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New Hepatitis C Drugs Offer Options but With Added Complications

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September hepc.bull -monthly newsletter (.pdf)
In This Issue
Research
The New Drugs / Kelly O’Dell
World Hepatitis Day Surrey—Report
A Promising Lesson
Hep C on the Internet / HepCBC Marathon
Conferences
PegCARE/PegAssist/Neupogen/Compensation

In Case You Missed It

From Medscape Medical News
Shorter Duration Telaprevir Therapy Effective in HCV
Emma Hitt, PhD
Authors and Disclosures

September 14, 2011 — In patients with chronic hepatitis C virus (HCV) genotype 1 infection, telaprevir for 12 weeks, in addition to 24 weeks of treatment with peginterferon and ribavirin, is noninferior to 12 weeks of treatment with telaprevir plus 48 weeks of treatment with peginterferon and ribavirin, according to findings of a phase 3 clinical trial.
Kenneth E. Sherman, MD, PhD, with the Division of Digestive Diseases, at the University of Cincinnati College of Medicine, in Cincinnati, Ohio, and colleagues reported their findings in the September 15 issue of the New England Journal of Medicine.

Telaprevir is an orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV protease. The researchers note that "a response-guided treatment regimen based on viral response may permit a shorter treatment duration while preserving high rates of sustained virologic response." The current study compared the safety and efficacy of response-guided therapy with 24-week vs 48-week treatment regimens of peginterferon/ribavirin in combination with telaprevir.

A total of 540 patients with chronic HCV genotype 1 infection who had received no prior treatment were given study drugs at 74 sites included in the trial. For the first 12 weeks, the patients were given 750 mg of telaprevir every 8 hours, 180 µg of peginterferon alfa-2a once per week, and 1000 to 1200 mg of ribavirin per day.

After week 12, telaprevir administration was stopped in all patients, and they continued to receive peginterferon and ribavirin only. After week 20, patients who had demonstrated extended rapid virologic response (whose HCV RNA levels had been undetectable at weeks 4 and 12) were randomly assigned to receive peginterferon and ribavirin for either 4 more weeks or 28 more weeks, whereas patients who did not show extended rapid virologic response received the 2 drugs for 28 more weeks.

The noninferiority trial compared rates of sustained virologic response in the group receiving peginterferon and ribavirin for 4 more weeks vs the group receiving the same drugs for 28 more weeks and established the noninferiority of the shorter treatment regimen.

Noninferiority Demonstrated
Overall, the rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 92% in the 24-week group vs 88% in the 48-week group had a sustained virologic response, indicating noninferiority with respect to efficacy in the 2 groups.
Adverse effects led 18% of study patients to discontinue treatment, but only 1% in the 24-week group discontinued vs 12% in the 48-week group (P < .001). Adverse events included rashes in 37% of patients and anemia in 39%.

"In our phase 3 study, 24 weeks of peginterferon and ribavirin treatment was noninferior to 48 weeks of treatment for patients infected with HCV genotype 1 who had not previously received treatment and who had undetectable HCV RNA levels at weeks 4 and 12," Dr. Sherman and colleagues conclude.

According to the researchers, this study supports the concept of response-guided therapy. "Relapse rates were low and were not significantly different between the 24-week group and the 48-week group," they write.
"In addition, response-guided therapy also resulted in decreased rates of adverse events and treatment discontinuation among patients who received treatment over the shorter period," they note.

Comment: Rapid Response May Be the Key
According to independent commentator David L. Thomas, MD, MPH, chief of infectious diseases at the Johns Hopkins School of Medicine in Baltimore, Maryland, these data "demonstrate that the two-thirds of persons who rapidly respond to treatment with peginterferon alfa, ribavirin, and telaprevir can effectively cut the duration of treatment in half."

"This finding, combined with the much greater success of treatment in those who took the HCV protease inhibitor compared to placebo, underscore just how far HCV treatment has advanced this summer," Dr. Thomas told Medscape Medical News.

"These findings and those for boceprevir, the other approved HCV protease inhibitor, should encourage all providers to test all their patients who might be at risk of HCV for infection and to engage all who are positive in a serious discussion as to whether treatment is right for them now," he said. "Even those who end up deciding to wait will want to be treated in the next few years, and it is crucial to get them into care."

The study was supported by Vertex Pharmaceuticals and Tibotec. Disclosure forms provided by the study authors are available with the full text of this article on the New England Journal of Medicine Web site. Dr. Thomas states that he is on the advisory board for Merck, the maker of boceprevir.
N Engl J Med. 2011;365:1014-1024.

People with Multiple Tattoos and/or Piercings Are Not at Increased Risk for HBV or HCV in The Netherlands
Anouk T. Urbanus, Anneke van den Hoek, Albert Boonstra, Robin van Houdt, Lotte J. de Bruijn, Titia Heijman, Roel A. Coutinho, Maria Prins Research Article, published 14 Sep 2011doi:10.1371/journal.pone.0024736
We found no evidence for an increased HBV/HCV seroprevalence among persons with multiple tattoos and/or piercings, which might be due to the introduction of hygiene guidelines for tattoo and piercing shops in combination with the low observed prevalence of HBV/HCV in the general population. Tattoos and/or piercings, therefore, should not be considered risk factors for HBV/HCV in the Dutch population. These findings imply the importance of implementation of hygiene guidelines in other countries...Full Text...

Transplants

Substitution Of Brand Name With Generic Drug Proves Safe For Transplant Recipients
A new study published in the American Journal of Transplantation reveals that substitution of a brand name immunosuppressive drug with a generic (manufactured by Sandoz) for preventing rejection of transplanted organs appears to be safe for transplant recipients.

Tacrolimus is an immunosuppressive drug that is used to prevent rejection of transplanted organs following organ transplantation.

In August 2009, another pharmaceutical company received approval from the FDA for a generic tacrolimus product. In the first formal study of its kind, Raman Venkataramanan, PhD, of the University of Pittsburgh, School of Pharmacy and School of Medicine, and researchers analyzed database information regarding tacrolimus concentrations and indices of liver and kidney function before and after generic substitution in 48 liver and 55 kidney transplant recipients.

Substitution of brand name tacrolimus product with the generic formulation resulted in an average reduction of 15.9% and 11.9% in concentration/dose ratio in clinically stable liver and kidney transplant patients, respectively. The substitution was safe, as no changes occurred in liver or kidney function and no acute rejection episodes occurred during the follow-up time period. An accompanying editorial by G.B. Klintmalm of Baylor University Medical Center, while offering a different viewpoint, also calls upon the FDA to change the requirements for approval of these drugs in order for the transplant community to trust and rely on generic immunosuppressive drugs for the treatment of transplant recipients.

Klintmalm notes that "in order to safely save healthcare dollars, it is urgent that the FDA step up to the plate to implement changes in its approval process for generics of critical-dose drugs." "Our findings suggest that transplant patients currently taking the brand name tacrolimus formulation may be safely switched to the generic product," Venkataramanan concludes. "However, on an individual basis, since some patients had significant changes in tacrolimus blood levels, increased monitoring of tacrolimus blood levels is necessary following the substitution to assure adequate drug concentrations. Long-term use of generic product will lead to cost savings."

Pharmaceuticals

Older pills often safer but many think new is better
In truth, the FDA approves a new drug when its benefits outweigh any known risks. FDA approval doesn't mean the drug's benefits are large compared to drugs already on the market. And risks for some drugs appear only after they've been used by millions of people and long after FDA approval. For instance, Merck & Co. withdrew the FDA-approved arthritis pill Vioxx after its heart risks surfaced.
The new survey, appearing in Monday's Archives of Internal Medicine, revealed a partial solution to consumer confusion: Simply worded cautions can make a difference in which drugs people choose......Continue Reading..

Safety of Imported Drugs Still not Assured, GAO Says
By John Gever, Senior Editor, MedPage Today
Published: September 14, 2011
WASHINGTON -- Although the FDA has made progress in inspecting overseas manufacturing facilities for finished drugs and pharmaceutical ingredients, the agency is still unable to guarantee safety of the drug supply chain, the Government Accountability Office reported.
"FDA needs to act quickly to implement changes across a range of activities in order to better assure the safety and availability of drugs for the U.S. market," according to Marcia Crosse, the GAO's director of healthcare, in written testimony submitted to the Senate Health, Education, Labor and Pensions committee.

The committee, chaired by Sen. Tom Harkin (D-Iowa), held a hearing Wednesday on the safety of the pharmaceutical supply chain.

Crosse told the committee that the FDA does appear to be conducting significantly more inspections of foreign facilities than in 2008, when the GAO issued a harsh critique of the FDA's oversight of imported drug products.

At that time, the FDA was inspecting about 8% of foreign facilities exporting to the U.S. each year, meaning that each facility would be inspected about once every 13 years on average -- compared with an average interval of 2.7 years for domestic plants.

According to the most recent data available to the GAO, "FDA's inspection efforts in fiscal year 2009 represent a 27% increase in the number of inspections it conducted, when compared to fiscal year 2007," Crosse indicated.

"However, FDA officials acknowledged that FDA is far from achieving foreign drug inspection rates comparable to domestic inspection rates," she added.
For its part, the GAO conceded that factors beyond the FDA's control hinder its foreign inspection efforts. For example, its inspectors do not alway enjoy the same access to facilities that is provided by domestic producers, and unannounced inspections are usually impossible.
The GAO also credited the FDA with progress in other areas.

Since 2008, for instance, it has established a registration system for facilities exporting to the U.S. and taken other steps to improve its records of such facilities. The agency has also begun working more closely with national regulators in other countries as well as drug manufacturers.
But these and other initiatives are not yet fully implemented and some remain in the planning stage, Crosse observed. The FDA still does not know for certain the locations or ownership of all foreign facilities exporting to the U.S. nor the specific products that they ship.

FDA officials told the GAO that U.S. law also limits its powers to police overseas drug production.
The FDA would like legislated authority that would allow the agency to suspend or cancel registrations of foreign facilities when they fail to supply correct, timely information, to require such facilities to use a unique identifier number (doing so is currently voluntary), and to conduct inspections on a flexible, risk-based schedule.

Deadly Drug Contamination Inevitable, FDA Tells U.S. Senate
Fatal drug contamination like a 2008 incident involving Baxter International Inc. (BAX)’s blood thinner Heparin that sickened and killed hundreds is inevitable unless the agency gets enhanced inspection and recall powers for non-U.S. factories, a top regulator said.
Another crisis is “not a matter of if, it’s a matter of when,” Deborah Autor, the Food and Drug Administration’s deputy commissioner for global regulatory operations and policy, told a U.S. Senate committee today....Continue Reading..


LISTEN: Should Doctors Disclose Drug Company Payments to Their Patients?
Last week, ProPublica updated its Dollars for Docs [1] news application -- a database detailing the payments physicians have received from pharmaceutical companies for speaking engagements, research, meals and other amenities. Currently, pharmaceutical and medical device companies are not required to disclose these payments, at least not until 2013 [2], and even then doctors won't have to share this information with their patients......Continue Reading..

Clinical Trials

OPINION: Consistent clinical research standards benefit patients around the world
Posted: 2011-09-14 14:19
By Joe Herring
Although the globalization of clinical trials has provided benefits to host countries, critics have focused on the rare but egregious examples of unethical practices. But large, coordinated trials by the contract research industry can encourage best practice, particularly if local countries adopt more consistent standards and oversight.

As economic prosperity comes to developing nations, diseases associated with Western lifestyles, such as cancer and diabetes, are crossing borders. Meanwhile, developing countries are quickly becoming consumers of biopharmaceutical products. With the shared burden of disease comes the need to obtain safety and efficacy profiles across worldwide populations in a way that mirrors global disease epidemiology and treatment.

Increasing access to allow for more people to participate will be instrumental in clinical trials of the future. Developed nations are home to just 15% of the world's population, yet they host three-quarters of all clinical trials. Clinical trials in emerging regions tend to take place in large urban centers where healthcare infrastructure can support research conducted according to Good Clinical Practice (GCP) and International Conference on Harmonization (ICH) standards. Compliance to these industry standards will strengthen the safety and quality of the research and increase public confidence in clinical trial participation.

Without further globalization, the pace of medical research would slow substantially. This is largely due to the reality that clinical trials are larger and more complex than they were ten years ago, and Western participation levels have peaked.
(Click here to continue reading.)

Hall Of Shame

NJ doctor loses license after hepatitis B outbreak
The Associated Press
Last modified: 2011-09-15
Published: Wednesday, Sep. 14, 2011 - 10:03 pm
TOMS RIVER, N.J. -- New Jersey officials have revoked the medical license of an oncologist they say committed "gross and repeated acts of negligence" that led to an outbreak of hepatitis B among his patients.

The Star-Ledger newspaper (http://bit.ly/nJvi6W ) reports that the state Board of Medical Examiners on Wednesday revoked Parvez Dara's license for four years and charged him $30,000 in civil penalties. His license already had been suspended for 2 1/2 years, meaning he can reapply in 18 months.

Prosecutors said conditions at Dara's office were rife for spreading infections. They say at least 29 of his patients have been infected with hepatitis B, a virus that affects the liver.
Dara's lawyer, Peter Korn, said evidence that the cases of hepatitis were linked was based on "flawed medical science."

The state had warned more than 5,000 patients at Dara's Toms River office to get tested.

Healthy You

Spicing Up Broccoli Boosts Its Cancer-Fighting Power
Teaming fresh broccoli with a spicy food that contains the enzyme myrosinase significantly enhances each food's individual cancer-fighting power and ensures that absorption takes place in the upper part of the digestive system where you'll get the maximum health benefit, suggests a new University of Illinois study. "To get this effect, spice up your broccoli with broccoli sprouts, mustard, horseradish, or wasabi. The spicier, the better; that means it's being effective," said Elizabeth Jeffery, a U of I professor of nutrition.

In the study, when fresh broccoli sprouts were eaten with broccoli powder, the scientists were able to measure bioactive compounds in the blood 30 minutes later. When these peaked at three hours, they were much higher when the foods were eaten together than when either was eaten alone. Urine samples corroborated the blood results, said Jenna Cramer, lead author of the study. It's no secret that many people cook the benefits right out of broccoli instead of steaming it lightly for two to four minutes to protect its healthful properties, she said. "However, this study shows that even if broccoli is overcooked, you can still boost its benefits by pairing it with another food that contains myrosinase," she said.

Myrosinase is the enzyme necessary to form sulforaphane, the vegetable's cancer-preventive component, co-author Margarita Teran-Garcia explained. Note what happened with the fresh broccoli sprouts and broccoli powder eaten in this experiment. The powder doesn't contain myrosinase, but it does contain the precursor to the anti-cancer agent sulforaphane. Eaten together, the sprouts were able to lend their myrosinase to the powder.

As predicted, both foods produced sulforaphane and provided greater anti-cancer benefit, Jeffery said. Other foods that will boost broccoli's benefits if they are paired together include radishes, cabbage, arugula, watercress, and Brussels sprouts. "Here's another benefit of protecting and enhancing the myrosinase in your foods," Jeffery said. "If myrosinase is present, sulforaphane is released in the ilium, the first part of your digestive system. Absorption happens well and quickly there, which is why we saw bioactivity in 30 minutes."

An earlier Jeffery study showed that microbiota are capable of releasing sulforaphane in the lower gut, but absorption happens more slowly in the colon than in the upper intestine, she said. Scientists say that as little as three to five servings of broccoli a week provide a cancer-protective benefit. "But it pays to spice it up for added benefits and find ways to make it appealing so you don't mind eating it if you're not a broccoli fan. I add fresh broccoli sprouts to sandwiches and add them as one of my pizza toppings after the pie is out of the oven," Cramer said.