Advances in newly developing therapy for chronic hepatitis C virus infection

Abstract

Chronic hepatitis C virus (HCV) infection afflicts a reported 170 million people worldwide and is often complicated by cirrhosis and hepatocellular carcinoma. Morbidity and mortality are decreased with the successful treatment of chronic HCV infection. Increased understanding of the HCV has allowed further development of new direct-acting antiviral (DAA) agents against the HCV and has also allowed the development of IFN-free oral treatment regimens. In late 2013 the first nucleotide polymerase inhibitor regimen with RBV alone for genotypes 2/3 and in combination with a 12-week regimen of PEG-IFN+RBV for genotypes 1, 4 was approved for use in the US. A number of promising new DAA regimens which are IFN-free are in phase 3 development and the first will likely be approved for use in the US in 2014. The currently approved regimens are discussed in detail and currently available data on future regimens are reviewed herein.

Keywords

direct-acting antiviral (DAA) / nucleotide polymerase inhibitors / protease inhibitors

1 Introduction

A greater understanding of the hepatitis C virus (HCV) genome and proteins has enabled efforts to improve efficacy and tolerability of HCV treatment. Notably, multiple direct-acting antivirals (DAAs)—medications targeted at specific steps within the HCV life cycle—have been developed (Fig. 1). DAAs are molecules that target specific nonstructural proteins within the HCV, which results in disruption of viral replication and infection. There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are NS3/4A protease inhibitors (PIs), NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase inhibitors (NNPIs), and NS5A inhibitors [1].

2 NS3/4A protease inhibitors

PIs are inhibitors of the NS3 protease, which is an enzyme involved in post-translational processing and replication of the HCV. The NS3 protease has a binding site, an NS2/NS3 proteinase substrate recognition site, a helicase RNA binding site, and a zinc binding site. NS3 forms a heterodimeric complex with NS4A, a membrane protein that acts as a cofactor. PIs disrupt the HCV by blocking the NS3 catalytic site or the NS3/NS4A interaction [2]. The NS3/NS4A protease blocks TRIF-mediated Toll-like receptor signaling and Cardif-mediated retinoic acid-inducible gene 1 (RIG-1) signaling, which results in impaired induction of IFNs, thereby blocking viral elimination [2].

In May 2011, the US Food and Drug Administration (FDA) approved the first DAAs, telaprevir and boceprevir, for the treatment of HCV [3,4]. Both compounds are first-generation PIs that were approved for use in conjunction with pegylated interferon (PEG-IFN) and ribavirin (RBV) in HCV genotype 1-infected (GT1) individuals. This includes compensated cirrhotics who are treatment-naïve or had failed previous therapy. Telaprevir and boceprevir increase SVR rates to 75% and 67%, respectively. The difficulties encountered with first-generation PIs include cumbersome use: each requires multiple pills to be taken three times a day, and telaprevir needs to be administered with at least 20 g of fat. In clinical trials, 10%−12% of patients discontinued therapy due to adverse events (AEs), and 36%−45% developed significant anemia (<10 g/dl) [5−8]. One of the significant AEs of telaprevir is a rash, occurring in up to 56% of cases. Most of these are mild; however, fatal and nonfatal serious skin reactions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis, have been reported in patients treated with telaprevir combination therapy [9].

First-generation PIs have also been found to have a low barrier to resistance. The HCV has pre-existing amino acid substitutions, which are usually found at low levels; however, these resistant strains may be selected within a short period of time once HCV treatment begins [10]. In addition to the problems with side effects and viral resistance, the use of first-generation PIs has also been significantly restricted due to a large number of drug-drug interactions with compounds that are commonly used for human immunodeficiency virus (HIV) infection, immunosuppression, hyperlipidemia, and pulmonary hypertension [3,4].

Second-generation PIs currently in development are generally thought to have fewer drug-drug interactions, improved dosing schedules, and less frequent and less severe side effects. Many of the second-generation PIs are macrocyclic molecules, which have been shown to be generally more potent and, depending on the location of the macrocycle, able to retain activity against resistant variants. Common wild-type and drug-resistant variants of the NS3 protein include Q80K, R155K, V36M/R155K, A156T, and D168A [11]. Second-generation PIs have also shown increased efficacy against genotype 1; however, they still have limited efficacy against other genotypes [12].

Simeprevir (SMV, Olysio^TM) is a second-generation PI that has now been approved for use in genotype 1-infected patients in the US as a single 150 mg capsule taken once daily with food [13]. Prescribing information does not recommend response-guided therapy (RGT), but rather a fixed duration of 12 weeks with PEG-IFN and weight-based RBV, followed by 12 weeks of PEG-IFN+RBV for treatment-naïve or relapse patients (including cirrhosis) or 36 weeks PEG-IFN+RBV for partial or null responder patients (including cirrhosis). Simeprevir is ineffective in GT1a patients with a baseline Q80K polymorphism, so screening for this mutation prior to therapy has been recommended. Treatment futility rules at weeks 4,12 and 24 are recommended, as well as sun protection measures due to photosensitivity. There are a number of drug-drug interactions that limit the use of this compound in HIV co-infected patients.

3 NS5A inhibitors

The NS5A enzyme plays a role in both viral replication and the assembly of the HCV [14,15]. NS5A inhibitors have been shown to significantly reduce HCV RNA and enhance SVR when given in conjunction with PEG-IFN+RBV [16]. As a class, these drugs are generally quite potent and are effective across all genotypes, but they have a low barrier to resistance and variable toxicity profiles. A number of NS5A inhibitors, such as ledipasvir (GS-5885) and daclatasvir (BMS-790052), are currently completing in phase 3 trials and preliminary results are very promising (discussed below).

4 NS5B RNA-dependent RNA polymerase inhibitors

NS5B is an RNA-dependent RNA polymerase involved in post-translational processing that is necessary for replication of the HCV. The enzyme has a catalytic site for nucleoside binding and at least four other sites at which a non-nucleoside compound can bind and cause allosteric alteration. The enzyme’s structure is highly conserved across all HCV genotypes, giving NS5B inhibitors efficacy against all six genotypes [2].

There are two classes of polymerase inhibitors: nucleoside/ nucleotide analogs (NPIs) and non-nucleoside analogs (NNPIs). The NPIs target the catalytic site of NS5B and result in chain termination while NNPIs act as allosteric inhibitors.

5 Nucleot(s)ide polymerase inhibitors (NPIs)

Nucleotide inhibitors are activated within the hepatocyte through phosphorylation to nucleoside triphosphate, which competes with nucleotides, resulting in chain termination during RNA replication of the viral genome. As a class, they have moderate to high efficacy across all six genotypes, have a very high barrier to resistance, are equally effective in genotypes 1a and 1b, and are taken once daily. However, the drug class as a whole has been plagued with toxicity problems limiting the number of drugs that have completed phase 3 development [2].

Sofosbuvir (SOF, Sovaldi^TM) is the first NS5B NPIs to be approved for use in the US. Sofosbuvir is a prodrug and undergoes intracellular metabolism to GS-461203, which is pharmacologically active and is incorporated into HCV RNA by NS5B polymerase where it acts as a chain terminator [17]. It is given as a single 400 mg tablet once daily with or without food [17]. Sofosbuvir efficacy has been established in GT 1, 2, 3 or 4 infection, including patients with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Mono-infected and HCV/HIV-1 patients with GT 1 or 4 infection are treated with 12 weeks in combination with PEG-IFN+RBV, whereas GT 2 and 3 patients are treated without PEG-IFN (GT 2 for 12 weeks and GT 3 for 24 weeks). Because no dose adjustment is needed for cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir, this drug regimen is a potential major breakthrough for HCV therapy in HIV co-infected, pre- and post-liver transplant and interferon (IFN)-ineligible patients .

Sofosbuvir has a very high resistance barrier [18,19]. Resistance testing in phase 2 trials (ATOMIC [20], PROTON [21] and ELECTRON [22]) and phase 3 trials (NEUTRINO [23], FISSION [23], POSITRON [24] and FUSION [24]) revealed that the S282T resistance mutation was not detected in any patient receiving sofosbuvir in combination with RBV with or without PEG-IFN. The S282T resistance mutation was detected in one patient with HCV genotype 2b infection who received sofosbuvir monotherapy in the phase 2 ELECTRON study [22].

The phase 3 non-placebo controlled, multicenter NEUTRINO trial examined the efficacy of 12 weeks’ therapy with sofosbuvir plus PEG-IFN+RBV in treatment-naïve patients with chronic HCV GT 1, 4, 5 or 6 infection (n = 327) [23]. A sustained virological response was seen 12 weeks (SVR12) after the end of treatment (primary endpoint) in 90% of patients. When analyzed by HCV genotype, a sustained virological response was seen in 89% of the patients (n = 291) with HCV GT 1 infection, in 96% (n = 28) with HCV GT 4 infection, in the 1/1 patient with HCV GT 5 infection and in 6/6 patients with HCV GT 6 infection. The presence of cirrhosis or a non-CC IL28B genotype were associated with a reduced SVR12 [23].

The phase 3 randomized, open-label, multinational FISSION trial examined the non-inferiority of 12 weeks’ therapy with sofosbuvir plus RBV (n = 256) versus 24 weeks’ therapy with PEG-IFN+RBV (n = 243) in treatment-naïve patients with chronic HCV GT 2 or 3 infection [23]. The SVR12 (primary endpoint) was 67% with sofosbuvir plus RBV and 67% with PEG-IFN+RBV. In patients with GTE2 there were very high (95%) while those with GT 3 were less impressive (56%) [23].

The phase 3 randomized, double-blind, multinational POSITRON trial compared the efficacy of 12 weeks’ therapy with sofosbuvir plus RBV (n = 207) with that of placebo (n = 71) in patients with chronic HCV GT 2 or 3 infection who were IFN-intolerant, -ineligible or-unwilling [24]. The SVR12 was significantly higher with sofosbuvir plus RBV than with placebo (78% vs. 0%; P<0.001). SVR12 rates were significantly lower among patients with HCV genotype 3 versus HCV genotype 2 infection [24].

The phase 3 randomized, double-blind, multinational FUSION trial examined the efficacy of sofosbuvir plus RBV for 12 weeks (n = 103) or 16 weeks (n = 98) in patients with chronic HCV GT 2 or 3 infection who had not responded to prior treatment with an interferon-containing regimen [24]. Among patients receiving 12 or 16 weeks’ therapy with sofosbuvir plus ribavirin, SVR12 was 50% and 73%, respectively; these rates were significantly (P<0.001) higher than the historical SVR of 25% seen in this patient population. Secondary analysis revealed that the SVR12 was significantly (P<0.001) higher with 16 than with 12 weeks’ treatment with sofosbuvir plus RBV, especially in the GT 3 patients. Sustained virological response rates were significantly lower among patients with HCV genotype 3 versus HCV genotype 2 infection [24].

The phase 3 randomized, double-blind, multinational VALENCE trial compared the efficacy of 12 weeks’ therapy with sofosbuvir plus ribavirin (n = 334) with that of placebo (n = 85) in patients who were treatment naïve or had not achieved an SVR with previous interferon-based treatment and who had chronic HCV GT 2 or 3 infection [25]. In patients with HCV GT 2 infection who received 12 weeks’ therapy with sofosbuvir plus RBV, the SVR12 was 93% overall, and 97% and 90% in treatment-naïve and treatment-experienced patients, respectively. In patients with HCV GT 3 infection who received 24 weeks’ therapy with sofosbuvir plus RBV, the SVR12 was 84% overall, and 93% and 77% in treatment-naïve and treatment-experienced patients, respectively [25].

The phase 3 non-comparative, multicenter PHOTON-1 trial examined the efficacy of sofosbuvir plus RBV in patients with chronic hepatitis C who were co-infected with HIV-1 [26]. Treatment-naïve patients had HCV GT 1, 2 or 3 infection, and treatment-experienced patients had HCV genotype 2 or 3 infection. Among patients with HCV GT 1 infection (n = 114) or HCV genotype 3 infection (n = 13) who received sofosbuvir plus RBV for 24 weeks, the SVR12 was 76% and 92%, respectively. Among patients with HCV GT 2 infection who received sofosbuvir plus RBV for 12 weeks (n = 26), the SVR12 was 88% [26].

In a phase 2 study patients with chronic hepatitis C (any genotype) and HCC who were awaiting liver transplantation (n = 61) received sofosbuvir plus ribavirin for up to 48 weeks [27]. All patients met the Milan criteria and had well compensated cirrhosis (MELD<15). Among the 36 patients who were evaluable 12 weeks post-transplantation, the virological response rate (primary endpoint) was 64% [27]. However, the SVR12 was clearly associated with clearance of virus for 4 weeks or more prior to transplant that resulted in cure of all but 1 of 28 patients. In a non-comparative, phase 2 trial treatment-naïve or treatment-experienced patients with recurrent HCV infection (any genotype) following liver transplantation (n = 40) received sofosbuvir plus RBV for up to 24 weeks [28]. Interim results indicate that a sustained virological response was achieved 4 weeks post-treatment in 21 of 26 evaluable patients (81%) [28].

6 Non-nucleoside polymerase inhibitors (NNPIs)

The antiviral potency of NNPIs as monotherapy is less than that of NS3 PIs. The four allosteric sites that act as targets for NNPIs are thumb domains 1 and 2 and palm domains 1 and 2. As a class, NNPIs are less potent, tend to only be effective in genotype 1, have a low to moderate barrier to resistance, and have variable toxicity profiles [2]. Consequently, this class of drug has been used primarily as an adjunct to more potent compounds with higher barriers to resistance (See Table 1 for summary of advantages and disadvantages of the 4 classes of drugs).

7 Cyclophilin b inhibitors

Cyclophilin B is expressed in many types of human tissue and is critical for HCV replication by a number of incompletely understood mechanisms, such as the modulation of NS5B activity. Debio-025 (alisporivir) is an orally bioavailable cyclophilin B inhibitor exerting an antiviral impact on both HCV and HIV replication. In clinical trials in HIV- and HCV-co-infected patients, treatment with 1200 mg alisporivir twice daily for 2 weeks led to a mean maximal log10 reduction of HCV RNA of 3.6 and of HIV DNA of 1.0 [29].

Combination therapy using alisporivir 200, 600, or 1000 mg and PEG-IFN α-2a was evaluated in a phase 2 trial in treatment-naïve patients infected with HCV genotypes 1, 2, 3, or 4 and showed mean log10 reductions in HCV RNA at day 29 of 4.75 (1000 mg), 4.61 (600 mg), and 1.8 (200 mg) across all 4 genotypes [30]. Alisporivir was generally tolerated but led to a reversible bilirubin increase. Development was put on hold in 2012 due to a death from pancreatitis in a patient who received the drug in combination with PEG-IFN-RBV [31]. The drug will now continue to be developed in interferon-free regimens.

8 Combination interferon-free regimens in development

Clearly IFN-free and RBV-free regimens are highly desirable due to the tolerability and safety issues associated with the two compounds. Many studies assessing the combination of 2 or more drugs without IFN or RBV have shown good efficacy in GT1b patients [32]. However, patients with GT1a infections, cirrhosis, prior treatment-failures, and HIV co-infection have proven to be more of a challenge. A number of recent studies not yet published have shown a significant breakthrough in these barriers with IFN-free and RBV-free regimens (for more information, see Table 1 “Phase 3 Trials of Interferon-free Regimens for the Treatment of HCV Infection” in Liang TJ, Ghany MG. Therapy of Hepatitis C — Back to the Future. N Engl J Med. Published on May 4, 2014, and updated on May 8, 2014, at NEJM.org. DOI: 10.1056/NEJMe1403619).

The combination of the NS5B NPI, SOF 400 mg, and the NS5A inhibitor, ledipasvir 90 mg (LDV), has been formulated in a fixed dose combination (FDC) tablet. This single tablet has proven extremely effective (SVR rates>95%) in GT1 treatment-naïve patients and in difficult-to-treat populations in a 12-week regimen [33]. In a recently presented update from the ELECTRON studies, it was demonstrated that the addition of RBV to the FDC of SOF/LDV substantially enhances cure rates in patients with cirrhosis [34]. Alternatively, rather than administering RBV, the addition of a 3rd DAA (GS-9669) also enhances cure rates [31]. A 6-week regimen of the FDC of SOF/LDV is associated with increased relapse rates compared to 8 or 12 weeks, suggesting that this duration may be too short.

A combination of a ritonavir-boosted PI, an NNPI, and RBV has also been investigated as a possible IFN-free regimen [35]. ABT-450, a PI, along with low-dose ritonavir (ABT-450/r), ABT-333 (an NNPI), and RBV were given to non-cirrhotic GT 1 patients in a phase 2a, open-label, multicenter study and showed very high SVR rates. Subsequently, a larger study (AVIATOR) used a regimen with the addition of ABT-267, an NS5A inhibitor, and showed SVR rates of 93%−99% in treatment-naïve and null-responder patients [36]. No relapses were seen after treatment in any patients who received quadruple therapy for 12 or 24 weeks, and there was no clinically significant difference in response based on sex, HCV subtype, IL28B genotype, or fibrosis stage. A recent presentation has shown that RBV is not necessary if this regimen is used in a GT1b-infected treatment-naïve or null responder population [37].

The 12-week, IFN-free and ribavirin-free all-oral 3 DAA regimen with the NS5A inhibitor, daclatasvir (DCV), the second-generation PI, asunaprevir (ASV) and the NNPI, BMS-791325 achieved SVR12 in>90% of patients even in GT1a or advanced fibrosis/cirrhosis [38]. This critical proof-of-concept study demonstrates that a combination of 3 DAAs without RBV can achieve SVR12 rates of 94% in a G1 treatment-naïve (TN) population. The data are a foundation for multiple large randomized phase 3 trials using this regimen in TNs, treatments-failure, cirrhotics, HIV co-infected and other genotypes, and thus it is important to the development of IFN- and RBV-free therapies for HCV.

The lack of efficacy seen in GT1a with the dual therapy published in 2012 [39] was successfully overcome simply by adding a NNPI. The implications may extent to other IFN-free DAA regimens in development, i.e., a NS5B NPI may not be required for the backbone of therapy, as it appears to be the case based on sofosbuvir studies [23,24]. Rather, a best-in-class drug, here daclatasvir for the NS5A class, may be added to 2 other relatively weak compounds and still have>90% SVR rates as an IFN-free regimen.

A randomized, open-label trial examined the efficacy of various regimens comprising sofosbuvir and daclatasvir in non-cirrhotic, treatment-naïve patients with chronic HCV GT 1, 2 or 3 infection [40]. SVR12 was seen in 15 of 15 (100%) patients with HCV GT 1 infection and in 14 of 16 (88%) patients with HCV GT 2 or 3 infection who received sofosbuvir for 7 days followed by sofosbuvir plus daclatasvir for 23 weeks, in 14 of 14 (100%) patients with HCV GT1 infection and in 14 of 14 (100%) patients with HCV GT 2 or 3 infection who received sofosbuvir plus daclatasvir for 24 weeks, and in 15 of 15 (100%) patients with HCV GT 1 infection and in 12 of 14 (86%) patients with HCV GT 2 or 3 infection who received sofosbuvir plus daclatasvir and ribavirin for 24 weeks [40]. In non-cirrhotic patients with HCV genotype 1 infection who had previous breakthrough, relapse or nonresponse to PEG-IFN+RBV in combination with telaprevir or boceprevir (n = 41), 24 weeks’ therapy with either sofosbuvir plus daclatasvir or sofosbuvir plus daclatasvir and ribavirin was associated with a sustained virological response rate at 4 weeks post-treatment of 100% [40].

Another once-daily PI in phase 3 development, faldaprevir, also allows for once daily dosing in comparison to telaprevir/boceprevir based HCV therapy with comparable high SVR rates when used in a triple therapy in HCV treatment-naive patients [41]. In an IFN-free combination with a NNPI, deleobuvir, faldaprevir has proved to be effective in GT1b, but not GT1a, patients and development of this regimen has been stopped [42].

Impressive SVR rates of>95% were obtained in the first all oral combination of a pan-genotypic potent PI, MK-5172 and a NNPI, MK-8742 in GT1a and GT1b patients [43]. In addition, ribavirin is not needed for treatment of GT1b patients. We have not yet seen this combination in more challenging patient populations such as cirrhotics and null-responders, however, these studies are ongoing.

Prior trials have shown that many G1 HCV-infected patients are ineligible for or intolerant to PEG-IFN-based regimens due to prior severe side effects, worsening of cytopenias, exacerbation of underlying psychiatric disorders, or autoimmune disorders. These patients will not be candidates for treatment with the approvals of SMV and SOF due to the inclusion of with PEG-IFN in the GT1 treatment regimens [23,24]. The results of the COSMOS study, combining SOF+SMV, suggest that these patients are likely to have excellent responses to 12 weeks of therapy of SMV+SOF with or without RBV, and that 24 weeks are unnecessary [44]. These patients achieved an overall SVR among 171 patients of 89%. These data suggest that this combination regimen is compelling, even if the patient is Q80K-postive. Patients who fell into this group had an SVR of 86%−90%, compared to 100% for those who were Q80K-negative.

Thus, in many ways, the future of HCV therapy has now arrived: we have IFN-free treatments that are FDA-approved for GT 2 and 3 and potential IFN-free regimens that are not FDA-approved, but have been shown effective for GT 1 patients. We are rapidly approaching an era where IFN-free regimens that are safe, easy to take, well tolerated and short duration will be available, likely in late 2014. We can anticipate at least 4 different IFN-free regimens that will be available by 2015, which will allow the treatment market to be more competitive (Table 2). Despite their high cost, these treatments should be cost-effective and available for many Americans under health care reform, thus reducing the disease burden of HCV for the next decade [45].

Compliance with ethics guidelines

Paul J. Pockros has received research support, speaking and consulting honoraria from Gilead, Janssen, BMS and Genentech; research and consulting from Abbvie, BI, Merck, Conatus, Beckman, RMS and research only from Novartis, Genfit and Takeda. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

References

[1] Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012; 19(7): 449−464

[2] Pockros PJ. New direct-acting antivirals in the development for hepatitis C virus infection. Therap Adv Gastroenterol 2010; 3(3): 191−202

[3] US Food and Drug Administration. Approval of Victrelis (boceprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV).

[4] US Food and Drug Administration. Approval of Incivek (telaprevir) a direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV).

[5] Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364(13): 1195−1206

[6] Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364(25): 2405−2416

[7] McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM; PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362(14): 1292−1303

[8] Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364(13): 1207−1217

[9] FDA Drug Safety Communication. Serious skin reactions after combination treatment with the hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin.

[10] Suzuki F, Sezaki H, Akuta N, Suzuki Y, Seko Y, Kawamura Y, Hosaka T, Kobayashi M, Saito S, Arase Y, Ikeda K, Kobayashi M, Mineta R, Watahiki S, Miyakawa Y, Kumada H. Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b. J Clin Virol 2012; 54(4): 352−354

[11] Ali A, Aydin C, Gildemeister R, Romano KP, Cao H, Ozen A, Soumana D, Newton A, Petropoulos CJ, Huang W, Schiffer CA. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol 2013; 8(7): 1469−1478

[12] Hunt D, Pockros P. What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr Gastroenterol Rep 2013; 15(1): 303

[13] Prescribing Information for OLYSIO TM (simeprevir): Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560. Issued 2013-November

[14] Evans MJ, Rice CM, Goff SP. Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci USA 2004; 101(35): 13038−13043

[15] Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 2008; 4(3): e1000032

[16] Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465(7294): 96−100

[17] Gilead Sciences Inc. Solvadi^TM (sofosbuvir) tablets, for oral use: US prescribing information. 2013.

[18] Svarovskaia ES, Dvory HS, Hebner C, . No resistance detected in four phase 3 clinical studies in HCV genotype 1−6 of sofosbuvir+ ribavirin with or without peginterferon. Hepatology 2013; 58(4 Suppl): 1091A−1092A (abstract No. 1843)

[19] Svarovskaia ES, Dvory-Sobol H, Gontcharova V, . Comprehensive resistance testing in patients who relapsed after treatment with sofosbuvir (GS-7977)-containing regimens in phase 2 studies. Hepatology 2012; 56(4 Suppl): 551A (abstract No. 753)

[20] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, Afdhal N, Vierling JM, Gordon SC, Anderson JK, Hyland RH, Dvory-Sobol H, An D, Hindes RG, Albanis E, Symonds WT, Berrey MM, Nelson DR, Jacobson IM. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381(9883): 2100−2107

[21] Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, Nelson DR, Dieterich DT, Jacobson IM, Jensen D, Abrams GA, Darling JM, Rodriguez-Torres M, Reddy KR, Sulkowski MS, Bzowej NH, Hyland RH, Mo H, Lin M, Mader M, Hindes R, Albanis E, Symonds WT, Berrey MM, Muir A. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13(5): 401−408

[22] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368(1): 34−44

[23] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Reddy KR, Jacobson IM, Kowdley KV, Nyberg L, Subramanian GM, Hyland RH, Arterburn S, Jiang D, McNally J, Brainard D, Symonds WT, McHutchison JG, Sheikh AM, Younossi Z, Gane EJ. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368(20): 1878−1887

[24] Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz E, Everson G, Bennett M, Schiff E, Al-Assi MT, Subramanian GM, An D, Lin M, McNally J, Brainard D, Symonds WT, McHutchison JG, Patel K, Feld J, Pianko S, Nelson DR; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368(20): 1867−1877

[25] Zeuzem S, Dusheiko GM, Salupere R, . Sofosbuvir+ ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology 2013; 58(4 Suppl): 733A−734A (abstract No. 1085)

[26] Sulkowski MS, Rodriguez-Torres M, Lalezari JP, . All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology 2013; 58(4 Suppl): 313A−314A (abstract No. 212)

[27] Curry MP, Forns X, Chung RT, . Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013; 58(4 Suppl): 314A−315A (abstract No. 213)

[28] Charlton MR, Gane EJ, Manns MP, . Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study. Hepatology 2013; 58(6 Suppl): 1378A (abstract No. LB-2)

[29] Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A, Siwak E, Cielniak I, Higersberger J, Kierkus J, Aeschlimann C, Grosgurin P, Nicolas-Métral V, Dumont JM, Porchet H, Crabbé R, Scalfaro P. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008; 47(3): 817−826

[30] Flisiak R, Feinman SV, Jablkowski M, Horban A, Kryczka W, Pawlowska M, Heathcote JE, Mazzella G, Vandelli C, Nicolas-Métral V, Grosgurin P, Liz JS, Scalfaro P, Porchet H, Crabbé R. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naïve hepatitis C patients. Hepatology 2009; 49(5): 1460−1468

[31] Pawlotsky JM, Sarin SK, Foster G, . Alisporivir plus ribavirin is highly effective as interferon-free or interferon add- on regimen in previously untreated HCV-GT2 or GT3 patients: SVR12 results from VITAL-1 phase 2b study[abstract No. LB 11]. 47th Annual 791 Meeting of the European Association for the Study of the Liver; 2012-Apr; Barcelona

[32] Au J, Pockros PJ. Novel therapeutic approaches for hepatitis C. Clin Pharmacol Ther 2014; 95(1): 78−88

[33] Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2014; 383(9916): 515−523

[34] Gane EJ, Stedman CA, Hyland RH, . Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: data from the ELECTRON trial. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract 73

[35] Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 2013; 368(1): 45−53

[36] Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, Everson GT, Kwo P, Foster GR, Sulkowski MS, Xie W, Pilot-Matias T, Liossis G, Larsen L, Khatri A, Podsadecki T, Bernstein B. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014; 370(3): 222−232

[37] Cohen DE, Xie W, Larsen L, . Safety of Ribavirin-containing Regimens of ABT-450/r, ABT-333, and ABT-267 for the Treatment of HCV Genotype 1 Infection and Efficacy in Subjects with Ribavirin Dose Reductions 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract 1118

[38] Everson GT, Sims KD, Thuluvath PJ, . Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naïve patients with chronic HCV genotype 1 infection. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract LB1

[39] Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366(3): 216−224

[40] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370(3): 211−221

[41] Jacobson IM, Asselah T, Ferenci P, . STARTVerso3: A randomized, double-blind, placebo-controlled Phase III trial of faldaprevir in combination with pegylated interferon alfa-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract 1100

[42] Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Müllhaupt B, Schuchmann M, Bourlière M, Buti M, Roberts SK, Gane EJ, Stern JO, Vinisko R, Kukolj G, Gallivan JP, Böcher WO, Mensa FJ. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med 2013; 369(7): 630−639

[43] Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract LB20

[44] Lawitz E, Vierling JM, Murillo A, . High efficacy and safety of the all-oral combination regimen, MK-5172/MK-8742+/ RBV for 12 weeks in HCV genotype 1 infected patients: the C-WORTHY Study. 64th Annual Meeting of the American Association for the Study of Liver diseases, November-1−5, 2013, Washington; abstract 76

[45] Jacobson IM, Ghalib RH, Rodriguez-Torres M, . SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver diseases, 2013-November-1−5, Washington, USA; abstract LB3

[46] Younossi ZM, Singer ME, Mir HM, Henry L, Hunt S. Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients. J Hepatol 2014; 60(3): 530−537

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg