Liver International
Review
Jerzy Jaroszewicz1, Robert Flisiak1, Geoffrey Dusheiko2
DOI: 10.1111/liv.12294
This article is protected by copyright. All rights reserved.
Accepted manuscript online: 2 AUG 2013 07:55AM EST, Manuscript Accepted: 24 JUL 2013, Manuscript Received: 30 MAY 2013
Running head: IFN-free therapies for HCV
Abstract
Weekly injections with pegylated-IFNa (PegIFN) combined with daily ribavirin are still the standard of care for chronic hepatitis C in most of the world. Sustained virological response (SVR) of 40-50% for patients infected with HCV genotypes (GT) 1 or 4 and 70-90% for genotypes 2-3 are achieved with this regimen. Triple therapy, registered in both the EU and USA, utilizing the first-generation direct protease inhibitors is able to increase the SVR rates to 75%, but its use is restricted to patients infected with HCV GT1. Additional limitations include challenging dosing schedules, complex treatment algorithms, limited efficacy in patients with previous null response to PegIFN/RBV therapy and additional side effects. There is also an important need for more effective antiviral therapy for difficult to treat populations with PEG-IFN intolerance, particularly those with cirrhosis and non-responders to previous therapies. All-oral, IFN-free therapies are an evolutionary step for future anti- HCV therapies. Initial results of clinical studies conducted during the last year give hope for “a pill for HCV” at least in selected CHC populations. In 2013 several clinical trials of alloral anti-HCV therapies had been completed, first all-oral combination submitted for registration and some conclusions could be drawn. However there is not yet a clear direction for IFN-free therapies in treatment naïve patients or more complex non responders.
Keywords: HCV, chronic hepatitis C, direct acting agents, interferon, IFN free, IFN sparing
Introduction
Nearly 2.4% of the world population is estimated to be infected with HCV. Persistent hepatitis C can result in hepatic cirrhosis and hepatocellular carcinoma [1-3]. Approximately 30% of HCV-infected individuals will develop liver cirrhosis within 20-30 years [4]. The current standard of care with pegylated IFNα (PegIFNα) -2a or -2b combined with daily ribavirin (RBV) is the standard of care in most regions of the world. Sustained virological response (SVR) of 40-50% for patients infected with HCV genotypes 1 or 4 and 70-90% for those infected with genotypes 2 or 3 are achieved [5-6]. The outcome of PegIFNα therapy largely depends on host factors (IL-28B genotype, serum IP-10), obesity, and stage of liver fibrosis and is often limited by various toxicities and/or drug intolerance [7-8].
In recent years significant progress in our understanding of the HCV life cycle has been made; replication of HCV in cell culture systems have allowed new targets for direct acting antivirals (DAA) to be developed. Several HCV proteins involved in viral replication have been identified as potential therapeutic targets of replication inhibitors. Promising results have been shown with inhibition of the HCV NS3/4A protease, which is involved in post-translational processing of HCV proteins, NS5B (RNA-dependent RNA polymerase) inhibitors and NS5A an enigmatic protein involved in as yet not fully understood stages HCV virion production. Triple therapy, registered in both the EU and USA, combined the firstgeneration direct acting antivirals (DAA) - protease inhibitors (boceprevir - BOC and telaprevir - TPV). This regimen increases SVR rates up to 75%; however their activity is restricted to HCV genotype 1 infection. [9-12]. Moreover, currently approved triple therapies possess numerous limitations restricting their clinical utility. These include challenging dosing schedules, complex treatment algorithms, improved but still limited efficacy in null responders to previous PegINFα/RBV therapy and several additional important side effects. Recently, somewhat discordant results on the frequency of adverse events between registration trails and real life practice in patients with cirrhosis have been reported for firstgeneration protease inhibitor. Interim analysis of the French, real life, early access program of triple therapy with BOC or TPV in 497 cirrhotic, previous non-responders to PegINFα/RBV treatment were evaluated. Of note, at least one serious adverse event was observed in 45.2% of TPV and 32.7% of BOC-treated patients. Premature discontinuation of therapy was recorded in 22.6% of subjects receiving TPV and 26.3% BOC [13]. However the high rates of serious adverse events in this cohort may also reflect the case mix of the population and a learning curve.
Thus there is a need for efficient and safe antiviral compounds for difficult to treat populations intolerant to interferon, particularly patients with cirrhosis and non-responders to PegIFNα/RBV. Development of pan-genotypic drugs and of interferon-sparing or interferon free combinations which could shorten, simplify and hopefully lower the cost of HCV management is an important unmet medical need.
Interferon free therapy in treatment naïve patients
Chronic hepatitis C is currently regarded as a curable infection; HCV is an RNA virus which replicates in the cytoplasm and is not integrated into the host genome. The first proof of concept studies of the potential efficacy of interferon free direct acting antivirals (formerly known as STAT-C) were published in 2003 [14, 15]. The INFORM trial [16] explored the efficacy of two DAAs combination, mericitabine (a nucleoside polymerase inhibitor) and danoprevir (a NS3/4A protease inhibitor) in 73 treatment naïve and SOC-experienced CHC patients. This combination resulted in potent suppression of viral replication (HCV-RNA decline from -3.7 to -5.2 log10 IU/mL) with no breakthroughs during 14 days of administration.
The current repertoire of anti-HCV investigational direct acting agents includes first and second generation NS3/4A protease inhibitors, nucleos(t)ide (NI) and non-nucleos(t)ide (NNI) inhibitors of NS5B RNA dependent RNA polymerase and NS5A complex inhibitors (Table 1). The ideal combination of DAAs with different mechanisms of action, potent efficacy, minimal resistance and limited side effects is yet to be determined. Several phase 1 and 2 clinical trials of all-oral anti-HCV therapies have been completed and will be reviewed below (Table 2).
Table 1. DAAs recently explored in IFN-free combinations.
(the most advanced a in development, listed in alphabetical order)
| Drug name | Drug category | Company |
| ABT-267 | NS5A inhibitor | AbbVie |
| ABT-333 | NNI NS5 inhibitor | AbbVie |
| ABT-450 | NS3/4A PI | AbbVie |
| Asunaprevir (BMS-650032) | NS3/4A PI | Bristol-Myers Squibb |
| BI-207127 | NNI NS5 inhibitor | Boehringer Ingelheim |
| Daclatasvir (BMS-790052) | NS5A inhibitor | Bristol-Myers Squibb |
| Danoprevir (RG7227) | NS3/4A PI | Roche |
| Faldaprevir (BI 201335) | NS3/4A PI | Boehringer Ingelheim |
| Ledipasvir (GS-5885) | NS5A inhibitor | Gilead |
| Mericitabine (RG7128) | NI NS5B inhibitor | Roche |
| Sofosbuvir (GS 7977) | NI NS5B inhibitor | Gilead |
| VX-222 | NNI NS5 inhibitor | Vertex Pharmaceuticals |
| Combination | HCV | SVR range | Reference |
| Sofosbuvir + RBV | 1/2/3 | 75-90 | 18 |
| Sofosbuvir + RBV +/- Ledipasvir | 1 | 84-100 | 19 |
| Sofosbuvir + RBV | 2/3 | 67 | 20 |
| ABT-450/r + ABT-267 + ABT-333 | 1 | 87-96 | 22 |
| Faldaprevir + BI 207127 + RBV | 1 | 39-69 | 23 |
| Daclatasvir + Sofosbuvir +/- RBV | 1/2/3 | 93-98 | 25 |
| Daclatasvir + Asunaprevir + BMS- | 1 | 94 | 27 |
| Alisporivir +/- RBV | 2/3 | 92 | 30 |
Direct acting antivirals plus ribavirin
RBV due to its antiviral and immunomodulatory activity is a crucial element of current anti-HCV therapies. Adding RBV to PEG-IFN increases the SVR by 25-30 % by reducing viral breakthroughs and relapses. However, RBV due to its extensive accumulation in erythrocytes leads to accelerated haemolysis and causes anemia [17]. Grade 2 anemia affects 19-23% of patients during triple therapy with BOC or TPV [13]. Whether RBV will be a crucial part of future IFN-free anti-HCV regimens remains unclear. Thus many phase 3 trials will include ribavirin free arms.
Encouraging data have been reported for the combination of sofosbuvir (SOF, a nucleotide NS5B inhibitor, previously known as GS-7977) in combination with low (600mg) or full dose (1000-1200mg, weight based) of RBV administered for 24 weeks in treatment naïve GT1 CHC patients in the NIH Spare cohort [18]. The first cohort included patients with mild fibrosis (F0-F2); the second cohort included a proportion of patients with advanced fibrosis (24% with full dose and 28% with low dose RBV). Twenty-four weeks of therapy with this regimen resulted in SVR12 of 90% with full dose RBV, and in the mild fibrosis arm. SVR4 of 64% for low dose and 75% for full dose of RBV (modified ITT analysis) were achieved. There were no cases of discontinuation due to AE and no grade 4 AE were observed, but low hemoglobin levels were noted in 7/35 (20%) of patients with full dose of RBV and only in 1/25 (4%) with low dose RBV.
The combination of sofosbuvir and RBV with or without ledipasvir (LDV, a NS5a inhibitor previously known as GS-5885) has also been evaluated as a part of the ELECTRON study. [19]. SOF+RBV therapy for 12 weeks in 25 treatment naïve patients resulted in SVR4 of 88% and SVR12 of 84%. Interestingly, coadministration of LDV, with sofosbuvir substantially improved response rates with an SVR12 of 100% in small numbers of naïve genotype 1 patients in this cohort. These preliminary results do not suggest an effect of HCV subtype IL28B genotype, or BMI. Twenty percent of patients suffered anemia in the triple therapy arm compared to none of this in the dual therapy arm. A phase 3 trial of fixed dose SOF/LDV will further evaluate the need for RBV and possibility of shortening therapy duration. The combination of SOF and RBV has been also assessed in GT2 and 3 HCVinfection in FISSION study [20, 21]. SOF and RBV for 12 weeks (n=256) resulted in the same SVR12 of 67% as achieved with the control arm of PEG-IFN/RBV for 24 weeks. Importantly SVR12 was substantially lower in HCV GT3 vs GT 2 (56 vs 97%) underlining the need of separate analysis of these genotypes. The most difficult to treat in this study were HCV-GT3 patients with cirrhosis with SVR12 of 34%. Although IFN-free therapy led to treatment discontinuation due to AEs in 1% vs 11% in IFN-containing arm the costs of the IFN arm will differ substantially. On April 8th 2013 sofosbuvir plus RBV as the first all-oral therapy for patients with GT 2 and 3 HCV infection has been submitted to US Food and Drug Administration (FDA) for approval (Gilead Press Release).
A four drug regimen of ritonavir (RTV) -boosted ABT-450 (a protease inhibitor), ABT-267 (a NS5A inhibitor), and ABT-333 (a non-nucleoside polymerase inhibitor) plus RBV has been explored in 438 treatment naïve GT1 CHC in the AVIATOR study [22]. The design of this study allowed testing of different regimens, therapy duration and the need for RBV. The quadruple combination was administered for 8, 12 or 24 weeks with an additional RBV-free arm for 12 weeks. Twelve weeks treatment with all three DAAs plus RBV produced the highest SVR rate. SVR12 was 99% and SVR 24 was 96%, in this arm. In the RBV-free arm SVR24 of 87% was observed and 5 cases of relapse were noticed (5/79). Importantly, no clinically meaningful differences between groups based on sex, HCV subtype, IL28B genotype, baseline HCV RNA or fibrosis stage were noted.
Faldaprevir, a NS3/4a inhibitor has been tested co-administered with BI 207127 (a nonnucleoside polymerase inhibitor) and RBV in treatment naïve CHC patients infected with HCV genotype 1 (Sound-C2 Study) [23] for 16, 28 or 40 weeks. Randomization to the RBV free arms was stopped early for lack of efficacy: SVR2 39% in ITT analysis after 28 weeks of therapy. The highest SVR (69%) were obtained after 28 weeks of therapy with faldaprevir once daily and BI 207127 twice daily plus RBV. High rates of virological failure occurred in subtype genotypes 1a.
In the Zenith study, VX-222 (a nonnucleoside polymerase inhibitor), telaprevir plus RBV were tested for efficacy in GT1 HCV-infection [24]. Dual therapy with VX-222 and TPV without RBV was previously associated with high rate of virologic breakthrough. VX-222 plus TPV was combined with RBV for 12 weeks; therapy was stopped in patients with an undetectable HCV-RNA at week 2 and 8. Twenty-four percent of patients reached this goal (11/46) and 9 of them had SVR12 (82%). In the remaining patients PEG-IFN+RBV was continued for the next 24 weeks with SVR12 of 89%.
Direct acting antivirals only (IFN-free, RBV-free therapies)
Daclatasvir (DCV, an NS5A inhibitor) and sofosbuvir have broad genotypic coverage and are administered once-daily [25, 26]. DCV 60mg and SOF 400mg have been tested with or without RBV for 12 and 24 weeks in genotype 1 and in GT2/3 CHC for 24 weeks. In GT1 patients, 12 weeks of therapy resulted in SVR4 of 96%. Response rates were not greater with 24-weeks of therapy (98%). Similarly, 24-weeks of therapy were sufficient to obtain SVR24 of 93% in HCV GT2/3 patients. Interestingly, virological response did not vary according to IL28B genotype, subtype (1a/b) or the administration of ribavirin. One out of 170 patients discontinued the study due to adverse events; low haemoglobin concentrations were observed in patients receiving RBV only.
Daclatasvir, asunaprevir (ASV, an NS3 PI inhibitor active against HCV GT 1 and 4) and BMS-791325 (an NNI NS5B inhibitor active against HCV GT1a/b) were evaluated for efficacy in treatment naïve GT1 patients [27]. Triple therapy was administered for 12 or 24 weeks at two doses of BMS-791325 (75mg and 150mg). In this study 50% had stage (F0-F1) disease and 44% stage F2-3 fibrosis. Overall SVR4 (for 24-week therapy) and SVR4 and SVR12 (for 12-week therapy) were 94%.
Host targeting agents plus ribavirin
In addition to direct acting antivirals a unique class of host targeting (HTA), anti-HCV compounds agents has been developed. These agents could theoretically increase the barrier to resistance. Currently the most advanced HTAs are cyclophilin inhibitors, microRNA inhibitors (both are non-immunomodulatory agents) and Toll-like receptor agonists. Alisporivir (ALV, previously known as Debio 025) is the most advanced nonimmunosupressive cyclophilin inhibitor in development for chronic hepatitis C with a pangenotypic activity [28, 29]. Resistance to ALV can occur through reduction of HCV dependence on host cyclophilins, but requires multiple nucleotide substitutions, including NS5A and NS2 mutations. Hyperbilirubinemia has been observed, and hypertriglyceridemia. In April 2012 FDA mandated a partial hold on the development of ALV after six cases of acute pancreatitis (including one fatal case), were reported. Since pancreatitis is known adverse event related to IFN alfa, it will be necessary to clarify if the combination of ALV with IFN indeed increases the risk. ALV may be further evaluated without IFN for genotype 2 and 3 patients, given its efficacy in these genotypes and the unmet need for effective genotype 3 IFN free treatment.
ALV as a part of IFN-free regimen was evaluated in 340 treatment naïve CHC patients with GT2/3 [30] in the VITAL-1 study. Patients were randomized to receive ALV monotherapy (1000 mg), ALV (600 or 800 mg) combined with RBV, ALV (600 mg) combined with PegIFNa2a or PegIFNa2a plus RBV as a SOC. Patients in ALV arms who were negative at week 4 (42%) continued initial treatment, while those who did not respond received triple therapy with ALV, PegIFNa2a and RBV starting from week 6. The SVR24 rate achieved with ALV/RBV (IFN-free) treatment was 92% (56/61 patients), which was higher than with ALV alone 72% (13/18) or with add-on PEG-IFN/RBV treatment - 70%. The rates of viral breakthrough in patients receiving ALV-based treatments were very low – 3.0% (9/299). Furthermore, IFN-free ALV treatment reported substantially lower rates of adverse events than with IFN [31].
In summary, initial data shows that SVR in the range of 90% should be realistic in selected treatment naïve CHC patients with all-oral combinations of DAA or HTA with or without RBV after 12/24 weeks of therapy. Ribavirin may be necessary in some combinations of DAA with lower barrier to HCV resistance. The further evolution IFNsparing therapies in this population most likely will concentrate on shortening duration of therapy, simplifying therapeutic regiments (once daily), and in improving safety. There is insufficient data on the efficacy of IFN-free therapies in HCV-infected populations with GT 4-6, as well as in patients with liver cirrhosis, decompensated liver disease, renal impairment, HIV coinfected patients or following liver transplantation who really need this kind of treatment because of IFN intolerance. The results achieved in GT3 patients need to be analysed separately from those in GT2 patients, particularly in prior non responders or those with cirrhosis.
Interferon sparing therapy in previous non-responders
As an effect of increased availability of anti-HCV therapies there is increasing proportion of chronic hepatitis C patients who failed to eradicate the virus. This population is heterogeneous with higher prevalence of factors associated with worse outcome of therapy, including advanced fibrosis, obesity, IL-28B CT/TT-genotype. Chronic HCV-infection is currently a leading indication for liver transplantation, and almost invariably leads to recurrent disease after post-transplant immunosupression [32].
The concept of IFN-free regimen has been explored for prior non-responders, particularly in null-responders who are in the greatest need for novel therapies. In a phase IIa study with daclatasvir and asunaprevir 110 non-cirrhotic patients infected with GT1 HCV and previous null response to pegIFN/RBV were randomized to five 24-week treatment arms [33]. Two of them were IFN and RBV-free (asunaprevir 200 mg was administered once or twice daily), one included triple therapy with RBV and two included study drugs plus PEG-IFN and RBV. The regimen was not successful in patients with genotype 1a due to high rate of virologic breakthrough and all patients were offered PEG-IFN but dual therapy may have a role in GT1b patientsIFN and RBV-free arms were associated with lower SVR12 ranging 65-78% depending upon the dose of ASV (200mg vs 400mg) compared to quadruple regimen (SVR12: 95% and 100%, respectively). Raised aminotransferase have been observed with a proportion of patients receiving ASV.
GT1 HCV infected patients with previous partial and null-response to PEG-IFN/RBV were also included in Matterhorn study [34]. IFN-free arms consisted of danoprevir boosted with ritonavir (DNV/RTV), mericitabine plus RBV while arms with PEG-IFN/RBV included DNV/RTV plus mericitabine (MCB) or MCB alone. All study drugs were administered for 24 weeks. Similarly to the previously mentioned study, HCV GT1a infected patients showed high relapse rate in the IFN-free arm and were excluded from further analysis. In both cohorts of previous partial and null-responders SVR12 were lower in IFN-free compared to PEG-IFN containing arms (39% and 55% vs. 86 and 84%). Additionally in the PEG-IFN arms there was a striking difference in SVR12 between HCV GT1b vs 1a patients (91-100% vs 30-75%) and importantly addition of MCB seemed to decrease the rate of relapses in HCV GT1a. All therapies were well tolerated, with 2% rates of discontinuation due to AE in triple and quadruple study arms.
A small number of HCV GT1 infected previous null-responders (n=29) was also included in the Electron study [19]. Patients received dual - sofosbuvir (SOF) plus RBV or triple – SOF/RBV/ledipasvir or SOF/RBV/GS-9669 therapies for 12 weeks. End of therapy (EOT) response rates reached 100% in all study arms. However SVR12 for dual therapy SOF/RBV declined to 10% (1/10) while it remained 100% (9/9) for triple regimen with ledipasvir. Sofosbuvir (400 mg once daily) in combination with RBV (1000-1200 mg) has also been tested in GT 2 or 3 HCV-infected patients who had failed prior interferon-based treatment in FUSION trial [35]. SOF/RBV were administered for 12 (n=103) or 16 weeks (n=98). Overall SVR12 was 50% for 12 weeks of therapy and 73% for 16-week therapy arm. While both study arms provided comparable efficacy in GT2 HCV-infection (SVR12: 86% vs 94%), in GT3 extension of therapy to 16 weeks improved SVR12 twofold (30% vs 62%), particularly in those with GT3 and liver cirrhosis (SVR12: 19% vs 61%).
Recently registered DAAs boceprevir and telaprevir combined with Peg-IFN/RBV yield improved but still unsatisfactory therapeutic results in this population. Current first generation protease inhibitor containing triple therapies are associated with fair 75-88% of SVR rates in relapsers, but partial and null responders to previous Peg-IFN/RBV therapy achieve significantly lower SVR rate (52-54% and 33% respectively) with these regimens [11, 12]. Resistance is detected in most patients who breakthrough or relapse. Therefore increasing number of CHC patients with first generation PI resistance can be predicated. may be foreseen. An important phase 2a [36] study has evaluated the efficacy and safety of daclatsvir and sofosbuvir with (n=21) or without RBV (n=20) in HCV GT 1-infected patients who failed prior treatment with TVR or BOC Therapy was administered for 24 weeks. A SVR12 was reported in 100% in the dual and 95% in the triple combination study arm. Importantly no discontinuations due to AEs were noted and neither baseline NS3 PI resistance variants nor use of RBV influenced response.
Recent data on all-oral anti-HCV therapies for previous non-responders to PEGIFN/ RBV are yet unsatisfactory. While it does not raise additional safety concerns SVR rates are suboptimal in null-responders. Lower virological response rates in this difficult-to-treat population are mainly due to viral breakthroughs and/or post-treatment relapses, which cannot so far be prevented by RBV or DAA alone. On the other hand 4-drug arms including PEG-IFNα seem to deliver excellent SVR rates (80-90%) in previous null responders. Since addition of PEG-IFNα can cause unacceptable side effects in difficult to treat populations with cirrhosis or post-transplant recurrent hepatitis C, interferon alpha containing quadruple regimens may not be practical for the majority of patients. It is possible that PEG-IFNλ (lambda) might prove safer and more effective in patients with cirrhosis but this remains unproven. [37]. It is important to underline that results of IFN-free therapies in previous nonresponders are preliminary, based on relatively small cohorts and apart from HCV GT subtype (1a vs 1b) do not explore yet the potential influence of other compounding factors on viral response (fibrosis, IL28 genotype etc.).
Conclusions
All-oral, IFN-free therapies are the natural step in evolution and future goal of anti- HCV therapies. Initial results of clinical studies conducted during last year give hope for “a pill for HCV” in selected CHC populations. Two main directions of upcoming anti-HCV strategies can already be envisaged. A simplification and shortening of therapies in treatment naïve patients but perhaps more complex, combination regimens may be required for previous non-responders to PEG-IFNα/RBV regimen.
The application of novel agents with a high safety profile and high barrier to resistance as well as multi/pangenotypic activity in treatment naïve CHC populations can lead to SVR rates above 90%. It is reasonable to speculate that in the next two years IFN-free therapies including two/three anti-HCV agents will be successful in the large majority of treatment naïve patients infected with HCV GT1, although questions remain for GT3. Priorities will be given to short duration (12-24 weeks) regimens with excellent safety profiles and allowing their implementation in primary health-care settings. The place of IFN sparing therapies or quadruple therapies remains undefined. The possible addition of PEG-IFN (including lambda) to novel DAAs and HTA could be crucial in preventing breakthroughs and/or relapses in some groups. In this setting ribavirin might continue to be a necessary component of such triple / quadruple therapies. Moreover, treating of previous non-responders, especially null-responders may require tailoring regimens for viral (HCV GT1 subtype) or host factors(IL28B genotype).
Of importance recent results of IFN-free therapies are often based on limited number of CHC patients and need to be verified in larger settings in various, heterogeneous populations. Results of these crucial, registration clinical trials are expected during coming 2-3 years. Moreover, IFN-free therapies have not been sufficiently evaluated in groups of the highest need for such regimens, included patients with decompensated liver cirrhosis and following liver transplantation. A pill for HCV, the Holy Grail of hepatology will certainly be reached but the clear path to it is yet to be found.
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