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eViralHepatitis Review
SPECIAL EDITION ISSUE 1
Individualizing Therapy in Patient Subpopulations Infected with HCV who have Genotype 3, Cirrhosis, are Interferon-Ineligible/Intolerant, or have Failed Previous Therapy
In this Issue...
This is part 1 of our two-part eViralHepatitis Review Special Edition focused on Patients with Hard-to-Treat HCV. This issue focuses on individualizing therapy in patients who have genotype 3 or cirrhosis, are interferon-ineligible/intolerant, or have failed previous therapy.
In this issue, eViralHepatitis Review Program Director Dr. Mark Sulkowski:
- Reviews the current clinical trial data presented at the 2014 American Association for the Study of Liver Diseases (AASLD)
- Interviews Dr. David Nelson from the University of Florida, author of a number of the studies reviewed and a presenter at AASLD 2014 (available through an audio link embedded in the body of this newsletter)
- Discusses patients with hard-to-treat HCV with eViralHepatitis Review Program Director Dr. Raymond Chung from Harvard Medical School and the Massachusetts General Hospital (also available through an audio link embedded in the body of this newsletter)
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LEARNING OBJECTIVES |
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After participating in this activity, the participant will demonstrate the ability to:
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Discuss the characteristics of "difficult to cure" patient populations in the era of interferon-based regimens and in the era of oral direct-acting antiviral regimens.
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Summarize strategies to increase HCV cure rates in patients with cirrhosis using oral direct acting antiviral regimens. |
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Identify appropriate treatment decisions based on both individual patient factors and emerging data on current and investigational HCV agents. |
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The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. |
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| IMPORTANT CME/CE INFORMATION |
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Accreditation Statements
Physicians
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
Nurses
The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.
credit designations
Physicians
The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses
This 1 contact hour educational activity is provided by the Institute for Johns Hopkins Nursing. Each activity carries a maximum of 1 contact hour or a total of 2 contact hours for the two activities in this program.
Successful Completion
To successfully complete this activity, participants must read the content, and then link to the Johns Hopkins University School of Medicine's website or the Institute for Johns Hopkins Nursing's website to complete the post-test and evaluation. A passing grade of 70% or higher on the post-test/evaluation is required to receive CE credit.
There are no fees or prerequisites for this activity.
Launch Date
January 21, 2015; activities expire 2 years from the date of publication.
The estimated time to complete this activity is one hour.
Internet CME Policy
The Office of Continuing Medical Education (CME) at the Johns Hopkins University School of Medicine is committed to protecting the privacy of its members and customers. The Johns Hopkins University SOM maintains its Internet site as an information resource and service for physicians, other health professionals, and the public.
Continuing Medical Education at the Johns Hopkins University School of Medicine will keep your personal and credit information confidential when you participate in an Internet-based CME program. Your information will never be given to anyone outside of the Johns Hopkins University School of Medicine program. CME collects only the information necessary to provide you with the services that you request.
Disclaimer Statement
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of the Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information for specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.
Statement of Responsibility
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.
Statement of Need
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Many clinicians are unaware of promising new oral treatment options for subpopulations of patients with difficult-to-treat HCV (eg, patients who have cirrhosis, patients with genotype 3 who have failed standard PEG-IFN/RBV, patients who are post-transplant, and patients who are coinfected with HIV) and how to match developing treatment regimens to appropriate patients. |
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Clinicians treating patients with HCV are unaware of the efficacy/safety data of many new investigational agents targeting the HCV life cycle (eg, NS3/4A PIs, NS5A, RNA-dependent RNA polymerase NS5B inhibitors, and cyclophilins). |
LEARNING OBJECTIVES
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Distinguish among the various classes and targets of current and investigational HCV agents. |
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Evaluate emerging data on current and investigational HCV agents and their impact on different hard-to-treat patient populations. |
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Identify appropriate treatment decisions based on both individual patient factors and emerging data on current and investigational HCV agents. |
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Intended Audience
The target audience (clinicians) for this initiative includes hepatologists, gastroenterologists, infectious disease physicians, primary care physicians (PCPs), and other clinicians involved in the care of patients with hepatitis C.
FACULTY DISCLOSURE
As a provider approved by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine Office of Continuing Medical Education (OCME) to require signed disclosure of the existence of financial relationships with industry from any individual in a position to control the content of a CME activity sponsored by OCME. Members of the Planning Committee are required to disclose all relationships regardless of their relevance to the content of the activity. Faculty are required to disclose only those relationships that are relevant to their specific presentation. The following relationship has been reported for this activity:
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Mark S. Sulkowski, MD, served as a consultant/scientific advisor for AbbVie, Inc., Achillion Pharmaceuticals, Bristol-Myers Squibb, Gilead, Janssen, and Merck. He has received grant/research funding from AbbVie, Inc., Bristol-Myers Squibb, Gilead, Janssen, and Merck. Dr. Sulkowski has served as a DSMB member for Gilead, and has served on a steering committee for Pfizer, Inc.
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Raymond T. Chung, MD, discloses that he has served as a principal investigator for AbbVie, Bristol-Myers Squibb, Gilead, and Mass Biologics.
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| No other planners have indicated that they have any financial interest or relationships with a commercial entity whose products or services are relevant to the content of their presentations. |
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| Guest Author Disclosures |
Confidentiality Disclaimer for CME Conference Attendees
I certify that I am attending a Johns Hopkins University School of Medicine CME activity for accredited training and/or educational purposes.
I understand that while I am attending in this capacity, I may be exposed to "protected health information," as that term is defined and used in Hopkins policies and in the federal HIPAA privacy regulations (the "Privacy Regulations"). Protected health information is information about a person's health or treatment that identifies the person.
I pledge and agree to use and disclose any of this protected health information only for the training and/or educational purposes of my visit and to keep the information confidential. I agree not to post or discuss this protected health information, including pictures and/or videos, on any social media site (e.g. Facebook, Twitter, etc.), in any electronic messaging program or through any portable electronic device.
I understand that I may direct to the Johns Hopkins Privacy Officer any questions I have about my obligations under this Confidentiality Pledge or under any of the Hopkins policies and procedures and applicable laws and regulations related to confidentiality. The contact information is: Johns Hopkins Privacy Officer, telephone: 410-735-6509, e-mail: HIPAA@jhmi.edu.
"The Office of Continuing Medical Education at the Johns Hopkins University School of Medicine, as provider of this activity, has relayed information with the CME attendees/participants and certifies that the visitor is attending for training, education and/or observation purposes only."
For CME Questions, please contact the CME Office
(410) 955-2959 or e-mail cmenet@jhmi.edu.
For CME Certificates, please call (410) 502-9634.
Johns Hopkins University School of Medicine Office of Continuing Medical Education
Turner 20/720 Rutland Avenue
Baltimore, Maryland 21205-2195
Reviewed & Approved by:
General Counsel, Johns Hopkins Medicine (4/1/03)
(Updated 4/09 and 3/14)
hardware & software requirements
To access activities, users will need:
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A computer with an internet connection |
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An HTML5 compliant web browser or Internet Explorer 8 (and higher) |
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Program Directors
Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/Hepatology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Raymond T. Chung, MD
Vice Chief, Gastrointestinal Unit
Medical Director, Liver Transplant Program
Massachusetts General Hospital
Boston, Massachusetts
Julie McArthur, MS, CRNP
Adult Nurse Practitioner
Division of Infectious Disease
Johns Hopkins University School of Medicine
Baltimore, Maryland
Heather Thomas, BSN
Research Nurse Manager
Division of Infectious Diseases
Johns Hopkins University School of Nursing
Baltimore, Maryland
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GUEST
AUTHORs OF THE MONTH |
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Commentary:
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 | Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/Hepatology
Johns Hopkins University School of Medicine
Baltimore, Maryland
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 | David R. Nelson, MD
Professor of Medicine
Assistant Vice President of Research
University of Florida
Gainesville, Florida
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 | Raymond T. Chung, MD
Vice Chief,
Gastrointestinal Unit
Medical Director, Liver Transplant Program
Massachusetts General Hospital
Boston, Massachusetts
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Guest
Faculty Disclosures
Dr. Sulkowski has indicated that he has served as a consultant/scientific advisor for AbbVie, Inc., Achillion Pharmaceuticals, Bristol-Myers Squibb, Gilead, Janssen, and Merck. He has received grant/research funding from AbbVie, Inc., Bristol-Myers Squibb, Gilead, Janssen, and Merck. Dr. Sulkowski has served as a DSMB member for Gilead, and has served on a steering committee for Pfizer, Inc.
Dr. Nelson has indicated that he has received research funding from AbbVie, Inc., Bristol-Myers Squibb, Gilead, Janssen, and Merck.
Dr. Chung had indicated that he has received research support from AbbVie, Bristol-Myers Squibb, Gilead, and Mass Biologics.
Unlabeled/Unapproved Uses
Dr. Sulkowski, Dr. Nelson, and Dr. Chung have indicated that there will be references to the clinical trial results for antiviral agents for HCV that reference the unlabeled/unapproved uses of daclatasvir, ombitasvir, dasabuvir, paritaprevir, asunaprevir, beclabuvir, grazoprevir (MK-5172), elbasvir (MK-8742), and GS5816.
Program
Directors' Disclosures |
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TO ACCESS THE
POST-TEST
Step
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Review the CE Information and study the educational content.
Step
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Click the post-test link at the end of the newsletter.
Step
3.
Follow the instructions to access a post-test.
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COMMENTARY & Review |
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The first human trial describing the use of interferon alfa to treat patients with non-A, non-B hepatitis was reported in 1986, demonstrating improvement in serum ALT levels in some but not most patients treated with this agent.1 Over the ensuing decade, hepatitis C virus was identified cause of non-A and non-B hepatitis, and molecular techniques were applied to test HCV RNA response during interferon therapy. With these advances, it quickly became apparent that the majority of patients treated with interferon alfa did not achieve sustained virologic response (SVR). Clinical trials were able to identify both patient and viral characteristics that were associated with failure to achieve SVR: genotype 1 infection; high HCV RNA level; black race; IL28B CT or TT genotype; cirrhosis; obesity; insulin resistance; and older age. Patients with a constellation of some or all of these factors were characterized as hard to treat and patients with HCV who had been treated with interferon alone or in combination with ribavirin and failed to achieve HCV RNA suppression were categorized as the hardest to treat (null responders). Indeed, until the advent of the first HCV direct acting antivirals in May 2011, these patients had no recommended treatment options available to them.
In 2014, the first highly effective, interferon-sparing HCV treatment regimen, sofosbuvir plus simeprevir entered clinical practice in the United States for treating patients with HCV genotype 1 infection. In the COSMOS trial, regimens were investigated with and without ribavirin for durations of 12 and 24 weeks in prior null responders to peginterferon/ribavirin with and without compensated cirrhosis. The results were remarkable – more than 95% of patients with most difficult-to-cure HCV achieved SVR. Thus, with the approval of these drugs and their use in clinical practice, the definition of a hard to treat patient had to be drastically revised. Data from the COSMOS study and other phase 2 or 3 clinical trials of the leading interferon-sparing, oral combination HCV DAA regimens including sofosbuvir/ledipasvir; sofosbuvir plus daclatasvir; paritaprevir/ritonavir/ombitasvir plus dasabuvir; daclatasvir/asunaprevir/beclabuvir; grazoprevir (MK-5172) plus elbasvir (MK-8742) have clearly demonstrated that some of the previously identified patient and virus factors no longer represent barriers to HCV cure. SVRs achieved in patients infected with HCV genotype 1 are greater than 95%, including patients with IL28B CT or TT genotype, patients who are African American, and those who failed to respond to prior treatment with peginterferon/ribavirin.2-5 Thus, patients with these characteristics are no longer considered "difficult to cure" in the era of potent, direct-acting, oral antivirals.
The common theme of these previously difficult-to-treat patient groups was an intrinsically poor antiviral response to interferon alfa. The poor response to interferon alfa appeared to be the result of characteristics of both the virus and the patients. Chronic infection with HCV genotype 1 was substantially more difficult to cure than infection with HCV genotype 2 or 3. In addition, those who had an inherited reduced ability to clear HCV infection spontaneously, defined by the rs12979860 (IL28B) genotype CT or TT, were also less likely to eradicate HCV infection with exogenous interferon compared to those with IL28B genotype CC.3 With the advent of interferon-free HCV treatment regimens, the intrinsic host response to the infection or to its treatment with interferon does not have a major impact in the ability to eradicate chronic HCV infection. Therefore, HCV cure rates among persons with IL28B genotype CT or TT, including African Americans, are similar to those among persons with IL28B genotype CC. In addition, many of the direct-acting antiviral agents currently approved or in late stage development were designed to target HCV genotype 1 infection and were selected for further testing in humans because of their potent antiviral activity demonstrated in vitro with HCV replicon systems that included nonstructural proteins derived from HCV genotype 1b and 1a variants.6 Many of the currently available anti–HCV drugs were specifically developed to target HCV genotype 1 infection, leading to higher HCV cure rates among patients infected with this strain and the removal of HCV genotype 1 infection from the category of difficult to cure. Last, the removal of interferon has also for the first time offered the potential for HCV cure to another group of patients: those who have contraindications to the use of interferon (ineligible) or who have suffered severe treatment-limiting side effects that preclude the use of interferon in the future (intolerant). In the absence of interferon, this group of patients – interferon ineligible or intolerant – can no longer be considered "difficult to cure."
The remarkable advances in the treatment of these previously hard to treat patients' leads to the question: Who are the difficult to treat patients in the era of interferon-free HCV treatment? In this context, several patient groups have emerged as harder to treat:
1) Patients with cirrhosis, particularly those with prior non-response to peginterferon/ribavirin based therapies.
In the several studies of oral, interferon-free antiviral regimens for the treatment of patients who failed to respond to prior treatment with interferon, patients with cirrhosis have had lower HCV cure rates than patients without cirrhosis. For example, in the ION-2 study of ledipasvir/sofosbuvir,7 the SVR rates among patients with cirrhosis who were assigned to 12 weeks of treatment were 82% to 86%; in contrast, the SVR rates among patients without cirrhosis were 95% to 100%. Longer duration of treatment with ledipasvir/sofosbuvir led to higher SVR rates among patients with cirrhosis (100%). Similarly, in the TURQUIOSE-II study of paritaprevir/ritonavir/ombitasvir plus dasabuvir plus ribavirin,8 the SVR rate among patients with cirrhosis and prior null response to peginterferon/ribavirin who were assigned to 12 weeks of treatment was 86.7%; in contrast, the SVR rates among the same patients who were assigned treatment for 24 weeks was 95.2%.
In the French SIRIUS study, 154 patients with cirrhosis who had failed prior telaprevir or boceprevir plus peginterferon/ribavirin therapy were randomized to one of two regimens: ledipasvir/sofosbuvir fixed-dose combination tablet once daily plus placebo twice daily for 24 weeks (n = 77) or placebo for 12 weeks followed by ledipasvir/sofosbuvir fixed-dose combination once daily plus placebo plus ribavirin twice daily for 12 weeks (n = 77). The HCV cure rate (SVR) was 96% for the 24-week combination and 97% for the 12-week combination plus ribavirin. Three relapses occurred in the 12-week group and two in the 24-week group; one patient in the 12-week group discontinued because of sepsis that occurred during the placebo phase and was excluded from the efficacy analysis. The combination with or without ribavirin was relatively well tolerated, and no patient discontinued due to adverse events during the active treatment phase in either group.
In a retrospective analysis (TURQUOISE-II) of the phase 3 clinical trial of paritaprevir/ritonavir/ombitasvir plus dasabuvir plus ribavirin in 380 patients with HCV genotype 1 infection and compensated cirrhosis, Fried and coworkers10 reported that the overall SVR rate was 91.8% and 96.5% in patients treated for 12 and 24 weeks, respectively. In the 12-week group, 17 of 208 patients (8.1%) did not achieve SVR, of which one patient failed because of on-treatment HCV breakthrough, and 12 patients experienced post-treatment viral relapse (of whom 11 patients were infected with HCV genotype 1a). In the 24-week group, six of 172 patients (3.4%) did not achieve SVR, three of whom failed due to on-treatment HCV breakthrough, and one patient with genotype 1 infection experienced post-treatment viral relapse. In a multivariate model, failure to achieve SVR was independently associated with genotype 1a infection, prior null response to peginterferon/ribavirin, and IL28B genotype TT. Patients with some or all of these baseline characteristics may benefit from 24 weeks of HCV treatment with this regimen.
In the UNITY-2 study, Muir and colleagues11 randomized 192 patients with HCV genotype 1 and compensated cirrhosis to the single-tablet, fixed-dose combination of daclatasvir (NS5A inhibitor)/asunaprevir (NS3 protease inhibitor)/beclabuvir (NS5B non-nucleoside polymerase inhibitor) with or without ribavirin for 12 weeks. While SVR rates were 90% or greater for most patient groups, higher rates of SVR were achieved in patients with genotype 1b infection, regardless of ribavirin coadministration, and in patients with genotype 1a infection who received ribavirin (figure below). Overall, the regimen was well-tolerated, and only four of 202 (1.9%) of patients stopped therapy because of adverse events; however, the investigators also reported that four patients had elevations in serum ALT levels to greater than five-fold the upper limit of normal, and one patient had concurrent elevations in ALT and total bilirubin. The researchers concluded that this regimen may be an effective option for HCV genotype 1 infected patients with cirrhosis. Patients with HCV genotype 1a infection benefited from the addition of ribavirin with higher SVR rates.
In the large phase 2b C-WORTHY Study,12 patients with HCV genotype 1 infection with cirrhosis (treatment-naïve and -experienced) and patients without cirrhosis and prior null-response to peginterferon/ribavirin were randomized to grazoprevir once daily plus elbasvir once daily, with or without ribavirin for 12 or 18 weeks. Among treatment-naïve patients with cirrhosis, SVR was achieved in 90% (RBV) and 97% (no RBV) of patients treated for 12 weeks and 97% (RBV) and 94% (no RBV) of patients treated for 18 weeks. Among prior null-responders with and without cirrhosis, SVR rates were 94% (RBV) and 91% (no RBV) in patients treated for 12 weeks and 100% (RBV) and 97% (no RBV) in those treated for 18 weeks. Overall, 161 of 170 (95%) of patients with cirrhosis achieved SVR, similar to the outcome among those without cirrhosis (79 of 183, 95%). The researchers reported that this regimen is being evaluated in phase 3 clinical trials as a single-tablet, fixed-dose combination of grazoprevir/elbasvir in multiple patient populations, including patients with Childs B cirrhosis.
2) Patients with HCV genotype 3 infection, particularly those with cirrhosis.
The first challenge in the treatment of patients with HCV genotype 3 infection is that the currently available HCV protease inhibitors (including simeprevir) do not have potent antiviral activity against this strain. The second challenge is that the currently recommended treatment for patients with genotype 3 infection, sofosbuvir plus ribavirin, must be administered for 24 weeks and, despite this prolonged course, has relatively low SVR rates among patients with cirrhosis who failed prior treatment. In the FISSION study, patients with HCV genotype 3 were randomized to treatment with sofosbuvir plus ribavirin for 12 weeks or peginterferon plus ribavirin for 24 weeks.13 In patients with HCV genotype 3 infection, SVR was achieved in 56% of those receiving sofosbuvir plus ribavirin and 63% of those receiving peginterferon–ribavirin. The SVR rate was particularly low, ~ 33% in both groups among patients with established cirrhosis. The combination of sofosbuvir plus ribavirin was more effective in the VALENCE study after administration for 24 weeks.14 In this study, SVR was achieved in 213 of 250 patients (85%) of patients with HCV genotype 3 infection who were treated for 24 weeks. However, the SVR rate as lower among patients with cirrhosis (68%) compared to those without cirrhosis (91%).
In the ALLY-3 study,15 152 patients with HCV genotype 3 (101 were previously untreated for hepatitis C and 51 were treatment-experienced) were treated with daclatasvir 60 mg daily plus sofosbuvir 400 mg daily for 12 weeks without ribavirin. Overall, SVR was achieved in 90% of previously untreated patients and 86% of treatment-experienced patients. Patients with cirrhosis had lower SVR rates than patients without cirrhosis. In the treatment-naive patient group, the SVR rate was 97% and 58% for patients without cirrhosis and with cirrhosis, respectively. In the treatment-experienced group, the SVR rate was 94% and 69% for patients without cirrhosis and with cirrhosis, respectively. The once-daily, two-tablet regimen was well tolerated with no treatment discontinuations due to adverse events. The researcher concluded that the combination of daclatasvir/sofosbuvir for 12 weeks led to high SVR rates among patient with HCV genotype 3 infection in the absence of cirrhosis (≥ 94%). Due to higher rates of post-treatment relapse, lower SVR rates were observed in patients with cirrhosis; this observation suggests that this patient group, cirrhotic patients with HCV genotype 3 infection, may benefit from the addition of ribavirin and/or longer duration of treatment (eg, 16 to 24 weeks).
In an open-label study conducted in New Zealand, Gane and colleagues16 treated 50 patients with HCV genotype 3 infection and prior non-response to peginterferon/ribavirin with the combination of ledipasvir/sofosbuvir plus ribavirin for 12 weeks. Patients with compensated cirrhosis (n = 22) were included in the study cohort. Overall, SVR was achieved in 82% of patients with genotype 3 infection. Patients with cirrhosis were more likely to experience post-treatment relapse, and as a result, had lower SVR rates (16 of 22 patients, 73%) compared to patients without cirrhosis (25 of 28 patients, 89%). Of interest, resistant associated variants to ledipasvir (NS5A inhibitor) were observed in only 1 of 6 patients with non-SVR and no patients had resistant associated variants to sofosbuvir (NS5B nucleotide inhibitor). The role of the combination of ledipasvir/sofosbuvir plus ribavirin for the treatment of HCV genotype 3 infection warrants further investigation in other clinical settings.
3) Patients in the "real world" with comorbid conditions that impact their ability to persist and adhere to a course of therapy.
In phase 3 clinical trials of interferon-free HCV treatments, patients were carefully selected for inclusion and had high rates of treatment persistence and adherence. There has been some question about the ability to generalize the observed high HCV cure rates to real-world settings, in which patients with multiple comorbidities may be treated in clinical practice, since translation of safety and efficacy from clinical trials to the community has not been smooth with previous HCV treatment with telaprevir and boceprevir. However, preliminary reports of the safety, tolerability, and efficacy of treatment with sofosbuvir-based regimens in the United States following the approval of these drugs are promising and suggest that, unlike interferon-based treatments, the experience observed in phase 3 clinical trials may translate well to the community with high levels of effectiveness. The major barriers to HCV cure may be patient access to these direct-acting, oral antiviral regimens and, among those with access, their ability to adhere to the regimen by taking the required pills each day for the entire recommended duration
In the phase 2 COSMOS study, the interferon-free, oral combination of simeprevir (once daily) and sofosbuvir (once daily) with and without ribavirin led to high SVR rates in patients infected with HCV genotype 1, including those with cirrhosis and those for whom prior treatment with peginterferon/ribavirin led to null response. Based on these data, the American Association for the Study of Liver Disease/Infectious Diseases Society of America recommended this regimen for patients in whom interferon-based treatment was contraindicated or had led to virologic non-response. As a result, the regimen of simeprevir plus sofosbuvir was incorporated in the clinical care of patients in the United States in 2014.
The aim of the study by Sulkowski and colleagues17 was to evaluate the safety and efficacy of simeprevir plus sofosbuvir therapy in a large, real-world population enrolled in the HCV-TARGET longitudinal observational study. Since January 2014, 989 patients started treatment with simeprevir plus sofosbuvir at academic (n = 38) and community medical centers (n = 15) in North America (n = 51) and Europe (n = 5) and were included in the analysis, with treatment outcome data available for 861 patients who had been followed to at least four weeks post treatment. The majority of patients were treated without ribavirin (n = 673). Most patients treated in the HCV TARGET cohort had failed prior treatment (60% including patients who had failed to respond to telaprevir or boceprevir therapy), and most had evidence of cirrhosis (57% including patients with prior hepatic decompensation). Overall, SVR4 (no HCV RNA detected at or beyond four weeks post-treatment) was observed in 88% of patients treated with simeprevir plus sofosbuvir with or without ribavirin for 12 weeks. SVR rates were higher among patients with genotype 1b infection compared to those with 1a infection but similar in patients for whom ribavirin was or was not prescribed. The likelihood of achieving SVR4 was higher in patients with high albumin levels and lower in those with prior hepatic decompensation and prior telaprevir or boceprevir based treatment. Treatment was well tolerated, and only 20 patients (2%) discontinued therapy due to adverse events. Taken together, this real-world experience demonstrates favorable outcomes with interferon-free, oral treatment with simeprevir plus sofosbuvir in clinical practice patients. This observation bodes well for the use of such therapies for the treatment of HCV infected patients outside the confines of clinical trials.
References
1. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: A preliminary report. N Engl J Med. 1986; 315:1575-1578.
2. McHutchison JG, Lawitz EJ, Shiffman ML et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009 Aug 6;361(6):580-593.
3. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009 Sep 17;461(7262):399-401.
4. Conjeevaram HS, Fried MW, Jeffers LJ, et al; Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006 Aug;131(2):470-477.
5. Fried MW, Jensen DM, Rodriguez-Torres M, et al. Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin. Hepatology. 2008 Oct;48(4):1033-43.
6. Lohmann V, Körner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 1999 Jul 2;285(5424):110-113.
7. Afdhal N, Reddy KR, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014 Apr 17;370(16):1483-1493.
8. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014 May 22;370(21):1973-1982.
9. Marc Bourlière et al. Ledipasvir/sofosbuvir fixed-dose combination is safe and efficacious in cirrhotic patients who have previously failed protease-inhibitor based triple therapy. Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract LB-6.
10. Fried MW et al. TURQUOISE-II: Regimens of ABT-450/r/ombitasvir and dasabuvir with ribavirin achieve high SVR12 rates in HCV genotype 1-infected patients with cirrhosis, regardless of baseline characteristics. Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract 84.
11. Muir AJ et al. All-oral fixed-dose combination therapy with daclatasvir/asunaprevir/BMS-791325, ± ribavirin, for patients with chronic HCV genotype 1 infection and compensated cirrhosis: UNITY-2 phase 3 SVR12 results. Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract LB-2.
12. Lawitz E et al. Efficacy and safety of grazoprevir (MK-5172) + elbasvir (MK-8742) with or without RBV in genotype 1 infected patients with cirrhosis or previous null response: Final results of the C-WORTHY Study (Parts A and B). Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract 196.
13. Lawitz E, Mangia A, Wyles et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 May 16;368(20):1878-1887.
14. Zeuzem S, Dusheiko GM, Salupere R, et al; VALENCE Investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993-2001.
15. Nelson DR et al. All-oral 12-week combination treatment with daclatasvir and sofosbuvir in patients infected with HCV genotype 3: ALLY-3 Phase 3 Study. Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract LB-3.
16. Gane et al. High efficacy of ledipasvir/sofosbuvir regimens for 12 weeks in patients with HCV genotype 3 or 6 infection. Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract LB-11.
17. Sulkowski MS et al. Safety and efficacy of sofosbuvir in combination with simeprevir +/- ribavirin in patients with Genotype 1: Interim results of a prospective, observational study. Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract 995.
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© 2015 JHUSOM, IJHN and eViralHepatitis Review
Presented by JHUSOM and IJHN.
This activity was developed in collaboration with DKBmed. |
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COMPLETE
THE
POST-TEST
Step
1.
Click on link to download instructions for the post-test and evaluation
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