Telaprevir/Combination DAAs/Shortening Therapy Duration - Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: Implications for treatment duration -
Hepatology June 2011
Jeremie Guedj and Alan S. Perelson
From Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM.
"we estimated that telaprevir induced a four-fold more rapid second-phase viral decline than IFN-based therapy.....Even if resistance was avoided by using an appropriate combination of DAAs, other factors might affect our prediction. First, the ability of IFN-sparing antiviral strategies to reach every viral population residing in the liver or in extrahepatic reservoirs is unknown. Second, the combination of several DAAs might increase toxicity and thus the adherence to treatment. How this may impact treatment duration has only been touched on in this study, and more data are needed to understand how the lack of adherence to treatment may favor the appearance and persistence of resistant virus.
Thus, attainment of SVR in less than 10 weeks in 95% of fully compliant patients would require combination drug regimens (1) that have a genetic barrier high enough so that resistance is avoided, (2) that have high drug penetration into all anatomical sites that contain infected cells, and (3) for which the pharmacokinetics of the drugs in the regimen allow the effectiveness of the regimen against viral production to be maintained at high levels throughout the course of treatment.
In summary, our finding that the second-phase slope increases with the effectiveness of therapy and our expectation that a combination of DAA agents will suppress the growth of drug-resistant variants holds open the promise that more effective therapies that use combinations of DAA agents may, one day, lead to SVR with treatment durations of 2-3 months."... Read More...
HCV Treaters Shortage Editorial - Distributive justice and the arrival of direct-acting antivirals: Who should be first in line? -
"The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice."
"On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity.....current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment......We propose a needs-based allocation system....patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need."...Read More..
Nature Outlook collection on hepatitis C -
- Published online
The US Food and Drug Administration's approval of two new medications for hepatitis C in May marked the dawn of an era in treating this insidious disease.
The hepatitis C virus (HCV) can lurk silently for decades. Indeed, most of those who will benefit from this advance have no idea about their improved prospects, because they are unaware they are infected. The coming years could bring a surge in cases of the chronic form in people who unwittingly contracted the virus back in the 1960s and 70s through sharing needles and blood transfusions. Many of these chronic infections will progress to cirrhosis of the liver, and some to liver cancer and liver failure. Hepatitis C is the leading reason for liver transplantations. Until now, the only treatment option has been a gruelling year-long regimen of interferon-α plus ribavirin. Cruelly, in people with a particular genetic make-up, even this nasty course of medication often doesn't work.
The newly approved antiviral drugs lead the way for many other therapies (page S5). But caution is in order. First, the new medications supplement — not replace — the current treatment. So patients will be subject to all the same side effects as before, plus possibly a few more. Moreover, as clinician and HCV activist Diana Sylvestre points out on page S11, there is a high risk that the virus will become resistant to the new drugs. Finally, on page S18 epidemiologist Brian Edlin argues US policy makers need to wake up to the lurking HCV threat, and take action. Meanwhile, Egypt is experiencing an HCV epidemic of greater intensity than that in the United States and Europe (page S12), exacerbated by the fact that the genotype of HCV in Egypt is rarely found elsewhere.
This Outlook was made possible by the financial support of Gilead Sciences, Inc., Merck and Boehringer Ingelheim. As always, Nature retains full responsibility for all editorial content.
Without question, the recent approvals of telaprevir (Vertex) and boceprevir (Merck) for the treatment of hepatitis C infection marks the beginning of a new time for hepatitis C. This advance is genuinely significant, and after all the me-too drugs and incremental gains we’ve all grown used to reading about, it’s exciting to see two medications that are making a real difference for a large portion of the 170 million people worldwide infected with the virus. The drugs are protease inhibitors; they work by blocking the enzyme that enables the virus to survive in a host.
And yet, much more remains. Here’s a look at what is still needed in the realm of hepatitis C care:
First, HCV comes in a variety of genotypes.
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Cirrhosis
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New classification rule identifies high-risk patients with variceal bleeding
NEW YORK (Reuters Health) - Most patients with acute variceal bleeding have a relatively low 6-week mortality risk after standard-of-care treatment, but those with high creatinine levels have a poor prognosis and therefore warrant aggressive intervention with early placement of a transjugular intrahepatic portosystemic shunt (TIPS).
That conclusion comes from a Spanish study, reported online in the American Journal of Gastroenterology on May 31.
The authors explain that after acute variceal bleeding, high-risk patients may benefit from an early decision for aggressive management while low-risk patients might be spared unnecessary interventions. However, the mortality risk among different subgroups of patients after currently recommended treatment with vasoactive drugs and endoscopic ligation is unknown.
To investigate, Dr. Salvador Augustin, with Hospital Universitari Vall d'Hebron in Barcelona, and colleagues analyzed outcomes in 162 cirrhotic patients with acute esophageal variceal bleeding treated with combined pharmacologic therapy (somatostatin plus antibiotics) and emergency endoscopic ligation.
Patients with Child-Pugh A severity or Child-Pugh B without active bleeding were classified as low risk; those with Child-Pugh B with active bleeding or Child-Pugh C disease were classified as high risk.
Among the 162 ligated patients, 23 (14%) rebled and 26 (16%) died in the first 6 weeks of follow-up, according to the report.
Stratified 6-week mortality was 7% in the low-risk group and 33% in the high-risk group. However, in the latter group, mortality was similar to the low-risk group at 8% among patients with creatinine levels <1.0 mg/dL, but was 46% among those with creatinine of 1.0 mg/dL or higher, Dr. Augustin and colleagues report.
They reiterate that early use of TIPS may lead to a change in the management of high-risk patients with acute variceal bleeding, and conclude, "In this observational study, we show that previous criteria to identify such patients may not be adequate, providing a new classification rule (Child-Pugh C with baseline creatinine >\= 1.0) to better identify a high-risk population in this setting, in order to optimize the use of TIPS in clinical practice and for research purposes."
SOURCE: http://bit.ly/k6Xdml
Am J Gastroenterol 2011.
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Cirrhosis
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New classification rule identifies high-risk patients with variceal bleeding
NEW YORK (Reuters Health) - Most patients with acute variceal bleeding have a relatively low 6-week mortality risk after standard-of-care treatment, but those with high creatinine levels have a poor prognosis and therefore warrant aggressive intervention with early placement of a transjugular intrahepatic portosystemic shunt (TIPS).
That conclusion comes from a Spanish study, reported online in the American Journal of Gastroenterology on May 31.
The authors explain that after acute variceal bleeding, high-risk patients may benefit from an early decision for aggressive management while low-risk patients might be spared unnecessary interventions. However, the mortality risk among different subgroups of patients after currently recommended treatment with vasoactive drugs and endoscopic ligation is unknown.
To investigate, Dr. Salvador Augustin, with Hospital Universitari Vall d'Hebron in Barcelona, and colleagues analyzed outcomes in 162 cirrhotic patients with acute esophageal variceal bleeding treated with combined pharmacologic therapy (somatostatin plus antibiotics) and emergency endoscopic ligation.
Patients with Child-Pugh A severity or Child-Pugh B without active bleeding were classified as low risk; those with Child-Pugh B with active bleeding or Child-Pugh C disease were classified as high risk.
Among the 162 ligated patients, 23 (14%) rebled and 26 (16%) died in the first 6 weeks of follow-up, according to the report.
Stratified 6-week mortality was 7% in the low-risk group and 33% in the high-risk group. However, in the latter group, mortality was similar to the low-risk group at 8% among patients with creatinine levels <1.0 mg/dL, but was 46% among those with creatinine of 1.0 mg/dL or higher, Dr. Augustin and colleagues report.
They reiterate that early use of TIPS may lead to a change in the management of high-risk patients with acute variceal bleeding, and conclude, "In this observational study, we show that previous criteria to identify such patients may not be adequate, providing a new classification rule (Child-Pugh C with baseline creatinine >\= 1.0) to better identify a high-risk population in this setting, in order to optimize the use of TIPS in clinical practice and for research purposes."
SOURCE: http://bit.ly/k6Xdml
Am J Gastroenterol 2011.
HCV Around The World
No check on drug companies fleecing hepatitis patients
PESHAWAR, June 9: The multinational pharmaceutical companies have been fleecing the hepatitis C patients for the last several years and there is still no check on them, doctors and patients say. “Majority of hepatitis C patients needs Interferon injections, which are usually given twice a week. A patient requires 72 injections to get fully recovered,” said a senior hepatologist. He said that the patients had been facing problems because price of the injection vary from shop to shop.
Some patients get the full dose (72 injections) for Rs45,000 while others buy the same for as low as Rs23,000, he said.
Interestingly, about 10 pharmaceutical companies have been marketing these injections and all offer different prices. The worst sufferers are the poor patients, who are unable to pay for the costly treatment of hepatitis C.
“I have paid Rs45,000 for a full dose of injections to a chemist in Peshawar. A man in my village has received the same injections by paying only Rs23,000,” said Jaffar Ali, a shopkeeper in Mardan. He said that he was a poor person and had borrowed the money from his neighbours.
Last year, the manufacturers of Interferon injection slashed the price from Rs72,000 to Rs45,000. “It means that these companies had been charging the patients exorbitant price from the past 10 years because now they are selling it at Rs45,000 and Rs23,000,” said a physician. It also shows the margin of profit being pocketed by the drug manufacturers from the past one decade, he said.
The patients visiting the Mercy Teaching Hospital, Kuwait Teaching Hospital and Prime Teaching Hospital – all affiliated with the Peshawar Medical College – are the beneficiaries of the lowest prices offered by the companies.
“We try to give financial benefit to all the patients. About 90 per cent of the patients belong to poor families and can not afford the expensive medication,” Dr Muhammad Subhan, the KTH medical superintendent, told this correspondent. He said that Interferon injections should be given on the prescription of a specialist doctor.
According to officials of the Khyber Pakhtunkhwa Hepatitis Control Programme about 10 per cent of the province`s population suffers from hepatitis C and the only treatment available for this is Interferon injection. Asked about the price difference, they said that fixation of drug prices was the domain of the federal government.
The price of another injection called Pegasys, which is also administered to the hepatitis C patients, was also reduced from Rs12,000 to Rs6,000, which shows how the MNCs have been fleecing the people.
Local pharmacists say that not only the MNCs but the distributors and chemists have also been earning a lot from sale of the hepatitis drugs.
They said that mostly the benefits were transferred by the pharmaceutical companies to the doctors and chemists, who prescribe and sell the medicines, respectively.
Grant To Pursue Innovative Research To Develop Personalized Medicine
10 June 2011
The Research Institute of the McGill University Health Centre (RI-MUHC) was one of three winners in the Fonds de la recherche en sante du Quebec (FRSQ) competition 2011-2012. The RI-MUHC won in the category of Projects for...
Pharmaceuticals
Vertex CEO outlines Incivek marketing plan: No TV ads.
Boston Business Journal - by Julie M. Donnelly
Date: Thursday, June 9, 2011, 2:39pm EDT - Last Modified: Thursday, June 9, 2011, 4:00pm EDT
Matthew Emmens doesn’t call the newly hired army of people who will sell the company’s freshly approved treatment for Hepatitis C, Incivek, salespeople or “drug reps.” He calls them “enablers,” people who will connect patients to the drug, which was found in one late-stage study to cure 79 percent of patients of a disease that is an epidemic among baby boomers.
In charting a course for Boston’s newest commercial pharmaceutical company, Emmens aims to change the language, and also the game, for a company that’s spent more than 20 years behind closed doors looking for cures. Vertex will move to two shiny new buildings on Boston’s Fan Pier in 2013, from its dank warren of 10 low-rise factory buildings near Central Square in Cambridge. In the meantime, it will also emerge from the shadows of peers like Genzyme Corp., now owned by French drug maker Sanofi, following a series of manufacturing missteps, and Biogen Idec, which this fall announced it would narrow its focus amid a major restructuring that claimed 650 jobs company-wide.
“I get a lot of calls from governors, some in states where I’ve put a headquarters before, who would like to have a growing business,” Emmens said, but that a number of factors, ...
Vertex Pharmaceuticals Inc. (Nasdaq: VRTX) CEO Matthew Emmens doesn’t call the newly hired army of people who will sell the company’s freshly approved treatment for Hepatitis C, Incivek, salespeople or “drug reps.” He calls them “enablers,” people who will connect patients to the drug, which was found in one late-stage study to cure 79 percent of patients of a disease that is an epidemic among baby boomers.
In charting a course for Boston’s newest commercial pharmaceutical company, Emmens aims to change the language, and also the game, for a company that’s spent more than 20 years behind closed doors looking for cures. Vertex will move to two shiny new buildings on Boston’s Fan Pier in 2013, from its dank warren of 10 low-rise factory buildings near Central Square in Cambridge. In the meantime, it will also emerge from the shadows of peers like Genzyme Corp., now owned by French drug maker Sanofi, following a series of manufacturing missteps, and Biogen Idec, which this fall announced it would narrow its focus amid a major restructuring that claimed 650 jobs company-wide.
Vertex, meanwhile, has become a darling of the political establishment, adding 200 new Massachusetts jobs over the past year, with a commitment to add 500 more between now and 2015. The company will receive a total of $72 million in state and city incentives associated with the move and the job creation.“I get a lot of calls from governors, some in states where I’ve put a headquarters before, who would like to have a growing business,” Emmens said, but that a number of factors, including the proximity to the airport, the incentives, the ability to design the new buildings, and the educated pool of workers here, gave Boston the edge. But he said, “In the end the shareholders don’t really care where you’re located.”
Integrating the new commercial team, which is currently siloed in one of the 10 buildings, has forced the longtime research and development company to be creative.
“When you bring in something different to an environment in nature, it develops antibodies. You don’t want that to happen, you don’t want (the commercial operation) to be a foreign object — to push it away or isolate it,” Emmens said. To that end, he launched two initiatives. First, Vertex hired outside consultants to invent a Vertex board game that includes all parts of the organization and takes employees through the process of getting a drug approved, including all the risk factors that could sink the drug, how to price it, etc. The goal is for the scientists to learn the business, and vice versa.
“There’s also an investment portion, they can only spend so much money,” Emmens said. Vertex itself, it should be noted, spent more than $4 billion between its launch and getting its first in-house drug approved on May 23.
Secondly, the scientists interviewed the sales candidates. If they weren’t truly interested in science, they didn’t get the job. It might seem obvious that those selling medicine should have a passion for it, but Emmens said it’s not always the case.
“If you look what pharma did over the past 15 years you see a lot of companies that brought in consumer goods people to be the head of marketing. I think that’s a real problem. This is not a consumer goods product.”
Emmens said there’s something else that’s a problem — direct-to-consumer advertising for drugs. The company doesn’t plan to run TV ads for Incivek.
“We are not a marketing company. Our mettle will be based on world-class science. Without that, there’s no place for a Vertex.”
Emmens says any ads will be for awareness of the disease and not for the drug itself. Vertex has launched a large Hepatitis C awareness campaign, called “Better to Know C,” which is running on the radio and on billboards in subways around the country, and began months before Incivek was approved. The goal is to decrease the number of Americans — estimated to be 3 million, or three-fourths of the total infected — who have the disease and don’t know their status. In addition, Vertex executives have said the complexity of the regimen — Incivek must be taken in concert with two other drugs — means the company will be involved in intensive education efforts with patients even after they are on therapy.
Emmens’ decisions not to do Incivek TV ads, and also to maintain a relatively small, 115-person sales team, is bold. After all, the company is going head-to-head with Emmens’ old employer, Merck and Co., whose Victrelis was approved by the FDA just days before Incivek. Emmens said of prospective patients, “I’d like them to go to their doctor. I think they’ll get the answer that I like.”
He might be right: Several analysts have said they expect Incivek, which is thought to have slightly better efficacy, will beat Merck’s drug. For instance, Joseph Schwartz, an analyst for Boston life science investment bank Leerink Swann, estimates Incivek will have a 2-to-1 market split over Victrelis.All of this optimism about the company’s future potentially puts Vertex in the bulls-eye of potential acquirers, but Emmens said that’s not in the plan.
“You should always be an acquisition target, it says you are doing well,” he said. “You should always be more expensive than anyone is willing to pay. That’s success. We intend to be an independent, successful company.”
Complementary and Alternative Medicine
Does It Work ?
Thursday, June 9, 2011 - 10:59
Does it work?", an online series by Dónal O'Mathúna in The Irish Times, explores the efficacy of herbal remedies frequently quoting Cochrane evidence, i.e. on ginko biloba (article, review), hawthorn (article, review) and vitamin B12 (article, review).
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Just In Case You Missed It
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Analysis finds mortality from all causes higher among hepatitis C-infected
Patients had higher risk of dying from both liver- and non-liver related causes
[EMBARGOED FOR JUNE 10, 2011] Although liver-related mortality among those infected with hepatitis C is well-documented, little is known about deaths in these patients that are not related to liver problems. A new study published in Clinical Infectious Diseases and now available online (http://www.oxfordjournals.org/our_journals/cid/cir306.pdf) soughtto determine mortality from all causes, including liver- and non-liver related deaths among hepatitis C patients in the general U.S. population. The analysis found mortality from all causes to be higher in these patients.
An estimated 4 million adults in the U.S. tested positive for hepatitis C, according to the Third National Health and Nutritional Examination Survey, a large, nationally representative survey, conducted from 1988 to 1994. During a follow-up period of almost 15 years, 614 deaths occurred among 9,378 adults assessed in this study.
Among 203 people with chronic hepatitis C infection, 44 died, nine from liver-related causes. The remaining 35 deaths were due to HIV infection, diabetes, heart disease, cancer, and other causes. Compared to individuals who tested negative for hepatitis C, patients with chronic hepatitis C infection had more than a two-fold risk of dying from both liver- and non-liver related causes.
"This should reinforce the importance of preventive measures, particularly among individuals at-risk for acquiring the disease, as well as early diagnosis, and improving access to care for those already infected, even in the absence of liver disease," said the lead author of the study, Dr. Samer El-Kamary, of the University of Maryland School of Medicine in Baltimore. "While a hepatitis C infection itself may not be the cause of death, patients with the disease may be at a higher risk of dying due to other high-risk behaviors that may have also caused the infection. Furthermore, it is possible that other comorbidities like diabetes and cardiovascular disease could get worse if there is an underlying hepatitis C infection."
Dr. El-Kamary added, "Given the low cost for hepatitis C tests, perhaps it would be advisable to consider more liberal early screening of patients if there is any suspicion of infection so they can be referred for treatment as early as possible."
Founded in 1979, Clinical Infectious Diseases publishes clinical articles twice monthly in a variety of areas of infectious disease, and is one of the most highly regarded journals in this specialty. It is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 9,000 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.
FDA Hepatitis Update - Labeling change for Intron A (Interferon alfa-2b) and PegIntron (Peginterferon alfa-2b)
On June 6, 2011, FDA approved a labeling change to the the WARNINGS and PRECAUTIONS: Neuropsychiatric Disorders subsection of both the Intron A (Interferon alfa-2b) and PegIntron (Peginterferon alfa-2b) labels to state that treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders.
Specifically, PegIntron or Intron A should be used with extreme caution in patients with a history of psychiatric disorders. Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is judged necessary in patients with prior history or existence of psychiatric condition or with history of substance use disorders, treatment requires individualized drug screening strategies and frequent psychiatric symptom monitoring. Early intervention for re-emergence or development of neuropsychiatric symptoms and substance use is recommended.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
An estimated 4 million adults in the U.S. tested positive for hepatitis C, according to the Third National Health and Nutritional Examination Survey, a large, nationally representative survey, conducted from 1988 to 1994. During a follow-up period of almost 15 years, 614 deaths occurred among 9,378 adults assessed in this study.
Among 203 people with chronic hepatitis C infection, 44 died, nine from liver-related causes. The remaining 35 deaths were due to HIV infection, diabetes, heart disease, cancer, and other causes. Compared to individuals who tested negative for hepatitis C, patients with chronic hepatitis C infection had more than a two-fold risk of dying from both liver- and non-liver related causes.
"This should reinforce the importance of preventive measures, particularly among individuals at-risk for acquiring the disease, as well as early diagnosis, and improving access to care for those already infected, even in the absence of liver disease," said the lead author of the study, Dr. Samer El-Kamary, of the University of Maryland School of Medicine in Baltimore. "While a hepatitis C infection itself may not be the cause of death, patients with the disease may be at a higher risk of dying due to other high-risk behaviors that may have also caused the infection. Furthermore, it is possible that other comorbidities like diabetes and cardiovascular disease could get worse if there is an underlying hepatitis C infection."
Dr. El-Kamary added, "Given the low cost for hepatitis C tests, perhaps it would be advisable to consider more liberal early screening of patients if there is any suspicion of infection so they can be referred for treatment as early as possible."
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NOTE: The study is available online. It is embargoed until 12:01 a.m. EDT on Friday, June 10, 2011: All-Cause, Liver–, and Non–Liver-Related Mortality Among HCV-Infected Individuals in the General US Population http://www.oxfordjournals.org/our_journals/cid/cir306.pdfFounded in 1979, Clinical Infectious Diseases publishes clinical articles twice monthly in a variety of areas of infectious disease, and is one of the most highly regarded journals in this specialty. It is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 9,000 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.
FDA Hepatitis Update - Labeling change for Intron A (Interferon alfa-2b) and PegIntron (Peginterferon alfa-2b)
On June 6, 2011, FDA approved a labeling change to the the WARNINGS and PRECAUTIONS: Neuropsychiatric Disorders subsection of both the Intron A (Interferon alfa-2b) and PegIntron (Peginterferon alfa-2b) labels to state that treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders.
Specifically, PegIntron or Intron A should be used with extreme caution in patients with a history of psychiatric disorders. Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is judged necessary in patients with prior history or existence of psychiatric condition or with history of substance use disorders, treatment requires individualized drug screening strategies and frequent psychiatric symptom monitoring. Early intervention for re-emergence or development of neuropsychiatric symptoms and substance use is recommended.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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