December 23, 2013

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 69–78, February 2014

Review Article

You have free access to this content

Raymond Schinazi1,*,Philippe Halfon2, Patrick Marcellin3, Tarik Asselah3,*

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12423

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: asunaprevir; daclatasvir; faldaprevir; pegylated interferon; ribavirin; simeprevir; sofosbuvir

Abstract

For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct-acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan-genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN-based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross-resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide [1]. HCV, identified in 1989, is an enveloped virus with a 9.6 kb single-stranded RNA genome [2], a member of the Flaviviridae family, genus Hepacivirus. The development of new molecules called direct-acting antivirals (DAA) is ongoing [3]. The aim of this review is to summarize recent results obtained with IFN-free regimens for HCV treatment.

Viral replication cycle and targets for drug development

The HCV replication cycle begins with virion attachment to its specific receptor. 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 followed by viral assembly. Potentially, each step of the viral cycle is a target for drug development. The knowledge of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors targeting these enzymes [4, 5]. Several findings suggest that HCV modulation of IFN induction and signalling attenuates the expression of IFN stimulated genes, allowing HCV to escape the antiviral actions of the host response [6, 7].

All the major HCV-induced enzymes, namely, NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RNA-dependent RNA polymerase (RdRp), are essential for HCV replication and are potential drug discovery targets (Fig. 1). Therefore, DAA with different viral targets, such as NS3 protease inhibitors, nucleoside/nucleotide analogue and non-nucleoside inhibitors of the RdRp, and NS5A inhibitors are under development. General characteristics of different classes of DAA are shown in Table 1.

liv12423-tbl-0001

liv12423-fig-0001

Figure 1. Hepatitis C virus (HCV) genome and potential drug discovery targets. 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. 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.

Protease inhibitors

The NS3 serine protease is located in the N-terminal region of NS3. The NS3 serine protease domain is associated with the NS4A cofactor to cleave four specific sites.

This enzyme has been extensively characterized at the biochemical level and its structure is known [4, 5]. The serine protease activity of NS3 is an attractive target for new drugs that could effectively block viral replication. The NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide a-ketoamid derivatives. In 2003, a macrocyclic protease inhibitor (BILN 2061; ciluprevir) that blocks HCV replication in the replicon model was shown to be effective in humans [8-10]. Characteristics of protease inhibitors are presented in Table 2.

liv12423-tbl-0002

Although proteases inhibitors are potent, they have several potential limitations. Protease inhibitors are highly specific and as the amino acid sequence of the NS3 protease domain differs significantly between HCV genotypes, they exhibit varying activities across genotypes. For instance, telaprevir is less effective in treatment-naïve subjects infected with genotypes other than genotype 1. Furthermore, as HCV has a high mutation replication rate, with a lack of proofreading, resistance is an issue for this class of drugs.

The genetic barrier to resistance is defined as the number of amino acid substitutions required to confer full resistance to a drug. Usually, DAA with a low genetic barrier to resistance require only one or two amino acid substitutions for high resistance. DAA with a high barrier to resistance usually require three or more amino acid substitutions in the same region to confer loss of activity.

The genetic barrier to protease inhibitors is usually low and resistance differs significantly between HCV genotypes. Viral resistance to telaprevir occurred much more frequently in genotype 1a compared with genotype 1b. This is believed to be the result of nucleotide differences at position 155 in HCV subtype 1a (AGA, encodes R) vs. 1b (CGA, also encodes R). The mutation most frequently associated with resistance to telaprevir was R155K; changing R to K at position 155 requires only one nucleotide change in HCV subtype 1a and two nucleotide changes in subtype 1b isolates [11] making GT1a more susceptible to emergence of resistance. As illustrated with the R155K mutation, which reduces replication capacity in the replicon model [12], resistance mutations frequently impair viral fitness. However, under antiviral pressure, during continued therapy, second site mutations are selected that restore fitness, explaining why the R155K primary mutation is frequently found in association with V36M in genotype 1a viruses. Therefore, it is recommended to immediately discontinue treatment in subjects with viral breakthrough and good adherence to therapy.

The main weaknesses of the first-generation PIs are their low genetic barrier to resistance and the fact that their effectiveness is limited to GT-1 patients. Second-wave PIs have a higher barrier to resistance, better activity against multiple genotypes except GT-3, more convenient dosing schedules and improved safety and tolerance [13-18]. Second-generation PIs are compounds that are broadly active against all genotypes and against viral isolates that carry resistance mutations for first-generation PIs. In combination with PR, the new PIs appear to achieve greater SVR rates than the first-generation PIs. These new treatments allow for more convenient administration schedules (one or two administrations per day); this could result in improved pharmacokinetics and better patient compliance. Besides, the safety profile seems to be good. The pan-genotypic activity of these new treatments provides new therapeutic options for a greater number of patients, in particular for those infected with GT-4.

Table 2 provides an overview of the efficacy and tolerance of the second-wave PIs that are currently developed. Few data are available concerning second-wave PIs for cirrhotic patients. In a phase IIb study, 83 GT-1 treatment-experienced cirrhotic patients were treated with simeprevir 100 or 150 mg QD and PR for 12, 24 or 48 weeks followed by PR alone up to week 48. The SVR rates were 73% for previous relapsers, 82% for partial responders and 31% for null responders (for those treated with 150 mg QD); in all cases, the SVR rates were higher than in the PR arms.

In the pivotal Phase 3 trials, C208, C216 and HPC3007, simeprevir in combination with PR was demonstrated to be superior to placebo (in combination with PR) in achieving an SVR in both HCV treatment-naïve subjects and relapsers [13, 14]. In the subgroup of subjects with the Q80K baseline polymorphism, a substantial impact on the efficacy of simeprevir was observed.

Polymerase inhibitors

Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. NS5B RNA polymerase inhibitors can be divided into two different types – nucleoside inhibitors (NI) and non-nucleoside inhibitors (NNI). NI mimic the natural substrates of the polymerase and are incorporated into the RNA chain causing direct chain termination [19, 20]. NI are compounds that require conversion to an active triphosphate form. As the active site of NS5B is highly conserved, NI are generally pan-genotypic (effective against all the different genotypes). However, single amino acid substitutions in every position of the active site may result in loss of function of the NI, but resistance to nucleoside analogue inhibitors is typically very low in humans as this virus has reduced fitness.

In contrast, NNI bind to several discrete sites outside of the HCV polymerase active centre, which results in conformational protein change before the elongation complex is formed [19, 20]. NS5B is structurally organized in a characteristic ‘right-hand motif’ containing finger, palm and thumb domains, and offers at least four NNI-binding sites, namely, benzimidazole (thumb 1)-binding, thiophene (thumb 2)-binding, benzothiadiazine (palm1)-binding and benzofuran-(palm 2)-binding sites.

Resistance is more frequent with NNI compared with NI. However, mutations at NNI-binding sites do not necessarily lead to impaired function of the enzyme. Characteristics of polymerase inhibitors are presented in Table 3.

liv12423-tbl-0003

NS5A inhibitors

The NS5A is a membrane-associated phosphoprotein present in basally phosphorylated (p56) and hyperphosphorylated (p58) forms [20-22]. It was previously reported that only p58-defective mutants could be complemented in trans, and NS5A is involved in HCV virion production, suggesting that different forms of NS5A exert multiple functions at various stages of the viral life cycle [21, 22]. The N terminus of NS5A (domain I) has been crystallized in alternative dimeric forms and contains both zinc- and RNA-binding domains, properties that have been demonstrated in vitro. NS5A has been shown to interact with a number of host proteins and plays a role in interferon resistancein vivo [20, 21]. Daclastavir is active at picomolar concentrations in vitro in HCV replicons expressing a broad range of HCV genotypes and acts in an additive to synergistic fashion with interferon and other DAAs [20-22]. The resistance profile of daclastavir reveals inhibitor sensitivity maps to the N terminus of domain 1 of NS5A [21]. It has been demonstrated that NS5A inhibitors could block hyperphosphorylation of NS5A, which is believed to play an essential role in the viral replication cycle.

Interferon-free combination trials

Several IFN-free combination trials are ongoing with different DAAs that target multiple viral sites: NS3/4a protease inhibitors, NS5B polymerase inhibitors (NI and NNI) and NS5A inhibitors. There have been major advancements in the last several years with large numbers of trials with various DAA showing increased SVR rates, favourable tolerability and shortened treatment duration with all oral regimens. The priorities for future combination are listed in Table 3. Fortunately, there will be opportunities to reduce cross-resistance[23]. Among unmet need, genotype 4-infected subjects need to be considered. Approximately 20% among the 170 millions of HCV-infected subjects worldwide are genotype 4 (approximately 34 millions). The standard treatment for HCV GT4 is PEG-IFN plus ribavirin for 48 weeks. Naive GT4 IL28B non-CC subjects have SVR rates lower than 50% with the standard PEG-IFN plus ribavirin for 48 weeks [24]. Furthermore, GT4 previous relapsers or non-responders have very low chance of being cured with the same regimen.

HCV drug development is shorter than, for example, HIV drug development because of short treatment duration, the option of open-label studies without the need of a control arm and also the primary end point for efficacy is SVR12 (12 weeks post-treatment follow-up), which is as relevant as 24 weeks to determine the SVR [25]. At present, several advanced studies of DAA combinations are ongoing, especially in more difficult-to-cure infected individuals.

IFN-free regimen for genotype 1-naïve and -experienced subjects

Results of IFN-free DAA regimens in treatment-naive GT1 individuals are presented in Figure 2 and for treatment-experienced GT1 in Figure 3.

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liv12423-fig-0003

Faldaprevir with or without RBV (Boehringer-Ingelheim)

SOUND-C2 is an open-label, randomized, Phase IIb study that enrolled 362 treatment-naïve HCV genotype-1 subjects into one of five treatment arms. The study evaluated the safety and efficacy of faldaprevir (protease inhibitor) and deleobuvir (polymerase inhibitor), with and without RBV [26, 27]. Final results from this study showed that up to 85% of HCV individuals infected with genotype-1b (GT-1b) achieved SVR. The optimal regimen was 28 weeks of faldaprevir (QD) and deleobuvir (BID). This study, which was the largest interferon-free trial of its kind to be conducted to date, included persons with cirrhosis. SVR was achieved in 70% overall subjects, compared with 85% seen in the prevalent GT-1b subject subgroup. Nine per cent of the total population had cirrhosis and this subgroup achieved SVR rates of up to 67% [26].

The most common adverse events (AEs) in SOUND-C2 were mild skin changes (itchy skin, rash or photosensitivity) or gastrointestinal disorders and transient indirect hyperbilirubinemia which sometimes presented as jaundice. Thirty six per cent of subjects experienced an AE, of which 12% were considered severe and 8% led to discontinuation of treatment. IFN-free phase III studies are ongoing.

Furthermore, faldaprevir plus deleobuvir plus PPI-668 (NS5A inhibitor) with or without ribavirin in persons with genotype 1a infection was studied [28]. Thirty-seven individuals with GT1a (without cirrhosis) were included. At week 4, HCV RNA was undetectable (<25 IU/ml) for 97% of subjects (35/36). SVR4 was available for 13 persons, and all had undetectable HCV RNA.

Aviator study: ABT-450/r, ABT-267, ABT-333 (Abbvie) with or without RBV

The Aviator phase 2b study assesses the safety and efficacy of ABT-450/r (dosed 100/100 mg to 200/100 mg QD), ABT-267 (25 mg QD), ABT-333 (400 mg BID) and RBV (weight based dosing) in non-cirrhotic treatment-naïve subjects and in prior PEG-IFN/RBV null responders for 8, 12 or 24 weeks [29]. ABT-450 is a ritonavir-boosted protease inhibitor [30]; ABT-267 is an NS5A inhibitor and ABT-333 is an NS5B polymerase NNI. Enrolment was open to GT1-infected individuals regardless of IL28B host genotype. SVR12 in treatment-naïve genotype 1 (GT1) subjects was 97.5% (77 of 79) and 93.3% (42 of 45) in GT1 null responder subjects. In GT1a subjects, SVR12 was achieved in 96% (52 of 54) of treatment-naïve subjects and 89% (25 of 28) of null responder subjects. In GT1b subjects, SVR12 was achieved in 100% of treatment-naïve (25 of 25) and null responder subjects (17 of 17). In addition, a separate Phase 2a, open-label study was conducted in treatment-naive and partial/null responders administered treatment for 12 weeks. A total of 19 subjects previously untreated subjects were enrolled in group 1, 14 previously untreated persons in group 2 and a total of 17 subjects with a null or partial response to previous therapy in group 3. Results from the 12-week triple-DAA regimen without RBV in treatment-naïve subjects showed that SVR12 was achieved in all individuals who completed treatment (95%) in group 1, 93% in group 2 and 47% in group 3.

The treatment was well tolerated. There was one treatment discontinuation in group 1 because of elevated levels of aspartate aminotransferase and alanine aminotransferase at week 2. No serious adverse event or death occurred in this study. The most common AEs were fatigue (47, 43 and 35%), nausea (21, 21 and 24%) and headache (26, 14 and 18%) for groups 1, 2, and 3 respectively.

Furthermore, ABT-450/r plus ABT-267 regimen was studied in genotype 1b-naive subjects (n = 42) and null responders (n = 40); all without cirrhosis [31] (PEARL I). SVR of 95.2% for treatment-naive subjects, and 90% for null responders was reported. The triple-DAA combination is currently being studied in Phase III clinical trials.

Sofosbuvir, GS-5885 and ribavirin (Gilead) (Electron study)

Interim data from the ongoing Phase 2 Electron study examining a 12-week course of therapy with the NS5B nucleotide inhibitor sofosbuvir, the NS5A inhibitor GS-5885 and ribavirin in subjects with genotype 1 chronic hepatitis C virus (HCV) infection were reported[32]. Among treatment-naïve individuals receiving this combination, 100% (n = 25/25) remained HCV RNA undetectable 4 weeks after completing therapy (SVR4). Among the nine genotype 1 previous null responders who were treated with sofosbuvir, GS-5885 and ribavirin for 12 weeks, three of the nine subjects have reached the 4-week post-treatment time point and all three remain HCV-negative. Both sofosbuvir in combination with RBV or GS-5885 plus RBV were well tolerated in this study. The most common AEs were headache, fatigue, upper respiratory tract infection and nausea. The most common clinically significant grade 3/4 laboratory abnormality was a haemoglobin reduction.

Phase 3 trial (ION-I) evaluating a fixed-dose combination of sofosbuvir and GS-5885 in treatment-naïve genotype 1 subjects are ongoing. This four-arm study is evaluating the fixed-dose combination with or without ribavirin for 12- and 24-week durations in 800 subjects, 20% of whom have evidence of cirrhosis.

Daclastavir (Bristol Myer Squibb) plus Sofosbuvir (Gilead) with or without RBV

This phase II trial was designed to test the combination of daclatasvir (NS5A inhibitor) and sofosbuvir in HCV GT1, 2 and 3, with or without RBV, for 12 or 24 weeks of therapy, and with or without a week-long run-in period with sofosbuvir [33].

A total of 44 subjects with the viral genotypes 2 and 3 were enrolled in three arms – one with a 7-day sofosbuvir run-in period followed by 23 weeks of the two together, one with the combination for 24 weeks and one with the combination plus ribavirin for 24 weeks. Eighty-eight per cent of subjects in the first group reached an SVR12, compared with 100% in the second group and 86% in the third group.

In genotype 1, the trial had 3 arms, with a total of 44 subjects with the same regimens as in the genotype 2/3 subjects. They also tested the combination with and without RBV for 12 weeks in a total of 82 subjects. All subjects receiving the first three regimens achieved an SVR12 and, all but one remained undetectable at SVR24. It was reported that out of the 82 subjects in the 12-week arms, 68 had reached 12 weeks post-treatment and all had SVR12.

Daclatasvir, asunaprevir and BMS-791325 (BMS)

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an NS3 protease inhibitor in Phase III development with daclatasvir. BMS-791325 is a NS5B polymerase NNI, currently in Phase II development for HCV as a component of daclatasvir-based treatment regimens. A Phase II study evaluated the above three different classes of DAAs – daclastavir, asunaprevir and BMS-791325 administered for 12 or 24 weeks in treatment-naïve persons with genotype 1 chronic HCV infection [34]. In the 24-week group, 94% achieved SVR4 and in the 12-week treatment group, SVR12 was achieved in 94% of persons. One hundred sixty-six naive GT1 subjects were treated (GT1a 82%; cirrhosis n = 15). SVR12 was 91% for GT1a and 94% for GT1b. Phase III trials with three DAA fixed-dose combination (BID) are anticipated.

Daclatasvir and asunaprevir in genotype 1b prior null responders

Previous data on daclastavir (NS5A inhibitor) and asunaprevir (protease inhibitor) have reported exciting results in genotype 1b null responders [35]. A phase III trial of daclatasvir plus asunaprevir was undertaken that evaluated either IFN ineligible naive/intolerant (n = 135) and non-responders to prior IFN-based therapy (n = 87) in Japanese subjects with genotype 1b infection. The study reported SVR24 rate of 87% in IFN ineligible/intolerant individuals and 81% in non-responders [36].

MK-5172 (QD) plus MK-8742 (QD) (NS5A inhibitor) with or without ribavirin (C-WORTHY Study) (MSD)

This is a Phase 2 study (n = 65) evaluating the combination of once-daily MK-5172 (protease inhibitor) plus MK-8742 (NS5A inhibitor) with or without ribavirin, administered for 12 weeks in genotype 1a- and 1b-naive subjects [37]. Remarkably, the two arms achieved an SVR12 of 100%: MK-8742 dose of 20 mg/day with ribavirin (21/21) and MK-8742 dose of 50 mg/day without ribavirin (12/12), both in combination with 100 mg/day MK-5172.

Simeprevir plus sofosbuvir with or without ribavirin in GT1-naive subjects and prior null responders (COSMOS study)

COSMOS is a Phase 2a, randomized, open-label study that evaluated once-daily combination of protease inhibitor, simeprevir plus sofosbuvir with or without ribavirin for 12 or 24 weeks in GT1-naive subjects (cirrhotic and non-cirrhotic) and prior null responders [38]. Cohort 1 (n = 80) randomized prior null responders persons with METAVIR scores F0-F2 and Cohort 2 (n = 87) evaluated prior null responder and treatment-naïve GT1 individuals with METAVIR scores F3-F4.

In cohort 1, prior null responders with Metavir F0-F2, SVR8 was 93% (without ribavirin) and 96% (with ribavirin). Viral relapse was observed in three subjects, all in GT1a with Q80K polymorphism mutation. In cohort 2, SVR4 results from the 12-week groups was 96% (with RBV) and 100% (without RBV). SVR4 in cirrhotics was 94% (17/18).

IFN-free regimen for genotype non-1 subjects

Data from several phase III studies of sofosbuvir for genotype non-1 subjects are available [39-41].

The FISSION trial was a randomized, open-label, active-controlled, phase III study of sofosbuvir plus RBV in naïve subjects with GT2 or GT3 HCV infection; subjects with the two genotypes were enrolled in approximately 1:3 ratio [39]. Subjects were randomly assigned in a 1:1 ratio to receive either 12 weeks of sofosbuvir plus RBV or 24 weeks of PEG-IFN/RBV. The doses of sofosbuvir and RBV were the same as those administered in the Neutrino trial. The dose of RBV for subjects in the PEG-IFN/RBV group was 800 mg daily. Sofosbuvir–RBV was shown to be non-inferior to PEG-IFN/RBV. At 12 weeks, the rates of SVR for subjects receiving 12 weeks of sofosbuvir/RBV and those receiving 24 weeks of PEG-IFN/RBV were each 67%. A SVR occurred in 97% of subjects with GT2 and in 56% of those with GT3 in the group receiving sofosbuvir/RBV, as compared with response rates of 78 and 63%, respectively, in the group receiving PEG-IFN/RBV. Among subjects with cirrhosis at baseline, 47% of those receiving sofosbuvir/RBV had a SVR, as compared with 38% of those receiving PEG-IFN/RBV.

The POSITRON trial was a blinded, placebo−controlled phase III study that compared 12 weeks of treatment with sofosbuvir and RBV with matching placebo in GT2 and GT3 HCV-infected subjects who had previously discontinued IFN-therapy because of unacceptable adverse events, who had a concurrent medical condition precluding therapy with an IFN−containing regimen, or who had decided against treatment with an IFN−containing regimen [34]. The most common reasons that IFN treatment was not an option were clinically significant psychiatric disorders (in 57% of subjects) and autoimmune disorders (in 19%).

The rate of SVR at 12 weeks after treatment was 78% among subjects receiving sofosbuvir/RBV compared with 0% among those receiving placebo (P < 0.001). Among subjects who received sofosbuvir/RBV, 93% of subjects with GT2 HCV infection had an SVR compared with 61% with GT3 HCV infection. Likewise, 81% of subjects without cirrhosis (92% of subjects with GT2 HCV infection and 68% of those with GT3 HCV infection) had a SVR as compared with 61% of subjects with cirrhosis (94% of subjects with GT2 HCV infection and 21% of those with GT3 HCV infection).

The FUSION study was a blinded, active−controlled phase III study involving GT2 and GT3 HCV-infected subjects who had no response to prior treatment with an IFN−containing regimen [40]. Approximately 75% of the previously treated subjects enrolled had either virological breakthrough during the prior treatment or virological relapse afterwards; the remainder did not have a response. The rates of SVR achieved were superior to the historical control rate of 25%, with rates of 50% in the 12-week group and 73% in the 16-week group (P < 0.001 for each comparison). Rates of SVR between the groups showed that subjects receiving 16 weeks of treatment had a significantly higher rate of SVR than subjects receiving 12 weeks of treatment (P < 0.001). The rates of SVR among subjects with GT2 HCV infection who received 12 weeks of treatment and those who received 16 weeks of treatment were 86 and 94%, respectively, compared with 30 and 62% for 12 and 16 weeks of treatment, respectively, among subjects with GT3 HCV infection.

Cirrhosis was associated with a decreased rate of SVR, particularly among subjects with GT3 HCV infection who received 12 weeks of treatment. Among subjects with cirrhosis who received 12 weeks of treatment, the rate of SVR was 31% (60% with GT2 HCV infection and 19% with GT3 HCV infection) as compared with 61% among subjects without cirrhosis (96% with GT2 HCV infection and 37% with GT3 HCV infection). Among subjects with cirrhosis who received 16 weeks of treatment, the rate of SVR was 66% (78% with GT2 HCV infection and 61% with GT3 HCV infection) as compared with 76% among subjects without cirrhosis (100% with GT2 HCV infection and 63% with GT3 HCV infection). Results of these trials are summarized in Figure 4.

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Figure 4. IFN-free trials for non-genotype 1 subjects

Conclusion

The standard of care for treatment of HCV GT1 improved with the introduction of telaprevir and boceprevir in 2011, which is used in combination with peg-IFN and RBV triple therapy. Triple therapy has improved SVR rates and treatment durations for many individuals with GT1 HCV infection. However, there has been a marked paradigm shift in the management of HCV infection as a result of the promising outcomes from recent studies with DAA combinations reporting increased SVR, low or no resistance and a good safety profile. There is a realistic hope for an all oral regimen against HCV in the near future, as several compounds with different mechanisms of action with synergistic interactions and pan-genotypic activity are in advanced drug development.

However, limitations to HCV treatment still exist particularly with comorbid conditions and in difficult-to-cure persons with advanced liver disease including those with decompensated cirrhosis. These individuals on newer therapy still have additional treatment-limiting adverse events and drug interactions. Furthermore, issues such as resistance and treatment failures, especially in the previously treated population, will need to be overcome with new drugs and combinations. Additional guidance may be obtained by genetic testing, but availability of alternative regimens for therapy is still needed for HCV. A pangenotypic once-daily or weekly regimens that will treat all populations with an SVR12 of greater than 95% is needed that can even be used safely in children and to prevent mother-to-child HCV transmission would be the ultimate goal. However, much progress has been made since HCV was first discovered in 1989. Based on the recent encouraging results from the widely studied IFN-free regimens in non-GT1 infection, it is possible that in the future, HCV may be the first chronic viral infection to be eradicated worldwide with one or more antiviral drug. The concept of treatment as prevention and a cure is gaining traction and will need to be applied globally to eradicate this virus from the face of the earth as we succeeded with smallpox in 1977.

Perspectives and therapeutic strategies

Simple strategies with complexes combination based or not based using back-bone of Nucleoside inhibitors are ongoing development regarding the availability of the new DAA:

In genotype 1 patients

  • Using nucleoside analogues the combination with PR+sofosbuvir have to be in balance with the IFN-free based on NI+NS5A±RBV or NI+PI±RBV
  • Without using nucleoside analogues: the combination with PR+PI have to be in balance with the IFN-free based on PI+NS5A±RBV or PI±NNI+RBV or PI±NNI+NS5A+RBV

In genotype 2 and 3 patients

  • i. Genotype 2: the combination of sofosbuvir plus RBV for 12 weeks that leads to SVR higher than 90% might be the next standard of care
  • ii. Genotype 3

Naïve: the combination of sofosbuvir plus RBV for 24 weeks that leads to SVR around 80%, or other DAAs in the near future, may be proposed

Treatment Experienced:

  • iii. In non-cirrhotic patients, the combination of SOF+RBV for 24 weeks-treatment lead to a 85% SVR

In cirrhotic patients, the combination of PR+RBV+SOF for 12 weeks of treatment leading to a 83% SVR has to be in balance with the combination of SOF+RBV for 24 weeks of treatment, which leads to a 60% SVR. In genotype 4 patients, there will be several possibilities: PEG-IFN plus RBV, combination of SOF + RBV for 16–24 weeks, triple therapy with SOF plus PEG-IFN/RBV, or Simeprevir plus PEG-IFN/RBV for 12–24 weeks. Future IFN-free regimen might be available for HCV genotype 4-infected patients.

Acknowledgments

This work was supported in part by CFAR NIH grant 2P30AI-050409 (to RFS) and by the Department of Veterans Affairs (to RFS). We thank Judy Mathew and Steve Coats for proofing this manuscript. Dr. Schinazi is the founder and a major shareholder of RFS Pharma, LLC.

Conflicts of interest: Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and MSD. Patrick Marcellin is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and MSD. Raymond Schinazi is the founder and major shareholder of RFS Pharma, LLC. Philippe Halfon is a speaker for Roche, Merck, Janssen and shareholder of Alphabio and Genoscience.

References

Source

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 11–12, February 2014

Review Article

You have free access to this content

Lawrence Serfaty*

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12407

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: boceprevir; low viral load; Pegylated interferon; rapid virological response; ribavirin; telaprevir

Abstract

Boceprevir and telaprevir-based triple therapy is now the standard of care for the treatment of genotype 1 patients. However, dual therapy with pegylated interferon and ribavirin should be discussed in treatment-naïve patients with good predictors of response. A recent published trial has shown in non-cirrhotic patients with low viral load at baseline, similar efficacy of a 24-week course of dual therapy vs a 24-week course of boceprevir-based triple therapy in case of rapid virological response. Accordingly, addition of protease inhibitor should be discussed after 4 weeks of dual therapy in this easy-to-treat population.

Boceprevir (BOC) and telaprevir (TPV) are direct acting antiviral agents that target the protease of the hepatitis C virus (HCV). In combination with pegylated interferon (PEG) and ribavirin (RBV) they increase the effectiveness of antiviral therapy in naïve patients infected with genotype 1 resulting in an increase in sustained virological response (SVR) from around 40% to nearly 70% or more [1, 2]. The major disadvantages of protease inhibitors (PIs) are the possible development of viral resistance (which may be long lasting and reduce future treatment options) and a range of side effects. Furthermore, PIs are expensive and substantially increase the overall cost of therapy. Therefore, while triple therapy is now the standard of care for treatment of genotype 1 patients [3], we will discuss whether dual therapy with PEG-IFN/RBV has still a place and in which subgroup of patients.

Predictors of response to PEG-IFN/RBV

The factors favouring response to PEG/RBV have been well-identified. In treatment-naïve patients with genotype 1, they are mainly age (<40 years), viral load (<600 000 IU/ml), absence of severe fibrosis and absence of insulin resistance [4]. Nucleotide polymorphisms on chromosome 19 upstream of the interleukin 28B (IL28B) gene have been found to be strongly associated with SVR [5, 6]. The statistical weight of this parameter appears to be similar to that of viral genotype. In CC homozygotes (rs12979860) of Caucasian origin (around 30% of patients) without severe fibrosis, the percentage of SVR was estimated to be 86% vs 36% and 43% for genotypes TT and CT respectively [7]. Analysis of viral kinetics indicated that a rapid virological response (RVR) was obtained in 30% of CC patients vs 5% of CT or TT patients. Therefore, around 80% of patients that achieved a RVR were CC homozygotes. The chance of achieving a SVR in patients achieving a RVR was greater than 90%, regardless of IL28B genotype. In contrast, in CC homozygotes who do not achieve a RVR the probability of achieving a SVR was only 60% [7]. Thus, by considering IL28B genotype and virological response at week 4 it is possible to identify a subgroup of patients with mild fibrosis in whom PEG-IFN/RBV therapy results in a SVR in 90% and in whom triple therapy would probably not be more effective. It is interesting to note that in this group, triple therapy can be shortened from 48 weeks to 24 or 28 weeks.

PEG-IFN/RBV in patients with low viral load and rapid virological response

In patients with low baseline viral load (<400 000 IU/ml) who achieve RVR, a short course (24 weeks) of PEG-IFN/RBV therapy is sufficient to obtain a SVR [8]. In these patients, PEG-IFN/RBV is still clearly the best option. Accordingly, French guidelines have recommended that PEG-IFN/RBV therapy should be considered the first-line treatment in treatment-naive genotype 1 patients with predictive factors for a good response to treatment [9]. A recently published trial has confirmed these recommendations [10]. In 233 treatment-naïve patients with HCV genotype1 without cirrhosis and with a low baseline viral load (<600 000 IU/ml) who are treated with PEG-IFN/RBV lead-in therapy, 101 (48%) with a RVR were randomized to 20 weeks of additional therapy with PEG-IFN/RBV or to 24 weeks of PEG-IFN/RBV/BOC. The rate of SVR was similar in both groups (88% vs 90%), regardless of viral subtype, IL28B or ethnicity. Safety was also similar for side effects, rates of dose reduction (33% vs 33%) or discontinuation (8% vs 6%). These results indicate that adding PI does not change the duration of therapy or efficacy of treatment in treatment naïve patients without cirrhosis with a low baseline viral load who achieve RVR.

PEG-IFN/RBV in treatment-experienced patients ?

Triple therapy is clearly the standard of care in treatment-experienced patients [3, 9]. However, PEG-IFN/RBV can be a therapeutic option in some patients with a resistant variant in whom PI treatment has failed. We reported the case of a patient who relapsed after a 12 week course of TPV-based triple therapy and who was cured by a 48 week-course of dual therapy despite the presence of a resistant variant[11]. While waiting for new molecules retreatment with reinforced regimen of PEG-IFN/RBV could be a therapeutic option in genotype 1-naïve patients who relapse after PI-based triple therapy.

Conclusion

In the setting of first generation PI-based triple therapy, dual therapy with PEG-IFN/RBV is still a therapeutic option in treatment-naïve patients with HCV genotype 1 and good predictors of response (absence of cirrhosis, low baseline viral load ± IL28B CC). In this subgroup of patients, triple therapy should be discussed depending on the RVR at the end of a 4-week course of dual therapy. This discussion could theoretically be extended to the use of next generation PIs based on triple therapy such as simeprevir or faldaprevir, for a treatment duration of at least 24 weeks [12, 13]. Regarding sofosbuvir-based triple therapy, the 12 weeks fixed duration for all patients should be a strong argument against the use of dual therapy, [14]. In the near future, all-oral regimens with high SVR rates and good safety will probably mean the end of interferon-based therapy for the treatment of chronic hepatitis C [15].

References

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Provided by NATAP

Reported by Jules Levin

64th Annual Meeting of AASLD, Washington DC, United States of America, November 2013 [Poster 1097]

Andrew Hill and Saye Khoo, Department of Pharmacology and Therapeutics, Liverpool University, UK
Bryony Simmons, Imperial College, London, UK
Nathan Ford, University of Cape Town, South Africa

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Ribavirin (generic) is a nucleoside analogue, with a relatively simple chemical synthesis (conversion factor (CF) x1). The daily dose is 1000-1200mg, with an overall dose of 84-100g for 12 weeks of treatment. Production costs were estimated at $0.25 to $0.75 per gram, giving an estimated cost of $21 to $76 for a 12 week course of treatment.

Daclatasvir (patent expiry 2027) is an NS5A inhibitor, and has a straightforward synthesis given its symmetry and the availability of cheap starting materials to synthesise the side-chains (CF x1-3). The daily dose is 60mg, with a total dose of 5g for 12 weeks of treatment. Production costs were estimated conservatively at $2 to $6 per gram, giving an estimated cost of $10 to $30 for a 12 week course of treatment.

Sofosbuvir (patent expiry 2029) is a nucleotide which requires a 2'-fluro-2'-methylfuranose intermediate. This cost-limiting material complicates synthesis (CF x4). The daily dose is 400mg, with a total dose of 34g for 12 weeks of treatment. Production costs were estimated at $2 to $4 per gram, giving an estimated cost of $68 to $136 for 12 weeks of treatment.

Faldaprevir (patent expiry 2025) is a protease inhibitor which requires a tetra-substituted quinoline and a vinyl-cyclopropane amino acid : this complicates the chemical synthesis (CF x10). The daily dose is 120mg, with a total dose of 10g for 12 weeks of treatment. Production costs were estimated at $10 to $21 per gram, giving an estimated cost of $100 to $210 for 12 weeks of treatment.

Simeprevir (patent expiry 2026) , a protease inhibitor, is a medium-ring macrocycle that utilises a novel, ring-closing metathesis reaction in the late stages of API manufacturing. Novel raw material include a tetra-substituted quinoline and a vinyl-cyclopropane amino acid: this significantly complicates synthesis (CF x10). The daily dose is 150mg, with a total dose of 13g for 12 weeks of treatment. Production costs were estimated at $10 to $21 per gram, giving an estimated cost of $130 to $270 for 12 weeks of treatment.

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REFERENCES

HCV epidemiology: Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17(2):107-15 doi: 10.111/j.1469-0691.2010.03432.x. http://www.ncbi.nlm.nih.gov/pubmed/21091831

Income classification: The World Bank income classifications, 2013. http://data.worldbank.org/about/country-classifications/country-and-lending-groups

Genotype prevalence: Alberti A, Negro F. The global health burden of hepatitis C virus infection. Liver International 2011;31(2) doi:10.1111/j.1478-3231.2011.02537.x. http://www.ncbi.nlm.nih.gov/pubmed/21651699

Costs of HIV drugs: Medecins Sans Frontières. Untangling the web of antiretroviral price reductions. 15th Edition - July 2012. http://utw.msfaccess.org/

Patent expiry dates of HCV drugs (all patents are subject to potential patent life extensions): Ribavirin: WHO, Application for inclusion of ribavirin in the WHO model list of essential medicines. Nov. 2006, page 2. http://archives.who.int/eml/expcom/expcom15/applications/newmed/ribaravin/ribavirin.pdf

Daclatasvir: Bristol-Myers Squibb Company, Form 10-K, year ending 2011, page 9. http://www.sec.gov/Archives/edgar/data/14272/000119312512066416/d302058d10k.htm

Sofosuvir: Pharmasset, Inc, Form 10-K, year ending 2011, page 26; Patent US7,429,572; composition of matter patent US7,964,580. http://quote.morningstar.com/stock-filing/Annual-Report/2011/9/30/t.aspx?t=:VRUS&ft=10-K&d=9038796906580b2535f464bf081028c1

Faldaprevir: Patents US7,585,845 (http://www.google.com/patents/US7585845 ) and US7,514,557 (http://www.google.com/patents/US7514557)

Simeprevir: Medivir annual report, 2012, page 18; Patent WO07/014926 http://www.medivir.se/v4/images/pdf/2013/Medivir-ENG-web_0403.pdf Retro-synthesis and identification of cost limiting materials

Witkowski JT, et al. Design, synthesis, and broad spectrum antiviral activity of 1-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem. 1972; 15(11): 1150-4
Gao M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465(7294): 96-100.

Peng G, et al.; Bristol-Myers Squibb Company. Process for synthesising compounds useful for treating hepatitis C. Patent Application WO2009/020825 A1. Feb 12, 2009.

Chun BK, Wang P.; Pharmasset, Inc. Preparation of 2'fluro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. Patent Application WO2006/031725 A3. Apr 16, 2009.

Chun BK, et al.; Pharmasset, Inc. Nucleoside phosphoramidates. Patent Appliation US2011/0251152 A1. Oct 13, 2011.

White PW, et al. Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. Antimicrob Agents Chemother. 2010; 54(11): 4611-8.

Llinas-Brunet M, et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem. 2010; 53(17): 6466-76.

Horvath A, et al.; Janssen Pharmaceuticals, Inc. Improved process for preparing an intermediate of the macrocyclic protease inhibitor TMC435. Patent Application WO2013/061285 A1. May 2, 2013.

DAA combinations (interferon-free): i-Base/Treatment Action Group. 2012
Pipeline Report: HIV, HCV, and TB drugs, diagnostics, vaccines, and preventative technologies in development. July 2012.http://www.pipelinereport.org/toc

SOUND-C2: Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor faldaprevir (BI 201335) and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin: final results of SOUND-C2 and predictors of response (Abstract 232). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_20.htm

AI444-040: Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.; AI444040 Study Group. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5a inhibitor) plus sofosbuvir (nucleotide NS5b inhibitor) with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3 (Abstract LB-2). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_06.htm

AI443-014: Everson GT, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection (Abstract LB-3). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_07.htm

AI447-011: Lok AS, Gardiner DF, Hezode C, et al. Sustained virologic response in chronic HCV genotype (GT) 1-infected null responders with combination of daclatasvir (DCV; NS5a inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV) (Abstract 79). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_15.htm

ELECTRON: Gane EJ, Stedman CJ, Hyland RH, et al. Once daily sofosbuvir (GS-7977) regimens in HCV genotype 1-3: The ELECTRON trial (Abstract 229). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_31.htm

SPARE: Osinusi A, Heytens L, Lee JY, et al. High Efficacy of GS-7977 in Combination with Low or Full dose Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype 1 Patients: Interim Analysis from the SPARE Trial (Abstract LB-4). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_08.htm

POSITRON: Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med; 2013;368:1867-1877. http://www.nejm.org/doi/full/10.1056/NEJMoa1214854

COSMOS: Lawitz E, Ghalib R, Rodriguez-Torres M, et al. SVR4 results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3-6; Atlanta, GA. http://www.natap.org/2013/CROI/croi_34.htm

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High price for Hep C drug sparks controversy

By Lou Chibbaro Jr. on December 23, 2013

Carl_Schmid_insert_courtesy_Schmid

Carl Schmid, deputy director of the AIDS Institute, said Sovaldi is expensive, ‘but this is remarkable progress and the cure rate is extremely high.’ (Photo courtesy of Schmid)

The pharmaceutical company Gilead Sciences received praise earlier this month for bringing to market a newly approved drug capable of curing the potentially fatal liver disease Hepatitis C without the serious and debilitating side effects caused by the existing drug used to treat the disease.

Experts say 20 percent of people with HIV are co-infected with Hepatitis C, which over a period of years can lead to death through liver cancer and liver failure. Physicians treating people with HIV, including Whitman-Walker Health’s medical director, Dr. Richard Elion, have called Gilead’s new drug a major breakthrough.

But at least two organizations that advocate for people with HIV and Hepatitis C have denounced Gilead for setting the wholesale price for its new drug Sovaldi at a level they consider exorbitant and which they say could lead to further escalating prices for AIDS drugs.

The AIDS Healthcare Foundation, the nation’s largest private organization providing medical services for people with HIV/AIDS, and the Fair Pricing Coalition, which advocates for affordable prices for prescription drugs for people with serious illnesses, called Gilead’s decision to set a wholesale acquisition cost of $84,000 for a 12-week treatment regimen of Sovaldi unprecedented.

“There can be no better example of the unbridled greed of the pharmaceutical industry than Gilead’s latest move: pricing its new hepatitis drug at $84,000 per 28-tablet bottle or $1,000 per pill,” said Michael Weinstein, president of AHF.

Lynda Dee, co-chair of Fair Pricing Coalition, called Sovaldi a “very safe and highly effective drug” but noted that it must be used in combination with other drugs to treat different Genotypes, or strains, of Hepatitis C.

She said that although the other drugs – pegylated interferon and ribavirin – are not as expensive as Sovaldi, the price tag for combination therapy with Sovaldi comes to $93,000 and $168,000 for various treatment regimens for a single person living with Hepatitis C.

“Gilead has set the bar dangerously high as other companies determine prices for similar Hepatitis C drugs as they enter the market,” Dee said.

In a statement released at the time the U.S. Food and Drug Administration approved Sovaldi for patient use on Dec. 6, Gilead said it had put in place a patient assistance program to ensure that people with Hepatitis C have access to Sovaldi regardless of their ability to pay for it.

The statement said the program provides assistance to “patients who are uninsured, underinsured or who need financial assistance to pay for the medicine.” The program, called Support Path, will provide Sovaldi “at no charge for eligible patients with no other insurance options,” according to the statement.

While praising Gilead for offering such a program, which is common within the pharmaceutical industry, critics say the high price for Sovaldi would likely prompt other companies to put in place similarly high pricing policies for other promising drugs about to be released for the treatment of both Hepatitis C and HIV/AIDS.

Some Wall Street analysts suggested Gilead’s price for Sovaldi may be justified when taking into consideration the amount it spent to bring such a beneficial drug to market. Bloomberg business news service reported that Gilead, which didn’t invent Sovaldi, paid $11 billion in 2011 to buy Pharmasset, Inc., the company that developed Sovaldi and other Hepatitis C drugs expected to be approved soon.

Bloomberg cited pharmaceutical industry observers who said the Hepatitis C drugs Gilead obtained through this purchase could pull in as much as $20 billion by 2020.

Clinical trials with patients monitored by the Food and Drug Administration demonstrated that Sovaldi had a cure rate of more than 90 percent for patients with the Genotype 2 strain of Hepatitis C following a 12-week regimen with the drug ribavirin. Patients with Genotype 3, another strain of Hepatitis C, had a similarly successful cure rate following a 24-week regimen of Sovaldi and Ribavirin, the trials showed.

For patients with Genotype 1 or 4 of the Hepatitis C infection, the Sovaldi treatment needed to be combined with pegylated alfa interferon, the drug of choice for Hepatitis C before the development of Sovaldi and other new drugs nearing completion of clinical trials, statements by Gilead and the FDA said. Interferon causes serious and debilitating side effects for most patients, forcing some to stop using it before the Hepatitis C virus can be eliminated, according to medical experts.

The good news, according to those monitoring Hepatitis C treatment developments, is that Gilead and other pharmaceutical companies are close to releasing other new drugs capable of effectively curing patients with the Genotype 1 and Genotype 4 strains without the need for Interferon.

“I believe that Sovaldi will have a major impact on public health by significantly increasing the number of Americans who are cured of Hepatitis C,” said Dr. Ira Jacobson, chief of the Division of Gastroenterology at Weill Cornell Medical College in New York City, who served as a principal investigator in the clinical trials of Sovaldi.

Carl Schmid, deputy director of the AIDS Institute, which advocates for people with HIV, said the ability of Sovaldi to actually cure patients with Hepatitis C makes it different from HIV drugs on the market, which keep most patients healthy but cannot cure HIV/AIDS.

“Yes, it’s expensive,” he said of Sovaldi. “But this is remarkable progress and the cure rate is extremely high.”

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Life-saving hepatitis C drug approved, but cost is high

Provided by IRIN

humanitarian news and analysis

a service of the UN Office for the Coordination of Humanitarian Affairs

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Photo: Wikipedia

Life-saving: the sofosbuvir molecule has been approved in the US and Europe for the treatment of hepatitis C

New York, 23 December 2013 (IRIN) - Following approvals in the US and Europe this month of a new drug to treat hepatitis C, activists are pushing for the medication to be made available in poor countries, a development reminiscent of the activism that forced down HIV/AIDS drug prices a decade ago in Brazil, South Africa and Thailand.

The World Health Organization (WHO) estimates that as many as 185 million people are infected with hepatitis C, which is often called a “viral time bomb” because it can exist, undiagnosed, in a person’s body for many years without causing symptoms.

According to the Open Society Foundations (OSF), more than 350,000 people die every year from liver disease related to the virus, and every year an estimated three to four million more people are infected.

Many of these people are co-infected with HIV; the illnesses are both blood-borne and have shared routes of transmission, particularly injecting drug use.

Unlike HIV, hepatitis C can be cured. But current treatment options have serious side effects, do not always work and are unaffordable for most people. The existing treatment, pegylated interferon, which is manufactured by Roche and Merck, can cost as much as US$18,000 for a 48-week course.

Interferon, which must be injected, can, in combination with the drug ribavirin, cure 40-70 percent of patients who use it. But its high cost has kept it out of reach for most patients, except in Egypt and Thailand, where the governments were able to negotiate significant price reductions with drug manufacturers.

“How have we got to a global system where new drugs being developed are out of reach of most of the population?”

The new drug, sofosbuvir, released by pharmaceutical giant Gilead, promises a leap forward in the hepatitis C treatment. It is orally administered, reduces treatment time to 12 weeks, has fewer side effects, and, if used in combination with other drugs, can achieve a 90 percent cure rate. The hitch?

The price tag.

In the US, which has some of the highest drug prices in the world, Gilead is expected to charge $80,000 for one course of treatment - more than four times the cost of interferon. While the cost of the drug is likely to be lower elsewhere, healthcare advocates fear the price will remain beyond the reach of poor people.

Pricing

Médicins Sans Frontières’ director of policy and analysis, Rohit Malpani, says the drug has been priced so high because it cost the company $11 billion to acquire Pharmasset, the original maker of the drug.

According to one analyst, Gilead has to make $4 billion on the drug annually, to justify the high cost of the buyout.

This is not a reflection of the research and development costs; it is an assessment of how much the company can get for it, Malpani adds. “Companies will engage in extensive studies to determine what the market will bear, but that is not the way that life-saving commodities should be priced.”

Access strategy

MSF’s Access Campaign, which lobbies for affordable medicines for resource-strapped communities, is waiting for Gilead to finalize its “access strategy” for poor countries after having received input from a range of organizations.

A Gilead spokesperson told IRIN that it would announce the details of its access programme early next year. The company says it is “committed to making its medicines available to patients, regardless of where they live or their ability to pay”, and that it is “working very closely with advocates in communities that are affected by hepatitis C to develop an appropriate access and pricing strategy”.

The spokesperson said Gilead wanted to “help ensure access to Sovaldi [the brand name for sofosbuvir] in resource-limited countries, especially countries that have a high hepatitis C burden”.
However, Malpani is not optimistic that the reduced price will be low enough to make the drug widely accessible. Furthermore, MSF believes Gilead is likely to offer “middle-income” countries - like China, Iran and Ukraine - a higher pricing strategy than that given to poor countries.
Ironically, 75 percent of the world’s poor reside in middle-income countries, Malpani said. “Our concern with Gilead’s access strategy is that it is likely to be unaffordable and punitive to the countries in that category,” he said.

MSF would like to set a target price for the drug of less than $500. However, according to an OSF report, "Unfortunately, past experience with HIV suggests that drug companies are unlikely to voluntarily extend significant discounts to middle-income countries, even if they may be open to reducing the price for the world's poorest."

According to one study, a 12-week course of sofosbovir could cost as little as $62-$134 to produce.
Asked why the drug was so expensive in the US, the Gilead spokesperson said: “We believe that the price of Sovaldi in the United States is fair, based on the value it represents to a larger number of patients.” A special programme for those unable to afford it would be available, he added.
“But the starting point is so outrageous, not even halving it would make it accessible,” says Els Torreele, director of OSF’s Access to Essential Medicines Initiative.

“How have we got to a global system where new drugs being developed are out of reach of most of the population? It’s totally normal today to price drugs at $100,000. Something is wrong with a system where drugs that so many people need are costing so much. This is not sustainable for anyone,” she said.

Daniel Wolfe, director of the International Harm Reduction Development Program at OSF, said that because of its association with HIV and drug use, hepatitis C is still highly stigmatized. “The experience of HIV has shown us that the combination of expensive medication and social stigma is deadly,” he said.

He added that companies are pricing their drugs for profit rather than public health concerns. “When governments are confronted by high prices for a stigmatized population affected, they tend to look the other way,” Wolfe said.

Patent worries

In India a “patent opposition” has been filed by the Initiative for Medicines Access and Knowledge (I-MAK) to stop Gilead from obtaining a patent on the drug there, which would clear the way for low-cost generics to be manufactured.

India has long been at the forefront of manufacturing generic life-saving drugs. Under its Patent Act, medications that are not new do not qualify for patent protection; I-Mak argues that sofosbuvir is “old science” stemming from a long line of antiretroviral drugs.

The World Trade Organization’s 1995 Trade-related Aspects of Intellectual Property Rights (TRIPS) agreement laid down minimum standards for patent laws. There is, however, “some flexibility for countries to determine what is meant under the criteria of patentability”, says Torreele, citing I-MAK’s case against Gilead’s sofosbuvir patent.

Since social activism helped force down the cost of AIDS drugs with generic alternatives over a decade ago, “the world has changed,” says Torreele. “The solutions to making HIV drugs affordable are not there anymore.”

While TRIPS makes allowances for governments to override patent laws to protect public health, “there is lots of pressure by the pharmaceutical industry on them to avoid these measures”.

And negotiations, spearheaded by the US, are currently taking place with 11 other countries to finalize the Transpacific Partnership Agreement, a trade deal that some worry could undermine the flexibility allowed by TRIPS.

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Theme (s): Aid Policy, Health & Nutrition, HIV/AIDS (PlusNews),

[This report does not necessarily reflect the views of the United Nations]

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