Hepatitis C Therapy in Non-genotype 1 Patients: The Near Future

From Journal of Viral Hepatitis

Hepatitis C Therapy in Non-genotype 1 Patients
The Near Future

Full Text @ Medscape

C. Wartelle-Bladou; G. Le Folgoc; M. Bourlière; L. Lecomte Authors and Disclosures Posted: 07/27/2012; J Viral Hepat. 2012;19(8):525-536.
© 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Summary. Worldwide, 50–70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations.

Introduction
There are approximately 170–200 million people chronically infected with hepatitis C virus (HCV) worldwide. Chronic hepatitis C can lead to cirrhosis and its subsequent complications such as hepatocellular carcinoma with more than 350 000 people dying each year from hepatitis C–related liver disease. Clearance of the virus is associated with improved histological outcomes, morbidity and mortality. The therapeutic goal is therefore to achieve a sustained virological response (SVR) defined as undetectable HCV RNA 6 months after cessation of therapy. Among the six identified HCV genotypes, genotype 1 (GT-1) is the most prevalent and was, until the approval in 2011 of two-first-generation NS3/4A protease inhibitors (PIs) in combination with pegylated interferon (PEG-INF)-α and ribavirin, the most difficult to cure. The launch in 2011 of boceprevir and telaprevir was a major landmark in the management of GT-1-infected patients. In association with PEG-INF and ribavirin, these two drugs increase the chances of cure by 30% with SVR rates in the range of 66–75% in naïve patients.[1–3] The benefit appears to be even more important in treatment-experienced patients in whom the chances of cure increase by 50–60% in relapsers, 40–45% in partial responders and 25% in null responders.[4,5]

However, this major advance benefits only GT-1 patients while there remains worldwide 50–70 million subjects infected with an HCV genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin (PR) remains the currently approved standard-of-care treatment (SOC). HCV genotypes present specific geographical distribution (Fig. 1), leading to a quasi-mono-genotypic HCV infection in some parts of the world such as Egypt, where the HCV infection prevalence reaches 15% in the general population with an almost exclusive GT-4 distribution. In such a country, chronic hepatitis C will exert an increasing substantial disease burden without more effective treatments.

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The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A PIs, nucleos(t)ide (NIs) and non-nucleoside inhibitors (NNIs) of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-proteins-directed antiviral agents are cyclophilin inhibitors and silibinin. Several drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds.

Current Standard-of-care Treatment Treatment Results in Non-GT-1 HCV Infection
The recommended first-line treatment for non-GT-1 chronic hepatitis C is based on the use of any of the two pegylated IFN-α available administered weekly subcutaneously and daily oral ribavirin.[6] PEG-IFN-α2a should be used at a dose of 180 μg once per week, whereas PEG-IFN-α2b should be used at a weight-based dose of 1.5 μg/kg per week. The ribavirin dose depends on the HCV genotype. Patients infected with GT-4, GT-5 or GT-6 should receive a weight-based dose of ribavirin of 15 mg/kg body weight per day. Patients infected with GT-2 or GT-3 can be treated with a flat dose of 800 mg of ribavirin daily; however, those with baseline factors predictive of a low responsiveness should receive a weight-based dose of ribavirin similar to GT-4, GT-5 and GT-6. Although initially the duration of treatment was fixed, 24 weeks for GT-2 and GT-3 and 48 weeks for GT-4, GT-5 and GT-6, the treatment duration should now be tailored to the on-treatment virological response in most non-GT-1 HCV patients.

Patients infected with GT-2 or GT-3 are not a homogenous population. There is now mounting evidence that these two genotypes should be distinguished from one another and not be anymore labelled together as the 'easy-to–treat' group. Indeed, SVR rates with a SOC 24-week treatment range from 75% to 97% and 62% to 92% in GT-2 and GT-3 patients, respectively.[7] Shortening the duration of treatment without compromising the chances of cure has been investigated in GT-2/GT-3 patients with conflicting results. A meta-analysis concluded that in rapid virological responders (RVR, defined as undetectable HCV RNA at 4 weeks), shortening of treatment duration to 16 weeks is possible in GT-2 patients or in GT-3 patients with an optimal weight-based ribavirin dose. Whatever the genotype, shortening of treatment duration is not recommended in cirrhotic patients. Extension of the treatment to 48 weeks is suggested in the absence of an RVR and/or in the presence of predictive factors of lower SVR such as advanced liver fibrosis or high BMI.[6] The impact of the IL28B polymorphism is unclear in GT-2/GT-3 patients. While some studies have failed to demonstrate any clear association between IL28B polymorphism and SVR,[8,9] others have reported a positive association between the favourable rs12979860 CC or rs8099917 TT genotype, respectively, with RVR, but not SVR,[10] suggesting an increased rate of relapse in this population along with higher pretreatment viral loads and ALT levels. Finally, two European studies showed that CC genotype is associated with SVR.[11,12] In an Italian study, IL28B CC genotype is highly predictive of SVR among non-RVR patients.[12]

In patients infected with GT-4, despite the lack of data validating the response-guided therapy concept, it has been suggested by an international panel that a response-guided approach similar to the one used in GT-1 patients may be considered.[13] Thus, RVR are highly likely to achieve SVR and are candidate to 24-week regimens in the absence of poor baseline predictive factor of response. Patients with RVR and pejorative predictive factors and complete early virological responders (EVR defined as undetectable HCV RNA at week 12) should be treated for 48 weeks. Patients with partial EVR (detectable HCV RNA but >2 log10 drop at week 12 and undetectable HCV RNA at week 24) may be considered for treatment prolongation to 72 weeks.[13] IL28B polymorphism is an important baseline predictive factor of response in GT-4 patients. Genotype CC in the SNP rs12979860 is associated with SVR but not with liver severity in these patients.[14,15] However, its predictive weight is lower than in GT-1 patients, and RVR remains the strongest predictive factor of response.[14]
In patient infected with GT-6, two studies evaluated response-guided therapy in a pilot trial and a randomized trial.[16,17] They demonstrated that patients with RVR could be treated for 24 weeks. However, those without RVR had very low SVR.[16] In GT-5-infected patients, there are no data on response-guided therapy, and 48-week regimens should therefore be recommended.

Apart from clinical trials, observation cohorts provide us with real-life results. In the PROPHESYS cohort, 37% of the 7163 patients included were infected with a non-GT-1 HCV. The observed SVR rates after SOC treatment were of 41%, 61%, 68% and 71% in GT-4, GT-3, GT-5/GT-6 and GT-2 patients, respectively.[18] In the German cohort, which included 23 893 patients, 39 patients were infected with GT-5 and 39 patients with GT-6. SVR after 48 weeks of treatment was 58% and 59% for GT-5 and GT-6, respectively.[19]

Current results of SOC treatment in non-GT-1 patients are not optimal especially in GT-4 and GT-3 patients.

Standard-of-care treatment will not be successful in 30–60% of patients. A second course of PEG-INF and ribavirin for a longer duration with an optimal dose of ribavirin is currently the only available option. This leads to unsatisfactory results with poor SVR rates ranging from 19% to 34% in previous nonresponders to 46% in relapsers.[6] Therefore, new treatments are urgently needed in this population.

Telaprevir and Boceprevir in Non-genotype 1 Hepatitis C Virus Infection
Telaprevir and boceprevir are orally available, first-generation PIs. Combined with PEG-IFN and ribavirin, both drugs have recently been approved for the treatment of naïve and treatment-failure GT-1-infected patients.

The antiviral activity of telaprevir against GT-2 and GT-3 HCV was investigated in a randomized, partially blinded study. The study design allowed evaluation of the intrinsic antiviral potency of the drug in the 9 GT-2 patients and 8 GT-3 patients randomized to an initial 2-week course of telaprevir monotherapy. A significant reduction in the HCV viral load (median HCV decrease – 3.27 log10 IU/L) was observed at day 3 in GT-2 patients compared with SOC. However, a virological breakthrough was observed in six of the nine patients within 15 days. Telaprevir monotherapy had no activity in GT-3 patients, with only a slight decrease in the HCV RNA levels (−0.54 log10 IU/L at day 3 and 15, respectively).[20] Triple therapy with telaprevir for 2 weeks induced a greater reduction in HCV RNA level compared with the SOC arm in GT-2 patients, but not in GT-3 patients.[20] Boceprevir monotherapy was evaluated in a phase I study in 40 GT-2/GT-3 patients in a 2-week dosing period. The maximum decrease in the viral load during the treatment period was observed in the 400 mg q.8 h arm in GT-3 patients with a mean – 1.71 log10 UI HCV RNA from baseline comparable with the viral drop seen in GT-1 patients.[21]

In a phase IIa study conducted in 24 GT-4 patients, triple therapy with telaprevir for 2 weeks induced a greater reduction in the HCV RNA level compared with the SOC arm. However, following triple regimen, PR for 46 weeks did not lead to a greater SVR compared with PR (62% in both groups).[22]
While telaprevir in association with PR demonstrated antiviral effectiveness in GT-2 patients, leading to an ongoing phase III trial in treatment-experienced patients, triple regimen with first-generation PI elicits no or limited antiviral effectiveness in GT-3 and GT-4 chronic hepatitis, confirming the need for more potent combinations.

Beyond Triple Therapy with First-generation Protease Inhibitors
The main compounds in clinical stage development for non-GT-1 HCV infection comprise DAAs, host-targeting antiviral agents and PEG-INF-λ.

Most second-wave PIs are macrocyclic. Their antiviral potency is similar or slightly better than first-generation PIs, but they exhibit a more favourable resistance profile and are easier to administrate.[23] TMC-435 inhibits HCV replication across all genotypes in preclinical protease biochemical assays, with an IC50 value below 13 nm except for GT-3a protease.[24] Danoprevir (DNV) has equipotent activity against HCV genotypes 1, 4 and 6 in vitro.[23] MK 5172 is a highly effective second-generation PI with subnanomolar in vitro IC50 values across all HCV genotypes. It is effective in vitro against the majority of first-generation PI resistance–associated variants and is the first pan-genotypic PI.[25] The safety profile of both second-wave and second-generation PIs appears to be good so far.

NS5B polymerase inhibitors comprise nucleoside(-tide) inhibitors (NIs) and non-nucleotide inhibitors (NNIs).[26] NIs binds to the NS5B active sites, causing chain termination and/or an increased number of errors when incorporated into a growing RNA chain. The NS5B's active site being well conserved, NIs tend to have a similar efficacy across all genotypes and present the highest barrier of resistance of all DAAs to date. In contrast, NNIs have shown a restricted spectrum of activity against the various HCV genotypes. They are mainly active against HCV GT-1 and present the lowest barrier of resistance. NS5B NIs appear therefore to be among the most promising pan-genotypic drugs.
Hepatitis C virus NS5A is a critically important viral protein in the virus replication, whose function is still not clearly elucidated.[27] BMS-790052 (Daclatasvir) is a first-in-class NS5A inhibitor which potently inhibits replicons representative of all six major genotypes with EC50 of <1 nm without overt cytotoxicity to host cells.[28]

Drugs targeting host proteins essential for the HCV replication may provide a greater barrier to resistance than DAAs. The first host-targeting compounds to emerge were the cyclophilin inhibitors, cyclophilin A being the putative protein involved. Debio 025 (alisporivir, ALV) is a selective cyclophilin inhibitor whose antiviral activity against HCV GT-1, 3 and 4 was demonstrated in a proof-of-concept study with no overt sign of upcoming resistance.[29] Seven-day intravenous treatment (20 mg/kg/day) with silibinin, whose mechanism of action is not yet completely understood, resulted in a mean decrease of 3 log10 IU/mL in HCV RNA in GT-1 patients. No data are available on the specific antiviral activities for non-GT-1 genotypes.[30]

Pegylated interferon lambda is a type III interferon with a marked antiviral C activity and a restricted distribution of receptors, mostly in the liver, leading to less hematopoietic side effects than PEG-IFN-α This was confirmed in a phase 2b study in terms of reduction in side effects, even in cirrhotic patients.[31–33] A recent study suggested that vitamin D could increase the response to PR treatment in HCV GT-1 patients.[34] This should be confirmed in other trials and in other HCV genotypes.

Where Are We Now in Clinic With New Compounds?

Genotype 2 and Genotype 3 Future Treatment

Second-Wave and Second-Generation Protease Inhibitors
TMC 435 monotherapy 200 mg daily for 7 days was investigated in GT-2–6 patients in a phase IIa study. The study confirmed the absence of activity observed in vitro in GT-3 infection and demonstrated a weak activity of the compound against GT-2.[35] In a phase 1 study with MK-5172 monotherapy 400 mg daily for 7 days, a maximum mean HCV RNA reduction from baseline of 5.4 and 3.98 log 10 UI/mL was observed in GT-1 and GT-3 patients, respectively.[36] Studies assessing MK-5172 with PR for 12 or 24 weeks are currently ongoing in GT-2/GT-3 patients (Table 1).

NS5B Nucleos(t)ide Inhibitors
 Mericitabine (RG7128) is a nucleoside analogue, whose antiviral activity was demonstrated in vitro across HCV genotypes. Mericitabine was evaluated in GT-2/GT-3 treatment-failure patients. After a 4-week triple combination, RG7128 1500 mg bid was discontinued and PR resumed for 20–44 weeks. Week 4 RVR rate was 95% in RG7128-treated patients vs 60% in the PR arm, demonstrating the antiviral potency of the molecule. In the absence of an RVR, no patient presented SVR whereas 68% of RVR patients were cured. SVR rates were less impressive, due to the short duration of the triple regimen (4 weeks), and did not differ among GT-2 and GT-3 RG7128 treated patients: 63% and 67%, respectively.[37] In patients treated with RG7128, SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%).[37]

PSI-7977 (now GS-7977) is a pyrimidine nucleotide analogue with a high antiviral activity across all genotypes and a high genetic barrier to resistance. It is safe, well tolerated and administrated once daily. PSI(GS)-7977 was evaluated in 25 naïve GT-2/GT-3 patients in the PROTON study. A 12-week triple combination of PSI(GS)-7977 400 mg once daily plus PEG-INF and weight-based ribavirin yielded a 100% SVR rate 24 weeks after the end of therapy.[38] Furthermore, in the ELECTRON study, an 8-week triple combination of PSI(GS)-7977 400 mg/day plus PEG-IFN and weight-based ribavirin yielded a 100% SVR rate 12 weeks after the end of therapy in the 10 treatment-naive GT-3 patients included.[39] Combination of PSI(GS)-7977 with ribavirin was further evaluated in the ELECTRON study with a 12-week treatment duration. The trial conducted in 40 treatment-naïve GT-2/GT-3 patients comprised one triple regimen arm, two INF-sparing arms and one INF-free arm.[40] SVR rates 12 weeks after cessation of treatment were 100% in all arms. Ten patients were enrolled in an additional 12-week PSI(GS)-7977 monotherapy. Whereas the EOT rate was 100%, four patients relapsed within the month following cessation of therapy, outlining the importance of ribavirin. There was no virological breakthrough identified and no premature discontinuation of treatment due to adverse events.[40] In subsequent arms of the ELECTRON study, 25 treatment-experienced GT-2/GT-3 patients were treated for 12 weeks with PSI(GS)-7977 and ribavirin. Whereas the EOT rate was 100%, three patients relapsed within the month following cessation of therapy, and SVR rates 4 weeks after cessation of treatment was 80%.[39] Other potent guanosine nucleotide polymerase inhibitors INX-189, active against GT-1, GT-2 and GT-3, are currently beginning phase II trial in naive GT-2 or GT-3 patients.

NS5A Inhibitors (NS5A Is)
Daclatasvir (BMS-790052) is, in vitro, a potent inhibitor of viral replication in all six major genotypes. There are two ongoing phase II studies in GT-2/GT-3 patients. The first one conducted in naive patients assesses the benefit of a triple regimen with daclatasvir 60 mg daily plus PR given for 16 or 24 weeks. The second study is being conducted in treatment-experienced patients and evaluates the benefit of a quadruple regimen comprising daclatasvir 60 mg daily, asunaprevir (NS3/4 PI) and PR given for 24 weeks (Table 1).

Cyclophilin Inhibitors
Alisporivir (Deb025) was investigated in GT-2/GT-3 naïve patients in a double blind, placebo controlled escalating dose-ranging with or without PEG-INF for 29 days in a phase II study.[41] HCV RNA levels at week 4 were reduced by −5.91 and −5.89 log10 IU/mL in the 600 and 1000 mg combination arms, respectively. Five of six patients in both groups had undetectable HCV RNA at the end of treatment, and one patient had a SVR after 28 days of Deb025.[41,42] In the phase II VITAL study, 346 GT-2/GT-3 naïve patients were randomized in five groups: (1) ALV 1000 mg qd; (2)ALV 800 mg qd + RBV 800 mg/day; (3) ALV 600 mg qd + RBV 800 mg/day; (4) ALV 600 mg qd + PEG-INFα-2a 180 μg/week; and (5) PEG-IFNα-2a 180 μg/week + RBV 800 mg/day.[43] All treatments were given for 24 weeks. In all ALV arms, patients received a leading dose of ALV 600 mg bid during the first treatment week. In each arm, in the absence of an RVR, patients were treated from week 6 to week 24 with a triple regimen ALV 600 mg qd + PEG-IFNα-2a 180 μg/week + RBV 800 mg/day. Whatever the ALV dose, SVR rates 12 weeks after the end of therapy were significantly higher in ALV-treated patients ranging in ITT analysis from 77% to 83%vs 58% in the control arm. Among the three IFN-free arms, 22%, 23% and 34% of patients in ALV 1000, 600 and 800 mg arm, respectively, reached RVR and were therefore maintained on the IFN-free regimen until week 24. The SVR rate 12 weeks after cessation of treatment was 82%, 93% and 91% in ALV 1000, 600 and 800 mg groups, respectively.[43] However, despite those encouraging results, the development of the molecule wad stopped due to the occurrence of six cases of acute pancreatitis including one fatal case.

IFN-free Regimen With Direct Antiviral Agents Combination With or Without Ribavirin
The ELECTRON study has demonstrated that a 12-week IFN-free regimen with PSI(GS)-7977 + RBV was able to cure ten naive GT-2/GT-3 patients without advanced disease. Moreover, the same regimen was able to cure '80% (SVR4)' of a larger cohort of treatment-experienced GT-2/GT-3 patients again without advanced fibrosis.[39]

The second IFN-free regimen phase II trial assessed the antiviral efficacy of daclatasvir (NS5A. I) in combination with GS-7977 (NS5B. NI) with or without ribavirin for 24 weeks in naive GT-2/GT-3 patients without advanced fibrosis.[44] There were three arms: (i) a first week of GS-7977 followed by 23 weeks of daclatasvir in combination with GS-7977, (ii) 24 weeks of daclatasvir and GS-7977 combination, (iii) 24 weeks of triple combination of daclatasvir, GS-7977 and ribavirin 800 mg/day. Combination was well tolerated, and early SVR rate 4 weeks after the end of therapy was 91% (40/44 patients). Two patients were lost to follow-up, one patient had a breakthrough and one patients relapsed 4 week after the end of therapy.

A third ongoing IFN-free regimen phase II trial assesses the antiviral efficacy of a regimen associating ABT-267 (NS5A. I) and ABT-450r, a ritonavir-boosted protease inhibitor, with or without ribavirin in naive GT-2/GT-3 patients (Table 1).

Interferon Lambda
Final data for GT-2/GT-3 patients of the EMERGE phase II study suggest a beneficial impact of PEG-INF-λ in GT-3 patients.[45] There were 60 GT-2 and 58 GT-3 patients enrolled in this trial evaluating different doses of PEG-IFN-λ (120, 180 and 240 μg) in association with RBV for 24 weeks. Whatever the PEG-IFN-λ dose, SVR rates 24 weeks after the EOT were numerically greater in GT-3 patients receiving PEG-INF-λ compared with the control SOC group (PEG-INFα-2a 180 μg plus ribavirin). SVR rates in GT-2 patients were similar in PEG-INF-λ and control arms. Flu-like symptoms, myalgia and pyrexia were significantly lower in PEG-INF-λ-treated patients. No reduction in the dose of ribavirin was needed in the PEG-INF-λ 180 μg group vs 23% in those treated with PEG-INFα-2a 180 μg.[45]

In Summary
The recently reported clinical results suggest that (i) an oral 'PEG-INF-free' 12-week treatment (GS-7977 with ribavirin for 12 weeks) can lead to definitive clearance of the virus in most naive and treatment-experienced GT-2/GT-3 HCV infection with mild or moderate fibrosis; (ii) ribavirin still matters in combinations including a single DAA; (iii) an oral, 'IFN-free', 'RBV-free' DAAs combination (daclatasvir and GS-7977 for 24 weeks) may achieve eradication of the virus in more than 90% of naive GT-2/GT-3. The high SVR rate, 4 weeks after EOT, needs to be confirmed with a longer follow-up, particularly in the absence of ribavirin in the regimen. Moreover, all these very encouraging results for IFN-free regimens need to be confirmed in patients with more advanced fibrosis and in null-responders to SOC. Meanwhile, triple regimen with GS-7977 plus PEG-IFN and ribavirin for 12 weeks appears to be conclusive, but must be confirmed in the most-difficult-to-treat patients. Candidate compounds, currently available for an oral, IFN-free combination in this population, are second-generation PI (MK-5172) as second-wave PI exerts no efficacy on GT-3, NS5A inhibitors, NS5B nucleoside or nucleotide inhibitors (Mericitabine, GS-7977) and cyclophilin inhibitors (ALV); however, this last compound is on hold due to toxicity. The association would ideally comprise at least one compound with a high barrier to resistance.
Several therapeutic combinations (triple combinations with PR, INF-free combinations and INF-free, ribavirin-free DAAs combinations) are currently evaluated both in naïve and in prior nonresponders GT-2/GT-3 patients (Table 1). Those studies need to address more rapidly the most-difficult-to-treat population.

Finally, switching from PEG-INFα to PEG-INF-λ may be an interesting alternative in GT-2/GT-3 patients. The lesser hematopoietic side effects with no need for RBV dose reduction may be of particular interest in GT-3 patients as an optimal dose of RBV appears essential in this subgroup to prevent relapse.

Genotype 4

Second-Wave and Second-Generation Protease Inhibitors
TMC 435 was investigated in 8 GT-4 patients during an 11-day monotherapy course. Mean viral decrease was −3.43 log10 UI/mL at day 3 and −3.52 at day 8.[35] A phase III study assessing the efficacy of triple regimen with TMC435 150 mg qd plus PR for 12 weeks fallowed by 12 or 24 weeks of PR is ongoing in naive and treatment-experienced GT-4 patients.

Danoprevir is also active against GT-4. Different doses of DNV boosted with ritonavir (DNVr 200/100, 100/100, 50/100 mg bid) for 24 weeks and DNVr100/100 for 12/24 weeks (response-guided arm) were evaluated in combination with PR in the DAUPHINE trial.[46] Thirty-three GT-4 patients were enrolled in this open-label, active-controlled phase IIb study. All DNVr-treated GT-4 patients achieved an SVR12, independently of the DNVr dose and the treatment duration. There were no DNVr-related grade 3/4 AE. Diarrhoea was the only side effect that occured in all DNVr arms with an 10% higher incidence than in the control group.

Asunaprevir, a second-wave PI, is studied in an ongoing trial in combination with PR for various duration – 24 to 48 weeks – in naïve GT-4 patients.
Lastly, among PIs, second-generation PI (as MK-5172) may be a good candidate for triple therapy; however, studies are pending.

NS5B Nucleos(t)ide Inhibitors
Mericitabine was evaluated in the 28 naive GT-4 patients who were included in the PROPEL study. This phase II, controlled trial evaluated an initial 8- or 12-week triple combination of mericitabine with PR followed by 12–36 weeks of PR. RVR and cEVR were higher among patients treated with mericitabine, but SVR and relapse rates were comparable to the PEG-IFN and ribavirin control arm.[47] This is due to the short duration of triple regimen. In the JUMP phase 2b study, five naive GT-4 patients alongside 166 GT-1 naive patients were randomized to SOC for 48 weeks or to triple therapy with mericitabine during 24 weeks, followed by 24 weeks of PR in those without eRVR.[48] In this study SVR rate was always superior in triple regimen arms compared with SOC. However, the 57% SVR rate is lower to what we reach with other triple regimens. Therefore, mericitabine may be more interesting as a compound used in a DAAs association than in a triple regimen with PEG-IFN and ribavirin.

GS-7977 in combination with PEG-IFN and ribavirin exhibits a rapid and drastic viral decay within the first 4 weeks of treatment similar across all genotypes.[49] Eleven GT-4 patients were included in the ATOMIC study and treated with GS-7977 400 mg once daily plus PEG-IFN and ribavirin for 24 weeks. All 11 patients were HCV RNA undetectable at week 4. At interim analysis, the eight patients evaluable 12 weeks post-treatment (three patients pending) had remained HCV RNA negative.[50]

NS5A Inhibitor Daclatasvir (BMS-790052) is, in vitro, a potent inhibitor of viral replication in all six major genotypes. Daclatasvir in association with PEG-IFN and ribavirin was evaluated in 30 GT-4 patients. Preliminary data reported that all 12 patients in the daclatasvir 60 mg qd arm had undetectable HCV RNA at week 12 compared with 58% in the 20 mg arm and 50% in the placebo arm.[51]

Cyclophilin Inhibitor (CI) our naïve GT-4 patients presented a viral decay of more than 2 log10 UI at week 4 in a phase 2a dose-ranging study of 29 days of the cyclophilin inhibitor ALV.[41] This weak antiviral activity preclude further study; however, due to this different mode of action, CI could be part of DAAs combination regimen. Unfortunately, the molecule was on hold due to toxicity.

Direct Antiviral Agents Combination With PEG-IFN and Ribavirin here are two ongoing studies evaluated in treatment-experienced GT-4 patients: the combination of daclatasvir (NS5A inhibitor) plus asunaprevir (PI) and PEG-IFN plus ribavirin for 24 weeks in the first study; and ritonavir-boosted DNV (PI) plus mericitabine (NS5B NI) and PEG-IFN plus ribavirin for 24 weeks in the second study (Table 1).

Nitazoxanide
Nitazoxanide (NTZ) is an antiparasitic drug efficient against cryptosporidium, giardia Lamblia and clostridium difficile. The postulated antiviral C mechanism of NTZ is believed to be through selective induction of a host protein kinase.[52] The STEALTH C trial was conducted in 96 GT-4 patients in two Egyptian centres. The SVR rate increased from 50% in the control SOC 48 weeks group to 79% in patients receiving 12 weeks lead-in phase of NTZ 500 mg twice daily followed by 36 weeks of triple combination.[53] Although these results are promising, the number of patients was small and the percentage of patients with advanced liver disease was low. Thus, further studies are needed to investigate NTZ in GT-4.

In Summary
Clinical results with DAAs are sparse for GT-4 patients, mostly derived from trials enrolling GT-1–4 patients with small numbers of GT-4 subjects included. However, the reported results are promising, demonstrating: (i) 100% RVR rates with a triple combination (GS-7977 + PR); (ii) high SVR rates with short 12-week combination regimens (GS-7977 + PR, DAN/r + PR). (iii) The efficiency of second-wave PIs in GT-4 HCV infection.
Potential INF-free therapeutic options consist in a combination of GS-7977 with RBV or a combination of two DAAs with or without ribavirin. Candidate DAAs are second-wave (DNV/r, TMC 435) and second-generation PIs (MK-5172), NS5A inhibitor (daclatasvir), NS5B NIs (mericitabine, GS-7977) and new cyclophilin inhibitor if available.

Genotype 5 and 6
Clinical results of the use of DAAs for GT-5 and GT-6 HCV infection are limited.
TMC 435 monotherapy induced a significant mean viremia decrease of −4.35 log10 UI/mL after 8 days in the GT-6 patients studied whereas the mean change was only – 2.19 in GT-5 patients (−2.71 at day 3).[35]

Five GT-6 patients were included in the ATOMIC study and treated with GS 797 400 mg once daily plus PEG-INF plus ribavirin for 24 weeks. The RVR rate at week 4 and the SVR rate 12 weeks after the end of the treatment were both 100%.[50]

Conclusion
Current results of SOC treatment in non-GT-1 patients are not optimal, especially in GT-4 and GT-3 patients.

New treatments are urgently needed in this subgroup. While telaprevir in association with PR has demonstrated antiviral effectiveness in GT-2 patients, the current available first-generation PIs (telaprevir and boceprevir) are not active against non-GT-1 HCV infection.

Evaluation of many promising molecules such as second-generation PIs, NS5A I and NS5B NIs, some with pan-genotypic activity, have begun, demonstrating potent viral efficacy with good safety profile in easy-to-treat patients. An all-oral PEG-INF-free regimen for 12 weeks was able to cure nearly all naive and treatment-experienced GT-2/GT-3 HCV infection with mild or moderate fibrosis. IFN- and RBV-free DAAs combination also appears very efficient in this population. These data need to be confirmed in treatment-experienced and advanced liver fibrosis populations.

Meanwhile, triple regimens with DAAs plus PEG-IFN and ribavirin appear to be very conclusive although results must be confirmed in difficult-to-treat patients. Whether or not PEG-IFN and/or ribavirin will remain in some patients the backbone of future DAAs combinations remains an open and unsolved issue.

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