February 14, 2011

Journal of Viral Hepatitis
Volume 18, Issue 3, pages 153–160, March 2011

S. Sockalingam 1,2,3, P. S. Links 3,4, S. E. Abbey 1,2,3

Article first published online: 10 NOV 2010
DOI: 10.1111/j.1365-2893.2010.01393.x
© 2010 Blackwell Publishing Ltd

Author Information
1 University Health Network, Toronto General Hospital, Toronto, ON, Canada
2 Medical Psychiatry Program, Toronto, ON, Canada
3 Department of Psychiatry, University of Toronto, Toronto, ON, Canada
4 Arthur Sommer Rotenberg Chair in Suicide Studies, Toronto, ON, Canada

* Correspondence: Sanjeev Sockalingam, University Health Network, Toronto General Hospital, 200 Elizabeth Street – 8EN-228, Toronto, ON M5G 2C4, Canada. E-mail: sanjeev.sockalingam@uhn.on.ca

Abstract

Keywords: depression; hepatitis C; interferon-alpha; suicide

Summary.Chronic hepatitis C (CHC) affects over 170 million individuals worldwide and is a growing public health concern. Despite the availability of CHC treatment, specifically interferon-α and ribavirin, treatment of CHC is limited by concerns about psychiatric side effects including risks of suicide. Although depression has been the focus of neuropsychiatric complications from interferon-alpha (IFNα), emerging evidence has contributed to our understanding of IFNα-induced suicidal ideation and attempts. Using Pubmed, we performed a literature review of all English articles published between 1989 and April 1, 2010 on suicide in untreated and IFNα-treated patients with CHC. References in all identified review articles were scanned and included in our review. A total of 17 articles were identified. Studies have suggested that the first 12 weeks of IFNα therapy are the high-risk period. Moreover, the emergence of suicidal ideation can be linked to neuropsychiatric abnormalities, specifically serotonin depletion. Pretreatment with antidepressant treatment should be reserved for high-risk groups, as this may reduce the risk of depression and thus decrease the suicide risk indirectly. Although there is a paucity of literature on suicide and suicide risk during IFNα therapy for CHC, recent studies on IFNα-induced depression have provided some potential insights into suicide in this patient population. Further research examining the effects of pharmacological and nonpharmacological interventions on suicide risk during IFNα treatment is needed.

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HIV Regimens Similar but Not Equivalent

By Michael Smith, North American Correspondent, MedPage Today
Published: February 14, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

A large clinical trial fell short of showing that two commonly used approaches to a first anti-HIV treatment regimen are formally equivalent.

But the two -- based on either the ritonavir-boosted protease inhibitor atazanavir (Reyataz) or the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva) -- still appeared to have similar efficacy, according to Eric Daar, MD, of Harbor-UCLA Medical Center in Torrance, Calif., and colleagues.

The failure to reach formal equivalence -- as defined before the study started -- was probably the result of a lower than expected rate of virologic failure two years into the study, Daar and colleagues reported online in Annals of Internal Medicine.

But a post-hoc analysis of the data suggested the probability of remaining free of failure differed by less than 10%, a threshold commonly used for defining equivalence, the researchers argued.

Treatment guidelines for initial HIV therapy suggest two nucleoside reverse transcriptase inhibitors combined with either a non-NRTI, a ritonavir-boosted protease inhibitor, or an integrase inhibitor, the researchers noted.

But there are limited data comparing atazanavir/ritonavir with efavirenz, they noted.

To help fill the gap, they conducted a randomized trial, in which the two lead compounds were added to common, once-daily combinations of nucleoside reverse transcriptase inhibitors -- either abacavir/lamivudine (Kivexa) or tenofovir/emtricitabine (Truvada).

The trial ran from September 2005 to November 2007, with a median of 138 weeks of follow-up, and the primary outcomes were time to virologic failure, safety, and tolerability.

All told, 1,857 patients were randomly assigned to one of the four treatment regimens and 1,331 completed the follow-up.

The primary efficacy hypothesis was that, within each of the NRTI arms, boosted atazanavir would be equivalent to efavirenz, Daar and colleagues noted.

The drugs were specified to be equivalent if a Cox proportional hazards model, using efavirenz as the reference, found the two-sided 95% confidence interval for the hazard ratio to be between 0.71 and 1.40.

But analysis showed:

• Among those randomized to the abacavir/lamivudine arms, the hazard ratio for time to virologic failure was 1.13 with a 95% confidence interval from 0.82 to 1.56. The difference was not statistically significant, at P=0.147.

• For those assigned to the tenofovir/emtricitabine arms, the hazard ratio was 1.01 with a 95% confidence interval from 0.70 to 1.46, which again was not significant, at P=0.37.

Although neither hazard ratio showed a significant difference, "neither met prespecified equivalence boundaries," the researchers reported.

However, analysis also showed that the probability of remaining free of virologic failure at week 96 was 83.4% for boosted atazanavir and 85.3% for efavirenz when they were combined with abacavir/lamivudine. The difference was -1.9 with a 95% confidence interval from -6.8 to 2.9, or 9.7 percentage points.

Values in the tenofovir/emtricitabine arms were 89% for boosted atazanavir and 89.8% for efavirenz, with a difference of -0.8 and a 95% confidence interval from -4.9 to 3.3, or 8.2 percentage points, the researchers reported.

Although the results did not meet the specified equivalence mark, the results suggest "for the first time in a large randomized study" that the two drugs have similar efficacy, the researchers argued.

They also found that safety and tolerability were slightly better for atazanavir than efavirenz when combined with abacavir/lamivudine, but there were no differences when they were combined with tenofovir/emtricitabine.

Daar and colleagues cautioned that when the study started it was not routine practice to test for HLA-B*5701 before using abacavir -- something that might have affected safety and tolerability results.

They also noted that study limitations include baseline drug resistance testing in only 40% to 50% of patients because of changing practices over time, premature unblinding of the NRTIs in the group of patients with high baseline viral loads, and change or discontinuation of the third drug in almost a third of patients.

The study was supported by the National Institute of Allergy and Infectious Diseases, and the National Center for Research Resources. Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided the study medications.

Daar reported financial links with Abbott Laboratories, Merck Laboratories, GlaxoSmithKline, Pfizer, Gilead Sciences, Bristol Myers Squibb, Tibotec, Schering-Plough, and Ardea Biosciences. Several authors reported being employed by the companies that supplied the study drugs.

Primary source: Annals of Internal Medicine
Source reference:
Daar ES, et al "Atazanavir plus ritonavir or efavirenz as part of a three drug regimen for initial treatment of HIV-1: A randomized trial " Ann Intern Med 2011.

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New hepatitis C drug

14 February 2011

Scientists in the UK have developed a compound to combat the hepatitis C virus that could be taken as a pill.

David Pryde and his team from Pfizer Global Research and Development, Sandwich, have made new compounds to activate a protein in the immune system called TLR7 - toll-like receptor 7 - which fights the infection. Toll-like receptors identify foreign DNA, such as a virus, and produce proteins that inhibit the virus' replication.

300 million people suffer from hepatitis C worldwide. The virus that causes the disease resides in the liver and can lead to cirrhosis, with some sufferers requiring liver transplants. Current treatments only cure half of patients and are administered intravenously. Recent research has focused on increasing the effectiveness of the drugs and on developing oral treatments.

Pryde's team made heterocyclic analogues based on the structure of purines, known activators of TLR7 and the basis of current oral drugs. 'The most potent TLR7 agonists are purine-based,' explains Pryde. 'But we wanted to design potent non-purine based agonists to maximise the chances of avoiding any unwanted off-target pharmacology.'


The compounds activate a protein in the immune
system, which fights hepatitis C

When they tested the compounds against a hepatitis C cell line, the team found that one of the compounds, a trifluoromethyl derivative, was highly selective for TLR7. The agonist also had comparable performance to injected alternatives at doses below 50mg.

'Medicinal chemistry is often castigated for surrendering synthetic elegance in order to gain compound access. Pryde elegantly repudiates this, accomplishing both elegance and access,' says Adam McCluskey, an expert in drug design and discovery from the University of Newcastle, Australia.

Pryde and his team hope to make the agonist more soluble and to increase its potency further before moving on to human trials.

Catherine Bacon

Link to journal articleThe discovery of a novel prototype small molecule TLR7 agonist for the treatment of hepatitis C virus infection
David C. Pryde, Thien-Duc Tran, Peter Jones, Gemma C. Parsons, Gerwyn Bish, Fiona M. Adam, Mya C. Smith, Donald S. Middleton, Nick N. Smith, Frederick Calo, Duncan Hay, Michael Paradowski, Katie J. W. Proctor, Tanya Parkinson, Carl Laxton, David N. A. Fox, Nigel J. Horscroft, Giuseppe Ciaramella, Hannah M. Jones, Jonathan Duckworth, Neil Benson, Anthony Harrison and Rob Webster, Med. Chem. Commun., 2011
DOI: 10.1039/c0md00197j

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Success rates for experimental drugs falls: study

By Bill Berkrot
NEW YORK
Mon Feb 14, 2011 8:09am EST

NEW YORK (Reuters) - The success rate in bringing new medicines to market in recent years is only about half of what it had been previously, but biotech drugs are twice as likely to gain U.S. approval than more traditional chemical drugs, according to a new study released on Monday.

And while oncology has been one of the hottest and most active therapeutic areas for drug development, drugmakers may want to take note of a finding that new cancer drugs have proven far more difficult to gain approval than medicines for infectious and autoimmune diseases.

Drugmakers have been complaining about the difficulty of bringing new products to market in a regulatory climate that has become increasingly unpredictable and more likely to err on the side of safety in deciding risk/benefit ratios of experimental medicines.

Data from this new study appears to bear that out.

"It ain't getting any easier to develop new therapies." said Alan Eisenberg, head of emerging companies and business development for the biotech trade group Biotechnology Industry Organization (BIO), putting the findings succinctly.

"Knowing more about the magnitude of risk can lead to smarter drug development as well as smarter investing," he said.

The study, covering 2004 through 2010, found the overall success rate for drugs moving from early stage Phase I clinical trials to FDA approval is about one in 10, down from one in five to one in six seen in reports involving earlier years.

The study, conducted by BIO and BioMedTracker, which collects data on drugs in development, reviewed more than 4,000 drugs from companies large and small and both publicly traded and private. It was released in conjunction with the annual BioCEO and Investor conference in New York.

Adding weight to the desire by major pharmaceutical companies to become increasingly involved in biotechnology was a finding that biologics had a 15 percent chance of going from Phase I through to FDA approval, compared with a 7 percent success rate for traditional small molecule chemical drugs.

When broken down by therapeutic categories, the highest overall success rate from Phase 1 through likelihood of approval was infectious diseases, such as hepatitis and HIV drugs, at 12 percent, followed by endocrine system drugs, featuring diabetes treatments, at 10.4 percent, and autoimmune diseases, such as rheumatoid arthritis, at 9.4 percent, the study found.

John Craighead, BIO's managing director for investor relations, said clinical trial goals and the approval pathways for infectious diseases and diabetes drugs are clear and very well-established.

"The Phase II results are very predictive of the Phase III outcomes and very predictive of approval," he said.

"The overall success rate in oncology was the lowest of the therapeutic areas that we looked at," he said, noting that cancer studies vary dramatically in design and extending survival sets a high bar for approval.

The cancer drug success rate was a mere 4.7 percent, with cardiovascular drugs second-worst at 5.7 percent, as regulators are increasingly demanding proof that heart drugs reduce heart attacks and strokes rather than just lower a risk factor, such as cholesterol levels.

The largest dropout rate along the clinical pathway came in advancing drugs from mid-stage Phase II studies to late-stage Phase III testing.

Some 63 percent of drugs in Phase I testing advanced to Phase II, but only 33 percent of Phase II drugs made it to Phase III, which requires a commitment to larger and much more expensive clinical trials. Phase III is typically the final stage of human testing before a new drug is submitted to regulators for an approval decision.

Not surprisingly, the numbers increase after that as the drugs had already shown success in the clinic.

Approval applications were filed for 55 percent of the drugs that made it to Phase III testing, and 80 percent of those gained eventual approval, although only about half were approved on their initial FDA review.

The 80 percent approval rate, while seemingly high, is down from 93 percent seen in studies of earlier years.

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Feb 14, 2011 11:31 ET

OREGON CITY, OR--(Marketwire - February 14, 2011) - The Caring Ambassadors Program (CAP) proudly announces the release of the new DVD series "Hepatitis C: Choices in Care -- Distinctive Viewpoints on Choices for Your Hepatitis C Journey." The 2-disc set offers over nine hours of leading expert physician interviews, patient consultations, panel discussions, Power Point presentations and 30 minutes of Qi Gong exercises specifically geared towards people living with hepatitis C.

About five million Americans are infected with HCV, making hepatitis C the most common chronic blood-borne viral illness in the U.S. HCV is the leading cause of chronic liver disease and liver cancer in the U.S. and the most common indication for liver transplantation. In January 2010, the Institute of Medicine (IOM) released its report, "Hepatitis and Liver Cancer, A National Strategy for the Prevention and Control of Viral Hepatitis." The committee found that many health care providers lack an adequate knowledge of HCV and that chronic hepatitis C patients are often confused about their treatment and disease management options.

The DVD series addresses these knowledge gaps by providing a shorter version of the book, Hepatitis C Choices, 4th Edition. The book presents evidence-based conventional and alternative treatment options and is the collective effort of leading medical experts and hepatitis C patient advocates. It is still the only book, and now DVD, of its kind.

"I was scared and did not know which way to turn when I was diagnosed with hepatitis C. I had a lot of unanswered questions," said Randy Dietrich, Board Chair of the Caring Ambassadors Program. "This information combined with the book was what I wanted to make an informed decision about my care."

The Caring Ambassadors Program produced "Hepatitis C: Choices in Care" to educate the public and health care community about hepatitis C. CAP believes it is vitally important that everyone with hepatitis C virus (HCV) know their disease status and have accurate and ample information to make the best health care decisions. Education is essential for making informed choices and taking charge of one's health.

"Hepatitis C: Choices in Care" is available for free viewing at the Caring Ambassadors Program Hepatitis C website at http://www.hepcchallenge.org/. The entire DVD series "Hepatitis C: Choices in Care" can also be purchased for $10.00 plus shipping and handling.

Contact:
Lorren Sandt
503-632-9030
Lorren@HepCChallenge.org

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