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GS-7977 Plus Ribavirin Will Displace the Current Proprietary Clinical Gold Standard, Telaprevir in Combination with Peg-IFNa/Ribavirin, According to Findings from Decision Resources

Stanford scientists model hepatitis C treatment options

Hepatitis C Articles 

Updates @ NATAP

Phase III BMS-790052 Add-On to Peg-Interferon Alfa-2a and Ribavirin in Naive Hepatitis C - (02/27/12)

APASL: Antiviral Activity of GS-9451, an HCV Specific NS3 Protease Inhibitor, in a Three-Day, Dose-Ranging, Monotherapy Study in Patients with Genotype 1 Hepatitis C Infection - (02/27/12)

APASL: Antiviral Activity and Characterization of Resistance in a Three Day Dose Ranging Study of GS-5885, a Novel HCV NS5A inhibitor - (02/27/12)

APASL: PEGINTERFERON LAMBDA-1a(LAMBDA) SHOWS SUPERIOR VIRAL RESPONSE WITH IMPROVED SAFETY AND TOLERABILITY VERSUS PEGINTERFERON ALFA-2a(ALFA-2a) IN PATIENTS WITH CHRONIC HCV INFECTION (G1/2/3/4): EMERGE PHASE 2bTHROUGH WEEK 12RESULTS - (02/27/12)

APASL: SAFETY AND EFFICACY OF PEGINTERFERON LAMBDA-1a (LAMBDA) COMPARED WITH PEGINTERFERON ALFA-2a (ALFA-2a) IN HCV-INFECTED PATIENTS (G1/2/3) WITH COMPENSATED CIRRHOSIS: EMERGE PHASE 2b EFFICACY AND SAFETY RESULTS THROUGH WEEK 12 - (02/27/12)

New HCV Drug Promising for Difficult-to-Treat Genotype 1 Patients

Robust Responses, But Some Treatment Failures; Adverse Events Raise Questions

by Christina Frangou 

Source: IDSE ISSUE: FEBRUARY 2012 | VOLUME: 1

San Francisco—A second Phase IIb study of a new oral therapy for hepatitis C, PSI-7977, taken once daily, increased sustained virologic response (SVR) rates up to 91% in patients with difficult-to-treat hepatitis C virus (HCV) genotype 1 infection—a substantial improvement from the 50% reported in patients who received standard peginterferon and ribavirin (Peg-IFN/RBV) therapy. The study also showed significant advantages of PSI-7977 in patients who typically have poor responses to interferon.

Investigators say the new drug has the potential to dramatically alter the treatment paradigm for patients with hepatitis C virus (HCV) infection. “That’s true for all genotypes and all patients,” said lead author Eric J. Lawitz, MD, medical director of Alamo Medical Research, in San Antonio.
Patients who have the interleukin-28B (IL28B) TT genotype generally have a much lower chance of responding to IFN than people with the CC or CT genotypes. Yet in this study, these patients achieved high SVR rates to PSI-7977. Of the 13 patients who carried the TT allele, all tested negative for HCV by the third week of treatment and achieved SVR at week 12.
“The high SVR of greater than 90% in HCV genotype 1 patients was independent of predictors of poor IFN response,” Dr. Lawitz said.

The trial—known as PROTON—was the second Phase IIb study of PSI-7977 presented at The Liver Meeting 2011. In the first study, the ELECTRON study, investigators reported that 100% of patients who received PSI-7977 without IFN achieved an SVR (see “New Polymerase Inhibitor Could Become Cornerstone of Interferon-free HCV Treatment Regimen”).

Results from the two studies sparked considerable excitement among attendees of The Liver Meeting about this investigational therapy.

“I think it’s proof of principle that the proper combination of direct-acting antivirals can, in fact, produce enough suppression of viral replication to result in extinction of infection without the benefit of a broadly acting antiviral like IFN,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, in Boston.
The PROTON study was designed to examine dose-dependent response rates for PSI-7977 in HCV genotype 1–infected patients. Investigators enrolled 121 treatment-naive patients with this genotype in a randomized, double-blind, placebo-controlled, dose-ranging fashion. All patients were at least 18 years old with an HCV RNA level of 50,000 IU/mL or greater, platelets greater than 90,000/mm³, neutrophils greater than 1,500/mm³, and a hemoglobin level of at least 11 g/dL, with no evidence of cirrhosis.

Trial participants were randomized in a 2:2:1 ratio to one of three treatment arms: PSI-7977 200 or 400 mg daily in combination with IFN and RBV (n=48 and n=47, respectively) or Peg-IFN/RBV alone (n=26). Patients in the PSI-7977 arms received triple therapy for 12 weeks, followed by an additional 12 weeks of Peg-IFN/RBV. All patients who achieved early rapid virologic response (RVR) discontinued therapy at 24 weeks, while all others continued therapy for a total of 48 weeks. Patients in the IFN and RBV arm received treatment for 48 weeks.

Analysis showed robust response rates among all PSI-7977 patients regardless of dose. Patients who received 200 mg daily showed an RVR rate of 98%, an early RVR rate of 98% and an end-of-treatment response rate of 91%. Patients receiving 400 mg showed a 98% RVR, 91% early RVR and 91% end-of treatment response through 24 weeks. In contrast, response rates among patients who received Peg-IFN/RBV alone were 19%, 50% and 50%, respectively.

In an as-treated analysis of patients who received at least eight weeks of PSI-7977, 88% of those in the 200-mg arm and 98% of those in the 400-mg arm achieved an SVR at 12 weeks.

Several failures occurred in the trial.
Three patients in the 200-mg arm who had viral suppression during the first 12 weeks of treatment with PSI-7977 experienced a virologic breakthrough during the follow-up treatment period with Peg-IFN/RBV. No breakthroughs were observed among patients in the 400-mg arm, although one patient had a viral relapse before SVR at 4 weeks. “This suggests that [the] 400-mg dose achieved a deeper viral suppression,” said Dr. Lawitz.

The extent of viral suppression may be the key difference between the 200- and 400-mg doses of PSI-7977, he said. PSI-7977 at a 400-mg dose may provide a more thorough viral suppression with lower risk for virologic breakthrough. Patients in both groups quickly became negative for HCV RNA after PSI-7977 was started, but patients who received the 200-mg dose had more virologic breakthroughs after the PSI-7977 therapy was completed. No patient in either treatment arm developed an S282T mutation.

Investigators said they were pleased to see that the adverse events reported in the PROTON trial were typical of those seen with Peg-IFN/RBV treatment, except for a small increase in insomnia. Overall, 15% of patients in the 400-mg arm and 8% of those in the Peg-IFN/RBV–only arm reported insomnia.

More cases of neutropenia occurred with PSI-7977 than with Peg-IFN/RBV, but it was unlikely that the difference was significant, said the investigators. Three patients who received PSI-7977 had grade IV neutropenia compared with none in the Peg-IFN/RBV arm. However, the numbers of patients were too low to result in meaningful conclusions.

Still, experts say more patients must be studied to confirm that the new drug is safe.

“The numbers for neutropenia and anemia are confusing to me. They are small numbers but I’m still not certain about the safety of this compound,” said Paul Pockros, MD, head of gastroenterology and hepatology, and director of the Center for Liver Diseases, Scripps Clinic, in La Jolla, Calif.
The study was not powered to detect differences in neutropenia and anemia between the three groups, but differences would be statistically significant if 1,000 patients had participated in the trial, Dr. Pockros explained. “Is this drug going to be safe in 1,000 patients?” he asked.

Dr. Lawitz said investigators would expect to see a difference in adverse events between the 200- and 400-mg arms in this trial if PSI-7977 increased the risk for neutropenia, but that was not the case, with more neutropenia and anemia occurring in the patients receiving the lower dose.
“To me, that suggests that this is a trial with small numbers, and when we get larger numbers the difference is probably not going to be significant,” he said.

PSI 7977, in combination with RBV as dual therapy, is set to enter Phase III trials

In The News

Math Can Save Tylenol Overdose Patients
New Way for Docs to Predict Who Needs Liver Transplants

Source University Of Utah

Feb. 27, 2012 – University of Utah mathematicians developed a set of calculus equations to make it easier for doctors to save Tylenol overdose patients by quickly estimating how much painkiller they took, when they consumed it and whether they will require a liver transplant to survive.

“It’s an opportunity to use mathematical methods to improve medical practice and save lives,” says Fred Adler, a professor of mathematics and biology and coauthor of a study that developed and tested the new method.

The study of acetaminophen – the generic pain and fever medicine sold as Tylenol and in many other nonprescription and prescription drugs – was set for publication within a week in Hepatology, a journal about liver function and disease.

Adler, math doctoral student Chris Remien and their colleagues showed that using only four common medical lab tests – known as AST, ALT, INR and creatinine – the equations can quickly and accurately predict which Tylenol overdose patients will survive with medical treatment and which will die unless they receive a liver transplant.

The researchers analyzed the records of 53 acetaminophen overdose patients treated at the University of Utah’s University Hospital to test the equations and show they quickly and accurately predicted, in retrospect, which patients survived and which died.

Speed is essential in listing acute liver failure patients as candidates for transplant, says study coauthor Norman Sussman, a former University of Utah liver doctor now at the Baylor College of Medicine in Houston.

If a doctor is uncertain and starts to treat an acetaminophen-poisoning patient with the antidote to combat liver failure – even though the patient may not survive with such medicine – their odds for getting a new liver are reduced.

“If I wait another day until I list them for transplant, the chance of getting a liver is that much lower,” Sussman says. “If you’re going to get someone transplanted, you have to do it fast or you miss the boat. The patient may pass the window when transplants can be done. They become too sick and can’t stand the transplant.”

The new method using calculus equations will let doctors rapidly determine if a patient can survive with antidote treatment or will die unless they get a transplant.

The study urges another clinical trial to prove the new method’s usefulness. Sussman plans to start a one-year prospective trial testing the method on 50 patients at the University of Utah and three hospitals in Houston.

If that trial proves the method can accurately predict ahead of time how Tylenol-poisoning patients will fare, “we believe we could create a tool available and immediately useful to clinicians,” Sussman says. Adler foresees a smartphone application.

Adler, Remien and Sussman conducted the study with University of Utah hepatologist Terry Box and Lindsey Waddoups, clinical research coordinator for the University of Utah’s gastroenterology division. The research was funded by a National Science Foundation grant to the University of Utah’s program in mathematical biology.

Painkiller Can Be a Killer

Acetaminophen – the primary generic name for the drug also known generically as APAP and paracetemol – is found in prescription medicines such as Tylenol with Codeine, Percocet or Vicodin, and in dozens of over-the-counter medications, including Tylenol, Anacin, Pediacare, Triaminic and combination cold medications like Nyquil.

Many people don’t realize the common analgesic can destroy the liver and kill at only about five times the recommended dosage – a narrow margin in medical terms.

“Acetaminophen is the leading cause of acute liver injury in the United States, accounting for some 56,000 emergency room visits, 26,000 hospital admissions and about 500 deaths annually,” Adler and his coauthors write.

The current maximum dose of acetaminophen is 4 grams (4,000 milligrams or eight 500 milligram tablets, for example) in 24 hours. There is not a lot of room for error between that 4-gram maximum and the 6 grams that can cause liver damage or the 20 grams that are considered likely to destroy 70 percent of liver cells and cause death.

Acetaminophen overdoses can be treated successfully if an antidote named N-acetylcysteine (N-Ac or “nack”) is administered within roughly 24 hours. After a certain time post-overdose, treatment becomes futile and the patient will die without a transplant.

Yet many overdose patients are confused or comatose, unable to say how much acetaminophen they took or when they took it, making it tough to predict their prognosis.

Life-Saving Calculus

The new method uses eight main “differential equations” – basic calculus equations that describe how changes in one variable affects changes in another variable over time. The equations simulate or “model,” step-by-step, how acetaminophen is metabolized in the liver, including production of NAPQI, a liver-destroying substance.

That makes it the first known “dynamical” model based on real biology – a contrast to the existing “statistical” method for determining how overdose patients fare.

The statistical method – known as the King’s College Criteria (KCC) – estimates who is likely to survive or die from acetaminophen toxicity using correlations between INR and creatinine lab tests and which patients actually did live or die in the past. The King’s College Criteria predict liver failure if INR exceeds 6.4, creatinine exceeds 3.4 and there is confusion, altered consciousness or coma due to liver damage.

The problem, says Adler, is the criteria “look at the statistical relationship between lab test results and patient outcome without understanding what’s happening inside the liver. It’s just statistics.”

The new method “tracks how the liver’s health changes over time,” he says.

The new equations use patients’ measured levels of AST, ALT and INR to estimate when they consumed acetaminophen and how much they took. By also considering creatinine levels, the new method accurately predicts which Tylenol overdose patients will survive with treatment and which will require a liver transplant to avoid death.

AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are enzymes that are released by dying liver cells, so higher levels indicate liver damage. INR (prothrombin time/international normalized ratio) measures how fast blood clots. Liver cells make clotting factors, so if the liver malfunctions, clotting is slower. Creatinine is a measure of kidney dysfunction, in this case secondary to liver damage.

Sussman says the King’s College Criteria are outdated and have grown less useful over time. When a patient arrives with lab results indicating liver failure, “your first decision has to be, ‘Do I list this patient for transplant?’” he says. “That was the purpose of the King’s College Criteria. You need to make an immediate decision: Do I think this patient will live or die? If I think they’ll live, I’m going to treat them [with the antidote]. If they’re going to die, the next question is, are they a candidate for transplant?”

“Our goal was to try to trace it back to: when did the damage start?,” he adds. “Once you know that and the peak damage reflected in the ALT, then you have the tools to predict survival or death.”

Of people who are liver transplant candidates, those with acute liver failure – half due to acetaminophen poisoning – go straight to the top of the liver transplant list, ahead of the vast majority of candidates who have chronic liver failure, such as from alcoholism, Sussman says.

Predicting Overdose Outcomes

The 53 patients whose records were analyzed for the new study varied in alcohol use, malnutrition status and whether they took too much acetaminophen in a suicide attempt, an accidental single overdose or a chronic, multiple-day overdose.

Two patients got liver transplants and were excluded from the analysis “because we don’t know if they would have died or recovered without transplant,” Remien says.

Of the 51 remaining patients, eight died and 43 survived. The study showed that when AST, ALT and INR tests on admission were crunched through the equations, and when creatinine levels exceeded 3.4, the method was highly accurate in predicting, retrospectively, whether overdose patients lived or died. Specifically, the method had:
100 percent sensitivity, meaning the method correctly predicted the deaths of all eight patients who actually had died. By comparison, the King’s College Criteria predicted only one of the eight deaths.
67 percent “positive predictive value,” meaning eight patients died out of 12 deaths predicted by the method.
91 percent specificity, meaning the method predicted 39 patients would survive out of the 43 that really did survive.
100 percent “negative predictive value,” meaning the method predicted 39 patients would survive and those 39 did survive.

Sussman says there were multiple reasons for the eight deaths. Some patients arrived too late to be treated, even by a transplant, and others didn’t qualify as transplant candidates, perhaps due to serious drug or alcohol abuse and lack of family support.

About 16,000 people now are on the liver transplant waiting list in the United States. About 5,000 to 6,600 Americans get liver transplants each year.

Adler emphasizes the new method is based on a typical acute liver failure patient and may need refinement to better predict the prognoses of certain special patients, including those taking other drugs, with chronic alcohol use or suffering anorexia.

Hepatitis C: A Deadly Disease with Few Symptoms
Source
A new study says deaths from Hepatitis C are increasing, especially among people 45 to 64 years old

A disease you may never have heard of now kills more Americans than HIV, the virus that causes AIDS, according to date from the Centers for Disease Control  (CDC). That disease is hepatitis C, a major cause of liver cancer and cirrhosis, which the CDC estimates has infected about 3.2 million Americans.

According to a new report published in the Annals of Internal Medicine, the CDC says that deaths from hepatitis C have been steadily increasing in the last decade with most of the deaths among people aged 45 to 64 years old. The virus is spread through injection drug use, blood transfusions received before screenings began in 1992 and through sexual contact. It can also be passed from mothers to newborns.
A major reason hepatitis C is so deadly is its stealth nature. Up to three-quarters of infected adults are unaware they are suffering from the virus because there are often no symptoms until the liver is damaged, which can take more than a decade.
 Some people do have symptoms, which can include:

• Jaundice (yellowish eyes or skin)
• Difficulty stopping bleeding and easy bruising
• Swollen stomach or ankles
• Fatigue
• Upset stomach
• Fever
• Loss of appetite
• Diarrhea
• Light-colored stools and dark yellow urine

Some public health specialists are recommending a one-time screening for all people born between 1945 and 1965 even if they have no symptoms. If you think you may have been exposed to Hepatitis C, ask your doctor for a screening blood test.
Chronic Hepatitis C can be treated effectively with a combination of two protease inhibitors called boceprevir and telaprevir along with interferon and an antiviral drug. The treatment generally takes 24 to 48 weeks.

Healthy You

Statin labels will come with new safety warnings

By Saundra Young, CNN

Source: CNN Health

updated 3:55 PM EST, Tue February 28, 2012

Washington (CNN) -- An entire class of statin drugs will get new labels that alert the public to safety concerns, the Food and Drug Administration announced Tuesday.
Statins, which treat cholesterol, now will come with labels that include a warning that the drugs, taken by almost 32 million Americans, can cause memory loss and confusion. The FDA says reports in general have not been serious, and the symptoms subsided when patients stopped taking the medications.

The new labeling will also warn doctors and patients that statins can cause hyperglycemia, an increase in blood sugar levels and increase the risk of Type 2 diabetes.
The FDA will no longer recommend routine and periodic monitoring of liver enzymes of patients taking statins. Instead, it said liver enzyme tests should be performed before a patient starts taking statins, and then only when clinically indicated. That's because according to the FDA, serious injury to the liver is rare, and routine monitoring doesn't detect or prevent it. The new label will tell patients who experience fatigue, loss of appetite, dark urine, upper stomach pain or jaundice to notify their doctor immediately.

There also will be a label change specific to lovastatin (Mevacor). Certain medicines interact with this particular statin, increasing the risk of myopathy, or muscle damage. The agency says some drugs should never be taken with Mevacor including protease inhibitors, a class of HIV drugs and certain drugs used to treat bacterial and fungal infections.

Continue Reading..

Sleeping Pills Linked to Almost Fourfold Increase in Death Risk
Source-ABC News 

By LARA SALAHI (@larasalahiabc)

Feb. 27, 2012 

Sleeping pills prescribed by your physician are supposed to ward off the myriad health problems that come with lack of sleep.

But adults who take sleeping pills in even small numbers over their lifetimes may be nearly four times more likely to die earlier compared to those who are not prescribed sleeping pills, according to new findings published Monday in the British Medical Journal. And those prescribed sleeping pills may also be more likely to be diagnosed with cancer, the study found.
Researchers looked at electronic medical records of nearly 35,000 patients, fewer than half of whom took such FDA-approved sleep medications as Ambien, Restoril, Lunesta, and Sonata. They found that even those who look fewer than 18 sleeping pills a year were at greater risk of death, compared to those who were not prescribed sleeping aids.

Continue reading.. 


HCV Blogs - For Your Reading Pleasure

Welcome to another edition of the Question of the Week.
Source: Oh My Aches and Pains

As you may already know, I started Hepatitis C treatment this past Thursday.  That means I am now on a very strict schedule when it comes to taking the 12 pills a day and the one shot a week that comprise the treatment.  And this new emphasis on being "on time" presents a big new challenge for me too! 

Stress, Stress And More Stress
Source : Suck It 'n' See - Living With Hep C

Mr C has been down the past few days. Waiting for his CRB to come through so he can start work, being skint and "having nothing to look forward to" is taking its toll. Thankfully, his health is remaining stable and his knee is back on the mend again.