A.
      The NS5A replication complex inhibitors: Difference makers?.
      Furthermore, NS5A inhibitors could block hyperphosphorylation of NS5A, which is believed to play an essential role in the viral replication cycle.
      Development milestones of approved DAAs are provided (Fig. 2B).

      Efficacy of direct-acting antivirals in genotype 4-5-6

      Direct-acting antivirals for HCV genotype 4 infection

      The efficacy of different DAAs in the treatment of HCV GT4 infection is summarised (Table 1).
      Table 1Trials of direct-acting antivirals for HCV GT4, GT5, and GT6.
      HCV GT4 infection
      RegimenTypePopulationDuration (wks)SVR12Ref.
      SOF-LDVPhase II, open label441293%
      • Abergel A.
      • Metivier S.
      • Samuel D.
      • Jiang D.
      • Kersey K.
      • Pang P.S.
      • et al.
      Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection.
      SOF-LDVPhase II, open label211295%
      • Kohli A.
      • Kapoor R.
      • Sims Z.
      • Nelson A.
      • Sidharthan S.
      • Lam B.
      • et al.
      Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study.
      SOF-LDVPhase III2558/1295/98%
      • Shiha G.
      • Waked I.
      • Soliman R.E.
      • Abdelrazek W.
      • Hassany M.
      • Fouad R.
      • et al.
      Ledipasvir/sofosbuvir in egyptian patients with chronic genotype 4 HCV infection.
      SOF-VELPhase III, randomised11612100%
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      SOF-VEL-VOXPhase III, randomised63/538/1292/100%
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.
      OBV-PTVPhase IIb, randomised42 (with RBV)12100%
      • Hezode C.
      • Asselah T.
      • Reddy K.R.
      • Hassanein T.
      • Berenguer M.
      • Fleischer-Stepniewska K.
      • et al.
      Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.
      44 (without RBV)91%
      OBV-PTV-RBVPhase III, randomised59 cirrhotics1297%
      • Asselah T.
      • Hézode C.
      • Qaqish R.B.
      • ElKhashab M.
      • Hassanein T.
      • Papatheodoridis G.
      • et al.
      Co-formulated ombitasvir and paritaprevir/ritonavir with ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a randomised, open-label trial.
      61 cirrhotics1696%
      OBV-PTV-RBVPhase III, randomised100 non-cirrhotics1294%
      • Waked I.
      • Shiha S.
      • Qaqish R.B.
      • Esmat G.
      • Yosry A.
      • Hassany M.
      • et al.
      Co-formulated ombitasvir and paritaprevir/ritonavir plus ribavirin for chronic hepatitis C virus genotype 4 infection in Egyptian patients with or without compensated cirrhosis (AGATE-II): a randomised, open-label trial.
      60 cirrhotics12/2497/93%
      GLE-PIBPhase II/phase III46893%
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
      761299%
      EBV-GRZPooled analysis111 naïve1296%
      • Asselah T.
      • Reesink H.
      • Gerstoft J.
      • de Ledinghen V.
      • Pockros P.
      • Robertson M.
      • et al.
      High efficacy of elbasvir and grazoprevir with or without ribavirin in 103 treatment-naive and experienced patients with HCV genotype 4 infection : a pooled analysis.
      8 experienced16100%
      HCV GT5 infection
      RegimenTypePopulationDuration (wks)SVR12Ref.
      SOF-LDVPhase II, open-label21 naïve1295%
      • Abergel A.
      • Asselah T.
      • Metivier S.
      • Kersey K.
      • Jiang D.
      • Mo H.
      • et al.
      Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study.
      20 experienced95%
      SOF-VELPhase III, assigned to SOF/VEL24 naïve1296%
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      11 experienced100%
      SOF-VEL/VOXPhase III,18894%
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.
      GLE-PIBPhase III, phase II28100%
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
      2612100%
      HCV GT6 infection
      RegimenTypePopulationDuration (wks)SVR12Ref.
      SOF-LDVPhase II, open label251296%
      • Gane E.J.
      • Hyland R.H.
      • An D.
      • Svarovskaia E.
      • Pang P.S.
      • Brainard D.
      • et al.
      Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection.
      SOF-LDVPhase II458/1295/100%

      Nguyen M, et al. LC2017-RS-1361.

      SOF-VELPhase III, randomised3812100%
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      SOF-LDV-VOXPhase III, randomised to 12 wks of SOF/LDV30/98/12100/100%
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.
      GLE-PIBPhase III; phase II10/198/1290/100%
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
      DCV, daclatasvir; DSV, dasabuvir; EBV, elbasvir; GLE, glecaprevir; GRZ, grazoprevir; GT, genotype; LDV, ledipasvir; OMV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; RTV, ritonavir; SOF, sofosbuvir; SVR12, sustained virological response at 12 weeks; VEL, velpatasvir; VOX, voxilaprevir.

      Historical perspectives: DDAs in HCV genotype 4

      In the early development phases of DAAs, daclatasvir in a daily dose of 60 mg in combination with PegIFN and RBV led to an SVR24 rate of 100% in 12 patients with HCV GT4 infection,
      • Hézode C.
      • Hirschfield G.M.
      • Ghesquiere W.
      • Sievert W.
      • Rodriguez-Torres M.
      • Shafran S.
      • et al.
      Randomized study of daclatasvir plus peginterferon alfa-2a and ribavirin for previously untreated chronic hepatitis C.
      and sofosbuvir plus PegIFN and RBV for 12 weeks resulted in a 96% SVR rate in 28 treatment-naïve patients with GT4 infection.
      • Lawitz E.
      • Mangia A.
      • Wyles D.
      • Rodriguez-Torres M.
      • Hassanein T.
      • Gordon S.C.
      • et al.
      Sofosbuvir for previously untreated chronic hepatitis C infection.
      The addition of simeprevir to PegIFN and RBV, in a response-guided therapy, leads also increased SVR.
      • Asselah T.
      • Moreno C.
      • Sarrazin C.
      • Gschwantler M.
      • Foster G.R.
      • Craxí A.
      • et al.
      Efficacy of a 12-week simeprevir plus peginterferon/ribavirin (PR) regimen in treatment-naïve patients with hepatitis C virus (HCV) genotype 4 (GT4) infection and mild-to-moderate fibrosis displaying early on-treatment virologic response.
      Interferon-free sofosbuvir-RBV was used for 12 or 24 weeks in clinical trials in Egyptian patients with GT4 infection, in the US
      • Ruane P.J.
      • Ain D.
      • Stryker R.
      • Meshrekey R.
      • Soliman M.
      • Wolfe P.R.
      • et al.
      Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry.
      and Egypt.
      • Doss W.
      • Shiha G.
      • Hassany M.
      • Soliman R.
      • Fouad R.
      • Khairy M.
      • et al.
      Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4.
      Twelve-week treatment was associated with suboptimal response (SVR at 12 weeks [SVR12] 68%–77%) and treatment for 24 weeks was associated with SVR rates of 90%–93%. Real-world results from patients treated in the national treatment programme in Egypt showed lower response rates in patients treated with sofosbuvir-RBV for 24 weeks (78.7% of 5,667 patients) and a 94% SVR12 among 8,742 patients treated with sofosbuvir and PegIFN plus RBV for 12 weeks.
      • Elsharkawy A.
      • Fouad R.
      • Elakel W.
      • El-Raziky M.
      • Hassany M.
      • Shiha G.
      • et al.
      Sofosbuvir based treatment regimens: Real life results of 14,409 chronic HCV genotype 4 patients.
      These regimens are no longer recommended, and no longer in use because of interferon-related adverse events or suboptimal response rates.
      Clinical trials of interferon-free sofosbuvir-simeprevir for 12 weeks showed SVR12 rates of 100% in patients with HCV GT4, with or without compensated cirrhosis in Spain
      • Buti M.
      • Calleja J.L.
      • Lens S.
      • Diago M.
      • Ortega E.
      • Crespo J.
      • et al.
      Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).
      and Egypt,
      • El Raziky M.
      • Gamil M.
      • Ashour M.K.
      • Abdel Sameea E.
      • Doss W.
      • Hamada Y.
      • et al.
      Simeprevir plus sofosbuvir for 8 or 12 weeks in treatment-naïve and -experienced hepatitis C virus genotype 4 patients with or without cirrhosis.
      whereas shortening treatment to eight weeks in patients without cirrhosis reduced response to only 75%.
      • El Raziky M.
      • Gamil M.
      • Ashour M.K.
      • Abdel Sameea E.
      • Doss W.
      • Hamada Y.
      • et al.
      Simeprevir plus sofosbuvir for 8 or 12 weeks in treatment-naïve and -experienced hepatitis C virus genotype 4 patients with or without cirrhosis.
      Real-world results of using this combination for 12-weeks resulted in an overall SVR12 rate of 94%.
      • Eletreby R.
      • Elakel W.
      • Said M.
      • El Kassas M.
      • Seif S.
      • Elbaz T.
      • et al.
      Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients.
      Although very limited data was available on the combination of sofosbuvir-daclatasvir in patients with HCV GT4 (four patients in the ALLY-1 trial,
      • Poordad F.
      • Schiff E.R.
      • Vierling J.M.
      • Landis C.
      • Fontana R.J.
      • Yang R.
      • et al.
      Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence.
      three with HIV co-infection in ALLY-2
      • Luetkemeyer A.F.
      • McDonald C.
      • Ramgopal M.
      • Noviello S.
      • Bhore R.
      • Ackerman P.
      12 Weeks of daclatasvir in combination with sofosbuvir for HIV-HCV coinfection (ALLY-2 Study): efficacy and safety by HIV combination antiretroviral regimens.
      and 19 with advanced liver disease in a real-world report from Europe
      • Welzel T.M.
      • Petersen J.
      • Herzer K.
      • Ferenci P.
      • Gschwantler M.
      • Wedemeyer H.
      • et al.
      Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort.
      ) all achieved SVR12. The national treatment programme in Egypt has treated large number of patients using sofosbuvir-daclatasvir for 12 weeks (with added RBV for treatment-experienced patients or patients with advanced fibrosis). Real-world results from the first 18,378 patients treated with this combination showed an overall SVR12 rate of 95% (95.4% in patients treated without RBV and 94.7% in patients treated with RBV).

      Omar H, El Akel W, Elbaz T, El Kassas M, El Saeed K, El Shazly H, et al. Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18,378 patients in Egypt. Submitted.

      Sofosbuvir-ledipasvir

      The HCV NS5B uridine nucleotide polymerase inhibitor, sofosbuvir, has nanomolar in vitro activity against all HCV genotypes. It has a favourable safety profile, and a high genetic barrier to resistance. The HCV NS5A inhibitor, ledipasvir, has nanomolar in vitro activity against HCV GT1, 4, 5 and 6. In a phase II, open-label study, 44 patients (22 treatment-naïve and 22 treatment-experienced) received ledipasvir and sofosbuvir orally once daily for 12 weeks.
      • Abergel A.
      • Metivier S.
      • Samuel D.
      • Jiang D.
      • Kersey K.
      • Pang P.S.
      • et al.
      Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection.
      Among study participants, HCV GT4 subtypes were well represented. Ten patients (23%) had compensated cirrhosis. All 44 patients completed the full 12 weeks of dosing. The SVR12 rate was 93% (41 of 44; 95% CI 81–99). SVR12 rates were similar between treatment-naïve (95%; 21 of 22) and treatment-experienced (91%; 20 of 22) patients. All three patients who did not achieve SVR12 had virological relapse within four weeks of the end of treatment; all three had baseline HCV RNA >800,000 IU/ml, a non-CC IL-28B genotype, and pretreatment NS5A resistance-associated variants. None of the patients who relapsed had cirrhosis.
      Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that ledipasvir had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t, despite the presence of resistance-associated substitutions (RASs).
      • Camus G.
      • Han B.
      • Asselah T.
      • Hsieh D.
      • Dvory-Sobol H.
      • Lu J.
      • et al.
      Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4.
      For the rare GT4b, ledipasvir median EC50 was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2–4 NS5A RASs, some including Y93H. Similarly, the two patients infected with HCV GT4r who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased ledipasvir susceptibility.
      Another study performed in the US, showed similar results; in 21 treatment-naïve and experienced patients infected with HCV GT4, 12 weeks of ledipasvir and sofosbuvir resulted in an SVR rate of 95% (20 of 21).
      • Kohli A.
      • Kapoor R.
      • Sims Z.
      • Nelson A.
      • Sidharthan S.
      • Lam B.
      • et al.
      Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study.
      A study performed in Egypt included 255 patients infected with GT4, where 170 treatment-naïve patients were randomised to sofosbuvir-ledipasvir treatment for 8 or 12 weeks, with or without RBV, and 85 treatment-experienced patients to treatment for 12 weeks with or without RBV.
      • Shiha G.
      • Waked I.
      • Soliman R.E.
      • Abdelrazek W.
      • Hassany M.
      • Fouad R.
      • et al.
      Ledipasvir/sofosbuvir in egyptian patients with chronic genotype 4 HCV infection.
      Among treatment-naïve patients treated for 12 weeks, SVR12 rates were 98%, irrespective of RBV intake, and among those treated for eight weeks, SVR12 rates were 95% without RBV, and 90% with RBV. All treatment-experienced patients treated for 12 weeks with RBV (including 11 sofosbuvir-experienced patients), and 34 of 36 patients treated without RBV responded to treatment.
      Data regarding these specific patient populations are now available, although the number of patients remains low.

      Sofosbuvir-velpatasvir

      Velpatasvir is a new pan-genotypic HCV NS5A inhibitor with picomolar in vitro antiviral activity against HCV GT1–6 and most NS5 resistance-associated variants. In the phase III ASTRAL-1 trial, treatment-naïve and treatment-experienced patients with chronic HCV GT1, GT2, GT4, GT5, or GT6 infections were randomised in a 5:1 ratio to receive a 12-week course of either sofosbuvir-velpatasvir or placebo.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      All 116 patients with HCV GT4 treated with sofosbuvir-velpatasvir achieved SVR, regardless of the presence of RASs.
      We recently analysed 501 patients from three large phase III trials (ASTRAL-1, -2, and -3) with compensated cirrhosis (Metavir F4) or advanced fibrosis (F3) who received sofosbuvir-velpatasvir for 12 weeks. Again all 60 patients with HCV GT4 infection achieved SVR.
      • Asselah T.
      • Bourgeois S.
      • Pianko S.
      • Zeuzem S.
      • Sulkowski M.
      • Foster G.R.
      • et al.
      Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1–6 and compensated cirrhosis or advanced fibrosis.
      . In vitro data confirmed that velpatasvir is potent against all GT4 isolates tested.
      • Camus G.
      • Han B.
      • Asselah T.
      • Hsieh D.
      • Dvory-Sobol H.
      • Lu J.
      • et al.
      Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4.

      Sofosbuvir-velpatasvir-voxilaprevir

      Voxilaprevir is a macrocyclic, pan-genotypic inhibitor of the NS3/4A protease with picomolar antiviral activity against HCV GT1–6 and an improved resistance profile in comparison to earlier protease inhibitors.
      The POLARIS-2 trial enrolled patients infected with all HCV genotypes. Compensated cirrhosis was allowed except for patients with HCV GT3 infection.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.
      Patients received either a fixed-dose combination of 400 mg of sofosbuvir, 100 mg of velpatasvir, plus 100 mg of voxilaprevir once daily for eight weeks or a fixed-dose combination of 400 mg of sofosbuvir plus 100 mg of velpatasvir once daily for 12 weeks. The overall SVR rate was 95% for the eight week three-DAAs regimen and 98% for the 12 week two-DAAs regimen. Hence, the primary efficacy endpoint of non-inferiority (5% margin) was not met.
      The SVR rate for GT4 was 94% for the eight week three-DAA regimen and 98% for the 12 week two-DAA regimen.

      Paritaprevir-ritonavir-ombitasvir

      Ombitasvir is a potent NS5A inhibitor and is co-formulated with paritaprevir, a potent NS3/4A protease inhibitor; paritaprevir is co-dosed with ritonavir to increase drug exposures. In a phase IIb study (Pearl study), 100% of patients (n = 91) with HCV GT4 infection, without cirrhosis, achieved SVR when treated with ombitasvir, paritaprevir, and ritonavir plus RBV for 12 weeks.
      • Hezode C.
      • Asselah T.
      • Reddy K.R.
      • Hassanein T.
      • Berenguer M.
      • Fleischer-Stepniewska K.
      • et al.
      Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.
      In this study of patients with GT4 infection, 100% of patients (n = 42) and 91% of patients (40 out of 44) achieved SVR when treated with paritaprevir-ritonavir-ombitasvir for 12 weeks plus RBV or without RBV, respectively. In a phase III, multicentre, randomised open-label trial, (Agate-I study) 120 patients with HCV GT4 infection and compensated cirrhosis in North America and Europe received paritaprevir-ritonavir-ombitasvir with weight based RBV for 12 weeks or 16 weeks; 97% of patients achieved SVR in the 12-week group and 98% achieved SVR in the 16-week group.
      • Asselah T.
      • Hézode C.
      • Qaqish R.B.
      • ElKhashab M.
      • Hassanein T.
      • Papatheodoridis G.
      • et al.
      Co-formulated ombitasvir and paritaprevir/ritonavir with ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a randomised, open-label trial.
      With high proportions of patients achieving SVR12, no posttreatment relapses, and a similar adverse event profile for the 12-week and 16-week treatment groups, 16-week treatment seems to provide no added benefit for patients with HCV GT4 infection and compensated cirrhosis.
      The companion AGATE-II study provides additional evidence of high efficacy (94–97%) of paritaprevir-ritonavir-ombitasvir plus RBV in patients with HCV GT4 infection, with or without cirrhosis, in Egypt.
      • Waked I.
      • Shiha S.
      • Qaqish R.B.
      • Esmat G.
      • Yosry A.
      • Hassany M.
      • et al.
      Co-formulated ombitasvir and paritaprevir/ritonavir plus ribavirin for chronic hepatitis C virus genotype 4 infection in Egyptian patients with or without compensated cirrhosis (AGATE-II): a randomised, open-label trial.

      Glecaprevir-pibrentasvir

      Glecaprevir is a potent NS3/4A protease inhibitor with nanomolar antiviral activity against HCV GT1–6 and most known NS3 RASs. Pibrentasvir is an NS5A inhibitor with picomolar antiviral activity against HCV GT1–6 and most NS5A RASs. This fixed-dose combination demonstrates synergistic antiviral activity and a high barrier to resistance.
      • Ng T.
      • Krishnan P.
      • Pilot-Matias T.
      • Kati W.
      • Schnell G.
      • Beyer J.
      • et al.
      In vitro antiviral activity and resistance profile of the next generation hepatitis C virus NS5A inhibitor pibrentasvir.
      The efficacy and safety of eight-week and 12-week glecaprevir-pibrentasvir treatment in non-cirrhotic patients with HCV GT4, GT5 or GT6 infections were reported recently (Surveyor-II, Part 4 and Endurance-4).
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
      The SVR12 rate (intention-to-treat population) in patients with GT4 infection treated for 12 weeks and eight-weeks was 99% (75/76) and 93% (43/46), respectively, with no virologic failures. The SVR12 rate (modified intention-to-treat population) was 100% (75/75) for 12 weeks, and 100% (43/43) for eight-weeks.

      Elbasvir-grazoprevir

      Elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A protease inhibitor, have demonstrated high in vitro potency against HCV GT4 replicons, as well as RASs that confer resistance to first-generation protease inhibitors and RASs related to treatment failures on daclatasvir and ledipasvir.
      • Asante-Appiah E.
      • Curry S.
      • McMonagle P.
      • Ingravallo P.
      • Chase R.
      • Nickle D.
      Antiviral activity and resistance analysis of NS3/4A protease inhibitor grazoprevir and NS5A inhibitor elbasvir in hepatitis C virus GT4 replicons.
      We conducted an integrated analysis to assess the efficacy of the once-daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without RBV in patients with HCV GT4 infections, enrolled in the phase II/III clinical programme with elbasvir-grazoprevir.
      • Asselah T.
      • Reesink H.
      • Gerstoft J.
      • de Ledinghen V.
      • Pockros P.
      • Robertson M.
      • et al.
      High efficacy of elbasvir and grazoprevir with or without ribavirin in 103 treatment-naive and experienced patients with HCV genotype 4 infection : a pooled analysis.
      Overall, among patients treated with 12 or 16 weeks of elbasvir-grazoprevir ± RBV, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naïve patients and 88.6% (39/44) in treatment-experienced patients. The SVR12 rates were 96.0% (97/101) in treatment-naïve patients treated with 12 weeks of elbasvir-grazoprevir, and 100% (8/8) in treatment-experienced patients treated with 16 weeks of elbasvir-grazoprevir plus RBV.
      • Asselah T.
      • Reesink H.
      • Gerstoft J.
      • de Ledinghen V.
      • Pockros P.
      • Robertson M.
      • et al.
      High efficacy of elbasvir and grazoprevir with or without ribavirin in 103 treatment-naive and experienced patients with HCV genotype 4 infection : a pooled analysis.
      Efficacy was not impacted by subtype. Finally, the regimens of 12 weeks of elbasvir-grazoprevir without RBV, and 16 weeks of elbasvir-grazoprevir plus RBV were efficacious in treatment-naïve and treatment-experienced patients with HCV GT4 infection, respectively. Baseline NS5A RASs did not affect the efficacy of elbasvir-grazoprevir in patients with GT4 infections.
      We must recall that elbasvir-grazoprevir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV who had stage 4-5 chronic kidney disease.
      • Roth D.
      • Nelson D.R.
      • Bruchfeld A.
      • Liapakis A.
      • Silva M.
      • Monsour Jr, H.
      • et al.
      Grazoprevir plus elbasvir in treatment-naive and treatment experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.
      Effectiveness and safety of elbasvir-grazoprevir in patients with chronic hepatitis C and chronic kidney disease has recently been confirmed in a real-world setting, with results from the Veterans Affairs System.

      Kramer JR, Puenpatom A, Erickson K, Cao Y, Smith DL, El-Serag HB, et al. Effectiveness of elbasvir/grazoprevir in patients with chronic hepatitis C and chronic kidney disease: results from the veterans affairs system. In: 68th annual meeting of the American association for the study of liver diseases, October 20–24. Washington DC, USA; 2017 [abstract 1113].

      An ongoing multi-site, open-label, partially randomised trial of the efficacy and safety of elbasvir-grazoprevir in French subjects with chronic HCV GT4 infection is evaluating an eight-week treatment duration (NCT03111108).

      Ravidasvir

      To date, only one trial has been performed with ravidasvir. Carried out in Egypt, it concluded that treatment with ravidasvir plus sofosbuvir, with or without RBV, was well-tolerated and associated with high SVR rate for patients infected with HCV GT4, with and without cirrhosis, regardless of previous interferon-based treatments.
      • Esmat G.
      • Elbaz T.
      • El Raziky M.
      • Gomaa A.
      • Abouelkhair M.
      • El Deen H.G.
      • et al.
      Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis c genotype-4.
      Confirmatory studies are needed.

      Direct-acting antivirals for HCV genotype 5 infection

      The efficacy of different DAAs in HCV GT5 infection is summarised (Table 1).

      Sofosbuvir-ledipasvir

      In a phase II, open-label study conducted in France, 21 treatment-naïve and 20 treatment-experienced patients with HCV GT5 infection were enrolled to receive a 12-week course of ledipasvir-sofosbuvir.
      • Abergel A.
      • Asselah T.
      • Metivier S.
      • Kersey K.
      • Jiang D.
      • Mo H.
      • et al.
      Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study.
      For the treatment-naïve patients with GT5 infection, 20 of 21 (95%) achieved an SVR12. For the treatment-experienced patients with GT5 infection, 19 of 20 (95%) achieved an SVR12. Ten patients had compensated cirrhosis and all achieved SVR12.

      Sofosbuvir-velpatasvir

      In the phase III ASTRAL-1 trial, because of the low prevalence of GT5 in the study regions, patients with GT5 did not undergo randomisation but were assigned to the sofosbuvir-velpatasvir group.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      Among the treatment-naïve patients treated with sofosbuvir-velpatasvir, 23 of 24 (96%) with GT5 infection achieved an SVR12. Among the treatment- experienced patients treated with sofosbuvir-velpatasvir, 11 of 11 (100%) achieved an SVR12.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.

      Sofosbuvir-velpatasvir-voxilaprevir

      In the POLARIS-2 trial, for the patients with GT5 infection treated for eight weeks, 17 of 18 (94%) achieved an SVR12. No patients were treated in the 12-week arm.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.

      Glecaprevir-pibrentasvir

      Efficacy of eight-week glecaprevir/pibrentasvir treatment and 12-week treatment in non-cirrhotic patients with HCV GT4, GT5 or GT6 infections were reported recently (Surveyor-II, Part 4 and Endurance-4).
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
      Eight weeks of treatment led to SVR in 2/2 patients (100%); and twelve weeks of treatment led to SVR in 26/26 patients (100%).
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.

      Direct-acting antivirals for HCV genotype 6 infection

      The efficacy of different DAAs in HCV GT6 infection is summarised (Table 1).

      Sofosbuvir-ledipasvir

      In an open-label, phase II study (LEPTON) performed in New Zealand, 25 treatment-naïve and treatment-experienced patients with HCV GT6 infection received ledipasvir-sofosbuvir for 12 weeks.
      • Gane E.J.
      • Hyland R.H.
      • An D.
      • Svarovskaia E.
      • Pang P.S.
      • Brainard D.
      • et al.
      Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection.
      Overall, 24 of the 25 patients (96%) achieved an SVR12. The one patient in this cohort who did not achieve an SVR12 dropped out of the study at week 8. Only two of the treatment-naïve patients with GT6 had cirrhosis.
      In a US study, 45 patients with HCV GT6 infection without cirrhosis were treated with ledipasvir-sofosbuvir for either eight or 12 weeks. All 25 patients treated for 12 weeks and 19/20 treated for only eight weeks achieved SVR, In the same study, 15 patients with HCV GT6 infection and cirrhosis were treated with ledipasvir-sofosbuvir for 12 weeks and 13 achieved SVR.

      Nguyen M, et al. LC2017-RS-1361.

      Sofosbuvir-velpatasvir

      In the phase III ASTRAL-1 trial, among the treatment-naïve patients treated with sofosbuvir-velpatasvir, all 38 patients with GT6 infection achieved an SVR12, including all three treatment-experienced patients.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      Treatment history, cirrhosis status and GT6 subtype (6a/b vs. 6c-l vs. 6 other) did not affect SVR rate.

      Sofosbuvir-velpatasvir-voxilaprevir

      In the Polaris II study, all 30 patients with GT6 infections treated with sofosbuvir-velpatasvir-voxilaprevir for eight weeks achieved SVR, as did all nine GT6 patients treated with sofosbuvir-velpatasvir for 12 weeks.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.

      Glecaprevir-pibrentasvir

      In Surveyor-II, Part-4, 9 of 10 patients (90%) with HCV GT6 infection, treated with glecaprevir-pibrentasvir for eight weeks achieved an SVR12.

      Hassanein T, Wyles D, Wang S, Kwo PY, Shiffman ML, Younes Z, et al. SURVEYOR-II, Part 4: Glecaprevir/Pibrentasvir Demonstrates High SVR Rates in Patients With HCV Genotype 2, 4, 5, or 6 Infection Without Cirrhosis Following an 8-Week Treatment Duration. AASLD 2016, Boston. #LB-15.

      In Surveyor-1 and in Endurance-4, all 30 patients without cirrhosis with HCV GT6 infection treated with glecaprevir-pibrentasvir for 12 weeks achieved SVR.
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
      To increase the body of data for GT5 and GT6, an open-label, multicentre study is evaluating the safety and optimum duration of glecaprevir-pibrentasvir in 80 patients with HCV GT5 and GT6 infections (NCT02966795). This phase IIIb study included patients with or without compensated cirrhosis and both treatment-naïve and treatment-experienced patients (who had failed either PegIFN with or without RBV or sofosbuvir plus RBV with or without PegIFN).

      Finally, what are the clinical benefits obtained by achieving SVR?

      The availability of pan-genotypic DAAs with excellent efficacy and good tolerability offers the unique opportunity to achieve HCV elimination worldwide.
      A remarkable revolution has recently been achieved with the availability of DAAs offering a high chance of cure and good tolerability. The primary goal of treatment is to achieve an SVR defined as undetectable serum HCV RNA 12 weeks after the end of treatment.
      • Martinot-Peignoux M.
      • Stern C.
      • Maylin S.
      • Ripault M.P.
      • Boyer N.
      • Leclere L.
      • et al.
      Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.
      An SVR has been shown to be durable on long-term follow-up and associated with the eradication of HCV infection, confirmed by undetectable HCV RNA in serum and the liver.
      • Maylin S.
      • Martinot-Peignoux M.
      • Moucari R.
      • Boyer N.
      • Ripault M.P.
      • Cazals-Hatem D.
      • et al.
      Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C.
      An SVR indicates that viral infection has been cured.
      In addition, viral eradication is associated with the regression of fibrosis, arresting of the progression of cirrhosis to decompensated cirrhosis, and significant improvement in clinical outcome and survival with a decreased incidence of complications, especially hepatocellular carcinoma (HCC).
      Protease inhibitors are contra-indicated in patients with decompensated cirrhosis. Treatment with sofosbuvir-velpatasvir with or without RBV for 12 weeks resulted in high rates of SVR in patients with HCV infection and decompensated cirrhosis, and tolerability is favourable.
      • Curry M.P.
      • O’Leary J.G.
      • Bzowej N.
      • et al.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      Moreover, patients with HCV chronic infection and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in hepatic venous pressure gradient at long-term follow-up.
      • Afdhal N.
      • Everson G.T.
      • Calleja J.L.
      • McCaughan G.W.
      • Bosch J.
      • Brainard D.M.
      • et al.
      Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension.
      The survival benefit conferred by DAAs in patients with decompensated cirrhosis was recently confirmed. Observed incidence of deaths in patients with hepatic decompensation in the SOLAR studies was compared with mortality predicted by survival models derived from patients with HCV and hepatic decompensation in the pre-DAA era. It showed that DAAs significantly reduced mortality risk in patients with decompensated HCV cirrhosis, by as much as 60% within the first year of therapy.

      Kim RW, Mannalithara A, Lee H, Osinusi A, Schall REA, Brainard DM. Survival benefit of direct acting antiviral therapy in patients with decompensated cirrhosis. Hepatology 2017;66:LB27.

      Treating the underlying disease with newly developed DAAs often improves perceived fatigue and patient-reported outcomes.
      • Younossi Z.M.
      • Stepanova M.
      • Asselah T.
      • et al.
      Hepatitis C in patients with minimal or no hepatic fibrosis: the impact of treatment and sustained virologic response on patient-reported outcomes.
      Healthy lifestyle changes are the cornerstone of treatment. The impact of SVR on morbidity and mortality are well recognised, although the true economic and social benefits can only be estimated on the assumption that HCV cure is not complicated by progression of the disease.
      Staging of disease either clinically or by laboratory analysis or radiologic approaches remains a key part of HCV management. Diagnostic tools are under development to better diagnose advanced fibrosis.
      • Appourchaux K.
      • Dokmak S.
      • Resche-Rigon M.
      • Treton X.
      • Lapalus M.
      • Gattolliat C.H.
      • et al.
      MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C.
      Patients with advanced cirrhosis will require continued care despite viral cure. The risk of HCC in patients with cirrhosis is reduced but not eliminated; patients treated with DAAs should continue to be closely monitored for HCC (ultrasound every six months). Surveillance is also advocated in patients who achieve SVR with any histological stage of hepatitis C who carry comorbidities such as alcohol consumption, diabetes and obesity, which are independent risk factors for HCC. Given the current controversy, until controlled clinical trials provide evidence of benefit or possible detriment, treatment is recommended for patients with cirrhosis to reduce the risk of progression of the underlying liver disease.

      Conclusion: what are the gaps to achieve HCV elimination worldwide?

      HCV GT4, GT5 and GT6 infections constitute almost one-quarter of all HCV infections globally and are the predominant infections in the Middle East, Africa and South-East Asia, respectively. However, development of non-IFN therapies which are active against HCV GT4, GT5, and GT6 has been slow, reflecting not only the lack of in vitro replication models, but also the low (<5%) prevalence of these genotypes in high-income countries where the pharmaceutical companies have targeted GT1. However, the greatest unmet medical need in high-income countries is now patients infected with GT3. This has driven the recent development of pan-genotypic DAA regimens, which also provide safe and effective treatment for patients infected with GT4, GT5 or GT6.
      HCV GT4, GT5 and GT6 have been neglected in the past, for many reasons, including the low prevalence in high-income countries where the DAAs have been developed. Data regarding these specific patient populations are now available, although the number of patients remains low. Guidelines will help the physicians to manage patients. The American Association for the Study of Liver Diseases/Infectious Diseases Society of America and the European Association for the Study of the Liver guidelines for HCV GT4, GT5 and GT6 are updated regularly.
      EASL Recommendations on Treatment of Hepatitis C 2016.

      HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org.

      For HCV GT5 and GT6 infection, sofosbuvir-velpatasvir, sofosbuvir-ledipasvir, for 12 weeks and glecaprevir-pibrentasvir for eight weeks in non-cirrhotic patients, and 12 weeks for compensated cirrhotic patient are approved.
      Treatment with DAAs result in high rates of cure in people who injects drugs (PWID) (Fig. 3). A first study has demonstrated that patients with HCV infection who were receiving opioid agonist therapy and treated with DAAs (elbasvir-grazoprevir) had high rates of SVR12, regardless of ongoing drug use.
      • Dore G.J.
      • Altice F.
      • Litwin A.H.
      • Dalgard O.
      • Gane E.J.
      • Shibolet O.
      • et al.
      Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial.
      In these studies, 0–3% of patients discontinued treatment because of adverse events. Compliance was excellent, even in patients taking illicit drugs while on treatment. Risk of reinfection appears low. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving opioid agonist therapy. Since then, different DAAs have demonstrated high efficacy and good compliance in PWID.
      • Lalezari J.
      • Sullivan J.G.
      • Varunok P.
      • Galen E.
      • Kowdley K.V.
      • Rustgi V.
      • et al.
      Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine.
      • Moser S.
      • Schütz A.
      • Marchart K.
      • Kalchbrenner D.
      • Rechberger G.
      • Luhn J.
      • et al.
      Directly observed therapy with sofosbuvir/ledipasvir for 8 weeks is highly effective in treatment-naïve, precirrhotic genotype 1 patients with borderline compliance receiving opioid agonist therapy.
      • Grebely J.
      • Dalgard O.
      • Conway B.
      • Cunningham E.
      • Bruggmann P.
      • Hajarizadeh B.
      • et al.
      Efficacy and safety of sofosbuvir/velpatasvir in people with chronic hepatitis C virus infection and recent injecting drug use: The SIMPLIFY study.
      HCV reinfection was analysed in patients on opioid agonist therapy and following elbasvir-grazoprevir therapy.
      • Dore G.
      • Grebely J.
      • Altice F.
      • et al.
      Hepatitis C virus (HCV) reinfection and injecting risk behavior following elbasvir (EBR)/grazoprevir (GZR) treatment in participants on opiate agonist therapy (OAT): Co-STAR part B [AASLD Liver Meeting abstract 195].
      Reinfection rates remained low in at risk populations. The reinfection rate was 2.3/100 person-years, with a persistent reinfection rate of 1.6/100 person-years.
      Figure thumbnail gr3
      Fig. 3Treatment with DAAs results in high rates of cure in people who inject drugs.
      • Dore G.J.
      • Altice F.
      • Litwin A.H.
      • Dalgard O.
      • Gane E.J.
      • Shibolet O.
      • et al.
      Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial.
      • Lalezari J.
      • Sullivan J.G.
      • Varunok P.
      • Galen E.
      • Kowdley K.V.
      • Rustgi V.
      • et al.
      Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine.
      • Moser S.
      • Schütz A.
      • Marchart K.
      • Kalchbrenner D.
      • Rechberger G.
      • Luhn J.
      • et al.
      Directly observed therapy with sofosbuvir/ledipasvir for 8 weeks is highly effective in treatment-naïve, precirrhotic genotype 1 patients with borderline compliance receiving opioid agonist therapy.
      • Grebely J.
      • Dalgard O.
      • Conway B.
      • Cunningham E.
      • Bruggmann P.
      • Hajarizadeh B.
      • et al.
      Efficacy and safety of sofosbuvir/velpatasvir in people with chronic hepatitis C virus infection and recent injecting drug use: The SIMPLIFY study.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBV, elbasvir; GRZ, grazoprevir; LDV, ledipasvir; OMV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SOF, sofosbuvir; SVR12, sustained virological response at week 12; VEL, velpatasvir.
      The availability of pan-genotypic DAAs with excellent efficacy and good tolerability offers the unique opportunity to achieve HCV elimination worldwide. IFN-free DAA combinations are now able to cure HCV in more than 95% of HCV-infected individuals after 8–12 weeks of treatment.
      Although national programmes are the goal for every country, we have yet to see a comprehensive and effective programme anywhere around the world, even in wealthier countries. However, Australia and Iceland are two examples where elimination strategies are well advanced.
      To date, 194 different countries have signed up to the World Health Organization 2011 resolution recognising viral hepatitis as a global health issue. In 2014, these countries accepted the ambitious targets for 2030 – 90% reduction in incidence and 65% reduction in mortality. Part of the strategy includes the formation of a national plan to increase testing and linkage to care.
      Programmes to eliminate HCV must include increased screening (risk based and universal), linkage to care, as well as increased access to treatment worldwide. The accuracy, affordability and acceptability of testing must be improved through the provision of HCV antigen or RNA testing. Point-of-care testing in countries with a high prevalence of HCV could also improve linkage to care through community-based “test and treat” programmes. Reducing the cost of DAAs will also be important. In low-income countries the combination of generic sofosbuvir and daclatasvir or sofosbuvir and velpatasvir could be considered for economic reasons, to enhance treatment rates across all HCV genotypes. Real-life data on treatment efficacy, tolerability and adherence are mandatory. Compliance to drug regimens will become a major issue to avoid failure. It will be mandatory to control the quality of generic drugs. Shortening treatment duration, removing the need for RBV and on-treatment monitoring should enhance treatment uptake and SVR. Patients who failed previous treatment and developed resistance-associated variants of NS5A, should be rescued with the newly approved sofosbuvir-based triple therapy or future combinations.
      • Bourlière M.
      • Gordon S.C.
      • Flamm S.L.
      • Cooper C.L.
      • Ramji A.
      • Tong M.
      • et al.
      Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection.
      • Poordad F.
      • Felizarta F.
      • Asatryan A.
      • Sulkowski M.S.
      • Reindollar R.W.
      • Landis C.S.
      • et al.
      Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment.
      Finally, the availability of affordable, efficient and safe DAAs with short treatment durations is paving the way for viral eradication.

      Financial support

      No financial support was received to produce this manuscript.

      Conflict of interest

      Professor Tarik Asselah is a speaker and investigator for AbbVie, Bristol-Myers Squibb, Janssen, Gilead, Roche and Merck. Professor Tarek Hassanein has received grants from AbbVie, Bristol-Myers Squibb, Eisai, Gilead Sciences, Ikaria, Janssen, La Jolla Pharmaceuticals, Merck, Mochida, NGM BioPharmaceuticals, Roche, Ocera, Sundise, Salix, Taigen, Takeda, Tobria, Vertex, and Vital Therapies, has served on advisory boards for AbbVie and Bristol-Myers Squibb, and is a speaker for Baxter, Bristol-Myers Squibb, Gilead, and Salix. Professor Imam Waked has been speaker for Roche, Merck, Bristol-Myers Squibb, Gilead Sciences, and Janssen, is an advisor for Janssen, Roche, Merck, and AbbVie, and has been a study investigator for Roche, Bristol-Myers Squibb, Gilead, Janssen, Pharco, and AbbVie. Doctor Abdellah Mansouri has nothing to declare. Professor Dusheiko currently acts as an advisor to Gilead Sciences, Bristol-Myers Squibb, Janssen and Merck. He has received speaking honoraria from Gilead Sciences, AbbVie, Bristol-Myers Squibb, Merck and Janssen in the past 2 years. He has received grant support from Gilead Sciences, AbbVie, Glaxo Smith Kline, Bristol-Myers Squibb, Janssen and Merck. Professor Edward Gane is a clinical investigator, or a member of Advisory Board or Speakers Bureau for Gilead Sciences, Merck, AbbVie, Roche, Janssen.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      TA designed, prepared and supervised the manuscript. All the authors contributed to the drafting of the review, the critical revision of the manuscript and the final approval of the version to be published.

      References

      1. WHO global hepatitis report 2017 (available : www.who.int/hepatitis/publications/global-hepatitis-report2017).

        • Messina J.P.
        • Humphreys I.
        • Flaxman A.
        • Brown A.
        • Cooke G.S.
        • Pybus O.G.
        • et al.
        Global distribution and prevalence of hepatitis C virus genotypes.
        Hepatology. 2015; 61: 77-87
        • Abdel-Razek W.
        • Waked I.
        Optimal therapy in genotype 4 chronic hepatitis C: finally cured?.
        Liver Int. 2015; 35: 27-34
        • 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: 887-891
        • Asselah T.
        • Perumalswami P.V.
        • Dieterich D.
        Is screening baby boomers for HCV enough? A call to screen for hepatitis C virus in persons from countries of high endemicity.
        Liver Int. 2014; 34: 1447-1451
        • Smuts H.E.
        • Kannemeyer J.
        Genotyping of hepatitis C virus in South Africa.
        J Clin Microbiol. 1995; 33: 1679-1681
        • Prabdial-Sing N.
        • Chirwa T.
        • Thaver J.
        • Smuts H.
        • Vermeulen M.
        • Suchard M.
        • et al.
        Hepatitis C genotype distribution in patient and blood donor samples in South Africa for the period 2008–2012.
        J Viral Hepat. 2016; 23: 881-888
        • van Doorn L.J.
        • Kleter G.E.
        • Stuyver L.
        • Maertens G.
        • Brouwer J.T.
        • Schalm S.W.
        • et al.
        Sequence analysis of hepatitis C virus genotypes 1 to 5 reveals multiple novel subtypes in the Benelux countries.
        J Gen Virol. 1995; 76: 1871-1876
        • Henquell C.
        • Cartau C.
        • Abergel A.
        • Laurichesse H.
        • Regagnon C.
        • De Champs C.
        • et al.
        High prevalence of hepatitis C virus type 5 in central France evidenced by a prospective study from 1996 to 2002.
        J Clin Microbiol. 2004; 42: 3030-3035
        • Martinot-Peignoux M.
        • Roudot-Thoraval F.
        • Mendel I.
        • Coste J.
        • Izopet J.
        • Duverlie G.
        • et al.
        Hepatitis C virus genotypes in France: relationship with epidemiology, pathogenicity and response to interferon therapy. The GEMHEP.
        J Viral Hepat. 1999; 6: 435-443
        • Legrand-Abravanel F.
        • Sandres-Sauné K.
        • Barange K.
        • Alric L.
        • Moreau J.
        • Desmorat P.
        • et al.
        Hepatitis C virus genotype 5: epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin.
        J Infect Dis. 2004; 189: 1397-1400
        • Abergel A.
        • Ughetto S.
        • Dubost S.
        • Bonny C.
        • Aublet-Cuvelier B.
        • Delarocque-Astagneau E.
        • et al.
        The epidemiology and virology of hepatitis C virus genotype 5 in central France.
        Aliment Pharmacol Ther. 2007; 26: 1437-1446
        • Karatapanis S.
        • Tsoplou P.
        • Papastergiou V.
        • Vasiageorgi A.
        • Stampori M.
        • Saitis I.
        • et al.
        Hepatitis C virus genotyping in Greece: unexpected high prevalence of genotype 5a in a Greek island.
        J Med Virol. 2012; 84: 223-228
        • 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. 2009; 137: 79-84
        • Jover R.
        • Pérez-Serra J.
        • de Vera F.
        • Alamo J.M.
        • Muñoz C.
        • Yago C.
        • et al.
        Infection by genotype 5a of HCV in a district of southeast Spain.
        Am J Gastroenterol. 2001; 96: 3042-3043
        • Wantuck J.M.
        • Ahmed A.
        • Nguyen M.H.
        Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6.
        Aliment Pharmacol Ther. 2014; 39: 137-147
        • Thong V.D.
        • Akkarathamrongsin S.
        • Poovorawan K.
        • Tangkijvanich P.
        • Poovorawan Y.
        Hepatitis C virus genotype 6: virology, epidemiology, genetic variation and clinical implication.
        World J Gastroenterol. 2014; 20: 2927-2940
        • Zhou N.
        • Hernandez D.
        • Ueland J.
        • Yang X.Y.
        • Yu F.
        • Sims K.
        • et al.
        NS5A Sequence heterogeneity and mechanisms of daclatasvir resistance in hepatitis C virus genotype 4 infection.
        J Infect Dis. 2016; 213: 206-215
        • Asselah T.
        • Bourliere M.
        Hepatitis C virus current and evolving treatments for genotype 4.
        Gastroenterol Clin North Am. 2015; 44: 859-870
        • Smith D.B.
        • Bukh J.
        • Kuiken C.
        • Muerhoff A.S.
        • Rice C.M.
        • Stapleton J.T.
        • et al.
        Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource.
        Hepatology. 2014; 59: 318-327
        • Estrabaud E.
        • Vidaud M.
        • Marcellin P.
        • Asselah T.
        Genomics and HCV infection: progression of fibrosis and treatment response.
        J Hepatol. 2012; 57: 1110-1125
        • Asselah T.
        • De Muynck S.
        • Broët P.
        • Masliah-Planchon J.
        • Blanluet M.
        • Bièche I.
        • et al.
        IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.
        J Hepatol. 2012; 56: 527-532
        • Bonny C.
        • Fontaine H.
        • Poynard T.
        • Hézode C.
        • Larrey D.
        • Marcellin P.
        • et al.
        Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study.
        Aliment Pharmacol Ther. 2006; 24: 593-600
        • Seto W.K.
        • Lai C.L.
        • Fung J.
        • Hung I.
        • Yuen J.
        • Young J.
        • et al.
        Natural history of chronic hepatitis C: genotype 1 vs. genotype 6.
        J Hepatol. 2010; 53: 444-448
        • Marcellin P.
        • Cheinquer H.
        • Curescu M.
        • Dusheiko G.M.
        • Ferenci P.
        • Horban A.
        • et al.
        High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials.
        Hepatology. 2012; 56: 2039-2050
        • 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
        • Asselah T.
        • Esmat G.
        • Sanai F.M.
        • Goulis I.
        • Messinger D.
        • Bakalos G.
        • et al.
        Simple predictive model for identifying patients with chronic hepatitis C and hepatitis C virus genotype 4 infection with a high probability of sustained virologic response with peginterferon alfa-2a/ribavirin: pooled analysis of data from two large.
        International Cohort Studies Adv Ther. 2016; 33: 1797-1813
        • Devaki P.
        • Jencks D.
        • Yee B.E.
        • Nguyen M.H.
        Sustained virologic response to standard interferon or pegylated interferon and ribavirin in patients with hepatitis C virus genotype 5: systematic review and meta-analysis of ten studies and 423 patients.
        Hepatol Int. 2015; 9: 431-437
        • Nguyen N.H.
        • McCormack S.A.
        • Yee B.E.
        • Devaki P.
        • Jencks D.
        • Chao D.T.
        • et al.
        Meta-analysis of patients with hepatitis C virus genotype 6: 48 weeks with pegylated interferon and ribavirin is superior to 24 weeks.
        Hepatol Int. 2014; 8: 540-549
        • Choo Q.L.
        • Kuo G.
        • Weiner A.J.
        • Overby L.R.
        • Bradley D.W.
        • Houghton M.
        Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.
        Science. 1989; 244: 359-362
        • Lohmann V.
        • Korner F.
        • Koch J.
        • Herian U.
        • Theilmann L.
        • Bartenschlager R.
        Replication of sub-genomic hepatitis C virus RNAs in a hepatoma cell line.
        Science. 1999; 285: 3
        • Blight K.J.
        • Kolykhalov A.A.
        • Rice C.M.
        Efficient initiation of HCV RNA replication in cell culture.
        Science. 2000; 290: 1972-1974
        • Lamarre D.
        • Anderson P.C.
        • Bailey M.
        • Beaulieu P.
        • Bolger G.
        • Bonneau P.
        • et al.
        An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.
        Nature. 2003; 426: 186-189
        • Zeuzem S.
        • Soriano V.
        • Asselah T.
        • Bronowicki J.P.
        • Lohse A.W.
        • Müllhaupt B.
        • et al.
        Faldaprevir and deleobuvir for HCV genotype 1 infection.
        N Engl J Med. 2013; 369: 630-639
        • Gao M.
        • Nettles R.E.
        • Belema M.
        • Snyder L.B.
        • Nguyen V.N.
        • Fridell R.A.
        • et al.
        Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
        Nature. 2010; 465: 96-100
        • Schinazi R.
        • Halfon P.
        • Marcellin P.
        • Asselah T.
        HCV direct-acting antiviral agents: The best interferon-free combinations.
        Liver Int. 2014; 34: 69-78
        • Kim J.L.
        • Morgenstern K.A.
        • Lin C.
        • Fox T.
        • Dwyer M.D.
        • Landro J.A.
        • et al.
        Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.
        Cell. 1996; 87: 343-355
        • Yao N.
        • Hesson T.
        • Cable M.
        • Hong Z.
        • Kwong A.D.
        • Le H.V.
        • et al.
        Structure of the hepatitis C virus RNA helicase domain.
        Nat Struct Biol. 1997; 4: 463-467
        • Halfon P.
        • Locarnini S.
        Hepatitis C virus resistance to protease inhibitors.
        J Hepatol. 2011; 55: 192-206
        • Koch U.
        • Narjes F.
        Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
        Curr Top Med Chem. 2007; 7: 1302-1329
        • Gish R.G.
        • Meanwell N.A.
        The NS5A replication complex inhibitors: Difference makers?.
        Clin Liver Dis. 2011; 15: 627-639
        • Hézode C.
        • Hirschfield G.M.
        • Ghesquiere W.
        • Sievert W.
        • Rodriguez-Torres M.
        • Shafran S.
        • et al.
        Randomized study of daclatasvir plus peginterferon alfa-2a and ribavirin for previously untreated chronic hepatitis C.
        Gut. 2015; 64: 948-956
        • Lawitz E.
        • Mangia A.
        • Wyles D.
        • Rodriguez-Torres M.
        • Hassanein T.
        • Gordon S.C.
        • et al.
        Sofosbuvir for previously untreated chronic hepatitis C infection.
        N Engl J Med. 2013; 368: 1878-1887
        • Asselah T.
        • Moreno C.
        • Sarrazin C.
        • Gschwantler M.
        • Foster G.R.
        • Craxí A.
        • et al.
        Efficacy of a 12-week simeprevir plus peginterferon/ribavirin (PR) regimen in treatment-naïve patients with hepatitis C virus (HCV) genotype 4 (GT4) infection and mild-to-moderate fibrosis displaying early on-treatment virologic response.
        PLoS One. 2017; 12: e0168713
        • Ruane P.J.
        • Ain D.
        • Stryker R.
        • Meshrekey R.
        • Soliman M.
        • Wolfe P.R.
        • et al.
        Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry.
        J Hepatol. 2015; 62: 1040-1046
        • Doss W.
        • Shiha G.
        • Hassany M.
        • Soliman R.
        • Fouad R.
        • Khairy M.
        • et al.
        Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4.
        J Hepatol. 2015; 63: 581-585
        • Elsharkawy A.
        • Fouad R.
        • Elakel W.
        • El-Raziky M.
        • Hassany M.
        • Shiha G.
        • et al.
        Sofosbuvir based treatment regimens: Real life results of 14,409 chronic HCV genotype 4 patients.
        Aliment Pharmacol Ther. 2017; 45: 681-687
        • Buti M.
        • Calleja J.L.
        • Lens S.
        • Diago M.
        • Ortega E.
        • Crespo J.
        • et al.
        Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).
        Aliment Pharmacol Ther. 2017; 45: 468-475
        • El Raziky M.
        • Gamil M.
        • Ashour M.K.
        • Abdel Sameea E.
        • Doss W.
        • Hamada Y.
        • et al.
        Simeprevir plus sofosbuvir for 8 or 12 weeks in treatment-naïve and -experienced hepatitis C virus genotype 4 patients with or without cirrhosis.
        J Viral Hepat. 2017; 24: 102-110
        • Eletreby R.
        • Elakel W.
        • Said M.
        • El Kassas M.
        • Seif S.
        • Elbaz T.
        • et al.
        Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients.
        Liver Int. 2017; 37: 534-541
        • Poordad F.
        • Schiff E.R.
        • Vierling J.M.
        • Landis C.
        • Fontana R.J.
        • Yang R.
        • et al.
        Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence.
        Hepatology. 2016; 63: 1493-1505
        • Luetkemeyer A.F.
        • McDonald C.
        • Ramgopal M.
        • Noviello S.
        • Bhore R.
        • Ackerman P.
        12 Weeks of daclatasvir in combination with sofosbuvir for HIV-HCV coinfection (ALLY-2 Study): efficacy and safety by HIV combination antiretroviral regimens.
        Clin Infect Dis. 2016; 62: 1489-1496
        • Welzel T.M.
        • Petersen J.
        • Herzer K.
        • Ferenci P.
        • Gschwantler M.
        • Wedemeyer H.
        • et al.
        Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort.
        Gut. 2016; 65: 1861-1870
      2. Omar H, El Akel W, Elbaz T, El Kassas M, El Saeed K, El Shazly H, et al. Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18,378 patients in Egypt. Submitted.

        • Abergel A.
        • Metivier S.
        • Samuel D.
        • Jiang D.
        • Kersey K.
        • Pang P.S.
        • et al.
        Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection.
        Hepatology. 2016; 64: 1049-1056
        • Camus G.
        • Han B.
        • Asselah T.
        • Hsieh D.
        • Dvory-Sobol H.
        • Lu J.
        • et al.
        Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4.
        J Viral Hepat. 2018; (in press)
        • Kohli A.
        • Kapoor R.
        • Sims Z.
        • Nelson A.
        • Sidharthan S.
        • Lam B.
        • et al.
        Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study.
        Lancet Infect Dis. 2015; 15: 1049-1054
        • Shiha G.
        • Waked I.
        • Soliman R.E.
        • Abdelrazek W.
        • Hassany M.
        • Fouad R.
        • et al.
        Ledipasvir/sofosbuvir in egyptian patients with chronic genotype 4 HCV infection.
        Hepatology. 2016; 64 ([AASLD 2016, Abstract # 879]): 436A-437A
        • Feld J.J.
        • Jacobson I.M.
        • Hezode C.
        • Asselah T.
        • Ruane P.J.
        • Gruener N.
        • et al.
        Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
        N Engl J Med. 2015; 373: 2599-2607
        • Asselah T.
        • Bourgeois S.
        • Pianko S.
        • Zeuzem S.
        • Sulkowski M.
        • Foster G.R.
        • et al.
        Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1–6 and compensated cirrhosis or advanced fibrosis.
        Liver Int. 2018; (in press)
        • Jacobson I.M.
        • Lawitz E.
        • Gane E.J.
        • Willems B.E.
        • Ruane P.J.
        • Nahass R.G.
        • et al.
        Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomised trials.
        Gastroenterology. 2017; 153: 113-122
        • Hezode C.
        • Asselah T.
        • Reddy K.R.
        • Hassanein T.
        • Berenguer M.
        • Fleischer-Stepniewska K.
        • et al.
        Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.
        Lancet. 2015; 385: 2502-2509
        • Asselah T.
        • Hézode C.
        • Qaqish R.B.
        • ElKhashab M.
        • Hassanein T.
        • Papatheodoridis G.
        • et al.
        Co-formulated ombitasvir and paritaprevir/ritonavir with ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a randomised, open-label trial.
        Lancet Gastroenterol Hepatol. 2016; 1: 25-35
        • Waked I.
        • Shiha S.
        • Qaqish R.B.
        • Esmat G.
        • Yosry A.
        • Hassany M.
        • et al.
        Co-formulated ombitasvir and paritaprevir/ritonavir plus ribavirin for chronic hepatitis C virus genotype 4 infection in Egyptian patients with or without compensated cirrhosis (AGATE-II): a randomised, open-label trial.
        Lancet Gastroenterol Hepatol. 2016; 1: 36-45
        • Ng T.
        • Krishnan P.
        • Pilot-Matias T.
        • Kati W.
        • Schnell G.
        • Beyer J.
        • et al.
        In vitro antiviral activity and resistance profile of the next generation hepatitis C virus NS5A inhibitor pibrentasvir.
        Antimicrob Agents Chemother. 2017; 61
        • Asselah T.
        • Kowdley K.V.
        • Zadeikis N.
        • Wang S.
        • Hassanein T.
        • Horsmans Y.
        • et al.
        Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis.
        Clin Gastroenterol Hepatol. 2018; (in press)
        • Asante-Appiah E.
        • Curry S.
        • McMonagle P.
        • Ingravallo P.
        • Chase R.
        • Nickle D.
        Antiviral activity and resistance analysis of NS3/4A protease inhibitor grazoprevir and NS5A inhibitor elbasvir in hepatitis C virus GT4 replicons.
        Antimicrob Agents Chemother. 2017; 61 ([pii: e00363-17])
        • Asselah T.
        • Reesink H.
        • Gerstoft J.
        • de Ledinghen V.
        • Pockros P.
        • Robertson M.
        • et al.
        High efficacy of elbasvir and grazoprevir with or without ribavirin in 103 treatment-naive and experienced patients with HCV genotype 4 infection : a pooled analysis.
        Hepatology. 2015; ([AASLD; abstract 251])
        • Roth D.
        • Nelson D.R.
        • Bruchfeld A.
        • Liapakis A.
        • Silva M.
        • Monsour Jr, H.
        • et al.
        Grazoprevir plus elbasvir in treatment-naive and treatment experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.
        Lancet. 2015; 386: 1537-1545
      3. Kramer JR, Puenpatom A, Erickson K, Cao Y, Smith DL, El-Serag HB, et al. Effectiveness of elbasvir/grazoprevir in patients with chronic hepatitis C and chronic kidney disease: results from the veterans affairs system. In: 68th annual meeting of the American association for the study of liver diseases, October 20–24. Washington DC, USA; 2017 [abstract 1113].

        • Esmat G.
        • Elbaz T.
        • El Raziky M.
        • Gomaa A.
        • Abouelkhair M.
        • El Deen H.G.
        • et al.
        Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis c genotype-4.
        J Hepatol. 2017; S0168–8278: 32286-32289
        • Abergel A.
        • Asselah T.
        • Metivier S.
        • Kersey K.
        • Jiang D.
        • Mo H.
        • et al.
        Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study.
        Lancet Infect Dis. 2016; 16: 459-464
        • Gane E.J.
        • Hyland R.H.
        • An D.
        • Svarovskaia E.
        • Pang P.S.
        • Brainard D.
        • et al.
        Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection.
        Gastroenterology. 2015; 149: 1454-1461
      4. Nguyen M, et al. LC2017-RS-1361.

      5. Hassanein T, Wyles D, Wang S, Kwo PY, Shiffman ML, Younes Z, et al. SURVEYOR-II, Part 4: Glecaprevir/Pibrentasvir Demonstrates High SVR Rates in Patients With HCV Genotype 2, 4, 5, or 6 Infection Without Cirrhosis Following an 8-Week Treatment Duration. AASLD 2016, Boston. #LB-15.

        • Martinot-Peignoux M.
        • Stern C.
        • Maylin S.
        • Ripault M.P.
        • Boyer N.
        • Leclere L.
        • et al.
        Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.
        Hepatology. 2010; 51: 1122-1126
        • Maylin S.
        • Martinot-Peignoux M.
        • Moucari R.
        • Boyer N.
        • Ripault M.P.
        • Cazals-Hatem D.
        • et al.
        Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C.
        Gastroenterology. 2008; 135: 821-829
        • Curry M.P.
        • O’Leary J.G.
        • Bzowej N.
        • et al.
        Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
        N Engl J Med. 2015; 373: 2618-2628
        • Afdhal N.
        • Everson G.T.
        • Calleja J.L.
        • McCaughan G.W.
        • Bosch J.
        • Brainard D.M.
        • et al.
        Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension.
        J Viral Hepat. 2017; 24: 823-831
      6. Kim RW, Mannalithara A, Lee H, Osinusi A, Schall REA, Brainard DM. Survival benefit of direct acting antiviral therapy in patients with decompensated cirrhosis. Hepatology 2017;66:LB27.

        • Younossi Z.M.
        • Stepanova M.
        • Asselah T.
        • et al.
        Hepatitis C in patients with minimal or no hepatic fibrosis: the impact of treatment and sustained virologic response on patient-reported outcomes.
        Clin Infect Dis. 2018; (in press)
        • Appourchaux K.
        • Dokmak S.
        • Resche-Rigon M.
        • Treton X.
        • Lapalus M.
        • Gattolliat C.H.
        • et al.
        MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C.
        Sci Rep. 2016; 12: 34935
      7. EASL Recommendations on Treatment of Hepatitis C 2016.
        J Hepatol. 2017; 66: 153-194
      8. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org.

        • Dore G.J.
        • Altice F.
        • Litwin A.H.
        • Dalgard O.
        • Gane E.J.
        • Shibolet O.
        • et al.
        Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial.
        Ann Intern Med. 2016; 165: 625-634
        • Lalezari J.
        • Sullivan J.G.
        • Varunok P.
        • Galen E.
        • Kowdley K.V.
        • Rustgi V.
        • et al.
        Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine.
        J Hepatol. 2015; 63: 364-369
        • Moser S.
        • Schütz A.
        • Marchart K.
        • Kalchbrenner D.
        • Rechberger G.
        • Luhn J.
        • et al.
        Directly observed therapy with sofosbuvir/ledipasvir for 8 weeks is highly effective in treatment-naïve, precirrhotic genotype 1 patients with borderline compliance receiving opioid agonist therapy.
        J Hepatol. 2017; 66: S740
        • Grebely J.
        • Dalgard O.
        • Conway B.
        • Cunningham E.
        • Bruggmann P.
        • Hajarizadeh B.
        • et al.
        Efficacy and safety of sofosbuvir/velpatasvir in people with chronic hepatitis C virus infection and recent injecting drug use: The SIMPLIFY study.
        J Hepatol. 2017; 66: S513
        • Dore G.
        • Grebely J.
        • Altice F.
        • et al.
        Hepatitis C virus (HCV) reinfection and injecting risk behavior following elbasvir (EBR)/grazoprevir (GZR) treatment in participants on opiate agonist therapy (OAT): Co-STAR part B [AASLD Liver Meeting abstract 195].
        Hepatology. 2017; 66
        • Bourlière M.
        • Gordon S.C.
        • Flamm S.L.
        • Cooper C.L.
        • Ramji A.
        • Tong M.
        • et al.
        Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection.
        N Engl J Med. 2017; 376: 2134-2146
        • Poordad F.
        • Felizarta F.
        • Asatryan A.
        • Sulkowski M.S.
        • Reindollar R.W.
        • Landis C.S.
        • et al.
        Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment.
        Hepatology. 2017; 66: 389-397