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Alan Franciscus

Editor-in-Chief

HCV Advocate



Showing posts with label ribavirin. Show all posts
Showing posts with label ribavirin. Show all posts

Thursday, October 29, 2015

Gilead Submits New Drug Application to U.S. Food and Drug Administration for Fixed-Dose Combination of Sofosbuvir/Velpatasvir for Treatment of All Six Genotypes of Hepatitis C

FOSTER CITY, Calif.–(BUSINESS WIRE)–Gilead Sciences, Inc. (Nasdaq:GILD) today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for an investigational, once-daily fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF), approved as Sovaldi® in December 2013, and velpatasvir (VEL), an investigational pan-genotypic NS5A inhibitor, for the treatment of chronic genotype 1-6 hepatitis C virus (HCV) infection. The NDA is supported by clinical studies exploring the use of 12 weeks of SOF/VEL for patients with genotype 1-6 HCV infection, including patients with compensated cirrhosis and 12 weeks of SOF/VEL with ribavirin for patients with decompensated cirrhosis.

“As the first fixed-dose combination of two pan-genotypic, direct-acting antivirals, SOF/VEL represents an important step forward in the treatment of patients with hepatitis C,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. “Genotype 1 is the most prevalent form of HCV in the United States, but worldwide, more than half of people living with HCV are infected with other genotypes. SOF/VEL complements our current HCV portfolio of Sovaldi and Harvoni, offering high cure rates and the potential to simplify treatment and eliminate the need for HCV genotype testing.”

The FDA has assigned SOF/VEL a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. The NDA for SOF/VEL is supported by data from four Phase 3 ASTRAL trials, which evaluated the fixed-dose combination in hepatitis C genotypes 1-6. Of the 1,035 patients treated with SOF/VEL for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 percent) achieved the primary efficacy endpoint of SVR12. The ASTRAL-4 study randomized 267 patients with decompensated cirrhosis (Child-Pugh class B) to receive 12 weeks of SOF/VEL with or without ribavirin (RBV), or 24 weeks of SOF/VEL. Those who received SOF/VEL plus RBV for 12 weeks achieved an SVR12 rate of 94 percent,while those who received SOF/VEL for 12 weeks and 24 weeks achieved SVR12 rates of 83 percent and 86 percent, respectively.

Read more....

Tuesday, October 13, 2015

SNAPSHOTS —Alan Franciscus, Editor-in-Chief

This month’s (October 2015) column features a variety of studies, including treatment of people with advanced liver disease, treating people who have not achieved a cure with direct acting antiviral therapy, including people who had developed RAVs.

Article:  Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease—M Charlton et al. 

Source:  Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.

Results and Conclusions
This was a phase 2 study of 337 patients with decompensated cirrhosis with genotype 1 (332 patients) and genotype 4 (5 patients) who received 12 or 24 weeks of Harvoni plus ribavirin twice daily.  None of the patients previously treated developed resistance to sofosbuvir.  People who had been previously treated with an NS5A inhibitor were excluded from the study. 

There were two groups in the study:
  •  Group A, who had NOT had a liver transplant: 59 patients with Child-Pugh class B cirrhosis and 49 patients with Child-Pugh class C  cirrhosis*
  •  Group B who HAD undergone liver transplantation:  111 patients without cirrhosis, 51 patients with Child-Pugh class A cirrhosis, 52 with Child-Pugh class B cirrhosis, 9 with Child-Pugh class C cirrhosis, and 6 with fibrosing cholestatic hepatitis*

 *Child-Pugh cirrhosis scoring is a system that uses various types of blood markers and liver disease progression such as ascites to evaluate a patient to establish the severity of cirrhosis and long-term patient survival.  The classes are A, B and C with A as the less severe and C as the most severe.  Cholestatic hepatitis is bile duct blockage with fibrosis.

Group A and B had 12- and 24-week treatment arms, but cure rates were similar regardless of treatment duration.
     
 The Bottom Line
In group A (those who had not received a liver transplant), the cure rate was 86% to 89%.  In group B (transplant group) the people who did not have cirrhosis or Class A cirrhosis—the cure rate was 96% to 98%.  Furthermore, in group B with class B cirrhosis (compensated) the cure rate was 85% to 88%, and those with class C cirrhosis (moderate impairment) achieved 60% to 75% cure rates. The people who had fibrosing cholestatic hepatitis achieved 100% cure rates.  There were 13 patients (4%) who discontinued treatment.  Ten patients died in the trial.  The deaths were mainly attributed to complications from hepatic decompensation or end-stage liver disease.

Editorial Comment
In the past, people with these types of severe disease progression have been very difficult to cure or even treat, but now with these ‘miracle’ drugs many people now have a second chance at life.  Now if we could just get these drugs to everyone with hepatitis C before this stage, we would eliminate the need to treat at these stages of disease severity. 

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Article:  Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent—X Forns et al.

Source:  J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.

Results and Conclusions
There were 79 HCV genotype 1 patients in the study. 
  • Sixty-six patients who had been previously treated patients with an NS3/4A protease inhibitor but had not been cured. 
  • Of the 13 remaining patients, 12 had discontinued treatment due to side-effect(s). 
  • Thirty-four patients had NS3 resistance-associated variants (RAVs), and eight patients had NS5A RAVs. 
  • Eight patients treated with the combination of grazoprevir and elbasvir plus ribavirin twice daily.

 The Bottom Line
The overall cure rates were 96% (76 of 79 patients)—this included 93% (63 of 66 patients) of the genotype 1a, one hundred percent of the patients (43 of 43 patients) who DID NOT have RAVs achieved a cure.  Ninety-one percent of those who DID have NS3 RAV’s were cured and 75% (6 of 8 patients) of those who had NS5A RAVs were cured.  Of those with cirrhosis 94% were cured with this combination. 

Editorial Comment
The addition of ribavirin to grazoprevir and elbasvir works to help cure resistance-associated variants in people who have been previously treated but who have not been cured.  It is also good strategy to treat other negative predictors to current  medications.
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Article:  Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens—D Wyles et al.  

Source:  Hepatology. 2015 Jun;61(6):1793-7. doi: 10.1002/hep.27814. Epub 2015 Apr 27.

Results and Conclusions
There were 51 genotype 1 patients enrolled in the study (Note: one patient was incorrectly typed as genotype 1, but was subsequently correctly genotyped as genotype 3).  All of the patients in this trial were previously treated with a sofosbuvir containing regimes in Gilead’s phase 1 or phase 2 studies.  The treatment duration in this study was 12 weeks. 
Breaking it down by type of prior type of non-response:
  • 25 pts (49%) had previously received sofosbuvir plus pegylated interferon plus ribavirin
  • 20 pts (39%) had previously received sofosbuvir plus ribavirin
  • 5 pts (10%) received sofosbuvir (sugar pill/placebo) plus pegylated interferon and ribavirin
  • 1 pt (2%) received GS-0938 only fourteen patients (27%) had compensated cirrhosis.

 The Bottom Line
The total number of patients who achieved a cure was 98% (50 of 51 patients).  Among those who had received a prior course of sofosbuvir 98% (44 of 45) were cured.  The only patient who did not achieve a cure was the patient who was originally misdiagnosed as a genotype 1. 

The most common side effects were fatigue, headache and diarrhea.  The patients in this trial are considered some the most difficult to treat—those who have not achieved a cure with a previous course of a direct acting antiviral medication, those with cirrhosis, and people with resistant antiviral variants (RAVs). 

Editorial Comment
The addition of ledipasvir and ribavirin to sofosbuvir increased the cure rates to 100% for genotype 1.  Excellent results!  This is a good strategy with another type of direct acting antiviral to stop the virus from replicating and escaping.

Gilead, Merck, AbbVie, Janssen, and Achillion are working on other HCV drugs that have a higher barrier to resistance to avoid the development of resistance and to work for people who are not responding to the current medications.

Friday, October 9, 2015

What the Heck are RAVs? —Alan Franciscus, Editor-in-Chief

RAVs are resistance associated variants.  RAVs occur during (viral breakthrough) and after treatment (relapse) with direct acting antiviral medications (inhibitors—protease, polymerase, NS5A).  In other words, someone is treated and not cured.
 
This can lead to a particular class of drugs (protease, polymerase, NS5A inhibitors) not working as well because a person has developed drug resistance.
 
In clinical trials of the direct acting antiviral medications, approximately 1% to 7% of the trial participants were not cured.  In real world settings it is likely higher because of many issues such as missed doses, LIFE, and various health and other issues not addressed in clinical trials.  
 
In this month’s Snapshots, I wrote about a couple of studies that addressed re-treatment.  To overcome the RAVs and other negative predictors of treatment response (previous treatment non-response, cirrhosis, etc.,) ribavirin was added to both re-treatment groups.  As a result, 75%-100% of the patients were cured.  There are drugs being developed that have a high barrier to resistance that will replace ribavirin.  Thankfully we have ribavirin now to help people in need of re-treatment and cure and, importantly, to prevent further hepatitis C disease progression.
 
The approach to retreatment of RAVs is rapidly evolving.  Some physicians are beginning to test for RAVs, but it is far from being a routine test.  Talk with your medical provider if you have questions.

If you are being re-treated with a direct acting antiviral medication, it is important to find an expert to consult with about the best HCV treatment regime for you.  

Tuesday, October 6, 2015

U.S. FDA Grants Priority Review For Daklinza (daclatasvir) sNDA


Three applications are under review for Daklinzain combination with sofosbuvir with or without ribavirin to treat chronic hepatitis C patients with decompensated cirrhosis, post-liver transplant recurrence of HCV, and coinfection with HIV-1

Bristol-Myers Squibb’s U.S. registration focus for Daklinza is based on addressing the treatment needs of challenging HCV patient populations

October 06, 2015 07:00 AM Eastern Daylight Time

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the U.S. Food and Drug Administration (FDA) has accepted for filing and review three supplemental New Drug Applications (sNDAs) for Daklinza (daclatasvir), an NS5A replication complex inhibitor, for use with sofosbuvir with or without ribavirin. The applications are for the treatment of patients with chronic hepatitis C (HCV) coinfected with human immunodeficiency virus (HIV-1), patients with advanced cirrhosis (including decompensated cirrhosis), and for patients with post-liver transplant recurrence of HCV.

In the U.S., the FDA grants priority review status when an investigational medicine, if approved, would offer a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. The FDA will review the three Daklinza sNDAs within a six-month timeframe.

“Hepatitis C is not a one-size-fits-all, monolithic disease. Our focus for the Daklinza-sofosbuvir regimen centers on addressing the needs of HCV patient subpopulations who need new options even in light of the extraordinary advances that have occurred in HCV treatment,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “We look forward to working with the FDA toward the goal of eventually helping many difficult-to-treat HCV patients.”

Daklinza was initially approved in the U.S. in July 2015 and is indicated for use with sofosbuvir for the treatment of patients with chronic HCV genotype 3 infection. The new sNDAs accepted by the FDA for review include data from the ALLY-1 and ALLY-2 clinical trials. ALLY-2 evaluated the once-daily 12-week combination of Daklinza and sofosbuvir for the treatment of patients with HCV coinfected with HIV-1, a patient population that historically has been challenging to treat, in large part due to the complexities of the overlapping therapeutic regimens used to treat each infection. ALLY-1 evaluated a 12-week regimen of daclatasvir and sofosbuvir once-daily with ribavirin for the treatment of patients with HCV with either advanced cirrhosis or post-liver transplant recurrence of HCV.

In May 2015, Daklinza with sofosbuvir received FDA Breakthrough Therapy Designation for HCV genotype 1 patients with advanced cirrhosis (Child-Pugh Class B or C) and those who develop genotype 1 HCV recurrence post-liver transplant. Breakthrough Therapy Designation, according to the FDA, is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for this designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

About Bristol-Myers Squibb in HCV

Bristol-Myers Squibb’s research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio is Daklinza, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden.

In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic HCV. Since then, daclatasvir-based regimens have been approved in more than 50 countries, including the United States, across Europe, and in numerous other countries in Central and South America, the Middle East and the Asia-Pacific region.

Indication and Important Safety Information - Daklinza™ (daclatasvir)

INDICATION

Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.

Limitations of Use:

Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).

WARNINGS and PRECAUTIONS

-- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.

Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
Bradycardia generally resolved after discontinuation of HCV treatment.
Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.

ADVERSE REACTIONS

The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).

DRUG INTERACTIONS

CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.

Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.

Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.

Please click here for the Daklinza full prescribing information.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information please visit www.bms.com or follow us on Twitter at twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that Daklinza will be approved for the additional indication mentioned above. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contacts
Bristol-Myers Squibb Company
Media:
Robert Perry, 609-419-5378
cell: 407-492-4616
rob.perry@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bill Szablewski, 609-252-5894
william.szablewski@bms.com

Thursday, September 17, 2015

3-Drug Therapy Deemed Effective Hepatitis C Treatment

An investigational combination of 3 interferon-free drugs has proven effective at treating hepatitis C virus (HCV) in a recent trial. The study, published in the Journal of the American Medical Association, examined a 12-week dose of daclatasvir, asunaprevir, and beclabuvir in patients with HCV-related liver cirrhosis. None of the 3 medications has yet been approved for use in the United States, although daclatasvir is currently under review by the FDA.

The researchers found that the combination cleared HCV in 93% of trial participants who had not been previously treated, as well as in 87% of those with past failed therapies. However, the addition of a fourth drug, ribavirin, increased the cure rate of patients with past failed therapies to 93%, comparable to that of patients who were receiving treatment for the first time.

“The development of interferon-free treatments has been a tremendous step forward in the standard of care,” said lead author Andrew Muir, MD, MHS, in a press release. “These drugs are highly effective and well tolerated by patients at all stages of liver disease.”

Read more.....

Thursday, September 10, 2015

FDA Issues Pediatric Warning for Copegus


Copegus (ribavirin) tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

August 2015

WARNINGS AND PRECAUTIONS

Impact on Growth in Pediatric Patients
  • During combination therapy for up to 48 weeks with PEGASYS plus ribavirin, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve. The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients


ADVERSE REACTIONS

Growth Inhibition in Pediatric Subjects
  • Pediatric subjects treated with PEGASYS plus ribavirin combination therapy showed a delay in weight and height increases with up to 48 weeks of therapy compared with baseline. Both weight for age and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight (64th mean percentile at baseline, 60th mean percentile at 2 years post-treatment) and height (54th mean percentile at baseline, 56th mean percentile at 2 years post-treatment). At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve. Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years posttreatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.
Source:  http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218877.htm

Wednesday, March 18, 2015

Sustained virological response represents a long-term cure for people with hepatitis C treated with sofosbuvir

Almost all patients with hepatitis C virus (HCV) alone or HIV and HCV co-infection who achieved sustained virological response (SVR) to treatment with sofosbuvir (Sovaldi) plus ribavirin or sofosbuvir/ledipasvir (Harvoni) still had undetectable HCV RNA up to two years later, confirming that SVR represents a cure, according to a poster presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA.

The advent of interferon-free therapy using combinations of direct-acting antiviral drugs has brought about a revolution in hepatitis C treatment. Sustained virological response, or continued undetectable HCV RNA at 12 or 24 weeks post-treatment, is considered a cure, but rare cases of apparent late relapse have been observed after this point. (More often, HCV recurrence is due to reinfection.) 

While some studies have detected residual bits of HCV in the blood or the liver after successful treatment, this does not appear to indicate ongoing active disease. Interferon-based therapy has been shown to have a late relapse rate below 5% – usually occurring within two years after treatment – but this is not yet well defined for interferon-free therapy because it is so new.

Read more...

Wednesday, March 11, 2015

Gilead Sciences (NASDAQ:GILD) and AbbVie (NYSE:ABBV) Trying to Make the Most from Market Share

Gilead Sciences (NASDAQ:GILD) share prices are dropping as a result of the FDA giving the approval to AbbVie (NYSE:ABBV) of its hepatitis C drug, Viekira Pak. Through drastic price cuts, Gilead Sciences (NASDAQ:GILD) is facing a tough time trying to become market leader. Both companies have confirmed that the price reductions are so that they can attract more customers yet investors may not consider this a positive sign.
After Gilead Sciences (NASDAQ: GILD) launched Sovaldi, its drug for oral hepatitis C, it revolutionized the treatment. Before this, patients of hepatitis C had to be treatment with cures that had significant side effects like ribavirin and peg interferon that lasted nearly 48 weeks and had only 50%-80% cure rates.
However, Sovaldi’s treatment doesn’t eliminate ribavirin from the core, but it does put aside peg interferon and gives cure rates of 90%. This is why doctors embraced the drug with open arms and turned it into the quickest drug to achieve such successful levels of treatment. It made nearly $10.3 billion sales in the previous year. However, Gilead Sciences (NASDAQ: GILD) strengthened its drug back in October, when it won the approval by the FDA for its drug Harvoni.

Wednesday, March 4, 2015

Nursing Times-NHS-NICE gives backing to hepatitis C drug in latest draft guidance

“The marketing authorisation for ledipasvir-sofosbuvir recommends treatment for hepatitis C genotypes 1, 3 – in combination with ribavirin – and 4”.

“Genotypes 1 and 3 hepatitis C account for the majority of chronic hepatitis C cases in England (46% and 43%, respectively). Genotype 4 hepatitis C accounts for around 4% of cases”.

“Ledipasvir-sofosbuvir, manufactured by Gilead, is administered orally as a single tablet – with or without ribavirin – and works by inhibiting the replication of the hepatitis C virus. It prevents hepatitis C virus replication by inhibiting the NS5A and NS5B proteins”.