HCV genotype 4 patients achieved SVR12 with triple therapy

HCV genotype 4 patients achieved SVR12 with triple therapy
May 23, 2014
Source - Healio

CHICAGO — Hepatitis C virus genotype 4-infected patients met sustained virologic response at 12 weeks with an all-oral triple therapy of daclatasvir, asunaprevir and the non-nucleoside NS5B inhibitor BMS-791325, according to research presented at Digestive Disease Week 2014.

Researcher Tarek Hassanein, MD, of the Southern California Liver Centers, and colleagues randomly assigned 21 treatment-naive hepatitis C virus genotype 4-infected patients to either 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg BMS-791325 (Bristol-Myers Squibb; n=11) twice daily or 150 mg BMS-791325 (n=10) twice daily for 12 weeks. Patients were primarily men (62%), white (91%) and noncirrhotic.

According to data, 10 of the 75-mg BMS-791325 patients achieved sustained virologic response at 12 weeks (SVR12), with the other missing patient meeting SVR24. Nine patients in the 150-mg BMS-791325 group achieved SVR12, with one patient still being followed.

There were no reports of patients experiencing virologic failure or post-treatment relapses; no serious adverse events (AE) were reported. The most common AE were headache (29%), nausea (14%) and pain (14%).

“One hundred percent of the patients with genotype-4 achieved an SVR at or after post-treatment week 12,” Hassanein said during his presentation. “There were no differences between the doses of [BMS-791325], and they were both effective.”

For more information:
Hassanein T. #763. Presented at: Digestive Disease Week 2014; May 3-6; Chicago.
Disclosure: The researchers report numerous relevant financial disclosures.

View Slides and DDW Coverage @ NATAP
DDW: All-Oral Therapy With Daclatasvir in Combination With Asunaprevir and BMS-791325 for Treatment-Naive Patients With Chronic HCV Genotype 4 Infection - (05/06/14) 

Sovaldi-Hepatitis C patients achieved SVR despite negative predictors

HCV patients treated with sofosbuvir maintained high SVR despite negative predictors
May 13, 2014

CHICAGO — Hepatitis C virus-infected patients with genotypes 1, 2 or 3 displayed high sustained virologic response rates after being treated with a sofosbuvir-based regimen despite the presence of negative predictors, according to data presented at Digestive Disease Week 2014.

Ira M. Jacobson, MD, chief of the division of gastroenterology and hepatology at Weill Cornell Medical College, New York, and co-chief medical editor of HCV Next, and colleagues performed univariate and multivariate regression analyses on 868 treatment-naive patients. The study included 339 patients with genotype 1 who received sofosbuvir (SOF) with pegylated interferon alfa plus ribavirin (PegIFN/RBV) for 12 weeks, 285 with genotype 2 who were treated with SOF with RBV for 12 weeks, and 244 genotype 3 patients who received 24 weeks SOF with RBV. Researchers sought to identify variables that may be associated with relapse and affected sustained virologic response (SVR) rates.

Full Story »

HCV Tuesday News -Liver biopsy is becoming an endangered procedure.

Digestive Disease Week 2014 

DDW Daily News
The newspaper is distributed in the convention center four times during the conference. Each issue focuses on one of the four DDW member societies, highlighting timely information and news about scheduled events and scientific sessions. 

DDW 2014 Issues:
Tuesday, May 6

With less invasive alternatives available, liver biopsy rarely needed Liver biopsy is becoming an endangered procedure.

NASH is an indication for liver transplant
Fatty liver disease is not end-stage liver disease and thus would not be an indication for liver transplantation, according to Kymberly D. Watt, MD, associate professor of medicine and medical director of liver transplantation at the Mayo Clinic and Foundation in Rochester, MN. The same can't be said for nonalcoholic steatohepatitis (NASH), however.
Read More

Despite effectiveness, colonoscopy faces increased competition
The data are clear: screening colonoscopy reduces colorectal cancer (CRC) morbidity and mortality. But payors are demanding higher quality at a lower price and new technologies offer tempting alternatives.
Read More

Joint symposium will examine quality indicators in GI surgery
Representatives from SSAT and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) will gather today for the annual Kelly and Carlos Pellegrini SSAT/SAGES Joint Luncheon Symposium, which is titled Quality Indicators — Defining It Before Someone Else Does It for Us! The symposium will examine quality indicators in gastrointestinal surgery.
Read More

Experts to summarize Best of DDW 2014
Representatives from each of the four participating DDW® societies will summarize the most important findings presented at this year's meeting during today's Best of DDW 2014 session. DDW Council Chair Lawrence S. Friedman, MD, AGAF, FASGE, and DDW Council Treasurer J. Sumner Bell, MD, AGAF, will moderate the session, a perennial favorite for meeting attendees.
Read More

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Click here to view the complete Tuesday issue of DDW Daily News on your computer or tablet. 

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Monday, May 5
Sunday, May 4
Saturday, May 3 

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Monday
Saturday  
Sunday

Study Provides More Evidence that Statins Help Slow Liver Fibrosis in Hepatitis C

Study Provides More Evidence that Statins Help Slow Liver Fibrosis in Hepatitis C

By Marcia Frellick | May 05, 2014

 

New research from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial cohort indicates that continuous statin use can significantly reduce liver fibrosis progression in patients with advanced chronic hepatitis C infection.

Study results, released Sunday at Digestive Disease Week 2014 in Chicago, IL, add to evidence demonstrating that statins have anti-proliferative, anti-angiogenic, and anti-inflammatory effects on hepatic cells.

Although animal models have demonstrated that statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, effectively prevent the progression of liver fibrosis, little human data was available.

Tracey G. Simon, MD, an internist in the Gastrointestinal Unit at Massachusetts General Hospital, and Brigham and Women's Hospital in Boston, MA, and colleagues studied 547 non-cirrhotic patients with chronic hepatitis C who previously had not responded to standard interferon therapy.

The patients had Ishak Fibrosis Staging scores ≥ 3 and underwent serial liver biopsies at baseline, 1.5 years, and 3.5 years after the trial began. Inflammation was graded on an 18-point histology activity index.

Patients reported statin use as part of the comprehensive medical history taken prior to enrollment and at each follow-up visit over the length of the study. Statin users were more likely to be African American, to have lower baseline alanine transferase (ALT) levels, and to be diabetic when compared to patient who reported no statin use.

The mean change in Ishak score over the study period for those who used statins was -0.34 during 3.5 years of observation, while the mean change in the Ishak score among those in the non-statin group was +0.42 [(SE 0.07), p= 0.006] after adjustment for baseline fibrosis score.

Continuous statin use was linked with a significant decrease in time to histological progression even after adjusting for known predictors of histological outcome, including diabetes, body mass index, platelets, and hepatic steatosis (HR 0.31, 95% CI 0.10 - 0.97).

Therapies to reduce the progression of liver scarring are critical as the damage keeps the liver from performing essential functions. Slowing the progression can slow hepatic decompensation and help patients live longer. However, some clinicians have been reluctant to initiate statin therapy along with treatment for hepatitis C without more evidence that they are safe and effective for this purpose.

The HALT-C researchers said further prospective studies with a large proportion of statin users are needed to define the optimal timing for starting statins, the ideal length of therapy, and the impact on those with less severe fibrosis or other etiologies of liver disease -

Source

Morning News Ticker - We Are on the Precipice of Treating Virtually Everyone with HCV

Digestive Disease Week 2014 
Read up on key sessions from day two of DDW®, and find out what today and tomorrow still have in store in the Monday issue of DDW Daily News — the official newspaper of Digestive Disease Week.

We Are on the Precipice of Treating Virtually Everyone with HCV
Posted by Rachel Steigerwald on May 4, 2014
Explore Sessions, Featured, Watch Videos

DDW TV interviewed Donald Jensen, MD, about his State-of-the-Art Lecture, Treatment of Hepatitis C: Interferon-Free at Last, taking place at DDW 2014. Dr. Jensen highlights the progress made in treating hepatitis C and how new therapies discussed at this session will change patient care.
Source



Ledipasvir and sofosbuvir (Solvaldi,) with or without ribavirin
Healio
DDW
SAPPHIRE-II: Interferon-free treatment combo a success for genotype 1 HCV 
Ira M. Jacobson
CHICAGO – A combination treatment of three direct-acting antivirals demonstrated significant efficacy against patients with hepatitis C genotype 1, suggesting that an interferon-free treatment is soon on the horizon for this group of patients.

High rates of SVR12 were seen across all patient groups, regardless of HCV subtype and prior treatment response, including a 95% SVR rate seen in prior null responders, according to results from the phase-3 SAPPHIRE-II study, presented here at Digestive Disease Week 2014.
Continue reading.. 

Healio
DDW
Two-drug, 12-week treatment successful for genotype 1 HCV
May 4, 2014
CHICAGO — A fixed-dose combination of ledipasvir and sofosbuvir for treatment-experienced patients with genotype 1 hepatitis C resulted in a sustained virologic response for almost all patients enrolled in the phase 3 ION-2 study...
Continue reading...

Healio
DDW
Difficult-to-treat HCV patients benefit from ledipasvir, sofosbuvir combo
CHICAGO — Treatment with sofosbuvir and ledipasvir is effective and safe for patients with hepatitis C who are typically considered difficult to treat, according to data from the ELECTRON-2 study presented here at Digestive Disease Week 2014.
This population of difficult-to-treat patients includes those with HCV genotype 3, decompensated patients with HCV genotype 1 and patients with HCV genotype 1 who have prior experience with sofosbuvir (Solvaldi, Gilead)....
Continue reading.. 

Fatty Liver
Medscape
DDW
Bariatric Surgery Improves Nonalcoholic Fatty Liver Disease  
Patients with nonalcoholic fatty liver disease who had bariatric surgery experienced a reduction in fat deposits and in early-stage fibrosis. 
Continue reading.. 

Healio
Lean NAFLD patients showed higher mortality rates than non-lean patients
May 4, 2014
CHICAGO — Lean patients with nonalcoholic fatty liver disease had a higher mortality rate compared with non-lean patients with nonalcoholic fatty...
Continue reading..

MedPage Today
DDW -  
Oral HCV Regimen Continues Strong Showing
CHICAGO -- An all-oral antiviral combination led to sustained virologic response (SVR) in more than 90% of patients with the most common type of hepatitis C (HCV) infection in North America. - Continue reading....

Editorial 
The New England Journal Of Medicine
DDW - Therapy of Hepatitis C — Back to the Future

Hepatitis C: Successful Treatment Without Interferon for HCV 3
MedicalResearch.com Interview with:
Stefan Zeuzem, M.D.
Professor of Medicine, Chief Department of Medicine
JW Goethe University Hospital
Frankfurt Germany 

MedicalResearch.com: What are the main findings of the study?
Dr. Zeuzem: Main finding is that also patients infected with HCV 3 can be cured with an IFN-free regimen. However, duration of therapy must be prolonged to 24 weeks. 

MedicalResearch.com: Were any of the findings unexpected?
Dr. Zeuzem: Treatment prolongation from 12 to 16 weeks already suggested that longer treatment duration will increase sustained virologic response (SVR) rates. The magnitude of sustained virologic response  rates with 24 wks SOF + RBV in HCV3 was unexpected.

MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Zeuzem: Standard of care for patients infected with HCV 2 is now confirmed to be 12 wks SOF + RBV, for HCV 3 infected patients an IFN-free regimen with chances of SVR > 90% is now also available. These options have already been included in the European label.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Zeuzem: The sustained virologic response rates for treatment-experienced patients with HCV 3 and liver cirrhosis are still “only” 60%. Here, further improvement is needed, likely by addition of another direct antiviral agent with a different mechanism of action and HCV3 activity. 
Citation: The New England Journal Of Medicine
DDW-Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3

The New England Journal Of Medicine
DDW - ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

Healthy Liver - Healthy Digestion
A focus on digestion and a somewhat familiar disorder called Functional Dyspepsia (FD).The medical term simply means - bad digestion, the symptoms vary but are frequently described as a full or bloated feeling after eating. Today,  Dr. Olafur S. Palsson offered commentary on the results of a statistical analyses estimating how common functional dyspepsia (FD) is in American adults, presented at this months DDW meeting.

View All DDW Updates On This Blog 

In The News

The Asia-Pacific Journal, Vol. 12, Issue 18, No. 2, May 5, 2014. 
Yellow Blood: Hepatitis C and the Modernist Settlement in Japan. 
Vivian Blaxell
Précis:
Japan has one of the highest rates of hepatitis C virus infection in the industrialized world. This endemic and the challenges it poses for the future of Japan’s healthcare system stem, ironically, from the formation of a modernist settlement beginning in the late 19^th century. Modern techno-scientific solutions to political problems inadvertently provided millions of opportunities for hepatitis C to spread in rural communities, among leprosy communities, the traumatized postwar community and into the national blood supply...
Continue reading.. 

Audio
New treatments for Hepatitis C
Listen now
Presented by Dr Norman Swan
Monday 5 May 2014 5:30PM
Chronic hepatitis C infections put people at high risk of cirrhosis of the liver, liver cancer and liver transplantation or even death after a long illness. In recent months the US has approved drugs which can raise the cure rate to 90% and higher, with fewer side effects and no need for injections. This medication is under evaluation in Australia, but will be almost unaffordable with costs around ...

Continue reading.......

May 05, 2014
Kaiser Health News:  

Who Should Get Pricey Hepatitis C Drugs?
Kaiser Health News staff writer Julie Appleby, working in collaboration with The Washington Post, reports: “Simple math illustrates the challenge facing U.S. taxpayers, consumers and insurers following the launch late last year of two expensive new drugs to treat hepatitis C. If all 3 million people estimated to be infected with the virus in America are treated at an average cost of $100,000 each, the amount the U.S. spends on prescription drugs would double, from about $300 billion in one year to more than $600 billion” (Appleby, 5/5).
Read the story.

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ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

Digestive Disease Week 2014

Original Article - NEJM

ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

Peter Ferenci, M.D., David Bernstein, M.D., Jacob Lalezari, M.D., Daniel Cohen, M.D., Yan Luo, M.D., Ph.D., Curtis Cooper, M.D., Edward Tam, M.D., Rui T. Marinho, M.D., Ph.D., Naoky Tsai, M.D., Anders Nyberg, M.D., Terry D. Box, M.D., Ziad Younes, M.D., Pedram Enayati, M.D., Sinikka Green, M.D., Yaacov Baruch, M.D., Bal Raj Bhandari, M.D., Florin Alexandru Caruntu, M.D., Ph.D., Thomas Sepe, M.D., Vladimir Chulanov, M.D., Ph.D., Ewa Janczewska, M.D., Ph.D., Giuliano Rizzardini, M.D., Judit Gervain, M.D., Ph.D., Ramon Planas, M.D., Christophe Moreno, M.D., Ph.D., Tarek Hassanein, M.D., Wangang Xie, Ph.D., Martin King, Ph.D., Thomas Podsadecki, M.D., and K. Rajender Reddy, M.D.

May 4, 2014DOI: 10.1056/NEJMoa1402338

Hepatitis C virus (HCV) infection is a worldwide health issue, with 3 million to 4 million new infections yearly and infection rates as high as 5% in some countries.1 Chronic infection leads to liver disease, cirrhosis, or liver cancer in a large proportion of infected persons, and hepatitis C accounts for 25% of all liver cancers, representing the leading indication for liver transplantation.1-3 Genotype 1 is the most common HCV genotype worldwide and includes 11 subgenotypes, of which 1a and 1b are responsible for the vast majority of infections.4 Genotype 1b infection is the most prevalent form worldwide, particularly in Europe and East Asia, whereas genotype 1a infection is more prevalent in North America.4

Approved treatments for HCV genotype 1 infection include peginterferon and ribavirin combined with a direct-acting antiviral agent.5-9 Peginterferon is associated with substantial adverse events, including influenza-like symptoms, depression, fatigue, and cytopenias that make it difficult for patients to adhere to treatment.10 Cure rates for genotype 1a and 1b infection may differ depending on the treatment regimen; rates are generally lower among patients with genotype 1a infection when the treatment regimen includes an NS3 protease inhibitor or an NS5A replication complex inhibitor6,8,11,12 and among patients with genotype 1b infection when the regimen includes the nucleotide analogue sofosbuvir.9 Data suggest that genotype 1a infection is more difficult to cure than genotype 1b infection owing to the development of resistance.7,13-17 Thus, careful assessment of the efficacy of individual regimens in patients with different subgenotypes of HCV infection is warranted.

Ribavirin is an important component of peginterferon-based therapy with first-generation protease inhibitors, but phase 2 clinical trials of interferon-free regimens based on direct-acting antiviral agents suggest that ribavirin may not always be required.16,18-20 Although ribavirin appears to have less toxicity in the absence of peginterferon,9,21 ribavirin is teratogenic and is associated with hemolytic anemia. Therefore, identifying patients who could be successfully treated without ribavirin is of great importance.

ABT-450, an inhibitor of the HCV nonstructural 3/4A (NS3/4A) protease, is administered with ritonavir (ABT-450/r) to increase ABT-450 plasma levels and half-life, permitting once-daily dosing.22 Ombitasvir (ABT-267) is an inhibitor of the HCV NS5A replication complex, and dasabuvir (ABT-333) is a nonnucleoside NS5B polymerase inhibitor. All three agents have potent activity against HCV genotype 1 in vitro.23 In a randomized, controlled, phase 2b study, a regimen of ABT-450/r, ombitasvir, and dasabuvir with ribavirin, administered for 12 weeks, was efficacious in previously untreated patients with HCV genotype 1 infection.18 In addition, all 25 patients with genotype 1b infection who were treated without ribavirin had undetectable HCV RNA levels 24 weeks after the end of therapy.

On the basis of these data, two separate phase 3 trials were designed to evaluate the role of ribavirin in the treatment of patients with genotype 1a or 1b infection. We assessed the efficacy and safety of a 12-week treatment regimen of coformulated ABT-450/r–ombitasvir and dasabuvir with or without ribavirin in previously untreated patients without cirrhosis who had HCV genotype 1a infection (PEARL-IV study) or genotype 1b infection (PEARL-III study). The double-blind, placebo-controlled design of these studies permitted a thorough assessment of the contribution of ribavirin to the adverse-event profile of the combination regimen.
Methods

Patients

Patients 18 to 70 years of age were eligible for enrollment if they had chronic HCV genotype 1 infection with an HCV RNA level of more than 10,000 IU per milliliter and had never received any antiviral treatment for HCV. Patients with genotype 1a infection were screened at 53 sites in Canada, the United States, and the United Kingdom (PEARL-IV study). Patients with genotype 1b infection were screened at 50 sites in Austria, Belgium, Hungary, Israel, Italy, Poland, Portugal, Romania, the Russian Federation, Spain, and the United States (PEARL-III study). For both studies, eligible patients had no evidence of cirrhosis as documented by means of a liver biopsy within the previous 24 months, transient elastography (FibroScan), or noninvasive assessment of serum markers (FibroTest). Patients were excluded if they had coinfection with human immunodeficiency virus or hepatitis B virus or if they had infection with any HCV genotype other than 1a (PEARL-IV study) or 1b (PEARL-III study). Detailed eligibility criteria and information on fibrosis scoring are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Designs

Patients in both studies were stratified according to IL28B genotype (CC vs. non-CC) and randomly assigned in a 1:2 ratio (genotype 1a study) or a 1:1 ratio (genotype 1b study) to receive either ribavirin twice daily according to body weight (1000 mg daily if the body weight was <75 kg and 1200 mg daily if the body weight was ≥75 kg) or matching placebo for 12 weeks. All the patients received open-label ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) for 12 weeks (Figure 1)
Visits were scheduled at weeks 0, 1, 2, 4, 6, 8, 10, and 12 of the treatment period, and patients were followed for 48 weeks after the treatment period. The investigators, patients, and study sponsor (AbbVie) were unaware of the treatment assignments and hemoglobin or hematocrit values. If a predefined toxicity criterion for hemoglobin values was met, all hematologic laboratory data were disclosed to the site investigator to allow for appropriate patient care. Additional details on study designs are provided in the Supplementary Appendix.

The studies were conducted in accordance with the International Conference on Harmonisation guidelines, applicable regulations, and guidelines governing clinical-study conduct and ethical principles that have their origin in the Declaration of Helsinki. All the patients provided written informed consent. The studies were designed by the study sponsor. The investigators and sponsor jointly conducted the study and gathered the data. The sponsor conducted the data analyses. All the authors signed a confidentiality agreement with the sponsor. The first draft of the manuscript was written by a sponsor-employed medical writer, with input from all the authors. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the data and analyses and for the fidelity of the studies to the protocol, available at NEJM.org.

Efficacy and Safety Assessments

Details of the collection of plasma samples, HCV RNA measurement, virologic-failure criteria, resistance testing, and logistic-regression analyses of response predictors are available in the Supplementary Appendix. Adverse-event assessment and clinical laboratory testing were performed at each study visit during treatment and in the follow-up period. Adverse events were reported from the time of study-treatment initiation until 30 days after the last dose. Data on serious adverse events were collected throughout the study.

Efficacy End Points

The primary efficacy end point for both studies was a sustained virologic response (a plasma HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. The primary objective of both studies was to assess the noninferiority of the rate of sustained virologic response at post-treatment week 12 in each study group, as compared with the historical rate with telaprevir plus peginterferon–ribavirin among previously untreated patients with the corresponding HCV subgenotype. The historical rate was 72% among patients with genotype 1a infection (95% confidence interval [CI], 68 to 75) and 80% among those with genotype 1b infection (95% CI, 75 to 84) (see the Supplementary Appendix for details). Secondary efficacy objectives in each study were to assess the noninferiority of the sustained-virologic-response rate in the group that did not receive ribavirin as compared with the group that received ribavirin, the superiority of the rate at post-treatment week 12 in each group as compared with the historical rate with telaprevir plus peginterferon–ribavirin in the corresponding patient population, the percentage of patients in each group with a hemoglobin level below the lower limit of the normal range at the end of treatment, and the percentage of patients in each group with virologic failure during treatment or relapse after treatment.

Statistical Analysis

Efficacy analyses were performed in the modified intention-to-treat population, defined as all randomly assigned patients who received at least one dose of a study drug. For the analysis of whether the rate of sustained virologic response with the interferon-free regimen was noninferior to the historical rate with telaprevir plus peginterferon–ribavirin, a noninferiority margin of 10.5 percentage points was used. To establish that the rate with the interferon-free regimen was noninferior to the historical rate, the lower boundary of the 95% confidence interval (based on the normal approximation to the binomial distribution) had to exceed 73% for the genotype 1b study and 65% for the genotype 1a study. Superiority could be established if the lower boundary of the confidence interval for the interferon-free regimen was greater than the upper boundary of the confidence interval for the historical rate: 84% for the genotype 1b study and 75% for the genotype 1a study. The assessment of the noninferiority of the regimen without ribavirin as compared with the regimen with ribavirin was based on a noninferiority margin of 10.5 percentage points.24 Details of the efficacy analyses, including the fixed-sequence testing plan for the primary and secondary end points, are provided in the Supplementary Appendix.

Safety analyses compared the rate of adverse events and laboratory abnormalities between treatment groups in each study with the use of Fisher's exact test. Sample-size determination is described in the Supplementary Appendix. SAS software for the UNIX operating system (SAS Institute) was used for all analyses. All statistical tests and all confidence intervals were two-sided, with a significance level of 0.05.

Results - Baseline Demographic and Clinical Characteristics

In the genotype 1a study, 305 of 436 screened patients underwent randomization and received at least one dose of a study drug (Figure S1 in the Supplementary Appendix). A total of 629 patients were screened for the genotype 1b study, of whom 419 underwent randomization and received at least one dose of a study drug. Baseline demographic and clinical characteristics were well balanced between the two groups in each study (Table 1) The majority of patients in the genotype 1a study were enrolled in North America, whereas the majority of patients in the genotype 1b study were enrolled in Europe. Among patients enrolled in the United States, blacks accounted for 14.2% of patients in the genotype 1a study (35 of 247 patients) and 21.1% of patients in the genotype 1b study (20 of 95 patients).

Efficacy Outcomes - Genotype 1a Study

After 12 weeks of treatment with ABT-450/r–ombitasvir and dasabuvir in the genotype 1a study, 97 of 100 patients who received the antiviral regimen with ribavirin had a sustained virologic response at post-treatment week 12, for a rate of 97.0% (95% CI, 93.7 to 100); 185 of 205 patients who received the regimen without ribavirin had a sustained virologic response, for a rate of 90.2% (95% CI, 86.2 to 94.3) (Figure 2) Hence, the sustained-virologic-response rates for the regimens with and without ribavirin were both noninferior and superior to the historical rate with telaprevir plus peginterferon–ribavirin in previously untreated adults with HCV genotype 1a infection and no cirrhosis. The regimen without ribavirin did not meet the noninferiority criterion as compared with the regimen with ribavirin, because the lower boundary of the confidence interval for the difference (−6.8 percentage points [95% CI, −12.0 to −1.5]) crossed the noninferiority margin of 10.5 percentage points. In addition, the upper boundary of the confidence interval did not cross zero, indicating a significant difference between groups.

A total of 18 patients with genotype 1a infection had virologic failure, 16 of whom received the regimen without ribavirin. Of the 3 patients with genotype 1a infection who received the regimen with ribavirin and did not have a sustained virologic response, 2 had virologic failure (1 had a rebound in HCV RNA levels during treatment and 1 had a relapse after treatment), and 1 did not complete follow-up testing at post-treatment week 12. Of the 16 patients with genotype 1a infection who received the regimen without ribavirin and had virologic failure, 6 had a virologic rebound during treatment and 10 had a relapse after treatment. All the patients with a relapse received at least 11 weeks of treatment. Adherence to the dosing regimen for each study drug was greater than 95% for 16 of the 17 patients with virologic failure for whom data were available; 1 patient who received the antiviral regimen without ribavirin and had a virologic rebound took 88.5% of the planned ABT-450/r–ombitasvir doses and 90.8% of the planned dasabuvir doses. On the basis of logistic-regression analyses of baseline demographic and clinical characteristics, only IL28B CC genotype, which has historically been associated with increased rates of response to treatment for HCV infection, was associated with an increased rate of sustained virologic response among patients with genotype 1a infection (P=0.03).

At the time of virologic failure, each of the 18 patients with genotype 1a infection and a virologic failure had at least one resistance-associated variant known to be selected by one of the three direct-acting antiviral agents included in the regimen. The most frequently detected variants in patients with virologic failure were D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B.

Genotype 1b Study

In this study, 209 of the 210 patients who received the antiviral regimen with ribavirin had a sustained virologic response at post-treatment week 12, for a rate of 99.5% (95% CI, 98.6 to 100.0); 207 of the 209 patients who received the regimen without ribavirin had a sustained virologic response, for a rate of 99.0% (95% CI, 97.7 to 100.0). Thus, the sustained-virologic-response rates among patients who received ribavirin and those who did not were both noninferior and superior to the historical rate with telaprevir plus peginterferon–ribavirin among previously untreated adults with HCV genotype 1b infection and no cirrhosis. In addition, the sustained-virologic-response rate among patients who did not receive ribavirin was noninferior to the rate among those who received ribavirin (difference, −0.5 percentage points [95% CI, −2.1 to 1.1]). Only one patient with genotype 1b infection had virologic failure during treatment; this patient, who received the antiviral regimen with ribavirin, had a virologic rebound during treatment. The two patients who received the regimen without ribavirin and did not have a sustained virologic response completed treatment but did not complete follow-up testing at post-treatment week 12 (Table 2)

Owing to the high rates of sustained virologic response, there were no significant predictors of virologic failure.

Adverse Events In both studies, adverse events were more frequently reported in the groups receiving antiviral regimens that contained ribavirin than in the groups that received the ribavirin-free regimen (P=0.03 in the genotype 1a study and P=0.003 in the genotype 1b study) (Table 3)

The most common adverse events reported in the two studies, headache and fatigue, did not differ significantly in either study between the group that received ribavirin and the group that did not receive it. Among other common adverse events, pruritus, nausea, and insomnia occurred at a higher frequency among patients who received ribavirin than among those who did not in one or both studies. The majority of adverse events in all treatment groups were mild; overall, two patients (both in the genotype 1a study) discontinued the study drugs owing to adverse events.

Serious adverse events occurred in eight patients in the genotype 1b study (four who received ribavirin and four who did not) and in four patients in the genotype 1a study (three who received ribavirin and one who did not). All patients with a serious adverse event had a sustained virologic response. Details of all serious adverse events are provided in Table S5 in the Supplementary Appendix.

Decreased Hemoglobin Levels

Among the patients in the genotype 1a study who had a hemoglobin level within the normal range at baseline, 42.0% of patients who received the antiviral regimen with ribavirin and 3.9% of patients who received the ribavirin-free regimen had a hemoglobin level below the lower limit of the normal range at the end of treatment (P<0.001). Similarly, in the genotype 1b study, 51.2% of patients who received ribavirin had a low hemoglobin level at the end of treatment, as compared with 3.4% of patients who did not receive ribavirin (P<0.001). A hemoglobin level of less than 10 g per deciliter at any time during treatment occurred in 4.0% of patients with genotype 1a infection who received ribavirin and in 9.0% of patients with genotype 1b infection who received ribavirin but did not occur in any patients who received the ribavirin-free regimen (Table 3). The ribavirin dose was reduced in accordance with the protocol because of a decreased hemoglobin level in 6 patients with genotype 1a infection who received ribavirin (6.0%) and in 16 patients with genotype 1b infection who received ribavirin (7.6%); all these patients had a sustained virologic response. Additional data on hemoglobin levels are provided in the Supplementary Appendix.

Other Laboratory Abnormalities

In both studies, the proportions of patients with elevations in the serum level of bilirubin were higher in the groups that received the ribavirin-containing regimen than in the groups that received the ribavirin-free regimen (Tables S6 and S7 in the Supplementary Appendix). Elevated levels of indirect (unconjugated) bilirubin primarily accounted for the abnormalities in both studies. Mean bilirubin levels peaked 1 week after the start of study-drug treatment and stabilized or normalized thereafter; maximal observed bilirubin levels were 6.5 mg per deciliter (110 μmol per liter) in the genotype 1a study and 9.4 mg per deciliter (160 μmol per liter) in the genotype 1b study. Elevations in the bilirubin level were not associated with elevations in aminotransferase levels. Additional details on laboratory abnormalities are provided in the Supplementary Appendix.

Discussion

In two phase 3 studies (PEARL-III and PEARL-IV), 90.2 to 99.5% of previously untreated patients with HCV genotype 1 infection and no cirrhosis had a sustained virologic response after 12 weeks of treatment with ABT-450/r–ombitasvir and dasabuvir with or without ribavirin. Response rates in all treatment groups were superior to the historical response rate with a peginterferon-containing telaprevir-based regimen.5 These findings suggest that in previously untreated patients with HCV infection and no cirrhosis, this 12-week regimen of three direct-acting antiviral agents is efficacious both with and without ribavirin.

We also assessed the contribution of ribavirin to the treatment response and safety profile of the regimen. The effect of ribavirin on the treatment response in patients with HCV genotype 1a infection differed from that in patients with genotype 1b infection. The inclusion of ribavirin did not significantly affect the sustained-virologic-response rate among patients with genotype 1b infection, because the rate was 99.0% in the group that did not receive ribavirin and 99.5% in the group that received it. Thus, in this patient population, the 12-week regimen of ABT-450/r–ombitasvir and dasabuvir resulted in similarly high rates of sustained virologic response with and without ribavirin, results that are consistent with those of a phase 2b study18 and phase 3 studies25,26 of this regimen. In contrast, although more than 90% of patients in each treatment group in the genotype 1a study had a sustained virologic response, the response rate in the group that that received the ribavirin-free regimen did not meet the criterion for noninferiority to the rate in the group that received the ribavirin-containing regimen owing to a higher rate of virologic failure with the ribavirin-free regimen. A total of 18 patients with genotype 1a infection had virologic failure, and only 2 of these patients received ribavirin. Hence, the use of ribavirin in this population appears to confer an additional benefit.

Regardless of whether the antiviral regimen included ribavirin, the rate of discontinuation of the study drugs owing to adverse events was low (<1%). As compared with the groups that did not receive ribavirin, the groups that did receive it had more adverse events, particularly pruritus, nausea, and insomnia — events that are known to be associated with ribavirin. In addition, laboratory abnormalities that have historically been associated with ribavirin — decreases in the hemoglobin level and increases in the total bilirubin level — were more common in the groups that received ribavirin. The pattern of bilirubin elevations across treatment regimens confirmed that the hyperbilirubinemic effect of ABT-450, an inhibitor of the bilirubin transporter OATP1B1, is enhanced by ribavirin-associated hemolysis. However, these abnormalities did not appear to affect the likelihood of treatment success and did not result in treatment discontinuation. Overall, the adverse events observed in these two phase 3 trials were consistent with those observed in past trials with these regimens.

Studies of direct-acting antiviral therapy have shown that these regimens can result in high rates of sustained virologic response. The role of and need for ribavirin in maximizing sustained-virologic-response rates in different patient populations remain incompletely characterized by clinical studies. Exploratory studies have shown sustained-virologic-response rates of 95% or higher when sofosbuvir is combined with other direct-acting antiviral agents (ledipasvir, daclatasvir, or simeprevir) with or without ribavirin, although these findings remain to be confirmed by larger trials.19,20,27,28 Although these results suggest that sufficiently efficacious ribavirin-free treatments may obviate the need for ribavirin in some patients, larger studies will be needed to determine which patient populations may require ribavirin for the greatest chance of virologic cure.

The PEARL-III and PEARL-IV studies were double-blind, randomized trials with large samples and a broad geographic scope of enrollment. The patient populations were representative of typical North American or European populations with genotype 1a or 1b infection, the two most prevalent subgenotypes in North America, Asia, and Europe. Rates of premature discontinuation and loss to follow-up were low in both trials. A limitation of the studies was the inability to completely conceal the ribavirin and placebo assignments from patients and investigators because of the characteristic adverse events and laboratory abnormalities associated with ribavirin. In addition, the studies did not include previously treated patients or patients with cirrhosis, although this regimen with ribavirin was associated with a high rate of sustained virologic response in these patient populations in recent studies.25,26

Although the two studies showed that premature discontinuation and serious adverse events were uncommon with the 12-week course of all-oral therapy that included ribavirin, as well as with the ribavirin-free regimen, some patients may benefit from a ribavirin-free treatment option, including patients with contraindications to ribavirin therapy, such as hemoglobinopathies and severe cardiac or pulmonary disease, and those with severe renal impairment. Given the known teratogenicity of ribavirin, a ribavirin-free regimen would also be preferable for some women of childbearing potential.

In conclusion, previously untreated patients with HCV genotype 1a or 1b infection and no cirrhosis who received ABT-450/r–ombitasvir and dasabuvir with or without ribavirin had high sustained-virologic-response rates that were superior to the historical response rate with peginterferon–ribavirin plus telaprevir. Although ribavirin did not improve the response in patients with genotype 1b infection, our findings suggest that ribavirin confers an additional benefit for patients with genotype 1a infection.

Sponsored by AbbVie.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Ferenci and Bernstein contributed equally to this article.

This article was published on May 4, 2014, at NEJM.org.

We thank the trial participants, investigators, and coordinators who made these studies possible; and Douglas E. Dylla, Ph.D., of AbbVie for medical writing support.

Source Information

The authors' affiliations are listed in the Appendix.

Address reprint requests to Dr. Ferenci at the Medical University of Vienna, Univ. Klinik für Innere Medizin III, Klinische Abteilung für Gastroenterologie und Hepatologie, Währinger Gürtel 18-20, 1090 Vienna, Austria, or at peter.ferenci@meduniwien.ac.at.

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Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3

Digestive Disease Week 2014

Original Article - NEJM

Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3

Stefan Zeuzem, M.D., Geoffrey M. Dusheiko, M.D., Riina Salupere, M.D., Ph.D., Alessandra Mangia, M.D., Robert Flisiak, M.D., Ph.D., Robert H. Hyland, D.Phil., Ari Illeperuma, M.S., Evguenia Svarovskaia, Ph.D., Diana M. Brainard, M.D., William T. Symonds, Pharm.D., G. Mani Subramanian, M.D., Ph.D., John G. McHutchison, M.D., Ola Weiland, M.D., Hendrik W. Reesink, M.D., Ph.D., Peter Ferenci, M.D., Christophe Hézode, M.D., and Rafael Esteban, M.D. for the VALENCE Investigators

May 4, 2014DOI: 10.1056/NEJMoa1316145

Of the six main genotypes of the hepatitis C virus (HCV), genotypes 2 and 3 account for approximately 30% of chronic infections worldwide.1 Although these two genotypes have historically been grouped together in treatment guidelines and clinical trials,2,3 accumulating evidence suggests that there are important clinical differences between them.1,4,5 HCV genotype 3 infection is associated with a higher incidence of hepatic steatosis, more rapid progression of fibrosis, and possibly a greater risk of hepatocellular carcinoma than is HCV genotype 2 infection.6 Moreover, patients with HCV genotype 3 infection are less responsive to peginterferon-based treatment than are patients with HCV genotype 2 infection.7-9 Until recently, peginterferon plus ribavirin administered for 24 weeks was the standard treatment for patients with either genotype 2 or genotype 3 infection.2,3 However, the ongoing discovery and development of agents that directly target various stages of HCV replication are likely to provide HCV-infected patients with effective interferon-free therapy.10-12

Sofosbuvir is an oral nucleotide analogue inhibitor of the HCV NS5B polymerase that is effective against HCV genotypes 2 and 3 when it is administered in combination with ribavirin.13,14 In phase 3 trials involving patients with HCV genotype 2 or 3 infection, therapy with sofosbuvir–ribavirin for 12 weeks resulted in rates of sustained virologic response of 67% among patients who had not undergone previous interferon-based therapy and 78% among patients for whom peginterferon therapy was not possible because of contraindications or in whom unacceptable side effects developed. Among patients who had undergone previous therapy, rates of sustained virologic response were 50% among those who received 12 weeks of sofosbuvir–ribavirin and 73% among those who received 16 weeks of the drug combination.14 In all the phase 3 studies of sofosbuvir–ribavirin, higher rates of sustained virologic response were observed among patients with genotype 2 infection than among those with genotype 3 infection.

We conducted a study of sofosbuvir and ribavirin that included patients who had not received previous treatment and those who had undergone previous treatment. The purpose of our study was to assess the efficacy of 24 weeks of sofosbuvir–ribavirin therapy in patients with HCV genotype 3 infection and to confirm previous findings with respect to 12 weeks of therapy in patients with HCV genotype 2 infection.

Methods

Patients

We enrolled patients from September 2012 through January 2013 at 77 sites in Europe. Eligible patients were 18 years of age or older and had chronic infection with HCV genotype 2 or 3, with serum HCV RNA levels of 10,000 IU per milliliter or higher. Patients could participate in the study regardless of whether they had received previous therapy for HCV infection with an interferon-based regimen. Some of the study patients either had not had a sustained virologic response after at least 12 weeks of previous treatment with an interferon-based regimen or had discontinued interferon treatment after no more than 12 weeks of treatment because of severe adverse reactions, psychiatric disease requiring hospitalization, major disability, or other recognized side effects of interferon. According to prespecified criteria, approximately 20% of patients who were enrolled could have cirrhosis. All patients provided written informed consent. Full eligibility criteria, including details of the assessment for cirrhosis and reasons for ineligibility for interferon treatment are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design

The study was initially designed as a multicenter phase 3 trial. Patients were randomly assigned, in a 4:1 ratio, to receive either sofosbuvir–ribavirin or matching placebo. Randomization was stratified according to status with respect to previous therapy (no previous therapy or previous therapy) and the presence or absence of cirrhosis at the time of screening. Sofosbuvir (Gilead Sciences) was administered orally at a dose of 400 mg once daily. Ribavirin (Ribasphere, Kadmon) was administered orally twice daily, with doses determined according to body weight (1000 mg daily in patients with a body weight of <75 kg and 1200 mg daily in patients with a body weight of ≥75 kg).

The study design originally called for all patients to receive 12 weeks of treatment with sofosbuvir–ribavirin or matching placebo. However, after the initiation of the study, newly available results from the FUSION phase 3 study of sofosbuvir strongly suggested that patients with HCV genotype 3 infection could benefit from extending treatment beyond 12 weeks.14 The study protocol was accordingly amended so that the study-group assignments were unblinded, the placebo group was terminated, patients with HCV genotype 2 infection were treated as originally planned for 12 weeks, and the treatment of patients with HCV genotype 3 infection was extended to 24 weeks. Patients with HCV genotype 3 infection who had already completed 12 weeks of treatment before the amendment was approved were not given additional treatment. Patients in the discontinued placebo group were offered open-label treatment with sofosbuvir–ribavirin in another clinical trial (ClinicalTrials.gov number, NCT01625338), with a duration based on the HCV genotype.

The study was redefined as a descriptive study to characterize sustained response rates in patients with HCV genotype 2 infection who were treated for 12 weeks and in patients with HCV genotype 3 infection who were treated for 24 weeks, with no plans for hypothesis testing. Details regarding the assessments that were used in the study are provided in the Supplementary Appendix.

Primary End Point

The primary efficacy end point was a sustained virologic response at 12 weeks after the end of treatment. This response was defined as a level of HCV RNA below the lower limit of quantification (25 IU per milliliter).

Study Oversight

This study was approved by the institutional review board or independent ethics committee at each participating site and was conducted in compliance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. The study was designed and conducted according to protocol by the sponsor (Gilead) in collaboration with the principal investigators. The sponsor collected the data, monitored the conduct of the study, and performed the statistical analyses. An independent data and safety monitoring committee reviewed the progress of the study. The investigators, participating institutions, and sponsor agreed to maintain the confidentiality of the data. All the authors vouch for the completeness and accuracy of the data and data analyses and for the fidelity of this report to the study protocol, which is available at NEJM.org. The manuscript was prepared by Gilead Sciences and the first author with input from all the authors.

Statistical Analysis

In the original analysis plan, we determined that a sample size of 320 patients in the sofosbuvir–ribavirin group and 80 patients in the placebo group would provide a power of 99% to detect a difference between the two groups, assuming rates of sustained virologic response of 45% and 5%, respectively, on the basis of a two-sided continuity-corrected chi-square test at a significance level of 0.05. As a result of the study amendment and unblinding of the study-group assignments, all the patients in the placebo group were discontinued from the study, and the primary objective was changed to provide descriptive estimates of efficacy within each active-treatment group, with no comparison with placebo and no hypothesis testing. We calculated the proportion of patients who had a sustained virologic response along with exact two-sided 95% confidence intervals constructed with the use of the Clopper–Pearson method for each active-treatment group and for subgroups. In an exploratory analysis, we performed a multivariate logistic-regression analysis involving baseline demographic and clinical characteristics, using a stepwise procedure to identify independent predictors of a sustained virologic response.

Results

Patients

A total of 475 patients were screened for enrollment (Figure S1 in the Supplementary Appendix). Of these patients, 421 underwent randomization and 419 began treatment.

The demographic and clinical characteristics of the patients at baseline are shown in
Table 1 Demographic and Clinical Characteristics of the Patients at Baseline.. 

Overall, 40% were women, 21% had cirrhosis, and 58% had been previously treated for HCV infection, of whom 30% had had no response. The characteristics of the patients were generally balanced among the study groups, with expected differences between patients with
HCV genotype 2 infection and those with HCV genotype 3 infection.

Efficacy

Patients receiving sofosbuvir–ribavirin had substantial reductions in circulating HCV RNA levels during the first weeks of treatment Table 2.

By week 4 of treatment, 99% of the patients had an HCV RNA level of less than 25 IU per milliliter. No patients in the placebo group had an HCV RNA level of less than 25 IU per milliliter at any time point.

Among patients with HCV genotype 2 infection who received 12 weeks of sofosbuvir–ribavirin, 68 of 73 (93%; 95% confidence interval [CI], 85 to 98) had a sustained virologic response 12 weeks after the cessation of treatment (Table 2). All 68 patients also had a sustained virologic response 24 weeks after treatment. Among patients with HCV genotype 3 who received 24 weeks of sofosbuvir–ribavirin, 213 of 250 patients (85%; 95% CI, 80 to 89) had a sustained virologic response 12 weeks after the cessation of treatment. Of these 213 patients, 206 had a sustained virologic response 24 weeks after treatment, 2 had a virologic relapse, 4 were lost to follow-up after post-treatment week 12, and 1 had an invalid HCV RNA result because the visit occurred outside the window of 24 weeks after treatment.

Exploratory analyses revealed that among patients with HCV genotype 2 infection, the rates of response were consistently high across subgroups Figure 1 and Table S1 in the Supplementary Appendix). Rates of sustained virologic response among patients with HCV genotype 3 infection varied according to treatment history and status with respect to cirrhosis. Among patients who had not received previous treatment, the rates of sustained virologic response were 92% among those with cirrhosis and 95% among those without cirrhosis (Figure S2 in the Supplementary Appendix).

However, among previously treated patients with HCV genotype 3 infection, the rates of sustained virologic response were lower: 62% among those with cirrhosis and 87% among those without cirrhosis. Among patients with HCV genotype 3 infection, overall response rates were 68% among those with cirrhosis and 91% among those without cirrhosis. In an exploratory multivariate regression analysis of patients with genotype 3 infection, four factors were independently associated with a sustained virologic response: a baseline HCV RNA level of less than 6 log10 IU per milliliter (odds ratio, 4.23; 95% CI, 1.21 to 14.81; P=0.02), female sex (odds ratio, 3.18; 95% CI, 1.22 to 8.31; P=0.02), absence of cirrhosis (odds ratio, 3.46; 95% CI, 1.60 to 7.48; P=0.002), and an age of less than 50 years (odds ratio, 2.82; 95% CI, 1.21 to 6.57; P=0.02) (Table S5 in the Supplementary Appendix).

Of the 334 patients receiving sofosbuvir–ribavirin, 1 had a virologic breakthrough during treatment. According to a subsequent pharmacokinetic analysis, this patient had undetectable drug levels during weeks 12 through 24 of treatment, suggesting nonadherence.

Viral Resistance Testing

The S282T variant is the only HCV mutation that has been found to reduce susceptibility to sofosbuvir in vitro. S282T variants were not detected at baseline in any patient, nor were they detected by means of deep sequencing at the time of virologic failure in the patients who did not have a sustained virologic response. Among the 41 patients with HCV genotype 3 infection who had virologic failure, the mutations that have been associated with sofosbuvir treatment — V321A and L159F — were detected in 2 and 6 patients, respectively. The V321A mutation was not observed at baseline in any patient, and L159F was not assessed at baseline in this study, since only short-fragment sequencing from NS5B positions 227–338 was performed. During in vitro testing, neither the V321A mutation nor the L159F mutation conferred resistance to sofosbuvir. The clinical significance of these mutations that develop during treatment is not known.

Adverse Events

Premature discontinuation of study treatment because of adverse events was uncommon in all the study groups. One patient in the placebo group discontinued therapy because of elevated alanine aminotransferase and aspartate aminotransferase levels, one patient with HCV genotype 3 infection receiving 12 weeks of treatment discontinued because of malaise and headache, and one patient with HCV genotype 3 receiving 24 weeks of treatment discontinued after attempting suicide. The most common adverse events are shown in Table 3.

Most adverse events occurred with similar frequency in the 12-week and 24-week treatment groups. Diarrhea and irritability were observed more frequently in the 24-week group than in the 12-week group. No single grade 3 or 4 adverse event occurred in more than 1% of patients receiving sofosbuvir for 12 or 24 weeks. (A complete list of serious adverse events is provided in Table S6 in the Supplementary Appendix.)

Among patients receiving 12 weeks of treatment with sofosbuvir–ribavirin, grade 3 laboratory abnormalities were reported in 19% of the patients and grade 4 abnormalities in 1%; among those receiving 24 weeks of therapy, such abnormalities were reported in 17% and 1% of the patients, respectively. Reductions in hemoglobin levels were observed, a finding that was consistent with the expected hemolytic anemia associated with ribavirin treatment: 6% of patients in both the 12-week and 24-week groups had hemoglobin levels of less than 10 g per deciliter, and one patient in each group had a hemoglobin level of less than 8.5 g per deciliter. Reductions in the dose of ribavirin were performed according to the prescribing information and did not adversely influence the treatment outcome (Table S2 in the Supplementary Appendix). The mean reduction in hemoglobin level at the end of treatment was 2.3 g per deciliter in the 12-week group and 2.1 g per deciliter in the 24-week group. Transient increases in total serum bilirubin were observed to have a temporal association with reductions in hemoglobin associated with hemolysis.

Discussion

This descriptive study of the oral regimen of sofosbuvir in combination with ribavirin, which was conducted at nearly 80 sites in Europe, confirmed findings from previous studies of sofosbuvir in similar populations in North America.13,14 We found high rates of sustained virologic response among patients with HCV genotype 2 infection and among those with genotype 3 infection, with a longer treatment duration providing benefit in the latter group.

Among patients with HCV genotype 2 infection, high rates of response and low rates of relapse were observed in all subgroups, indicating the efficacy of 12 weeks of treatment in patients with this genotype. For patients infected with HCV genotype 3, extending sofosbuvir–ribavirin treatment to 24 weeks resulted in substantially higher rates of response and lower rates of relapse than previously reported with the same regimen for 12 weeks and 16 weeks, regardless of the status with respect to previous therapy and the presence or absence of cirrhosis.12 Extending the duration of treatment from 12 weeks to 24 weeks was not associated with increases in the severity or frequency of adverse events, nor in the rate of treatment discontinuation, which was approximately 1% in both the 12-week and 24-week groups. In addition, the absence of virologic breakthrough during treatment and the absence of resistance-associated variants in patients who had a virologic relapse confirm that the sofosbuvir–ribavirin regimen has a high barrier to resistance.

These findings provide further confirmation of important differences in response to treatment between HCV genotype 2 and genotype 3 and the need for a longer treatment duration with sofosbuvir–ribavirin in patients with HCV genotype 3 infection. The biologic bases and the host or viral factors that account for the differences in treatment responsiveness between the two genotypes are not well understood. Between-genotype differences in response were not evident during treatment, since the kinetics of the viral decline during the first weeks of treatment were nearly identical in patients with genotype 2 infection and those with genotype 3 infection. However, in a multivariate regression analysis of results, we identified four possible predictors of a sustained virologic response among patients with genotype 3 infection: female sex, absence of cirrhosis, younger age, and a low viral load at baseline. These four factors have also been regarded as predictors of a response to interferon-based treatment.15,16 It should be noted that the results of this multivariate analysis cannot be regarded as definitive without validation in another cohort.

Previously treated patients with HCV genotype 3 infection and cirrhosis had the lowest rate of sustained virologic response (62%, in 29 of 47 patients). The cause or causes for this finding are not known. Small differences among subgroups in the rate of viral decline during the first weeks of treatment were no longer evident by week 4 (Table S3 in the Supplementary Appendix).

Our study has several limitations. First, the original design of this study specified 12 weeks, rather than 24 weeks, of treatment for patients with genotype 3 infection and included comparisons with patients in the placebo group. The revised design resulted in a descriptive study, without any hypothesis testing or formal statistical comparisons. Second, given that few liver-biopsy specimens were available for the study population, questions regarding the extent of liver disease, including steatosis and its association with relapse among patients with genotype 3 infection, cannot be adequately addressed. Third, although response rates with 12 weeks of treatment were high among patients with HCV genotype 2 infection who had characteristics associated with a lower response, the small numbers preclude definitive conclusions regarding the possible benefits of a longer duration of therapy or the addition of peginterferon in harder-to-treat patients.

In conclusion, the oral sofosbuvir–ribavirin regimen resulted in high rates of sustained virologic response both in patients with HCV genotype 2 infection and in those with genotype 3 infection. This treatment offers an alternative to a peginterferon-based regimen and may make possible treatment of a substantial number of patients with HCV infection who are ineligible to receive interferon because of absolute or relative contraindications.

Presented in part at the annual meeting of the American Association for the Study of Liver Diseases, Washington, D.C., November 1–5, 2013.

Supported by Gilead Sciences.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on May 4, 2014, at NEJM.org.

We thank the patients and their families and the site personnel; Minnie Kuo of Gilead Sciences for providing assistance in the conduct of the study; and David McNeel and Kellie Chu of Gilead Sciences for providing editorial assistance.

Source Information

From the Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany (S.Z.); Royal Free Hospital and University College London School of Medicine, London (G.M.D.); Tartu University Hospital, Tartu, Estonia (R.S.); Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy (A.M.); Medical University of Bialystok, Bialystok, Poland (R.F.); Gilead Sciences, Foster City, CA (R.H.H., A.I., E.S., D.M.B., W.T.S., G.M.S., J.G.M.); Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm (O.W.); Academic Medical Center, Amsterdam (H.W.R.); Medical University of Vienna, Vienna (P.F.); Hôpital Henri Mondor, Assistance Publique–Hôpitaux de Paris, Université Paris-Est, INSERM Unité 955, Créteil, France (C.H.); and Hospital Universitario Val d'Hebron, Barcelona (R.E.).

Address reprint requests to Dr. Zeuzem at the Johann Wolfgang Goethe University Medical Center, Theodor Stern Kai 7, 60590 Frankfurt, Germany, or at zeuzem@em.uni-frankfurt.de.

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