Sofosbuvir Works for Patients Who Cannot Take Peginterferon

Published in Journal Watch Gastroenterology May 24, 2013

Two phase III studies confirm the efficacy of a sofosbuvir and ribavirin therapy in patients with HCV genotype 2 or 3 infection for whom peginterferon is not an option.

In patients infected with hepatitis C virus (HCV) genotype 2 or 3, treatment with peginterferon plus ribavirin has a sustained virologic response (SVR) of 70% to 85%. However, adverse effects of peginterferon are a barrier to treatment for many patients. Now, two industry-funded, phase III trials have evaluated the efficacy of sofosbuvir (400 mg daily) plus ribavirin (1000 mg–1200 mg daily) in these patients.

In a blinded, placebo-controlled trial, investigators randomized 280 patients for whom peginterferon therapy was not an option (e.g., adverse effects, contraindications for interferons, and patient refusal) to receive sofosbuvir/ribavirin or matching placebo for 12 weeks. In a blinded, active-control trial, researchers randomized 202 patients with prior nonresponse to peginterferon therapy to receive 12 or 16 weeks of sofosbuvir/ribavirin. The primary endpoint in both studies was SVR at 12 weeks after therapy ended.

In patients for whom peginterferon therapy was not an option, SVR was 78% for treatment with sofosbuvir/ribavirin compared with 0% for placebo (P<0.001). In previously treated patients, SVR was 50% for 12 weeks of therapy versus 73% for 16 weeks (P<0.001). SVR rates were lower for patients with genotype 3 versus genotype 2 in both treatment-naive patients (61% vs. 93%) and treatment-experienced patients who received therapy for 12 weeks (30% vs. 86%) or 16 weeks (62% vs. 94%).

SVR rates were lower in patients with cirrhosis than without, both in treatment-naive patients (overall, 61% vs. 81%; genotype 3 vs. 2, 21% vs. 94%) and treatment-experienced patients (overall, 66% vs. 76%; genotype 3 vs. 2 in 16-week group, 61% vs. 78%). In both studies, investigators found no evidence of resistance development, and discontinuation rates were low (1%–2%).

Comment: Oral sofosbuvir plus ribavirin is effective in patients with HCV genotypes 2 or 3 for whom peginterferon-based therapy is not an option or was previously ineffective. Of note, these sustained virologic response rates for sofosbuvir plus ribavirin are comparable to or higher than those previously reported for therapy with peginterferon plus ribavirin in this population.

— Atif Zaman, MD, MPH

Citation(s):

Jacobson IM et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013 May 16; 368:1867. (http://dx.doi.org/10.1056/NEJMoa1214854)

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Australia's PBAC recommends use of XIFAXAN 550 mg for hepatic encephalopathy

Published on May 24, 2013 at 7:23 AM

Norgine today announced that the Australian assessment body the Pharmaceutical Benefits Advisory Committee (PBAC) has recommended the use of XIFAXAN 550 mg in the prevention of the recurrence of hepatic encephalopathy (HE) where other treatments have failed or are contraindicated; a potentially life-threatening neuropsychiatric condition associated with liver disease.

XIFAXAN 550 mg is the only treatment that has demonstrated a reduction in the recurrence of episodes of overt HE and hospitalisation due to HE compared with placebo in a 6-month randomised, double blind, placebo-controlled study in which ~91% patients were taking concomitant lactulose in both arms, in patients who were in remission from HE, resulting from chronic liver disease.

The PBAC announced its final decision as follows:

The PBAC recommended listing of rifaximin on the basis of high clinical need, improved clinical benefit over the existing treatments and acceptable cost effectiveness.

On the basis of the information available to it at the April 2013 meeting, the PBAC considered that there was no longer a requirement for a managed entry scheme approach.

This outcome represents the first acceptance for use made by a health technology assessment (HTA) process for XIFAXAN 550 mg in their healthcare system based on cost effectiveness review. Norgine and Alfa Wassermann are working closely with other HTA bodies across Europe including the National Institute for Health and Care Excellence (NICE) and The Scottish Medicines Consortium (SMC) to ensure patients have appropriate access to this important medicine. The review processes are currently underway and Norgine expects these bodies to make their decision in the second half of 2013.

'It's critical that we deliver medicines that treat serious conditions and improve quality-of-life as well as alleviate the cost burden on healthcare systems caused by hospital admissions," said Peter Martin , Norgine Chief Operating Officer.

"XIFAXAN 550 mg provides healthcare professionals with a world-leading treatment option for patients with hepatic encephalopathy, which is a recognised growing problem that may lead to premature death," added Peter Martin .

Norgine currently holds marketing rights for XIFAXAN 550 in: Australia, Belgium, Denmark, Egypt, Finland, France, Germany, Ireland, Luxembourg, the Netherlands, New Zealand, Norway, Switzerland, Sweden and the UK.

In Europe, XIFAXAN® 550 mg /TARGAXAN® 550 mg is already available in Denmark, Germany and in the UK for healthcare professionals to prescribe in accordance with local guidance.

SOURCE Norgine

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Marijuana tied to better blood sugar control

By Genevra Pittman

NEW YORK | Thu May 23, 2013 3:44pm EDT

NEW YORK (Reuters Health) - People who had used marijuana in the past month had smaller waists and lower levels of insulin resistance - a diabetes precursor - than those who never tried the drug, in a new study.

The findings, based on surveys and blood tests of about 4,700 U.S. adults, aren't enough to prove marijuana keeps users thin or wards off disease. And among current pot smokers, higher amounts of marijuana use weren't linked to any added health benefits, researchers reported in The American Journal of Medicine.

"These are preliminary findings," said Dr. Murray Mittleman, who worked on the study at Beth Israel Deaconess Medical Center in Boston.

"It looks like there may be some favorable effects on blood sugar control, however a lot more needs to be done to have definitive answers on the risks and potential benefits of marijuana usage."

Although pot smoking is a well-known cause of "the munchies," some previous studies have found marijuana users tend to weigh less than other people, and one suggested they have a lower rate of diabetes. Trials in mice and rats hint that cannabis and cannabinoid receptors may influence metabolism.

The new study used data from a national health survey conducted in 2005-2010. Researchers asked people about drug and alcohol use, as well as other aspects of their health and lifestyle, and measured their insulin and blood sugar levels.

Just under 2,000 participants said they had used marijuana at some point, but not recently. Another 600 or so were current users - meaning they had smoked or otherwise consumed the drug in the past month.

Compared to people who had never used pot, current smokers had smaller waists: 36.9 inches versus 38.3 inches, on average. Current users also had a lower body mass index - a ratio of weight to height - than never-users.

When other health and lifestyle measures were taken into account, recent pot use was linked to 17 percent lower insulin resistance, indicating better blood sugar control, and slightly higher HDL ("good") cholesterol levels.

However, there was no difference in blood pressure or blood fats based on marijuana use, Mittleman's team found.

A CAUSAL LINK?

Mittleman said that in his mind, it's still "preliminary" to say marijuana is likely to be responsible for any diabetes-related health benefits.

"It's possible that people who choose to smoke marijuana have other characteristics that differ (from non-marijuana smokers)," and those characteristics are what ultimately affect blood sugar and waist size, he told Reuters Health.

Dr. Stephen Sidney from the Kaiser Permanente Division of Research in Oakland, California, said he wonders if cigarette smoking may partially explain the association. Marijuana users are also more likely to smoke tobacco, he told Reuters Health.

"People who use tobacco oftentimes tend to be thinner," said Sidney, who has studied marijuana use and weight but didn't participate in the new study. "So I really wonder about that."

Another limitation with this and other studies, Sidney and Mittleman agreed, is that all of the data were collected at the same time, so it's unclear whether marijuana smoking or changes in waist size and blood sugar came first.

"The question is, is the marijuana leading to the lower rate (of diabetes) or do they have something in common?" said Dr. Theodore Friedman, who has studied that issue at Charles R. Drew University of Medicine and Science in Los Angeles.

He and his colleagues think the link is probably causal. "But it's really hard to prove that," Friedman, who also wasn't involved in the new research, told Reuters Health.

One possibility is that the anti-inflammatory properties of marijuana help ward off diabetes, he said. But he agreed that more research is needed to draw out that link.

"I want to make it clear - I'm not advocating marijuana use to prevent diabetes," Friedman said. "It's only an association."

SOURCE: bit.ly/10Ty3La The American Journal of Medicine, online May 16, 2013.

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Spring Bank Pharmaceuticals Initiates a Phase I Clinical Trial for SB 9200 in HCV-infected Patients

MILFORD, Mass., May 23, 2013 /PRNewswire/ -- Spring Bank Pharmaceuticals, Inc., a biopharmaceutical company developing innovative medicines for the treatment of viral infections, today announced that it has initiated dosing in a Phase I study of SB 9200, its investigational, once daily, oral therapy for the treatment of HCV infection. This study will be conducted in healthy, HCV-infected patients and is designed to assess both the safety and antiviral efficacy of SB 9200. SB 9200 is a first-in-class drug for the treatment of chronic HCV infections and is based on the Company's proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology platform. It has a unique mechanism of antiviral action involving the selective activation of the host-immune response in HCV-infected cells.

"The initiation of this clinical trial is an important milestone for our Company," said Doug Jensen , Spring Bank 's CEO. "This trial should not only give us proof of concept in HCV, but also will facilitate the advancement of our technology in other viral diseases such as HBV and RSV." SB 9200 is the first of a potentially important new class of drug based on Spring Bank 's proprietary "SMNH" technology platform. The Phase I clinical trial has been designed to provide a significant amount of data related not only to safety of SB 9200 but also the antiviral activity against multiple HCV genotypes.

"Unlike other classes of drugs for HCV infection that act directly on the virus, SB 9200 targets host cytosolic sensor proteins, RIG-I and NOD2," states Dr. Kris Iyer , CSO and Co-founder of Spring Bank . "This leads to the selective activation of the host immune response in the presence of viral infection." By way of its novel mechanism of action, SB 9200 is ideally suited for combination with other classes of HCV antivirals, including direct-acting antiviral agents (DAA) currently in clinical development. In preclinical studies, SB 9200 has shown synergistic antiviral activity when combined with other anti-HCV compounds and has demonstrated an excellent safety profile. In in vitro studies, the compound has demonstrated potent antiviral activity against multiple HCV genotypes 1a, 1b and 3. Thus, this novel mechanism of action is suggestive of pan-genotypic activity and potentially a high barrier to resistance. Moreover, this novel mechanism of action suggests it could have pan-genotypic activity and potentially a high barrier to resistance. These attributes could lead to the use of SB 9200 as part of an Interferon-free, all-oral regimen for HCV therapy.

The Phase I trial is currently being conducted in Australia with plans to expand into clinical sites in New Zealand. The trial is being conducted in two parts. Part A is a single ascending dose of SB 9200 to evaluate the safety and tolerability of a single oral dose of SB 9200, with 8 treatment naive Genotype 1 patients being enrolled into four sequential cohorts of 2 patients each with increasing doses ranging from 100-800mg. Part B of the study is a randomized, double blind, placebo-controlled multiple ascending dose escalation of once daily doses of SB 9200 once a day for 7-14 days. Part B will enroll approximately 40 HCV patients with 5 dosing cohorts, randomized 6:2 active versus placebo. The final dosing cohort will be in Genotype 2/3 patients to demonstrate pan-genotypic activity. The primary endpoint for both parts of the trial is safety. Secondary objectives include an analysis of dose versus viral load reduction, liver function, safety labs, host immune expression, as well as characterization of plasma and urine pharmacokinetics and assessment of pharmacodynamic activity.

About Spring Bank Pharmaceuticals

Spring Bank Pharmaceuticals is engaged in the discovery and development of an entirely new class of pharmaceuticals based on the Company's proprietary SMNH, "Small Molecule Nucleic Hybrid" technology program. The company's lead compound, SB 9200, is a potential breakthrough drug for the treatment of HCV and HBV. The Company also has preclinical programs for the development of immune-modulating therapies against Respiratory Syncytial Virus (RSV) infections, a Broad-Spectrum Antiviral, and a SMNH based therapy to treat Chronic Obstructive Pulmonary Disease (COPD). For more information please visit our website: www.springbankpharm.com

Contact: Douglas Jensen (508) 473-5993 Ext.105

SOURCE Spring Bank Pharmaceuticals, Inc.

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Hepatitis C treatment challenged by rising costs

Provided by Healio

May 23, 2013

The total spending trend for hepatitis C-related medications rose 33.7% in 2012 compared with 2011, according to a recent Express Scripts report. The increase is primarily due to new medications on the market, experts said. In a field where the medications did not change for about a decade, major cost increases associated with changes in hepatitis C-related treatments are challenging patients and clinicians but also showing promise for better cure rates.

Incidence rate for hepatitis C

The incidence rate for hepatitis C has remained generally unchanged in recent years, clinicians note.

“The incidence of hepatitis C has not really spiked in the last couple years,” Andrew J. Muir, MD, director of hepatology at Duke University, told Healio.com. “Awareness on the part of clinician providers as well as the patients themselves has led to more people being in our clinics and to more overall awareness of hepatitis C.”

Muir said most patients he sees were infected years ago and are just now presenting with complications from advanced hepatitis C.

“We are seeing increased rates of cirrhosis and liver transplants and liver cancer all related to hepatitis C. But, new cases of hepatitis C are somewhat reduced compared with 20 years ago,” Muir said.

Bruce R. Bacon, MD, James F. King MD Endowed Chair in Gastroenterology, professor of internal medicine, Saint Louis University School of Medicine, is seeing similar patterns in his practice.

“The incidence rate has not changed,” he told Healio.com. “What has changed is that there is a little bit of increased awareness, so a few more people are being diagnosed.”

Jumps in treatment costs

Researchers of the Express Scripts report credited the rise in the total spending trend for hepatitis C-related medications to the release of two protease inhibitor (PI) drugs that help treat genotype 1 hepatitis C. Incivek (telaprevir, Vertex Pharmaceuticals) and Victrelis (boceprevir, Merck) were released in May 2011, and experts agree these drugs have helped to drive treatment cost increases.

“Overwhelmingly, what has made the difference … is the increased cost for new treatments,” Bacon said. “We used the same treatment of pegylated interferon-alfa and ribavirin since 2001 to 2011. So, for 10 years the treatment regimen that we used didn’t change.”

With the availability of Incivek and Victrelis, patient options and costs changed. According to the Express Scripts report, 4 months after market availability for the two new drugs, more than 46% of patients treated for hepatitis C had been prescribed one of the new PIs.

“In 2011, for most patients of hepatitis C, when the two new drugs telaprevir and boceprevir were added to the current regimen of pegylated interferon-alfa and ribavirin, there was a substantial increase in cost,” Muir said.

The total spending trend for hepatitis C-related medications had the largest increase — 194.8%, or more than 10 times the total trend for any other specialty therapy class — in 2011 compared with 2010 among drugs for all observed major illnesses, according to the Express Scripts report. In 2011, the average cost for a hepatitis C prescription was estimated at $3,370, compared with $1,389 in 2010, the report said.

Along with the prescription costs, the current regimen, even with telaprevir or boceprevir, requires frequent lab tests, close monitoring and follow-up clinician visits, which drive up overall costs, Muir said.

More predicted cost jumps

Spending for hepatitis C-related medications will continue to grow, the report researchers predicted. As new treatments and screening guidelines are introduced, spending is estimated to grow by 32.3% in 2013 and 56.3% in 2014. Experts note, however, the cost of new treatments is not yet apparent.

“The hepatitis C treatment field is evolving,” Muir said. “There are a number of medications that are in phase 3 trials that are hopefully going to be approved in a couple of years.”

Some of those medications are initially going to be administered with peginterferon-alfa and ribavirin and some without interferon. The cost of those new drugs is unclear, according to Muir.

Better cure rates with increased costs

Clinicians are seeing better cure rates with telaprevir and boceprevir and hope for fewer side effects with new interferon-free treatments that are currently being studied. Side effects associated with interferon therapy include fatigue, anemia, depression, rash and flu-like symptoms.

Within the next 18 to 24 months, Muir anticipates that most Americans will be eligible for an interferon-free regimen that produces a greater response rate and “much better side effect profile.”

“Between 2001 and 2011, when we didn’t have telaprevir and boceprevir for genotype 1 patients, who are the most common in the United States — about 70% to 75% of all patients — we could only cure about 40% of those patients,” Bacon said. “Now with telaprevir and boceprevir we can cure between 70% and 75% of those patients. With newer agents that are in the pipe for another year or two, we are going to be able to cure 90% to 100% of these patients.

“So with the increase in costs with telaprevir and boceprevir, we are getting results. We are getting better cure rates. And, with the next round of treatments in the next couple of years, we are going to get even better cure rates. It is going to cost a little bit more, but fortunately it is going to be associated with fewer side effects.”

Financial burden

The promise of better cure rates and fewer side effects has prompted some patients to elect to wait for interferon-free medications.

“We [Bacon and fellow hepatologists] have large backlogs of patients who are waiting for new medicines,” Bacon said. “Mostly, these are patients who have been treated before with interferon and don’t want to deal with the side effects again.”

With patients awaiting interferon-free regimens and the cost estimated to rise considerably, the cost burden on the health care system is going to go up considerably within the next 1 to 2 years, explained Bacon. These costs also may cause patients to forgo treatment altogether.

“We are seeing across the country that increasingly Americans are on high deductible health plans. Health care is becoming increasingly unaffordable,” Neel T. Shah, MD, executive director and founder of the nonprofit, Costs of Care, told Healio.com. “Traditionally, we are not trained to think about how patients will pay for care, but it is becoming increasingly important that we do that.

“There is very good evidence from other aspects of health care that when you increase the proportion that patients have to pay, they forgo treatments, even treatments that are necessary.”

“It is difficult to answer the question about costs and what it is going to be like because it is challenging for the patients to keep up,” Muir said, “and it’s actually challenging for the payers to plan on what a likely budget will be for a patient and the population with hepatitis. Because we have many patients who are uninsured or underinsured, we hope they will benefit from new health care legislation.

“This is a rapidly evolving field and people do essentially need to stay tuned. The big picture message is that hepatitis C treatment is getting better as far as better response rates and better side effect profiles in the next couple of years,” Muir said, adding that increased awareness and screening are important parts of this picture.

“If we can treat the patients before they develop advanced complications and cure them of their hepatitis C, then we can prevent them from going on to develop the complications of cirrhosis and liver cancer. The goal is to cure the disease,” Muir said.

Disclosure: Muir has received grant support from Abbott Laboratories, Achillion Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, and Vertex Pharmaceuticals.

Bacon has received research support from Roche/Genentech Laboratories, Bristol-Myers Squibb and Abbott Laboratories. He is a consultant, on the speakers’ bureau and has received research support from Merck. He has received research support, is a speaker on the hepatitis advisory board and on the Data and Safety Monitoring Board for Gilead Sciences. He has received research support, is a speaker and is on the hepatitis advisory board for Kadmon Pharmaceuticals; he has received research support, is an advisory board and Data and Safety Monitoring Board member, and is a speaker for Vertex Pharmaceuticals; and is a Data and Safety Monitoring Board member for ISIS Pharmaceuticals.

Shah is on the advisory board for Haymarket Media’s electronic Monthly Prescribing Reference (eMPR) and also receives funding from the ABIM Foundation.

- Suzanne Bryla Reist

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Risks small between HCV patients’ use of DAAs, neuropsychiatric events

Provided by Healio

Sockalingam S. BMC Gastroenterol. 2013;doi:10.1186/1471-230X-13-86.

May 24, 2013

The risks for neuropsychiatric adverse events among patients with hepatitis C virus being treated with direct-acting antivirals appear minimal, but the risks for drug-drug interactions are high, according to recent study results.

Researchers conducted a literature search of PubMed from 2000 to April 2013 using the search terms, “hepatitis C” and “boceprevir” or “telaprevir,” along with “mental disorders,” “psychotropic drugs” and “drug interactions.” The analysis was designed to evaluate studies on neuropsychiatric adverse effects as a result of direct-acting antivirals (DAAs) and drug-drug interactions (DDIs) involving psychotropic medications and DAAs among hepatitis C virus (HCV) patients.

For lack of published literature, researchers also included data collected from major trials for protease inhibitors telaprevir and boceprevir and their association with psychiatric adverse events. In reviewing studies that included triple therapies of pegylated interferon-alfa, ribavirin and either telaprevir or boceprevir and those without DAAs, researchers determined there were no significant differences in neuropsychiatric side effects. Events included anxiety, depression, insomnia, fatigue and irritability. Trials excluded patients with significant psychiatric illness, possibly resulting in underestimated rates for neuropsychiatric adverse events, researchers wrote.

Researchers also examined DDIs between DAAs and anticonvulsants, antipsychotics, antidepressants and benzodiazepines. Contraindications existed between DAAs and carbamazepine, triazolam, oral midazolam, pimozide and St. John’s Wort. In some cases, DDIs potentially can occur via cytochrome P450 and p-glycoprotein induction, researchers said.

“Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high,” the researchers concluded. “Additional drug interaction studies between DAAs and commonly used psychotropic agents are urgently needed. The results of these studies will be essential to guiding clinicians presented with challenges in interpreting DDI risks related to psychiatric care in the era of HCV triple therapy.”

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

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Rise Up to HIV Re-Launches the No Shame About Being HIV Positive Anti Stigma Campaign

The No Shame About Being HIV Positive campaign, a project of Rise Up To HIV, launched in January of 2013. This campaign quickly grew to over 400 photos accompanied by testimonials by people living with HIV and AIDS and our allies; see how you can join the campaign!

Minneapolis, MN (PRWEB) May 23, 2013

The campaign was readily featured by major HIV/AIDS social media outlets like The Body, Huffington Post, Poz Magazine, Positive Aware, Positive Lite and others.

“By showing our faces, sharing our experiences, letting people know there is nothing to be ashamed of, we affirm ourselves as human beings with dignity, and we call attention to a disease that needs not be there; says Mario Ferri long term survivor of HIV”

The campaign has served as a source of inspiration and as a launching platform for many HIV/AIDS advocates and activists all across the globe. This Summer of 2013, we are accepting photos and stories to be featured in the follow up campaign titled “The Summer of No Shame About Being HIV Positive”. Goals of the campaign are to help reduce stigma and fear, educate, and inspire others to share their experiences, strengths and hope while LIVING with HIV/AIDS. We are also interested in developing a more permanent online tribute to those who have participated and to the overall HIV/AIDS Movement (name of project TBA).

Driven by people living with HIV/AIDS and our allies in the cause the campaign is harnessing the power of social media, which allows communities of people impacted by HIV to share their stories with all of us regardless of our status. “Understanding that someone who is HIV+ is living next door, teaching our children or is our relative or partner is still difficult for some folks. Let’s work towards ending the stigma of HIV and work towards building a more cohesive world” says Kevin Maloney Founder of Rise Up To HIV and the No Shame About Being HIV Positive Campaign.

How to join the campaign:

1) E-mail your photo and story (e mail on right side of press release)

2) Or visit the page of the campaign and message the page with your photo and story http://www.facebook.com/riseuptohivandhcv

What is HIV/AIDS Related Stigma?

HIV/AIDS-related stigma refers to prejudice, negative attitudes, abuse and maltreatment directed at people living with HIV and AIDS. The consequences of stigma are wide-ranging: being shunned by family, peers and the wider community; poor treatment in health care and education settings; erosion of rights; psychological damage; and has an overall negative effect on the success of HIV testing and treatment.

##############################################################################

Rise Up To HIV is a volunteer grassroots movement blazing a trail in social media with it's commitment to highlighting relevant news stories and showcasing individuals impacted by HIV/AIDS in communities across the globe.

Mission
To educate, inspire, empower, advocate, network and partake in social change through unilateral and collaborative social media efforts of organizations, PLWHA, and our supporters with diverse backgrounds from all over the world.

Vision
To create positive change for individuals, families and communities through an army of compassionate individuals and organizations with a goal of reducing stigma as we march towards the cure for HIV/AIDS.

About the Founder:
Visit http://www.riseuptohiv.org/about-the-founder/.

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Delayed versus immediate treatment for patients with acute hepatitis C: a randomised controlled non-inferiority trial

The Lancet Infectious Diseases, Volume 13, Issue 6, Pages 497 - 506, June 2013

doi:10.1016/S1473-3099(13)70059-8 Cite or Link Using DOI

This article can be found in the following collections: Global Health; Public Health; Nutrition & Metabolism (Undernutrition); Paediatrics (Paediatrics-other)

Published Online: 22 March 2013

Katja Deterding MD a b, Norbert Grüner MD a e, Peter Buggisch MD a g, Johannes Wiegand MD a f, Prof Peter R Galle MD a h, Prof Ulrich Spengler MD a i, Holger Hinrichsen MD a j, Prof Thomas Berg MD a f k, Andrej Potthoff MD a b, Prof Nisar Malek MD a l, Anika Großhennig PhD c, Prof Armin Koch PhD c, Prof Helmut Diepolder MD a e, Stefan Lüth MD a g, Sandra Feyerabend MD a, Prof Maria Christina Jung MD a e, Magdalena Rogalska-Taranta PhD a d, Verena Schlaphoff PhD a d, Markus Cornberg MD a b, Prof Michael P Manns MD a b , Prof Heiner Wedemeyer MD a b , for The Hep-Net Acute HCV-III Study Group

Summary

Background

Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa monotherapy is very effective, with cure rates of greater than 85%. However, spontaneous clearance of HCV occurs in 10—50% of cases. We aimed to assess an alternative treatment strategy of delayed antiviral therapy in patients who do not eliminate the virus spontaneously compared with immediate treatment.

Methods

In our open-label phase 3 non-inferiority trial, we enrolled adults (≥18 years) with acute hepatitis C but no HIV or hepatitis B co-infection at 72 centres in Germany. We randomly allocated patients with symptomatic acute hepatitis C (1:1) to receive immediate pegylated interferon alfa-2b treatment for 24 weeks or delayed treatment with pegylated interferon alfa-2b plus ribavirin (for 24 weeks) starting 12 weeks after randomisation if HCV RNA remained positive. We used a computer-generated randomisation sequence and block sizes of eight, stratified by bilirubin concentration. We assigned all asymptomatic patients to immediate treatment with pegylated interferon alfa-2b for 24 weeks. The primary endpoint was sustained HCV RNA negativity in all randomly allocated participants who completed screening (intention-to-treat analysis), with a non-inferiority margin of 10%. For the primary analysis, we calculated the virological response of patients in the immediate and delayed treatment groups and an absolute risk difference stratified by bilirubin status. The trial was stopped early on advice from the study advisory committee because of slow recruitment of participants. This study is registered, number ISRCTN88729946.

Findings

Between April, 2004, and February, 2010, we recruited 107 symptomatic and 25 asymptomatic patients. 37 (67%) of 55 symptomatic patients randomly allocated to receive immediate treatment and 28 (54%) of 52 symptomatic patients randomly allocated to receive delayed treatment had a sustained virological response (difference 13·7%, 95% CI −4·6 to 32·0; p=0·071). 18 (72%) of 25 asymptomatic patients had a sustained virological response. 22 (42%) of 52 symptomatic patients allocated to receive delayed treatment did not complete follow-up compared with 20 (25%) of 80 symptomatic or asymptomatic patients assigned immediate treatment (p=0·037). 11 symptomatic patients (21%) assigned delayed treatment had spontaneous HCV clearance. 14 patients who received delayed pegylated interferon alfa-2b plus ribavirin treatment and completed follow-up achieved sustained virological response.

Interpretation

Delayed treatment is effective although not of equal efficacy to immediate treatment; coupled with the rate of spontaneous clearance it can reduce unnecessary treatment in closely monitored populations. Immediate treatment seems preferable in populations where loss to follow-up is great.

Funding

German Network of Competence on Viral Hepatitis (HepNet, funded by the German Federal Ministry of Education and Research, grants 01KI0102, 01KI0401, and 01KI0601), MSD, Schering-Plough.

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