Reviews in Medical Virology

REVIEW

Rev. Med. Virol. 2015; 25: 254–267. Published online 4 June 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/rmv.1842

Development of antiviral drugs for the treatment of hepatitis C at an accelerating pace Erik De Clercq* Rega Institute for Medical Research, KU Leuven, Leuven, Belgium

S U M M A RY Anno 2015, the race for developing the ideal therapy, or what is now called “cure,” for hepatitis C virus infection has continued unabatedly. The targets (NS3/4A protease, NS5A protein, and NS5B polymerase) have remained the same, and the number of compounds [direct-acting antivirals (DAAs)] interacting with these targets has continued to increase. Whereas pan-genotypic activity has remained a mandatory requirement, the problem of virus drug resistance has become less crucial. The need for combining DAAs acting at different sites has remained compelling, with the drugs used for combinations emanating from the same pharmaceutical company, that is, Gilead (sofosbuvir and ledipasvir) (Gilead Sciences, Foster City, CA, USA) (AbbVie, North Chicago, IL, USA), AbbVie (ABT/r, ombitasvir, and dasabuvir), and BMS (Bristol-Myers Squibb), (New York City, NY, USA) (asunaprevir and daclatasvir) among the leading contenders. At stake is the definitive cure of HCV infection [as reflected by a sustained viral response (SVR) after 12 weeks of treatment]. This SVR is expected to reduce cirrhosis and hepatocellular carcinoma, two complications inherently linked to HCV infection. Unlike hepatitis B virus and human immunodeficiency virus, HCV infection can be definitely and permanently cured by antiviral therapy because HCV has no long-term reservoir in the body. Peginterferon combined with ribavirin and even the first-wave protease inhibitors telaprevir and boceprevir now belong to the milestones that had an important, although historical, role in the final conquest of hepatitis C. Copyright © 2015 John Wiley & Sons, Ltd. Received: 17 March 2015; Revised: 4 May 2015; Accepted: 5 May 2015

INTRODUCTION With the advent of sofosbuvir and simeprevir, which were both approved by the US Food and Drug Administration (FDA) for the treatment of HCV infections at the end of 2013 (December and November, respectively) [1], treatment of HCV infections has entered a new era. While the introduction of interferon (later followed by pegylated interferon) in combination with ribavirin provided an SVR of about 50%, after a treatment duration of 48 weeks, the introduction of simeprevir and sofosbuvir allowed an SVR of quasi-100% to be achieved within a treatment period of only 12 weeks (Table 1) [2]. I have previously reviewed the role of sofosbuvir in the current context of HCV treatment [3] and surveyed the landscape of *Correspondence to: E. De Clercq, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: [email protected] Abbreviations used /r, boosted by ritonavir; DAAs, direct-acting antivirals; FDA, Food and Drug Administration; HCC, hepatocellular carcinoma; PR, peginterferon and ribavirin; PROs, patient-reported outcomes; SVR, sustained viral response.

Copyright © 2015 John Wiley & Sons, Ltd.

the DAAs against HCV [4], but the progress in this field has been so tremendous that it needs another review on the “state of the art” anno 2015. The life cycle of HCV and the targets for antiviral therapy are reviewed in Figure 1 [5]. The most important DAAs and molecular targets for their interaction are described in Figure 2 [6]. Examples where 100% SVR12 (SVR at 12 weeks) with these DAAs were achieved are pointed out in Figure 3. Anti-HCV agents could be schematically divided into two classes: (i) those that are targeted at host factors (i.e. CD81, SCARB1, OCLN, CLIDNI, cyclophilin A, and miR122) and (ii) those that are targeted at viral factors (E1/E2, p7, NS3/4A, NS4B, NS5A, and NS5B; those targeted at the NS5B can be divided into nucleoside type of inhibitors and non-nucleosidic inhibitors) [7]. Those that are targeted at NS3/4A, NS5A, and NS5B (nucleoside type of inhibitors and non-nucleosidic inhibitors) have been reviewed on previous occasions [4,8–10]. In all cases, the genotype studied was genotype 1, except for sofosbuvir for which all six genotypes were studied (and found sensitive, although genotype 3 to a lower extent) [10].

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Table 1. HCV therapies of the past, present, and future [2]

Therapy IFNα IFNα + RBV PegIFN 2a/2b PegIFN + RBV PegIFN + RBV + telaprevir PegIFN + RBV + boceprevir PegIFN + RBV + simeprevir PegIFN + RBV + sofosbuvir Simeprevir + sofosbuvir Sofosbuvir + ledipasvir

Treatment SVR-12/24 duration weeks (%) (weeks) 16 42 39 55 ~70–75 ~70–75 ~80 ~90 100 ~100

PegIFN, pegylated interferon; RBV, ribavirin.

48 48 48 48 48 48 48 12 12 12

While an SVR12 has been considered to herald a definite cure of the disease, this is only a tentative assumption: sensu stricto, an SVR12 does not guarantee a complete clearance of the virus and/or absence of the possibility of later relapses. Later relapses may, in fact, also be introduced by new infections. TELAPREVIR AND BOCEPREVIR (TABLE 2) Both telaprevir (Incivek® Vertex Pharmaceuticals, Cambridge, MA, USA) and boceprevir (Victrelis® Merck & Co., Inc., Whitehouse Station, NJ, USA) were approved for clinical use in 2011, in combination with peginterferon and ribavirin (PR). In the treatment of HCV genotype 1 infection in patients with cirrhosis, among patients given telaprevir, 72.2% of relapsers, 40% of partial responders, and 19.4% of null responders achieved SVR12; among those given boceprevir, 53.9% of relapsers, 38.3% of

Figure 1. The life cycle of hepatitis C virus and targets for antiviral therapy. HCV polyprotein processing is targeted by NS3/4A inhibitors (“protease inhibitors”). HCV RNA replication is targeted by NS5B polymerase inhibitors (“nucleosides and non-nucleosides”), NS5A inhibitors, and cyclophilin A inhibitors. NS5A inhibitors interfere with HCV replication, assembly, and release. Specific inhibitors of viral entry are targeted at claudin 1 (CLDN1), low-density lipoprotein receptor (LDL-R), or scavenger receptor B1 (SR-B1). According to Lange et al. [5]

Copyright © 2015 John Wiley & Sons, Ltd.

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Figure 2. Most important targets for direct-acting antivirals: protease inhibitors targeted at NS3, NS5A inhibitors targeted at NS5A, and polymerase inhibitors (nucleosides and non-nucleosides) targeted at NS5B. According to Schinazi et al. [6]. Abbreviations as in ref. 6. The DAAs are tabulated in Table 2 (NS3/4A protease inhibitors), Table 3 (NS5A inhibitors), Table 4 (NS5B polymerase “nucleoside” inhibitors) and Table 5 (NS5B polymerase “non-nucleoside” inhibitors).

partial responders, and none of null responders achieved SVR12 [11]. Drug resistance is a factor that should be considered in NS3/4A protease inhibitor therapies for HCV-infected patients; and A156F/N/V, V36A + R155K/T, V36M + R155T, V36A/M + A156T, T54A + A156S, T54S + A156S/T, and V36M + T54S + R155K have proven to confer high-level resistance to telaprevir [12]. Telaprevir could achieve an SVR of 84% [13], and its dosage (normally 3 × 750 mg every 8 h daily) could be simplified to 1125 mg twice daily [14]. In patients with cirrhosis [15] and liver transplant recipients [16], telaprevir and/or boceprevir is much less efficient than in the absence of these complications. Rash is common in telaprevir-treated patients [17], and anemia is a known complication for both telaprevir [18–20] and boceprevir [21], which means that treatment with telaprevir or boceprevir should be cautiously monitored from a dermatological and hematological viewpoint, and according to Virlogeux et al. [22], for renal functions as well. Yet, telaprevir and boceprevir could both be considered as costeffective, when combined with PR [23–25]. Also, no drug interactions have been noted with telaprevir or boceprevir when combined with other drugs such as darunavir [26], dolutegravir [27], cyclosporin [28], or hypericin (St John’s wort [29]). Copyright © 2015 John Wiley & Sons, Ltd.

SIMEPREVIR (SOVRIAD AND OLYSIO®) (TABLE 2) Following telaprevir and boceprevir, simeprevir (TMC435) (Johnson & Johnson, New Brunswick, NJ, USA) [30] is the third HCV NS3/4A protease inhibitor to be approved by the US FDA for clinical use in the treatment of HCV genotype 1 infections in combination with PR. In the pivotal phase III clinical trials, simeprevir was administered once daily at 150 mg for 12 weeks in combination with PR for 24 or 48 weeks [31]. In these pivotal studies (QUEST-1 and QUEST-2), simeprevir achieved an SVR12 in 80% or 81% of the patients [32,33]. In treatment-experienced HCV genotype 1-infected patients (in Japan), SVR12 rates were 52.8% (SMV12) and 35.8% (SMV24), respectively, for prior nonresponders; in these studies, the simeprevir dosage was 100 mg once daily [34]. In patients with HCV genotype 1, who relapsed after previous therapy, the SVR12 rate was 79.2% following simeprevir (150 mg, once daily) and PR [35]. In treatment-experienced patients, 12, 24, or 48 weeks of simeprevir (100 or 150 mg once daily) in combination with 48 weeks of PR invariably increased the SVR rates at 24 weeks, to 86–89% in the best case [36]. The addition of simeprevir to the PR regimen allowed the majority of patients to Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv

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Figure 3. SVR12 obtained for different drug combinations. According to Schinazi et al. [6]

shorten their therapy duration to 24 weeks [37,38]. Side effects specifically due to simeprevir were not noted, except for a mild, reversible jaundice [39]. OTHER NS3/4A PROTEASE INHIBITORS: FALDAPREVIR, DANOPREVIR, VANIPREVIR, AND GRAZOPREVIR (TABLE 2) Initial results indicate that various protease inhibitors hold promise for the treatment of HCV infections, when combined with PR. For example, faldaprevir, when administered at 240 mg once Copyright © 2015 John Wiley & Sons, Ltd.

daily, could achieve an SVR24 of up to 83% in Japanese patients [40]. Danoprevir/r (twice daily, 100 mg every 12 h) and PR could achieve an SVR24 in 67% (88% in genotype 1b, as compared with 25% in genotype 1a) of prior null responders [41]; in treatment-naïve patients, SVR24 rates with danoprevir went up even to 96.6% in genotype 1b and 100% in genotype 4 [42]. For vaniprevir and PR, the SVR24 in cirrhotic patients with null or partial response to prior therapy was 42.1%, resistance-associated mutations being found at Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv

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Table 2. NS3/4A protease inhibitors Telaprevir (Incivek®) Boceprevir (Victrelis®) Simeprevir (TMC 435), Sovriad, Olysio® Paritaprevir (ABT-450)/r Asunaprevir (BMS-650032) Faldaprevir (BI-201335) Danoprevir (ITMN-191, RG7227) Sovaprevir (ACH-1625) Vedroprevir (GS-9451) GS-9256 Vaniprevir (MK-7009) Grazoprevir (MK-5172) positions 155, 156, and 168 of the HCV protease gene [43]. Finally, grazoprevir (MK-5172), given once daily at 100, 200, 400, or 800 mg, combined with PR for 24 or 48 weeks, achieved an SVR24 in, respectively, 89%, 93%, 91%, and 86% of treatment-naïve patients with HCV genotype 1 infection without cirrhosis [44]. NS5A INHIBITORS (TABLE 3) The first-in-class NS5A inhibitor is daclatasvir (BMS790052), for which extremely low EC50 (50% effective (= inhibitory) concentration) values (i.e. 9 pM) were found to inhibit genotype 1b replicons [45]. Daclatasvir, in combination with PR, achieved an SVR24 in 90% of treatment-naïve HCV genotype 1, compared with 62.5% with PR alone [46]. Combined with PR, daclatasvir (at a dosage of 60 mg) even achieved a 100% success rate in SVR24 in Japanese HCV genotype 1 patients [47]. Daclatasvir may lead to resistance quasispecies emerging over time, especially in patients who do not rapidly respond to

Table 3. NS5A inhibitors Daclatasvir (BMS-790052) Ledipasvir (GS-5885) Ombitasvir (ABT-267) ACH-3102 Samatasvir (IDX719) Elbasvir (MK-8742) AZD-7295 GSK2336805 PPI-668 GS-5816 Copyright © 2015 John Wiley & Sons, Ltd.

E. De Clercq daclatasvir [48]. Genotype 1b has the highest relative resistance barrier and genotype 2a the second lowest, the relative order of resistance barrier to daclatasvir being 1b > 4a ≥ 5a > 6a ~ 1a > 2a > 3a [49]. Daclatasvir has the potential to be an effective agent for HCV genotypes 1–6 but should be used in combination therapy [50]. Ledipasvir should, in principle, lead to the emergence of variants (i.e. M28T, Q30R, L31M, and Y93C) causing cross-resistance to daclatasvir or other NS5A inhibitors [50]. Again, ledipasvir, like daclatasvir, should be used in combination, and for ledipasvir, the ideal partner should be sofosbuvir, which has now been launched as a fixed-dose drug combination pill (Harvoni®, Gilead Sciences, Foster City, CA, USA once daily (consisting of 400 mg sofosbuvir and 90 mg ledipasvir). ABT-267 is an NS5A inhibitor active against HCV genotypes 2a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a, thus truly pan-genotypic [51]. ABT-267 could be combined with other DAAs such as paritaprevir (ABT-450)/r and ABT-333. Also, samatasvir (IDX719) has been heralded as a pan-genotypic NS5A inhibitor active against HCV genotypes 1, 2, 3, and 4 [52]. It could be administered as a once-daily dose at 25–100 mg in combination with other DAAs such as simeprevir. NS5B (NUCLEOSIDE-TYPE) INHIBITORS (TABLE 4) Mericitabine (RG-7128) is the only nucleoside-type NS5B inhibitor that after the success obtained by sofosbuvir is still being pursued as a potential antiviral drug for HCV treatment. As it stems from the era that interferon and ribavirin, when combined, constituted the standard of care for HCV infections, mericitabine was combined with PR in the treatment of HCV infections [53]. This approach will no longer be implemented in the future. Several nucleoside/nucleotide analogues, once upon a time considered for clinical development, have been discontinued for varying reasons [54]. Sofosbuvir was approved by the US FDA in December 2013 for the treatment of HCV genotype 1 infection in combination with PR [55]. Sofosbuvir

Table 4. NS5B polymerase inhibitors (“nucleoside”) Sofosbuvir (GS-7977), Sovaldi® Mericitabine (RG-7128) Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv

Treatment of hepatitis C accelerating was quoted as being effective, in combination with ribavirin, in the treatment for 12 weeks of HCV genotype 1, 2, or 3 infections [56]. However, sofosbuvir plus ribavirin is clearly less effective against HCV genotype 3 than against HCV genotype 2, especially in cirrhotic patients [57]. Patientreported outcomes (PROs) are minimally impacted by sofosbuvir + ribavirin regimens for 12 weeks [58]; also, patients with cirrhosis showed improvement in some aspects of their PROs [59]. In genotype 2, sofosbuvir and ribavirin for 12 weeks achieved an SVR of ≥90% with little effect from cirrhosis, but genotype 3 was less responsive, especially in the presence of cirrhosis [60]. Sofosbuvir is renally eliminated and does not require adjustment (once-daily dose of 400 mg) in mild to moderate renal insufficiency, or in any degree of hepatic impairment; it is not metabolized by cytochrome P450 isoenzymes, nor does it induce or inhibit the metabolism of agents that are substrates of these enzymes [61]. Sofosbuvir has a high barrier to resistance; in vivo, a double mutation (L159F/L320F) may emerge that confers low-level resistance to both mericitabine and sofosbuvir [62]. So, the question arises as to whether any nucleoside/ nucleotide could do better than sofosbuvir to treat hepatitis C [63]. The principal limitation is its lower efficacy in genotype 3, but this can be largely overcome if sofosbuvir is combined with another DAA, as in the fixed-dose drug combination with ledipasvir (Harvoni®). COMBINATIONS OF DIRECT-ACTING ANTIVIRALS (FIGURE 4) Asunaprevir (200 mg, once or twice daily) plus daclatasvir (60 mg, once daily) plus PR achieved an SVR12 rate of 95% in HCV genotype 1 null responders [64]. In Japanese patients, who were interferon ineligible/intolerant, daclatasvir (60 mg, once daily) plus asunaprevir (100 mg, twice daily) achieved an SVR24 of 87.4%, in 80.5% of nonresponder (null and partial), 90.9% of cirrhotic, and 84.0% of non-cirrhotic patients [65]. In treatmentnaïve patients with HCV genotype 1 infection, the combination of daclatasvir, asunaprevir, and BMS-791325 achieved an SVR12 of 92% [66]. The SVR12 ranged from 83% to 100% if paritaprevir/r plus dasabuvir (ABT-333) plus ribavirin (without interferon) was administered to HCV genotype 1 patients [67]. The SVR12 rate was greater than 95% following retreatment of Copyright © 2015 John Wiley & Sons, Ltd.

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Figure 4. Possible and practical combinations (excluding (pegylated) interferon and ribavirin)

HCV genotype 1 patients with paritaprevir/r plus ombitasvir (ABT-267) plus dasabuvir plus ribavirin (without interferon) [68]. The SVR12 rate went up further to 98.0% if paritaprevir/r plus ombitasvir plus dasabuvir plus ribavirin was given to patients with HCV genotype 1b infection without cirrhosis [69]. SVR rates after 12 and 24 weeks in HCV genotype 1 patients with cirrhosis were 91.8% and 95.9%, respectively, following treatment with paritaprevir/r, ombitasvir, dasabuvir, and ribavirin [70]. From the studies of Ferenci et al. [71], it appeared that ribavirin is no longer needed, at least in the treatment of HCV genotype 1b infection, where paritaprevir/r–ombitasvir and dasabuvir achieved an SVR of 99.5% with ribavirin, as compared with 99.0% without ribavirin. Thus, in conclusion, paritaprevir, ritonavir, ombitasvir, and dasabuvir achieved a quasi-100% sustained virologic response without ribavirin in treatment-experienced patients with HCV genotype 1b infection [72]. VX-222 (400 mg, twice daily), in combination with telaprevir and PR, achieved an SVR24 of 90% in the treatment of HCV genotype 1 [73]. For Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv

260 mericitabine in combination with ritonavir-boosted danoprevir and ribavirin, the SVR rates were much less impressive: SVR24 of 25% in genotype 1a and 63.6% in genotype 1b patients [74]. Also, for the combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with HCV genotype 1 infection, an SVR12 in up to 63% of patients was noted [75], a performance that should be much improved upon if this combination were extended to sofosbuvir. Indeed, sofosbuvir (400 mg, once daily) in a fixed-dose combination, termed Harvoni®, with ledipasvir (90 mg) brought about an SVR12 of 95%, or even 100%, in HCV genotype 1 infections [76]. Similarly, the combination of sofosbuvir with GS-9669 proved highly effective in treatment-naïve patients with HCV genotype 1 infection [77]. The combination of ledipasvir and sofosbuvir accomplished a sustained virologic response of 99% in HCV genotype 1 infection [78], a performance that could hardly be improved upon, unless the total duration of treatment was reduced from 12 to 8 weeks (which afforded a sustained virologic response of 94% as compared with 95% for 12 weeks of treatment) in HCV genotype 1 infection without cirrhosis [79]. The combination of grazoprevir (MK-5172) and elbasvir (MK-8742), with or without ribavirin, for 12 weeks in patients with HCV genotype 1 monoinfection and HIV/HCV coinfection without cirrhosis achieved SVR rates of 87–98% [80]. Similar efficacy was observed in previously untreated patients with cirrhosis and patients with previous null response (with or without cirrhosis) [81]. Another combination, requiring the cooperation of two companies (Gilead Sciences and BMS), is that of sofosbuvir with daclatasvir, which has been found to be effective in previously untreated patients as well as those treated with telaprevir or boceprevir and which resulted in a sustained virologic response in 98%, 92%, and 89% of the patients with genotypes 1, 2, and 3 HCV infection, respectively [82]. As a commentary on this article, Asselah [83] noted that HCV genotype 4 patients were neglected, although they represent the majority of new infections (40 million worldwide) without access to therapy. HOST-TARGETING AGENTS In addition to the DAAs, host-targeting agents have been pursued, that is, alisporivir, a cyclophilin Copyright © 2015 John Wiley & Sons, Ltd.

E. De Clercq inhibitor [84], and HCV entry inhibitors including CD81-specific, scavenger receptor class B type I-specific, or claudin-1-specific antibodies or smallmolecule inhibitors erlotinib and dasatinib [85]. These compounds may act additively, or even synergistically, with the DAAs. A compound that somehow is not a hosttargeting agent, but does not belong to the classical DAAs, is GS-563253, which interacts directly with HCV particles, likely with E2, and inhibits virus infectivity [86]. NEW DIRECT-ACTING ANTIVIRALS Various new DAAs have been identified within the last year, which could potentially enrich the current pipeline: one of these compounds is BMS-605339, a tripeptidic acylsulfonamide, targeted at the NS3/4A protease inhibitor [87]. The other new DAAs are targeted at an allosteric site of the HCV NS5B polymerase, that is, the tricyclic indole derivative compound 34 [88]. BMS-791325 binds to the thumb site I of NS5B polymerase [89], and GS9669 binds to the thumb site II of NS5B polymerase [90]. Two newly developed compounds bind to the palm I site of NS5B polymerase: RG7109 (compound 41 [91]) and compound 2b in the work of Manfroni et al. [92]. Two new inhibitors act as nucleoside/nucleotide prodrugs: 2′-deoxy-2′spirooxetane ribonucleosides [93], which actually emanated from their spirocyclopropyl counterpart [94], and GS-6620, the first C-nucleoside HCV polymerase inhibitor ever found to demonstrate antiviral activity in HCV-infected patients [95].

Table 5. NS5B polymerase inhibitors (“non-nucleoside”) NNI site 1 Deleobuvir (BI-207127) NNI site 2 VX-222 NNI site 3 Setrobuvir (ANA-598) Dasabuvir (ABT-333) ABT-072 NNI site 4 Tegobuvir (GS-9190) NNI, non-nucleosidic inhibitor.

Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv

Treatment of hepatitis C accelerating “DIFFICULT-TO-TREAT” HCV-INFECTED PATIENTS Approximately 30% of HIV-infected patients are coinfected with HCV [96]. They belong to the difficult-to-treat HCV-infected patients [97,98]. HIV accelerates HCV-related fibrosis progression; and successful HCV therapy is associated with halting fibrosis progression [99]. Successful treatment of HCV, as mirrored by an SVR, does not mean that patients “cured” from their HCV infection should make them exempt of further vigilant monitoring [100]. While in HCV/HIV-coinfected patients, HIV, with the current means, cannot be considered amenable to eradication, however, envisioning HCV eradication is a possible task [101]. In HCV/HIV-coinfected patients, the primary goal, from the HCV side, should be targeted at halting the early stages of liver fibrosis [102]. From the HIV side, the necessary emphasis should be put on antiretroviral treatment [103–105]. But, in HCV/HIV-coinfected liver transplant recipients, the need for better tolerated and more efficacious HCV therapies is most welcome [106], and this is where the new DAAs such as sofosbuvir and ledipasvir could make the (expected) difference. In addition, difficult-to-treat patients should also include those with kidney failure or hematological malignancies and posttransplant populations. HEPATOCELLULAR CARCINOMA Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death; it mainly develops in patients with cirrhosis [107]. Cirrhosis is the most important risk factor for HCC, whether the cirrhosis is caused by chronic viral hepatitis (either HBV or HCV), alcoholic liver disease, autoimmune disease, primary biliary cirrhosis, and metabolic diseases such as hereditary hemochromatosis, α1-antitrypsin deficiency, or nonalcoholic fatty liver disease; in the Western hemisphere, HCC occurs in a background of cirrhosis in 90% of the cases [108]. The fact that HBV or HCV infection is the leading etiology for HCC makes HCC prevention a major goal of antiviral therapy [109]. Chronic HBV infection is associated with a 5-fold to 100-fold increase in the risk of HCC, whereas HCV infection is associated with a 15-fold to 20-fold increased risk of HCC [110]. This underscores the importance of antiviral therapies for either HBVor HCV, or both, in the prevention of HCC. The first evidence showing that combination therapy of peginterferon with ribavirin decreased Copyright © 2015 John Wiley & Sons, Ltd.

261 the risk of HCC, and improved survival in HCV/HBV dually infected patients, was reported by Liu et al. [111]. The combination of peginterferon with ribavirin can lower the HCC incidence in responders, particularly for aged and male patients [112], but even if interferon is used as an adjuvant after curative treatment of HBV/HCV-associated HCC, it may be beneficial, especially for HCVrelated HCC [113]. What happens to the liver after a virological cure of HCV, that is, SVR? If the patient has advanced fibrosis, he (or she) will still be at risk for post-SVR HCC [114]. Also, occult hepatitis B infection is an independent risk factor for developing HCC, especially in patients with advanced fibrosis or cirrhosis [115]. Increased gamma-glutamyl transferase (transpeptidase) levels would strongly correlate with the risk for HCC development in non-cirrhotic patients achieving a sustained virological response [116]. HCV GENOTYPE 3: THE NEW VILLAIN? HCV genotype 3 has long been considered as an easy-to-treat infection with higher cure rates (~70%) than other viral genotypes when using PR. For HIV/genotype 3 HCV coinfection, it has even been suggested to shorten the duration of treatment with PR from 48 to 24 weeks [117]. However, the unexpectedly lower performance of sofosbuvir in the treatment of genotype 3 HCV infection has put genotype 3 in the limelight as “the new villain” [118]. HCV genotype 3 is now associated with a significantly increased risk of developing cirrhosis and HCC compared with HCV genotype 1 [119]. Genotype 3 has become the most difficult to treat among the various HCV genotypes [120]. CONCLUSIONS The second wave of HCV treatment (the first one being that of telaprevir and boceprevir) has moved away from interferon and now contains for HCV genotype 1 infection, principally sofosbuvir, ledipasvir, the ABT compounds, faldaprevir, asunaprevir, and daclatasvir [121]. The goal has become to develop therapies that lead to a cure that is safe, widely accessible and available, and effective against all HCV genotypes, and at all stages of the disease [122]. A once-daily pill for HCV, since the advent of Harvoni® (a fixed-dose drug containing 90 mg ledipasvir and 400 mg sofosbuvir), is no longer a myth [123]. Also, for the treatment of HCV Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv

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infection in liver transplant patients, the DAAs offer “a flood of opportunity” [124]. We are entering a new era of therapy for HCV infection, that is, the interferon-free era [125]. Peginterferon may remain useful for salvage therapy, but its days as a mainstay of HCV therapy are definitely gone [126]. It is now possible to cure chronic HCV in the vast majority of patients without interferon [127]. Peginterferon may even negatively affect PROs [128]. What is the future of ribavirin for therapy for hepatitis C [129]? It will probably follow the same path as peginterferon, although it may still retain some utility if only for its low cost. With the second wave of HCV treatment, and in particular sofosbuvir and simeprevir, HCV infection cure rates over 90% have been achieved [130–132]. The current success obtained with the DAAs, and in particular sofosbuvir, made Christian Trépo hilarious when he wrote in Liver International [133] that “this unprecedented therapeutic victory … matched the triumphs over smallpox, polio and tuberculosis.” This sharply contrasted with the subsequent article of Boccaccio and Bruno [134]. In combination with other compounds, that is, GS-5816 (an NS5A inhibitor) and GS-9857 (an NS3/4A inhibitor), sofosbuvir may be considered as the backbone of the first all-oral, pan-genotypic three-drug regimen, capable of suppressing genotypes 1, 2, 3, and 4 [135]. HCV is known to cause several extrahepatic manifestations, including stroke, cardiac failure, and renal insufficiency that could be prevented by antiviral therapy [136]. In diabetic patients, antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes [137]. For the first-wave NS3/4A protease inhibitors telaprevir and boceprevir, development of resistanceassociated variants (i.e. at amino acid positions 36 and/or 155 (telaprevir) or 54 (boceprevir)) could contribute to treatment failure [138,139]. Yet, telaprevir and boceprevir may soon become history [140], and then the following question comes up: do we still need resistance testing [141]? For simeprevir, the

appearance of the Q80K variant may argue against its use although this variant disappeared in the majority of the patients. For sofosbuvir, the emergence of the S282T variant has been observed only occasionally; also, this variant reverted to wild type within several weeks. Drug interactions between sofosbuvir and most antiretroviral agents do not appear to be of clinical relevance or to require dosage modifications [142]. This means, according to Ann Kwong [143], that there are two outstanding issues: (i) diagnosis (in the USA, most people with chronic HCV infection do not know that they are infected and, if not treated, may develop advanced liver disease) and (ii) costs of treatment (which may be prohibitively high in resource-poor countries). In the industrialized countries, currently, the main approach to reduce the HCV disease burden is by increasing awareness of both the public and healthcare providers to HCV; in resource-limited countries, where the disease is mainly transmitted through blood transfusions and invasive medical procedures, reduction of the HCV burden has been hampered by limited access to treatment, largely owing to the costs of drugs [144]. These and several other issues have been addressed by Pawlotsky [145]. Sofosbuvir has been priced at $84 000 for a 12-week treatment, which corresponds to $1000 per pill per day [146]. Predicted manufacturing costs for 12-week courses of DAAs are $21–63 for ribavirin, $10–30 for daclatasvir, $68–136 for sofosbuvir, $100–210 for faldaprevir, and $130–270 for simeprevir. This would make the large-scale manufacture of two-drug to three-drug combinations of HCV DAAs a feasible goal with a minimum target price of $100–250 per 12-week treatment course [147]. CONFLICT OF INTEREST The author has no competing interest. ACKNOWLEDGEMENTS I thank Mrs. Christiane Callebaut for her proficient editorial assistance.

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SUPPORTING INFORMATION Additional supporting information (chemical structures of the DAAs) may be found in the online version of this article at the publisher’s website.

Copyright © 2015 John Wiley & Sons, Ltd.

Rev. Med. Virol. 2015; 25: 254–267. DOI: 10.1002/rmv