May 28, 2013

Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies

Volume 144, Issue 7 , Pages 1450-1455.e2, June 2013

Jianmeng Chen, Jeffry Florian, Wendy Carter, Russell D. Fleischer, Thomas S. Hammerstrom, Pravin R. Jadhav, Wen Zeng, Jeffrey Murray, Debra Birnkrant,

Received 18 December 2012; accepted 27 February 2013. published online 07 March 2013.


Background & Aims

Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development.


We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals.


The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection.


SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.

Keywords: Therapy, Outcome, Effectiveness, Quantification

Abbreviations used in this paper: AIMS, Antiviral Information Management System, CHC, chronic hepatitis C, DAA, direct-acting antiviral, HCV, hepatitis C virus, NPV, negative predictive value, PPV, positive predictive value, SVR, sustained virologic response

Author names in bold designate shared co-first authorship.

Conflicts of interest This authors disclose the following: Jadhav Pravin was employed by Merck after completion of this study. The remaining authors disclose no conflicts.

Funding This project was supported by funding through a critical path grant and in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and Center for Drug Evaluation and Research.

PII: S0016-5085(13)00288-6


© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.


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European Commission Approves Stribild®, a New Single Tablet Regimen for the Treatment of HIV-1 Infection


FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 28, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorization for Stribild®(elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg), a single tablet regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild. This approval allows for the marketing of Stribild in all 27 countries of the European Union.

“Single tablet regimens make it easier for HIV patients to take their treatment consistently every day, which may improve their health outcomes,” said Jürgen Rockstroh, MD, Professor of Medicine, University of Bonn, Germany and a lead investigator for one of the Stribild pivotal studies. “Stribild is a highly effective and well tolerated HIV treatment regimen, and is an important addition to the growing arsenal of simplified therapies in Europe.”

This approval is supported by 48-week data from two pivotal Phase 3 studies in which Stribild met its primary objective of non-inferiority compared to Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg) (Study 102) and to a regimen containing ritonavir-boosted atazanavir plus Truvada®(emtricitabine/tenofovir disoproxil (as fumarate)) (Study 103).

“We look forward to making Stribild available to HIV-treating physicians and their patients throughout the European Union as quickly as possible,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences.

Stribild is also approved in the United States, Canada, Australia, South Korea, Japan and Turkey.

Stribild is the third single tablet HIV regimen developed by Gilead to become available in Europe. The first, Atripla, was approved in the European Union in 2007 and is marketed by Gilead in partnership with Bristol-Myers Squibb and Merck & Co. The second, Eviplera®▼ (emtricitabine/rilpivirine/tenofovir disoproxil (as fumarate) 245 mg)), is marketed by Gilead and Janssen R&D Ireland and received European marketing authorization in November 2011.

About Stribild

Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil (as fumarate) 245 mg.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights.

Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body.

Marketing applications for elvitegravir and cobicistat as standalone agents are currently under review in the European Union. In the United States, on April 29, 2013, Gilead announced it had received Complete Response Letters from the U.S. Food and Drug Administration (FDA) on its New Drug Applications for elvitegravir and cobicistat as standalone agents. The company is working to address the questions raised in FDA’s letters as quickly as possible.

Elvitegravir and cobicistat as standalone agents are investigational products and their safety and efficacy have not yet been established.

EU Important Product Information About Stribild

Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. Lactic acidosis has a high mortality and patients at increased risk should be followed closely.

Stribild should not be taken with any of the following due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild:

  • alpha 1-adrenoreceptor antagonists: alfuzosin
  • antiarrhythmics: amiodarone, quinidine
  • anticonvulsants: carbamazepine, phenobarbital, phenytoin
  • antimycobacterials: rifampicin
  • ergot derivatives: dihydroergotamine, ergometrine, ergotamine
  • gastrointestinal motility agents: cisapride
  • herbal products: St. John’s wort (Hypericum perforatum)
  • HMG Co-A reductase inhibitors: lovastatin, simvastatin
  • neuroleptics: pimozide
  • PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension
  • sedatives/hypnotics: orally administered midazolam, triazolam

As a fixed combination, Stribild should not be administered concomitantly with other medicinal products containing tenofovir disoproxil (as fumarate), lamivudine or adefovir dipivoxil used for the treatment of hepatitis B virus infection.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil (as fumarate).

Patients who have previously discontinued treatment with tenofovir disoproxil (as fumarate) due to renal toxicity should not be treated with Stribild.

Patients should have creatinine clearance calculated and urine glucose and urine protein determined prior to initiating Stribild therapy.

Stribild should not be initiated in patients with creatinine clearance below 70 mL/min. It is recommended that Stribild is not initiated in patients with creatinine clearance < 90 mL/min unless, after review of the available treatment options, it is considered that Stribild is the preferred treatment for the individual patient.

Creatinine clearance, serum phosphate, urine glucose and urine protein should be monitored every four weeks during the first year and then every three months. More frequent monitoring of renal function should be considered in patients at risk for renal impairment.

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Patients who experience a confirmed increase in serum creatinine of greater than 26.5 μmol/L (0.3 mg/dL) from baseline should be closely monitored for renal safety.

Renal function should be re-evaluated within one week if serum phosphate is < 0.48 mmol/L (1.5 mg/dL) or creatinine clearance decreases to < 70 mL/min during Stribild therapy.

If creatinine clearance is confirmed as < 50 mL/min or serum phosphate decreases to < 0.32 mmol/L (1.0 mg/dL) then Stribild should be discontinued.

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil (as fumarate) and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil (as fumarate) without cobicistat.

Stribild should be avoided with concurrent or recent use of a nephrotoxic medicinal product due to the increased risk of renal adverse reactions (with the tenofovir disoproxil (as fumarate) component of Stribild).

Bone abnormalities (infrequently leading to fractures) may be associated with proximal renal tubulopathy and appropriate consultation should be obtained if suspected.

Stribild has not been studied in patients with severe hepatic impairment (CPT Score C).

Discontinuation of Stribild therapy in patients co-infected with HIV and hepatitis B virus (HBV) may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Stribild should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post treatment exacerbation of hepatitis may lead to hepatic decompensation.

Immune Reactivation Syndrome has been reported in patients treated with combination therapy, including the components of Stribild.

Combination therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown.

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 worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

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 in Europe may not see advantages of Stribild over other HIV therapies and may therefore be reluctant to prescribe the product. In addition, pending marketing applications for elvitegravir and cobicistat as standalone agents in the United States and Europe may not be approved or approvals may be delayed, including due to Gilead’s inability to address the questions raised in FDA’s complete response letters. Further, any marketing approvals, if granted, may have significant limitations on their use. 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 March 31, 2013, 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.

EU Summary of Product Characteristics for Atripla, Eviplera, Stribild and Truvada are available at

Eviplera, Stribild and Truvada are registered trademarks of Gilead Sciences, Inc.
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

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

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936
Stephen Head, +44 (208) 587-2359 (Europe)
Erin Rau, 650-522-5635 (U.S.)