Saturday, January 30, 2016

Looking For A Hep C Price War? Merck Just Started It

Looking For A Hep C Price War? Merck Just Started It
Jan. 29, 2016 12:29 PM ET
About: Merck & Co Inc. (MRK), GILD

If the sector wants signs that the drug pricing debate is having an effect on new launches, look no further than Merck & Co’s (NYSE:MRK) new hepatitis C pill Zepatier. The New Jersey group says it will charge $54,600 for the three-month course of medication, a significant discount on the list price and probably even the off-invoice charge for its main rival, Gilead Sciences’ (NASDAQ:GILD) Harvoni.

Assuming further rebates, Merck’s combination of grazoprevir and elbasvir could come within a price that cost-effectiveness assessors estimate is sufficient to justify paying for treatment of all patients, not just the sickest. The emerging price war confirms the sellside’s belief that 2015 was hep C’s peak year.

Merck ushers in price war for hepatitis C medicines with new drug 
JANUARY 29, 2016
By comparison, the list price for the Harvoni drug sold by Gilead Sciences is $94,500, while AbbVie charges $83,300 for its Viekira Pak for 12-week regimens. List prices, however, do not reflect any rebates, which can vary. Despite receiving such partial refunds, though, many insurers and government health programs have restricted coverage of these treatments in order to contain costs.
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Chronic hepatitis C: This and the new era of treatment.

*Abstract, discussion and conclusion provided below please, click here to review the full text article. 

World J Hepatol. 2016 Jan 18; 8(2): 92–106.
Published online 2016 Jan 18. doi: 10.4254/wjh.v8.i2.92

Chronic hepatitis C: This and the new era of treatment.
Bertino G1, Ardiri A1, Proiti M1, Rigano G1, Frazzetto E1, Demma S1, Ruggeri MI1, Scuderi L1, Malaguarnera G1, Bertino N1, Rapisarda V1, Di Carlo I1, Toro A1,Salomone F1, Malaguarnera M1, Bertino E1, Malaguarnera M1.

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Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.

Boceprevir; Daclatasvir; Dasabuvir; Direct-acting antiviral agents; Faldaprevir; Hepatitis C; Ledipasvir; Nucleoside inhibitors; Ombitasvir; Ritonavir; Simeprevir; Sofosbuvir; Telaprevir

Core tip: This review analyzes the current therapies for chronic hepatitis C and the future challenges of the research. So it tries to give an update on the research of hepatitis C virus (HCV) infection, providing a critical view of the emerging therapies and their impact on the future management of HCV infection. Since novel treatments for HCV infection are highly efficacious but costly, priority should be given to patients with advanced hepatic fibrosis, which is a disease that cannot be deferred.

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Today, it can be anticipated that the future of HCV infection treatment seems very bright after the addition of first-generation HCV PIs as well as SMV and the first-in-kind HCV RNA polymerase inhibitor, ‘‘sofosbuvir’’, in the standard of care (i.e., PEG-IFN/RBV). However, the real success of these drugs is very much dependent on careful monitoring of viral load and resistance, patterns of response to previous treatment, side effects and drug-drug interactions. Moreover, the logical meaning of novel emerging therapies must be to achieve high SVR and thorough clearance of the virus from treated patients. Nevertheless, the triple therapeutic regimens have several limitations. First, concomitant use of PEG-IFN plus RBV is essential to prevent the emergence of viral escape mutants and viral breakthrough during triple therapy. Second, triple therapy becomes less effective in prior null responders to PEG-IFN plus RBV and cannot be administered to patients who are contraindicated for PEG-IFN or RBV. To overcome these limitations, in the near future, many patients will be treated with two or more DAAs with or without IFN-α plus RBV based combination therapies. Currently, the approval of sofosbuvir- and SMV-based IFN-free regimens is an indication in this way. Triple and quadruple treatment regimens including multiple DAAs with or without PEG-IFN and RBV will likely be a suitable option for difficult-to-treat populations and for the prior null responders. All-oral IFN free regimens including drugs with a high genetic barrier to antiviral resistance (e.g., NS5B inhibitors) and high antiviral efficacy (e.g., NS3/4A PIs or NS5A inhibitors) may be a potent option for numerous patients contraindicated for PEG-IFN plus RBV. All oral regimens consisting of daclatasvir plus sofosbuvir once daily presented higher rates of SVR in untreated HCV GT-1, -2 and -3 infected patients and in HCV GT-1 infected patients who had failed previous treatment with PIs. We hope that such combinational treatment strategies will become ‘‘the weapon’’ to treat the majority of HCV infected patients who represent the difficult population (i.e., IL-28 polymorphism, HCV genotypes 1 and 4 subtypes, receipt of RBV, and the emergence of resistant variants) and will be more efficient to access the treatment in the near future. The testing of adenovirus vector based vaccines, which escalate the innate and acquired immune response against the most conserved regions of HCV genome in chimpanzees and humans, may be a promising therapeutic approach against HCV in the near future, although its fate still needs to be exploited fully in diverse HCV populations. One thing must be of special concern is whether the newly developed or being developed DAAs added in triple or quadruple therapies are safer or not than antiretroviral and traditional IFNs. Overall, the achievements in the field of HCV medicines may predict that we are near to complete elimination of HCV disease in the world[140]. The real challenges that our efforts must be directed are: (1) the effectiveness of IFN-free regimens in HCV-3, especially in cirrhotic non-responders; in this setting, combination with PEG-IFN is still possible; (2) the effectiveness of IFN-free regimens in decompensated cirrhosis are scarce in relation to the current correlation data between SVR and clinical outcome (literature confirms that the results of IFN-free regimens are good in compensated cirrhosis even if further clinical development is necessary in certain groups to improve SVR rates); (3) the development of new treatment strategies for patients who show resistance to new drugs; and (4) free-access to care[141]. In fact, many patients with CHC have mild disease and are currently excluded from the interferon-free treatment. In the near future we will inevitably prioritize this category in order to prevent progression to cirrhosis, decompensation and HCC.

Ribavirin: Past, present and future

World J Hepatol. 2016 Jan 18; 8(2): 123–130.
Published online 2016 Jan 18. doi: 10.4254/wjh.v8.i2.123
PMCID: PMC4716528
Ribavirin: Past, present and future
Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques
Sophie Alain, Pierre Marquet, Denis Sautereau,Annick Rousseau, Paul Carrier
Author information ► Article notes ► Copyright and License information ►
Ribavirin: Past, present and future
Core tip: Ribavirin plays a crucial role when associated with peginterferon, preventing relapses and breakthroughs and doubling the support vector regression rate. Its antiviral effect is weak and ribavirin could enhance the response of interferon-stimulated genes in the combination. Ribavirin is still useful in the era of approved new direct acting antiviral agents (DAAs), in order to shorter treatment duration in genotype 1 or 4 cirrhotic patients, in all options available for genotype 3 cirrhotic patients, and as the only drug associated with sofosbuvir in genotype 2. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized.


Before the advent of direct acting antiviral agents (DAAs) ribavirin played a crucial role in the treatment of chronic hepatitis C associated to pegylated interferon[]. This combination is still relevant in many parts of the world which do not have access to new therapies because of cost issues[]. Although the role of ribavirin in the era of DAAs will probably decrease in the future with the arrival of second generation drugs, it remains essential in strategies decreasing treatment duration or in some difficult situations. The goal of this review is to briefly recall the recent past of ribavirin and consider its present and potential future.


So far, multiple mechanisms of action of ribavirin have been described. The antiviral mechanism is probably the best documented, the erroneous incorporation of ribavirin triphosphate into replicating RNA strands inhibiting chain elongation[]. In vitro, in the hepatitis C virus (HCV) RNA replication system, ribavirin reduces HCV replicon colony-forming efficiency in a dose-dependent manner, reinforcing this hypothesis[]. The inhibition via inosine monophosphate dehydrogenase of the de novo synthesis of GTP, required for the synthesis of viral RNA, is another but probably weak potential mechanism of action[]. However, the mutagenesis hypothesis remains controversial[]. The last most attractive mechanism of action is that ribavirin could enhance the response of interferon-stimulated genes making cells more sensitive to exogenous interferon and increasing the production of endogenous interferon[].
Two phases of plasma HCV RNA decline in patients treated with peginterferon and ribavirin have been described: A rapid first phase in the first two days[] reflecting the genesis and release of new virions and a slower second phase corresponding to the elimination of infected cells. The impact of the first-phase decline is weak (0.5 log) and goes unnoticed during double therapy, but is enhanced in patients treated with ribavirin alone[]. The second slope probably reflects the interferon-stimulated genes’ response and the production of endogenous interferon.
Multiscale models recently considered the possible effects of DAAs on intracellular HCV RNA production, degradation, assembly and secretion as virus into the circulation[]. The first-phase decline represents the viral clearance. The second represents the loss of intracellular viral RNA by export and degradation as well as the elimination of infected cells. The third represents a combination of the reduction in intracellular viral RNA production and the elimination of infected cells. Nowadays, there are no data available on the role of ribavirin in this setting, but we may imagine that ribavirin might impact the second- and the third-phase decline.


Clinical history
Ribavirin, a guanosine analog is active against many DNA and RNA viruses and has clinical applications in respiratory syncytial infection in children, and Lassa Fever infection[,]. Di Bisceglie et al[] first showed that ribavirin could double the efficiency of standard alfa interferon. A similar synergy was observed with the association of peginterferon and ribavirin[,], ribavirin impacting favourably the number of relapses and breakthroughs[]. A total daily dose of ribavirin during the first three months > 10.6 mg/kg of body weight was predictive of sustained virological response (SVR)[,] and ribavirin had to be administered for the total duration of treatment[]. A pilot study also showed, that the use of high doses of ribavirin early during treatment led to high sustained virological rates[]. The same team proposed to optimize the dose of ribavirin using a formula based on renal function and body weight[].
Pharmacokinetics of ribavirin
Ribavirin is a drug typically adapted for therapeutic drug monitoring: Long half-life, large inter-individual variability of the dose-concentration relationship, and narrow therapeutic zone. After the first oral dose, a rapid absorption phase is observed with a maximum concentration at 1.5 h, followed by a rapid distribution phase (half-life of 3.7 h), and a long elimination phase of about 100 h post-dose[]. The monitoring of ribavirin plasma concentrations during double therapy initially used trough concentrations at week 4 and week 8 of treatment[,]. However, trough concentrations had a lower influence than the genotype and the viral load on SVR[].
We secondly showed that ribavirin plasma exposure after the first dose [i.e., measured by the interdose area under the concentration curve, area under the curve (AUC0-12h) or abbreviated AUC0-4h] was strongly linked to SVR and was probably a more relevant tool[]. Using receiver operating characteristic curve analysis, we defined an AUC0-4h threshold of 1755 μg/h per litre at day 0 as a target for ribavirin early dose adjustment, AUC0-4h being estimated using 3 blood samples (0.5, 1 and 2 h after the first dose) and Bayesian estimation. When comparing adapted and non-adapted patients with a suboptimal exposure to ribavirin at day 0 (i.e., D0 AUC0-4h < 1755 μg/h per litre), the difference of SVR reached nearly 30%, enhancing the benefit of adapted dose in this population (unpublished results).
Ribavirin and anemia during peginterferon and ribavirin treatment
Ribavirin-induced haemolytic anaemia is a frequent adverse event leading to drug discontinuation in 36% of the cases in real-life studies[], even if this anemia is reversible and dose-dependent. Medullar regeneration is partially prevented by various degrees of bone marrow suppression due to interferon impact. The prevalence of anaemia is high, with Hb level < 11 g/dL in 30% and < 10 g/dL in 9% to 13% of the patients[,] with 10% to 15% of the patients presenting with an Hb decline of more than 5 g/dL. Erythropoietin has been shown to improve the ribavirin treatment maintenance and tolerance[,] but did not prove its impact on SVR.
Interferon-free regimens DAAs currently approved by FDA and EMEA are used in combinations: Pangenotypic polymerase inhibitor sofososbuvir (Sovaldi®) associated with NS5A inhibitors ledipasvir (associated with sofosbuvir: Harvoni®) or daclatasvir (Daklinza®) (genotype 1, 3, 4), or with a protease inhibitor simeprevir (Olysio®) (genotype 1, 4); triple combination paritaprevir boosted with ritonavir (protease inhibitor), ombitasvir (NS5a inhibitor) (Viekirax®) and quadruple combination of paritaprevir, ritonavir, ombitasvir and dasabuvir (Exviera®) a polymerase inhibitor are also available for genotype 1, 4 patients.
Most of the time, these regimens give more than 90% SVR rate without the addition of ribavirin. However, ribavirin is still relevant in some circumstances.
Ribavirin and sofosbuvir alone are efficient in the treatment of most cases of G2 infected patients
Sofosbuvir and ribavirin combination is recommended in both European Association for the Study of the Liver (EASL) and French guidelines in G2 patients for 12 wk mainly[] except for cirrhotic experienced-patients (24 wk)[]. In this particular population, the only way to reduce treatment duration to 12 wk with similar SVR (95% to 100%) is to add peginterferon[,].
Nowadays, ribavirin remains essential for the last difficult-to-treat cirrhotic G3 patients
HCV G3 patients were first treated with sofosbuvir and ribavirin for 24 wk in phase III trials; response rates were 91% in patients without cirrhosis and only 68% in patients with cirrhosis, respectively[]. Recently, the Boson study showed the potential superiority of a peginterferon sofosbuvir and ribavirin regimen for 12 wk with a 91% to 86% SVR in naive and pre-treated cirrhotic patients respectively[]. Another strategy using sofosbuvir daclatasvir without ribavirin for 12 wk in G3 cirrhotic patients led to a weak 63% rate of SVR[]. Results of the French initial authorization for new DAAs are in favour of a 24-wk treatment but the sofosbuvir daclatasvir and ribavirin strategy for 12 wk was not available[]. This option could be a pertinent alternative to the 24-wk sofosbuvir daclatasvir association. Currently, EASL and French expert advices recommend treating patients with sofosbuvir daclatasvir for 24 wk, in the absence of the results of a new trial evaluating sofosbuvir daclatasvir ribavirin for 12 wk.
To sum up, all options currently available for cirrhotic G3 patients contain ribavirin and we have to wait for the results of new associations like sofosbuvir and the pangenotypic GS 5816 (astral 3 waiting results) or more sophisticated triple strategies like grazoprevir elbasvir and sofobuvir[].
Ribavirin is still necessary for G1a patients treated with ritonavir-boosted paritaprevir, ombitasvir and dasabuvir
The approval of the triple combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir in patients infected with G1 was supported by six phase III clinical trials. In PEARL-IV, in patients infected with subtype 1a, the SVR rates were 97% and 90% with and without ribavirin respectively, suggesting that, unlike for G1b, ribavirin is needed in the 12-wk regimen for this subtype[]. Moreover, considering treatment-experienced cirrhotic patients with subtype 1a infection a 24 wk-treatment duration with ribavirin was needed[].
Reducing treatment duration to 12 wk in G1 or G4 cirrhotic patients is feasible thanks to ribavirin
In compensated and decompensated cirrhosis: Recent data suggest that the addition of ribavirin allows the treatment duration to be limited to 12 wk in patients with advanced liver disease, including patients with compensated cirrhosis (especially if they are treatment-experienced), patients with decompensated cirrhosis and subjects in pre- and post-liver transplant setting.
Twelve weeks with ribavirin or 24 wk without ribavirin are equivalent in compensated cirrhosis: In the Sirius study[], ledipasvir-sofosbuvir plus ribavirin for 12 wk and ledipasvir-sofosbuvir for 24 wk provided similar high SVR12 rates in previous non-responders with HCV G1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat experienced patients with cirrhosis in case of no contra-indications to ribavirin.
Of note, in cirrhotic pre-treated patients with platelet count < 75000/mm3, the SVR rate is suboptimal (84%)[] and EASL guidelines recommend to extend the ribavirin-associated regimen to 24 wk in this subgroup.
In a post-hoc analysis of data from seven clinical trials which evaluated the efficacy and safety of the fixed-dose combination of ledipasvir and sofosbuvir, with and without ribavirin in 513 treatment-naive and previously treated patients with G1 HCV compensated cirrhosis, Reddy et al[] suggested the usefulness of ribavirin in the subpopulation of treatment-experienced patients receiving 12 wk of treatment (SVR12 rate of 90% vs 96% with ribavirin).
Finally in the hepather cohort[], difficult-to treat G1 (88% cirrhotics) patients receiving sofosbuvir daclatasvir and ribavirin achieved a SVR4 of 100% not different from sofosbuvir daclatasvir for 24 wk (SVR4 95%). In a multivariate analysis, factors associated with SVR in cirrhotics were the addition of ribavirin (OR = 6.3; P = 0.057) and a treatment-duration of 24 wk (OR = 4.3; P = 0.008).
Similarly, results from the same cohort study showed a benefit in the pre-treated cirrhotic population infected with G4 and receiving sofosbuvir daclatasvir or sofosbuvir simeprevir, with ribavirin[].
Same results are observed in decompensated cirrhosis in the pre and post-transplant setting except for Child Pugh C patients: The association of sofosbuvir ledipasvir and ribavirin for 12 wk in the pre and post transplant setting led to more than 85% to 95% SVR in cirrhotic patients[,]. However, in one study, the response rate was much lower (under 60%) in Child Pugh C patients suggesting a prolongation of treatment course to 24 wk[].
In non-cirrhotic G1 patients, ribavirin does not help to reduce treatment duration under 8 wk
Among previously untreated patients with HCV G1 infection and without cirrhosis in the phase III ION 3 study, the 8-wk ledipasvir-sofosbuvir regimen showed no inferiority to the 12-wk regimen[]. One interesting hypothesis could have been to further reduce the treatment duration by adding ribavirin to the combination.
However, in the electron study, among treatment-naive patients receiving 6 wk of sofosbuvir, ledipasvir and ribavirin, only 17 of 25 (68%) achieved an SVR12. The addition of ribavirin in this setting does not seem to be an appropriate strategy[].
Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful
In Reddy’s study[], 91% of G1 cirrhotic patients with NS5A resistance-associated variants (RAVs) at baseline and treated with sofosbuvir-ledipasvir achieved SVR12 (95%CI: 84-96), as compared with 98% (407 of 417) of those without baseline NS5A RAVs (95%CI: 96-99). This difference appeared to be mitigated by the addition of ribavirin to the regimen (88% of SVR without vs 94% with ribavirin).
The addition of ribavirin with DAAs combinations leads to more frequent but mild adverse events
In the main studies comparing interferon-free DAAs combinations with or without ribavirin for 12 wk, adverse events (AEs) were significantly higher (about 10%) when ribavirin was included in the strategy: Particularly fatigue, insomnia, pruritus, cough and of course all grades of anemia but only 5% of grade 3 and 4. Treatment discontinuation due to AEs (4%) was slightly more frequent. However, these AEs were not significantly higher in compensated cirrhotic patients when a 12-wk regimen with ribavirin was compared to a 24-wk regimen without ribavirin[]. Erythropoietin (EPO) was not used except in advanced cirrhotic disease and reduction of ribavirin dosage (9%) was most of the time sufficient with no impact on SVR[].
Of course, these AEs were more tolerable than in regimens including interferon, and even more than in triple therapy with first generation protease inhibitors.
There is probably no more place for ribavirin dose adjustment during treatment with DAAs
In the NIAID SPARE trial, Rower et al[], showed that ribavirin-monophosphate concentrations in red blood cells at day 14 were related to anaemia and SVR. A therapeutic range was identified for ribavirin-monophosphate in persons with HCV G1 disease receiving 24 wk of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in this interferon-free regimen. However, Jacobson et al[] showed in cirrhotic G1 patients, that ribavirin dose reduction due to anemia in the triple Abbvie combination (10% of the cohort) did not impact the SVR. One may hypothesize that the monitoring of ribavirin dose in G1 patients will not be useful when using at least two very potent new DAAs, unlike what was observed with the association of peginterferon and ribavirin or sofosbuvir and ribavirin.


Preliminary data with second generation interferon-free DAAs combinations without ribavirin suggest that ribavirin future is jeopardized even in difficult-to-treat patients
New double combinations: Grazoprevir elbasvir without ribavirin for 12 wk is efficient in difficult-to-treat G1 and G4 patients. In a phase II study (C-Worthy), high SVR12 rates were achieved irrespective of the use of ribavirin or of the extension of treatment duration from 12 to 18 wk in two cohorts of G1 patients, i.e., cohort 1, naive cirrhotic patients and cohort 2 previous null responders with or without cirrhosis. The SVR rate without ribavirin was 97% and 91% in the two cohorts respectively[]. In the Edge study, considering G1 and 4 patients (35% cirrhosis), the association of grazoprevir elbasvir gave similar results with and without ribavirin for a 12- or 16-wk duration (92% to 97%). Interestingly however, SVR rates were higher for the 16 wk + ribavirin arm regardless the status of the patient, the presence of cirrhosis and the presence of NS5A mutation (97%)[] suggesting a small residual role of ribavirin. In a phase II preliminary study, the same combination without ribavirin was effective and well tolerated in G1 Child B-cirrhotic patients[] leading to a 90% SVR. The combination of grazoprevir and elbasvir was useless or suboptimal for G3 and G2 patients respectively even with the addition of ribavirin and G5 patients, interestingly, still needed ribavirin[,].
The sofosbuvir GS-5816 (pangenotypic NS5a inhibitor) combination without ribavirin was clearly efficient in G3 non cirrhotic patients (100% SVR) and more efficient than other previous combinations in experienced cirrhotic patients (88%). However in the latter case, the addition of ribavirin seemed to bring a mild benefit (96% of SVR)[].
Multiple DAAs combinations without ribavirin in difficult-to-treat patients: In G1 naive or pre-treated cirrhotic patients, the association of daclatasvir NS5A pangenotypic inhibitor, asunaprevir NS3 protease inhibitor and beclabuvir NS5B non nucleosidic polymerase inhibitor without ribavirin, gave high response rates in naive patients (93%). However, ribavirin could still be useful in pre-treated patients (93% vs 87% SVR with and without ribavirin, respectively)[].
In G3 cirrhotic patients, preliminary results showed that the association of grazoprevir elbasvir sofosbuvir without ribavirin gave a 91% SVR suggesting that this combination could be an ideal strategy for these difficult to treat population[]. Of course, these results have to be confirmed.
Renal insufficiency: It will be soon possible to avoid ribavirin
Ribavirin use is problematic in this setting due to the management of severe anemia and the delicate dose adjustment which is not standardized (200 mg × 3/wk to 200 mg/d) and requires ribavirin concentration measurement especially in hemodialysis.
Today, no DAA association is recommended in patients with estimated glomerular filtration rate < 30 mL/mn, especially because the key tool of the approved associations, sofosbuvir and its main metabolite are eliminated by the kidney and the appropriate dosing is not known. Preliminary studies however showed that the simeprevir sofosbuvir (200 mg/d) association without ribavirin gave a SVR rate of 88% to 100% with a quite good tolerance[,].
The paritaprevir/ritonavir ombitasvir dasabuvir combination was also very efficient (100% response) but G1a subtype still needed ribavirin[].
Finally, in the largest study so far, out of 226 G1 patients with severe renal insufficiency, 191 with chronic kidney disease stage 5 and 179 hemodialysed showed a 99% SVR when treated with grazoprevir elbasvir for 12 wk without ribavirin with an excellent tolerance[].
These encouraging results will probably lead us to treat hemodialysed patients if no transplant perspective is envisaged, or before kidney transplantation, as HCV negatively impacts these patients’ prognosis.


Even if new DAAs are cost-effective, at their current prices, they are not cost-saving, and the addition of ribavirin with approved DAAs interferon-free regimens is probably the best option to decrease treatment duration without impacting SVR. The next step of course is one pill of DAAs a day without ribavirin to treat all patients whatever the stage of the disease or the genotype, with no side effects and for the shortest treatment duration possible. Even if second generation drugs do not yet fulfil all the criteria and probably will not for the next 5 years, they dangerously jeopardize ribavirin future.


We thank Céline Rigaud for her help and Sarah Demai for her proofreading of English.


Conflict-of-interest statement: The authors have no conflict of interest concerning this work.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Peer-review started: September 5, 2015
First decision: October 16, 2015
Article in press: January 4, 2016
P- Reviewer: Mattner J, Rajeshwari K, Urganci N S- Editor: Qiu S L- Editor: A E- Editor: Liu SQ


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