Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world?

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Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev. Anti Infect. Ther. 12(7), 763–773 (2014)

Ivan Gentile*, Antonio Riccardo Buonomo, Emanuela Zappulo and Guglielmo Borgia Department of Clinical Medicine and Surgery, University of Naples “Federico II”, via S. Pansini 5, I-80131 Naples, Italy *Author for correspondence: Tel.: +39 081 746 3178 Fax: +39 081 746 3190 [email protected]

About 2% of the world’s population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90–100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world. KEYWORDS: ABT-450 • asunaprevir • daclatasvir • dasabuvir • interferon-free • ledipasvir • MK-5172 • MK-8742 • ombitasvir • sofosbuvir

WHO estimates that about 2% of the world’s population is chronically infected with hepatitis C virus (HCV) [1]. The RNA genome of HCV is subject to a high rate of spontaneous mutations because its polymerase lacks a proof-reading function and because of the huge number of viral particles produced daily in the human host. Thus far, 7 major genotypes (classified 1–7) and 67 subtypes (classified with letters) have been identified [2]. Chronic HCV carriers are at significant risk of developing liver cirrhosis within two to three decades. Once cirrhosis is established, patients can progress toward severe and life-threatening complications (e.g., ascites, jaundice and esophageal variceal bleeding) or hepatocellular carcinoma [3–6]. Several factors (hepatitis B virus or HIV coinfection, alcohol abuse, iron overload and diabetes mellitus) accelerate the progression of the disease [5,7–14]. Moreover, HCV infection is associated with significant morbidity and mortality also in organs other than liver, such as mixed cryoglobulinemia, HCV-related arthritis and non-Hodgkin lymphoma [5,15,16]. Although the incidence of HCV infection has declined in recent decades thanks to informahealthcare.com

10.1586/14787210.2014.929497

improvements in its prevention (e.g., use of disposable syringes and screening blood used for transfusion), new cases of infection continue to occur mostly in subjects who undergo hemodialysis, surgery, endoscopy tattooing or piercing or who practice unprotected sex or intravenous drug use [3,4,17–21]. Treatment of HCV infection is based on antiviral therapy with two or three drugs. This therapy can completely eradicate the infection, as documented by the absence of circulating HCV genome (HCV-RNA) 3–6 months after therapy withdrawal (sustained virological response [SVR]). Patients who achieve an SVR remain HCV-free throughout their life and have a low risk of disease progression [22–27]. For more than 10 years, antiviral treatment of HCV infection consisted of a combination of pegylated-interferon and ribavirin (PR). In patients in whom this combination was not contraindicated, it was associated with an SVR of about 40–50% in case of genotype 1 infection and of about 70–80% in cases of genotype 2–3 infection. However, various groups of patients had a lower chance of being cured and were therefore designated

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Gentile, Buonomo, Zappulo & Borgia

‘difficult-to-treat’, that is, those with liver cirrhosis or high stage of fibrosis, those carrying the IL-28B gene TT polymorphism, patients who did not achieve a rapid virological response on-treatment (RVR, namely undetectable levels of HCV RNA at the 4th week of therapy), who had a high baseline viral load, high ferritin or homocysteine levels and low baseline levels of vitamin D [28–35] and patients who failed to respond to previous antiviral treatment. Recently, a new class of drugs active against HCV (called ‘direct antiviral agents’, DAA) has become available. The first age of this class was the protease inhibitors boceprevir or telaprevir. However, they were used only for genotype 1 infection and only in association with PR [36–41]. This triple therapy increased the rate of SVR in naı¨ve patients with genotype 1 to about 70% [36–40,42,43]. Interferon-based therapies have several limitations and drawbacks. • They are not suitable for patients with decompensated liver disease (e.g., with ascites), who are the very subjects that most urgently need treatment; • Paradoxically, they are less effective in patients with an advanced disease (e.g., those with cirrhosis), but work well in subjects with a mild disease; • They are contraindicated in patients with psychiatric disorders, autoimmune disease or generally in patients with severe impairment of one or more organs. Therefore, the therapy is often contraindicated in elderly patients [40,44]; • They are poorly tolerated. In fact, interferon is associated with influenza-like symptoms, decreased platelet and white cell count, autoimmune disorders, depression; ribavirin can cause hemolytic anemia, cough and diarrhea [45–48]; • A non-negligible percent of patients do not achieve viral clearance with these interferon-containing regimens and therefore their hepatic disease and extrahepatic disorders continue to progress. In this scenario, several pharmaceutical companies are developing oral antiviral drugs against HCV that can be combined in regimens that do not require interferon to yield a high rate of viral clearance [49–53]. This review deals with the most promising interferon-free combinations that are or will be available in the near future. Class of antivirals active against HCV

Several direct antivirals active against HCV are in clinical development. Only a few of them are commercially available (see later). The most representative classes are protease inhibitors, NS5A inhibitors and non-nucleotide and nucleotide polymerase inhibitors [54]. • Protease inhibitors act by inhibiting the active site of NS3/NS4 protease. This viral enzyme processes the polyprotein (which is the result of viral genome translation) into the single proteins that have structural or functional activity. Inhibition of this step dramatically reduces viral replication. Therefore, these drugs are usually potent antivirals. However, they have a low-medium barrier to resistance and their 764

antiviral activity is restricted to one or few HCV genotypes. The second-generation protease inhibitors (MK-5172 and ACH-2684) have a medium barrier to resistance and pangenotypic activity [55]. The first-generation drugs (boceprevir and telaprevir) were poorly tolerated, whereas tolerability was better with second-wave or second-generation drugs (simeprevir, danoprevir, asunaprevir or MK-5172) [56]. • Protein NS5A is essential for HCV replication and for the release of viral particles. This concept, as well as the lack of a human homologous protein, have made NS5A protein an intriguing target for DAAs. Drugs of this class (such as ledipasvir, daclatasvir and ABT-267) have a very high antiviral power (50% effective inhibitory concentration [EC50] of picomolar magnitude). Moreover, as the domain I of the NS5A protein is conserved across the different genotypes, NS5A inhibitors usually have pan-genotypic activity. The barrier to resistance of this class of drugs is low, whereas their tolerability and safety are good. • Polymerase inhibitors target protein NS5B, which is an RNA-dependent RNA polymerase. These drugs are divided into two categories: non-nucleoside inhibitors (i.e., allosteric inhibitors of the polymerase) and nucleos(t)ide analogs (i.e., inhibitors of the active site of the enzyme). The non-nucleoside NS5B inhibitors bind the polymerase and cause a conformational change that ultimately reduces its enzymatic activity. Their antiviral activity is medium and usually genotype-restricted. Genetic barrier to resistance is low and escape mutations have a high fitness (i.e., a high replication capacity). Tolerability is good [50,54,57]. As the enzyme resembles a ‘right hand’ in 3D structure studies, its domains are called ‘fingers’, ‘palm’ and ‘thumb’. Based on their binding site, non-nucleoside NS5B inhibitors are classified as palm I (ABT-333), palm II (GS-9190), thumb I (BMS-791325) and thumb II (GS-9669 or VX-222) [55]. Notably, in terms of resistance, each subgroup seems to act as a separate class of drugs. In fact, at least for some molecules (e.g., GS-9669), it has been demonstrated that no cross-resistance occurs among the four classes of non-nucleoside NS5B inhibitors [58]. • The mechanism of action of nucleoside/nucleotide analogs differs from that of the non-nucleoside inhibitors of NS5B. In fact, the former act by competing with the natural nucleotide for the incorporation in the viral chain of RNA and cause its early termination [59]. Mutations in the active site of polymerase have a dramatic impact on viral fitness. For this reason, this enzyme is highly conserved across the different genotypes and consequently these drugs have a high pan-genotypic antiviral activity. For the same reason, genetic barrier to resistance results finally high as strains with mutations have a low fitness. Tolerability and safety of the drugs that pass the Phase I studies are good. Sofosbuvir (SOF) is the first nucleotide inhibitor approved for the treatment of HCV infection. The results of the efficacy of different combinations of antivirals are summarized in TABLE 1.

Expert Rev. Anti Infect. Ther. 12(7), (2014)

68 genotype 2, 127 genotype 3

143 genotype 2, 135 genotype 3 73 genotype 2, 250 genotype 3

60 genotype 4 34 genotype 1, 1 genotype 2, 5 genotype 3, 1 genotype 4, 3 genotype mixed 33 genotype 1, 6 genotype 3, 1 genotype 4 50 genotype 1 34 genotype 1, 3 genotype 2, 10 genotype 3, 3 genotype 4

FUSION

POSITRON

VALENCE†

Ruane

Forns

Charlton

ERADICATE

Afdhal

Sofosbuvir was administered at 400 mg once daily; ledipasvir was administered at 90 mg once daily; simeprevir was administered at 150 mg once daily; dasabuvir was administered at 250 mg twice daily; ombitasvir was administered at 25 mg once daily; daclatasvir was administered at 60 mg once daily; asunaprevir was administered at 100 mg twice daily; MK-5172 was administered at a dose of 100 mg once daily. † After amendment of the protocol. ‡ Pegylated-interferon could be added at the physician’s discretion. Treatment lasted 48 weeks in 1 patient, 36 weeks in 4 patients, 24 weeks in 19 patients. Dose of peg-IFN and RBV were at the physician’s discretion. § Preliminary data, not based on the whole sample. { Dose of RBV started at 400 mg/day and increased based on hemoglobin levels up to 1200 mg/day. # SVR-12 results are available and are presented only for F0-F2 cohort. †† 473 patients were treated with the antiviral combination, 158 received placebo. ‡‡ 297 patients were treated with the antiviral combination, 97 received placebo. §§ In naı¨ve cohort, 203 patients received the active combination and 102 placebo. ASN: Asunaprevir; DCV: Daclatasvir; LDV: Ledipasvir; PR: Pegylated-interferon + ribavirin; RBV: Ribavirin; RTV: Ritonavir; SMP: Simeprevir; SOF: Sofosbuvir.

[70]

[71]

[93] [75]

77% (SVR4)§

100% (SVR4)§ HCV-RNA undetectable at weeks 24 of treatment§: • 100% in child A patients • 93% in child B patients

SOF + RBV{ for up to 24 weeks

SOF + LDV for 12 weeks • SOF + RBV for 48 weeks • Observation for 24 weeks and then treatment as in arm 1

HIV/HCV coinfected, naı¨ve Compensated or decompensated cirrhosis

All had HCV recurrence after liver transplantation, 40% had cirrhosis

All had severe HCV recurrence after liver transplantation

60%§ 50%§

• SOF + RBV for 12 weeks • SOF + RBV for 24 weeks SOF + RBV SOF + PR‡

[65]

[62]

[62]

[69]

Genotype 2: 93% Genotype 3: 85%

• 78% (93% for genotype 2 and 61% for genotype 3) • 0%

• 50% (86% for genotype 2 and 30% for genotype 3) • 73% (94% for genotype 2 and 62% for genotype 3)

• 67% (97% for genotype 2 and 56% for genotype 3) • 67% (78% for genotype 2 and 63% for genotype 3)

• 67.7% (SVR 4) • 96.5% (SVR4)

SOF + RBV for 12 weeks for genotype 2† SOF + RBV for 24 weeks for genotype 3†

• SOF + RBV for 12 weeks • Placebo

• SOF + RBV for 12 weeks • SOF + RBV for 16 weeks

• SOF + RBV for 12 weeks • PR for 24 weeks

53.3% experienced, 23.3% had cirrhosis

58% experienced, 21% had cirrhosis

Interferon intolerant, ineligible or unwilling, 16% had cirrhosis

All experienced, 34% had cirrhosis

All naı¨ve, 20% had cirrhosis

[63]

137 genotype 2, 359 genotype 3

FISSION

Ref.

Sofosbuvirbased combinations

SVR12

765

Arms

informahealthcare.com

Type of patients

Patients (n), genotype

Name of trial or first author

Drug/drugs

Table 1. Overview of the main trials that evaluated the efficacy of interferon-free antiviral combinations in the treatment of HCV infection.


IFN-free therapies for chronic hepatitis C

Perspective

766 Experienced, non-cirrhotic

167 genotype 1

631†† genotype 1

394‡‡ genotype 1

380 genotype 1

COSMOS

SAPPHIRE -I

SAPPHIRE-II

TURQUOISE-II

222 subtype 1b

Naı¨ve, non-cirrhotic

647 genotype 1

ION-3

Kumada

80 patients null-responders, METAVIR F0-F2, 87 patients both naı¨ve and nullresponders, METAVIR F3-F4

440 genotype 1

ION-2

135 ineligible/intolerant and 87 non-responders to PR, 10% had cirrhosis

Both naı¨ve and experienced, all patients had cirrhosis


Experienced, 20% had cirrhosis

Naı¨ve, 16% had cirrhosis

865 genotype 1

ION-1

Type of patients



+ RBV for 24 + RBV for 12

for 24 weeks weeks for 12 weeks weeks

[81]

• 91.8% • 95.9%

87.4% in ineligible/intolerant cohort and 80.5% in nonresponder cohort

• ABT-450/RTV (150/100 mg/day) + ombitasvir + dasabuvir + RBV for 12 weeks • ABT-450/RTV (150/100 mg/day) + ombitasvir + dasabuvir + RBV for 24 weeks DCV + ASN for 24 weeks

[85]

[80]

[79]

96.3%

ABT-450/RTV (150/100 mg/day) + ombitasvir + dasabuvir + RBV for 12 weeks

ABT-450/RTV (150/100 mg/day) + ombitasvir + dasabuvir + RBV for 12 weeks

SMP SMP SMP SMP

96.2%

[74]

79.2%# 93.3% 96.3% 92.9%

+ + + +

weeks for 12 weeks weeks for 24 weeks

SOF SOF SOF SOF

for 12 + RBV for 24 + RBV

[66]

LDV LDV LDV LDV 94% 93% 95%

weeks for 12 weeks weeks for 24 weeks

SOF + LDV for 8 weeks SOF + LDV + RBV for 8 weeks SOF + LDV for 12 weeks

+ + + +

+ + + +

[67]

SOF SOF SOF SOF

SOF SOF SOF SOF 94% 96% 99% 99%

for 12 + RBV for 24 + RBV

Ref. [68]

LDV LDV LDV LDV

SVR12 99% 97% 98% 99%

Arms


DCV + ASN

ABT-450/RTV + ombitasvir + dasabuvir

Drug/drugs

Table 1. Overview of the main trials that evaluated the efficacy of interferon-free antiviral combinations in the treatment of HCV infection (cont.).


Perspective Gentile, Buonomo, Zappulo & Borgia



65 genotype 1

94 genotype 1

C-WORTHY Part B

66 genotype 1

Everson

C-WORTHY Part A

305 naı¨ve, 205 non-responder, 235 interferon ineligible/ intolerant, 16% of the naı¨ve cohort, 31% of the nonresponder cohort and 47% of the ineligible/intolerant cohort had cirrhosis

745 subtype 1b§§

HALLMARKDUAL



Naı¨ve, non-cirrhotic, 74% were infected with subtype 1a

Type of patients



• MK-5172 + MK-8742 (50 mg once daily) + ribavirin for 8 weeks • MK-5172 + MK-8742 (50 mg once daily) + ribavirin for 12 weeks • MK-5172 + MK-8742 (50 mg once daily) for 12 weeks

• MK-5172 + MK-8742 (20 mg once daily) + ribavirin for 12 weeks • MK-5172 + MK-8742 (50 mg once daily) + ribavirin for 12 weeks • MK-5172 + MK-8742 (50 mg once daily) for 12 weeks

• DCV + ASN (200 mg twice daily) + and BMS-791325 (75 mg twice daily) for 24 weeks • DCV + ASN (200 mg twice daily) + and BMS-791325 (75 mg twice daily) for 12 weeks • DCV + ASN (200 mg twice daily) + and BMS-791325 (150 mg twice daily) for 24 weeks • DCV + ASN (200 mg twice daily) + and BMS-791325 (150 mg twice daily) for 12 weeks

DCV + ASN for 24 weeks

Arms

[86]

[87]

[88]

[88]

94% 94% 94% 89%

• • • •

• 100% • 96% • 100%

• 93% (SVR8) • 100% (SVR8) • 100% (SVR8)

Ref.

90% in naı¨ve cohort 82% in non-responder and in ineligible/intolerant cohort

SVR12


MK-5172 + MK-8742

Drug/drugs

Table 1. Overview of the main trials that evaluated the efficacy of interferon-free antiviral combinations in the treatment of HCV infection (cont.).



Perspective

767

Perspective



SOF-based combinations

The combination of SOF plus ribavirin has already been approved in the USA and Europe for the treatment of patients with HCV genotype 2 or 3 infection [60–64]. The results of the first four large Phase III studies conducted are remarkable. In naı¨ve patients with genotype 2 infection, the association of SOF and ribavirin for 12 weeks resulted in an SVR in 93% of cases [62]. In naı¨ve patients with genotype 3 infection, 24 weeks of this association resulted in a similarly high rate of SVR (85%) [49,65]. The SVR rate in genotype 3 patients was lower in experienced patients with liver cirrhosis (SVR = 60%). The very recent ION-3 Phase III trial tested the interferon-free combination of SOF, the NS5-A inhibitor ledipasvir with or without ribavirin for 8 or 12 weeks in 647 genotype 1 non-cirrhotic, naı¨ve patients [66]. The SVR rate was very high (93–95%). Neither the presence of ribavirin nor the duration of therapy affected the SVR rate. A similar study (ION-2) tested the interferon-free combination of SOF, ledipasvir with or without ribavirin for 12 or 24 weeks in 440 genotype 1 experienced patients [67]. Again, the results were remarkable (SVR: 94–99% in all arms). Finally, the ION-1 study assessed the efficacy and safety of SOF and ledipasvir with or without ribavirin in 865 naı¨ve genotype 1 patients (16% with cirrhosis, 67% with subtype 1a infection) [68]. The efficacy and safety of the SOF-ledipasvir combination (SVR: from 97 to 99%), administered for 12 or 24 weeks, were excellent both with and without ribavirin. In a small study of 60 patients, the combination of SOF and ribavirin administered for 24 weeks resulted in a very high SVR4 rate (96.5%) also in patients with genotype 4 [69], whereas the rate of viral clearance was lower (67.7%) when the association was administered for 12 weeks [69]. The efficacy and tolerability were found to be good also in patients with recurrence after liver transplantation [70,71]. Moreover, the results of pre-transplantation treatment with SOF and ribavirin were very promising in 61 HCV-positive patients (most with genotype 1) who were transplanted for hepatocellular carcinoma [72]. This combination prevented reinfection of the transplanted liver in 64% of the 41 patients with undetectable HCV RNA before transplantation [72]. SOF has been administered also in combination with simeprevir, a once-daily ‘second wave’ protease inhibitor that has recently been approved by the US FDA for the treatment of chronic hepatitis C together with PR [73]. In a recent Phase II study, SOF + simeprevir for 12 or 24 weeks, with or without ribavirin (COSMOS study) resulted in high rates of SVR (from 79 to 100%) in 167 patients with genotype 1 infection, regardless of the duration of treatment and the addition of ribavirin [74]. Based on these excellent results, two Phase III trials are currently investigating the efficacy and safety of this association (OPTIMIST-1 and 2). The preliminary results of a Phase II trial of the efficacy of SOF and ribavirin in patients with HCV-related liver cirrhosis and portal hypertension with or without decompensation have recently become available [75]. In the first 50 patients (most infected with genotype 1), the SOF and ribavirin combination 768

for 24 weeks produced a high on-treatment rate of viral suppression (93–100% at the end of treatment), a decrease in aminotransferase levels and an improvement of albumin levels and platelet count. Moreover, episodes of ascites and hepatic encephalopathy resolved in some treated patients. Notably, the tolerability of SOF combinations has been excellent in all trials completed to date [64,76,77]. Moreover, no strain with mutations conferring resistance to SOF was detected in all Phase III trials. ABT-450/ombitasvir/dasabuvir/ribavirin combination

The large Phase IIb AVIATOR study evaluated various combinations, durations and dosages of the following drugs: the ‘second wave’, once-daily protease inhibitor ABT-450 (plus ritonavir [RTV] to booster the inhibitor’s pharmacokinetics), the NS5A inhibitor ABT-267 (now called ‘ombitasvir’), the non-nucleoside polymerase inhibitor ABT-333 (now called ‘dasabuvir’) with or without ribavirin in 571 HCV genotype 1 patients without cirrhosis, naı¨ve (n = 438) and null responders (n = 133). SVR rates were very high in all arms: between 83 and 96% in naı¨ve patients and between 89 and 95% in experienced subjects. Tolerability and safety were good [78]. The results of three Phase III studies have recently become available. The large SAPPHIRE-I trial evaluated the efficacy and safety of ABT-450/RTV, ombitasvir, dasabuvir and ribavirin for 12 weeks in 631 treatment-naı¨ve non-cirrhotic, genotype 1 patients [79]. Patients were randomized to the active arm or placebo (rate 3:1). Also the patients in the placebo arm received the combination after 12 weeks of observation. The SVR rates in patients in the active arm were outstanding, SVR being 96.2% (95.3% in subtype 1a patients and 98% in subtype 1b patients). Only 8 of the 473 treated patients (1.7%) experienced virological failure (7 relapses and 1 breakthrough). Resistance mutations to one or more drugs of the combination were detected in all eight cases. In detail, all virological failures were associated with mutations to NS5A inhibitors and all but one mutations to NS3 inhibitors (notably D168V), whereas five patients also carried mutations to non-nucleoside NS5B inhibitors (notably S556G). The rate of treatment discontinuation was very low (0.6%) and the combination was well tolerated. The incidence of nausea, pruritus, insomnia, diarrhea and asthenia was higher in the active arm than in the placebo arm. The most frequent laboratory abnormalities were anemia (grade 1 in 47.5% and grade 2 in 5.8%) and increased total bilirubin (>3 mg/dl in 2.8% of cases). The SAPPHIRE-II trial evaluated the same combination (ABT-450/RTV, ombitasvir, dasabuvir and ribavirin) administered for 12 weeks in 394 non-cirrhotic experienced patients with genotype 1 infection [80]. Patients received the active combination or placebo in a 3:1 ratio for 12 weeks. After this period, the patients in the placebo arm also received the active combination. The results were very similar to the SAPPHIRE-1 trial, namely, SVR = 96.3% (96% for subtype 1a and 96.7 for subtype 1b). Tolerability and safety were also very similar to the previous study as was the pattern of resistance [80]. Expert Rev. Anti Infect. Ther. 12(7), (2014)



Finally, the TURQUOISE-II study evaluated the same combination (ABT-450/RTV, ombitasvir, dasabuvir and ribavirin) administered for 12 or 24 weeks in 380 naı¨ve or experienced patients with genotype 1 HCV infection-related liver cirrhosis [81]. The SVR rates were 91.8% in the 12-week arm and 95.9% in the 24-week arm. Fatigue, headache and nausea were the most common clinical adverse events. Anemia occurred in 7.2% of patients in the 12-week arm and in 11% of those in the 24-week arm. Only a few patients (2.1%) discontinued treatment due to adverse events. Daclatasvir/asunaprevir combination

Three Phase II studies examined the interferon-free combination of the NS5A inhibitor daclatasvir and the second-wave protease inhibitor asunaprevir [82–84]. In all three studies, the SVR rate was high in patients infected by subtype 1b and not satisfactory in patients with subtype 1a [82–84]. Consequently, the two Phase III trials that evaluated this combination enrolled only patients with subtype 1b infection. The first one was carried out in Japan and evaluated the daclatasvir/asunaprevir combination administered for 24 weeks in 222 HCV genotype 1b patients ineligible/intolerant to interferon or non-responders to PR [85]. In this study, the SVR rate was 87.4% in the ineligible/ intolerant group and 80.5% in the non-responder group. Notably, 9.9% of all patients had liver cirrhosis. The SVR in cirrhotic patients was as high as 90.9%. Tolerability and safety profile was good. In fact, 16 patients had a grade 3–4 ALT elevation and 10 of these patients had to discontinue treatment because of this. However, no case of liver decompensation was recorded. A global large Phase III trial (HALLMARK-DUAL) evaluated the same combination administered for 24 weeks in 745 genotype 1b patients (305 naı¨ve, 205 previously partial or null-responders and 235 interferon ineligible/intolerant) [86]. Naı¨ve patients were randomized 2:1 in the combination and placebo arms. Placebo was administered for 12 weeks after which patients in this arm were rolled over into a study with daclatasvir and asunaprevir. Patients with cirrhosis constituted 16% of the naı¨ve cohort, 31% of the non-responder cohort and 47% of the ineligible/intolerant cohort. SVR12 rates were 90% in naı¨ve patients, 82% in non-responder patients and 82% in intolerant/ ineligible patients. The presence of liver cirrhosis did not affect SVR rate (84% in those with cirrhosis vs 85% in those without cirrhosis) neither did the IL-28B polymorphism, age, gender, race or baseline viral load. The most common clinical adverse events were headache, fatigue, diarrhea, nausea, asthenia, but serious adverse events occurred in 5–7% across the three cohorts and led to discontinuation in 1–3% of cases. Laboratory abnormalities were: increase in ALT >five fold upper normal values (in 2–3% of cases) and increase in total bilirubin >2.5-fold upper normal values (0–1% of cases). Interestingly, the rate of adverse events in naı¨ve patients was similar in combination-treated arm and in the placebo arm! In an attempt to increase the probability of curing patients with subtype 1a infection, a triple association of the nonnucleoside NS5B HCV polymerase inhibitor BMS-791325 informahealthcare.com

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plus daclatasvir and asunaprevir was tested [87]. In this trial, 66 genotype 1, naı¨ve, non-cirrhotic patients were randomized in four groups: daclatasvir/asunaprevir/BMS-791325 (75 mg twice daily) for 24 weeks; daclatasvir/asunaprevir/BMS-791325 (75 mg twice daily) for 12 weeks; daclatasvir/asunaprevir/ BMS-791325 (150 mg twice daily) for 24 weeks; daclatasvir/ asunaprevir/BMS-791325 (150 mg twice daily) for 12 weeks. Seventy-four percent was infected with subtype 1a. SVR12 rates were 94, 94, 94 and 89%, in groups 1, 2, 3 and 4, respectively [87]. Headache, asthenia, diarrhea and nausea were the most common adverse events. Interestingly, no grade 3–4 aminotransferase or bilirubin elevation occurred. MK-5172/MK-8742 combination

MK-5172 is a second-generation protease inhibitor that overcomes several major limitations of the first-generation NS3 protease inhibitors. In fact, it can be administered once-daily, has a higher barrier to resistance than the first-generation ‘first wave’ protease inhibitors, has a wider range of antiviral activity (it is active at least against HCV genotypes 1 and 3) and it exerts good antiviral power against most variants associated with resistance to the first-generation protease inhibitors. Its tolerability is good and is better than boceprevir or telaprevir [56]. C-WORTHY is an ongoing Phase IIb trial that is testing the efficacy of the combination of the protease inhibitor MK-5172 (at 100 mg once daily) and the NS5A inhibitor MK-8742 (at 20 or 50 mg once daily) (± ribavirin) in 159 treatment-naı¨ve HCV genotype 1-infected patients [88]. In part A of the study, 65 patients were treated for 12 weeks as follows: subjects with subtype 1a were randomized (1:1 ratio) to MK-5172/MK8742 (20 mg)/ribavirin arm or MK-5172/MK8742 (50 mg)/ribavirin arm. Patients with genotype 1b were randomized 1:1:1 in one of the first two arms or in a third ribavirin-free arm (with MK-8742 dosed at 50 mg once daily). In part B of the study, 94 patients were treated as follows: subjects with subtype 1a were randomized (ratio 1:1:1) to MK-5172/MK-8742 (50 mg)/ribavirin for 8 weeks; MK-5172/MK-8742 (50 mg)/ribavirin for 12 weeks or MK-5172/MK-8742 (50 mg) for 12 weeks. All subjects with subtype 1b were allocated to the second arm. The two parts of the study were analyzed together. In the ribavirincontaining arms, patients with subtype1a constituted 100% of patients in the 8-week regimen and 61% of those in the 12-week regimen. In the ribavirin-free arm, patients with subtype 1a constituted 68% of cases. An SVR4-24 was achieved by 83 and 94% in the ribavirin-containing 8- and 12-week arm, respectively and by 98% in the ribavirin-free arm. Expert commentary

The data reported in the present review are truly amazing. All the interferon-free combinations described resulted in viral clearance in almost all cases, regardless of the staging of the disease and of unsuccessful previous antiviral therapies. Moreover, the safety profile of interferon-free combinations was generally optimal with few side effects. These powerful combinations will make HCV infection a curable disease in almost all cases and 769

Perspective



even in patients with severe comorbidities who are currently excluded from interferon-based therapies. However, even in such a wonderful scenario, some issues remain open: • These drugs are very expensive. This is justified if we consider that anti-HIV or HBV drugs are generally administered lifelong, whereas anti-HCV antivirals are administered for a limited period of time. For this reason, the price must be high in order to recover the enormous costs of preclinical and clinical research of these agents. However, because several pharmaceutical companies are planning to market diverse combinations of these agents in the near future, the price will probably decrease. Finally, agreement with low-resource countries could allow the use of these combinations worldwide, which is desirable from an ethical point of view, and is necessary to decrease the number of carriers and finally the spread of the disease. • Therapy can be administered only after a diagnosis. This obvious concept hides an important issue in the field of HCV infection. Because the disease is often asymptomatic until the most advanced stages of the disease, only screening programs can identify all HCV-infected subjects who can benefit from treatment. A large screening program is ongoing in the USA among subjects born between 1945 and 1965, which is the population cohort with the highest prevalence of HCV infection in the country [89]. • Very few data are available about the efficacy and safety of interferon-free therapies in patients with advanced disease. As occurs in the setting of HBV infection [90], it is possible, but it is not yet demonstrated, that eradication of HCV infection can be associated with an improved quality of life and an increased disease-free survival even in patients with decompensated disease. • These drugs should be tested in ‘orphan’ indications: for example, in patients with renal failure or undergoing hemodialysis or as a preventive measure to reduce vertical transmission (e.g., in cases of unintended pregnancy or discovery of HCV infection during pregnancy) as happens for HBV infection [91,92].

In conclusion, the era of interferon-free combinations is very near. It will be characterized by the possibility of curing all patients with HCV infection using well-tolerated drugs that have the potential to improve survival and quality of life of patients. Screening programs are mandatory to diagnose and treat HCVpositive patients in a timely fashion, and, therefore, realize the dream of many physicians, namely, an HCV-free world. Five-year view

In the field of HCV infection, the next 5 years will be revolutionary and exciting. Physicians concerned with the treatment of HCV-related chronic hepatitis or liver cirrhosis will have several highly active, safe and tolerable drugs. The interferon era will gradually fade, and HCV infection will become a curable disease in nearly all cases regardless of stage of disease, presence of ascites, platelet count, comorbidities, age, gender, genotype and race. The first pangenotypic combinations will be based on SOF. Then several combinations will become available. The availability of multiple drugs and combinations will allow the physician to tailor the combination to the patient’s condition in terms of comorbidities, pattern of adverse events and use of concomitant drugs. Screening programs are necessary to diagnose the disease in a ‘treatable’ phase, that is, before severe and sometimes irreversible complications (e.g., hepatocellular carcinoma) take place. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. Writing assistance was provided by Jean Ann Gilder (Scientific Communication srl., Naples, Italy) and was funded by the Department of Clinical Medicine and Surgery of the University of Naples “ Federico II” .

Key issues • Two percent of the world’s population is chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of liver cirrhosis and hepatocellular carcinoma. • Antiviral treatment can interrupt and even revert the chain of events that lead from HCV-related chronic hepatitis to HCV-related cirrhosis and its complications. • Antiviral therapy was based on interferon. Some interferon-free therapies are currently available in the USA and Europe (sofosbuvirbased combinations). • Interferon-free approaches overcome the limitations of interferon and are therefore suitable for patients with contraindications to interferon (e.g., those with ascites). • Other interferon-free combinations will be available in the near future. They include the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination and the MK-5172/MK-8742 combination. • The efficacy of these combinations is excellent (rate of viral clearance of 90–100%). Tolerability and safety are optimal. • The only problem of these drugs is their high cost. Should this problem be overcome, these treatments will lead to, what has long been a chimera, namely, an HCV-free world.

770



C: a complex interplay. Biomed Res Int 2013;564645(10):17

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773

Emerging therapies for hepatitis C.

New hepatitis C therapies.

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis.

Oral antiviral therapies for chronic hepatitis C infection.

New Therapies for Hepatitis C Virus Infection.

Nitazoxanide for chronic hepatitis C.

Aminoadamantanes for chronic hepatitis C.

Hepatitis C (chronic).

Sofosbuvir-ribavirin duo for chronic hepatitis C.

Emerging treatments for chronic hepatitis C.

Sofosbuvir approved for chronic hepatitis C infection.

Ribavirin treatment for chronic hepatitis C.

[Therapy of chronic hepatitis C].

Adiponectin in chronic hepatitis C.

Chronic hepatitis C: future treatment.

hepatitis C virus coinfected patients.

Drug therapies for chronic hepatitis C infection: a cost-effectiveness analysis.

Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for chronic hepatitis C.

Screening for hepatitis C.

Sofosbuvir: a novel oral agent for chronic hepatitis C.

Sofosbuvir: A novel treatment option for chronic hepatitis C infection.

A pilot study of ribavirin therapy for chronic hepatitis C.

New Direct-Acting Antiviral Therapies for Treatment of Chronic Hepatitis C Virus Infection.

[All-oral, interferon-free therapies for patients with chronic genotype 1 hepatitis C virus infection].