HCV drugs - A review of 2012 and a peek at 2013

HCV drugs - A review of 2012 and a peek at 2013

Today this blog offers a look back at the two new drugs approved in 2011 to treat hepatitis C, and a few promising therapies in development.

In May of 2011 the U.S. Food and Drug Administration approved Incivek (telaprevir) and Vicrelis/Boceprevir to treat hepatitis C patients chronically infected with genotype 1.

Among treatment-naive people with HCV genotype 1 these two new direct-acting antiviral agents boceprevir or telaprevir have increased SVR more than 75%.

Both protease inhibitors are taken with a combination of pegylated interferon and ribavirin. Treatment duration is a total of 24, 36 or 48 weeks.

Telaprevir and Boceprevir
In a study of veterans infected with hepatitis C virus (HCV) genotype 1, the direct-acting antiviral drugs boceprevir and telaprevir, in combination with pegylated interferon and ribavirin, produced robust antiviral responses at 24 weeks and at the end of therapy, read the December 2012 article from Medscape here.

Telaprevir and Boceprevir Offer Similar Efficacy For Most Patients?
Reported by (Reuters Health)
As there are no head-to-head comparison trials so far, Dr. Kiernan and colleagues used a Bayesian mixed treatment comparison model to explore the relative differences in efficacy between boceprevir and telaprevir when used as a third agent (with pegylated interferon and ribavirin) in HCV genotype 1 treatment. She added, "For patients who have experienced a previous treatment relapse, our research would suggest that telaprevir would be a better choice." .... continue reading

Of Interest
Incivek (Telaprevir)-Hepatitis C Geno 2 Patient Treated

Side Effects
Anemia  (including severe anemia) and neutropenia, have been reported to be significantly higher with boceprevir triple therpay than with pegylated interferon and ribavirin alone, and telaprevir is associated with a serious rash. In clinical data a rash was reported in 56% of patients using telaprevir . We can compare that to 32% of patients reporting a rash receiving standard of care (pegylated interferon and ribavirin). The rash was found to be mild to moderate although severe in 1% of patients and resulted in stopping treatment for 6% of patients.

Recently Vertex announced that the INCIVEK^® (telaprevir) label in the United States has been updated to include a Boxed Warning stating that fatal and non-fatal serious skin reactions have been reported in patients taking INCIVEK combination treatment.

Included below are links to the recent updates
HCV Drug Incivek (telaprevir) - View Rash Grade 1 and 2
FDA Podcast: Serious skin reactions with Hepatitis C drug Incivek (telaprevir) 

As for boceprevir anemia was seen in about 50 % of patients undergoing therapy - compared to 30% receiving standard therapy.

According to new data presented by Merck at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) drug-induced anemia during triple therapy with boceprevir can be managed by ribavirin dose reduction or by the addition of erythropoietin.

The November 2012 press release from Merck -
Merck Reports New Phase III Analyses on Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy, Including Cirrhotic Patients

Jan 6 2013 - HCV triple-therapy genotype 1: management of side-effects

How to optimize HCV therapy in genotype 1 patients: management of side-effects
Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the ‘flu’-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers.........

Cirrhosis and Triple Therapy
In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen. The full article written by Neil Osterweil is available here.

Cirrhosis - Interferon-free
Reported by Keith Alcorn - November 2012
The first major data on interferon-free hepatitis C treatment in people with cirrhosis show that treatment using BI-201335 – now known as faldaprevir – and BI-207127 with ribavirin can be safe, and proved effective in up to 69% of patients, according to results from the SOUND-C2 study presented this week at the 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, read the full article here.

Standard Therapy Improves Survival In Patients With Cirrhosis
According to a study reported this month in the December 26, 2012, issue of JAMA, sustained virological response to hepatitis C interferon-based treatment is associated with improved survival in patients with advanced disease.

Read all updates here: Hepatitis C Cirrhosis Patients with Sustained Treatment Response Have Lower Risk of Death

December 2012

Liver Meeting Roundup

by Megan Block, MPH

Boston—The Liver Meeting 2012 featured the latest in research, treatment guidelines and advances in the field of hepatology. Here, we highlight some the most compelling presentations related to treatment for patients infected with the hepatitis C virus (HCV) and HIV.

A Shortfall in Statin Use.
A study from the University of North Carolina at Chapel Hill suggests that providers are hesitant to prescribe statins to patients with dyslipidemia and chronic liver disease, despite data and guidelines supporting the safe use of the drugs in this patient population.

The cross-sectional study identified 1,198,221 patients with dyslipidemia. Statin use was compared in patients with HCV without cirrhosis, patients with compensated cirrhosis of any etiology and a group of controls without liver disease. The investigators found that statins were prescribed to 1,055 (28.7%) of the HCV-infected patients, 1,092 (34.1%) of the patients with compensated cirrhosis and 710,564 (59.6%) of control patients. Patients with HCV or compensated cirrhosis thus were significantly less likely than controls to receive statins (odds ratio, 0.31; 95% confidence interval, 0.29-0.32). The authors recommended increased education to change providers’ perceptions of statin hepatoxicity risk among patients with chronic liver disease.

“This study confirms that statins are underused in the HCV population and those with liver cirrhosis. As pharmacists, we can and should do a better job in educating patients and physicians about the safety of statins in this population,” said specialty pharmacist Janet Nguyen, PharmD, BCPS, vice president of network strategy at ModernHealth in Monrovia, Calif. “We should be doing a review of their medication profile and identifying opportunities to provide interventions for patients who should be put on a statin for their cardiovascular benefits.”

Response-Guided Therapy.
Current guidelines state that patients who are coinfected with HCV and HIV should be treated for 48 weeks, especially if polymerase chain reaction (PCR) tests for HCV remain positive at four weeks. But Canadian researchers presented data suggesting that response-guided therapy (RGT)—usually with pegylated interferon plus ribavirin (PR)—can significantly shorten the duration of therapy.

In the study, researchers at Toronto General Hospital used electronic medical records to identify all patients with HCV genotype 2 or 3 with HIV coinfection. PCR tests for HCV were performed every four weeks of drug therapy until a negative result (<50 IU/mL) was achieved.
In the intent-to-treat analysis, 23 of 35 patients were treated with the RGT protocol, and 20 patients completed their treatment. According to the researchers, only one patient needed the full 48 weeks of therapy to achieve a sustained virologic response (SVR)—a finding that was especially striking, considering the fact that less than half of the patients (nine) had a negative PCR HCV test at four weeks.

Based on the results, “the use of response-guided therapy allows [treatment] to be shortened in the majority of individuals” with HIV and HCV coinfection, the researchers concluded.

Positive Telaprevir Data.
Researchers from the University of Milan in Italy presented a study on the use of telaprevir (Incivek, Vertex) for patients with HCV genotype 1 with severe fibrosis or compensated cirrhosis. In the open-label, early-access program spanning 16 countries, patients were treated for 12 weeks with telaprevir and PR, followed by PR. At four weeks, 54% of patients had undetectable HCV RNA and at 12 weeks, 79% had undetectable viral loads. Serious adverse events occurred in 14% of patients, which is similar to rates from Phase III registration trials.

“The study results are consistent with what we have seen with other telaprevir studies,” commented Dr. Nguyen. “There is still a misnomer out in the community with what telaprevir can do for patients. It is a potential cure for HCV and people still don’t realize that. In this study, and other studies, even patients who had partial or null response to therapy in the past have hope with this therapy.”

Impact on Quality of Life.
Another study presented at The Liver Meeting evaluated the quality of life (QoL) in patients with chronic HCV who achieved SVR versus non-SVR after IFN-based HCV treatment. German researchers found that SVR had a significant effect on liver-related morbidity, and improved QoL and productivity. Specifically, 759 of 1,355 patients achieved SVR after first therapy and only three of those developed a liver-related clinical event compared with 31 non-SVR patients. Increased QoL (scored on the Short Form-36 Health Survey) and productivity (measured by higher frequency of employment, higher number of working hours and lower number of outpatient and inpatient visits after HCV treatment) also were significantly associated with patients who achieved SVR.
Source - Infectious Disease Special Edition

Future Therapies

In the future HCV therapies are likely to shorten treatment duration and be used without interferon. Listed below are some early results from a few of those drugs now in clinical trials.

Sofosbuvir (formerly referred to as both GS-7977 and PSI-7977) is a nucleotide analog polymerase inhibitor
In November Gilead Sciences reported a 100 percent cure rate using the investigational nucleotide sofosbuvir (formerly referred to as GS-7977), the NS5A inhibitor GS-5885 and ribavirin in patients with genotype 1.  In the Electron study 25 geno 1 treatment-naïve patients who were treated for 12 weeks with a combination of three drugs: sofosbuvir, ribavirin and GS-5885 resulted in the an undetectable virus four weeks after completing therapy.

November 2012 Press Release
Gilead Announces 100 Percent Sustained Virologic Response Rate (SVR4) for an Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and Ribavirin in Treatment-Na ïve Genotype 1 Hepatitis C Infected Patients

Hepatitis C Medicine Trial Shows 100% Cure Rate
Nov 10 2012 (Reuters) - Gilead Sciences Inc on Saturday reported a 100 percent cure rate using a combination of drugs in a small number of patients with the most common and hardest to treat form of hepatitis C.

Rival Abbott Laboratories Inc, meanwhile, said a trio of its oral medicines to treat hepatitis C produced unprecedented cure rates in a larger number of patients who had failed to benefit from standard treatment, as well as very high cure rates for newly treated patients.

Data from both companies' mid-stage trials were released Saturday at the annual meeting of the American Association for the Study of Liver Disease in Boston. Gilead's study, dubbed Electron, examined 25 patients with genotype 1 chronic hepatitis C virus (HCV) infection who were treated for 12 weeks with a combination of three drugs: sofosbuvir, ribavirin and GS-5885....

Also in November Gilead reported results examining sofosbuvir (GS-7977) plus ribavirin in patients with genotype 2 or 3
Phase 3 POSITRON study examining a 12-week course of once-daily sofosbuvir plus ribavirin (RBV) in patients with genotype 2 or 3 chronic hepatitis C virus (HCV) infection who are not candidates to take interferon (IFN).

The study found that 78 percent of patients remained HCV RNA undetectable 12 weeks after completing therapy (SVR12). The safety profile of sofosbuvir was similar to that observed in previous studies, and there were few treatment discontinuations due to adverse events.
POSITRON is the first of three Phase 3 studies to be completed that are evaluating sofosbuvir therapy in HCV genotype 2 or 3 infected patient populations.

“We look forward to sharing data from additional Phase 3 studies in early 2013, and expect to submit our first regulatory filings for sofosbuvir by mid-2013.”, read the press release here.

In November  Shilpa Siddhi, M.S., M.B.A. @ Seeking Alpha reported on Gilead's nucleotide NS5B inhibitor sofosbuvir (GS-7977). The article discusses geno 1, 2, and 3 Phase II and III studies using  sofosbuvir with ribavirin, with or without pegylated interferon. The article included a chart on  Gilead's Phase II results. Also included from the article is a chart on the HCV drugs currently in development.

The complete article - New Second Generation Combination Therapy For HCV - First Or Best In The Market (Part 1), is available here.

.

Gilead's HCV Phase II Trial Details and Results

Source: LifeSci Advisors

Click To Enlarge



 HCV drugs approved and currently in development

Source: LifeSci Advisors

Click To Enlarge

 
In January 2013 - Gilead Provided An Update on Hepatitis C Development Programs Including - Sofosbuvir (GS-7977)

Press Release:
Gilead Update - 2nd Phase 3 Study of Sofosbuvir and GS-5885 to Begin Later this Month
-- Sustained Virologic Response Achieved with Oral Regimen of Sofosbuvir, GS-5885 and Ribavirin in 9/9 Null Responder Genotype 1 Hepatitis C Patients --
 -- Second Phase 3 Study Evaluating Fixed-dose Combination of Sofosbuvir and GS-5885 to Begin Later this Month --
Continue Reading....

Stay Updated - 2013 Sofosbuvir

2013 Investment Commentary - Sofosbuvir (GS-7977)
Hepatitis C Market-Sofosbuvir's (GS-7977) Potential
Gilead's lead 'nuc' sofosbuvir anchoring what could become the first interferon-free regimen 

November 2012 - Daclatasvir, Asunaprevir and BMS-791325
Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 Achieved SVR12 of 94% in Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C Infection in Phase II Trial

First presentation of results from this investigational interferon-, ribavirin- and ritonavir-free regimen Phase III development anticipated to begin in 2014

In November Bristol-Myers announced for the first time Phase II data demonstrating that the 12-week Triple DAA treatment regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 achieved sustained virologic response 12 weeks post-treatment (SVR₁₂) in 94% (15/16) of treatment-naïve, genotype 1 chronic hepatitis C patients.

The remaining one patient had undetectable viral load at the end of treatment and was lost to follow-up until approximately 24 weeks post-treatment; in preliminary data, this patient has achieved SVR₂₄. The Phase II results from this interferon-, ribavirin- and ritonavir-free investigational regimen combining three different classes of direct-acting antivirals (DAAs) – an NS5A replication complex inhibitor (DCV), an NS3 protease inhibitor (ASV) and an NS5B non-nucleoside polymerase inhibitor (BMS-791325) – were presented today at the American Association for the Study of Liver Diseases congress in Boston, read more here.

Triple Therapy With Daclatasvir, Asunaprevir, and BMS-791325 Produces Very High SVR12 Rates in Treatment-Naive Patients With Genotype 1 HCV
In a randomized phase IIa trial, SVR12 rates of 94% were observed with the peginterferon/ribavirin-sparing regimen, and therapy was generally well tolerated.

*Free registration required

October 2012 - ABT-450/r, ABT-267, ABT-333 and ribavirin

Abbott's Investigational Interferon-Free Hepatitis C Treatment Regimen
In October Abbott announced initial results from "Aviator," a phase 2b study of its interferon-free, investigational regimen for the treatment of hepatitis C (HCV).

Initial results show sustained virological response at 12 weeks post treatment (SVR12) in 99 percent of treatment-naïve (n=77) and 93 percent of null responders (n=41) for genotype 1 HCV patients taking a combination of ABT-450/r, ABT-267, ABT-333 and ribavirin for 12 weeks, based on an observed data analysis. Read the press release here.

December 2012 - Simeprevir (TMC435)
 
In December Medivir announced phase III data for Simeprevir (TMC435), administered with pegylated interferon and ribavirin - demonstrating efficacy and safety in genotype 1 hepatitis C patients
Top-line results from three pivotal phase III trials examining the one pill, once-daily, investigational protease inhibitor, simeprevir (TMC435), administered with pegylated interferon and ribavirin.
Results from the QUEST-1 and QUEST-2 trials found that 80% and 81% of treatment-naive patients with chronic genotype 1 hepatitis C infection who were treated with simeprevir achieved sustained virologic response 12 weeks after the planned end of treatment (SVR12).

Results from the PROMISE trial found that 79% of prior relapsed patients treated with simeprevir achieved SVR12. All three studies utilized response-guided treatment (RGT) criteria and 85%, 91% and 93 % of the patients, respectively, were eligible to stop all treatments after 24 weeks, press release available here.

Jan 2013 New Publications

Hepatitis C-Interferon free therapy with direct acting antivirals:asunaprevir; daclatasvir; faldaprevir; simeprevir; NS5A inhibitors; NS5B polymerase inhibitors; protease inhibitors; ribavirin; sofosbuvir
The current treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct-acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. Major progress has been made in the past few years: numerous ongoing trials with different compounds, increasing sustained virological response (SVR) rates with oral regimens and shortened treatment duration. Combinations of antivirals with additive potency that lack cross-resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN......
Continue reading...

HCV Studies Give Hope for Interferon-Free Therapy
Investigational agents that act directly against the hepatitis C virus (HCV) may allow previously untreated patients to avoid interferon therapy, long a standard of care, researchers said.

Two phase IIa studies, reported in the Jan. 3 issue of the New England Journal of Medicine, found promising results with different agents, either without interferon or with reduced use of the drug.
Both studies also found less impressive outcomes among patients previously treated unsuccessfully with the standard combination of ribavirin and pegylated interferon.

The investigational drugs were ABT-450, an inhibitor of the viral NS3 protease, boosted with low-dose ritonavir, and ABT-333, a non-nucleoside NS5B polymerase inhibitor.
Continue reading...

Also see: Hepatitis C - 2013 Interferon Free Combinations

HCV: second-generation protease inhibitors
Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection.

Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor.

Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone

ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing

MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.

ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b

Telaprevir	Approved	First generation
Boceprevir	Approved	First generation
Simeprevir	Phase 3	Second wave
BI1335	Phase 3	Second wave
Asunaprevir	Phase 3 (all oral)	Second wave
Danoprevir/r	Phase 2	Second wave
Sovaprevir	Phase 2	Second wave
ABT450/r	Phase 2	Second wave
MK 5172	Phase 2	Second generation
ACH 2684	Phase 2	Second generation

Read more........

 Jan 2013 Investment Commentary - ACH-2684, 2928, 3102 and 1625

Achillion: Poised For Growth And Now Is The Time To Buy
What is notable is that Achillion has 4 drugs in the mix; ACH-2684, 2928, 3102 and 1625. Each of which are showing strong promise at various phase I and II trials, and can either work independently or in combination in an oral fashion, not injections.

Additional Information On Key Developments

This review only touches on a hand full of drugs in development to treat HCV. For more information visit NATAP with detailed information on all the investigational drugs currently making their way down the pipeline.

HCV Advocate - Top News of 2012
A milestone—GS-7977
Outbreaks of HCV in Health Care Settings
First National Helpline
DAA’s and Transplant Patients
and more........

Gastroenterology Top Stories of 2012

Gastroenterology Top Stories of 2012
A perspective on the most important research in the field from the past year

In keeping with our holiday tradition of highlighting the year's top stories from Journal Watch Gastroenterology, I have selected 10 stories that I believe will be of keen interest to all gastroenterologists. Here's a brief overview.

In the esophageal disease arena, we now know that endoscopic ablative therapies have become the standard of care in managing dysplastic Barrett esophagus, but incident cancers and recurrent dysplasia are being seen after successful complete ablation. Thus, continued surveillance of these patients is required. As for eosinophilic esophagitis, we can now add food elimination diets (e.g., dairy, wheat) to our therapeutic armamentarium.

With regard to colonic disease, we now have proof that we can prevent both distal and proximal colon cancer with high-quality colonoscopy, but high-quality colonoscopy requires an optimal bowel prep (split-dose, PEG-based) and skilled colonoscopic technique. Accomplishing colon cancer prevention is really in our hands — by performing careful, high-quality colonoscopy. Also, we now know that the best treatment for C. difficile colon infection is fecal transplantation. I eagerly await the release of a commercial preparation, which could transform this potentially debilitating and difficult disease into a mere nuisance for both patients and doctors alike.

When it comes to chronic pancreatitis, we have learned that smoking may be an equally important risk factor as alcohol, and our interventions should be aimed at both.

Finally, for liver disease, every year seems to bring major shifts in diagnostic and therapeutic advancements. This year is no exception, with emerging evidence that we are nearing an effective oral therapy for hepatitis C infection. Furthermore, although still unclear, it seems that screening for hepatocellular carcinoma in patients with chronic liver disease does result in improved outcomes.
Our gastroenterology top stories of 2012 are:

Esophagus
Ablative Therapy for Barrett Esophagus: Caveat Emptor
Esophagectomy Is Not Justified for Mucosal Neoplasia in Barrett Esophagus
Elimination Diet Works for Eosinophilic Esophagitis in Adults

Colon
Screening Colonoscopy Prevents Cancer in Both Proximal and Distal Colon
Split-Dose Colon Preparation Should Be Standard of Care
More Postcolonoscopy Cancers Attributable to Colonoscopic Versus Polyp Factors
Fecal Transplantation Effective for C. difficile Infection

Liver
Next-Generation Protease Inhibitor Effective for HCV Infection
Support for a 6-Month Surveillance Interval for Hepatocellular Carcinoma

Pancreas
Smoking Increases the Risk for Acute Pancreatitis

The year has taught us a lot, and I look forward to all we will learn in 2013.

As always, we count on your feedback in order to provide the most clinically relevant medical information to help you in your practices, so please send us your comments and suggestions at jwgastro@mms.org.

Happy holidays to all of you.
— M. Brian Fennerty, MD

Published in Journal Watch Gastroenterology December 28, 2012

ClinicalTrials.gov: "Hepatitis C Virus" updated in the last 60 days

 ClinicalTrials.gov: hepatitis c | "Hepatitis C Virus" | updated in the last 60 days

Safety and Efficacy Study of Peginterferon Lambda-1a vs. Peginterferon Alfa-2a, Plus Ribavirin in Subjects With Genotype 1 Hepatitis C 
‎Wednesday, ‎December ‎19, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C Virus (HCV)
Interventions: Biological: Peginterferon Lambda-1a; Drug: Ribavirin; Biological: Peginterferon alfa-2a
Sponsors: Bristol-Myers Squibb; Bristol-Myers Squibb
Not yet recruiting - verified December 2012 

A Study to Evaluate the Efficacy and Safety of Boceprevir Added to Standard of Care Therapy in Previously Treated Participants With Chronic Hepatitis C Genotype 1 and Cirrhosis (MK-3034-105)
‎Wednesday, ‎December ‎19, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C
Interventions: Drug: boceprevir; Biological: PegIFN-2b; Drug: RBV
Sponsors: Merck; Merck
Not yet recruiting - verified December 2012 

Efficacy and Safety of MP-424, Peginterferon Alfa-2a (PEG-IFN Alfa-2a), and Ribavirin(RBV) in Treatment-Naïve or Relapsed Hepatitis C 
‎Thursday, ‎December ‎13, ‎2012, ‏‎12:00:00 PM
Condition: Chronic Hepatitis C (CHC)
Interventions: Drug: MP-424; Drug: RBV; Drug: PEG-IFN alfa-2a
Sponsors: Mitsubishi Tanabe Pharma Corporation; Mitsubishi Tanabe Pharma Corporation
Recruiting - verified December 2012 

Efficacy and Safety of MP-424, Interferon Beta (IFN Beta), and Ribavirin(RBV) in Treatment-Naïve or Having Received Interferon Based Therapy With Chronic Hepatitis C (CHC) 
‎Thursday, ‎December ‎13, ‎2012, ‏‎12:00:00 PM
Condition: Chronic Hepatitis C(CHC)
Interventions: Drug: MP-424; Drug: RBV; Drug: IFN beta
Sponsors: Mitsubishi Tanabe Pharma Corporation; Mitsubishi Tanabe Pharma Corporation; Toray Industries, Inc
Recruiting - verified December 2012 

An Observational Study of Pegasys (Peginterferon Alfa-2a) and Copegus (Ribavirin) on Predictive Values of RVR on Sustained Virological Response in Different Stages of Liver Fibrosis in Treatment-Naïve Patients With Chronic Hepatitis C Genotype 1 
‎Wednesday, ‎December ‎12, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C, Chronic
Intervention:
Sponsors: Hoffmann-La Roche; Hoffmann-La Roche
Recruiting - verified December 2012 

A Study of Ritonavir-Boosted Danoprevir in Combination With Pegasys (Peginterferon Alfa-2a) and Copegus (Ribavirin) in Patients of Asian Origin With Chronic Hepatitis C Genotype 1 With or Without Cirrhosis 
‎Tuesday, ‎December ‎11, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C, Chronic
Interventions: Drug: danoprevir + ritonavir; Drug: danoprevir + ritonavir; Drug: peginterferon alfa-2a [Pegasys]; Drug: peginterferon alfa-2a [Pegasys]; Drug: ribavirin [Copegus]; Drug: ribavirin [Copegus]
Sponsors: Hoffmann-La Roche; Hoffmann-La Roche
Not yet recruiting - verified December 2012 

Safety and Efficacy Study in Subjects With Chronic HCV and Underlying Mild or Moderate Hemophilia 
‎Monday, ‎December ‎03, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C Virus
Interventions: Biological: Pegylated-Interferon-lambda; Drug: Ribavirin; Drug: Daclatasvir
Sponsors: Bristol-Myers Squibb; Bristol-Myers Squibb
Not yet recruiting - verified December 2012 

Algeron (Cepeginterferon Alfa-2b) Compared With PegIntron (Peginterferon Alfa-2b) for Treatment of Chronic Hepatitis C 
‎Friday, ‎November ‎30, ‎2012, ‏‎12:00:00 PM
Conditions: Hepatitis; Hepatitis C
Interventions: Drug: Algeron; Drug: PegIntron
Sponsors: Biocad; Biocad
Active, not recruiting - verified November 2012 

DAA Based Therapy for Recently Acquired Hepatitis C (DARE-C) 
‎Wednesday, ‎November ‎28, ‎2012, ‏‎12:00:00 PM
Condition: Early Chronic Hepatitis C
Intervention: Drug: TPV/PEG-IFN/RBV
Sponsors: Kirby Institute; Kirby Institute; Janssen-Cilag Ltd.
Not yet recruiting - verified December 2012 

Acupuncture as an Adjunctive Treatment for Hepatitis C Patients 
‎Monday, ‎November ‎26, ‎2012, ‏‎12:00:00 PM
Conditions: Hepatitis C (HCV); Acupuncture
Intervention: Device: Acupuncture
Sponsors: Ziv Hospital; Assy Nimer
Not yet recruiting - verified December 2012 

Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of GS-5816 in Subjects With Chronic HCV Infection 
‎Monday, ‎November ‎26, ‎2012, ‏‎12:00:00 PM
Condition: Chronic Hepatitis C Virus
Intervention: Drug: GS-5816
Sponsors: Gilead Sciences; Gilead Sciences
Recruiting - verified November 2012 

A Follow-up Evaluation for Safety in Subjects Who Participated in a Phase 1 Study With BMS-986094 (INX-08189) 
‎Tuesday, ‎November ‎20, ‎2012, ‏‎12:00:00 PM
Conditions: Healthy; Hepatitis C
Interventions: Drug: BMS-986094/INX-08189; Drug: Placebo matching BMS-986094/INX-08189
Sponsors: Bristol-Myers Squibb; Bristol-Myers Squibb
Recruiting - verified December 2012 

A Study to Assess the Safety, Tolerability and Efficacy of TMC435 Along With Pegylated Interferon Alpha-2a (Pegasys) and Ribavirin (Copegus) Triple Therapy in Chronic Hepatitis C Genotype-1 Infected Patients Co-infected With Human Immunodeficiency Virus-Type 1 
‎Monday, ‎November ‎12, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C Virus Genotype-1
Interventions: Drug: TMC435; Drug: Pegylated interferon alpha-2a; Drug: Ribavirin
Sponsors: Janssen Research & Development, LLC; Janssen Research & Development, LLC
Active, not recruiting - verified December 2012 

Safety and Efficacy of Sofosbuvir/GS-5885 Fixed-Dose Combination (FDC) +/-Ribavirin in HCV Genotype 1 Subjects 
‎Saturday, ‎November ‎10, ‎2012, ‏‎12:00:00 PM
Condition: Chronic Hepatitis C Virus
Interventions: Drug: Sofosbuvir/GS-5885 400/90 mg; Drug: Ribavirin
Sponsors: Gilead Sciences; Gilead Sciences
Recruiting - verified December 2012 

An Efficacy, Pharmacokinetics, Safety and Tolerability Study of TMC435 as Part of a Treatment Regimen for Hepatitis C-Infected Patients 
‎Friday, ‎November ‎09, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C, Chronic
Interventions: Drug: TMC435; Drug: Peginterferon-alpha (PegIFNα-2a); Drug: Ribavirin (RBV); Drug: Placebo
Sponsors: Janssen R&D Ireland; Janssen R&D Ireland
Recruiting - verified December 2012 

IFN-free Combination Therapy in HCV-infected Patients Treatment-naive:HCVerso1 
‎Tuesday, ‎November ‎06, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C, Chronic
Interventions: Drug: BI 207127; Drug: Ribavirin (RBV); Drug: Ribavirin (RBV); Drug: Ribavirin (RBV); Drug: BI 201335 (Faldaprevir); Drug: BI 201335 (Faldaprevir); Drug: BI 207127; Drug: BI 207127; Drug: Faldaprevir (BI 201335)
Sponsors: Boehringer Ingelheim Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals
Recruiting - verified December 2012 

Phase 3 Study of BI 207127 in Combination With Faldaprevir and Ribavirin for Treatment of Patients With Hepatitis C Infection, Including Patients Who Are Not Eligible to Receive Peginterferon 
‎Friday, ‎November ‎02, ‎2012, ‏‎12:00:00 PM
Condition: Hepatitis C, Chronic
Interventions: Drug: BI 207127-placebo: 8-week treatment; Drug: Ribavirin: 24-week treatment; Drug: BI 207127: 24-week treatment; Drug: Faldaprevir: 24-week treatment; Drug: Faldaprevir: 24-week treatment; Drug: BI 207127: 24-week treatment; Drug: Ribavirin-placebo: 8-week treatment; Drug: Faldaprevir-placebo: 8-week treatment; Drug: Faldaprevir: 16-week treatment; Drug: Ribavirin: 16-week treatment; Drug: RBV: 24-week treatment; Drug: BI 207127: 16-week treatment
Sponsors: Boehringer Ingelheim Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals
Recruiting - verified December 2012

HCV Drug Incivek (telaprevir) - View Rash Grade 1 and 2

Clinical Updates  

          
New treatments of hepatits C and their cutaneous side effects

Nicolas Dupin

18 December 2012
A new era in hepatitis C virus (HCV) treatment has begun with the recent approval by the US Food and Drug Administration of the new HCV direct-acting antivirals (DAAs) boceprevir and telaprevir as part of triple-combination therapy with the existing peginterferon/ribavirin regimen. Phase III trials of DAA-based combination therapy in treatment-naïve and previously treated HCV genotype-1-infected patients indicate that significant improvements in sustained virological response rates can be achieved, compared with peginterferon/ribavirin alone. Furthermore, DAAs offer the potential to reduce overall treatment duration to less than 48 weeks in around half of treatment-naïve patients. Whilst these new drugs are quite efficient for the treatment of hepatitis C, they bring additional patient management considerations for HCV-treating physicians. Dermatological adverse events (AEs), in particular, have been reported with a higher frequency in trials of the HCV protease inhibitors telaprevir¹ than with peginterferon/ribavirin alone. The mechanism of these side effects is currently unclear; although, these preliminary data suggest that the management of dermatological reactions will remain important going forwards.

In phase II/III trials on telaprevir, dermatological AEs were recorded using special search categories (SSC) for 'rash' and 'pruritus'. The majority of events recorded with the 'rash' SSC term can be more accurately described as eczematous dermatitis, associated with pruritus and xerosis. During the telaprevir/placebo treatment phase, rash and pruritus were among the AEs occurring more frequently (>5% difference) with telaprevir than placebo. During the telaprevir/placebo dosing phase, 55% and 51% of patients treated with T12PR had rash and pruritus, respectively, compared with 33% and 26% of placebo-treated patients.²

In the telaprevir trials, rash events were graded by severity into four grades.

Over 90% of rash events with telaprevir were Grade 1 or 2 (mild/moderate).

Of the 746 (55%) cases of rash (SSC), 495, 186 and 65 were Grades 1, 2 and 3, respectively, representing 37%, 14% and 5% of the overall T12PR-treated population.

In the majority (92%) of cases, progression of rash to a more severe grade did not occur.

A small proportion (6% [78/1346]) of all T12PR-treated patients required discontinuation of telaprevir as a result of skin conditions. Following treatment discontinuation, symptoms commonly resolved. Approximately 50% of rash events started during the first 4 weeks, with the remaining 50% starting between weeks 5-12. The median time to onset of rash (any grade) was 25 (range 1-350) days.

A systematic retrospective assessment by expert dermatologists was made of all 221 Grade 3 rash events, rash events leading to discontinuation of any study drugs, or rash serious AEs occurring in phase III telaprevir trials. In total, 208 (94%) of these cases were reported in patients receiving telaprevir-based therapy (n=1257). This assessment revealed 13 patients receiving a telaprevir-based regimen who presented with a suspected severe cutaneous adverse reaction (SCAR).

Three cases of Stevens-Johnson Syndrome (SJS; one definite, one probable and one possible) and 11 cases of drug reaction with eosinophillia with systemic symptoms (DRESS; one definite, two probable, eight possible) were reported (in one patient, both diagnoses were suspected). Among the three SJS cases, one occurred 11 weeks after telaprevir discontinuation and was not considered related to telaprevir. Of the two suspected SJS cases that occurred during the telaprevir treatment phase, one was considered by the expert dermatologists as possible SJS, and the other as probable SJS. Among the 11 suspected cases of DRESS, three were confirmed and one was already published.³ All cases of reported SJS resolved, 10 cases of reported DRESS resolved, one patient was lost to follow up.

Interestingly, the rate of discontinuation of all study drugs as a result of cutaneous AEs was lower in telaprevir phase III trials than in phase II trials, following incorporation of a rash management plan into the study protocols. Although a rash management plan was implemented during the ongoing phase II trials, the majority of patients had already completed the telaprevir dosing period by this time. All patients in phase III trials, however, were treated following the implementation of the rash management plan at the beginning of the trials. The rash management plan outlined in the phase III trial protocols provides clear guidance for HCV-treating physicians on how to classify and manage rash events, with the objective of minimizing the impact of cutaneous reactions while enabling continuation of antiviral therapy where possible.

Grade 1 or 2 (mild or moderate) rash does not require treatment discontinuation, and can be primarily treated using emollients/moisturizers and topical corticosteroids. Regular follow up is important, with advice to the patient to limit exposure to sun/heat and wear loose-fitting clothes. Grade 3 rash requires immediate discontinuation of telaprevir.⁴Symptomatic treatment as above may also be employed. Ribavirin interruption (with or without peginterferon) is required within 7 days of stopping telaprevir if the Grade 3 rash does not improve, or sooner if it worsens.

However, in case of any reasonable suspicion or diagnosis of SJS, toxic epidermal necrolysis (TEN), DRESS (also known as drug hypersensitivity syndrome, or drug hypersensitivity syndrome), erythema multiforme, acute generalized exanthematous pustulosis, or a skin rash that is considered life-threatening, patients in phase III telaprevir trials were required to immediately and permanently discontinue all medication.

In conclusion, while telaprevir is very efficient for treating patients with hepatitis C, it is associated with a high frequency of dermatological AEs that are not severe. However, the pooled data from all patients who received telaprevir reported a few SCARs that may have been life-threatening. Therefore, patients receiving telaprevir with a rash need thorough evaluation of the severity, and physicians should look for alert criteria of both SJS/TEN (rapidly progressing exanthema, skin pain, mucosal involvement at> 2 sites, blisters or epidermal detachment, atypical/typical target) and DRESS (onset from 6-10 weeks after first dose, rapidly progressing exanthema, prolonged fever, facial oedema). While most of mild rash could be managed by a hepatologist, moderate and severe rash need to be evaluated without delay by a dermatologist who will help to optimize the management and monitoring of the patient.

Figure 1.

• Eczema-like eruption
• Grade 2 rash
• Treatment should be pursued
• Patient must be followed frequently
• Topical steroids should be prescribed regularly

Figure 2.

• Extensive rash with target lesions grade 3 rash
• Telaprevir must be stopped definitively

References

1. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-16.
2. Cacoub P, Bourlière M, Lübbe J, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol. 2012;56:455-63.
3. Montaudié H, Passeron T, Cardot-Leccia N, Sebbag N, Lacour JP. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology. 2010;221:303-5.
4. Dupin N, Mallet V, Carlotti A, Vallet-Pichard A, Pol S. Severe skin rash in case of readministration of telaprevir in a patient who previously experienced a non severe rash. Hepatology. 2012;55:2042-3.

https://www.dermquest.com/expert-opinions/clinical-updates/2012/new-treatments-of-hepatits-c-and-their-cutaneous-side-effects/

Related------------
Podcast Dec 26 2012
FDA Drug Safety Podcast: Serious skin reactions after combination treatment with the Hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin

2012 - Latest advances in curing hepatitis C

New On The Website

Dec 28

 Watch

 

The Latest Advances in Hepatitis C Treatment -- Mitchell Shiffman, MD

Dr. Mitchell Shiffman, of the Liver Institute of Virginia, talks with Hepatology Digest at the American Association for the Study of Liver Diseases about the latest advances in curing hepatitis C, specifically about the role of peginterferon in the era of triple therapy for HCV.

Important News about Medicaid Managed Care & Hepatitis C

Tens of thousands of New York’s most vulnerable patients enrolled in Medicaid managed care plans are being forced to use mail order pharmacies to fill their HCV specialty prescriptions. This policy is detrimental to the long term medical outcome for chronically ill marginalized patients living with hepatitis C (HCV).

Peg-Interferon Plus Ribavirin Safe and Effective in Children
Joe Barber Jr, PhD
Children and adolescents infected with hepatitis C virus (HCV) can be safely and effectively treated with peg-interferon (PEG-IFN) in combination with ribavirin (RBV), according to the findings of a meta-analysis and review.    

Dueling HCV Screening Recommendations

The CDC's recommendations were made because the agency estimated that between 45% and 85% of adults with chronic HCV do not know they are infected. HCV is often asymptomatic and without risk factors for screening, the infection could go undiagnosed until after the liver has sustained significant damage.

Effects of HCV on IFN-Gamma and -Alpha Signalling

In summary, we demonstrate a novel relationship between HCV infection and IFN responsiveness using a well-defined HCV continuous culture system

Hepatitis C Response to Interferon May Improve Survival

Among patients with chronic hepatitis C virus (HCV) infection and advanced hepatic fibrosis, those who achieve a sustained virological response (SVR) to interferon-based therapy are much less likely to die from any cause, according to the findings of a multicenter, long-term follow-up study.

 

Scripps Florida Scientists Develop New Compound (SR9238) That Reverses Fatty Liver Disease

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have developed the first synthetic compound that can reverse the effects of a serious metabolic condition known as fatty liver disease. True to its name, the disease involves an abnormal buildup of fat in the liver.

 

A Trio Of MicroRNAs Contributes To Liver Cancer Progression

MicroRNAs are small RNA molecules that regulate the expression of various genes. In this issue of the Journal of Clinical Investigation, researchers led by Shelly Lu at the University of Southern California identified a...

 

Is Your Sex Life Over if You Have Hep C?

As long as you are aware of how to proceed safely, having Hepatitis C does not need to hinder your sex life.

 

Hepatitis C Management: A Flu-Fighting Berry

Armed with elderberry, those with Hepatitis C have a helpful tool to persevere through this cold and flu season.

 

Investment Commentary

 

2012 Roundup -- HCV Treatments

 

Off Topic

 

Videos Highlight Behavior and Health

Behavior and social factors play key roles in illness and health. NIH has released new videos that highlight outstanding findings in behavioral and social science research.

“Understanding our behavior and making better decisions puts us in charge of our own health,” says Dr. Robert Kaplan, director of NIH’s Office of Behavioral and Social Sciences Research. “These short films highlight some of the benefits of behavioral and social science research—both for us as individuals and for society as a whole.”

The videos feature prominent scientists describing their work. They focus on mindless eating, risk-taking related to substance abuse, diabetes management and the evolution of skin pigmentation. The videos are available at http://obssr.od.nih.gov/video and on the NIH YouTube channel at http://www.youtube.com/user/NIHOD.

“There are personal take-aways in each of these films, ”Kaplan says, “but they also demonstrate both the excitement and reward of behavioral and social science research. I hope every viewer learns something useful. And I hope we’re engaging the next generation of researchers to enter this dynamic and productive field.”

Watch - Insulin for Prediabetes?

I want to discuss a patient of mine. He is a man in his 50s. He is not overweight, although he has a family history of type 2 diabetes. His body mass index is about 23, which is not bad. One caveat, though, is that his son, who was about 12 years old when I first saw the patient, has type 1 diabetes.

Fibromyalgia Underdiagnosed, Report Mayo Clinic Experts

The first population study to compare the prevalence of diagnosed fibromyalgia (FM) to the general population prevalence of people reporting symptoms that met the updated 2010 American College of Rheumatology (ACR) diagnostic criteria indicates that FM may be more common than previously thought and that most FM cases are not being diagnosed, especially in men.

 

Interventions To Improve Patient Adherence to Hepatitis C Treatment: Comparative Effectiveness

Research Review - Final – Dec. 20, 2012 

Interventions To Improve Patient Adherence to Hepatitis C Treatment: Comparative Effectiveness

View Full PDF 1.1 MB

Contents
Executive Summary .....................................ES-1
Introduction ........................................................1
Condition Definition .......................................... 1
Prevalence and Disease Burden .......................... 1
Etiology and Natural History of Hepatitis C Infection ............ 1
Hepatitis C Virus Genotypes and Detection ................. 2
Treatment of Chronic Hepatitis C Infection ..............2
Adherence in the Context of Chronic Hepatitis C Treatment .......... 4
Risk Factors for Nonadherence to Antiviral Treatment .............. 5
Association of Adherence With Sustained Viral Response .............. 6
Interventions for Improving Adherence ................. 7
Scope and Purpose .............. 7
Key Questions ...................... 8
Methods..................................9
Topic Development and Refinement ........................ 9
Analytic Framework ................. 9
Literature Search Strategy .................... 10
Process for Study Selection ................... 10
Data Abstraction and Data Management ................ 12
Individual Study Quality Assessment ...................... 12
Data Synthesis ............................. 13
Grading the Strength of Evidence .................. 13
Applicability ...................... 14
Review Process .................. 14
Results..................................15
Literature Search ................. 15
Characteristics of Included Studies ............. 16
Results of Included Studies .......................... 30

Key Question 1 (Intermediate and Final Health Outcomes) and Key Question 2
(Treatment Adherence) .......................... 30
System-Level Interventions Versus Usual Care .......................30
Regimen-Related Interventions Versus Usual Care ..................33
Patient-Level Interventions Versus Usual Care ........................34
Adverse Event Management Interventions Versus Usual Care/Placebo .........37

Does the Comparative Effectiveness of Treatment Adherence Interventions Differ
by Patient Subgroups?.........................40
Key Question 3. Harms ...................... 40
Summary and Discussion .....................47
Overview of Main Findings ................. 47
Outcomes of Adherence Interventions .................. 48
Strength of Evidence .............................. 48
Health Outcomes ..................................... 48
Intermediate Outcomes ............................ 49
Findings in Relationship to What Is Already Known .................... 53
Applicability of the Evidence to the United States Health Care System ....... 53
Limitations ............................ 54
Potential Limitations of Our Approach................54
Limitations of the Literature ................................55
Implications for Clinical and Policy Decisionmaking............... 56
Evidence Gaps................................... 57
Future Research ................................ 57

Year in Review-CDC Says Test 'Boomers' for Hepatitis C

CDC Says Test 'Boomers' for Hepatitis C

Year in Review

By John Gever, Senior Editor, MedPage Today

Published: December 27, 2012

Our Year in Review series highlights the major medical news stories of 2012. The CDC early in the year suggested one-time hepatitis C screening for all baby boomers. Here is the original article on the CDC guidance, published May 18. In a companion article, you'll find out what has happened since.

ATLANTA -- With "baby boomers" believed to account for 75% of the hepatitis C infected population in the U.S. -- the CDC is recommending that everyone ages 47 to 67 be tested for infection.

The CDC estimates that some 2 million Americans born from 1945 to 1965 are infected with HCV -- that's about 3% of the boomer generation. But because many years usually elapse before noticeable symptoms develop, most don't know they are infected.

The CDC said one-time HCV testing of all "baby boomers" "could identify more than 800,000 additional people with hepatitis C, prevent the costly consequences of liver cancer and other chronic liver diseases, and save more than 120,000 lives."

"CDC believes this approach will address the largely preventable consequences of this disease, especially in light of newly available therapies that can cure up to 75% of infections," the agency said in a statement issued Friday.

Most boomers do not have the risk factors that, until now, the CDC had used as the basis for testing recommendations. Those risk factors include use of illegal injected drugs, receiving blood products or organ transplants before HCV testing became routine, known exposures to HCV, presence of hepatitis symptoms, and all patients with HIV.

Vietnam era veterans -- all baby boomers -- are a well-known risk group due to blood exposure in military field hospitals as well as drug use.

Infection with HCV often leads to liver cancer. However, the recent introduction of HCV protease inhibitors, including telaprevir (Incivek) and boceprevir (Victrelis), has made the disease more manageable, possibly even curable.

The recommendation will be open for public comment from May 22 to June 8, after which the CDC will release a final version.

The CDC also set Saturday, May 19, as "National Hepatitis Testing Day," and announced that it would make a total of $6.5 million in grants to make testing available to specific populations including Asian American Pacific Islander communities (which have high rates of hepatitis B infection) and injection drug users, as well as members of the "boomer" generation.

Trying to halt hepatitis C's molecular hijacking

Trying to halt hepatitis C's molecular hijacking

AURORA, Colo. (Dec. 27, 2012) – Researchers at the University of Colorado School of Medicine have figured out intimate details of how the hepatitis C virus takes over an invaded cell, a breakthrough that could point to way for new treatments for the virus.

Hep C hijacks the machinery by which a cell makes proteins and uses it instead to create proteins for the virus. Over the last two decades, researchers have figured out that Hep C uses an RNA molecule to do this. Now they're trying to fill in the details.

One key detail is reported in a paper published online Dec. 23 in Nature Structural and Molecular Biology. It's written by Jeffrey Kieft, PhD, an associate professor at the CU medical school's Department of Biochemistry and Molecular Genetics and an Early Career Scientist of the Howard Hughes Medical Institute, and his former graduate student, Megan Filbin, PhD, a graduate of the Program in Molecular Biology.

Working with researchers from the lab of Tamir Gonen at the Janelia Farm Research Campus of the Howard Hughes Medical Institute, Kieft used ultra high-power electron microscopes to take images of individual RNA molecules from Hep C as they interacted with the cell's machinery. The researchers combined those images with a variety of other experiments and these clues led them to identify a new way that the virus' RNAs takes over the cell's machinery.

Specifically, the researchers focused on how a ribosome, the cell's protein-making factory, can be manipulated by the Hep C RNA to affect a part of the protein process called translocation. And they saw something else – that even very small changes in the interactions important for that hijacking process can be blocked.

"This points the way to developing drugs to fight hepatitis C in ways that current therapies do not," Kieft says.

###

Faculty at the University of Colorado School of Medicine work to advance science and improve care. These faculty members include physicians, educators and scientists at University of Colorado Hospital, Children's Hospital Colorado, Denver Health, National Jewish Health, and the Denver Veterans Affairs Medical Center. The school is located on the Anschutz Medical Campus, one of four campuses in the University of Colorado system. To learn more about the medical school's care, education, research and community engagement, please visit its web site.

For additional news and information, please visit the University of Colorado Denver newsroom.

http://www.eurekalert.org/pub_releases/2012-12/uocd-tth122712.php

FDA Podcast: Serious skin reactions with Hepatitis C drug Incivek (telaprevir)

FDA Drug Safety Podcast: Serious skin reactions after combination treatment with the Hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin

Click here to listen
Run Time: 00:5:46
December 26, 2012

Transcript

Narrator: Welcome to the FDA Drug Safety Podcast from the Division of Drug Information.

Today’s Topic: Serious skin reactions after combination treatment with the Hepatitis C drugs Incivek, active ingredient telaprevir, peginterferon alfa, and ribavirin US Public Health Service CDR Ray Ford from the division will provide you with additional information about this communication.

CDR Ford: On December 19, 2012, the FDA issued a Drug Safety Communication informing the public that the Agency has received reports of serious skin reactions, some fatal, in patients taking the hepatitis C drug Incivek in combination with the drugs peginterferon alfa and ribavirin, known as Incivek combination treatment. Significantly, some patients died when they continued to receive Incivek combination treatment after developing a worsening, or progressive rash and systemic symptoms. As a result, FDA has added a boxed warning to the Incivek drug label stating that Incivek combination treatment must be immediately stopped in patients experiencing a rash with systemic symptoms or a progressive severe rash. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions. Typical systemic symptoms and signs may include fever, nausea, diarrhea, mouth sores or ulcers, facial swelling (or edema), red or inflamed eyes, or swelling or inflammation of the liver (or hepatitis). All patients with serious skin reactions should also receive urgent medical care.

FDA received reports from Japan of two cases, one fatal, of a serious skin reaction called toxic epidermal necrolysis (or TEN) in patients who were taking Incivek with peginterferon alfa and ribavirin. In the fatal case, the patient continued the Incivek combination regimen for a period of time after symptoms developed.

The Incivek drug label already contains information on the risk of serious skin reactions. Serious skin reactions, including drug rash with eosinophilia and systemic symptoms (or DRESS) and Stevens-Johnson Syndrome (SJS) have been previously reported in patients taking Incivek combination treatment. These serious skin reactions required hospitalization, and in some cases, death was reported. The signs and symptoms of DRESS may include rash, fever, facial swelling, and evidence of internal organ involvement (e.g., hepatitis). Patients may or may not have eosinophilia. The signs and symptoms of SJS may include fever, lesions, and ulcerations on the eyes or lips.

These types of serious skin reactions (TEN, DRESS, and SJS) may be considered different varieties along a spectrum of serious skin reactions and can be difficult to tell apart from each other. When any of these serious skin reactions occur, it is necessary for healthcare professionals to immediately stop all three components of Incivek combination treatment and the patient should receive urgent medical care. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions.

Incivek’s manufacturer, Vertex Pharmaceuticals Incorporated, agreed at the time of marketing approval to investigate, through genetic analysis, the factors associated with serious skin reactions following Incivek combination treatment. The purpose of the investigation is to determine whether such serious skin reactions may be linked to the genetic makeup of the patient. FDA will continue to communicate to health professionals and the public any relevant information that becomes available about the risk of serious skin reactions associated with Incivek use.

At this time FDA recommends that Healthcare Professionals be aware of the following:

• Make sure your patients know that rash may occur with Incivek combination treatment, and explain the signs and symptoms of severe skin reaction and when to seek care.
• If serious skin reactions occur, all three components of Incivek combination treatment, including peginterferon alfa and ribavirin, must be immediately discontinued, and the patient should receive urgent medical care. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions.
• The FDA is requiring the addition of a statement to the Warnings and Precautions section of Incivek’s label (PDF - 495KB)² that the incidence of anemia is higher, and the median time to onset of anemia is shorter, among patients on Incivek combination treatment compared to those who received peginterferon alfa and ribavirin alone. The shortest reported time to a clinical intervention (such as blood transfusion, ribavirin dose reduction, or initiation of an erythropoiesis-stimulating agent) is 10 days.
• Adverse events involving Incivek, peginterferon alfa, ribavirin and/or any other drugs also suspected to contribute to serious skin reaction should be reported to the FDA MedWatch program at www.fda.gov/medwatch³.

Narrator: Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. A link to this communication, including the complete Data Summary, can be found at www.fda.gov/DrugSafetyCommunications⁴. If you have drug questions, you can reach us at druginfo@fda.hhs.gov.

And follow us on Twitter @FDA_Drug_Info for up to the minute important drug information. Know the moment it happens.

Retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3

Research article
The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil

Simara Artico, Karine Medeiros Amaral, Candice Beatriz Gonçalves and Paulo Dornelles Picon

For all author emails, please log on.

BMC Infectious Diseases 2012, 12:377 doi:10.1186/1471-2334-12-377

Published: 27 December 2012

Astract (provisional)

Background

More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR).

Methods

From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight <= 75 Kg and 1,250 mg if >= 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN.

Results

The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely.

Conclusions

This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Boceprevir added to peginterferon/ribavirin increased SVR rates in chronic HCV patients

Boceprevir added to peginterferon/ribavirin increased SVR rates in chronic HCV patients

Flamm SL. Clin Gastroenterol Hepatol. 2013;11:81-87.
December 27, 2012
Patients with chronic hepatitis C previously treated with pegylated interferon were more likely to achieve sustained virologic response with the addition of boceprevir in a recent study.

In a double-blind trial, 201 patients with chronic HCV genotype 1 were randomly assigned to receive 4 weeks of lead-in treatment with 180 mcg peginterferon alfa-2a once weekly along with daily weight-based ribavirin (PEG2a/R), then either 44 weeks of PEG2a/R with 800 mg boceprevir (BOC/PEG2a/R) (n=134) or placebo (n=67) three times daily. All participants had undergone prior treatment with interferon but had not achieved sustained virologic response (SVR).

Significantly more patients in the treated group achieved SVR at 24 weeks than placebo patients (64% to 66% vs. 21%, P<.0001). SVR rates were higher for treated patients among those who relapsed (70% vs. 28%) or had been nonresponsive (47% vs. 5%) during prior therapy. Among those who had poor treatment response during lead-in, 39% in the treated group experienced SVR compared with 0% in the placebo group. Patients who had good response during lead-in therapy experienced SVR in 71% of cases in the treated group and 25% in the placebo group.

Multivariate analysis indicated that receiving boceprevir (OR=12.0; 95% CI, 4.6-31.1) and prior relapse (OR=4.4; 95% CI, 1.7-11.6) were associated with SVR. A decline in HCV RNA of 1-log₁₀ or more also was independently predictive of SVR, and the addition of treatment response at week 4 to the model increased predictive value (OR=7.9; 95% CI, 2.0-31.6). No evaluated baseline factors were predictive of treatment response.

All participants reported at least one adverse event; but more treated patients discontinued therapy or underwent dose modification because of adverse events (P<.05). Commonly reported events included anemia, neutropenia, dysgeusia, diarrhea and rash, all of which occurred more frequently among treated patients.

“The results of this phase 3 trial show that boceprevir is safe and effective when combined with PEG2a/R in difficult-to-treat patients,” the researchers concluded. “This study and the RESPOND-2 study are the first large phase 3 trials to demonstrate a direct acting antiviral agent may be combined with either of the commercially available peginterferons to significantly increase SVR in patients who failed prior therapy.”

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

http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B4E855BCD-1FAC-4BCA-A019-9683E4E6A636%7D/Boceprevir-added-to-peginterferonribavirin-increased-SVR-rates-in-chronic-HCV-patients

Hepatitis C Cirrhosis Patients with Sustained Treatment Response Have Lower Risk of Death

HCV Treatment
Hepatitis C Cirrhosis Patients with Sustained Treatment Response Have Lower Risk of Death

Published on Thursday, 27 December 2012 00:00
Written by Liz Highleyman

Hepatitis C patients with cirrhosis who achieve sustained virological response to interferon-based therapy have a reduced risk of all-cause mortality, liver-related death or transplantation, liver cancer, and liver failure compared with non-responders, according to a study described in the December 26, 2012, issue of JAMA
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HCV Therapy Response Tied to Survival (CME/CE) 12/26/2012 MedPage Today Gastroenterology
(MedPage Today) -- Response to hepatitis C (HCV) treatment is associated with improved survival in patients with advanced disease, researchers reported.
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SVR reduced all-cause mortality risk in patients with HCV, advanced fibrosis
Van der Meer AJ. JAMA. 2012;308:2584-2593.

• December 26, 2012

Patients with chronic hepatitis C and advanced hepatic fibrosis were less likely to die from any cause or from liver-related issues after achieving sustained virologic response to interferon-based therapy in a recent study

In an international, multicenter study, researchers evaluated 530 patients with chronic HCV and cirrhosis or advanced fibrosis (defined as Ishak scores between 4 and 6), who received interferon-based treatment between 1990 and 2003. Incidence of all-cause or liver-related mortality, liver failure, hepatocellular carcinoma (HCC) and liver transplant was recorded over a median of 8.4 years of follow-up.

Sustained virologic response (SVR) occurred in 36% of cases, including 125 participants who achieved SVR with initial treatment and 67 who experienced SVR with retreatment after a median of 5.8 years.

During follow-up, 113 participants died, including 13 who achieved SVR. Investigators noted a significant difference in the 10-year cumulative all-cause mortality rates for the groups (8.9% for patients who achieved SVR vs. 26% for those who did not, P<.001).
Liver-related death occurred in three SVR cases and 70 non-SVR cases, and liver transplant was not required for patients who achieved SVR. Transplant was necessary for 46 patients without SVR (including 13 who subsequently died). Researchers calculated 10-year cumulative liver transplant or liver-related mortality incidence rates of 27.4% for patients who did not achieve SVR and 1.9% who did. HCC occurred in seven SVR cases and 76 non-SVR cases, for cumulative incidence rates of 5.1% and 21.8%, respectively. Four SVR patients experienced liver failure compared with 111 without SVR, with incidence rates of 2.1% and 29.9%, respectively (P<.001 for all comparisons).

Multivariate analysis indicated associations between SVR and reduced risk for all-cause (HR=0.26, 0.14-0.49) and liver-related mortality or liver transplant (HR=0.06, 0.02-0.19). Patients who achieved SVR also were less likely to develop HCC (aHR=0.19, 0.08-0.44) or liver failure (aHR=0.07, 0.03-0.20) (95% CI for all).

“Our study indicates that SVR was associated with improved overall survival in patients with chronic HCV infection and advanced hepatic fibrosis,” the researchers concluded. “In addition, we were able to further establish and quantify the risk reduction of HCC, liver failure and liver-related mortality or liver transplantation in patients with SVR.”

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

http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B5EAD6CCE-5148-49E0-A619-955294E144FF%7D/SVR-reduced-all-cause-mortality-risk-in-patients-with-HCV-advanced-fibrosis