Hepatitis C News; Rivals go head to head-Merck’s Victrelis (boceprevir)& Johnson/Vertex’s Incivek (telaprevir)

Hepatitis C rivals go head to head
The field of hepatitis C treatment has two new groundbreaking medicines to treat the condition.
Merck’s Victrelis (boceprevir) and Johnson & Johnson/Vertex’s Incivek (telaprevir) were both launched in the US in May, and Victrelis has now been given the green light in Europe.
The drugs have much in common; both are oral protease inhibitors, and promise to significantly improve treatment when added to the current standard treatments for the disease. An estimated 270-300 million people world have the disease.Both drugs are expected to reach blockbuster status, but which will win out in the battle for market share? Many analysts are predicting Vertex and J&J’s Incivek will prevail because it has shown a higher cure rate, and a simpler and faster simpler dosing regimen.But Vertex, which has never launched a drug before, will have to overcome the might of Merck and its new US marketing partner Roche.
Victrelis versus Incivek
Current hepatitis C treatments produce only limited success in treating patients with the disease. The current standard treatments are peginterferon alfa and ribavirin taken for 48 weeks, but less than 50% of patients respond to this therapy.The two new protease inhibitors promise to help more patients, and to lower the viral load of the disease down to an undetectable level, considered a cure for the disease.Both Incivek and Victrelis are licensed in the US to treat hepatitis C genotype 1 infection with compensated liver disease, including cirrhosis, in combination with peginterferon alfa and ribavirin. The new drugs can be given to patients who have been previously untreated or who have failed previous interferon and ribavirin therapy. Victrelis had a 66% sustained viralogic response (SVR) - as close to a cure as possible - in late-stage studies, but Incivek produced a significantly higher rate of 79 per cent. Incivek has a further advantage - patients who respond well to the drug can stop treatment at just 24 weeks rather than the nearly year-long 48 weeks of the current drug regimen. Safety data suggests Incivek is generally well-tolerated, but about half of patients developed a skin rash or itching, while a small number developed the severe Stevens-Johnson Syndrome.Merck’s Victrelis has a few factors in its favour - is likely to cost less (depending on the duration of treatment) and has had no cases of the Stevens-Johnson Syndrome. However Merck’s drug has a more complicated dosing regimen, which is expected to count against it.
The marketing battle
Merck has shown its determination to win the US marketing battle by signing a co-marketing deal with Roche. This means Vertex will have to compete with two of the biggest and most experienced salesforces in the sector. Vertex has a sales team of 115, a fraction of the numbers Merck and Roche will be able to muster. But Vertex’s chief executive Matthew Emmens believes the company can hold its own against its bigger competitors, thanks to the already high level of awareness among their target audience, and the advantages of its drug.
Vertex’s belief in the superiority of its product is reflected in its price, which is $49,200 for a 12-week course. This cost is much higher than Victrelis, and is equivalent to the price of a whole 48 week treatment with Merck’s drug. Vertex justifies the high price on the promise of a shorter treatment period, but patient advocacy groups have already criticised the high costs patients and insurance systems will have to pay.
European approvals
The FDA made a speedy decision on Victrelis and Incivek, fast-tracking the drugs because of their groundbreaking status. The drugs have been given similar priority status in Europe, and Victrelis has just gained final EU approval. Vertex says it hopes for a European approval, where its partner Johnson & Johnson holds the marketing rights, by the end of the year.Liver experts are already familiar with what Victrelis and Incivek will offer, and are looking further ahead to continued progress. Researchers are now looking to combine molecules or produce a single agent to simplify treatment and do away with interferon, which produces flu-like symptoms and other side effects. There is also a need for drugs to treat a wider spectrum of virus genotypes, and to address viral resistance to drug treatment.

Transplant

Sex-based disparities in liver transplant rates in the USA
This month's issue of the American Journal of Transplantation reports sex-based disparities in liver transplant rates in certain regions of the USA.
Dr Amit Mathur and colleagues characterized sex-based differences in access to deceased donor liver transplantation.
Scientific Registry of Transplant Recipients data were used to analyze 78,998 adult candidates listed before or after implementation of Model for End-Stage Liver Disease (MELD)-based liver allocation.
The team's primary outcome was deceased donor liver transplantation.
Cox regression was used to estimate covariate-adjusted differences in transplant rates by sex.
Females represented 38% of listed
Some areas had more than a 30% lower transplant rate for females
American Journal of Transplantationpatients in the pre-MELD era and 35% in the MELD era.
The team found that females had significantly lower covariate-adjusted transplant rates in the pre-MELD era, and in the MELD era.
In the MELD era, the disparity in transplant rate for females increased as waiting list mortality risk increased, particularly for MELD scores of 15 or more.
Substantial geographic variation in sex-based differences in transplant rates was observed.
Some areas of the United States had more than a 30% lower covariate-adjusted transplant rate for females compared to males in the MELD era.
Dr Mathur's team concludes, "The disparity in liver transplant rates between females and males has increased in the MELD era."
"It is especially troubling that the disparity is magnified among patients with high MELD scores and in certain regions of the United States."
Am J Transplant 2011: 11(7):1435–144319 July 2011

Transplant error finds more at fault
A probe into the UPMC kidney transplant error found a nephrologist was also to blame
Tuesday, July 19, 2011
By Sean D. Hamill, Pittsburgh Post-Gazette
The results of a positive hepatitis C test sat in a living donor's medical record at UPMC for more than two months before her kidney was transplanted into a man who did not have the virus, according to the findings of a federal investigation into the case.
But despite at least six chances to review the test result and possibly stop the transplant because of the potentially lethal hepatitis C infecting the donor, none of the doctors or nurses involved in the case did so, according to the Centers for Medicare and Medicaid Services (CMS) investigation.
Though UPMC has pegged the blame for the bungled transplant on the lead surgeon, who was demoted, and the transplant coordinator, who was suspended, CMS investigators say the transplant nephrologist, who reviewed the donor's condition prior to surgery, also was at fault. It is not known if the nephrologist was also disciplined.
CMS's investigation found UPMC committed two violations that are "condition" level, which is the most serious level and require that CMS do a follow-up with the hospital to ensure it has corrected the problems. CMS also found six lesser violations -- two of them "standard" level and four "element" level.
In the report, UPMC detailed its plan of correction and the various steps it has taken to ensure such a mistake doesn't occur again, most of which included adding additional people and checks and balances.
Dr. Abhinav Humar, UPMC's transplant chief, said Monday in emailed responses to questions: "We are however confident that our plan of correction is sound as it was approved by UNOS."
UNOS is the United Network for Organ Sharing, which oversees the nation's transplant centers and on Thursday gave UPMC to go-ahead to restart its kidney program. It had been closed since May 6, when UPMC voluntarily shut down the program because of the medical error.
The investigation's findings were made following CMS's on-site investigation June 7 and 8 at UPMC Presbyterian-Shadyside hospital -- which is how CMS in its report described the location of the transplant center.
CMS did not have the power to decide if UPMC could continue to do transplants or not. But it does have the power to decide if transplant centers like UPMC's get Medicare funding for surgeries -- a financial blow that could shut down most kidney transplant programs since more than 50 percent of kidney transplants are funded by Medicare.
CMS's investigation found that the donor, a woman who did not know that she was hepatitis C positive, was tested the morning of Jan. 26 and the positive hepatitis C test results came back the same day "with recommended follow-up testing to be completed," according to CMS's report.
That information was found in the donor's medical record. But the report does not indicate if the test was done in-house, when UPMC received the report, or whether the results were returned in a paper form or sent electronically to UPMC's computers.
"From our perspective, it's really irrelevant whether it's from a printout from a computer or written in ink," said CMS spokesman Martin Kennedy.
CMS's mandate is to follow Medicare rules for the standard of care for patients, and the standard of care does not consider what role paper or electronic records played in a medical error, Mr. Kennedy said, just whether the information was documented.
CMS also does not dwell on why something happened, so the report also does not indicate what excuses, if any, the doctors and nurse gave investigators for why they missed the results.
Dr. Humar said Monday in his statements that there was no other explanation for why everyone missed the test result.
Last week, Dr. Humar said that despite UPMC having one of the nation's most celebrated electronic records system, the surgeon and nurse in the case missed the result in the paper record. The paper test result was scanned in and was part of the electronic medical record, he said, but it also was not checked.
Sources have said that there was a highlight on the hepatitis C test result when it was put into UPMC's electronic medical record system but that everyone involved in the case missed it.
After the test result came in Jan. 26, there were two forms in the medical record that should have included the hepatitis C result, but it was never included on them, CMS reported.
There were then two meetings -- Feb. 17 and March 23 -- of the multidisciplinary selection committee to review the donor's status, but she was given final approval at the March 23 meeting, with no documentation of her hepatic C status.
Then on April 1, the lead surgeon in the case -- whom sources say was nationally known laprascopic nephrectomy expert Henkie Tan -- completed a "Transplant Surgery Consultation" note, but he showed no documentation of evidence of a possible hepatitis C result.
The woman's kidney was then removed April 6 and transplanted into the man. The woman and the man are a couple who live together. It is not known if he has been infected with the virus.
UPMC discovered the woman was hepatitis C positive after a follow-up test on April 22 came back on May 2. Four days later, the living donor kidney program was shut down.
Sometime early in the process, the transplant nephrologist met with the patient for an evaluation. UPMC's own policies required the nephrologist to take part so that the donor is "screened and evaluated ... with a complete history and physical examination."
PDF
» See a draft of the Health and Human Services report on UPMC's live donor program.
In an interview by CMS investigators, the unnamed nephrologist said he "did not see the living donor patient or review the medical record after the initial visit."
CMS found that this was an element level violation on par with the errors by Dr. Tan and the nurse -- whom sources say is nationally known transplant coordinator Mimi Funovits.
But Dr. Humar said in an email reply to a question that UPMC's practice was for the nephrologist "to review the patient and the results that were available at the time of the initial evaluation. The donor surgeon and coordinator would review the labs that came back later, before verbally presenting it to the committee."
Dr. Humar wrote, "our protocol now has the coordinator, nephrologist and surgeon independently review all the tests when they are back before the patient is presented to the committee."
CMS will make an unannounced return visit to UPMC sometime within the 60 days after the report was completed on June 24.
Sean D. Hamill: shamill@post-gazette.com or 412-263-2579.
Read more: http://www.post-gazette.com/pg/11200/1161338-114.stm#ixzz1SYeiUcjv

Metastatic parasitic tumors are no contraindication to liver transplants
The latest issue of Liver Transplantation investigates wether possible recurrence of disease contraindicate liver transplants in patients with end-stage alveolar echinococcosis.
Liver transplantation is currently contraindicated in patients with residual or metastatic alveolar echinococcosis lesions.
Dr Dominique Angèle Vuitton and colleagues from France evaluated the long-term course of such patients who underwent liver transplantation and were subsequently treated with benzimidazoles.
Clinical, imaging, serological, and therapeutic data were collected from 5 patients with residual/recurrent AE lesions who survived for more than 15 years.
Since 2004, [18F]-2-fluoro-2-deoxyglucose (FDG)–positron emission tomography (PET) images were available, and the levels of serum antibodies against Echinococcus multilocularis–recombinant antigens were evaluated.
The research team found that median survival time after liver transplantation was 21 years.
Benzimidazoles can control recurrent lesions after transplant
Liver Transplantation
These patients were from a prospective cohort of 23 patients with AE who underwent liver transplantation.
The team observed that 5 of 8 patients with residual/recurrent alveolar echinococcosis, and 4 of 9 patients without residual/recurrent alveolar echinococcosis were alive in 2009.
The team found that high doses of immunosuppressive drugs, the late introduction of therapy with benzimidazoles, its withdrawal due to side effects, and nonadherence to this therapy adversely affected the prognosis.
Anti-Em2plus and anti-rEm18 Ab levels and standard FDG-PET enabled the efficacy of therapy on the growth of lesions to be assessed.
However, the research team noted that meaningful variations in antibody levels were observed below diagnostic cutoff values.
In monitoring alveolar echinococcosis lesions, the team observed that images of FDG uptake taken 3 hours after its injection were more sensitive than images obtained 1 hour after its injection.
Dr Vuitton and colleagues conclude, "Benzimidazoles can control residual/recurrent alveolar echinococcosis lesions after liver transplantation."
"Using anti-rEm18 or anti-Em2plus antibody levels and the delayed acquisition of FDG-PET images can improve the functional assessment of disease activity."
"The potential recurrence of disease, especially in patients with residual or metastatic alveolar echinococcosis lesions, should not be regarded as a contraindication to liver transplantaion when alveolar echinococcosis is considered to be lethal in the short term."
Liver Transplant 2011: 17(7): 855–6519 July 2011

Fatty Liver

Pierre Gholam, MD, discusses a particular case of non alcoholic fatty liver disease.
Photo: Pierre Gholam, MD
A 46 year old Caucasian female presents to the Liver Clinic with the finding of asymptomatic elevation of her liver enzymes. Blood tests had been checked routinely as part of an annual check up with her primary care physician. The patient has a history of hypertension for which she has been on Diovan for many years. She has been overweight for most of her adult life and currently weighs 186 pounds (Body Mass Index of 32). She does not report any abdominal pain, swelling in the lower extremities, excessive itching and has never been jaundiced. She had a cholecystectomy at age 27 but has never had a blood transfusion. She got a tattoo at a local parlor 5 years ago. She has never used illicit drugs. She is lifetime non smoker. She consumes 3 glasses of wine per week.
Her vital signs are notable for a blood pressure of 150/90 but are otherwise unremarkable.
On physical exam, she has an obese abdomen but no organomegaly. The rest of the exam is unremarkable. She states that she has had a mostly sedentary lifestyle over the past decade with steady weight gain during that period.
Repeat testing in liver clinic reveals the following: ALT 89, AS7 67, Alkaline Phosphatase 82, Total Bilirubin 0.4, Albumin 4.0. Additional work up in liver clinic includes serological testing for viral hepatitis B and C which is negative. Testing for the autoimmune makers Anti-Nuclear Antibody (ANA) and Anti Smooth Muscle Antibody (ASMA) shows no detectable titers. Her ferritin is mildly elevated at 321. Transferrin saturation is normal at 33%. Ceruloplasmin and Alpha One Anti-trypsin levels are normal.
Ultrasound of the liver reveals diffuse increase in echogenicity consistent with fatty infiltration.
She returns to the office following the completion of her work up to discuss the results. She is told that, in the presence of sonographic findings consistent with fatty infiltration and in the absence of heavy alcohol consumption and any other causes of chronic liver disease, the most likely diagnosis is Non Alcoholic Fatty Liver Disease (NAFLD). NAFLD is a common condition affecting about 1 in 5 Americans. Risk factors for NAFLD include obesity as well as metabolic risk factors namely hypertension, hypertriglyceridemia and hyperglycemia. Mild elevations in ferritin are not uncommon in NAFLD and do not usually reflect iron overload. NAFLD encompasses a spectrum of disease severity ranging from simple triglyceride deposition in the liver with no evidence of inflammation or scarring to a more progressive condition associated with inflammation of liver cells and progressive fibrosis which can lead to cirrhosis. The latter is known as Non Alcoholic Steatohepatitis (NASH). An exact estimate of the prevalence of NASH is not known but it is thought to occur in about 3-7% of the general population. Risk factors for NASH appear to include diabetes and older age. Currently, the only test that can distinguish between NASH and simple fatty liver is a liver biopsy which also provides prognostic information.
Unfortunately, there are no current proven therapies for NASH. Vitamin E appears to confer some benefit in a randomized controlled trial but the risks and benefits of long term vitamin E therapy need to be considered before such intervention is implemented. PPAR-gamma agonists such as pioglitazone and rosiglitazone may provide some improvement in histology while on therapy but also result in net weight gain and may have additional adverse events with prolonged therapy. Diet and exercise is advised as it appears to be a promising intervention and would also improve her cardiovascular risk.
She decides to pursue a liver biopsy which shows some lobular inflammation and pericellular fibrosis consistent with mild NASH. She is also placed on a statin for an elevated LDL which is safe in the setting of chronic liver disease as long as liver enzymes are appropriately monitored and therapy stopped if ALT increases 3 fold or more from its baseline. Her liver enzymes remain stable while being monitored during statin therapy. A year later, she has lost 25 pounds through diet and exercise and her ALT is 61. The plan is to follow her in clinic every 6 months and enroll her in clinical trials for NASH as they become available.
Dr. Pierre Gholam is Medical Director, Liver Disease Center of Excellence, Digestive Health Institute, University Hospitals in Cleveland. He is also an assistant professor at Case Western Reserve University.
MD News July/August 2011, Cleveland/Akron/Canton

Tim Horton's worker diagnosed with Hep A
A Tim Horton's employee in Labrador City, N.L., is confirmed to have Hepatitis A, prompting health officials to offer the vaccine free to the coffeeshop's customers.
The staffer recently returned from out of the country, said Labrador-Grenfell Health in a news release.
"While we believe the risk to the public is low, anyone who consumed food and/or beverages from Tim Horton's from July 3 to July 6, 2011, and experiences symptoms over the next six weeks should see their family doctor," said Medical Officer of Health Dr. Ada Bennett.
Hepatitis A is a liver disease caused by a virus transmitted through contaminated food or water. Symptoms are generally mild and may include fever, tiredness, loss of appetite, diarrhea, nausea, abdominal discomfort, joint pain, darkening of the urine and yellowing of the skin or eyes (i.e., jaundice). Most people fully recover in a few weeks without any long-term effects.
Anyone who has already received the two-dose Hepatitis A vaccine or the three-dose Twinrix vaccine doesn't require any further immunization.

HIV

Antiretroviral treatment is HIV prevention: The proof is here
A special press conference at the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention will today feature a panel consisting of researchers from the CDC TDF2 study, the Partners PrEP Study and the HPTN 052 study.

Medicines Patent Pool Licenses First HIV and HBV Drugs
Full story: HIV and Hepatitis
UNITAID and the Medicines Patent Pool -- an initiative to make drugs more widely available at reduced cost -- announced its first pharmaceutical company agreement

Stem Cells

Opinion: Stem cell clinics ripping off patients
By Arthur Caplan, Ph.D.
COMMENTARY
No one likes a bully. Intimidation is a rotten way to get what you want. Yet, incredibly, that is exactly what some in the stem cell therapy industry are trying to do to a group of scientists trying to speak up about the often fraudulent nature of their business. There has been a lot of publicity about stem cells in biomedical research over the past few years. Only a few days ago a 36-year old patient with end-stage esophageal cancer was given an artificial windpipe made from a synthetic scaffold that had been seeded with his own stem cells.
Yankee pitcher Bartolo Colon, who suffered from a series of arm and shoulder injuries that sidelined him for more than a year, found his way to a little-known clinic in the Dominican Republic to pursue an emerging treatment. He had stem cells, made from his fat and bone marrow, shot into his arm. This highly experimental procedure has been shown to work so far in race horses. Colon has been back pitching and doing well....Continue Reading...

Adult-Derived Stem Cells Could Pave The Way For New Treatment Of Diabetes
Stem cells from early embryos can be coaxed into becoming a diverse array of specialized cells to revive and repair different areas of the body. Therapies based on these stem cells have long been contemplated for the treatment of diabetes, but have been held back by medical and ethical drawbacks. Now researchers at Tel Aviv University are capitalizing on the "memories" of stem cells generated from adult cells to bring new hope to sufferers of juvenile or type 1 diabetes, which affects three million people in the United States. Prof. Shimon Efrat of TAU's Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine, says these "induced pluripotent stem cells," derived from adult cells, represent an embryonic-like state. To some degree, he found, the cells retain a "memory" of what they once were - when created from pancreatic beta cells, the cells responsible for the production of insulin, these pluripotent cells prove more efficient than their embryonic counterparts in creating insulin-producing cells. Prof. Efrat says that this discovery promises to advance the development of cell replacement therapy for diabetics, possibly leading to an effective alternative to organ transplants. His research, pursued with his PhD student Holger Russ and in collaboration with Prof. Nissim Benvenisty and Ori Bar-Nur from the Hebrew University, was recently published in the journal Cell Stem Cell. Choosing adult over embryo Diabetes is caused by the destruction of pancreatic beta cells, and the idea of using stem cells as a method of correcting this deficiency in diabetic patients is nothing new. Embryonic stem cells have been the preferred choice, since they can be easily grown in the lab in almost unlimited numbers, and can form any cell type in the body. "But turning them into pancreatic beta cells is not an easy task," says Prof. Efrat, who notes that the process has remained inefficient despite a long struggle for improvement. Instead, he was inspired to test the efficiency of pluripotent stem cells that were derived from adult insulin-producing cells themselves. "When generated from human beta cells, pluriponent stem cells maintain a 'memory' of their origins, in the proteins bound to their genes," says Prof. Efrat. As though receiving a prompt from their past life, the cells already have some understanding of their purpose, making them more efficient in generating beta cells. Avoiding the transplant list Today, diabetics can opt for an organ transplant to replace damaged pancreatic beta cells, but that is a long and arduous road, limited by a shortage of organ donors, and patients can wait years. Currently, Prof. Efrat notes, the ratio of donors to potential recipients is about one to 1,000. A better option is sorely needed, and stem cells present a viable hope for the future. The discovery made by Prof. Efrat and his fellow researchers was licensed to a start-up company that promotes the research and development of technology of innovative treatments for diabetes.
Source: George Hunka American Friends of Tel Aviv University

Off The Cuff

Personalized medicine
ScienceDaily (July 18, 2011) — Although personalized medicine is a term used in science and medicine that holds significant promise of improved treatment, it may set up unrealistic expectations in patients, states an editorial in CMAJ (Canadian Medical Association Journal).
The mapping of the human genome was a major scientific milestone that has opened the door to new approaches to understand and treat disease. Cancer and cardiovascular disease are two areas in which genomics are showing promise for treatment advances, although challenges remain.
"Despite a few successes, patients would be foolhardy to expect anything more than a small number of additional tailored interventions," write Dr. George Browman, University of British Columbia and member of CMAJ's editorial board, and Dr. Paul Hébert, Editor-in-Chief, CMAJ, with the editorial advisory team. "They should not expect the cures for all common diseases."
The authors write that a simple, targeted solution is unrealistic because of the complex interplay between genes, proteins, cell metabolism and environmental influences. Also, there is a significant time lag in getting new therapies into practice.
"For the public at large, the term 'personalized medicine' does not spark images of abstract science and technology," they state. "The image it creates is just the opposite: most people would conceive personalized medicine to be what's commonly called patient-centred or person-centred care -- a more humane, empathetic approach to care focused on individuals and shaped by their needs and circumstances, rather than cell-level scientific manipulations."
The authors call for increased focus and awareness on the person as a whole and how biology, environment and needs interact.

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