Hepatitis C Infection Treatment Will Be Discontinued

Hepatitis C Infection Treatment Will Be Discontinued

The Food and Drug Administration (FDA) is informing that Victrelis (boceprevir; Merck) 200mg capsules will be discontinued.

Victrelis is a HCV NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis Cgenotype 1 infection, in combination with peginterferon alfa and ribavirin in adult patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy including prior null responders, partial responders, and relapsers.

Victrelis works by covalently, yet reversibly, binding to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells.

Victrelis is estimated to be available until December 2015. Discontinuation of Victrelis is not related to any product safety or efficacy matters.

For more information call (877) 888-4231 or visit Victrelis.com.

Hepatitis C drug Victrelis (boceprevir) gets pulled from manufacturer

The pharmaceutical company, Merck, has announced that they will stop the manufacture and distribution of their hepatitis C (HCV) protease inhibitor Victrelis by December 2015. As the landscape of HCV treatment has rapidly evolved, providers are no longer prescribing the medication and patients are no longer taking it in favor of newer regimens that are easier to take, and have shorter treatment durations and higher cure rates. In a similar move, Vertex discontinued their HCV drug Incivek (telaprevir) in October 2014.

Continue reading....

Hepatitis C:Drug–drug interaction (DDI) may not be reflected in prescribing information

Medication use and medical comorbidity in patients with chronic hepatitis C 

The latest issue of the European Journal of Gastroenterology & Hepatology evaluates the high utilization of drugs with interaction potential in patients with chronic hepatitis C from a US commercial claims database

With the advent of the direct-acting antiviral agents, significant drug–drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection.

However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential.

Using a large US commercial insurance database, Dr Julie Lauffenburger and colleagues examined medication use and comorbidity burden among adult patients with a chronic HCV diagnosis from 2006 to 2010.

Medications were examined in terms of total number of prescription claims, proportion of patients exposed, and DDI potential with the prototypical CYP3A direct-acting antiviral agents boceprevir and telaprevir, for which data were available.

Patient comorbidity burden was high and increased over the study period.

Medication use was investigated in 53,461 patients with chronic HCV.

The researchers found that 53% of the top 40 most utilized medications were classified as having interaction potential, with 62% of patients receiving at least one of the top 22 interacting medications by exposure.

Of these, 59% and 41% were listed in a common DDI resource but not in medication-prescribing information.

The team noted that 77% had not been investigated in DDI studies.
The research team found that 41% and 36% did not have clear recommendations for DDI management, and only 14% and 23% carried a recommendation to avoid coadministration for boceprevir and telaprevir, respectively.

Dr Lauffenburger's team commented, "Practitioners may expect a medication with CYP3A DDI potential in two-thirds of patients with HCV and may expect almost one-half of the most frequently used medications to have CYP3A DDI potential."

"However, DDI potential may not be reflected in prescribing information."

European Journal of Gastroenterology & Hepatology:

October 2014 - Volume 26 - Issue 10 - p 1073-1082

doi: 10.1097/MEG.0000000000000152

Original Articles: Hepatitis

Hepatitis - FDA Label update for Victrelis (boceprevir)

The Victrelis (boceprevir) label has been updated to include the following information under Section 5 Warnings and Precautions:

5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa)

 Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.

Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.

Refer to the Package Inserts for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.

Additionally section 6.2 Postmarketing Experience was updated to include agranulocytosis, pancytopenia, thrombocytopenia, pneumonia and sepsis.

The corresponding patient information and Medication Guide were also updated to reflect these changes.

The complete revised label can be viewed at Drugs@FDA.

Victrelis is a product of Merck Sharp & Dohme Corp.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble

Division of Antiviral Drug Products

Food and Drug Administration

Boceprevir vs Telaprevir: Comparison of Hepatitis C virus protease inhibitors in the USA

Comparison of Hepatitis C virus protease inhibitors in the USA

Full Text Available, here

The most recent issue of the Alimentary Pharmacology & Therapeutics compares the effectiveness of the hepatitis C virus protease inhibitors boceprevir vs telaprevir in a large cohort in the USA.

Limited data exist on the effectiveness of boceprevir and telaprevir in routine practice.

Dr Backus and colleagues from California, USA assessed the comparative effectiveness of boceprevir and telaprevir regimens.

In this observational, intent-to-treat cohort analysis of hepatitis C genotype 1-infected veterans initiated on peginterferon/ribavirin and boceprevir or telaprevir, the researchers determined sustained virological response, treatment discontinuation rates and adverse hematological events.

Inverse probability-of-treatment weighting was used to estimate the effect of one drug over the other, with matched pairs and unweighted logistic regression on the entire cohort for comparison.

Of 835 veterans, sustained virological response occurred in 50% and 52% receiving boceprevir- and telaprevir-based treatment, respectively.

The research team found no significant differences occurred among cirrhotics, null responders, partial responders and relapsers.

The researchers noted that early discontinuation rates for boceprevir and telaprevir, respectively, were 31% and 28% by week 24, and 54% and 45% by 48 weeks.

The team found that the choice of telaprevir over boceprevir was significantly associated with SVR in multivariate models.

Rates of hematological adverse events in boceprevir- and telaprevir-treated patients were 59% vs 51% with anemia, 41% vs 48% with thrombocytopenia, 41% vs 27% with neutropenia.

Dr Backus' team comments, "Sustained virological response was more likely with telaprevir-based regimens compared with boceprevir-based regimens in routine medical practice, after accounting for patient differences."

"Early discontinuation and haematological events, however, were similar."

Full Text Available, here

Abstract - Aliment Pharmacol Ther 2014: 39(1): 93–103
09 December 2013

Source

Triple therapy effective in cirrhotic patients with HIV/HCV

Joop Arends, MD, PhD, an infectious disease specialist at the University Medical Center Utrecht in the Netherlands, discusses his presentation at EACS 2013 on the effect of triple therapy (telaprevir or boceprevir with pegylated interferon and ribavirin) on HIV/HCV coinfected patients with cirrhosis. In the study, triple therapy using either telaprevir or boceprevir was effective at 24 weeks, but severe anemia was common in the cohort.

http://video.healio.com/video/Triple-therapy-effective-in-cir

Real-world SVR rate about 33% with hepatitis C triple therapy

Real-world SVR rate about 33% with hepatitis C triple therapy

By: M. ALEXANDER OTTO, Family Practice News Digital Network

DENVER – Only one-third of a group of patients with hepatitis C achieved a sustained virologic response when a protease inhibitor was added to standard ribavirin and interferon dual therapy, a real-world finding that flies in the face of reported response rates closer to 90%, according to Dr. Arpita Sheth who presented a poster at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Of 42 patients at the Veterans Affairs hospital in East Orange, N.J., who started on triple therapy with the protease inhibitor boceprevir, 9 had to drop out because of previously recognized adverse events, including thrombocytopenia, neutropenia, anemia, and depression. Five other patients did not comply with treatment, and treatment failed in 10. About half of the patients were new to therapy and the rest either non- responders to dual-therapy or triple-therapy relapsers.

Of the 18 who completed treatment, 9 achieved SVR [sustained virological response] at 3 months and 5 at 6 months. The four remaining patients relapsed.

"The incremental gain of adding protease inhibitors to the traditional regimen of ribavirin and interferon has a potential SVR rate of 33% (14/42) among retreaters and naive-to-treatment patients. Treatment should be evaluated at a more realistic number of 33% success [rather] than the 80%-90% SVR rate so frequently quoted from the FDA registration trials," concluded Dr. Sheth, a fellow at Rutgers New Jersey Medical School in Newark, in her presentation. 

The real-world rate is lower, at least in Newark’s VA population. To avoid disappointment, "we should always make our patients aware of that; we’ve seen a lot of patients get upset that they didn’t really get cured" with triple therapy, she said at the meeting. The findings from the study conducted by Dr. Sheth and her associates was published earlier (N. Engl. J. Med. 2011;364:1207-17).

The results probably had something to do with "the patient population we had. They do have some underlying history that includes depression, alcohol use, drug use, and a lot of other things. Even though [most] said they were compliant, I don’t think [compliance was] what they reported," Dr. Sheth said. 

About a third of patients in the study required erythropoietin to maintain their hemoglobin at 10 g/dL or higher while on triple therapy. 

Dr. Sheth and her team reported that they have no disclosures. 

http://www.familypracticenews.com/news/infectious-diseases/single-article/real-world-svr-rate-about-33-with-hepatitis-c-triple-therapy/e2f64491385001c6ca18670bf0d8636d.html

Treatment approaches- Treat HCV now or wait and management of adverse events

Hi Folks,
When a new HCV learning activity is released online this blog provides background information, and links to the new video, article or CME.

In July and August two learning activities were published over at Medscape, both presented in an interview format.

*Like any site offering continuing medical education (CME), it requires a free quick registration to participate.

In the most recent CME, Paul Y. Kwo, MD, professor of medicine at Indiana University School of Medicine describes a case scenario of a 59-year-old man with hepatitis C who has cirrhosis thus motivated to begin treatment now instead of waiting for future therapies.

As noted by Dr. Kwo in the CME;

With new agents on the horizon, it is important to identify those patients who cannot afford to wait for new treatments. There are also patients whose clinical characteristics allow for treatment delay but who are highly motivated and wish to initiate treatment right away.

In regard to side effects Dr. Kwo remarked:

There are some other issues to be aware of with both of these HCV protease inhibitors.^[7,13] Gastrointestinal side effects occur with both telaprevir and boceprevir. Boceprevir causes dysgeusia, which usually does not lead to treatment discontinuation. Clinicians should also know that boceprevir is associated with slightly higher levels of neutropenia as well as anemia. There are some perianal symptoms with telaprevir that sometimes require management.^[7,13] We use topical hydrocortisone cream. Mesalamine suppositories and topical lidocaine can also be used to address this issue during the 12 weeks of telaprevir therapy. To address the gastrointestinal issues associated with the protease inhibitors as well as with PEG-IFN and RBV, we may use loperamide or fiber supplements.

Click here to begin.

In the second CME Andrew J Muir, MD., Director of GI/Hepatology Research at Duke Clinical Research Institute discusses eligibility and adherence in standard therapy for genotype 1 patients comprising of HCV protease inhibitor-based triple therapy -Telaprevir or Boceprevir.

Dr. Muir discusses the standard of care for HCV genotype 1 patients

The current standard of care for treatment of chronic HCV genotype 1 infection in the United States is the combination of PEG-IFN-alfa, RBV, and one of the HCV NS3/4A protease inhibitors boceprevir or telaprevir.^[1] In clinical studies, the addition of boceprevir or telaprevir to the previous standard of care for these patients (ie, PEG-IFN plus RBV) was associated with a significantly increased rate of sustained virologic response (SVR) in both treatment-naïve and previously treated patients

Dr. Muir comments on the promise of new agents to treat hepatitis C;

The guidelines recommend that treatment should be considered in all patients who qualify; we take that approach on a case-by-case basis to determine whether treatment is appropriate for an individual patient at this time. A number of the new HCV agents are expected to become available in the next few years, and we expect that there will be an IFN-free regimen available for HCV genotype 2 and 3 by late 2013, and hopefully for genotype 1 by 2015 or so. The question, then, is this: Should you treat the patient now, or wait until these new therapies are available?

Click here to begin.
                         
Medscape Education Gastroenterology

CME Released: 08/14/2013
Timely and Appropriate Care for Chronic HCV Infection: Therapy Selection and Adverse Event Management
On June 17, 2013, Medscape spoke to Paul Y. Kwo, MD, professor of medicine at Indiana University School of Medicine and medical director of liver transplantation at Indiana University Health, Indianapolis, to discuss the current HCV treatment approaches and provide a case-based illustration of the decision of whether a patient is a candidate for treatment with the current standard of care, and to detail management of adverse events associated with HCV therapy.

CME Released: 07/31/2013
Providing Timely and Appropriate Care for Chronic HCV Infection: Patient Readiness and Likelihood of Response
This represented a new paradigm in the management of HCV. On May 29, 2013, Medscape spoke to Andrew J Muir, MD, Associate Professor of Medicine and Director of GI/Hepatology Research at Duke Clinical Research Institute in Durham, North Carolina, to discuss the current HCV treatment approaches and provide a case-based illustration of the decision whether a patient is a candidate for treatment with the current standard of care.

Hepatitis C- High discontinuation rate noted for direct-acting antiviral therapy

High discontinuation rate noted for direct-acting antiviral therapy

By: DENISE NAPOLI, IMNG Medical News

Despite high rates of early clinical response, 30% of veterans taking direct-acting antivirals for hepatitis C discontinued treatment by week 24.

The findings highlight "the challenges associated with maintenance of these regimens" in a real-world cohort, wrote Pamela S. Belperio, Pharm.D., and colleagues. The study appears in the August issue of Clinical Gastroenterology and Hepatology.

Dr. Belperio of Veterans Affairs Palo Alto (Calif.) Health Care System, looked at 859 patients registered with the VA’s Clinical Case Registry for HCV who initiated triple therapy with pegylated interferon, ribavirin, and either boceprevir (n = 661) or telaprevir (n = 198) before Jan. 1, 2012, at 94 different VA facilities.

The authors determined how long the patient took the drug by looking at medication dispensed dates, and patients were classified as having response rates of "undetectable" if HCV RNA levels at their most recent assay were undetectable.

Patients’ mean age was 57 years; most of the patients were male. Patients with HIV or hepatitis B virus coinfection, hepatocellular carcinoma, or liver transplantation were excluded.

Even so, "Up to 13% of boceprevir-treated veterans and 24% of telaprevir-treated veterans would have been excluded from the phase III trials [of these therapies] based on hematologic exclusion criteria used in the telaprevir trials," Dr. Belperio wrote.

Despite this, the authors found that by week 12, 76% of all treatment-naive, noncirrhotic patients taking boceprevir had achieved undetectable viral loads, as had 78% of telaprevir patients.

By 24 weeks, those numbers were 74% for boceprevir patients and 60% for telaprevir patients.

However, the researchers also found that about one-third of patients discontinued treatment with either boceprevir or telaprevir before 24 weeks (30% and 34%, respectively; P = .37), with an incidence of hematologic adverse events that was both higher and more pronounced than has been reported in clinical trials of direct-acting antivirals (DAAs), wrote Dr. Belperio.

Indeed, anemia of at least grade 1 (hemoglobin below normal limits but greater than or equal to 10 g/dL) occurred in 50% of patients in both DAA groups, "which is up to a 15% increased incidence of anemia over what has been reported elsewhere."

There was also significant thrombocytopenia for both drugs, which Dr. Belperio said was four times higher than in clinical trials. In fact, her group reported that 66% of patients taking boceprevir had grade 1 thrombocytopenia. (platelets below normal limits but greater than or equal to 75,000/mm3), as did 59% of patients taking telaprevir.

"This may reflect the greater proportion of cirrhotic patients in our cohort compared with the clinical trials; however, it is concerning given the limited strategies currently available to manage thrombocytopenia and the unknown effect that PEG dose reductions may have on sustained virologic response in the context of DAA-based therapies," they wrote.

There also was a portion of patients for whom treatment was determined to be futile, according to Food and Drug Administration specifications: 9% of patients receiving boceprevir at week 12 and 5% at week 24, as well as 6% of telaprevir patients at week 4, 4% at week 12, and 7% at week 24.

The authors conceded several limitations to this study, including that they were unable to assess reasons for early treatment discontinuation.

Nevertheless, the data "offer clinicians a perspective on expectations of early response and safety of DAA regimens in routine clinical practice, allowing a more nuanced discussion between providers and patients regarding the risks and benefits of embarking on DAA-based treatment."

The authors disclosed that one coinvestigator has previously received grant support from Gilead Sciences, maker of HCV therapies. They disclosed no other conflicts of interest.
08/01/13

http://www.gihepnews.com/single-view/high-discontinuation-rate-noted-for-direct-acting-antiviral-therapy/de644968728281122928cb4c50eb579f.html

Triple therapy underutilized in HCV

Triple therapy underutilized in HCV 

By: DENISE NAPOLI, IMNG Medical News

Fewer than 20% of patients with hepatitis C virus genotype 1 receive triple therapy with boceprevir or telaprevir, according to Dr. Emerson Y. Chen and colleagues. The results are in the August issue of Clinical Gastroenterology and Hepatology.

The "disappointingly low use of the new therapies, even after a decade without novel medications," suggests that real-world use of these drugs is hampered by factors including safety and the low predicted response rates in prior nonresponders, they wrote.

Dr. Chen of the University of Texas Southwestern Medical School, Dallas, looked at 487 patients with HCV genotype 1 presenting to one of two academic outpatient hepatology practices in Dallas and Miami.

The majority of patients were between 50 and 60 years of age, male, and white. More than two-thirds had private insurance, and half of the patients were treatment naive.

Overall, the authors found that 91 patients (18.7%) were started on triple therapy (boceprevir or telaprevir plus pegylated interferon and ribavirin) while the remaining 396 patients remained untreated.

Dr. Chen then assessed the reasons for treatment deferral. The most common, he found, was contraindication (50.5%), including complications of liver disease and medical comorbidities. The next biggest reason cited for treatment deferral was "patient choice" (22.5%), which included concerns about side effects, limited success rates, financial issues, or inability to commit time for treatment. Finally, the presence of less advanced liver disease (17.4%) and the anticipation (among providers and patients alike) of better future therapies (9.6%) were also factors in triple therapy refusal.

"Although several expert panels for treatment recommendations are available, there exists an uncertainty among providers regarding selecting patients without major contraindications for triple therapy now over newer direct-acting antiviral therapy later," they added.

Next, the researchers compared the triple therapy patients with therapy deferrals.

In univariate analysis, they found that about three-fourths of patients who chose to initiate triple therapy had fibrosis stage 3 or were cirrhotic, although less than 10% had a history of overt decompensation.

"In contrast, among those who deferred treatment, more than 20% had decompensated liver disease, and 46% had early [an] fibrosis stage," they wrote.

Looking at patients’ mean Model for End-Stage Liver Disease scores, cirrhotic patients who deferred treatment registered a 9.3, compared with 7.3 for patients who elected to undergo triple therapy treatment (P less than .001). Additionally, 90% of cirrhotic patients on treatment were Child-Pugh class A compared with 63% in the nontreatment group (P = .003).

Commenting on the findings, Dr. Chen wrote that "although patients with mild fibrosis or persistently normal liver function tests have often not been recommended for repeat biopsy or treatment, they would likely benefit from treatment before they become older or develop contraindications.

"Nevertheless, many hepatologists appear to be recommending deferral of treatment for patients with mild to moderate fibrosis, waiting for the second-generation direct-acting antivirals with even higher sustained virologic response rates" and fewer side effects.

"Newly diagnosed treatment-naive patients along with those with less advanced liver disease will benefit from society-wide consensus regarding therapy initiation now or at a later time."

The authors disclosed funding from the Doris Duke Charitable Foundation and the University of Miami. Two authors disclosed ties to Merck, maker of boceprevir and ribavirin, and Vertex, which makes telaprevir.

08/01/13
http://www.gihepnews.com/single-view/triple-therapy-underutilized-in-hcv/e0fffac94f561b3865bd4904d07050eb.html 

Management of anemia induced by triple therapy in patients with chronic hepatitis C

Management of anemia induced by triple therapy in patients with chronic hepatitis C: challenges, opportunities and recommendations

Manuel Romero-Gómez , Marina Berenguer, Esther Molina , José Luis Calleja

Received 6 May 2013; received in revised form 20 June 2013; accepted 8 July 2013. published online 17 July 2013.

Accepted Manuscript
To read the body of this article, please view the PDF online

Abstract
The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon + ribavirin increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy.

Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalasemic type hemolytic anemia and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and Epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance.

In the transplantation setting, adding a protease inhibitor to peginterferon + ribavirin results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for Epoetin, transfusions and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5 g/dL and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Hepatitis C- Are Patients Receiving the Latest Anti-HCV Drugs?

Are Patients Receiving the Latest Anti-HCV Drugs?

Posted on July 22, 2013

by Kristine Novak, PhD, Science Editor

Less than 20% of patients infected with the most common Hepatitis C virus (HCV) genotype receive the latest drugs approved by the US Food and Drug Administration (FDA), according to the August issue of Clinical Gastroenterology and Hepatology. This low percentage could result from concerns of side effects or patient hopes that more effective medications will soon become available.

The anti-HCV drugs boceprevir and telaprevir, approved by the FDA in May 2011, were found to be highly effective in phase 3 clinical trials. When one of these drugs is given in combination with pegylated interferon and ribavirin (triple therapy), rates of sustained virologic response are 70%–80% in patients with HCV genotype 1 infection. Furthermore, these drugs have been reported to reduce mortality from liver diseases, including hepatocellular carcinoma, hepatocellular failure, and complications of portal hypertension.

Emerson Chen et al. investigated how many patients with HCV genotype 1 infection actually started this treatment regimen within the 12 months after their FDA approval.

They found that only 18.7% of patients seen at hepatology practices in Dallas and Miami from June 2011 through February 2012 began the triple therapy–about the same percentage as those receiving dual therapy (with only pegylated interferon and ribavirin) before boceprevir and telaprevir were approved. So, rates of treatment with triple therapy have not increased beyond levels seen in the prior decade with dual therapy, despite the proven efficacy of the new agents.

In analyzing patients’ charts, Chen et al. found that the reasons patients were not given the triple therapy included contraindications (in 50.5%, including non-hepatic disorders, decompensated liver disease, and adverse events during prior treatment), patient choice (22.5%), and less-advanced liver disease (17.4%).

Among the patients who did receive triple therapy, 15% discontinued prematurely because of serious adverse events such as anemia, dehydration, and rash.

Treatment experience and the extent of liver fibrosis seemed to be the most important determinants for initiation of triple therapy.

Patients who had HCV relapse after previous treatments are prime candidates for triple therapy, compared with prior non-responders and treatment-naive patients. Chen et al. found that patients with stage 3−4 fibrosis were also considered prime candidates for triple therapy—they have the highest risk for disease progression and development of liver-related complications.

The factors that affected initiation of triple therapy in this study were similar to those for dual therapy before 2011. Although race, marital status, and insurance were previously reported to be important, these associations were not observed by Chen et al.

The authors propose that the disappointingly low use of the new therapies, even after a decade without novel medications, could result from the continued requirement for interferon, the safety profile of the new drugs, low predicted rates of response for patients that did not respond to previous therapy, and hopes that interferon-free regimens could be around the corner.

Expanding HCV screening to people born between 1945 and 1965—the age group in whom up to 75% of HCV-related deaths occur—could increase the number of treatment-naive patients seeking HCV therapy.

Read the article online.

Chen EY, Sclair SN, Czul F, et al. A small percentage of patients with hepatitis c receive triple therapy with boceprevir or telaprevir. Clin Gastroenterol Hepatol 2013;11:1014-1020.e2.

http://agajournals.wordpress.com/

Video Vignettes -Current Outlook On Hepatitis C Treatment

When a new learning activity pertaining to HCV is released online this blog provides readers with background information and links to the new video, article or CME.

The Doctor's Channel released a four part video series last month offering key information for anyone considering triple therapy. Sofosbuvir is also included in the series, as is the future of HCV therapy. Highlights of the four part webcast are provided below.

Unfortunately like any CME it requires a quick free registration. Before each webcast participants will be prompted to complete a few pre-test questions. Rather the questions are answered correctly or not will not interfere with viewing the presentation. Although, I know the majority of you reading this will answer them all correctly.

Click here to register, and here to view the webcast.

The discovery, development, and availability of direct-acting antiviral agents (DAAs) offers new treatment options and the possibility of improved outcomes for newly diagnosed patients as well as those who have experienced a relapse or failed to respond to previous treatment. However, their use introduces new challenges and adds to the complexity of HCV treatment and care. With rapid advancements in the field and new agents offering potential improvements in outcomes, shorter treatment durations, and unique adverse event profiles, clinicians must stay informed of the evolving data in order to counsel patients appropriately—in particular, those who may wish to discuss the benefits and risks of initiating therapy now vs delaying treatment. This program will consist of a series of four video vignettes presenting interviews with clinical experts who will explore some of the most pressing issues in the management of patients with HCV.

          

Part 1 

The Evolution of SOC in HCV 

What Have we Learned about Starting Therapy Today?

Discussed Topics
The biggest surprises after the approval of Telaprevir and Boceprevir

Side effects:
1-Anemia
2-Drug to drug interactions
3-Fragility of patients with more advanced disease
 

8:20

Part 2

Integrating Triple Therapy into Practice

What are the Issues?

Discussed Topics
1-Adherence to therapy
2-Patient selection
3-Who should be treated now versus waiting
4-Updating the patient during therapy
5-Modification of ribavirin
6-Patients with advanced fibrosis

 

8:45

Part 3

Treating Special Populations with HCV

What Works? What Doesn't?

Discussed Topics
1-Decompensated liver disease
2-Patients with cirrhosis, transplant recipients, and patients who are coinfected with HIV.
3-Examine clinical data about the safety and efficacy of investigational HCV treatments and the risk-benefits of treating now versus waiting

 

9:17  

Part 4

What’s Coming Up the Therapeutic Pipeline?

Will They Change the SOC?

Discussed Topics
1-Genotype 1 Sofosbuvir + Interferon + Ribavirin
2-Genotype 2 and 3 Sofosbuvir + Ribavirin
3-Which patients will benefit from interferon-sparing drugs
4-Off label usage/ mix and  match therapy
5-The future of HCV therapy

 

Boceprevir- Adherence to Assigned Dosing Regimen in Chronic Hepatitis C

Adherence to Assigned Dosing Regimen in Chronic Hepatitis C

Discussion Only

Abstract and Introduction

Materials and Methods

Results

Discussion
The present retrospective analysis of two large registration trials indicates that adherence to duration of treatment with P plus R plus BOC is an important factor associated with achieving SVR in patients with chronic hepatitis C genotype 1 infection. In particular, adherence to treatment duration appeared to be more important than adherence to the dosing interval with BOC in achieving SVR in the overall, nonblack and black populations.

Patients who discontinued treatment due to meeting the futility rules would have been defined as having low adherence rates to the duration of treatment. Approximately 9% and 19% of the treatment-naïve patients and those who failed previous treatment met the futility rules, respectively. However, patients who discontinued treatment could still have been defined as having high adherence rates to the t.d.s. dosing interval with BOC. Therefore, protocol-defined discontinuations (or early discontinuations due to adverse events) may have influenced the adherence rates to the duration of treatment, but may not have had an effect on the adherence rates to the t.d.s. dosing interval with BOC.

These results indicate that higher SVR rates were achieved when patients adhered to ≥80% of the treatment duration when compared with <80% of the treatment duration. In SPRINT-2, previously untreated patients with treatment duration adherence of ≥80% and BOC dose adherence of <80% had high SVR rates (78–100%) and in RESPOND-2, SVR rates in patients who had failed previous therapy and had good adherence to the treatment duration of ≥80% were still high (83–100%) even with <80% adherence to the doses of BOC. In addition, black and nonblack patients who adhered to ≥80% of the assigned dosing interval achieved similar SVR rates. It is important to note that non-adherence to the assigned duration of treatment includes patients who met futility rules or discontinued due to adverse events or other reasons.

Although the approved dosing of BOC every 8 h was effective, the present analysis indicates that strict adherence to the 7- to 9-h BOC dosing interval had minimal impact on SVR among patients who were otherwise adherent to the assigned duration of therapy. Specifically, different rates of adherence to the t.d.s. dosing interval with BOC (<60% to >80%) did not impact the SVR rates except for patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC. Different rates of adherence before or after treatment week 8 did not differentially impact SVR rates or the emergence of resistance. Adherence rates above or below 80% did not impact the emergence of resistance.

In these Phase 3 registration trials, it is not surprising that patients had high rates of adherence to the study drug, BOC, and that patients who were adherent to BOC were likewise adherent to both P and R. Accordingly, it was not possible to discern whether adherence to an individual agent within this triple drug regimen, by itself, influenced overall response rates. These findings are consistent with the HCV anti-viral pivotal registration trials of a decade ago,^[2] wherein most patients managed to achieve the goals of 80% adherence to their study medication doses of P and R and treatment durations. At that time, it was conjectured that such high patient motivation and careful management in the context of controlled trials at tertiary referral centres might not be representative of patients treated in the community. Subsequent studies over the past 10 years, however, have confirmed that patients who were treated with P and R in the community were, in fact, largely reflective of the patients treated within clinical trials.^[8] In one small analysis, however, including 23% who were HIV co-infected, 7% of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of R in the last 7 days, with the authors noting that self-reported dose non-adherence to hepatitis C treatment occurs frequently.^[9]
                       
Moreover, often in the real world setting, patients who ordinarily would not be considered candidates for anti-viral therapy are treated with HCV anti-virals, including those with serious psychiatric disorders and those with recent injection drug use. Among a group of 109 Australian patients with recently acquired HCV infection, many of whom were recent injection drug users, an exceptionally high rate of adherence to therapy was observed with the interesting observation that patients with no 'tertiary education' were less likely to have '80/80' P adherence, whereas injection drug use prior to or during treatment, however, did not impact such adherence.^[10] Regarding underlying depression and anxiety, at least two European studies[11, 12] confirmed that aggressive and pre-emptive therapy of such psychiatric conditions allows for the optimisation of adherence and virological efficacy to anti-viral treatment in hepatitis C. Such observations were corroborated by a recent report by Schaefer et al., ^[13] showing that prophylactic therapy with antidepressants may lessen the depression adverse events associated with interferon therapy in patients with hepatitis C infection.

The concept of anti-viral therapy adherence as it relates to efficacy became known in the HIV era, and it was recently emphasised that the term 'non-adherence' differs in how it is used in the HCV from the HIV literature. Weiss et al.^[14] note that in HIV, non-adherence refers primarily to patient-missed doses, whereas in HCV, the term refers primarily to dose reductions by the clinician and early treatment discontinuations. The authors propose that investigators codify such terminology, noting correctly that such compliance measures will become increasingly important to future treatment given the potential for resistant mutations emerging in the HCV direct-acting anti-viral agents.

In a report by Lo Re et al., utilising an adherence calculation that assessed pharmacy refill data, the investigators found that adherence of ≥85% to pegylated interferon and ribavirin was associated with increased HCV suppression and early virological response during the initial phases of HCV anti-viral therapy during the period of rapid virological decay compared with <85% adherence.^[15] Decreases in HCV viral load with adherence levels of 90–99% or 100–109% were similar to that with 85–89% adherence. This indicated that an adherence level of ≥85% achieved the maximal decrease in HCV viral load. Recently, Lo Re et al. reported that early virological response and SVR rates were increased with higher levels of adherence to P and R.^[16]
                       
Moving forward to a new generation of HCV therapy with agents that have specific actions on the replication cycle of the HCV RNA virus has mandated a re-evaluation of the role of patient adherence to such therapy. Using additional agents with defined half-lives reinforces the need for patient adherence to maximise the chance of sustained viral eradication and minimise the possibility of resistance. The present report is reassuring because it validates the continued inherent motivation of the HCV-infected patient to undergo an arduous and sometimes protracted course of therapy. In the absence of serological tags of seroconversion or other markers to denote the point at which no further virological suppression is required to achieve a cure from therapy, duration of on-treatment viral negativity remains a surrogate indicator. The current findings strengthen the need for patient adherence in the new anti-viral era, but distinguish the heightened importance of adherence to duration, with somewhat lesser importance of the need for adherence to the t.d.s. dosing interval with BOC. Future regimens involving therapy with once-daily agents should allow for improved patient compliance and potentially, improved anti-viral outcomes.

http://www.medscape.com/viewarticle/806314_4

Hepatitis C Triple Therapy Scores in Large Clinical Trial

July
Infectious disease special edition

Hepatitis C Triple Therapy Scores in Large Clinical Trial

by Christina Frangou

Patients with the most prevalent type of hepatitis C virus (HCV) infection have a substantially higher likelihood of achieving a sustained virologic response (SVR) with a triple therapy that includes an HCV protease inhibitor, a recent report confirmed. The findings validate triple therapy as the first-line treatment for genotype 1 hepatitis C (Ann Intern Med 2013;158:114-123).

Donald M. Jensen, MD, a professor of medicine and the director of the Center for Liver Diseases at the University of Chicago Medicine, said that the Annals study confirms previous research and an FDA review. “Triple therapy with a protease inhibitor is the current standard of care,” Dr. Jensen said.

After the drugs were approved in 2011, triple therapy quickly became the general practice in urban centers throughout the United States and the regimen has been adopted slowly as standard treatment throughout the rest of the country, added Paul Pockros, MD, the director, Center for Liver Diseases, Scripps Clinic, San Diego. “I think [triple therapy] is widely adopted now,” said Dr. Pockros, who was not involved in the study.

In the report, lead author Roger Chou, MD, from the Division of General Internal Medicine and Geriatrics at Oregon Health & Science University, in Portland, and his colleagues assessed 379 studies identified by searching multiple databases dating between 1947 and August 2012. Their analysis revealed that, for HCV genotype 1 infection, “fair-quality trials” demonstrated that triple therapy with pegylated interferon (PEG-IFN), ribavirin and either boceprevir or telaprevir increases the likelihood for achieving SVR by between 22% and 31% compared with dual therapy not including a protease inhibitor.

Triple therapy for HCV genotype 1 infection also was associated with a shorter duration of treatment, “an important consideration given the high frequency of adverse effects associated with interferon-based therapy,” the authors said.

Their findings also confirm the well-documented increase in adverse events (AEs) for triple-therapy regimens. Compared with dual therapy, triple therapy including boceprevir was associated with a greater risk for hematologic AEs, and triple therapy including telaprevir was linked to higher rates of anemia and rash.

The authors said their findings have important implications for treatment as well as screening because “screening benefits depend in part on the effectiveness of available treatments.”

Precedent-Setting

Further reviewing the trial results, the investigators reported that no study in the past 70 years has focused on long-term clinical outcomes after treatment. Instead, studies rely on SVR as the primary outcome measure. The authors said that it is difficult to evaluate long-term clinical outcomes other than SVR because HCV infections develop over many years.”

50% Mortality Risk Reduction

However, the authors said evidence suggested that SVR is associated with a lower risk for all-cause mortality. The strongest evidence comes from a cohort study published in 2011 that showed SVR was associated with a 30% to 50% reduction in mortality risk, after adjusting for confounders (Clin Gastroenterol Hepatol 2011;9:509-516). Dr. Chou and his colleagues said the study provides “strong evidence” that virologic and clinical outcomes are linked.

That may be the most important finding in the report, commented Andrew J. Muir, MD, MHS, the clinical director of hepatology, Department of Medicine at Duke University in Durham, N.C. “This has been an area of controversy in the field for a number of years,” Dr. Muir said. “With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes. The lack of clear clinical benefit also kept some [practitioners] from accepting the value of hepatitis C treatment.”

The investigators also reported that dual therapy with PEG-IFN alfa-2b was associated with a reduced rate of SVR by about 8% compared with PEG-IFN alfa-2a. However, PEG-IFN alfa-2b was associated with a lower risk for serious AEs, “suggesting potential trade-offs between benefits and harms,” said the authors. For patients with HCV genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood for achieving SVR than was therapy for 24 weeks, and lower doses of PEG-IFN alfa-2b were less effective than standard doses, according to evidence from two to four fair-quality trials.

Across all regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis and patients with higher viral load, the researchers noted.

The study was supported by the Agency for Healthcare Research and Quality. The authors reported no relevant conflicts of interest.

http://www.idse.net/ViewArticle.aspx?d=Hepatitis&d_id=213&i=July+2013&i_id=977&a_id=23518

Hope for HCV Patients Who Failed Therapy With Telaprevir or Boceprevir

Clinical Care Options
Hope for HCV Patients Who Failed Therapy With Telaprevir or Boceprevir

Mark S. Sulkowski, MD - 6/28/2013

*Free registration required to view article and links

Sky-High Expectations, Tempered by Reality
In 2011, the FDA approved the first 2 DAAs: boceprevir and telaprevir. They represented a new era of agents that directly attacked the hepatitis C virus itself, instead of working indirectly by stimulating the patient’s native antiviral immune system. With the new DAAs in combination with peginterferon/ribavirin came higher rates of SVR and the perception that hepatitis C therapy had turned a corner into a very promising future. However, not every patient benefited from that promise, and for an unfortunate group of patients who failed to achieve SVR with triple therapy, the future has been clouded with uncertainty, including questions over the clinical significance, if any, of the selection and enrichment of a population of telaprevir- and boceprevir-resistant HCV variants to protease inhibitors that they invariably developed.

A Robust Pipeline
Now, we’re beginning to recognize that these patients are not without HCV treatment options. New classes of drugs with multiple agents in development are extending and expanding the optimism first engendered by the first-generation DAAs. In clinical trials, drugs from classes as diverse as NS3/NS4A protease inhibitors, nucleos(t)ide analogues, NS5A inhibitors, and NS5B polymerase inhibitors are demonstrating greater efficacy with fewer adverse events and shorter treatment courses with and without peginterferon/ribavirin.

Initial clinical trials have reported very promising efficacy in HCV treatment-naive patients as well as those who have failed previous therapy with peginterferon/ribavirin, including “null” responders. Amidst this flood of new data, those patients who did not achieve SVR when treated with telaprevir or boceprevir finally have data that are very encouraging. At the 2013 European Association for the Study of the Liver conference, my colleagues and I presented data demonstrating that an all-oral, once-daily combination of sofosbuvir and daclatasvir, without even ribavirin, administered for 24 weeks produced 12-week SVR rates of 95% to 100% in genotype 1 HCV–infected virologic nonresponders to previous telaprevir- or boceprevir-based therapy. Indeed, the overall SVR rate was 100%. These rates remained constant even in the presence of baseline NS3 variants conferring resistance to these first-generation protease inhibitors. Although not yet presented in a scientific forum, similar treatment success was recently announced in the LONESTAR study in which triple therapy failures were treated with sofosbuvir and ledipasvir with and without ribavirin.

Reassurance for DAA “Pioneers”
Such was the excitement generated by the first DAAs that many patients and clinicians were quick to take advantage of them. Fortunately, many patients treated with telaprevir or boceprevir triple therapy achieved SVR. However, for an unfortunate minority of these DAA “pioneers,” treatment failed either due to toxicity or virologic failure. For these patients, we now have very promising data that should reassure them that they have not reached the end of their treatment options. I believe the important message here is that a cure is not only possible for patients who failed previous HCV protease inhibitors, but it may be even be “easy” in the future using combinations of oral DAAs that attack the virus at the viral polymerase (nucleos(t)ide analogues) and the NS5A glycoprotein. While we wait for the approval and greater availability of such therapies, I’ve been educating my patients about these future approaches and focusing my attention on modifiable factors to improve hepatic health, namely avoiding alcohol, achieving or maintaining a normal body mass index and, perhaps, consuming more coffee. Yes, more coffee; I’ll save further discussion of coffee and the liver for another time!

Your Thoughts?
How do you manage your DAA treatment failure patients? Are you counseling your patients to begin treatment with the new drugs as soon as they become available, or are you urging patience to wait for the optimal regimens to be identified??

Topics: HCV - Treatment 

 

Related from CCO-

HCV Approved & Phase III - Source: 2013 Annual Meeting of the European Association for the Study of the Liver*  

 

Healio: HCV triple therapy post-liver transplant yields moderate response, significant adverse events

HCV triple therapy post-liver transplant yields moderate response, significant adverse events
June 27, 2013

Liver transplant recipients with hepatitis C experienced moderate early response rates but frequent side effects from triple therapy with antivirals in a recent study.

Researchers evaluated 60 liver transplant recipients with recurrent HCV genotype 1 and significant fibrosis who underwent treatment with pegylated interferon alfa-2a and ribavirin (PEG/RBV) and either telaprevir (TVR) (n=35) or boceprevir (BOC) (n=25), with a minimum follow-up of 12 weeks (mean follow-up, 35 weeks).
Full Story » 

USPSTF recommends HCV testing for high-risk adults, baby boomers June 26, 2013
The United States Preventive Services Task Force recently recommended screening for adults at high risk for hepatitis C virus infection and one-time screening for all Americans born between 1945 and 1965 because the birth cohort is at greater risk for infection compared with other age groups.
Full Story

 Meta-analysis linked NAFLD, vitamin D deficiency
June 26, 2013
Researchers performed a systematic review of 17 case-control and cross-sectional studies, assessing the association between nonalcoholic fatty liver disease (NAFLD) and serum levels of 25-hydroxy vitamin D (25[OH]D). Included studies were selected from PubMed and EMBASE databases and published before April 22, 2013, evaluated vitamin D levels among cases and controls, and were based in North America (six studies), Asia (four studies) and Europe or Israel (seven studies).
Full Story...

Webcast - Managing Rashes Associated with Anti-HCV Triple Therapy

When a new educational resource is released online this blog provides readers with background information and links to the new activity.

Last month over at Projects In Knowledge three new learning activities were launched all discussing HCV triple therapy.

The first update includes two new chapters added to the sites "HCV Care and Guidance e-handbook," also called "The Living Medical eTextbook."

Chapter 10 and 11 updates:
Chapter 10 offers current data on efficacy, safety and response to first-generation protease inhibitors in HCV patients with compensated cirrhosis; Hepatitis C Treating Hepatitis C in Patients with Cirrhosis  and chapter 11 highlights important recent data and label updates for boceprevir and telaprevir; Anti-Hepatitis C Triple Therapy Update

*Additional chapters are provided below.

Webcast - Managing Rashes Associated with Anti-HCV Triple Therapy

A new webcast hosted by Anne Croghan, ARNP, will discuss dermatologic adverse events associated with HCV triple therapy.

Hepatitis C — Managing Rashes Associated with Anti-HCV Triple Therapy
By: Anne Croghan, ARNP

Dermatologic adverse events related to anti-HCV triple therapy are a challenge for both clinicians and patients. Boceprevir and telaprevir each have had recent label changes related to dermatologic events. Join Anne Croghan, ARNP, for this webcast in which she discusses rash assessment, symptom control, medication management, monitoring and referral, and patient education. “Managing Rashes Associated with Anti-HCV Triple Therapy,” is part of the HCV Care and Guidance: Practical Education and Resources for Nurse Practitioners and Physician Assistants program. 

Free Registration
As with any CME free registration is required. Once this is accomplished participants taking part in the webcast can skip the pre-test and go directly to the webcast by clicking on the "Activity Button."

May 29, 2013 two new e-handbook chapters offered
Practical Education and Resources

NEW Chapter 10 Hepatitis C - Treating Hepatitis C in Patients with Cirrhosis
By: P. Horne, BSN, MSN

Boceprevir and telaprevir triple therapies offer an improved opportunity for sustained virologic response (SVR) in patients with HCV-related compensated cirrhosis. SVR rates are significantly higher compared with traditional combination therapy in treatment-naive as well as treatment–experienced patients, ... Boceprevir and telaprevir triple therapies offer an improved opportunity for sustained virologic response (SVR) in patients with HCV-related compensated cirrhosis. SVR rates are significantly higher compared with traditional combination therapy in treatment-naive as well as treatment–experienced patients, particularly those who were prior relapsers. In this e-handbook chapter, Patrick M. Horne, BSN, MSN, reviews the importance of diagnosing cirrhosis prior to starting anti-HCV therapy and highlights efficacy and safety data, as well as on-treatment monitoring tips. “Treating Hepatitis C in Patients with Cirrhosis,” is part of the HCV Care and Guidance: Practical Education and Resources for Nurse Practitioners and Physician Assistants program.  

NEW Chapter 11  Anti-Hepatitis C Triple Therapy Update
By: Sherilyn C. Brinkley, MSN, CRNP

Since the approval of boceprevir and telaprevir triple therapy in 2011, studies in real-life clinical settings as well as retrospective reviews of phase III data have been undertaken to better understand how to optimize success with these first-generation protease inhibitors. Join Sherilyn C. Brinkley, MSN, CRNP, for this e-handbook chapter, in which she highlights important recent data and label updates for boceprevir and telaprevir triple therapy. “Anti-Hepatitis C Triple Therapy Update,” is part of the HCV Care and Guidance: Practical Education and Resources for Nurse Practitioners and Physician Assistants program.  

Other topics offered in the e-handbook
Chapter 1 Getting Ready for Direct-Acting Antiviral (DAA) Therapy
Chapter 2 What You Need to Know About the New Direct-Acting Antiviral (DAA) Regimens Chapter 3 Hematologic Adverse Effects
Chapter 4 Dermatologic Adverse Effects
Chapter 5 Gastrointestinal Adverse Effects
Chapter 6 Neuropsychiatric Adverse Effects
Chapter 7 Understanding Drug-Drug Interactions in this New Triple-Therapy Era
Chapter 8 Treating HCV in Special Populations
Chapter 9 Predictors of Response
Chapter 10 Treating Hepatitis C in Patients with Cirrhosis
Chapter 11 Anti-Hepatitis C Triple Therapy Update

Related
Video- Hepatologist Urges caution among clinicians in the administration of telaprevir
High Incidence of Telaprevir-associated Severe Rash Leading to Discontinuation
HCV  Drug Incivek (telaprevir) - View Rash  Grade 1 and  2 

SVR after triple therapy maintained long-term durability in HCV patients

SVR after triple therapy maintained long-term durability in HCV patients

Rutter K. Aliment Pharmacol Ther. 2013;38:118-123.

Source - Healio

June 20, 2013

Nearly all patients with chronic hepatitis C who achieved sustained virologic response to therapy with pegylated interferon, ribavirin and direct-acting antivirals continued to have undetectable HCV RNA over long-term follow-up in a recent study.

Researchers followed 103 white patients with chronic HCV who had participated in randomized, controlled trials or an extended access program in which they achieved sustained virologic response (SVR) at 24 weeks after completing combination therapy with peginterferon alfa-2a and ribavirin and a direct-acting antiviral (DAA). Evaluated DAAs included protease inhibitors (90.3% of cases), NS5B polymerase inhibitors (6.8%) and both in combination (2.9%). Patients were followed for a median of 21 months after achieving SVR (range 7 to 64 months).

The cohort included 80 treatment-naive patients, 17 who had been nonresponsive and six who had relapsed during prior therapy. Nearly all patients were infected with HCV genotype 1, including 34 with genotype 1a and 67 with 1b, while two patients had genotype 4.

Relapse occurred in two patients who had genotype 1b and had been treated with faldaprevir. Both patients achieved undetectable HCV RNA levels at 4 weeks, and cloning sequencing after relapse indicated identical sequences to those observed at baseline. Viral resistance was unseen in either case.

One treatment-naive, noncirrhotic woman who relapsed had detectable HCV RNA 8 months after therapy cessation, which increased to pretreatment levels in subsequent months. Retreatment with 24 weeks of peginterferon, ribavirin and telaprevir resulted in undetectable RNA levels. The second relapser, a treatment-naive cirrhotic man, had detectable HCV RNA 12 months after therapy ended that returned to pretreatment levels shortly after detection.

“To the best of our knowledge, this is the first study reporting long-term virological outcomes in patients with hepatitis C after successful antiviral triple therapy,” the researchers wrote. “Our study shows that HCV eradication by triple therapy remains durable and confirms an excellent long-term prognosis of HCV patients with SVR. To assess the long-term clinical benefit of triple therapy, studies with a longer follow-up and larger patient numbers are needed.”

Disclosure: See the study for a full list of relevant disclosures.

Perspective

William Carey

Sustained virological response, historically, has been tantamount to a cure in patients who are treated for hepatitis C. The problem, of course, is that with every change in therapy, it's necessary to validate that the concept of SVR - no virus detectable in the blood 6 months after stopping treatment - actually applies. It applies for pegylated interferon and ribavirin, and now we're seeing evidence that it also applies when we're using direct-acting antiviral agents in addition.

[This is] an important study to do. I think the strength of it is that it has at least a moderate number of patients, over 100, and they found, not surprisingly, that SVR 24 weeks after stopping treatment seems to be associated with permanent eradication of detectable virus. Again, this is not surprising, but still an important detail that needs to be hammered out, and the study goes a long way toward doing that.

The limitations of the study are that they looked at many different direct-acting agents, and so the number of patients treated with any particular direct-acting agent is somewhat limited. This really comes into focus when we look at the two breakthrough patients: They were both treated with the same drug. So [the study] raises, but doesn't answer the question: "Is faldaprevir different than the other agents that were tested?" It's really impossible to say, because the numbers are too small, but it raises the question of whether this agent is going to be associated with a higher rate of breakthrough than the other agents tested here.

Instead of 100 patients, I'd like to see 1,000, and certainly there are many many hundreds of patients who have been in randomized trials, and this data is or will soon become available. So I think that this is a good beginning, but we just need to see larger numbers, and we need to see numbers that are specific to each and every direct-acting antiviral drug.

William Carey, MD

 Professor of medicine, Cleveland Clinic Liver College of Medicine

Founding member, Cleveland Clinic Hepatology section

Disclosures: Dr. Carey reported no relevant financial disclosures.

http://www.healio.com/infectious-disease/hepatitis-resource-center-2013/svr-after-triple-therapy-maintained-long-term-durability-in-hcv-patients

After HCV treatment failure, some success with boceprevir-IFN-ribavirin

After HCV treatment failure, some success with boceprevir-IFN-ribavirin

By: NEIL OSTERWEIL, Internal Medicine News Digital Network

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company.

Three of his coauthors are employees of Merck, and one is a board member.

http://www.internalmedicinenews.com/news/across-specialties/single-article/after-hcv-treatment-failure-some-success-with-boceprevir-ifn-ribavirin/ba9ec84505627d1515ea4ff6229c145f.html

Triple therapy for hepatitis C is effective after liver transplantation, but side-effects are common

Triple therapy for hepatitis C is effective after liver transplantation, but side-effects are common

Liz Highleyman

Produced in collaboration with hivandhepatitis.com

Published: 16 May 2013

Adding the approved HCV protease inhibitor telaprevir (Incivo or Incivek) to pegylated interferon and ribavirin can increase sustained viral response rates even for difficult-to-treat liver transplant recipients, but adverse events are common, researchers reported at the 48^th International Liver Congress (EASL 2013) last month in Amsterdam.

While many hepatitis C patients await interferon-free direct-acting antiviral regimens, others have advanced liver disease and need treatment now. This group includes liver transplant recipients, as HCV almost always recurs and infects the new liver in the absence of treatment

 

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