Ribavirin Steady-State Plasma Level Is a Predictor of Sustained Virological Response in Hepatitis C-Infected Patients Treated With Direct-Acting Antivirals

Aliment Pharmacol Ther. 2017 Sep 07.

Ribavirin Steady-State Plasma Level Is a Predictor of Sustained Virological Response in Hepatitis C-Infected Patients Treated With Direct-Acting Antivirals

M. van Tilborg, F. I. Lieveld, E. J. Smolders, K. J. van Erpecum, C. T. M. M. de Kanter, R. Maan, M. van der Valk, J. E. Arends, A. S. M. Dofferhoff, H. Blokzijl, M. Bijmolen, J. P. H. Drenth, R. J. de Knegt, D. M. Burger, on behalf of the HepNed Study Group M van Tilborg et al.

DOI: 10.1111/apt.14288

Summary
Background: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients.

Aim: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR).

Methods: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses.

Results: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL).

Conclusion: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

DISCUSSION ONLY

Full Text Available Online

In this prospective study, the influence of RBV steady-state plasma level on achieving SVR in HCV-infected patients treated with the combination of DAAs and RBV was determined. The main finding of this study is that a higher RBV steady-state plasma level is an independent predictor of achieving SVR. In addition, the optimal RBV steady-state plasma level therapeutic range that balances SVR with risk of anaemia was found to be 2.28-3.61 mg/L.

Despite the great successes of DAAs, some patients remain difficult-to-cure.[29] Adding RBV to DAAs in these patients can increase SVR rates.[8, 30] Studies in the interferon era established that higher RBV steady-state plasma levels were positively correlated with SVR.[12, 23, 31, 32] We similarly found that higher RBV steady-state plasma levels led to a 1.8-fold increase in SVR in DAA-treated patients. This demonstrates that higher RBV plasma levels are effective to improve response rates, particularly in difficult-to-cure patients with a lower a priori chance of achieving SVR. Possibly, therapeutic drug monitoring can help achieving these high RBV plasma levels.

A recent study including patients treated with sofosbuvir/RBV found no association between RBV steady-state plasma levels and SVR.[13] However, this study had a small sample size of 47 treatment naive, predominantly genotype 1-infected, noncirrhotic patients and retrospectively analysed RBV plasma samples. Moreover, SVR rates were low (55%), probably because sofosbuvir/RBV is a suboptimal treatment for genotype 1,[17, 18] and these results should, therefore, be carefully interpreted. Our study, however, represents a large real-world cohort of mainly difficult-to-cure patients on various DAA combinations with prospectively analysed plasma samples and SVR rates similar to clinical trials and real-world cohorts.[17, 18]

In case the addition of RBV is considered beneficial and is administered, it is important to balance efficacy and side effects. Although side effects of RBV in combination with DAAs are generally considered very mild, almost one in five of our patients developed significant anaemia. This study found an optimal RBV steady-state plasma level therapeutic range of 2.28-3.61 mg/L. Interestingly, this study as well as studies with triple-therapy including a first-generation DAA[32, 33] found somewhat higher therapeutic ranges compared with studies done with PEG-IFN/RBV alone.[23, 34, 35] The most likely explanation for this is that PEG-IFN contributes to anaemia through bone marrow suppression and as such augments the toxicity of RBV at any given dose/concentration. Another explanation for this could be that with the excellent safety profile of DAAs, sicker patients than those in the PEG-IFN/RBV era can now be treated.[36] A significant proportion of our patients had (decompensated) cirrhosis, were liver transplant recipients and/or had renal impairment, which could result in higher RBV levels. Finally, to significantly increase the likelihood of achieving SVR in the context of the already highly effective DAAs, a more pronounced increase in RBV exposure is necessary.

Still, the question remains if and how RBV therapeutic drug monitoring should be implemented in the treatment of patients without difficult-to-cure characteristics. With current DAA regimens lasting only 12 weeks,[17, 18] when reaching RBV steady-state plasma level, only 4 weeks of treatment are left to adjust RBV dosage. Thus, for most patients, RBV exposure could perhaps best be monitored based on toxicity instead of RBV steady-state plasma levels. However, retreatment of patients who fail therapy is considerably more expensive than therapeutic drug monitoring, and reaching adequate RBV plasma levels is not a certainty when relying on toxicity alone. Comorbidities, hepatic and/or renal dysfunction and ITPA gene polymorphism[37, 38] can affect RBV pharmacokinetics and thus RBV steady-state plasma levels without evident toxicity.[39] For example, if a patient has a stable haemoglobin level, it is uncertain whether RBV steady-state plasma level will be in or below the therapeutic range. Assessment of RBV plasma level at week 8 of treatment (RBV steady-state plasma level) may be too late for intervention. An option for therapeutic drug monitoring and intervention at an earlier stage is measuring RBV plasma levels at treatment week 2. Van Vlerken et al reported that a week 2 RBV level of ≥1.29 mg/L predicted adequate RBV steady-state plasma levels at week 8 in patients treated with PEG-IFN/RBV.[23] Future studies are needed to determine if this also applies to patients treated with DAAs.

Especially in patients with impaired renal function, therapeutic drug monitoring is important. This study found that despite the Food and Drug Administration and European Medicines Agency recommending RBV dose reduction in patients with eGFR <50 mL/min,[40, 41] they still received usual weight-based start dosages. As a result, these patients required more dose adjustments, resulting in lower average RBV doses, but still higher RBV steady-state plasma levels and high anaemia rates. This study indicates that patients with a renal function <90 mL/min (especially those ≤50 mL/min) should be monitored closely during treatment, so that RBV can be timely adjusted when necessary.

To the best of our knowledge, this is the largest prospective study analysing the association between RBV steady-state plasma level and SVR in the current DAA era. Nevertheless, some limitations are present. First, all four participating centres used different assays to measure plasma RBV. However, we expect the influence of the different assays to be very limited, since all assays are validated according to international standards and have undergone strict evaluation and comparison in the Dutch quality control programme. In addition, logistic regression analyses did not show a centre effect. Second, due to the real-life nature of the study, RBV dose adjustment and selection of DAA regimen were at the discretion of the treating physician, thus leading to variation. Nonetheless, DAA regimens were selected according to international and national guidelines. In hindsight, while previously recommended by guidelines,[42] sofosbuvir/RBV is now considered a suboptimal treatment for genotype 3 patients with cirrhosis, which has led to a high proportion of relapsers within this population. Therefore, DAA regimen and HCV genotype were excluded in our logistic regression model. However, even in sensitivity analyses where DAA regimen, HCV genotype (as a combined variable or as separate variables) or both variables were added to the model, RBV steady-state plasma level still remained an independent predictor of SVR. For dose adjustments and other factors that could have influenced RBV exposure, we tried to account by adjusting for average RBV dose during the entire treatment, presence of cirrhosis and creatinine levels in our logistic regression models. Lastly, influence of ITPA gene polymorphism was not assessed.

In conclusion, a higher RBV steady-state plasma level is an independent predictor of SVR in patients treated with DAAs.

Full Text

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Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES

A. A. Butt^1,2,3,*, P. Yan¹, K. Marks³, O. S. Shaikh^1,4, K. E. Sherman⁵

Version of Record online: 26 JUL 2016

DOI: 10.1111/apt.13748

Background

Ribavirin is a key component of several hepatitis C virus (HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear.

Aim
To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens.

Methods
We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA.

Results
We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group.

Conclusions
In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established.

Discussion Only

Full Text Article Available @ Alimentary Pharmacology & Therapeutics

In this large national observational study of HCV infected persons in actual clinical settings, ribavirin use was not associated with any clinically meaningful differences in SVR rates among patients treated with newer DAA regimens. Presence of cirrhosis at baseline, HCV subtype and prior treatment status did not affect these results. Number of HCV genotype 1a infected persons treated with PrOD (without ribavirin) was too small to make any conclusions in this group (n = 6).

Our study demonstrates that treatment for HCV infection with newer oral regimens is associated with high SVR rates in actual clinical settings, and that these rates are comparable to those seen in clinical trials.[23] We have previously shown that treatment with sofosbuvir-based regimens in actual clinical settings is associated with SVR rates similar to clinical trials,[8] and this study provides similar assurance with PrOD regimen in similar settings. To our knowledge, this is among the first and largest study with data from actual clinical settings, that compares the three commonly used newer DAA agents.

Ribavirin was considered an important part of the treatment regimen with pegylated interferon and first generation DAAs. However, its role in all-oral regimens of newer DAAs is less clear. In one recent trial, virological failure was more common without ribavirin than with ribavirin among HCV genotype 1a infected patients but not among those with genotype 1b infection.[10] In another trial, ledipasvir + sofosbuvir + ribavirin for 12 weeks and ledipasvir + sofosbuvir without ribavirin for 24 weeks provided similar SVR12 rates in previous nonresponders with HCV genotype 1 and compensated cirrhosis.[24] Use of ribavirin is associated with significant haematological toxicity and drug–drug interactions, and it is a highly teratogenic agent.[25, 26] In a recent analysis of 1952 patients enrolled in phase III ION clinical trials, treatment-related adverse events were observed in 71% of patients treated with RBV, but in only 45% of patients treated without RBV.[26] While most adverse events were mild in severity and not associated with treatment discontinuation, there is some cost and risk to adding ribavirin to the regimen. Regimens without ribavirin are attractive in such settings.

The strongest and most consistent predictor of achieving SVR was duration of treatment. This is not surprising, and is consistent with numerous previous studies which have assessed patients treated in actual clinical settings.[8, 9] Future studies should assess the role of treatment adherence upon virological outcomes in these patients. Presence of cirrhosis at baseline was associated with a numerically large reduction in SVR rates (37% lower SVR rates for PrOD, 44% for sofosbuvir/simeprevir, 53% for sofosbuvir/ledipasvir), though this did not reach statistical significance in the PrOD group.

The newer treatment regimens remain associated with a low rate of adverse haematological adverse events.[27] Although anaemia was more common in those who received ribavirin, severe (grade 3/4) anaemia remains uncommon overall. In previous studies, we have shown that haematological parameters revert towards baseline after completion of treatment, providing some reassurance regarding the safety of these regimens.[9]

While our study provides new and important clinical information about newer DAA regimens derived from a well-established national database, there are certain limitations that need to be addressed when analysing administrative databases. The information in such databases is collected as part of routine clinical care, and is thus not always collected at rigorously defined time-points during the course of treatment. Given this is an observational study and not a randomized study of ribavirin use, confounding by indication is of concern. Persons who received ribavirin may have been harder to treat; however, in multivariate analysis controlling for these baseline predictors did not reveal a benefit of ribavirin use. Laboratory testing was performed at different laboratories, and subtle differences in results may affect overall results. Definition of cirrhosis was based on a non-invasive clinical marker (FIB-4 score), which was based on routine laboratory testing which may have been performed at different time-points prior to baseline. Number of persons in HCV genotype 1a PrOD group was too small (n = 6) to make any conclusions, and clinical trials data suggest that adding ribavirin in genotype 1a patients may be of some benefit.[10] We also did not analyse the role of resistance associated mutations upon virological response rates.

In conclusion, in HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens are associated with high rates of SVR in actual clinical settings, which are comparable to those achieved in clinical trials (except PrOD genotype 1a with cirrhosis where number was too small). Addition of ribavirin to the regimen does not appear to enhance SVR rates in a clinically meaningful way, with the caveat that the number of persons in HCV genotype 1a PrOD group was too small to make any conclusions.

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1. Summary
2. Introduction
3. Methods
4. Results
5. Discussion
6. Authorship
7. Acknowledgements
8. References
9. Supporting Information
   
   

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 ►

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Abstract

Before the advent of direct acting antiviral agents (DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-to-treat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs.

Keywords: Ribavirin, Hepatitis C, Peginterferon, Direct acting antiviral agents

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.

INTRODUCTION

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[1]. This combination is still relevant in many parts of the world which do not have access to new therapies because of cost issues[2]. 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.

RIBAVIRIN: MECHANISMS OF ACTION

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[3]. 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[4]. 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[5]. However, the mutagenesis hypothesis remains controversial[6]. 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[7].

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[8] 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[9]. 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[10]. 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.

PAST OF RIBAVIRIN: COMBINATION THERAPY PEGINTERFERON AND RIBAVIRIN

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[11,12]. Di Bisceglie et al[13] first showed that ribavirin could double the efficiency of standard alfa interferon. A similar synergy was observed with the association of peginterferon and ribavirin[14,15], ribavirin impacting favourably the number of relapses and breakthroughs[16]. 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)[14,17] and ribavirin had to be administered for the total duration of treatment[16]. A pilot study also showed, that the use of high doses of ribavirin early during treatment led to high sustained virological rates[18]. The same team proposed to optimize the dose of ribavirin using a formula based on renal function and body weight[19].

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[20]. The monitoring of ribavirin plasma concentrations during double therapy initially used trough concentrations at week 4 and week 8 of treatment[21,22]. However, trough concentrations had a lower influence than the genotype and the viral load on SVR[21].

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[23]. 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[24], 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[14,15] 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[25,26] but did not prove its impact on SVR.

PRESENT OF RIBAVIRIN: TREATMENT WITH NEW DAAS

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[27] except for cirrhotic experienced-patients (24 wk)[28]. In this particular population, the only way to reduce treatment duration to 12 wk with similar SVR (95% to 100%) is to add peginterferon[29,30].

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[27]. 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[30]. Another strategy using sofosbuvir daclatasvir without ribavirin for 12 wk in G3 cirrhotic patients led to a weak 63% rate of SVR[31]. 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[32]. 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[33].

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[34]. Moreover, considering treatment-experienced cirrhotic patients with subtype 1a infection a 24 wk-treatment duration with ribavirin was needed[35].

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[36], 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%)[37] 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[37] 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[38], 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[39].

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[40,41]. 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[42].

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[43]. 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[44].

Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful

In Reddy’s study[37], 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[36]. 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[45].

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[46], 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[45] 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.

FUTURE

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[29]. 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%)[47] 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[48] 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[49,50].

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)[51].

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)[52].

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[33]. 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[53,54].

The paritaprevir/ritonavir ombitasvir dasabuvir combination was also very efficient (100% response) but G1a subtype still needed ribavirin[55].

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[56].

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.

CONCLUSION

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.

ACKNOWLEDGMENTS

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

Footnotes

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: http://creativecommons.org/licenses/by-nc/4.0/

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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