Liver International
Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C
Volume 32, Issue Supplement s1, pages 108–112, February 2012
Review Article
Peter Ferenci
Article first published online: 29 DEC 2011
DOI: 10.1111/j.1478-3231.2011.02705.x
© 2012 John Wiley & Sons A/S
Abstract
Due to the side effect profile of pegylated interferons interferon treatment has become the holy grail of drug development for chronic hepatitis C. The precise role of interferon in treatment of hepatitis C is not fully understood, besides its antiviral effects interferon is an immune modulator. Nevertheless, recent proof of concept studies indicated, that cure of chronic hepatitis C can be achieved without interferon. Various compounds achieved this goal, like the polymerase inhibitor PSI 7977, the combination of NS5a inhibitor (daclatasvir) and a protease inhibitor (asunaprevir) and the cyclophillin antagonist alisporivir. Various other combinations are investigated currently. Providing that phase 3 studies will confirm these exciting data, direct acting antivirals or host targets will replace peginterferon/ribavirin combination therapy.
The current standard of care (SoC) for treatment of chronic hepatitis C is still a combination of a pegylated interferon-α2 (PEG-IFN) with ribavirin (RBV) [1]. Recently, the first two direct-acting antivirals (DAA) were licensed in the USA and the European Union. In combination with PEG-IFN/RBV, telaprevir and boceprevir significantly increases the rate of cure of chronic hepatitis C, genotype 1, both in naïve and treatment-experienced patients [2, 3, 4]. Nevertheless, treatment is still restricted to patients who can tolerate PEG-IFN and RBV. As many as 50% of patients, including those with the greatest need of effective treatment such as those with advanced liver disease, cannot receive the new triple therapy. Thus, an interferon-free treatment regimen is required .
Investigation of DAA combination regimens has exploded in the last 12 months. This is possible because of the diversity of antiviral mechanisms besides protease inhibitors that are now in Phase II of the drug development pipeline for hepatitis C [5]. Diverse mechanisms are important because they often have different resistance profiles, and antiviral combinations are being assembled with new compounds with non-overlapping profiles to provide a greater barrier to antiviral resistance. Other factors that are important when assembling optimal combinations include the safety and tolerability profile of each agent, compatible pharmacokinetic profiles and a low potential for unfavourable drug–drug interactions.
The role of interferon in the treatment of chronic hepatitis C
Although interferon (IFN) has been used to treat chronic hepatitis C for more than 25 years, its precise role in eradicating the hepatitis C virus (HCV) still remains unknown. Determining the mechanism(s) involved in an IFN-induced cure is mandatory if IFN-free treatment regimens are to be developed. IFNs play a pivotal role in the outcome of a viral infection. IFNs are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumour and immunomodulatory properties. The first response of an organism to intruding pathogens is an inflammatory reaction that includes secretion of cytokines and chemokines. These signalling molecules activate or attract innate immune cells, such as neutrophils, macrophages, natural killer (NK) cells, and dendritic cells (DCs), to orchestrate an effective response at the site of infection. Induction of innate immune mechanisms is not pathogen-specific, but is dependent upon interactions between pathogenic factors and host-cell determinants. During viral infection, some of the most prominent cytokines produced are IFNs. The importance of IFNs goes beyond their antiviral activities and includes numerous immunoregulatory functions that affect both innate and adaptive immunity [6]. IFN-induced clearance of HCV is both cytolytic (clearance of HCV-infected hepatocytes) and non-cytolytic (intra-cytoplasmic destruction of HCV without cell injury).
Innate immunity can be principally affected by HCV at the level of both: (i) type I IFN production by infected hepatocytes and (ii) the signals provided by the relative receptors (IFNAR-1/2) once they are engaged by soluble type I IFNs (mainly produced by plasmacytoid dendritic cells). If these defects are combined with a low viral load or infection by HCV strains that are highly susceptible to the antiviral effects of IFN, the spread of the HCV virus is contained, and the functions of dendritic cells, NK, B and T cells would not be heavily affected. Induction of type I IFN production in HCV-infected cells (i.e. hepatocytes) either on contact with TLR3 in the endosomal compartments, or upon recognition of the polyuridine motif of the HCV 30 untranslated region (UTR) by the retinoid acid-inducible gene I (RIG-I) in the cytoplasm, may be affected by HCV [7, 8, 9]. Thus, the initial response to HCV infection might not be sufficient to induce effective primary or secondary CD8 T-cell responses [10]. In chronic HCV infection, two major pathways, T-cell exhaustion and viral escape, contribute to CD8+ T-cell failure. In vivo models of HCV infection demonstrate selective impairment of T cells infiltrating HCV-infected livers because of the high concentrations of viral proteins produced at the site of infection, which may play a role in HCV persistence by affecting local adaptive immune responses [9].
The immunomodulatory activity of PEG-IFN-α and RBV induced T-cell immune responses may be important to eliminate chronic HCV infection [11]. In a prospective study, the kinetics of T-cell responses to HCV antigens (NS3-4 and core) correlated with virological outcome in patients undergoing PEG-IFN-α2a/RBV therapy. NS3-4-directed T helper cell type 1 (Th1) responses were detected in 77% of patients with a significant decline in viremia at treatment week 4, but were not detected in those with a slower viral decline. HCV-specific T-cell reactivity was uncommon at baseline, but increased markedly during antiviral therapy, peaking at around treatment weeks 4–8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production [12]. The detectability of NS3-4-directed Th1 responses was associated with faster viral clearance, was short-lived and was not associated with the final treatment outcome [13]. This may be explained because HCV abolishes the blockade of the adaptative immune response by inhibiting viral replication. T-cell activation was transient, but not always sufficient to clear infected hepatocytes. Thus, if rapid inhibition of HCV replication by DAA is sufficient to restore adaptative immunity, exogenous IFN administration may not be necessary.
The other important role of IFN is the inhibition of viral replication. In drugs with a low genetic barrier such as first generation protease inhibitors, IFN and RBV are required to block the emergence of DAA resistant viral strains [14, 15]. Potential strategies to overcome this problem are: (i) DAA combinations including polymerase inhibitors with a high barrier to resistance; (ii) triple DAA therapy; and (iii) combinations of two DAAs with a lower genetic barrier to resistance plus RBV. A mathematical model by Perelson et al. [16] suggests that IFN-free regimens will need to contain three or four distinct antiviral mechanisms to obtain a sustained viral response (SVR) before the development of resistance.
Proof-of-concept studies
The first published trial with an all-oral combination treatment with two experimental anti-HCV drugs [mericitabine, a nucleoside polymerase inhibitor (NI); and danoprevir, an NS3/4A protease inhibitor] in patients with chronic HCV infection was the INFORM-1 study [17]. Patients with chronic hepatitis C, genotype 1, received up to 13 days of oral combination treatment with mericitabine (500 or 1000 mg twice daily) and danoprevir (100 or 200 mg every 8 h or 600 or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or a web response system to either active treatment or placebo. The primary outcome was a change in HCV RNA concentrations from baseline to day 14 in patients who received 13 days of combination treatment. Eighty-eight patients were randomly assigned to a drug treatment regimen (n = 74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n = 14, all of whom received at least one dose). The median change in HCV RNA concentrations from baseline to day 14 ranged from −3.7 to −5.2 log10 IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentrations from baseline to day 14 was −5.1 log10 IU/mL in treatment-naive patients and −4.9 log10 IU/mL in previous SoC non-responders. The combination of RG7128 and danoprevir was well tolerated with no severe treatment-related or adverse events, no grade 3 or 4 changes in laboratory parameters and no safety-related treatment discontinuations. Virological breakthrough, with the selection of resistant variants, has not yet been observed in short-term clinical studies of the NS3/4A protease inhibitor danoprevir plus the NI, mericitabine, suggesting that inclusion of an NI in DAA combination therapy may be an attractive strategy. However, additional efficacy (SVR) and safety data from longer term treatments are still required. A phase 2a study is ongoing (Matterhorn study).
In another study [18], the combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127 and RBV was shown to have a rapid and strong activity against HCV genotype-1 with no severe adverse events. Thirty-two treatment-naïve patients with chronic HCV genotype-1 infection were randomly assigned to groups that were administered 400 or 600 mg BI 207127, three times a day (TID), plus 120 mg BI 201335, once a day and 1000–1200 mg RBV per day for 4 weeks. The primary efficacy endpoint was virological response (HCV RNA < 25 IU/mL at week 4). The virological response rates were 47, 67 and 73% at days 15, 22, and 29, respectively, in the group receiving BI 207127 400 mg TID; a higher response rate was observed in patients with genotype-1b compared with genotype-1a. The virological response rates were 82, 100 and 100%, respectively, in the group receiving BI 207127 600 mg TID, and did not differ among genotypes. One patient in the group receiving 400 mg TID had a virological breakthrough [≥1 log [10] rebound in HCV RNA] at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash and photosensitivity. There were no severe or serious adverse events; none of the patients discontinued treatment early.
The results of a proof-of-concept study for SVR with a PEG-IFN-free treatment regimen in HCV patients was recently reported. Four of eleven genotype 1 patients, who were non-responders to PEG-IFN/RBV treatment, achieved a SVR after 24 weeks of treatment with the combination of an NS5A inhibitor and an NS3/4A protease inhibitor, with only one relapse in this cohort [19], especially in patients with genotype 1b [20]. This suggests that HCV can be eradicated in chronically infected patients with a PEG-IFN-free DAA combination regimen, and supports investigations of various DAA combinations to improve SVR rates without PEG-IFN.
These observations provide a proof-of-concept for an oral approach to the treatment of HCV, including a combination of DAA without PEG-IFN.
ZENITH is an ongoing Phase 2 study of multiple 12- and 24-week response-guided treatment regimens with VX-222 (400 or 100 mg), a polymerase inhibitor in development, in combination with telaprevir [21]. The all-oral treatment arms (VX-222 400 or 100 mg plus telaprevir 1125 mg BID) were discontinued because of a pre-defined stopping rule in relation to viral breakthrough. The two treatment arms including PEG-IF and RBV (quadruple therapy) could stop all treatments at week 12, if hepatitis C virus was undetectable at weeks 2 and 8. Twenty-six of fifty-nine (44%) patients qualified for 12 weeks of therapy, and 88.4% of these had a SVR. The remaining patients received an additional 12 weeks of PEG-IFN/RBV. SVR was achieved in 96%. The overall SVR rate was 86.4%.
Another approach is the combination of nucleoside polymerase inhibitors (PSI-7997 with PSI-938) [22] with promising initial data. The approach of combining three non-cross resistant DAAs with a lower genetic barrier to resistance, i.e. an NNI plus a NS3/4A protease inhibitor and an NS5A inhibitor, is well supported by mathematical analyses. Rong et al. demonstrated that resistant variants against the three drug classes are unlikely to pre-exist before treatment initiation, and emergence is unlikely to occur during therapy [23]. However, drug–drug interaction and overlapping safety profiles remain an issue.
A third highly attractive strategy is to combine two DAA with a lower genetic barrier to resistance, plus RBV. A trial evaluating GS-9256 plus tegobuvir, with or without RBV demonstrated the central role of RBV in the decrease in HCV RNA and the reduction of viral breakthroughs for DAA combinations with a low barrier to resistance. Unfortunately, this study was interrupted because of safety concerns (Table 1).
Finally, a new class of drugs called cyclophilin inhibitors may be used in an IFN-free approach. Alisporivir (DEB025) is the first in this class of drugs, and is currently under investigation. Unlike other compounds under development that target the virus directly, Alisporivir is a host targeting antiviral that targets host proteins essential for the replication of HCV. As these proteins play a key role in the replication of all types of HCV, alisporivir may offer an effective treatment option for a broad range of HCV forms and be effective against other common HCV genotypes. High SVR rates were obtained in combination with PEG-IFN/RBV [24]. INF-free regimens in patients with genotypes 2 and 3 were recently presented [25, 26]. Alisporivir as IFN-free therapy achieves early on-treatment viral response in up to half of G2/3 patients by treatment week 6 and in most patients who reached end of treatment [25]. In a phase 2a study PSI 7977 in combination with ribavirin reached a 100% cure rate in just 12 weeks [26].
Summary
As a result of the side effects of IFN, there is ongoing search for interferon-free antiviral approaches to cure chronic hepatitis C. The FDA, EMA as well as patient advocacy groups are strong proponents of investigating antiviral drug combinations prior to approval of individual components. Although proof-of-concept studies confirm that such approaches may be feasible, at present, only oral combinations together with PEG-IFN/RBV offer the best chances for cure even in non-responders to SoC treatment. The best drug combinations must prevent the emergence of drug resistant viral strains, have a high degree of safety and efficacy, an easy treatment algorithm and short treatment duration. The treatment should work for all genotypes. Although the ideal drug has not yet been found there is an urgent medical need because patients with advanced liver disease or organ transplant patients (excluding liver transplants) cannot tolerate IFN and are in great need of effective treatment.
Conflicts of interest
Dr Ferenci is a member of the global advisory board and of the speaker bureau of ROCHE. He also receives an unrestricted research grant from ROCHE Austria. He is also member of the global advisory boards of Vertex/Tibotec, Böhringer-Ingelheim, MSD and Rottapharm-Madaus, and serves as advisor to Pfizer, Novartis, Achilleon, GSK.
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