Showing posts with label geno5. Show all posts
Showing posts with label geno5. Show all posts

Monday, May 14, 2018

Elbasvir and grazoprevir with or without ribavirin, treatment–naive participants HCV genotype 2, 4, 5 or 6

Patients with non-genotype 1 HCV infection differ with regard to response to DAAs. This study evaluated the efficacy and safety of EBR/GZR, with or without RBV, in HCV genotype 2, 4, 5, or 6 infection.

A. Brown C. Hézode E. Zuckerman G. R. Foster A. Zekry S. K. Roberts F. Lahser C. Durkan C. Badshah B. Zhang M. Robertson J. Wahl E. Barr B. Haber on behalf of the C‐SCAPE Study Investigators

J Viral Hepat. 2018;25(5):457-464. 

Introduction
People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group of individuals who differ with regard to their profile of response to all–oral, direct–acting antiviral regimens.[1,2] The recent approval of sofosbuvir/velpatasvir for people infected with HCV genotypes 1–6 now provides a single treatment option across genotypes. However, prior to the introduction of sofosbuvir/velpatasvir, treatment recommendations for genotype 2, 3, 5 and 6 were based on small studies with limited numbers of participants, or on subgroup analyses where small numbers of participants were enrolled alongside participants with genotype 1 or 4 infection.

The fixed–dose combination of elbasvir (EBR, MK–8742), an NS5A inhibitor, and grazoprevir (GZR, MK–5172), an NS3/4A protease inhibitor, is approved in the US, Europe and Canada as a treatment for HCV genotype 1 and 4 infection.[12] In those with HCV genotype 1 or 4 infection, EBR/GZR has shown efficacy in the subpopulations of treatment–naive people,[13] HIV/HCV co–infected people,[14] people who have previously failed treatment[15,16] and people with chronic kidney disease.[17] In vitro, EBR and GZR have shown pangenotypic potency in HCV replicons;[18,19] however, less has been reported about the clinical efficacy and safety of EBR/GZR in people with HCV nongenotype 1/4 infection. The phase 2 C–SCAPE study evaluated the efficacy and safety of EBR/GZR, with or without ribavirin (RBV), in treatment–naive participants with HCV genotype 2, 4, 5 or 6 infection...

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Wednesday, May 9, 2018

HCV genotype 4, 5 and 6 Cure Rates In Clinical Trials

In Case You Missed It

Journal of Viral Hepatitis
First published: 8 May 2018

HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct‐acting antiviral regimens
S. D. Boyd P. Harrington T. E. Komatsu L. K. Naeger K. Chan‐Tack J. Murray D. Birnkrant K. Struble

First published: 25 March 2018 https://doi.org/10.1111/jvh.12896

Full-Text Article
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Summary
Multiple direct‐acting antiviral (DAA)‐based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post‐treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Discussion
The recent FDA approvals of various IFN‐free DAA regimens provide highly effective treatment options for HCV GT 4, 5 or 6 infection. Individual registrational trials generally demonstrated high SVR12 rates in these populations, with virologic failure occurring in a small proportion of patients. To conduct a more comprehensive analysis of HCV GT 4, 5 and 6 patient populations in HCV DAA clinical trials, including treatment outcomes and viral subtypes represented, we conducted independent analyses of 18 registrational trials submitted to FDA from 2014 to 2017 in new drug applications (NDAs) for elbasvir/grazoprevir, glecaprevir/pibrentasvir, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

The analysis population comprises a substantially larger data set compared to individual clinical development programs for GT 4, 5 and 6 and allows for several observations. First, the combined clinical trial data in this analysis confirm that approved regimens for GT 4, 5 and 6 are all highly efficacious, with SVR12 rates similar to GT1. Overall, only a few participants did not achieve SVR12 with one of the FDA‐approved DAA regimens. No trends emerged associating virologic failure with baseline viral load, cirrhosis or prior treatment experience. Although limited sample sizes prevented statistical cross‐regimen comparisons, no clear differences in treatment efficacy emerged between any regimen with a reasonable sample size, and the few occurrences of virologic failure were distributed across different regimens.

A second observation is that the SVR12 rates for the most prevalent GT4 and GT6 subtypes either exceeded or corresponded with the SVR12 rates overall for these GTs. While the SVR12 rate for non‐4a, non‐4d GT4 subtypes was numerically lower, virologic failures in this group occurred only among participants with one of two uncommon subtypes, 4b and 4r. Extensive HCV genetic variability exists at multiple key NS5A resistance‐associated amino acid positions, both across and within different HCV subtypes.40 Recent studies have shown that reduced susceptibility to ledipasvir for some GT 4b and 4r isolates is associated with the presence of NS5A resistance‐associated substitutions, which may explain occurrences of ledipasvir/sofosbuvir virologic failure among patients with these subtypes.21, 41 Nevertheless, more data are needed with various NS5A inhibitor‐containing regimens before we can draw firm conclusions about the impact of NS5A genetic variability on treatment outcomes for patients with GT 4b, 4r and other less common subtypes. Importantly, the combined SVR12 rate for non‐4a, non‐4d GT4 subtypes across clinical trials still exceeded 90%. Because SVR12 rates were 100% for the most common GT6 subtypes, and only one participant with GT6 infection did not achieve SVR12, we cannot speculate on whether any of the less common GT6 subtypes may have a different response rate.

A third observation is our analysis confirms that the most common subtypes for GT4 and GT6 represented in clinical trials are consistent with previously published reports of subtype distribution in the United States, Europe and regions where these GTs are highly prevalent.40, 42, 43 For example, subtype 4a was not only the most common GT4 subtype in clinical trials that largely recruited participants located in the United States and Europe but is also the most common subtype in geographic areas with a high prevalence of GT4, such as Egypt.40, 42 Possibly, GT4 participants migrated from geographic areas where this genotype is highly prevalent, but specific demographic data such as geographic location of initial infection or country of origin usually were not available. Similarly, the two most common GT6 subtypes 6a and 6e observed in clinical trials are similar to previous reports.40

One limitation of our clinical trial analyses is the number of participants with uncommon subtypes was either low or not represented. This limitation makes it difficult to understand if treatment efficacy truly varies for certain infrequent subtypes and if baseline factors such as baseline viral load, presence of cirrhosis, HCV treatment history, or presence of baseline resistance‐associated substitutions affect response rates among different subtypes. However, we find the results reassuring because the SVR12 rates were close to 100% for the most common subtypes, and the overall SVR12 rates were high in the combined populations. Another limitation is that certain parts of the world (eg Sub‐Saharan Africa) are not well represented in clinical trials, and GT 4, 5 or 6 subtypes or other viral genetic characteristics may differ in these underrepresented regions.

This compilation of data from participants with HCV GT 4, 5 or 6 provides the largest pool of clinical trial data for FDA‐approved DAA regimens for these less common GTs. Combined clinical trial data enhance descriptive subgroup analysis such as frequency of viral subtypes and confirms high SVR12 or low virologic failure rates across FDA‐approved regimens. The geographic distribution of viral subtypes in our clinical trial database is consistent with the existing information on the general prevalence of these subtypes.

Overall, the data presented provide comprehensive information about efficacy including SVR and virologic failure rates. These analyses may be useful for clinicians treating patients with HCV GT 4, 5 or 6.

Tuesday, September 26, 2017

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret
Asselah T, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.09.027.
September 26, 2017
Most patients with hepatitis C genotype 2, 4, 5 or 6 who received Mavyret for 8 weeks achieved sustained virologic response with a high safety profile, according to results from three phase 3 studies. The rate of virologic failure was less than 1%.

Friday, August 18, 2017

Hepatitis C - Newly Approved Mavyret Has High Response Rates

The Lancet
Download Full Text Article - PDF provided by Henry E. Chang‏ via Twitter:

Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial
Xavier Forns, Samuel S Lee, Joaquin Valdes, Sabela Lens, Reem Ghalib, Humberto Aguilar, Franco Felizarta, Tarek Hassanein, Holger Hinrichsen, Diego Rincon, Rosa Morillas, Stefan Zeuzem, Yves Horsmans, David R Nelson, Yao Yu, Preethi Krishnan, Chih-Wei Lin, Jens J Kort, Federico J Mensa

Summary Background
The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis......
Continue reading....

The Lancet
Download Full Text Article - PDF provided by Henry E. Chang‏ via Twitter:

Comment 
New anti-HCV drug combinations: who will benefit?
Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/S1473-3099(17)30486-3
In The Lancet Infectious Diseases1 Xavier Forns and colleagues present the results of a phase 3 trial assessing the efficacy and safety of 12 weeks of treatment with glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) in patients with chronic hepatitis C virus (HCV) genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Of 146 enrolled patients, 145 (99%, 95% CI 98–100) achieved a sustained virological response. The study did not include patients with decompensated cirrhosis; the same is true for studies of sofosbuvir, velpatasvir, and voxilaprevir.2....
Continue reading......

Newly Approved Hepatitis C Drug Has High Response Rates
By Amy Orciari Herman
Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Nearly all patients with chronic hepatitis C virus (HCV) infection treated with glecaprevir-pibrentasvir achieved sustained virologic response after 12 weeks of therapy, according to results of an industry-funded, phase 3 trial in the Lancet Infectious Diseases. The once-daily combination drug (brand name, Mavyret) was approved by the FDA earlier this month to treat all HCV genotypes.

The trial enrolled 146 adults with HCV genotype 1a, 1b, 2, 4, 5, or 6 and compensated cirrhosis who either had not been previously treated, or had not responded to interferon-based treatment or to treatment with sofosbuvir plus ribavirin (with or without pegylated interferon). At 12 weeks after treatment ended, all but one patient had sustained virologic response. A patient with HCV genotype 1a and a history of treatment with pegylated interferon plus ribavirin relapsed at week 8.

Nearly 70% of patients had adverse events, most of which were mild (e.g., fatigue). No serious events were related to the study drug.

Link(s):
The Lancet
Lancet Infectious Diseases article (Free abstract)
Lancet Infectious Diseases comment (Subscription required)
Background: Physician's First Watch coverage of glecaprevir-pibrentasvir (Free)
Source-

Tuesday, May 23, 2017

Updated - HCV Guidance website

In Case You Missed It
Updated Thursday, April 27, 2017



Guidelines
HCV Guidelines
The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) with the International Antiviral Society developed a living document with ever evolving guidelines to treat HCV.
Homepage - HCV Guidelines

Stay current with all guideline updates, click here.

What’s New and Updates/Changes
This version of the Guidance has been updated to reflect several key developments as indicated below. Updated references have been provided throughout the Guidance.

Global Changes Occurring throughout the document:
  • RAV changed to RAS
  • Standardized renal function parameter from CrCI to eGFR
     
Initial Treatment:
Retreatment:
Decompensated:
Renal:
Upcoming Updates:
  • Guidance will be forthcoming regarding treatment of adolescents living with chronic HCV given recent FDA-approvals

Sunday, November 13, 2016

AASLD 2016 Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis

Nov 13
Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis
By Debra Hughes, MS
Patients with chronic hepatitis C virus (HCV) genotypes (GT) 2, 4, 5, or 6 infection without cirrhosis had SVR12 rates of 97% after 8 weeks of treatment with co-formulated glecaprevir/pibrentasvir, investigators from the SURVEYOR-II, Part 4, concluded at The Liver Meeting® 2016.​

Press Release
Nov 11
Update AbbVie's Glecaprevir/Pibrentasvir (G/P) Acheive High SVR12 Rates at 8 Wks Genotypes 1-6
- 97.5 percent of chronic HCV infected patients without cirrhosis and new to treatment across all major genotypes (GT1-6) achieved SVR12 with 8 weeks of G/P
- Across the 8-week arms of three registrational studies, no patients discontinued treatment due to adverse events
- G/P is an investigational, pan-genotypic, once-daily, ribavirin-free regimen for the treatment of chronic HCV

Additional updates @ MPR
Current updates: Conference Reports
Updates On This Blog: AASLD 2016

Saturday, January 16, 2016

HCV NEXT January Issue - 2015: The Good The Bad The Ugly

Responsive to Treatment Elusive to Detection: 
HCV Genotypes 5 and 6

"HCV Next" offers information on a range of topics, which include diagnosis, new combination therapies, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.

The following articles appeared in the January print edition of HCV NEXT, provided online at Healio.

EDITORIAL
Looking Back, Looking Ahead at Treatment Developments
2015: The Good The Bad The Ugly
HCV Next, January 2016

After 2014, a year of first implementations of direct-acting antiviral therapies, 2015 brought even more changes and challenges in hepatitis C virus research, diagnosis, treatment and access.

We saw much good: approvals in difficult-to-treat genotypes, breakthrough designations for soon-to-come drugs that hold promise for underserved populations and a successful continuous updating of the HCV guidelines document jointly maintained by the AASLD and IDSA.

Yet there was the bad: real-world experiences with rapidly approved drugs proven to produce drug-drug interactions and unforeseen toxicities.

And the ugly seems to be getting uglier, with ongoing denials of treatment for patients who have not yet progressed in severity of their disease.

Please see my Looking Back, Looking Ahead article for a more detailed breakdown on what 2015 brought to our community and what I foresee in the coming year.

— Michael S. Saag, MD
Co-Chief Medical Editor
HCV Next

Table of Contents

MEETING NEWS COVERAGE

SPECIAL SERIES

THE BIG PICTURE

TREND WATCH


Thursday, November 12, 2015

FDA Approves New Indications for Harvoni®, Gilead's Once-Daily Single Tablet Regimen for Chronic Hepatitis C

U.S. FDA Approves New Indications for Harvoni®, Gilead's Once-Daily Single Tablet Regimen for Chronic Hepatitis C

Date(s): 12-Nov-2015 5:54 PM

For a complete listing of our news releases, please click here

- Label Expanded to Include Patients with Genotypes 4, 5 and 6 and Patients Co-Infected with HIV -

- Use of Harvoni in Combination with Ribavirin for 12 Weeks Can be Considered for Treatment-Experienced Genotype 1 Patients with Cirrhosis -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Nov. 12, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Harvoni® (ledipasvir/sofosbuvir) for expanded use in patients with genotype 4, 5 and 6 chronic hepatitis C virus (HCV) infection and in patients co-infected with HIV. In addition, Harvoni plus ribavirin (RBV) for 12 weeks was approved as an alternate therapy to 24 weeks of Harvoni for treatment-experienced, genotype 1 patients with cirrhosis. Harvoni received regulatory approval for the treatment of chronic HCV genotype 1 infection in adults in the United States in October 2014.

"Harvoni - the first and only single-tablet regimen for the treatment of HCV - continues to demonstrate high cure rates and a tolerable side effect profile across a range of patient populations, including those who have historically been considered among the most difficult to cure," said Norbert Bischofberger, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. "We are pleased that the Harvoni label and prescribing information now includes guidance for health care providers on its use in these important HCV patient populations."

Genotypes 4, 5 and 6

The supplemental new drug application (sNDA) approval for HCV genotypes 4-6 was supported by data from the open-label trials 1119 and ELECTRON-2. Study 1119 evaluated Harvoni for 12 weeks in patients with HCV genotype 4 or 5 who were treatment-naïve and treatment-experienced with or without cirrhosis. Results showed that 93 percent (41/44) of those with genotype 4 and 93 percent (38/41) of those with genotype 5 achieved SVR12. ELECTRON-2 evaluated Harvoni for 12 weeks in treatment-naïve or previously-treated patients with genotype 6 HCV infection with or without cirrhosis. In this study, 96 percent (24/25) of patients achieved SVR12.

The most common adverse events (in at least 10 percent of subjects) were asthenia (18 percent), headache (14 percent) and fatigue (10 percent).

Patients Co-Infected with HIV

Patients with HCV/HIV co-infection represent approximately 30 percent of the total HIV-infected population in the United States. Compared with HCV infection alone, HIV/HCV co-infection is associated with an increased risk of cirrhosis and the subsequent complications of end-stage liver disease and hepatocellular carcinoma (liver cancer).

The sNDA approval for patients with HCV/HIV-1 co-infection was supported by data from the Phase 3 open-label ION-4 study, which evaluated Harvoni for 12 weeks for the treatment of genotypes 1 or 4 chronic HCV infection among patients co-infected with HIV. Data demonstrate that 96 percent (321/335) of patients achieved SVR12. The study included HCV treatment-naïve (45 percent) and treatment-experienced (55 percent) patients, including patients with compensated cirrhosis (20 percent). The majority of patients were taking one of three HIV antiretroviral (ARV) regimens: tenofovir disoproxil fumarate (TDF) and emtricitabine with efavirenz (Atripla®), raltegravir or rilpivirine (Complera®).

The most common adverse events (in at least 10 percent of subjects) were headache (20 percent) and fatigue (17 percent).

Treatment-Experienced Patients with Cirrhosis

The sNDA approval of Harvoni with RBV for 12 weeks for genotype 1 treatment-experienced HCV patients with cirrhosis was supported by data from the Phase 2 SIRIUS study, which evaluated Harvoni plus RBV for 12 weeks or Harvoni without RBV for 24 weeks in genotype 1 HCV-infected patients with compensated cirrhosis who failed prior therapy. Ninety six percent (74/77) of patients treated with Harvoni plus RBV for 12 weeks, and 97 percent (75/77) of patients treated with Harvoni for 24 weeks without RBV, achieved SVR12.

The most common adverse reactions (occurring in at least 10 percent of subjects) among patients receiving Harvoni plus RBV for 12 weeks were asthenia (36 percent), headache (13 percent) and cough (11 percent). In patients receiving Harvoni for 24 weeks, these were asthenia (31 percent), headache (29 percent) and fatigue (18 percent).

The European Medicines Agency also recently approved updates to the Harvoni label to allow for the use of shorter durations of therapy with Harvoni in combination with RBV. Specifically, these include the use of Harvoni plus RBV for 12 weeks in genotypes 1 and 4 HCV-infected patients with compensated cirrhosis, decompensated cirrhosis and post-liver transplant patients. The new label also includes data further supporting use of Harvoni for 12 weeks in patients with genotypes 1 or 4 who are co-infected with HIV and in patients who had previously failed treatment with sofosbuvir plus RBV with or without pegylated interferon.

Important Safety Information for Harvoni

Contraindications

If Harvoni is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions

Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Harvoni due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John's wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (=10%, all grades) adverse reactions were fatigue, headache and asthenia.

Drug Interactions

In addition to rifampin and St. John's wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that physicians may not see the benefits of prescribing Harvoni. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full Prescribing Information for Harvoni is available at www.gilead.com.

US full Prescribing Information for Atripla and Complera, including BOXED WARNING for both products, are also available at www.gilead.com.

Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

Complera, Sovaldi and Harvoni are registered trademarks of Gilead Sciences, Inc. or its related companies.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

View source version on businesswire.com: http://www.businesswire.com/news/home/20151112006728/en/

Source: Gilead Sciences, Inc.
Gilead Sciences, Inc.
Patrick O'Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

Saturday, April 25, 2015

Geno 2-5: Gilead Results of Sofosbuvir-Based Regimens in Chronic Hepatitis C Patients

Gilead Announces Results From Studies Evaluating Sofosbuvir-Based Regimens in Chronic Hepatitis C Patients With Genotypes 2-5

-- High Cure Rates Observed Across a Range of Genotypes --

VIENNA, Austria--(BUSINESS WIRE)--Apr. 25, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from two studies evaluating the safety and efficacy of investigational uses of sofosbuvir-based regimens in chronic hepatitis C virus (HCV)-infected patients with genotypes 2, 3, 4 and 5. Results from the BOSON study of Sovaldi® (sofosbuvir 400 mg) in combination with ribavirin (RBV) or with pegylated interferon (PEG)/RBV demonstrated high cure rates across all patients with genotypes 2 and 3. Separately, results from a Phase 2 study demonstrate the safety and efficacy of Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) in patients with genotypes 4 or 5 infection. Data from both studies will be presented in oral sessions at the 50th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress™ 2015) in Vienna, Austria.

Sovaldi and Harvoni are each approved in the United States for the treatment of chronic HCV infection. Sovaldi is used in combination with other agents and its efficacy has been established in patients with genotypes 1-4; Harvoni is indicated for patients with genotype 1.

BOSON (Study GS-US-334-0153, #LB05), a randomized Phase 3 study of 592 patients, evaluated the safety and efficacy of Sovaldi plus RBV for 16 or 24 weeks compared with Sovaldi plus PEG/RBV for 12 weeks among treatment-naïve or treatment-experienced genotype 3 patients with and without cirrhosis and treatment-experienced genotype 2 patients with cirrhosis. Thirty-seven percent of study participants had cirrhosis.

Among genotype 3 patients, rates of sustained virologic response 12 weeks after treatment (SVR12) were highest among those receiving Sovaldi plus PEG/RBV for 12 weeks (93 percent, n=168/181), compared to those receiving Sovaldi plus RBV for 24 weeks (84 percent, n=153/182) or for 16 weeks (71 percent, n=128/181). Treatment-experienced genotype 3 patients with cirrhosis receiving Sovaldi plus PEG/RBV demonstrated SVR12 rates of 86 percent (30/35).

Genotype 2 patients also demonstrated high SVR12 rates across all treatment arms. SVR12 rates among patients receiving Sovaldi plus PEG/RBV were 94 percent (15/16), and 100 percent (17/17) and 87 percent (13/15) for those receiving Sovaldi plus RBV for 24 and 16 weeks, respectively.

Sovaldi plus PEG/RBV and Sovaldi plus RBV were well tolerated. The most common adverse events in the study were fatigue, headache, insomnia and nausea. Overall, six patients (1 percent) discontinued treatment due to adverse events, one of whom was treated with Sovaldi plus PEG/RBV.

“It remains difficult to achieve a virological response in genotype 3, which is one of the most prevalent genotypes in the world, with higher prevalence in Europe and Asia,” said Graham R. Foster, FRCP, PhD, Professor of Hepatology, The Liver Unit, Queen Mary's University of London, Barts Health, London, United Kingdom. “These results are compelling because they represent the highest cure rates observed among treatment-experienced, cirrhotic genotype 3 patients in any Phase 3 clinical trial to date.”

In a separate open-label Phase 2 study of Harvoni conducted in France (Study GS-US-337-1119, O056), results demonstrated high SVR rates in both treatment-naïve and treatment-experienced patients with chronic HCV genotypes 4 or 5 infection, 50 percent of whom had cirrhosis.

Ninety-three percent of patients with genotype 4 (41/44) and 95 percent of patients with genotype 5 (39/41) achieved SVR12. Response rates were similar among both treatment-naïve and -experienced patients and regardless of cirrhosis.

The most common adverse events (affecting more than 10 percent of patients) were asthenia, headache and fatigue. Most adverse events were mild or moderate in severity and none resulted in treatment discontinuation. There were no grade 3 or 4 clinical laboratory abnormalities.

“HCV genotype 4 and 5 are less prevalent than other genotypes and therefore, have traditionally not been closely studied,” said Armand Abergel, MD, PhD, Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire-Estaing, Université d'Auvergne, Clermont-Ferrand, France. “These data provide important evidence that the all-oral, ribavirin-free Harvoni regimen is both safe and effective for many patients with genotype 4 or 5, regardless of prior treatment experience.”

The safety and efficacy of these investigational uses of Harvoni and Sovaldi have not been established.

Important Safety Information About Sovaldi

Contraindications

Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to Sovaldi combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral (DAA): Amiodarone is not recommended for use with Sovaldi in combination with another DAA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Pregnancy: Use with ribavirin or peginterferon alfa/ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20 percent, all grades) adverse reactions for:

Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia

Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

Important Safety Information About Harvoni

Warnings and Precautions

Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Harvoni due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (≥10 percent, all grades) adverse reactions were fatigue and headache.

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

About Gilead

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that Gilead may observe unfavorable results from additional clinical trials involving Sovaldi and Harvoni for various patient populations, including those with genotype 2, 3, 4 and 5 HCV. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full Prescribing Information for Sovaldi and Harvoni is available at www.gilead.com.

Sovaldi and Harvoni are registered trademarks of Gilead Sciences, Inc., or its related companies.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Friday, January 9, 2015

Hepatitis C Update-Treatment Of Genotypes 1,2,3,4,5,and 6

HCV Treatment and Genotypes 

Good day folks, we have a few website updates from Hepatitis C Online, an interactive website from the University of Washington.

The site has comprehensive information on the diagnosis, monitoring, treatment and management of hepatitis C and offers a free online Hepatitis C Course, using AASLD/IDSA/IAS-Recommendations for Testing, Managing, and Treating Hepatitis C.

The hepatitis C patient will have an opportunity to the explore over 7 different modules, slide lectures, and read key data from published studies using new direct-acting antiviral agents.

Updated January 9 2015 
This month, Hepatitis C Online updated Module 5;Treatment of Chronic Hepatitis C Infection.

Click on each lesson to review the course module, or download PDF, I highly suggest the latter for easy viewing.

Genotype 1
PDF - Treatment of HCV Genotype 1
Lesson 1: Treatment of HCV Genotype 1
Contents: Introduction
Genotype 1: Initial Treatment and Retreatment with Prior Relapse
Genotype 1: Retreatment of Patients with prior Treatment Failure
Genotype 1: Future Treatment Options
Summary Points
Reference

Genotype 2
Contents: Introduction
Genotype 2: Initial Treatment and Retreatment with Prior Relapse
Genotype 2: Retreatment of Prior Nonresponders
Genotype 2: Future Treatment Options
Summary Points

Genotype 3
PDF - Treatment of HCV Genotype 3
Lesson 3: Treatment of HCV Genotype 3
Contents: Introduction
Genotype 3: Initial Treatment and Retreatment with Prior Relapse
Genotype 3: Retreatment of Prior Nonresponders
Genotype 3: Future Treatment Options
Summary Points

Genotype 4
Contents: Introduction
Genotype 4: Initial Treatment and Retreatment with Prior Relapse
Genotype 4: Retreatment of Prior Nonresponders
Genotype 4: Future Treatment Options
Summary Points

Genotype 5 or 6
Genotype 5 or 6: Initial Treatment and Retreatment with Prior Relapse
Genotype 5 or 6: Retreatment of Prior Nonresponders
Genotype 5 or 6: Future Treatment Options
Summary Points

Index
Genotypes 1-6
Module 5; Treatment of Chronic Hepatitis C Infection

Liver International
Volume 35, Issue Supplement s1, pages 1–3, January 2015

A special supplement of Liver InternationalProceedings of the 8th Paris Hepatitis Conference International Conference on the Management of Patients with Viral Hepatitis, is open access this month. This issue will include review articles on both HCV and HBV, with treatment strategies for HCV genotype 2, 4, and HCV-1b. Additional articles include HIV/HCV co-infection, end stage liver disease, liver cancer, and the dire universal need for affordable IFN-free regimens. 

Highlights
Optimal IFN-free therapy in treatment-naïve patients with HCV genotype 1 infection
Optimal therapy in genotype 4 chronic hepatitis C: finally cured?
Optimal therapy of genotype-2 chronic hepatitis C: what's new?
How to optimize current therapy in hepatitis C virus genotype 1 patients. Predictors of response to interferon-based therapy with second wave direct acting antivirals
Pegylated interferon based therapy with second-wave direct-acting antivirals in genotype 1 chronic hepatitis C

In Case You Missed It

November 2014
Hepatitis C Genotype 3
Written by Mr. Alan Franciscus, published in HCV Advocate's November Newsletter.
In the past, HCV genotype 3 was thought to be one of the easiest to cure. As a result there was little incentive to develop newer therapies especially since there were fewer people with genotype 3 in developed countries. Now it has turned out that treatment of genotype 3 is the hardest to cure with HCV inhibitor therapy compared to HCV genotypes 1, 2 and 4. 

Of Interest
AASLD @ HepMag.com
Eight weeks of Gilead Sciences’ Sovaldi and GS-5816, with or without ribavirin, cured high rates of people with genotype 3 of hepatitis C virus (HCV), but yielded unsatisfactory results among those with genotypes 1 and 2.

Genotypes 3 and 6
Harvoni Posts Good Cure Rates for Hepatitis Genotypes 3 and 6
Twelve weeks of Gilead Sciences’ Harvoni (ledipasvir/sofosbuvir) plus ribavirin cured 73 percent to 89 percent of people with genotype 3 of hepatitis C virus (HCV), while 96 percent of people with genotype 6 were cured without ribavirin in a recent trial, the National AIDS Treatment Advocacy Project (NATAP) reports.

Insulin resistance and liver steatosis in HCV genotype 3
Three main types of steatosis in the patients with Hepatitis C virus (HCV) infection are known: a metabolic type associated with metabolic syndrome and two viral types: one that seems to be directly triggered by the virus and one that could originate from the interference of the virus in the mechanisms of insulin resistance. The first viral type is particularly widely considered to be predominant and, perhaps, strictly linked to HCV genotype 3 infection and its intra-hepatic viral load. This evidence is supported by the resolution of steatosis in most patients infected with genotype 3 virus after HCV eradication by antiviral therapy.

Enjoy the weekend!
Tina

Wednesday, June 4, 2014

My Treatment Approach to Chronic Hepatitis C Virus (Genotypes 1-6)


Hello Folks,
Its June and time for me to take a short sabbatical with the family, we shall be traveling by boat, plane and train!

I leave you all with an article by liver specialist, and expert on treating HCV, the renowned Mitchell L. Shiffman, MD., and colleagues. The article offers a summary of the good doctors treatment strategies for HCV genotypes 1-6; published online: May 24, 2014

**For additional information on treating HCV according to genotype, click here.

Upon my return both the blog and website will be updated, see you all in a few weeks.

Stay safe and healthy!
Always Tina 

My Treatment Approach to Chronic Hepatitis C Virus
Mitchell L. Shiffman, MD, April G. Long, NP, Amy James, FNP, Phillip Alexander, NP
DOI: http://dx.doi.org/10.1016/j.mayocp.2014.04.013
Source: Mayo

Abstract
The treatment of chronic hepatitis C virus (HCV) is evolving rapidly. In 2014, the standard of care and new backbone of HCV treatment is the polymerase inhibitor sofosbuvir (SOF). Our treatment approach in patients with HCV genotype 1 is 12 weeks of SOF, peginterferon (PEGINF), and ribavirin (RBV). In patients with cirrhosis or extrahepatic manifestations of HCV who cannot tolerate PEGINF, we use 12 weeks of SOF and simeprevir. The latter is less costly and more effective than SOF and RBV for 24 weeks. Our treatment approach in all patients with genotype 2 is SOF and RBV for 12 weeks. Hepatitis C virus genotype 3 is now the most costly and difficult to cure. Our approach to treatment-naive patients with genotype 3 is SOF and RBV for 24 weeks. In patients who have previously undergone PEGINF and RBV treatment, we use PEGINF, SOF, and RBV for 12 weeks, which is equally if not more effective and less costly than SOF and RBV for 24 weeks. Patients with cirrhosis who cannot tolerate PEGINF should be treated for 24 weeks with SOF and RBV, although the sustained virologic response is suboptimal.

Chronic hepatitis C virus (HCV) affects an estimated 4 million persons in the United States and 300 million persons worldwide.1 In the 1960s through the 1980s, most US patients were infected with HCV through the transfusion of blood products and injection drug use. These patients have been infected for 30 to 50 years, and this is the primary driver for the increasing rates of cirrhosis and hepatocellular carcinoma (HCC) in the United States today.2 Many of these patients are asymptomatic, and the disease remains undiagnosed. The need to identify these patients is why the US Preventive Services Task Force and the Centers for Disease Control and Prevention have recommended that all persons born between 1945 and 1965 be screened for HCV.3, 4

Long-term studies conducted over the past 2 decades have found that a sustained virologic response (SVR) is long-lasting and that HCV can be “cured.”5, 6 Patients who achieve an SVR have improvement in liver histologic features and regression of fibrosis.7, 8 Patients with cirrhosis who achieve an SVR rarely experience hepatic decompensation and have a 10-fold decrease in the risk of HCC and a significant reduction in mortality.9, 10, 11

For the past 15 years, interferon and then peginterferon (PEGINF) have been the backbone of HCV treatment on which ribavirin (RBV) and more recently HCV protease inhibitors have been added.12 In late 2013, the treatment of chronic HCV entered a new era when 2 new oral antiviral agents, simeprevir (SMV) and sofosbuvir (SOF), were approved by the US Food and Drug Administration (FDA). Simeprevir is a protease inhibitor, and its approval by the FDA was based on studies in which it was used with PEGINF and RBV in patients with HCV genotype 1.13 Although SMV inhibits the NS3/4A protease like telaprevir (TPV) and boceprevir (BOC), it is taken only once daily, has fewer adverse effects and drug-drug interactions, and appears to have a somewhat higher SVR rate.14

Sofosbuvir is a polymerase inhibitor that is highly effective in suppressing replication in all HCV genotypes.15 It is also taken once daily and has few drug-drug interactions and minimal adverse effects. Resistance is extremely rare, and SVR rates of over 90% are achieved in most patients with HCV. In 2014, SOF has become the new backbone of HCV treatment.

The treatment of HCV continues to evolve rapidly. Several pharmaceutical companies have developed and are currently testing combinations of oral antiviral agents for HCV (Table 1).16, 17, 18, 19, 20

Two of these treatments have already completed phase 3 clinical trials, and an all-oral antiviral treatment for HCV genotype 1 is expected to be available before the end of 2014. The current dilemma for physicians wanting to treat HCV and patients who want to be cured of this virus is not whether HCV should be treated but rather what agents should be used and when treatment should be initiated. This article summarizes the data that led to the FDA approval of SMV and SOF and describes our treatment approach to patients with chronic HCV in 2014. Given the rapid proliferation of new oral antiviral agent combinations for treatment of HCV, this approach will need to be modified in 2015.

Table 1 
 

Simeprevir
Simeprevir is a pangenotypic NS3/4A protease inhibitor that is effective in vitro against HCV genotypes 1 through 6.21 To date, clinical trials have been completed only in patients with genotype 1. A study in patients with HCV genotype 4 is currently under way. Preliminary data from this study suggest that PEGINF, SOF, and RBV could achieve SVR rates approaching 80%.22 Simeprevir is highly effective and has been approved by the FDA for treatment of patients with chronic HCV genotype 1. Simeprevir binds to the same site as TPV and BOC. It has not been studied in patients in whom TPV or BOC treatment failed or resistance to TPV or BOC developed. Given its mechanism of action, it is unlikely to be effective and should not be used in these patients.13
Simeprevir is used as triple therapy with PEGINF and RBV for 12 weeks, followed by an additional 12 weeks of PEGINF and RBV (total duration of therapy, 24 weeks) in all patients who are treatment naive or who have had a relapse while taking PEGINF and RBV, including those with cirrhosis. Approximately 80% of patients achieve a rapid virologic response (RVR), and HCV RNA is undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately 90%.23, 24, 25 As opposed to TPV and BOC, for which the duration of therapy is adjusted on the basis of whether an RVR is achieved, response-guided therapy is not necessary with SMV. In patients who have no response to PEGINF and RBV, 12 weeks of SMV, PEGINF, and RBV is followed by 36 weeks of PEGINF and RBV (total duration of therapy, 48 weeks). The SVR rate in these patients is 53% to 65%.26 All patients with HCV RNA levels greater than 25 IU/mL at weeks 4, 12, or 24 should stop treatment. Although controlled clinical trials comparing the SVR rates of the 3 protease inhibitors have not been conducted, each has been evaluated against a placebo control with PEGINF and RBV. Comparison of the improvement in SVR over control for the 3 protease inhibitors suggests that RVR and SVR rates are somewhat higher with SMV compared with TPV or BOC.13

Simeprevir offers considerable advantages over TPV and BOC, the most important of which is that SMV does not cause additional anemia compared with PEGINF and RBV.23, 24, 25, 26 In phase 2 and 3 clinical trials, patients treated with SMV, PEGINF, and RBV did not have any adverse events with greater frequency than those taking PEGINF and RBV. Simeprevir is taken as a single once-daily tablet, no special diet is required, and far fewer drug-drug interactions have been observed.
The success in patients treated with SMV, like other protease inhibitors, is dependent on an effective interferon response, which is modulated by IL28B genotype.27 In treatment-naive patients, the SVR approaches 90% in patients with IL28B CC genotype and declines in patients with the CT and TT genotypes.23, 24 In patients with a previous nonresponse to PEGINF and RBV, the SVR rates during retreatment with SMV triple therapy follow a similar trend of interferon responsiveness: higher rates of SVR with a previous partial response and lower SVR rates in previous nonresponders.26

The primary limitation of SMV is that a sequence variation at the Q80K loci of HCV significantly limits the antiviral efficacy of this protease inhibitor and reduces SVR to values that are similar to that achieved with PEGINF and RBV.23, 24, 25, 26 This sequence variation is present in about 40% of patients with HCV genotype 1a. It is not present in HCV genotype 1b. The FDA has suggested that all patients with genotype 1a undergo resistance testing for the presence of the Q80K sequence variation in HCV and that the physician strongly consider using a treatment other than SMV if this sequence variation is present.

The Q80K sequence variation has the greatest impact and considerably lowers SVR in patients who are genetically less sensitive to PEGINF. In contrast, patients with IL28B CC genotype, who are highly sensitive to interferon, have similar SVR rates regardless of the presence or absence of the Q80K sequence variation.23, 24, 25, 26 We therefore disagree with the FDA recommendations somewhat and strongly believe that patients with HCV genotype 1a and Q80K who have IL28B CC genotype could be treated successfully with SMV, PEGINF, and RBV. We do not recommend and we do not treat our patients who have HCV genotype 1 with SMV, PEGINF, and RBV. However, if a physician or payer chooses this regimen, our recommendation would be to test those patients with genotype 1a for IL28B genotype. If the patient has IL28B CC genotype, then no viral resistance testing is necessary. If the patient has IL28B CC or TT genotype, the patient would then need to be tested for Q80K, and if absent, they could also be treated with SMV, PEGINF, and RBV. In contrast, if the patient has IL28B CT or TT genotype and Q80K sequence variation, we would not recommend SMV. 

Sofosbuvir
Sofosbuvir is the first polymerase inhibitor to be approved by the FDA for the treatment of chronic HCV.15 It is a nucleotide analogue that inhibits the NS5B polymerase and is effective in all HCV genotypes. Sofosbuvir is incorporated into the growing RNA sequence during replication and acts as a chain terminator. A specific sequence variation in the polymerase, S282T, is resistant to SOF by preventing incorporation of the nucleotide analogue into the growing polypeptide chain. However, this sequence variation also impacts the ability of HCV RNA to elongate with normal nucleotides and is therefore a nonviable sequence variation that cannot persist long-term. Resistance to SOF is therefore extremely uncommon and was not observed in any patient treated in the phase 3 clinical trials.28, 29, 30 Virtually all patients treated with SOF have undetectable HCV RNA within 2 to 4 weeks of initiating treatment, and all patients are treated for a fixed duration (12 or 24 weeks) on the basis of their genotype.

Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5, and 6.28 This was a single-arm study with no comparison with PEGINF and RBV. More than 90% of patients treated with SOF triple therapy had undetectable HCV RNA within 2 weeks, and virtually all patients achieved an RVR. The overall SVR rate was 90%; the SVR rate was 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All 7 patients with HCV genotypes 5 and 6 achieved an SVR. Sofosbuvir triple therapy has not been evaluated in patients in whom either PEGINF and RBV or triple therapy with a protease inhibitor failed. However, because protease inhibitors and SOF have a completely different site of action, there is no virologic reason why SOF should not be equally effective in patients in whom treatment with a protease inhibitor failed. In treatment-naive patients with HCV genotype 1 who have the least favorable treatment response characteristics—Metavir fibrosis score of F3 or F4, high viral load, IL28B non-CC genotype—the SVR rate with SOF, PEGINF, and RBV was 71%. In contrast, the SVR rate for patients with these characteristics treated with PEGINF and RBV with or without a protease inhibitor is only 3% to 50%. On the basis of these data, the FDA recommended that all patients with chronic HCV genotypes 1 and 4, regardless of treatment history, could be treated with SOF, PEGINF, and RBV for 12 weeks.

The combination of SOF and RBV represents the first interferon-free regimen approved by the FDA to treat patients with chronic HCV. Sofosbuvir and RBV were studied in 4 clinical trials in patients with genotypes 2 and 3.28, 29, 30 In patients with HCV genotype 2, SOF and RBV for only 12 weeks yielded superior SVR rates compared with PEGINF and RBV for 24 weeks. In patients without cirrhosis, SOF and RBV achieved SVR rates of 90% to 97%. In patients with cirrhosis, the SVR ranged from 60% to 94%. The lowest SVR in patients with genotype 2 was observed in a single study that included only 10 patients in whom previous treatment with PEGINF and RBV had failed.29 Extending the duration of SOF and RBV from 12 to 16 weeks in this study yielded an SVR of 78%. Excluding this one study, the SVR in patients with cirrhosis was 90%. The overall SVR rate for all patients with cirrhosis included in all 4 registration studies was 84%; in patients with cirrhosis and previous PEGINF and RBV treatment, the SVR was 82%. On the basis of these data, the FDA recommended that all patients with genotype 2 could be treated with SOF and RBV for 12 weeks.
In patients with genotype 3, treatment with SOF and RBV for 12 weeks yielded an SVR rate of only 61% to 68% in treatment-naive patients without cirrhosis and 21% to 34% in patients with cirrhosis.28, 29, 30 These SVR rates are somewhat lower, or at best similar, to that observed with 24 weeks of PEGINF and RBV. In patients in whom previous PEGINF and RBV therapy failed, 12 weeks of SOF and RBV yielded SVR rates of only 19% and 37% in patients with and without cirrhosis, respectively. Extending the duration of SOF and RBV to 16 weeks in patients with previous PEGINF and RBV failure did not significantly change the SVR in patients without cirrhosis but increased the SVR in patients with cirrhosis to 61%. The highest SVR rates in patients with genotype 3 were observed when the duration of SOF and RBV was extended to 24 weeks.

In the treatment-naive population, the SVR rate was 92% to 93% in patients with or without cirrhosis. In patients in whom previous treatment with PEGINF and RBV failed, 24 weeks of SOF and RBV achieved an SVR rate of 85% in patient without cirrhosis but only 60% in patients with cirrhosis.30 On the basis of these data, the FDA recommended that all patients with HCV genotype 3 could be treated with SOF and RBV for 24 weeks.

Sofosbuvir and RBV were also studied in patients with genotypes 1, 2, and 3 who had coinfection with human immunodeficiency virus (HIV).31 The duration of treatment was 24 weeks for patients with genotypes 1 and 3 and 12 weeks for patients with HCV genotype 2. Sustained virologic response rates of 76%, 88%, and 92% were observed for patients with genotypes 1, 2, and 3, respectively. This study led the FDA to approve SOF and RBV for the treatment of HCV in patients coinfected with HIV. This represents the first antiviral agent to be approved for treatment of HCV-HIV coinfection. The results of this study supported the FDA recommendation to use SOF and RBV for 24 weeks in patients with HCV genotype 1 who had intolerance or contraindications to the use of PEGINF.

Sofosbuvir and RBV have also been studied without PEGINF in patients with HCV and HCC awaiting liver transplant and in patients with post–liver transplant HCV recurrence. The pretransplant HCC study patients who met criteria for the MELD exception were treated with SOF and RBV up until the time they underwent liver transplant.32

Treatment was stopped at the time of the transplant. Overall, 64% of patients did not have HCV recurrence after the transplant. In patients with undetectable HCV RNA for at least 30 days before undergoing transplant, 95% did not experience HCV recurrence. These data led the FDA to approve SOF and RBV for use in patients with HCC awaiting liver transplant.

Two studies have been conducted in the post–liver transplant population.33, 34 One study included patients with stable normal graft function at least 6 months after transplant.33 These patients were treated with SOF and RBV for 24 weeks. Of the 40 patients in this study, 83% had genotype 1. All patients had undetectable HCV RNA within 4 weeks of initiating SOF and RBV. Only data on HCV RNA undetectable 4 weeks after stopping treatment (SVR-4) are available to date, but this level was achieved in 77% of the patients. The other posttransplant study was a compassionate use program for patients with severe HCV recurrence after transplant.34 Most of these patients had either fibrosing cholestatic hepatitis within the first year or had development of decompensated recurrent cirrhosis 2 or more years after their transplant. Of the 20 patients treated with SOF and RBV for 24 weeks, all had undetectable HCV RNA, 64% had clinical improvement, and 60% achieved an SVR; 30% of patients died of complications of their advanced liver disease despite achieving a virologic response.
Sofosbuvir is an extremely safe antiviral agent with minimal adverse effects.15 In a study in which SOF and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only adverse effects occurring more frequently with SOF and RBV than with placebo were anemia and pruritus, both of which were attributed to RBV.29 In the 5 phase 3 clinical trials, the drop-out rate due to adverse events was greatest in the placebo-treated group (4%); the drop-out rate was only 2% in patients treated with PEGINF, SOF, and RBV for 12 weeks and less than 1% in all SOF and RBV treatment groups.

Combining SOF and SMV in Patients With Genotype 1
The combination of SOF and SMV for either 12 or 24 weeks with or without RBV has been evaluated in 167 patients with HCV genotype 1.35 No single arm of this 2-cohort, 4-arm study had more than 54 patients, and only SVR-4 data are currently available for half the patients. However, the results are extremely noteworthy. Sustained virologic response rates of 93% to 100% were observed in all but one of the groups regardless of whether patients were treated for 12 or 24 weeks and whether they received RBV or not. The lowest SVR (79%) was observed in the group treated with SOF, SMV, and RBV for 24 weeks in which 4 patients had nonvirologic failure. All 14 patients with cirrhosis achieved SVR-4 within just 12 weeks of initiating SOF and SMV. Of the 7 patients with cirrhosis and previous nonresponse, all achieved SVR. In patients with genotype 1a and the Q80K sequence variation, the SVR rate was 90%. In patients without this sequence variation, the SVR rate was 100%.

Adding PEGINF to SOF and RBV in Patients With Genotype 3
Of all patients with HCV, those with genotype 3 have the most difficulty achieving a cure. Many believe this is difficulty is related to the much higher hepatic content of micovesicular steatosis that is unique to patients with HCV genotype 3.36 Sustained virologic response in patients with genotype 3 is also negatively impacted by previous nonresponse to PEGINF and RBV. In patients without cirrhosis, a previous nonresponse to PEGINF and RBV is associated with a reduction in SVR from 93% to 85%, and in those with cirrhosis, the SVR is reduced from 92% to 60%.28, 29, 30 This negative impact of previous PEGINF and RBV treatment is also observed in patients with genotype 2 but to a far lesser extent. In patients with genotype 2 who have previously undergone PEGINF and RBV treatment, the SVR in response to SOF and RBV is reduced from 97% to 91% in those without cirrhosis and from 100% to 88% in those with cirrhosis.

The SVR in patients with HCV genotype 3, especially patients previously treated with PEGINF and RBV, appears to be enhanced by adding PEGINF to SOF and RBV.37 In a small study of only 24 patients with genotype 3 and previous nonresponse to PEGINF and RBV (half of whom had cirrhosis), 12 weeks of treatment with PEGINF, SOF, and RBV yielded an SVR of 83% in patients with and without cirrhosis. In the same study, 14 patients with HCV genotype 2, cirrhosis, and previous nonresponse to PEGINF and RBV achieved an SVR of 93% when re-treated with PEGINF, SOF, and RBV.

Our Treatment Approach
In January 2014, a joint guideline for treating HCV was issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.38 These recommendations and the FDA recommendations for use of SOF39 are summarized in Table 2. Our treatment approach to chronic HCV at the Liver Institute of Virginia in 2014 is based on the available data and focuses on maximizing SVR while also respecting the cost of treatment (Table 2). In several situations, we believe the American Association for the Study of Liver Diseases/Infectious Diseases Society of America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.


Table 22014 Treatment Recommendations for Patients With HCV
VariableAASLD/IDSAFDALIV
Genotype 1: Treatment naive and prior PEGINF and RBV relapse
 INF tolerant, no cirrhosis or compensated cirrhosisPEGINF, SOF, and RBV for 12 wk
 INF intolerant, no cirrhosisSOF and SMV ± RBV for 12 wkSOF and RBV for 24 wkDefer treatment
 INF intolerant, cirrhosis

SOF and SMV for 12 wk
Genotype 1: Prior PEGINF and RBV nonresponse
 INF tolerant, no cirrhosis or compensated cirrhosisSOF and SMV ± RBV for 12 wkPEGINF, SOF, and RBV for 12 wk
 INF intolerant, no cirrhosisSOF and SMV ± RBV for 12 wkSOF and RBV for 24 wkDefer treatment
 INF intolerant, cirrhosis

SOF and SMV for 12 wk
Genotype 1: Prior treatment with PEGINF, RBV, and TPV or BOC
 INF tolerant, no cirrhosis or compensated cirrhosisSOF for 12 wk, PEGINF and RBV for 12-24 wkPEGINF, SOF, and RBV for 12 wk
 INF intolerant, no cirrhosisNRSOF and RBV for 24 wkDefer treatment
 INF intolerant, cirrhosis

SOF and SMV for 12 wk
Genotype 2
 Treatment naive or PEGINF-RBV relapse, no cirrhosis or compensated cirrhosisSOF and RBV for 12 wkSOF and RBV for 12 wkSOF and RBV for 12 wk
 Prior PEGINF-RBV nonresponse, no cirrhosisSOF and RBV for 12 wk

 Prior PEGINF-RBV nonresponse, cirrhosisSOF and RBV for 12-16 wk

Genotype 3
 Treatment naiveSOF and RBV for 24 wkSOF and RBV for 24 wkSOF and RBV for 24 wk
 Prior PEGINF-RBV, INF tolerant, no cirrhosis or compensated cirrhosis

PEGINF, SOF, and RBV for 12 wk
 Prior PEGINF-RBV, INF intolerant, no cirrhosis

Defer treatment
 Prior PEGINF-RBV, INF intolerant, cirrhosis

SOF and RBV for 24 wk
Genotype 4
 INF tolerantPEGINF, SOF, and RBV for 12 wk
 INF intolerantSOF and RBV for 24 wkSOF and SMV for 12 wk
Genotypes 5 and 6
 INF tolerantPEGINF, SOF, and RBV for 12 wkNAPEGINF, SOF, and RBV for 12 wk
 INF intolerantNRNASOF and RBV for 24 wk
AASLD = American Association for the Study of Liver Diseases; BOC = boceprevir; FDA = Food and Drug Administration; IDSA = Infectious Diseases Society of America; INF = interferon; LIV = Liver Institute of Virginia; NA = not approved; NR = no recommendation; PEGINF = peginterferon; RBV = ribavirin; SMV = simeprevir; SOF = sofosbuvir; TPV = telaprevir.

Genotypes 1, 4, 5, and 6
Genotype 1 is the most common form of HCV worldwide. Genotype 4 is the dominant genotype in Egypt and the Middle East, genotype 5 is frequent in South Africa, and genotype 6 is common in Vietnam and Cambodia.40 In the United States, genotypes 4 through 6 are uncommon and rarely seen except in immigrants from the aforementioned regions of the world.

In patients with genotypes 1, 4, 5, or 6 without cirrhosis, our treatment approach is PEGINF, SOF, and RBV for 12 weeks. The SVR rate is 92% or greater, and less than 2% of these patients will be unable to tolerate this regimen. For patients who have not achieved an SVR during previous treatment with PEGINF and RBV or PEGINF, RBV, and either TPV or BOC, our approach is the same. Patients without cirrhosis who prefer not to be treated with PEGINF or have intolerance or contraindications to PEGINF can defer treatment and wait for an FDA-approved all-oral antiviral combination. Two such regimens are expected to be available before 2015. We do not promote either SOF and RBV for 24 weeks or SOF and SMV for 12 weeks in patients without cirrhosis.
In patients with cirrhosis and genotypes 1, 4, 5, or 6, our approach is still PEGINF, SOF, and RBV for 12 weeks as long as the platelet count and serum albumin level are normal and there is no history of hepatic decompensation or evidence of esophageal varices or subclinical hepatic encephalopathy. In contrast, we would not treat patients with cirrhosis and any of these laboratory or clinical abnormalities with a PEGINF-containing regimen. In a previous study in which patients with these characteristics were treated with PEGINF, RBV, and either TPV or BOC, more than half experienced severe anemia, 25% discontinued treatment, and 1% to 2% died as a result of hepatic decompensation.41 In our opinion, the risk that this poor outcome could also occur with a 12-week PEGINF and RBV–containing regimen is considerable. In addition, the SVR that could be achieved with PEGINF, SOF, and RBV is reduced to 80% or less in such patients.

In patients with genotype 1 or 4 and cirrhosis who have intolerance or contraindications to PEGINF, our treatment approach is SOF and SMV for 12 weeks. In patients with HCV-induced extrahepatic manifestations such as symptomatic cryoglobulinemia, glomerulonephritis, or B-cell lymphoma, regardless of fibrosis stage, we also use SOF and SMV. We do not believe that testing for the Q80K sequence variation is necessary when treating patients who have genotype 1a with SOF and SMV. The SVR when this sequence variation is present is still 90%, and there is no suggestion from the data that adding RBV or extending the duration of therapy to 24 weeks enhances SVR. We do not recommend 24 weeks of SOF and RBV in these patients; the cost of this regimen is prohibitive, and the SVR rate is estimated to be only in the 70% to 75% range, approximately 20% lower than that observed with SOF and SMV. We also do not recommend deferring treatment in this population, and payers should recognize their need for treatment. These patients have cirrhosis, are at risk for development of severe and life-threatening complications of cirrhosis, and should not have to wait for an alternative all-oral regimen.

In patient with genotypes 5 or 6, cirrhosis, and intolerance or contraindications to PEGINF, we use SOF and RBV for 24 weeks. Although this regimen is costly, this group represents only a limited number of patients with HCV, and no alternative treatment is on the horizon. Simeprevir has activity against HCV genotypes 5 and 6 in vitro, but without any clinical data to support its use, it is difficult to recommend this treatment.

Our treatment approach to patients with HCV genotype 1 does not include TPV, BOC, or SMV in combination with PEGINF and RBV. All of these antiviral agents have a lower SVR rate and require a longer duration of PEGINF and RBV compared with an SOF-containing regimen.

Genotype 2
Our treatment approach for all patients with genotype 2, regardless of fibrosis stage, is SOF and RBV for 12 weeks. This group includes patients with cirrhosis in whom PEGINF and RBV failed previously. The SVR rate in this nonresponse subpopulation with cirrhosis is 88% but exceeds 90% in all other subpopulations. A more effective, less costly regimen is unlikely to be developed for patients with HCV genotype 2 in the foreseeable future.

Genotype 3
Patients with genotype 3 are now the most difficult and costly to treat and the most controversial regarding recommendations for treatment. Treatment-naive patients, regardless of the degree of fibrosis, require twice the duration of SOF and RBV (24 weeks) and twice the cost to achieve an SVR of at least 90%. We believe that SOF, RBV, and PEGINF for 12 weeks would yield an SVR of at least 90% and be more cost-effective, but with no data in the treatment-naive population, this approach is difficult to adopt. Therefore, our approach to treatment-naive patients with genotype 3 with or without cirrhosis is SOF and RBV for 24 weeks.

In patients with genotype 3 who have previously undergone PEGINF and RBV treatment and do not have cirrhosis, 24 weeks of SOF and RBV is nearly twice as costly yet offers an SVR similar to 12 weeks of PEGINF, SOF, and RBV (85% vs 83%, respectively). Because only 12 weeks of PEGINF is generally tolerated, we use the cheaper regimen (PEGINF, SOF, and RBV for 12 weeks). Patients with genotype 3 who do not have cirrhosis and are intolerant of PEGINF can defer treatment until a more cost-effective therapy is available. In patients with cirrhosis who do not have contraindications to PEGINF, our approach is to also use PEGINF, SOF, and RBV. The SVR with this treatment is also 83% compared with only 60% for 24 weeks of SOF and RBV. In patients with cirrhosis that is too advanced for PEGINF (see criteria outlined in the “Genotypes 1, 4, 5, and 6” section) and patients with PEGINF intolerance for other reasons, we have no choice but to use the inferior and more costly treatment (SOF and RBV for 24 weeks).

Recommendations
For 2014, SOF has replaced PEGINF as the backbone of HCV therapy. Sofosbuvir is superior to all other currently available antiviral agents with respect to efficacy, adverse effects, drug-drug interactions, viral resistance, and duration of therapy. Peginterferon should still be used in many patients with genotype 1 and in selected patients with genotype 3 because it offers higher efficacy and is less costly than 24 weeks of SOF and RBV. In 2015, another era of HCV treatment will begin, and our need for PEGINF and possibly RBV will no longer exist. Patients with genotype 1 and no cirrhosis may choose to defer treatment until then.

References
  1. 1Armstrong, G.L., Wasley, A., Simard, E.P., McQuillan, G.M., Kuhnert, W.L., and Alter, M.J. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006; 144: 705–714
  2. 2Davis, G.L., Alter, M.J., El-Serag, H., Poynard, T., and Jennings, L.W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010; 138: 513–521
  3. 3Moyer, V.A. and US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013; 159: 349–357
  4. 4Smith, B.D., Morgan, R.L., Beckett, G.A., Falck-Ytter, Y., Holtzman, D., and Ward, J.W. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012; 157: 817–822
  5. 5Swain, M.G., Lai, M.Y., Shiffman, M.L. et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010; 139: 1593–1601
  6. 6Manns, M.P., Pockros, P.J., Norkrans, G. et al. Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin. J Viral Hepat. 2013; 20: 524–529
  7. 7George, S.L., Bacon, B.R., Brunt, E.M., Mihindukulasuriya, K.L., Hoffmann, J., and Di Bisceglie, A.M. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009; 49: 729–738
  8. 8Shiffman, M.L., Hubbard, S., Long, A. et al. Five year prospective evaluation of liver histology in patients with chronic hepatitis C virus following treatment with interferon/peginterferon and ribavirin. J Hepatol. 2009; 50: S52
  9. 9van der Meer, A.J., Veldt, B.J., Feld, J.J. et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012; 308: 2584–2593
  10. 10Backus, L.I., Boothroyd, D.B., Phillips, B.R., Belperio, P., Halloran, J., and Mole, L.A. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol. 2011; 9: 509–516.e1
  11. 11Morgan, T.R., Ghany, M.G., Kim, H.Y...., and HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010; 52: 833–844
  12. 12Ferenci, P. Treatment of chronic hepatitis C—are interferons really necessary?. Liver Int. 2012; 32: 108–112
  13. 13You, D.M. and Pockros, P.J. Simeprevir for the treatment of chronic hepatitis C. Expert Opin Pharmacother. 2013; 14: 2581–2589
  14. 14Shiffman, M.L. and Benhamou, Y. Patients with HCV and F1 and F2 fibrosis stage: treat now or wait?. Liver Int. 2013; 33: 105–110
  15. 15Koff, R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014; 39: 478–487
  16. 16Kowdley, K.V., Lawitz, E., Poordad, F. et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014; 370: 222–232
  17. 17Lawitz, E., Poordad, F.F., Pang, P.S. et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. ([published correction appears in Lancet. 2014;383(9920):870]) Lancet. 2014; 383: 515–523
  18. 18Everson, G.T., Sims, K.D., Rodriguez-Torres, M. et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014; 146: 420–429
  19. 19Lawitz, E, Hezode, C, Gane, E et al. Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null-response: the C-WORTHY Study. J Hepatol. 2014; 60: S25–26
  20. 20Zeuzem, S., Soriano, V., Asselah, T. et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013; 369: 630–639
  21. 21Talwani, R., Heil, E.L., Gilliam, B.L., and Temesgen, Z. Simeprevir: a macrocyclic HCV protease inhibitor. Drugs Today (Barc). 2013; 49: 769–779
  22. 22Moreno C, Hezode C, Marcellin P, et al. Simeprevir with peginterferon/ribavirin in treatment-naïve or -experienced patients with chronic HCV genotype 4 infection: a phase III study. Paper presented at: 14th European AIDs Conference; October 16-19, 2013; Brussels, Belgium.
  23. 23Manns, M., Marcellin, P., Poordad, F.P.F. et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. ([abstract 1413]) J Hepatol. 2013; 58: S568
  24. 24Jacobson, I., Dore, G.J., Foster, G.R. et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial. ([abstract 1425]) J Hepatol. 2013; 58: S574
  25. 25Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial [published online ahead of print March 3, 2014]. Gastroenterology. http://dx.doi.org/10.1053/j.gastro.2014.02.051.
  26. 26Zeuzem, S., Berg, T., Gane, E. et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014; 146: 430–441
  27. 27Thompson, A.J., Muir, A.J., Sulkowski, M.S. et al. IL28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010; 139: 120–129.e18
  28. 28Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887
  29. 29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013; 368: 1867–1877
  30. 30Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. ([AASLD abstract 1085]) Hepatology. 2013; 58: 733A
  31. 31Sulkowski, M.S., Rodriguez-Torres, M., Lalezari, J.P. et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). ([AASLD abstract 212]) Hepatology. 2013; 58: 313A
  32. 32Curry, M.P., Forns, X., Chung, R.T. et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. ([AASLD abstract 213]) Hepatology. 2013; 58: 314A
  33. 33Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study [AASLD abstract LB2]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.
  34. 34Forns, X., Fontana, R.J., Moonka, D. et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. ([AASLD abstract 1084]) Hepatology. 2013; 58: 732A
  35. 35Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study [AASLD abstract LB3]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.
  36. 36Restivo, L., Zampino, R., Guerrera, B., Ruggiero, L., and Adinolfi, L.E. Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-α-2a plus ribavirin and RVR. J Viral Hepat. 2012; 19: 346–352
  37. 37Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study [AASLD abstract LB4]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.
  38. 38American Association for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/full-report-view. Revised March 21, 2014. Accessed April 19, 2014.
  39. 39Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc; December 2013. http://www.gilead.com/∼/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf.
  40. 40Nguyen, M.H. and Keeffe, E.B. Chronic hepatitis C: genotypes 4 to 9. Clin Liver Dis. 2005; 9: 411–426
  41. 41Hézode, C., Fontaine, H., Dorival, C...., and CUPIC Study Group. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013; 59: 434–441