Antiviral therapy of hepatitis C in 2014: Do we need resistance testing?

Antiviral Research
Available online 25 February 2014
In Press, Uncorrected Proof — Note to users

Commentary

Maximilian David Schneider, Christoph Sarrazin

Highlights

• Hepatitis C virus resistance-associated variants (RAVs) pre-exist in quasispecies and can be selected under drug exposure.
• NS3/4A protease inhibitors and NS5a inhibitors have a low genetic barrier to resistance and a high level of cross-resistance.
• No significant resistance concerns have been observed for nucleoside polymerase inhibitors.
• Resistance testing can be useful in special cases, such as DAA-experienced patients, HCV-subtype 1a.
• Combination therapy with different classes of DAA can overcome antiviral resistance in the future.

Abstract

The treatment of chronic hepatitis C has fundamentally changed since the approval of the first direct-acting antivirals (DAA) in 2011. In addition to telaprevir and boceprevir, in 2014 two new NS3 protease inhibitors (simeprevir and faldaprevir), one non-nucleoside polymerase inhibitor (sofosbuvir) and one NS5a replication complex inhibitor (daclatasvir) have expanded the treatment options for chronic hepatitis C. Resistance-associated variants (RAV) are naturally produced during the HCV life cycle. The frequency of RAVs within HCV quasispecies mainly depends on their replicational fitness. Variants conferring resistance to nucleos(t)ide analogues have not been detected, and the majority of NS3 protease-resistant variants are present at low frequencies (0.1–3%) before initiation of DAA-based therapies. However, the Q80K variant conferring resistance to simeprevir has been observed in 9–48% of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Resistant variants are detectable in the majority of patients with treatment failure to NS3 protease inhibitor- or NS5a inhibitor-based antiviral therapy. Long-term follow-up studies by population-based sequence analysis have shown the disappearance of resistant variants in the majority of patients, with median times to loss of mutations of 4–64 weeks. For the nucleotide analogue sofosbuvir, the emergence of the S282T resistant variant has been observed only in single patients, with reversion to wild-type within several weeks. Data are sparse on retreatment of patients with the same DAA or the same class of DAAs. However, retreatment with a different class of DAAs after failure of NS3 protease inhibitor-based therapy has been successful in small studies. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”

Keywords: Hepatitis C virus; Direct-acting antivirals; Drug resistance; Sequencing

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New study uses Lumosity games to detect subtle cognitive impairments in patients with cirrhosis

Provided by News-Medical.net

Published on March 6, 2014 at 12:10 AM

Peer-reviewed study published in the American Journal of Gastroenterology

A new study from the University of Washington has found that performance on Lumosity games can distinguish between patients with cirrhosis of the liver, pre-cirrhotic patients, and healthy controls. The study used Lumosity games as psychometric tests to detect subtle cognitive impairments in patients with cirrhosis. The study is published in the March issue of the American Journal of Gastroenterology.

Studies have found that an estimated 60-80 percent of cirrhosis patients experience cognitive dysfunction, which can range from subtle neurocognitive abnormalities in those with minimal hepatic encephalopathy (MHE) to overt hepatic encephalopathy (OHE), a toxic condition that can lead to confusion, fatigue, or coma. Clinical testing can detect cognitive changes in cirrhotic patients with OHE, but currently no gold standard exists for the clinical assessment of MHE.

"Subtle cognitive impairments in cirrhosis patients are commonly undiagnosed, and are associated with poor self-reported quality of life, driving accidents, falls, or the development of OHE." said George Ioannou, M.D., M.S., Associate Professor at the University of Washington School of Medicine, Division of Gastroenterology and Staff Physician at VA Puget Sound Health Care System, and senior author on the study. "This finding is interesting because it suggests a new, easily accessible and affordable approach to identifying early cognitive impairments in patients with cirrhosis, which can potentially improve quality of life and prevent the onset of OHE."

The study administered three types of psychometric tests in cirrhotic patients without OHE (n = 31), patients with pre-cirrhotic chronic liver disease (n = 28), and normal controls (n = 16). The tests included:

1. The Number Connection Test A (NCT-A) presents test-takers with 25 numbers arranged in an arbitrary sequence that are to be connected as quickly as possible in the correct sequence.

2. The Inhibitory Control Test (ICT) presents a random sequence of letters among which test-takers need to discern interchanging X's and Y's and press a button when either of these two letters follows the other.

3. Five Lumosity games administered on an iPad, including Speed Match - an adaptation of the N-back that challenges speed and information processing; Color Match - an adaptation of the Stroop task that challenges flexibility and response inhibition; Memory Matrix - a visual pattern memory task that challenges memory and spatial recall; Lost in Migration - an adaptation of the Flanker task that challenges attention and selective attention; and Chalkboard Challenge - an arithmetic comparison task that challenges problem solving and quantitative reasoning.

   Unlike the NCT-A or ICT, Lumosity games were able to reliably differentiate cirrhosis patients without OHE from pre-cirrhotic patients. Specifically, the results for Color Match and Memory Matrix were found to be statistically significant in differentiating between those with cirrhosis and pre-cirrhotic patients (p = 0.009 and p = 0.04 for Color Match and Memory Matrix respectively), as well as between normal controls and those with cirrhosis (p = 0.04 and p = 0.04) when adjusted for age and educational attainment. Higher scores on these two games were also associated with a reduced likelihood of cirrhosis, suggesting the combination of Color Match and Memory Matrix may improve cirrhosis detection. Test-retest reliability, as measured by Pearson's r correlation coefficient, for each Lumosity game ranged from r = 0.75 to 0.84 compared to the NCT, where r = 0.75, suggesting repeatability of the Lumosity games.

   "We created Lumosity to be an accessible tool for both consumers and researchers, and we're excited that our cognitive training program can be used in a variety of ways to study cognitive function in specific populations," said Joe Hardy, Ph.D., VP of Research & Development at Lumosity. "This study is a novel use-case of Lumosity and we welcome additional research using Lumosity to detect subtle cognitive impairments in those with cirrhosis of the liver and in other conditions."

   Lumosity's research platform, the Human Cognition Project (HCP), works with researchers from around the world in an effort to better understand the workings of the human mind and brain. Researchers receive free access to Lumosity's tools, and in certain cases, limited data regarding performance on Lumosity's cognitive training games. Current research projects on Lumosity include topics such as decision-making, multitasking, nutrition, TBI, cancer/chemofog, schizophrenia, stroke, MCI, emotion regulation, aging, ADHD, and PTSD.

   Source: Lumosity

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Shorter Treatment Strategy Beats Hepatitis C

Published: Mar 6, 2014
By Ed Susman , Contributing Writer, MedPage Today

BOSTON -- A 6-week treatment regimen appeared to be as effective as the more standard 12 weeks of therapy for patients with hepatitis C virus infection, researchers reported here at the annual Conference on Retroviruses and Opportunistic Infections.

In a pilot study that treated 20 patients in each of three arms, all patients treated with the combination of sofosbuvir (Sovaldi, nucleotide NS5B inhibitor) 400 mg with ledipasvir (NS5A inhibitor) 90 mg once daily for 12 weeks achieved a sustained virologic response at 12 weeks' post-treatment (SVR12), reported Anita Kohli, MD, an infectious disease fellow at the National Institutes of Health Clinical Center in Bethesda, Md.

But she also noted that two regimens using the same backbone and adding either the investigative agent GS-9669 (non-nucleoside NS5B inhibitor) 500 mg once daily or GS-9451 (a protease/NS3/4 inhibitor) 80 mg once daily for 6 weeks had similar outcomes: 95% of patients on GS-9669 achieving an SVR12, and 100% of patients on GS-9451 achieving an SVR12.

The one patient in the study who failed to achieve an SVR12 relapsed before SVR4; that individual had stage 3 liver disease, a high viral load, and unfavorable genotype, Kohli said.

All patients in all 3 arms were naive to treatment for hepatitis C virus. All patients were included in the 12-week arm, but patients diagnosed with cirrhosis were excluded from the 6-week trials.

"These results are not statistically significantly different from each other," Kohli told MedPage Today at a press briefing sponsored by the conference organizers.

"We find these results very promising. This was a pilot study," Kohli said. "We will follow these patients out to 48 weeks to see if the results are maintained."

A cure in the context of HCV is a sustained virologic response -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.

"What we have learned from this trial is that we can treat patients for shorter durations of therapy and we see that 6 weeks is effective," Kohli said.

"Secondly, these regimens are very simple -- 1, 2, or 3 pills a day. Third, our patient population is one that is historically very difficult to treat -- more than 80% of the patients were African American, most had genotype 1a, most had high viral loads, 25% to 30% of the patients had advanced-stage liver disease.

"The reason we wanted to look at the short-duration therapies is because we think it is very important in treatment of hepatitis C globally in limited resource settings. We really need very simple treatments for the 150 million to 180 million people globally," she said.

All the treatment regimens avoided the use of interferon, once the mainstay of treatment of hepatitis C virus, but a therapy that is difficult to tolerate for many patients. The use of interferon-free directly acting antiviral agents is an emerging approach to improve the efficacy and tolerability of therapy for hepatitis C virus, Kohli said.

However, she noted that the efficacy of interferon and ribavirin-free regimens shorter than 8 to 12 weeks has not been reported. One study evaluating sofosbuvir, ledipasvir, and ribavirin for 6 weeks showed an SVR12 rate of only 68%, she said. She also noted that the optimal combination of directly acting antiviral agents not been established.

Press conference moderator Jean-Michel Pawlotsky, MD, PhD, professor of medicine at Hopital Henri Mondor Creteil/University of Paris-Est, told MedPage Today that, while the results of the SYNERGY trial look interesting, they are not ready for routine implementation.

"There are very small numbers in this study," he said. "We have to see how this will apply to real-life patients. The danger is always to undertreat patients. If the time is too short and it works in a trial and you start treating real-life patients you can have failures. So we really need to extend this trial. It is interesting because it shows that some people can be cured in a very short duration of treatment."

Pawlotsky said he would not be comfortable treating his patients in this manner without more extensive studies.

Ledipasvir is not currently approved in the U.S. Its manufacturer, Gilead, filed last month for FDA approval of the drug in a fixed-dose combination with sofosbuvir.

The study was funded by the National Institutes of Health.

Kohli disclosed no relevant relationships with industry.

Pawlotsky disclosed no relevant relationships with industry.

Primary source: Conference on Retroviruses and Opportunistic Infections
Source reference: Kohli A, et al "Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: Final results of the SYNERGY trial" CROI 2014; Abstract 27LB.

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BIT225 HIV/HCV Trial Patients Virus Free at Six Months

6 March 2014

The Manager Companies
ASX Limited
20 Bridge Street
Sydney NSW 2000

• Study evaluated BIT225 in patients co-infected with HIV and HCV
• All HCV genotype 3 patients completing treatment are virus-free at 24 weeks
• Preliminary data from subset of patients shows benefit extends out to 48 weeks

Sydney, Australia, 6 March 2014 – Australian drug development company Biotron Limited
(ASX:BIT) today announced additional interim positive data from a key phase 2 trial of its lead
antiviral drug, BIT225, in patients co-infected with HIV and Hepatitis C virus (HCV).

Analysis of blood samples from patients indicated that all of the HCV genotype 3 patients completing treatment are virus free at the 24 week (6 month) time point. This extends previous data
that showed patients had undetectable virus levels at 12 weeks.

Response to treatment at this time point is generally a good indication of final outcome at 48 weeks. Preliminary data from patients who have completed 48 weeks of treatment indicate that they remain virus free at this key time point.

Under the protocol of this open label pilot study, 12 patients received IFN/RBV for 7 days before
commencing treatment with BIT225. They then received 300 mg BIT225 twice daily plus IFN/RBV
for 28 days. After that time, patients continued to take IFN/RBV for 48 weeks.

Biotron Managing Director Dr Michelle Miller commented; "This 24 week data further validates the
efficacy of BIT225 as a potential new therapy for HCV and, in particular, for this difficult to treat
group of HIV/HCV co-infected patients who typically have more serious HCV infection and lower
response rates to treatment with existing standard therapies."

In vitro assays have shown that BIT225 has pan-genotypic activity. Previous clinical trials of
BIT225 have focused on patients infected with the genotype 1 variant of the virus, which is the most
common genotype in Western populations. This data further extends the Company's clinical data
portfolio to include genotype 3, which is endemic in south-east Asia.

In HCV, BIT225 targets the p7 protein which is responsible for virus assembly. BIT225 also
impacts on the assembly of the HIV virus and specifically targets the virus in reservoir cells. No
existing therapy works in this way.

Dr Miller further commented; "Both the HIV and HCV viruses present substantial challenges and there is global demand for novel therapeutics. We look forward to progressing commercialisation of this important compound as a valuable new therapy that is synergistic with current and future treatment strategies."

Enquiries

Dr Michelle Miller
Managing Director
Biotron Limited
+61-2 9805 0488 +61-(0)412313329

Rudi Michelson
Monsoon Communications 
+61-3 9620 3333

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Faldaprevir NDA has been accepted for review by U.S. FDA as part of a combination regimen for patients with chronic hepatitis C

March 06, 2014

Boehringer Ingelheim Announces Phase 3 SVR12 Results in HCV/HIV Co-Infected Patients Treated with Faldaprevir

Additional drug-drug interaction data for faldaprevir combined with commonly prescribed HIV medications also presented at CROI 2014
Faldaprevir NDA has been accepted for review by U.S. FDA as part of a combination regimen for patients with chronic hepatitis C

For U.S. Media Only

Ingelheim, Germany and Ridgefield, CT, March 6, 2014 – Today Boehringer Ingelheim announced results from STARTVerso^®4 in patients with HCV/HIV co-infection. Hepatitis C viral cure 12 weeks after the conclusion of treatment (SVR12) was achieved by 72% of all patients in the trial. Patients were enrolled in either 120mg or 240mg faldaprevir dose groups. Further, 80% of all patients were eligible for randomization to a shortened duration of treatment (24 versus 48 weeks) because they achieved protocol-defined early treatment success (ETS)* and 86% of these patients achieved SVR12. STARTVerso^®4 is a Phase 3 trial that enrolled 308 hepatitis C (HCV) treatment-naïve or experienced patients with HCV/HIV co-infection and evaluated the efficacy and safety of the investigational compound faldaprevir in combination with pegylated interferon and ribavirin (PegIFN/RBV).

“The SVR12 data from STARTVerso^®4 are encouraging, especially given the inclusion of patients with cirrhosis,” said Peter Piliero, MD, vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “Comprehensive data from our STARTVerso^® clinical trial program, including data from patients with HCV/HIV co-infection, have been filed with the FDA as part of our New Drug Application for faldaprevir.”

In each faldaprevir dose group, 71% (120mg) and 72% (240mg) of patients achieved SVR12. SVR12 results were consistent across patients regardless of HCV genotype-1 subtype (GT1a or GT1b), presence of compensated cirrhosis, dose and duration of faldaprevir, and duration of PegIFN/RBV. In a post hoc analysis, 75% of patients with the Q80K variant achieved SVR12 compared with 71% of patients who did not have the variant.

Serious adverse events (AEs) were reported in 32 patients (10%). To date, 24 patients have prematurely discontinued faldaprevir due to AEs. The most frequent AEs in STARTVerso^®4 were nausea (37%), fatigue (34%), diarrhea (27%), headache (25%) and weakness (23%). Patients will be followed to 24 weeks after the conclusion of treatment (SVR24).

In separate poster presentations at CROI, investigators described the results from analyses that evaluated drug-drug interactions of faldaprevir with common HIV medications, including: efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir and tenofovir. In each of these analyses, there was no clinically relevant effect of faldaprevir on the pharmacokinetics of any of the HIV medications studied. Patients in STARTVerso^®4 already taking ritonavir-boosted HIV protease inhibitors (darunavir or atazanavir) or efavirenz were enrolled into the 120mg and 240mg faldaprevir groups, respectively.

Boehringer Ingelheim HCV Development Update
The New Drug Application (NDA) for faldaprevir has been accepted for filing by the U.S. Food and Drug Administration (FDA). Faldaprevir is currently under review as a component of a combination antiviral treatment regimen for the treatment of chronic HCV infection in adult patients who are treatment-naïve or have been previously treated with interferon-based treatment, as well as those with compensated liver disease, cirrhosis, or HCV/HIV co-infection. The FDA target action date for faldaprevir is in the fourth quarter of 2014.

The NDA submission for faldaprevir is supported by Boehringer Ingelheim’s STARTVerso^® (NCT01343888, NCT01297270, NCT01358864, NCT01399619) clinical trial program, a multi-study Phase 3 trial program that evaluated faldaprevir for 12 or 24 weeks in combination with pegylated interferon and ribavirin (PegIFN/RBV). The four trials that make up this program studied treatment-naïve, treatment-experienced, and HCV/HIV co-infected patients with chronic genotype-1 (GT1) HCV. The primary efficacy endpoint of each STARTVerso^® trial is viral cure 12 weeks after the conclusion of treatment (SVR12).

In November 2013, Boehringer Ingelheim announced that the faldaprevir application for marketing authorization is under review by the European Medicines Agency (EMA). If authorized by the European Commission, faldaprevir could be available for marketing in the EU in the second half of 2014.

Following an assessment of the blinded Phase 3 trial data from HCVerso^® 1 and 2 for the combination of deleobuvir, faldaprevir and ribavirin, Boehringer Ingelheim has decided to halt further development of deleobuvir-containing HCV regimens. Ongoing regulatory reviews of faldaprevir are not affected by the decision on the deleobuvir-containing regimens.

About Faldaprevir
Faldaprevir is an investigational, oral protease inhibitor that is specifically designed to target viral replication in the liver. Faldaprevir is an investigational compound that has not been approved by the FDA; its safety and efficacy have not been established.

About Boehringer Ingelheim in Hepatitis C Virus (HCV)
In partnership with the scientific community, our clinical trial program is rigorously designed to find answers to the challenges that HCV patients face, including those who are the most difficult to cure. Our pivotal HCV clinical trials for faldaprevir, STARTVerso^®, included four trials that studied treatment-naïve, treatment-experienced, and HCV/HIV co-infected patients with chronic GT1 HCV.

Hepatitis C is a blood-borne infectious disease and a leading cause of chronic liver disease, transplant and failure that affects as many as 150 million people globally. In the United States, approximately 3.2-5.2 million people have chronic HCV infection. Since 1999 there has been a significant increase in deaths due to chronic HCV, which accounts for 15,000 deaths in the United States per year.

STARTVerso^® is a registered service mark of Boehringer Ingelheim International GmbH.

About Boehringer Ingelheim
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim’s culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

For more information please visit www.us.boehringer-ingelheim.com.
*ETS = protocol-defined early treatment success (week 4 below limit of quantification [BLQ] and week 8 below limit of detection [BLD]).

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