By continuing to browse this site you agree to us using cookies as described in About Cookies
Wiley Online Library is migrating to a new platform powered by Atypon, the leading provider of scholarly publishing platforms. The new Wiley Online Library will be migrated over the weekend of February 24 & 25 and will be live on February 26, 2018. For more information, please visit our migration page: http://www.wileyactual.com/WOLMigration/
Correspondence Dr Tarik Asselah, INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, and Service d'Hépatologie, Hôpital Beaujon, 100 Bd du Gl Leclerc, 92118 Clichy, France Tel: +33(0) 140875579 Fax: +33(0) 147309440 e-mail: firstname.lastname@example.org
Chronic hepatitis C is among the leading causes of chronicliver disease worldwide, with approximately 170 million people infected. The severity of disease varies from asymptomaticchronic infection to cirrhosis and hepatocellular carcinoma.
Recently,advances have been made, with the combination of pegylated interferon (PEG-IFN) and ribavirin leading to a sustained virological response (SVR) in approximately 55% of cases. In genotypes 2 or 3, SVR rates reach 80%; in genotype 1 SVR rates is 50%. Furthermore, SVR appears to be long lasting, associated probably with a reduction in the risk of cirrhosis and hepatocellular carcinoma. Despite this progress, treatment failure still occurs in about halfof the patients. Furthermore, therapy results in several side effects and high costs. These limitations have led to important development of novel compounds under the name of specifically targeted antiviral therapy for HCV (STAT-C). Also, considering side effects and treatment cost, prediction of virologicalnon-response is mandatory. The management of chronic hepatitis C must include better knowledge of viral cycle and mechanisms of non response. The development of new molecules such as HCV enzyme inhibitors is ongoing. The aim of this review is to summarize results obtained with STATC: protease and polymerase inhibitors.
specifically antiviral therapy for hepatitis C virus;
sustained virological response.
Hepatitis C virus is a major cause of chronic liver disease, with about 170 million people infected worldwide (1). HCV, identified in 1989, is an enveloped virus with a 9.6 kb single-stranded RNA genome (2–7), a member of the Flaviviridae family, genus Hepacivirus. Error-prone replication of HCV, resulting in a complex quasispecies population within each infected individual, enables rapid adaptation to changing environments. Six HCV genotypes and a large number of subtypes have been identified (3). The HCV virion is made of a single-stranded positive RNA genome, contained in a capsid, itself enveloped by a lipid bilayer within which two different glycoproteins are anchored. The HCV lifecycle starts with virion attachment to its specific receptor (Fig. 1). Several candidate molecules have been suggested to play a role in the receptor complex, including tetraspanin CD81, the scavenger receptor B I (SR-BI), the adhesion molecules DC-SIGN and L-SIGN and the low-density lipoprotein receptor (4). Recently, the tight-junction components claudins (mainly CLDN-1) have been identified as additional key factors for HCV infection (5–6). The CD81 partner EWI-2wint inhibits HCV entry, suggesting that, in addition to the presence of specific entry factors in the hepatocytes, the lack of a specific inhibitor can contribute to the hepatotropism of HCV (7).
The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases (8–10). All the HCV enzymes – NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp – are essential for HCV replication, and are therefore potential drug discovery targets (Fig. 2). After the structures of HCV protease and HCV polymerase were solved, numerous groups used a structure-based drug design to develop inhibitors to these enzymes (11–15).
Until recently, the absence of a cell culture model supporting full replication of HCV, and of convenient animal models, has limited the knowledge of the HCV lifecycle and testing for antiviral molecules. Chimpanzee is the only animal model for HCV infection (8). The development of subgenomic HCV RNA replicon capable of replication in the human hepatoma cell line, Huh 7, has been a significant advance (9–10). Recently, complete replication of HCV in a cell culture has been achieved (16–18). These models will improve our understanding of HCV replication and testing for antiviral molecules.
Results of standard of care: combined pegylated-interferon and ribavirin
The prognosis of chronic hepatitis C depends on the progression of fibrosis, which determines the risk of developing cirrhosis and its complications. Knowledge of the natural history and the factors associated with the progression of fibrosis is essential for the patient's management, because in patients with mild disease we can wait and see and in patients with advanced disease treatment is mandatory (19). The major factors known to be associated with fibrosis progression are male gender, older age at infection, excessive alcohol consumption, immunosuppression and insulin resistance (20–21). Insulin resistance is the main feature of the metabolic syndrome, a common metabolic disorder that is a result of the increasing prevalence of obesity worldwide. Of course, the natural history of liver fibrosis in chronic hepatitis C is influenced by both genetic and environmental factors (22).
Management of patients with chronic hepatitis C should be global, and all factors associated with a rapid progression of fibrosis should be identified, including those affecting the response to treatment [such as excess alcohol consumption, obesity and insulin resistance (23)], and treated.
The main treatment goal in chronic hepatitis C is the prevention of cirrhosis and hepatocellular carcinoma by eradicating the virus. Recently, advances have been made in treatment with a combination of PEG-IFN and Ribavirin. At present, in a patient with hepatitis C, therapy results in a sustained response in approximately 55% of cases (24–26).
In patients with HCV genotype 2 or 3, the SVR rates reach 80%; in genotype 1 patients, the SVR rates reach 50%. Based on existing results, the SVR with this treatment option appears to be long lasting, to be associated with a histological benefit and is also probably associated with a reduction in the risk of cirrhosis and hepatocellular carcinoma.
Predictive factors of response to treatment
Because a significant number of patients will fail to respond to current treatment, display a virological relapse or will have significant side effects that will need discontinuation of treatment, it is of major interest both in an economic approach and for the patient care to predict those patients who will fail to respond as early as possible, and ideally at baseline (before treatment).
The probability of SVR essentially depends on the genotype and viral load (24–26). Younger age, female gender, and the absence of or minimal fibrosis are also associated with a better rate of response. In patients with HCV genotype 2 or 3, the SVR rates reach 80%; in genotype 1 patients, the SVR rates reach 50%. Recent studies allow a better monitoring of patients, which allows optimization of treatment schedule according to the characteristics of the patients.
In genotype 1 patients, a reduction in HCV RNA serum levels by <2 log10 copies/ml after the first 12 weeks of treatment compared with the baseline is clearly associated with almost no chance of an SVR (negative predictive value, 97–100%). Thus, treatment can be discontinued because the probability of an SVR in these cases is approximately 0–3%. However, the positive predictive value is low, and this information is available only after 12 weeks of treatment.
More recently, studies have focused on a rapid virological response (week 4) (RVR) with very good results (27).
Liver molecular signature of response
Gene expression profiling studies (microarrays and/or large-scale real-time quantitative reverse transcriptase polymerase chain reactions) are a promising approach to understand the involvement of several altered molecular pathways in the genesis of disease. Liver gene expression profiling can be studied in chronic hepatitis C according to the response of therapy (28–29). Also, knowledge of antiviral actions of IFN is crucial for the discovery of new markers of treatment response. In a recent study, 58 genes associated with liver gene expression dysregulation during chronic hepatitis C were selected to study gene expression according to the response to PEG-IFN plus Ribavirin (29). Supervised class prediction analysis identified a two-gene (IFI27 and CXCL9) signature, which accurately predicted the treatment response in approximately 80% of patients, with a predictive accuracy of 100 and of 70% in Non Responders (NRs) and Sustained Virological Responders (SVRs) respectively. In conclusion, this study demonstrated that NR and SVR patients have different gene expression profiles before treatment. The most notable changes in gene expression were mainly observed in the IFN-stimulated genes. In NRs, the failure to respond to exogenous PEG-IFN could indicate a blunted response to IFN. This raises the possibility that, in NRs, the IFN-stimulated genes are already maximally induced. The genes included in the signature encode molecules secreted in the serum and provide a logical functional approach for the development of serum markers to predict a response to treatment.
Specifically targeted antiviral therapy for the hepatitis C virus: protease and polymerase inhibitors
The development of new molecules such as viral enzyme inhibitors (proteases and polymerases) is necessary. Understanding the tridimensional structures of viral proteases and helicases was an important step in developing new drugs because specific inhibitors could be developed for these enzymes (11–15). Several years ago, a protease inhibitor that blocks viral C replication in the replicon model was shown to be as effective in humans (30–32). The development of this molecule was discontinued because of cardiac toxicity observed in the chimpanzee. Several STAT-C are in development (Fig. 4).
An antiprotease NS3-NS4A called telaprevir is being developed by the companies Vertex Pharmaceuticals Inc. (Cambridge, MA) and Tibotec BVBA (Mechelen, Belgium). In a phase I–II trial in 34 patients with genotype 1, at a dose of 750 mg, 3 times/day, a marked reduction in the viral load of approximately 4–5 log has been observed (33). When this antiprotease is used in combination with PEG-IFN, a reduction in the viral load of more than 4 log has been observed at day 14 (Fig. 3A).
Resistant variants to HCV emerge rapidly during telaprevir monotherapy treatment (34). When telaprevir is combined with PEG-IFN α-2a plus Ribavirin, the antiviral activity is improved and the incidence of resistance is greatly reduced. Rapid reductions in the viral load are achieved and, in some patients, serum HCV RNA is suppressed to below the limit of detection (<10 IU/ml) within 14 days (35).
In the randomized, double-blind, placebo-controlled phase II Prove-1 (USA) and Prove-2 (Europe) trials, telaprevir is being administered for 12 weeks with PEG-IFN α-2a plus Ribavirin (36–37). Preliminary data from these trials show that the triple-therapy regimen increases the rate of RVR at week 4 and SVR (Fig. 3B and C).
The Prove-1 trial (36) included 250 treatment-naïve genotype 1 chronic hepatitis C patients in the US. Participants were randomly assigned to four regimens:
•Telaprevir (750 mg/8 h) plus PEG-IFN α-2a plus Ribavirin for 12 weeks (n=17).
•The same regimen, followed by PEG-IFN/Ribavirin without telaprevir for 12 weeks (n=79).
•The same regimen, followed by PEG-IFN/Ribavirin without telaprevir for 36 weeks (n=79).
•Standard therapy with PEG-IFN/Ribavirin (no telaprevir) for 48 weeks (n=75).
Patients in all telaprevir arms were significantly more likely to achieve an RVR, or undetectable HCV RNA (<10 IU/ml) at week 4, compared with the standard therapy control group (79 vs 11% respectively). The same was also true for an early virological response at week 12 (70 vs 39% respectively). During the first 12 weeks, 91% of patients in the telaprevir arms achieved undetectable HCV RNA, compared with 43% in the standard therapy group. At the end of treatment, the proportion of patients with undetectable HCV RNA was significantly higher in the 48-week telaprevir group compared with the 48-week standard therapy group (65 vs 45%). Six months after completion of therapy, the SVR rate was substantially higher in the 24-week telaprevir arm compared with the 12-week telaprevir arm (61 vs 35% respectively). Among patients who achieved an RVR, the relapse rate was 33% in the 12-week telaprevir group compared with 2% in the 24-week telaprevir group.
Adverse events leading to treatment discontinuations were more frequent in the telaprevir arms than in the standard therapy group (13 vs 3% respectively). Skin rashes, gastrointestinal events and anaemia were more common, and rashes were more severe, in the telaprevir arms. ‘Serious’ adverse events were reported by 11% of patients in the telaprevir arms compared with 5% in the standard therapy group.
In the Prove-2 study (37), 323 chronic HCV genotype 1-infected treatment-naïve patients without cirrhosis were included. The patients were randomized to receive:
•Standard of care (SOC): PEG-IFN α-2a plus Ribavirin plus placebo for 48 weeks (n=82).
•Telaprevir plus PEG-IFN for 12 weeks (n=78).
•Telaprevir plus PEG-IFN plus Ribavirin for 12 weeks (n=82).
•Telaprevir plus PEG-IFN plus Ribavirin for 12 weeks, and then PEG-IFN/Ribavirin for 12 weeks (n=81).
The SVR was 68% in the triple-therapy arm (telaprevir plus PEG-IFN plus Ribavirin for 12 weeks, followed by PEG-IFN plus Ribavirin for 12 weeks) and 48% in the SOC regimen (Fig. 3B). Virological breakthrough (defined at week 12 in patients with HCV RNA increase by >1 log10 from nadir or >100 IU/ml after previously undetectable HCV RNA) was 2% when both triple-therapy arms were combined and 26% in the combination of telaprevir plus PEG-IFN without Ribavirin. The most common adverse events included pruritus, rash, anaemia, fatigue, weakness and headaches. In conclusion, a reduced course of 24 weeks of treatment with 12 weeks of triple therapy (telaprevir plus PEG-IFN plus Ribavirin), followed by 12 weeks of SOC increase the SVR by 20% (from 48 to 68%). It seems that Ribavirin reduces breakthrough and relapse rates.
In summary, the results of Prove-1 and Prove-2 demonstrate that Ribavirin is essential to maximize SVR rates in patients treated with telaprevir with a reduction of relapse. Also, SVR rates as high as 65% may be possible in genotype 1 patients treated with a 12-week triple-therapy regimen, followed by a 12-week standard combination-therapy regimen. Telaprevir was associated with increased rates of certain adverse effects including rash, gastrointestinal events and anaemia. The rate of discontinuation for adverse events during the first 12 weeks of Prove-1 and Prove-2 was two- to three-fold higher in recipients of telaprevir-based triple therapy than with the SOC. The maculopapular rash has generated the most concern, but this event resolved upon treatment discontinuation in all patients. Data on the efficacy of the drug in patients with genotypes other than 1 and in non-responders are needed. Telaprevir is now in phase III of clinical development.
Boceprevir, developed by the company Schering Plough (Kenilworth, NJ) is a small molecule that is a specific inhibitor of the viral protease NS3-NS4A. It is presented in the form of a capsule that is rapidly absorbed orally with a half-life of 7–15 h and a maximum concentration and area under the curve that increases in relation to the dose. After 14 days of monotherapy at 400 mg, 3 times/day, the viral load is significantly reduced by approximately 1.5 log in non-responders to PEG-IFN. Moreover, the association of PEG-IFN α-2b with boceprevir results in a marked reduction in the viral load of approximately 2.5 log after 13 days of treatment in non-responders to PEG-IFN or PEG-IFN plus Ribavirin (38).
Hepatitis C virus SPRINT-1 is a phase 2 study in HCV genotype 1 patients evaluating boceprevir (800 mg TID) in three treatment regimens (39):
•4 weeks of combination standard treatment (PEG-IFN α-2b plus Ribavirin) (lead-in), followed by addition of boceprevir to the combination for a total of 28 or 48 weeks;
•Boceprevir in combination with PEG-IFN plus Ribavirin for 28 or 48 weeks; and
•Boceprevir in combination with PEG-IFN/low-dose Ribavirin for 48 weeks, compared with PEG-IFN α-2b plus Ribavirin for 48 weeks.
Interim results concluded that boceprevir, when combined with SOC, appears to be safe for use up to 48 weeks and substantially improves SVR rates with 28 weeks of therapy and can nearly double the SVR compared with the current SOC (48 weeks) in this trial. Use of a 4-week lead-in with SOC before the addition of boceprevir appears to reduce the incidence of viral breakthrough. The most common adverse events reported in the boceprevir arms were fatigue, anaemia, nausea and headache.
TMC435350 (TMC435) is an NS3/NS4A protease inhibitor developed by Tibotec/Medivir (Mechelen, Belgium). A double-blind, placebo-controlled phase IIa trial is ongoing to assess the antiviral activity, safety and pharmacokinetics of once-daily (q.d.) regimens of TMC435 in HCV genotype 1 treatment-naïve patients (40). The results of the first 28 days of treatment of Cohort 1 (25 or 75 mg TMC435 vs placebo) were reported recently. Patients were randomized to receive either 7 days of monotherapy of TMC435 or placebo, followed by 21 days of triple therapy with TMC435 or placebo, PEG-IFN α-2a and Ribavirin (panel A), or 28 days of triple therapy with TMC435 or placebo, PEG-IFN α-2a and Ribavirin (panel B). After day 28, patients continue on PEG-IFN α-2a/Ribavirin alone for a total of 24 or 48 weeks at the discretion of the investigator. Twenty-five patients were enrolled in each panel of cohort 1 (n=50). No serious or severe adverse events were related to TMC435. The most common side effects reported were nausea, diarrhoea and headache. The mean reductions of HCV RNA from baseline at day 7 with TMC435 alone and in triple therapy were 2.63 and 3.47 log10 IU/ml, respectively, in the 25 mg arm and 3.43 and 4.55 log10 IU/ml in the 75 mg arm. In the 75 mg 4-week triple-therapy arm, no viral breakthrough was observed; 9/9 patients achieved HCV RNA below the lower limit of quantification (<25 IU/ml) and 8/9 patients achieved undetectable HCV RNA (<10 IU/ml) at day 28 (RVR=89%). In conclusion, TMC435 at doses of 25 and 75 mg q.d. was well tolerated and demonstrated dose-dependent antiviral activity, both alone and in combination with PEG-IFN α-2a/Ribavirin. Cohort 2 investigating 200 mg q.d. is ongoing.
ITMN-191 is an oral, highly potent, selective inhibitor of the HCV NS3/4A serine protease, developed by Intermune Inc. (Brisbane, CA). In a double-blind, randomized, placebo-controlled study, four cohorts of treatment-naïve HCV genotype 1 patients and one cohort of non-responders were randomized to receive ITMN-191 or matched placebo for 14 days (41). Cohorts consisted of eight and two patients receiving ITMN-191 and placebo respectively. Fifty patients were randomized and all completed the study. ITMN-191 was safe and well tolerated. ITMN-191 reduced HCV RNA in a dose-dependent manner with both q8 and q12 h schedules; reductions occurred rapidly and were typically sustained through day 14. Viral variants with reduced drug sensitivity were observed in the subset of patients who experienced a virological rebound but not in those who experienced a continual decline in HCV RNA. In conclusion, ITMN-191 was safe and well tolerated. Treatment resulted in rapid and sustained reductions in HCV RNA, with a median reduction at day 14 of 3.8 log10 in patients receiving 200 mg q8 h. The treatment response was lower in the NR cohort; this observation will inform regimen selection in future studies in this population. Based on these findings, a phase 1b study to assess the safety and efficacy of ITMN-191 in combination with PEG-IFNα-2a plus Ribavirin is currently underway.
BI201335 is an HCV NS3 protease inhibitor being developed by Boehringer Ingelheim Pharma (Ridgefield, CT). A multiple rising dose study evaluated safety and antiviral activity in treatment-naïve patients with chronic HCV genotype 1 infection as monotherapy for 14 days, followed by triple combination therapy with PEG-IFN and Ribavirin for an additional 14 days (42). Thirty-four patients were randomized (2 placebo:6 active) to four dose groups of q.d. BI201335: 20 mg (n=8), 48 mg (n=9), 120 mg (n=9) or 240 mg (n=8). A rapid decline of the viral load was observed in all patients, with the maximal decline 2–4 days after starting BI201335. With the exception of one patient in the 20 mg cohort, all patients on BI201335 achieved more than a 2 log10 viral load decline during the monotherapy period. The median (range) maximal reductions in viral load during 14-day monotherapy for the 20, 48, 120 and 240 mg groups were 3.0 (1.5–3.9), 3.6 (3.1–3.8), 3.7 (3.3–4.1) and 4.2 (3.6–4.8) log10 respectively. Viral load rebound during treatment was seen in the first 14 days of monotherapy in a majority of patients. Population sequencing of the NS3/4A protease at baseline and rebound during treatment revealed selection of variants that confer in vitro resistance to BI201335. These results indicate that BI201335 as monotherapy for 14 days, followed by a combination with PEG-IFN and Ribavirin for an additional 14 days was well tolerated and induced a strong and rapid antiviral response.
In PEG-IFN plus Ribavirin treatment-experienced patients with chronic hepatitis C genotype 1 infection, a multiple rising dose study evaluated the safety and antiviral activity of BI201335 for 28 days as combination therapy with PEG-IFN plus Ribavirin (43). Nineteen patients were assigned to receive BI201335 q.d. doses of 48 mg (n=6), 120 mg (n=7) or 240 mg (n=6) in combination with PEG-IFN α-2a plus Ribavirin for 28 days. The primary endpoint was a ≥2 log10 reduction in the viral load from baseline at any time up to day 28. All patients achieved a viral load decline higher than 2 log10 with triple combination therapy. The median (range) maximal viral load decline during 28-day combination therapy for 48, 120 and 240 mg dose cohorts was 4.8 (3.4–5.9), 5.2 (3.9–6.0) and 5.3 (4.8–6.1) log10 respectively. Virological rebound during treatment was observed during the first 28 days of BI201335 and PEG-IFN plus Ribavirin dosing in 2/6 patients in the 48 mg and in 1/7 patients in the 120 mg dose groups. In these patients, population sequencing of the NS3/4A protease at baseline and at viral rebound during treatment revealed selection of variants in the NS3 protease domain shown to confer in vitro resistance to BI201335. No rebound during treatment was seen in the 240 mg q.d. dose cohort: 5/6 patients had viral load <25 IU/ml at day 28. The sixth patient had a 4.7 log decline in viral load from baseline on day 28, and the viral load was <25 IU/ml at the next visit, day 42. These results indicate that BI201335 given q.d. in combination therapy with PEG-IFN plus Ribavirin for 28 days was well tolerated and induced a strong and rapid antiviral response. The results support further study of BI201335 as a potent protease inhibitor for naïve genotype 1 patients and also PEG-IFN plus Ribavirin treatment-experienced HCV patients.
MK-7009 is a rapidly reversible non-covalent competitive inhibitor of the non-structural 3/4A protease of the HCV, developed by Merck & Co., Inc. (Whitehouse Station, NJ) that exhibits good inhibitory potency against genotypes 1 and 2. Initial studies evaluated the safety, tolerability and pharmacokinetics following single-dose and multiple-dose administration of MK-7009 in healthy male subjects (44). There were no serious adverse experiences reported, nor were there any discontinuations. MK-7009 was generally safe and well tolerated and exhibited plasma pharmacokinetics that allow twice-daily (b.i.d.) dosing. This profile allows further clinical evaluation of MK-7009, including in HCV-infected patients.
Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Nucleoside analogue polymerase inhibitors are compounds that require conversion to an active triphosphate form and act as chain terminators. They inhibit initiation of RNA transcription and elongation of a nascent RNA chain. In contrast to the nucleoside analogues, which target the active site of HCV polymerase, non-nucleoside inhibitors have been designed to bind to several discrete sites on HCV polymerase. The resistance profiles of nucleoside analogue and non-nucleoside inhibitors seem to be distinct from each other and from those of individual protease inhibitors. Thus, it is possible that agents from different classes will act in a complementary fashion to increase efficacy and prevent development of resistance.
R1626 is an oral prodrug of a potent and selective nucleoside analogue polymerase inhibitor (R1479) (45). Dose-dependent reductions in HCV RNA of up to 3.7 log10 were obtained after 14 days when R1626 was administered at a dose of 1500–4500 mg/day in patients infected with the HCV genotype 1 (45). After 14 days of treatment, 5/9 patients treated with the highest dose had undetectable HCV RNA. Reversible reductions in haemoglobin levels and white blood cell counts were detected in patients treated with the drug. The combination of R1626, PEG-IFN α-2a and Ribavirin produces synergistic reductions in serum HCV RNA levels in patients infected with HCV genotype 1 (46). A synergistic antiviral effect was observed when R1626 was combined with PEG-IFN α-2a±Ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. There was no evidence of development of viral resistance. Dosing of R1626 was limited by neutropenia.
R7128 is a prodrug of PSI-6130, a cytidine analogue inhibitor of HCV polymerase inhibitor that produces at least additive reductions in HCV RNA levels when administered with the SOC. In a phase I trial, the combination of R7128 1500 mg b.i.d. plus PEG-IFN α-2a and Ribavirin reduced serum HCV RNA levels by a mean of 5.12 log10 IU/ml in 20 treatment-naïve patients with HCV genotype 1 infection (vs 2.95 log10 IU/ml in 10 patients treated with placebo plus the SOC) (47). A total of 17/20 (85%) of patients in the triple therapy group had undetectable HCV RNA (<15 IU/ml) at week 4 compared with 1/10 (10%) in the control group. Headache, chills, fatigue, nausea and fever were the most common adverse events across all treatment groups. Grade 4 neutropenia was reported in 1/20 patients in each dosing cohort and in 1/10 placebo recipients.
Furthermore, a study was designed to evaluate R7128 in combination with SOC in genotype 2 and 3 patients (48). Twenty-five (20 active/5 placebo) patients with genotypes 2 (n=10) and 3 (n=15) who had previously not achieved an SVR with IFN-based therapy were enrolled. Preliminary data were available for 25 patients through day 14. These preliminary results suggest that R7128 (1500 mg b.i.d.), combined with PEG-IFN and Ribavirin in prior genotype 2/3 non-responders to IFN-based therapy, provides a high RVR (≥86%), with an acceptable side-effect profile.
Non nucleoside analogues
GS-9190 is a non-nucleoside polymerase inhibitor that is being evaluated in treatment-naïve genotype 1 patients enrolled in an ongoing phase I dose-escalation study (49). The plasma pharmacokinetic profile was dose proportional in patients who received single oral doses of 40–2400 mg. The mean terminal elimination half-life of the drug was estimated to be 10–13 h, which suggests that the drug is suitable for q.d. or b.i.d. dosing. Maximum median reductions in serum HCV RNA levels of 0.46–1.49 log10 IU/ml were obtained 24 h after administration of a single dose and mean reductions of 1.4 and 1.7 log10 IU/ml, respectively, were obtained after 8 days of treatment with 40 and 120 mg b.i.d. Further development of GS-9190 is on-hold, as a possible but not confirmed QT elongation was observed. A specific QT study in healthy volunteers has been mimicked to further evaluate this finding.
Results from a new non-nucleoside inhibitor, PF-00868554, developed by Pfizer Global Research and Development (New London, CT), were presented recently (50). Thirty-one healthy male subjects completed the study with no serious adverse events, drug discontinuation or dose reductions when the drug was given twice a day for 14 days. Another study with patients infected with HCV, treatment-naïve patients, is currently underway.
In chronic hepatitis C, despite the progress attained with the SOC (PEG-IFN plus Ribavirin), treatment failure still occurs in about half of the patients. Furthermore, therapy results in several side effects and high cost. The development of new drugs is mandatory and will depend on better knowledge of the viral cycle and mechanisms of non-response.
The development of new molecules such as viral enzyme inhibitors (protease and polymerase) is ongoing. Promising results have been reported with two protease inhibitors (telaprevir and boceprevir) that are currently in phase III. Several other protease and polymerase inhibitors are under development.
In the near future, it is likely that IFN-based therapy plus Ribavirin will remain the backbone of the treatment of chronic hepatitis C. PEG-IFN and Ribavirin are needed in order to prevent HCV resistance to STAT-C drugs, and subsequently increase SVR. Genotypic and phenotypic resistance tests will also enter the therapeutic arena. Once several STAT-C agents become available, treatment strategies will include a combination of several drugs with different mechanisms of action (protease inhibitors plus polymerase inhibitors) that could hopefully result in IFN- and/or Ribavirin-sparing regimens. In the future, there might be combinations of antivirals having additive potency, lacking cross resistance and with a good safety profile. Studies of virus-host interaction are also important since antiviral therapy focuses on targeting cellular genes that are critical for viral replication and pathogenesis. Several new technologies have contributed to the identification of such genes for hepatitis C virus (51).
We thank Jean-Pierre Laigneau (from INSERM, Centre de Recherche Bichat-Beaujon CRB3, Paris, 75018 France) for the medical illustrations.
Conflicts of interest
Tarik Asselah is a speaker for Roche, Schering Plough, Gilead and Bristol-Myers Squibb; Patrick Marcellin has the following relationship with manufacturers of a commercial products(s). Roche: investigator, speaker and expert, Schering Plough: investigator, speaker and expert, Gilead: investigator, speaker and expert, BMS: investigator, speaker and expert, GSK: investigator, speaker and expert, Vertex: investigator and expert, Idenix-Novartis: investigator, speaker and expert, Valeant: investigator and expert, HGS: investigator and expert, Pharmasset: investigator and expert, Cytheris: investigator and expert, Intermune: investigator and expert, Wyeth: investigator and expert, Tibotec: investigator and expert. Yves Benhamou has not declared any conflicts of interest.