Liver cancer without cirrhosis surprisingly common: Is NAFLD the cause?

Liver cancer without cirrhosis surprisingly common: Is NAFLD the cause?

By: PATRICE WENDLING, Family Practice News

May. 30, 2014 

Vitals 

Key clinical point: A significant proportion of NAFLD-related HCC patients have no cirrhosis at presentation, so clinicians need to maintain a high index of suspicion. 
Major finding: Up to 13% of patients with HCC in the United States may not have underlying cirrhosis.
Data source: A retrospective cohort study of 1,500 veterans with HCC.
Disclosures: Dr. Mittal reported no conflicting interests. Lead author Dr. El-Serag reported consulting fees and grant/research support from Gilead Sciences.

CHICAGO – A full 13% of patients diagnosed with hepatocellular carcinoma did not have underlying cirrhosis in a national sample of 1,500 veterans.

Although hepatocellular carcinoma (HCC) in patients with cirrhosis typically arises against a background of alcohol abuse or hepatitis C virus infection, this entity was strongly associated with nonalcoholic fatty liver disease (NAFLD) and idiopathic HCC.

"While this represents a small proportion, this poses a logistical problem for HCC surveillance, given the large population with NAFLD and no real identifying features of who is going to develop HCC," Dr. Sahil Mittal said at the annual Digestive Disease Week.



Patrice Wendling/Frontline Medical News
Dr. Sahil Mittal

Despite a threefold increase in HCC in the United States over the last 3 decades and emerging evidence for NAFLD presenting in the absence of cirrhosis, this is the first study to assess the prevalence and risk factors for HCC without cirrhosis in a national sample of HCC patients, he said.

The investigators, led by Dr. Hashem B. El-Serag, section chief, gastroenterology and hepatology, Baylor College of Medicine, Houston, performed a chart review of 1,500 veterans with a confirmed diagnosis of HCC randomly selected between 2005 and 2011. Of these, cirrhosis was absent in 43 (3%), highly improbable in 151 (10%), and definite in 1,201 (80%), with the diagnosis unclear because of insufficient data in 105 (7%).

As expected, HCC patients with cirrhosis were significantly more likely than those with no or probable no cirrhosis to abuse alcohol (84% vs. 67.4% vs. 63.6%; P less than .01) and to have hepatitis C infection (72.2% vs. 42% vs. 44.4%; P less than .01), said Dr. Mittal, also with Baylor’s College of Medicine.

Hepatitis B infection was similar in all three groups (5% vs. 4.7% vs. 2%).

In contrast, NAFLD was more common in patients with no or probably no cirrhosis than in those with cirrhosis (14% vs. 20.5% vs. 5.8%; P less than .01), as was idiopathic HCC (18.6% vs. 27.8% vs. 8.2%; P less than .01), he said.

"NAFLD is associated with a significantly increased risk of HCC in the absence of cirrhosis, compared with hepatitis C or alcohol," he said.

With regard to clinical factors, sex and race did not differ between groups. However, the no and probably no cirrhosis patients were significantly older than were those with HCC accompanied by cirrhosis (65.5 years, vs. 69.7 years vs. 62.6 years) and significantly more likely to have comorbidities associated with metabolic syndrome, such as hypertension (88.4% vs. 86.8% vs. 72.6%), myocardial infarction (11.6% vs. 18.5% vs. 7.5%), and peripheral vascular disease (11.6% vs. 20% vs. 9.5%), Dr. Mittal reported. The differences among groups were statistically significant with P values of less than .01.

The investigators then performed logistic regression analysis to examine predictors of HCC without cirrhosis. After adjustment for confounders, they found NAFLD was more than threefold likely (odds ratio, 3.1) and idiopathic HCC more than twofold likely (OR, 2.8) in patients with HCC without cirrhosis, compared with patients with hepatitis C–related HCC.

This entity of HCC in the absence of cirrhosis was also associated with the metabolic syndrome–related comorbidities of hypertension (OR, 1.8) and myocardial infarction (OR, 1.8).

The findings suggest that the risk of HCC in patients with NAFLD is increased not only because of progression to cirrhosis, but possibly through other alternative noncirrhosis pathways, Dr. Mittal said in an interview. This has important implications for understanding the pathogenesis of HCC, as well as for HCC screening in NAFLD patients.

"Due to the high prevalence of NAFLD in the general population, conventional screening by ultrasonography may not be a feasible strategy, especially if one cannot rely on cirrhosis as the main predisposing lesion to HCC," he said. "Studies are needed to identify risk factors and biomarkers that can identify NAFLD patients at higher risk of developing HCC. Future research is also needed to investigate the role of chemoprevention."

Dr. Mittal reported no conflicting interests. Lead author Dr. El-Serag reported consulting fees and grant/research support from Gilead Sciences.

pwendling@frontlinemedcom.com

Sovaldi : A medical breakthrough actually worth paying for

Joel W. Hay: A medical breakthrough actually worth paying for
By JOEL W. HAY / Contributing Writer
Published: May 29, 2014 Updated: 5:55 p.m.

“Are you experiencing ‘Restless Eyebrow Syndrome?’ Ask your doctor if Firmbrowlta is right for you.”

Pharmaceutical companies are often criticized for charging high prices for medications that add negligible benefits and sometimes for even concocting questionable new conditions and syndromes just to sell their latest drug. There is, however, a new class of drugs entering the market that represents a major breakthrough in treating and even curing a disease plaguing tens of millions of patients worldwide.

Hepatitis C, or HCV, is responsible for more deaths in the United States than HIV/AIDS and Hepatitis B combined. It is also the leading cause of liver cancer, as well as the No. 1 reason for liver transplants in the U.S. Some 3.2 million individuals in the U.S. are infected with HCV, close to five times the number who have HIV. Given the nature of HCV, often referred to as the “silent killer,” only half of these individuals have been tested and know their status, about a third have been referred to care, and only 5 percent to 6 percent have been successfully treated.

On top of these sobering statistics, the existing treatment options for individuals with hepatitis C are, literally, nauseating. The current standard of care for HCV patients is a cocktail of three drugs, one being interferon, which must be administered in weekly injections and is often accompanied by unendurable side effects of anemia, rash, depression, and flu-like symptoms. These side effects can persist throughout the entire 48 weeks required by current treatments.

However, there’s light at the end of the tunnel for Americans suffering from the disease. There are currently a host of new oral, injection-free, interferon-free treatments in clinical trials. This is very big news for those currently infected with HCV.

It is expected that a large portion of the patients that were previously referred for care, but unsuccessfully treated, will now have a better (and far more pleasant) chance at being cured.

Of course, these new breakthrough treatments will come at a price, and a very high one at that. In fact, the cost of these all-oral treatments is expected to be around $150,000 for a 12-week regimen. Sovaldi, the first of the new class of HCV drugs to be approved by the FDA, costs $1,000 per pill.

So is this yet another case of Big Pharma holding patients hostage with their colossal prices? Not quite. If price is truly a reflection of value (as it should be), then it should come as no surprise that these new oral treatments hit the market at a higher price than their clinically inferior predecessors.

After all, the new therapies are proving to have substantially higher efficacy, with shorter treatment duration, and fewer undesirable consequences than the interferon-based therapies. We conducted an economic analysis showing that these drugs actually deliver excellent health care value despite their high cost, because they prevent liver disease, liver failure, cancer and premature death.

However, the value of these new drugs doesn’t stop at the patient level. A recent study in the Journal of Hepatology estimated the total cost of HCV in the United States to be $6.5 billion, which is expected to rise to $9.1 billion by 2024. Much of this cost is due to infected individuals foregoing (or failing) the treatments, and consequently transitioning into very costly health states such as cirrhosis, liver cancer, and eventual liver transplants.

This new generation of treatments will therefore not only have an unprecedented impact on patient health, but in the long run also help tackle the enormous economic and medical burden associated with HCV.

Moreover, with a large percentage of infected Americans being institutionalized, or on some type of government program, including Obamacare, this is something every taxpayer should appreciate.

The arrival of this new class of drugs cannot come soon enough, and, apparently, Medicare agrees. In a statement last week, Medicare officials embraced the guidelines laid out by the American Association for the Study of Liver Diseases, which recommend the use of these new oral therapies – even though the FDA has not yet approved most of the drugs.

We shouldn’t let price sticker shock distract us from the true value of new HCV drugs, as they could very well eradicate hepatitis C entirely. Yes, these drugs are expensive but much less expensive than treating progressive liver disease for a lifetime. If we don’t give reasonable economic rewards to pharmaceutical companies when they invent genuine breakthrough products they’ll go back to concocting treatments for silly things like “restless eyebrow syndrome.”

Joel W. Hay is a professor at the USC Schaeffer Center for Health Policy and Economics.

Related: Reducing the cost of new hepatitis C drugs 
An index of articles pointing the reader to current information and controversy over the high price of Solvadi -
Why does Gilead's Sovaldi cost $84K in the U.S. and $57K in Britain?
At $1,000 per pill, new Hepatitis C drug has insurers and CCOs scratching their heads
The Price is Right: New Hepatitis C Drug is Really a Priceless Breakthrough....

Curing Hepatitis C - U.S. Health Care System Is 'Penny Wise & Pound Foolish'

U.S. Health Care System Is 'Penny Wise & Pound Foolish'

Thu, 05/29/2014 - 2:58pm

The Pharmaceutical Research and Manufacturers of America (PhRMA) President and CEO John Castellani released the following statement on the cost and value of medicines:

“It is penny wise and pound foolish to focus solely on the price of a new medicine while completely ignoring the value it provides to patients and the health care system broadly. Curing Hepatitis C not only dramatically improves patients’ lives, but has the potential to save the U.S. health care system as much as $9 billion per year by preventing expensive hospitalizations and avoiding thousands of liver transplants that routinely cost over $500,000 each. The health improvements and cost-savings new medicines provide explain why, despite repeated claims to the contrary, prescription drug spending continues to be a small and declining share of overall health care cost growth – a reality that often gets ignored in the public debate about drug costs.

“The increased attention on the cost of new medicines is being fueled by the fact that we have an outdated insurance model that is forcing patients to pay an ever-growing share of their prescription drug costs. Insurers are increasingly imposing unprecedented cost-sharing on patients that deters them from utilizing the medicines they need to manage – or even cure – their disease while covering the vast majority of costs of more expensive hospitalizations and services these medicines could prevent. We have a Blockbuster insurance model in a Netflix world and patients are being harmed as a result.

“The country needs to have a much broader discussion on how to best create a more sustainable, 21st century health care system that protects patients and incentivizes the development of new treatments that can do for other diseases what medicines have done for HIV, Hepatitis C, and many forms of cancer.”

Date: May 29, 2014
Source: PhRMA

FDA UPDATE - Sometimes Drugs and the Liver Don't Mix

Sometimes Drugs and the Liver Don't Mix

The liver is a remarkable, if underappreciated, organ. It turns the nutrients in our diets to substances the body can use and converts toxins into harmless substances or makes sure they are removed from the body

When the liver is working well, our metabolism hums along in equilibrium. But drugs and dietary supplements can sometimes wreak havoc with that system, leading to dangerous liver problems. The Food and Drug Administration (FDA) is working to prevent drug-induced liver injuries.

“Any drug may cause dangerous liver problems but, fortunately, such problems only occur rarely,” says John R. Senior, M.D., an FDA gastrointestinal medical reviewer and consultant in hepatology, which includes study of the liver. “It is challenging to predict how drugs will affect the liver because each patient is different in how they respond to a given drug. Our goal is to prevent the toxicity of drugs.”

Acute liver failure is a rapid deterioration of the organ’s ability to function. Data suggest that prescription and over-the-counter drugs (OTC) and dietary supplements cause more acute liver failure cases than all other reasons combined.

FDA has identified several instances of liver damage caused by dietary supplements. For example, the agency has issued public health warnings and sent warning letters to companies marketing supplements for weight loss and muscle building. In one instance, a Texas-based company agreed to recall and destroy certain dietary supplement products after discovering a link between the supplement and cases of liver failure and non-viral hepatitis.

No Easy Way to Identify the Vulnerable
Finding even a few cases of serious liver toxicity in clinical trial subjects exposed to a drug can be a reason for discontinuing the trial. Also, cases of serious liver toxicity have prompted FDA to request sponsors to withdraw their approved drugs from the market.
Senior explains there’s no easy way to identify the people who might be vulnerable. “The drug-disease relationship is not so simple,” he says. “Identifying drugs that may cause liver injury only solves half the problem. The other half: Drugs that appear to be safe in pre-clinical studies still may be harmful to some patients.”

Meanwhile, we have an aging population that is more dependent on drugs. “The more medications you take, the more likely you are to have trouble,” Senior says.

A few drugs are toxic to the liver only when used in excess. One example is acetaminophen.
“Acetaminophen when used as labeled is generally considered to be safe. But overdoses of acetaminophen are the most common cause of drug-related liver injury, whether these occur accidentally or otherwise,” says Mark Avigan, M.D., a medical reviewer at FDA with a background in gastroenterology and hepatology. “With acetaminophen overdoses, some people get a more severe reaction than others.”

Acetaminophen is an active ingredient in hundreds of OTC and prescription medicines commonly used to treat musculoskeletal pain and fever, allergies, coughing, colds, flu, and even sleeplessness. Overdoses leading to serious liver injury have resulted from consumers inadvertently taking both OTC and prescription drugs containing acetaminophen.

Inadvertent overdoses with prescription drugs that contain acetaminophen and a narcotic have been responsible for a significant proportion of all the cases of acetaminophen-related liver failure in the United States, some of which have resulted in liver transplant or death.FDA has taken steps to keep consumers safe. In early 2014, FDA requested withdrawal of over 120 applications for combination prescription acetaminophen drug products containing more than 325 mg acetaminophen per dosage unit. The agency also has reminded pharmacists and physicians to stop prescribing and dispensing combination prescription acetaminophen products containing more than 325 mg. It is FDA’s understanding that as a result, all manufacturers have discontinued marketing combination prescription drug products that contain more than 325 mg of acetaminophen.

Some antibiotics and nonsteroidal anti-inflammatory medications also have been tied to liver damage.
Hepatitis, a liver inflammation, can have several potential causes. Drugs may induce a form of hepatitis that closely resembles viral hepatitis (liver inflammation caused by viral infection). 

Signs and Symptoms
How can you recognize the signs of liver problems?
Avigan says you might feel tired and have a poor appetite. In more extreme cases, your eyes and skin become yellowish (jaundice) and your skin becomes very itchy. “Your skin itches because the liver is not properly clearing toxins from the body,” he says.

When patients taking a drug they have not used before get those symptoms, they should seek immediate medical attention and stop using that drug if it is identified as the cause, Avigan cautions.
If the symptoms surface and the patient has been taking a medication for a long time, there could be another cause. Senior says it’s difficult to be certain that the symptoms were caused by a drug and not something else. Obesity and excessive consumption of alcohol also can damage the liver.

Considering Risks and Benefits
Patients should discuss the risks and benefits of any drug with their doctors when they start treatment, Avigan says. They should also discuss dietary supplements with their clinician before taking them.
Some life-saving drugs are the only options for very sick patients.

“Before approving or denying approval of a drug, we evaluate its risks and work to identify its liver injury potential, even if only one in 10,000 people will be badly affected,” Avigan says. “With some drugs, for example for cancer patients, the benefits of treatment might far outweigh the risks.”

The liver can regenerate even when 65% of it is destroyed or surgically removed, as in a cancer treatment. This versatile organ is often capable of adapting and becoming tolerant of various foreign agents, including drug products. But if the liver isn’t healthy, complications from drug interactions can be even worse.

This article appears on FDA's Consumer Updates page, which features the latest on all FDA-regulated products.
May 28, 2014

How Long Should HCV Treatment Last? Study Suggests Answers Are Complex

How Long Should HCV Treatment Last? Study Suggests Answers Are Complex

Translational researchers tracked in real-time how virus replicates and how drug clears HCV from liver, plasma
Released: 5/28/2014 1:00 PM EDT
Source Newsroom: University at Buffalo

Newswise — BUFFALO, N.Y. – As new treatments for hepatitis C virus (HCV) are approved, biomedical scientists are exploring their mechanisms and what they reveal about the virus. An online publication this month in Hepatology is the first to report real-time tracking of viral decay in the liver and blood in 15 patients with HCV.

Led by Andrew H. Talal, MD, University at Buffalo professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition and corresponding author, the study is the first to trace in real-time how the drug telaprevir inhibits viral replication in the liver and how it clears HCV from infected cells and plasma of infected patients.
The study was sponsored by Vertex Pharmaceuticals, which makes telaprevir, an HCV protease inhibitor.

“Our findings begin to define for how long patients may need to be treated in order to achieve viral eradication,” explained Talal.

“There has been no precise definition of the duration of treatment based upon serial measurements of the virus in the liver,” said Talal. “This is the first time that serial measurements in the liver have been performed during antiviral therapy.”

In previous studies, a more invasive procedure – core needle biopsy – was used to sample the liver in HCV infection. In the current study, fine needle aspiration was used; this method is better tolerated by patients and allows for repeated sampling at more time points than core needle biopsy.
“Fine needle aspiration enables us to sample the liver repeatedly during the course of treatment, to better understand what’s happening with the virus, how these drugs work and how to tailor therapy to the patient,” Talal explained.

In the study, conducted at Weill Cornell Medical College in New York City, 15 patients with chronic HCV infection were treated with telaprevir-based triple therapy (consisting of telaprevir/pegylated interferon alfa/ribavirin), an HCV treatment regimen that was approved by the Food and Drug Administration in 2011.

Fine needle aspiration of the liver was performed before treatment on all 15 patients and at these intervals following treatment: ten hours, on days 4 and 15, and at week eight. Viral kinetics, resistance patterns, drug concentrations and host transcription profiles were measured.
Of particular interest were the study’s findings regarding the rate of decay for viral ribonucleic acid (RNA), an indicator of how quickly the virus is being eradicated.

“We found that HCV RNA decay in the liver lagged behind that in the peripheral blood, which has implications for how long the virus may persist in the body and the possible duration of treatment needed,” said Talal.

They also found higher levels of the drug in blood than in the liver.

“These findings can affect the duration of therapy,” said Talal, adding that they can also help to identify when drug-resistant variants of the virus emerge in blood and in the liver.

The findings also may have relevance to the development of other methods of treating HCV, such as vaccines that could be used to control the infection, he added.

Talal conducts research on HCV in the Clinical and Translational Research Center in the School of Medicine and Biomedical Sciences and he sees patients as a physician with UBMD, the physician practice plan of the UB medical school. Talal has had additional research projects funded by Vertex Pharmaceuticals.

In addition to Talal, who has an adjunct appointment at Weill Cornell, co-authors of the paper are: Rositsa B. Dimova, PhD, research assistant professor in the departments of medicine and biostatistics at UB; Marija Zeremski, PhD, senior research associate at Weill Cornell and research assistant professor of medicine at UB; Christine M. Cervini, RN, staff associate in medicine and Ira M. Jacobson, MD, chief of the division of gastroenterology and hepatology, both of Weill Cornell; Eileen Z. Zhang, Min Jiang, Marina S. Penney, James C. Sullivan, Martyn C. Botfield, Ananthsrinivas Chakilam and Rishikesh Sawant, all of Vertex Pharmaceuticals and Ann D. Kwong, of InnovaTID Pharmaceuticals, formerly of Vertex Pharmaceuticals. Jacobson has served as a paid consultant to Vertex.

Insurers scrutinize drug costs after $84,000 Sovaldi surprise

Insurers scrutinize drug costs after $84,000 Sovaldi surprise

By Caroline Humer and Deena Beasley

NEW YORK/LOS ANGELES Wed May 28, 2014 4:46pm EDT

(Reuters) - Shocked by the rapid adoption of a new $84,000 hepatitis C treatment, U.S. health insurers are trying to make sure they aren’t blindsided by other drugs being developed and are looking for ways to limit their use from the day they are launched.

Manufacturer Gilead Sciences Inc says 30,000 people have received hepatitis drug Sovaldi so far, and that sales hit a record-breaking $2.3 billion within a few months. The treatment, typically 84 pills taken over 12 weeks, completely cures the disease in more than 90 percent of patients.

As many as 3.2 million Americans are infected by hepatitis C, and the cost of giving most of them Sovaldi would surpass $200 billion. Some insurers have already put conditions on who can get the drug, and states including California and Texas have slowed or put treatment on hold while they study what to do.

Insurers warned that these unforeseen costs will cut 2014 earnings and require rate hikes. Now, at industry conferences, in conversations with investors, and in private, they are pushing Gilead’s rivals, a group that includes AbbVie Inc, Merck & Co and Bristol-Myers Squibb Co, to discount their own new hepatitis C treatments when they come to market starting this fall. Such a high-profile campaign by insurers before drugs are even approved is new.

They are also signaling they will restrict who can get coverage for new cholesterol drugs being developed by Amgen Inc, Pfizer Inc and a partnership of Regeneron Pharmaceuticals Inc and Sanofi SA.

By law, insurers cannot deny access to new drugs if they represent a real improvement for patients, leaving drug companies with the upper hand in most price discussions. When comparable competitors, or a generic version is on the market about a decade later, insurers have room to steer patients away from the new drugs, and pharmaceutical companies cut prices steeply and give big discounts.

But insurers have not faced such a highly effective drug aimed at a widespread disease that is so expensive and so quickly adopted. The previous record for a drug reaching blockbuster status was set in 2011, when hepatitis C therapy Incivek from Vertex Pharmaceuticals raked in $1.56 billion for the entire year. Sovaldi has sold more in a quarter of the time.

As a result, insurers are taking a harder line on which patients should get Sovaldi, based on the drug’s clinical data.

Sovaldi is “game-changing” for insurers' thinking, said John Whang, co-president of Reimbursement Intelligence, a consulting firm that helps pharmaceutical companies set prices. The only way for them to respond is to control the volume of treatment used, he said.

PUBLIC SHAMING

In a sign of how serious the industry has become, the largest insurer lobby group last week took Gilead to task at a public conference.

“The company in this case is asking for a blank check and you can’t give anyone anymore a blank check because it will blow up family budgets, state Medicaid budgets, employer costs and wreak havoc on the federal debt," said Karen Ignagni, president of America’s Health Insurance Plans.

Gilead argues that Sovaldi’s price is worth it, since it will replace even costlier spending on hospital visits and treatments for cirrhosis or liver failure. It has not budged on price for the hepatitis C drug, although Gregg Alton, Gilead's executive vice president for corporate and medical affairs, acknowledged that insurers are going to start negotiating.

U.S. drug spending reached a record $329 billion in 2013, driven by a double-digit increase in prices for new cancer, HIV and hepatitis C therapies. Express Scripts, the nation’s largest pharmacy benefit manager, expects spending on such specialty drugs to rise an additional 63 percent from 2014 to 2016, driven by an 1,800 percent increase in hepatitis C drug costs.

Successful drugs can cost $1 billion to bring to market, including spending on research, development and marketing. Supporters of drug companies say big advances necessitate high prices.

"We are the only country in the world that pays exorbitant prices to provide innovation first here, but that's what we need and that's what the American people have come to expect," said Richard Burr, a Republican Senator from North Carolina who has spent decades working on bipartisan health bills.

LIMITING USE

Hepatitis C complications can take years to develop, which gives insurers and government health agencies leeway to determine when treatment should start.

Many insurers, which manage most of the 150 million people covered by employer-based plans as well as some government Medicare and Medicaid plans, require patients to get authorization before using Sovaldi. Some limit the drug to patients with a certain genetic type of the disease.

Express Scripts has been pushing for all but the sickest patients to wait for new therapies that are expected to compete head-to-head with Sovaldi late this year. It is also pressing rival manufacturers for low prices, hoping to avoid the shock of Sovaldi, which sped through trials and regulatory approval and caught insurers by surprise.

"In this particular case there was very little discussion pre-launch. But other companies are now already discussing potential future price points in response," said Steve Miller, Express Scripts Chief Medical Officer.

AbbVie and Merck both declined to comment on whether discussions with insurers about their new drugs were underway.

Gilead, which says it discussed the Sovaldi launch with insurers, is in talks over which patients should be treated with its next hepatitis C pill. That will be a two-drug combination that will eliminate the need for a companion drug that nearly doubles Sovaldi’s current total cost.

Industry analysts expect the company will price it closer to Sovaldi’s $84,000 than to the $150,000 cost of a combination of Sovaldi and a Johnson & Johnson drug that some doctors prescribe.

Mick Kolassa, chairman of pricing consultancy Medical Marketing Economics, in Oxford, Mississippi, who advises pharma companies, says insurers are being aggressive. “We are seeing some of them step up and flex their muscles,” he said.

CHOLESTEROL DRUGS IN SIGHT

More scrutiny of new pricing is likely ahead as the country comes to terms with how it should pay for expensive drugs, according to John Castellani, Chief Executive Officer of leading drug industry lobby group Pharmaceutical Research and Manufacturers of America or PhRMA.

Sovaldi has shown that patients are bearing too much of the drug's costs because of rising co-payments, co-insurance and deductibles, he told Reuters, laying the blame on factors controlled by insurance companies.

But patient advocates are not choosing sides yet, which may have the effect of giving insurers room for action.

“I think the fault lies with both the for-profit insurers and the drug companies," said Anne Donnelly, director of healthcare policy at the San Francisco-based Project Inform, which advocates for hepatitis C patients. The system has not changed to reflect the impact of new effective, expensive drugs, she said.

The next big price battle centers on a new class of cholesterol drugs known as PCSK9 inhibitors, which help the liver to clear “bad” LDL cholesterol from the blood.

Large-scale studies show the new drugs can help patients who cannot tolerate, or get enough benefit from, the most widely-used cholesterol drugs, statins. The PCSK9 therapies are expected to cost thousands of dollars a year, far above the price of statins sold as generics.

Drugmakers are expected to push for the new medicines to be used by 7 million to 20 million people, or up to 30 percent of the 71 million Americans with high cholesterol. Insurers already are questioning whether the estimates of use are legitimate.

“There is really no need to take these new medications and spread them out across a larger community of people who will respond to existing treatments, many of which are generic,” Aetna Inc’s National Medical Director for Pharmacy Policy Ed Pezalla said in an interview.

(The story corrects to Reimbursement Intelligence from Intelligence Reimbursement, to Whang as co-president from president, to Steve Miller from Stuart Miller)

(Editing by Michele Gershberg and Peter Henderson)

Related - May 28
The Price is Right: New Hepatitis C Drug is Really a Priceless Breakthrough
As an infectious disease physician I greet the release of path-breaking new treatments for any infecting pathogen with excitement. Such innovations represents another instance of man’s mind succeeding in the continual war with microbes.

Hepatitis C is a scourge that is the leading cause for liver transplantation infecting close to 4 million Americans and over 180 million individuals globally. The historical treatments for this virus have been long, cumbersome, and laden with horrible side effects. The newest drug in our armamentarium, Sovaldi (sofosbuvir), offers the promise of substantially shortening treatment regimens while, at the same time, enhancing treatment response. In short, this is a wonder drug that we all should be grateful to scientists for developing and pharmaceutical companies for funding..

‘National Dialogue’ Urged On Cost Of New Hepatitis C Drug  
By Julie Appleby | Kaiser Health News, Wednesday, May 28, 3:55 PM
The outcry continues over the $1,000-a-pill hepatitis C drug made by California-based Gilead Sciences.  While the drug is a significant advance over older treatments for the viral liver disease, the price set by the company “represents an abuse of market power,” said John Rother, president and CEO of the National Coalition on Health Care, which includes businesses, unions, insurers, consumers and some drugmakers, including Teva Pharmaceuticals and the Generic Pharmaceutical Association  On Wednesday, the group urged a “national dialogue” on the cost, saying Sovaldi’s price tag threatens the budgets of government run-health programs as well as the premiums for everyone who has private insurance...

Related: Reducing the cost of new hepatitis C drugs 
An index of articles pointing the reader to current information and controversy over the high price of Solvadi. 

‘National Dialogue’ Urged On Cost Of New Hepatitis C Drug

‘National Dialogue’ Urged On Cost Of New Hepatitis C Drug

By Julie Appleby | Kaiser Health News, Wednesday, May 28, 3:55 PM

The outcry continues over the $1,000-a-pill hepatitis C drug made by California-based Gilead Sciences.

While the drug is a significant advance over older treatments for the viral liver disease, the price set by the company “represents an abuse of market power,” said John Rother, president and CEO of the National Coalition on Health Care, which includes businesses, unions, insurers, consumers and some drugmakers, including Teva Pharmaceuticals and the Generic Pharmaceutical Association

On Wednesday, the group urged a “national dialogue” on the cost, saying Sovaldi’s price tag threatens the budgets of government run-health programs as well as the premiums for everyone who has private insurance.

With more such “specialty drugs” in the pipeline for other conditions that affect millions of people, the group says the drug industry must find “a more sustainable approach” on prices for new products – although it stopped short of giving examples of how that might be done.
The U.S. currently spends more than $300 billion on pharmaceuticals each year.  Simply covering the cost of Sovaldi for the more than 3 million Americans who are estimated to have hepatitis C could double that.

Gilead has staunchly defended Sovaldi’s price, saying the cost – at least $84,000 for a typical patient – is justified because the drug is curative for many and could slow health spending on costly complications of hepatitis over time.

“Sovaldi … represents a finite cure, an important point to consider when comparing the price of a pill or bottle to the lifetime costs of treating a chronic disease,” said spokeswoman Cara Miller. Paying for the new drug will fall on private insurers, and taxpayers through government programs such as Medicaid and Medicare, and could also lead to higher premiums.

All insurers are currently setting guidelines for the use of Sovaldi and another new costly hepatitis C drug called Olysio. While some are making it broadly available, others are saying some patients with mild liver damage should wait for treatment. More hepatitis C drugs are expected on the market as early as this fall – and, unlike Sovaldi, may not require the use of additional drugs that add costs as well as difficult side effects.

The drug industry has long noted that prices reflect the cost of researching and developing drugs. The industry is on the offense, with its lobbying arm saying in a blog post Wednesday that prescription drugs account for only 9 cents of every dollar spent on health care. The Pharmaceutical Research and Manufacturers Association of America is also circulating charts this week touting advances in cancer treatments – and noting that the average sales price of cancer drugs covered by Medicare has not risen faster than medical inflation.

If all drugmakers were to justify high prices by saying their products could reduce costs over time by preventing complications, “it could bankrupt the system,” said Rother.

Rother says that officials from Gilead have talked with his group, but so far only in a “defensive” posture over the price. Instead, he wants them to “engage” in conversations about ways to lower the drug’s price.

The coalition joins others – notably pharmacy manager Express Scripts – in calling for a “national dialogue” on drug pricing, although it could not point to an example where that has lowered drug prices in the past.

Prices for drugs in the U.S. are generally what the market will bear – and the market is snapping up Sovaldi even at its high price.  In first quarter earnings, Gilead said the drug brought in $2.1 billion in revenue.

“This is an issue other countries have solved,” said Debra Whitman, executive vice president of policy at AARP and a board member of the coalition. She noted that Sovaldi costs $66,000 per 12-week treatment in Germany and $57,000 in Great Britain.

Among the differences in those countries is that regulators are far more involved in approving drugs for use in national health plans – and negotiating how much is paid for them. In England, for example, the cost as well as the effectiveness of drugs is part of the evaluation about whether to approve them for use in the national plan.

Rother said the coalition is not calling for price controls and doesn’t think Congress should get involved. “They don’t need to have a direct role,” said Rother. But, he cautioned, if negotiations with drugmakers fail, the industry will ultimately find itself facing lawmakers. “The hope is we can resolve this quickly and through the private sector,” he said.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation.

 http://www.washingtonpost.com/national/health-science/and8216national-dialogue-urged-on-cost-of-new-hepatitis-c-drug/2014/05/28/f437589a-e6a1-11e3-a70e-ea1863229397_story.html

Hepatitis C - Sofosbuvir-regimen outperformed other therapies in reducing liver complications

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Sofosbuvir-regimen outperformed other therapies in reducing liver complications in HCV patients
May 27, 2014
CHICAGO — Chronic hepatitis C virus-infected patients treated with a sofosbuvir-based regimen showed a reduced number of liver disease complications, compared with patients receiving other treatments, according to research presented at Digestive Disease Week 2014.

Sammy Saab, MD, MPH, AGAF, of UCLA Medical Center, and colleagues used a decision-analytic Markov model to compare health outcomes among chronic hepatitis C virus (HCV) patients with genotypes 1 to 4 who received a combination of sofosbuvir (SOF; Sovaldi, Gilead Sciences) and other therapies with HCV patients who did not. Outcome measures included complications resulting in mortality, liver transplantation, compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma.
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Nosocomial infections among cirrhotic patients increased, associated with mortality 

Singal AK. Aliment Pharmacol Ther. 2014;doi:10.1111/apt.12797.

The rates of hospitalized patients with cirrhosis who were diagnosed with bacterial infections have increased and contributed to overall mortality, according to data from a new study.

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Area poverty rate linked to incidence of certain cancers
May 27, 2014

Incidence of certain cancers in specific neighborhoods varied considerably based on the area’s poverty level, according to study results.

Researchers determined males were more sensitive to the associations between cancer rates and poverty, particularly for liver and interhepatic bile duct, lung and bronchus, anus, colon and rectum, oral cavity, pharynx and miscellaneous cancers.

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Sofosbuvir in the Treatment of Hepatitis C-A Review of Its Clinical Potential

Therapeutic Advances in Gastroenterology

Sofosbuvir, a NS5B Polymerase Inhibitor in the Treatment of Hepatitis C

A Review of Its Clinical Potential

Abstract
Treatment of chronic hepatitis C (HCV) is currently undergoing a significant change. Traditional interferon-based therapy has been limited by both efficacy and tolerability, and many direct acting antiviral (DAA) drugs are emerging. Sofosbuvir (GS-7977) is a HCV NS5B nucleotide polymerase inhibitor that has now been evaluated extensively in phase II and III interferon-free clinical trials. The focus of this review is on the clinical potential of sofosbuvir in the treatment of HCV. Sofosbuvir has a pan-genotypic effect on HCV, although viral genotype-specific differences in sustained virological response (SVR) have emerged in phase III clinical trials. Sofosbuvir has been studied both as dual therapy with ribavirin and also as triple therapy with either NS5A inhibitors or a protease inhibitor. High rates of SVR have been reported with these interferon-free combinations, particularly with genotypes 1 and 2, and the safety profile has been very favourable in both cirrhotic and noncirrhotic patients, without issues of viral resistance. Interferon-free, once-daily treatment of HCV is now becoming a reality.

Introduction
Chronic hepatitis C virus (HCV) infection is a cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. For the past two decades, interferon-based therapy has been the cornerstone of HCV treatment, but success has been limited by poor tolerability and suboptimal sustained virological response (SVR) rates, even when combined with ribavirin. Boceprevir and telaprevir were the first direct-acting antiviral (DAA) drugs to be approved for the treatment of HCV in 2011, and resulted in improved SVR rates from approximately 40–44% to 68–75% in treatment-naïve patients with genotype 1 HCV [Jacobson et al. 2011; Poordad et al. 2011]. However, because of rapid emergence of viral resistance with protease inhibitor monotherapy, these agents are only effective when used as triple therapy in conjunction with peginterferon and ribavirin. Consequently the use of these NS3/4 protease inhibitors adds to the adverse event profile of peginterferon plus ribavirin, particularly in patients with cirrhosis where cytopaenias and other serious adverse events represent a significant safety concern [Fontaine et al. 2013].

There are three major classes of DAA drugs currently in phase III clinical trials: NS3/4A protease inhibitors, NS5A inhibitors and NS5B polymerase inhibitors, which can be subdivided into nucleoside inhibitors or nonnucleoside inhibitors. The NS5B polymerase is responsible for viral RNA replication, and the catalytic site of the NS5B protein is highly conserved across the different HCV genotypes, making nucleos(t)ide inhibitors that target this protein appealing as a treatment option. The nucleoside analogues interfere with the viral lifecycle by inducing a chain termination event and breaking transcription of the viral polyprotein [Sofia et al. 2010]. In general terms, they also have reasonably high potency and a high barrier to viral resistance. In contrast, the nonnucleoside inhibitors that target allosteric sites on NS5B tend to display lower potency and a low barrier to viral resistance.

Sofosbuvir, also known as GS-7977 (and previously known as PSI-7977), is a nucleotide inhibitor of NS5B and this review will consider its clinical potential as a promising drug for the treatment of HCV infection.

Pharmacology of Sofosbuvir
Sofosbuvir is a prodrug of 2'-deoxy-2'-fluoro- 2'-C-methyluridine monophosphate that is converted within hepatocytes to its active uridine triphosphate form, causing chain termination during replication of the viral genome [Murakami et al. 2010]. In vitro, the active triphosphate inhibits recombinant NS5B polymerases from HCV genotypes 1-4 with similar half maximum inhibitory concentration values for each genotype, indicating broad activity across HCV genotypes [Lam et al. 2012]. The chemistry of sofosbuvir has previously been reviewed [Herbst and Reddy, 2013] and will not be reviewed in detail in this paper.

Sofosbuvir is primarily eliminated from the body via the kidney as GS-331007 (formerly called PSI-6206), an inactive nucleoside metabolite. Single-dose pharmacokinetics of sofosbuvir were studied in subjects with normal renal function (estimated glomerular filtration rate [eGFR] > 80 ml/min), mild (eGFR 50–80 ml/min), moderate (eGFR 30–49 ml/min) and severe (eGFR < 30 ml/min) renal impairment. The area under the curve (AUC) of GS-331007 and, to a lesser extent, sofosbuvir increased with decreased renal status. There was a linear relationship between GS-331007 renal clearance and creatinine clearance. Subjects with mild, moderate and severe renal impairment had approximately 56%, 90% and 456% higher GS-331007 AUC, respectively, than subjects with normal renal function [Cornpropst et al. 2012]. Further studies are required to determine the safe use of sofosbuvir in patients with severe renal impairment.

In a study of hepatic impairment, HCV-infected subjects with moderate hepatic impairment were administered sofosbuvir 400 mg QD for 7 days; sofosbuvir was generally well tolerated and resulted in similar systemic exposure to GS-331007 as noncirrhotic subjects. Significant declines in HCV RNA were observed in all subjects over 7 days of dosing [Lawitz et al. 2012]. Therefore, dose modifications are not required in hepatic impairment.

There is no clinically significant interaction of sofosbuvir with food, or with coadministration of methadone, cyclosporine or tacrolimus [Denning et al. 2011; Mathias et al. 2012].

Clinical Trial Data
In the initial phase II studies, sofosbuvir was evaluated in combination with peginterferon and ribavirin (PEG/RBV). In a 28-day, dose-ranging trial in subjects infected with genotype 1 HCV, 64 patients were randomized to receive one of three once-daily doses of oral sofosbuvir (100, 200 or 400 mg) or placebo plus peginterferon and ribavirin for 28 days, after which all patients continued to receive peginterferon and ribavirin for a further 44 weeks [ClinicalTrials.gov identifier: NCT01054729].

Patients in the sofosbuvir/peginterferon/ribavirin groups showed mean reductions in HCV RNA >5 log10IU/ml for all doses versus 2.8 log10IU/ml for placebo/peginterferon/ribavirin after 28 days. Although response during the 28-day sofosbuvir/placebo phase of the study was nearly identical for all three sofosbuvir groups, differences emerged during the peginterferon and ribavirin phase of dosing, with SVR24 of 56% for the 100 mg group as compared with 83% and 80% for the 200 and 400 mg groups, respectively [Rodriguez-Torres et al. 2013]. The 200 and 400 mg doses were therefore selected for further evaluation in phase IIb trials.

PROTON
PROTON was a double-blind, randomized, placebo- controlled, dose-ranging phase II study that demonstrated that sofosbuvir was highly effective against genotypes 1, 2 and 3 HCV when used in combination with peginterferon and ribavirin as 12-week triple therapy, followed by additional peginterferon and ribavirin in the genotype 1 patients, with SVR12 results greater than 90% in all sofosbuvir-containing arms of the study [Lawitz et al. 2013c] (Table 1) - See Below.

ATOMIC
The ATOMIC study explored shorter treatment durations of sofosbuvir-based triple therapy, and randomized 316 treatment-naïve patients with genotype 1 HCV into three treatment arms that included sofosbuvir 400 mg plus peginterferon and ribavirin therapy of 12 or 24 weeks duration, and one arm who received sofosbuvir triple therapy for 12 weeks, and then subjects were randomized to receive a further 12 weeks of sofosbuvir alone or with ribavirin [Kowdley et al. 2013]. A total of 11 patients with genotype 4 and 5 patients with genotype 6 were also included in cohort B of the study (Table 1)-See Below, SVR rates remained greater than 90% in all arms of this study, with minimal differences in SVR seen in patients with factors traditionally associated with reduced response to interferon-based therapy such as high baseline viral load, patients with non-CC IL28B genotypes or bridging fibrosis on liver biopsy [Kowdley et al. 2013]. The findings also suggested that there was no additional benefit from extending sofosbuvir triple therapy beyond 12 weeks.

ELECTRON
Following on from PROTON and ATOMIC, the ELECTRON study evaluated sofosbuvir in interferon- sparing and interferon-free regimens for the treatment of HCV infection in noncirrhotic patients (Table 1)-See Below. In the initial cohort, 40 treatment- naïve patients with genotype 2 or 3 HCV were randomized to four groups, all containing sofosbuvir 400 mg/day and weight-based ribavirin. Three of the groups also received peginterferon for 4, 8 or 12 weeks. All 40 patients had a SVR at week 24, irrespective of whether or not they received peginterferon [Gane et al. 2013c]. Two additional cohorts of patients with genotype 2 or 3 infection received either sofosbuvir monotherapy for 12 weeks, resulting in 60% SVR24, or sofosbuvir-based triple therapy for 8 weeks, with 100% SVR24.

Two groups of patients with HCV genotype 1 infection also received sofosbuvir and ribavirin for 12 weeks without peginterferon, including 25 treatment-naïve patients and 10 prior null responders to peginterferon. Among patients with genotype 1 infection, 84% of previously untreated patients and 10% of prior null responders achieved SVR24 in this interferonfree regimen. Again, a high proportion of patients had a non-CC IL28B genotype, and 89% were infected with genotype 1a which has been associated with lower response rates to other DAA therapy such as telaprevir- or boceprevir-based triple therapy. This study was proof of concept that SVR can be obtained with sofosbuvir-based, interferon-free regimens in genotypes 1, 2 and 3 HCV infection, and also demonstrated an ongoing role of ribavirin in preventing relapse after treatment.

Later cohorts of ELECTRON explored sofosbuvir/ribavirin in treatment-experienced patients with genotypes 2 and 3 and also cohorts with shorter durations of treatment and lower doses of ribavirin [ClinicalTrials.gov identifier: NCT01260350], although these results have only been partially published in abstract form [Gane et al. 2012], and weight-based ribavirin dosing has been used for ongoing clinical development with sofosbuvir-dual therapy. Patients with genotype 1 HCV were also treated with triple therapy combinations of sofosbuvir/ribavirin and additional DAA drugs including the NS5A inhibitor ledipasvir (LDV; GS-5885) in a once-daily fixed dose combination, or the HCV NS5B nonnucleoside inhibitor GS9669. With both of these triple therapy combinations, excellent SVR rates have been reported in both treatment-naïve patients and also null responders who are traditionally resistant to other forms of DAA triple therapy with first-generation protease inhibitors [Gane et al. 2013a; Gane et al. 2013b] (Table 1)-See Below.

LONESTAR
The LONESTAR study continued to evaluate different lengths of therapy (8 or 12 weeks) with the fixed-dose combination of sofosbuvir and ledipasvir with or without ribavirin in patients with genotype 1 HCV (Table 1). Cohorts included both treatment-naïve GT1 patients, and also 40 patients who had previously failed therapy with an HCV-specific protease inhibitor-based regimen. Half of these patients had compensated cirrhosis. SVR4 rates of at least 95% in all cohorts have been reported in a recent Gilead press release [Gilead Sciences, 2013], and phase III trials are planned with the fixed-dose combination of sofosbuvir and ledipasvir.

Daclatasvir and Sofosbuvir
Two clinical trials have evaluated sofosbuvir in combination with the NS5A inhibitor daclatasvir. The first trial reported was of treatment-naïve patients with HCV genotypes 1, 2 and 3 who were randomized to daclatasvir plus sofosbuvir with or without ribavirin for a total treatment duration of 24 weeks although some arms had a 1-week sofosbuvir lead-in phase before the daclatasvir was added. SVR12 was achieved in 100% of genotype 1 patients and 86–100% of patients in the genotype 2/3 cohort [Sulkowski et al. 2012].

The combination of daclatasvir and sofosbuvir has also been evaluated in 41 HCV genotype 1 patients who had previously failed protease-inhibitor- based triple therapy with either telaprevir or boceprevir and were treated with 24 weeks of sofosbuvir plus daclatasvir, with or without ribavirin [Sulkowski et al. 2013]. Impressively, SVR12 rates of 95–100% were obtained, whether or not the combination included ribavirin, demonstrating that this combination of sofosbuvir with an NS5A inhibitor is an effective therapy even in people with NS3A protease inhibitor resistance.

COSMOS
The COSMOS study is evaluating a once-daily regimen of the NS3/4A protease inhibitor simeprevir (TMC435) plus sofosbuvir with or without ribavirin for 12 or 24 weeks in HCV genotype 1 patients (Table 1). Cohort 1 consists of patients with prior null response to peginterferon with mild to moderate fibrosis, and preliminary results from the 12-week cohort have been recently presented showing SVR4 rates of 96% and 93% for patients with and without ribavirin, respectively [Lawitz et al. 2013b]. Cohort 2 includes both peginterferon null responders and treatment-naïve patients with advanced fibrosis and a recent press release reports SVR4 results of 96–100% in the 12-week group [Medivir, 2013].

Phase III Trials of Sofosbuvir
Four phase III trials of sofosbuvir have been published to date, all evaluating sofosbuvir 400 mg plus ribavirin (weight-based dosing) for at least 12 weeks in patients with chronic HCV (Table 2)-See Below.

In the FISSION study, 499 treatment-naïve patients with genotype 2 or 3 HCV were randomized to sofosbuvir 400 mg plus ribavirin for 12 weeks or peginterferon plus ribavirin for 24 weeks in a noninferiority trial. In this trial, despite a marked difference in the RVR rates (99% versus 67%, respectively), the SVR12 rates were identical at 67% [Lawitz et al. 2013d] (Table 2)-See Below. Notably, in this study there was a marked difference in response rates between patients with genotype 2 (97% SVR 12) and genotype 3 (56% SVR12) HCV, and between cirrhotic (47% SVR12) and noncirrhotic (72% SVR12) patients.

The NEUTRINO study was a 12-week open label study of sofosbuvir plus ribavirin in treatment naive patients with HCV genotype 1, 4, 5 or 6 (of whom 98% had genotype 1 or 4). SVR12 rates of 90% were observed overall, with 81% response rates in genotype 1 with cirrhosis. These cirrhotic patients also had extremely low rates of treatment discontinuation of only 2%, suggesting that this combination is safe and extremely well tolerated even in cirrhotic patients [Lawitz et al. 2013d].
POSITRON evaluated sofosbuvir plus ribavirin compared with placebo in patients with genotype 2 and 3 HCV in whom interferon was not an option (previously intolerant of interferon, unwilling or unable to take interferon). Overall SVR12 rates in the sofosbuvir/ribavirin group were higher than in FISSION (78%), possibly because of the higher proportion of genotype 2 patients who again demonstrated significantly higher SVR12 rates (92%) than genotype 3 (68%). Degree of liver fibrosis did not appear to significantly influence outcomes in genotype 2 patients (94% SVR12 even in those with cirrhosis), but in genotype 3 patients, SVR12 rates were low at 21% in patients with cirrhosis [Jacobson et al. 2013].

FUSION
The FUSION study was a blinded, active-control study involving patients with genotype 2 or 3 HCV who had not had a response to prior treatment with an interferon-containing regimen. Patients were randomly assigned to either 12 weeks of sofosbuvir and ribavirin followed by 4 weeks of matching placebo, or 16 weeks of sofosbuvir and ribavirin. One third of participants were cirrhotic. Overall rates of SVR were significantly higher in the 16-week arm (73%) than in the 12-week arm (50%), and again the genotype 2 patients had higher SVR rates (86% and 94% for 12 and 16 weeks, respectively) than genotype 3 patients (30% and 62% respectively for 12 and 16 weeks) [Jacobson et al. 2013]. Cirrhosis was associated with a decreased rate of SVR, particularly in genotype 3 receiving 12 weeks of therapy rather than 16 weeks (SVR 19% versus 61%). In genotype 2 patients SVR rates ranged from 60% to 78% in cirrhotic patients, and up to 100% in noncirrhotic patients without cirrhosis who were treated for 16 weeks.

Potential for Sofosbuvir in Liver Transplantation
One obvious clinical need is for data regarding safety and efficacy of sofosbuvir in patients who have decompensated chronic liver disease, are peri-transplant or post-liver-transplant. The excellent safety data to date and the lack of significant drug interactions makes sofosbuvir an appealing choice to be studied in these groups. To date there is one case report published of a patient with severe recurrent cholestatic hepatitis C, 6 months post-transplant, who was effectively rescued and achieved SVR with treatment with sofosbuvir and daclatasvir in combination [Fontana et al. 2013]. This is promising, and results of future trials of sofosbuvir in these types of patient groups are awaited with interest.

Adverse Events
Treatment discontinuations because of adverse events have been uncommon in these sofosbuvirbased interferon-free treatment regimens. In phase III trials, treatment discontinuation rates of 1–2% were seen in the sofosbuvir plus ribavirin cohorts, as compared with 11% among patients receiving peginterferon–ribavirin for 24 weeks. Adverse events associated with ribavirin therapy (fatigue, insomnia and anaemia) were commonly reported, and headache was also frequently reported. Haematologic abnormalities were more common among patients who received interferon than among patients who did not in FISSION and ELECTRON [Gane et al. 2013c; Lawitz et al. 2013d].

Neutropenia and thrombocytopenia were not generally seen in groups who did not receive interferon. Depression is a common side effect of interferon therapy, and in the FISSION study, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir plus ribavirin. In a recent analysis of the impact of HCV treatment on quality of life, in the FISSION and POSITRON trials, sofosbuvir plus ribavirin was associated with better health-related quality of life than peginterferon plus ribavirin, and was similar to patients not receiving active treatment. Achieving SVR on sofosbuvir plus ribavirin was also associated with improvement in health-related quality of life [Younossi et al. 2013].

Concordance Data: SVR At Weeks 4, 12 and 24
Traditionally, with interferon-based therapy for HCV, the absence of detectable virus 24 weeks after completing treatment has been used to define SVR24. However, recent analyses have suggested that SVR12 and SVR24 are concordant across treatments that include peginterferon/ribavirin and also peginterferon/ribavirin triple therapy including telaprevir and boceprevir, with positive predictive values of 98% for SVR12 and 91% for SVR4 [Chen et al. 2013]. The concordance of SVR4, SVR12 and SVR24 has been assessed in the sofosbuvir phase II program including 590 patients. High levels of concordance were observed between SVR4 and later time points and positive predictive values and sensitivity of SVR4 for SVR12 and SVR24 were greater than 98.5% [Lawitz et al. 2013a]. Increasing reliance on these earlier time points of SVR4 and SVR12 to determine outcomes is almost certainly accelerating the pace of drug development.

Viral Resistance
Viral mutations in the HCV NS3 and NS5B regions have been associated with resistance to protease and nonnucleoside inhibitors, and can be present even in previously untreated patients with HCV infection. The S282T mutation has been identified as the common mutation selected in replicon studies with sofosbuvir, and this change can confer resistance to sofosbuvir [Lam et al. 2012]; however, this mutation is not generally present in untreated patients with HCV, and has very poor replicative fitness [Kuntzen et al. 2008]. In the initial large phase II and III studies involving sofosbuvir the S282T mutation was not detected on deep-sequencing assays in any patient receiving sofosbuvir and is in marked contrast with the rapid emergence of viral resistance that has been observed with other classes of DAA in patients who had breakthrough during treatment or relapse after completion of therapy [Gane et al. 2013c; Jacobson et al. 2013; Lawitz et al. 2013d]. Encouragingly, the emerging data suggest that sofosbuvir/NS5A inhibitor combination therapy is highly effective in NS3A protease-inhibitor experienced patients, even when they have protease inhibitor resistance [Sulkowski et al. 2013].

Conclusions and Future Directions
Although sofosbuvir is by no means one of the first DAA drugs to reach phase III clinical trials, the collective trial data for sofosbuvir do represent a significant paradigm shift in the management of HCV infection. With sofosbuvir-based regimens, successful interferon-free treatment of HCV is now achievable across multiple genotypes, but different patterns of genotypic response to treatment have emerged compared with those seen in traditional interferon-based therapy. It is now clear that in the current DAA era, genotypes 2 and 3 should be evaluated quite separately, as SVR rates in genotype 3 patients are significantly lower than those seen in genotype 2 [Jacobson et al. 2013; Lawitz et al. 2013d]. Genotype 2 is a readily treatable strain of HCV, with superb SVR rates with sofosbuvir/ribavirin dual therapy even in patients with established cirrhosis.

In contrast, the presence of advanced liver fibrosis has a significant detrimental effect on SVR rates in genotype 3 patients when a 12-week regimen is used. The FUSION data strongly suggest that for this group of patients, at least 16 weeks of therapy is needed for the dual sofosbuvir/ribavirin regimen, and the results of ongoing trials evaluating a 24-week duration of treatment are awaited with interest. The other strategy that could be considered is addition of another DAA to the regimen, but until these data are available to clarify the optimal interferon-free treatment of genotype 3 HCV patients with advanced fibrosis or previous treatment failure, there may be an initial role for continuing to use peginterferon together with sofosbuvir in this group of patients.

For genotype 1 HCV, the NEUTRINO data have shown the highest yet reported SVR rates for patients with genotype 1 HCV and cirrhosis when treated with sofosbuvir/ribavirin dual therapy, and this is particularly notable for the lack of significant adverse events, in contrast with the ongoing emerging data about safety of protease inhibitor/peginterferon-based triple therapy. However this dual therapy is not sufficient for the genotype 1 null responder group. Emerging phase II data in genotype 1 patients of triple therapy regimens of sofosbuvir plus ribavirin combined with an NS5A inhibitor, either daclatasvir or ledipasvir, demonstrate SVR rates close to 100%, in both treatment-naïve and null-responder patients, with potential to further shorten the duration of therapy to 8 weeks with this triple therapy approach, utilizing the fixed-dose once daily regimen of sofosbuvir/ledipasvir. Data on the effectiveness of this combination in cirrhotic genotype 1 null responders is awaited. A new era of successful interferon-free DAA therapy for HCV is emerging, with potential to broaden treatment of HCV to include patient groups who have either avoided or not been suitable for previous interferon- based therapy, and it is likely that sofosbuvir will form the backbone of this treatment approach.

 References
 

Table 1.  Phase II studies of sofosbuvir.

Study	Design	Genotype	RVR	EOT (%)	SVR4	SVR12
PROTON [ClinicalTrials.gov identifier: NCT01188772] [Lawitz et al. 2013c]
	SOF 200 mg/PEG/RBV 12 wk + 12–36 wk PEG/RBV (RGT) (n = 48)	1	98	94		90
	SOF 400 mg/PEG/RBV 12 wk + 12–36 wk PEG/RBV (RGT) (n = 47)	1	98	100		91
	Placebo/PEG/RBV 12 wk + 36 wk PEG/RBV (n = 26)	1	19	62		58
	SOF 400 mg/PEG/RBV 12 wk (n = 25)	2 & 3	96	100		92
ATOMIC [ClinicalTrials.gov identifier: NCT01329978] [Kowdley et al. 2013]
	SOF 400 mg/RBV/PEG 12 wk (n = 52)	1	94	98	94	90
	SOF 400 mg/RBV/PEG 24 wk (n = 125)	1, 4 & 6	98	99	94	93
	SOF 400 mg/RBV/PEG 12 wk + SOF 400 mg/RBV 12 wk or SOF 400 mg 12 wk (n = 155)	1	97	99	93	91
ELECTRON [ClinicalTrials.gov identifier: NCT01260350]
Part 1 (randomized) [Gane et al. 2013c]	1. SOF 400 mg/RBV 12 wk (n = 10) 2. SOF 400 mg/RBV 12 wk +PEG (wk 1–4) (n = 9) 3. SOF 400 mg/RBV 12 wk +PEG (wk 1–8) (n = 10) 4. SOF 400 mg/RBV/PEG 12 wk (n = 11)	2 & 3 2 & 3 2 & 3 2 & 3100	100 100 100	100 100 100 100	100 100 100 100	100 100 100 100
Part 2 [Gane et al. 2013c]	5. SOF 400 mg 12 wk (n = 10)	2 & 3	100	100	60	60
[Gane et al. 2013c]	6. SOF400 mg/RBV/PEG 8 wk (n = 10)	2 & 3	100	100	100	100
[Gane et al. 2013c]	7. SOF 400 mg/RBV 12 wk (n = 10 null responders)	1	100	100	10	10
Part 3 [Gane et al. 2013c]	8. SOF 400 mg/RBV 12 wk (n = 25; naïve)	1	100	100	88	84
[Gane et al. 2012]	9. SOF 400 mg/RBV 12 wk (n = 25; treatment experienced)	2 & 3	100	100	80	68
Part 4	10. SOF 400 mg/RBV 8 wk (n = 25) 11. SOF 400 mg/RBV800 mg 12 wk (n = 10)	2 & 3, naïve 2 & 3, naïve				64
[Gane et al. 2013a, 2013b]	12. SOF/ledipasvir 90 mg/RBV 12 wk (n = 9)	1; null	89	100	100	100
[Gane et al. 2013a, 2013b]	13. SOF/ledipasvir 90 mg/RBV (n = 25)	1; naïve	100	100	100	100
Part 5 [Gane et al. 2013a, 2013b]	14. SOF/GS9669 500 mg/RBV 12 wk (n = 10)	1; null	100	100	100	100
[Gane et al. 2013a, 2013b]	15. SOF/GS9669 500 mg/RBV (n = 25)	1; naïve	92	100	92	92
COSMOS [Lawitz et al. 2013b]
	1. Simeprevir 150 mg/SOF 400 mg ± RBV
	12 wk: SMV/SOF/RBV (n = 27)	1, noncirrhotic null responders	85	100	96	96% SVR 8
	SMV/SOF (n = 14)		57	100	93	93% SVR 8
	24 wk: SMV/SOF/RBV (n = 24)		82	83
	SMV/SOF (n = 15)		67	90
[Medivir, 2013]	2. 12 wk: SMV/SOF/RBV (n = 27)	1, naïve & null responders with advanced fibrosis			96
	SMV/SOF/(n = 14)				100
	24 wk: SMV/SOF/RBV SMV/SOF
LONESTAR [Gilead Sciences, 2013]
	SOF/ledipasvir FDC 8 wk (n = 20)	1, naïve				95% SVR8
	SOF/ledipasvir FDC + RBV 8 wk (n = 21)	1, naïve				100% SVR8
	SOF/ledipasvir FDC 12 wk (n = 19)	1, naïve			100
	SOF/ledipasvir FDC 12 wk (n = 19)	1, protease inhibitor experienced			95
	SOF/ledipasvir FDC + RBV 12 wk (n = 21)	1, protease inhibitor experienced			95
Daclatasvir plus sofosbuvir
[Sulkowski et al. 2012]	SOF 400 mg/daclatasvir 60 mg ± RBV:
	SOF for 7 days then DCV/SOF 23 wk (n = 15) or	1; noncirrhotic, naïve	100	100	100	100
	DCV/SOF 24 wk (n = 14) or		100	100	100	100
	DCV/SOF/RBV 24 wk (n = 15)		100	100	100	100
	SOF for 7 days then DCV/SOF 23 wk (n = 16) or	2 or 3; noncirrhotic, naïve	100	94	88	88
	DCV/SOF 24 wk (n = 14) or		100	100	100	100
	DCV/SOF/RBV 24 wk (n = 14)		100	100	86	86
[Sulkowski et al. 2013]	Daclatasvir 60 mg/SOF 400 mg 24 wk (n = 21) or	1; previous failed TVT or	100	100	100	100
	Daclatasvir 60 mg/SOF 400 mg/RBV 24 wk (n = 20)	BOC; noncirrhotic	95	100	100	95

PEG, peginterferon; RBV, ribavirin; SOF, sofosbuvir; FDC, fixed-dose combination; EOT, end of therapy; RVR, rapid virological response (viral load undetectable by week 4 on treatment); SVR, sustained virological response; TVT, telaprevir-based triple therapy; BOC, boceprevir-based triple therapy; wk, week.

Blank spaces in the table represent incomplete or unpublished data.

 

Table 2.  Phase III studies of sofosbuvir.

Study	Design	Genotype	RVR	EOT (%)	SVR4	SVR12
FISSION [ClinicalTrials. gov identifier: NCT01497366] [Lawitz et al. 2013d]	SOF 400 mg/RBV 12 wk (n = 253) or PEG/RBV (n = 243)	2 & 3; naïve	99 67	98 89	74 74	67 (G2 97; G3 56) 67
NEUTRINO [ClinicalTrials.gov identifier: NCT01641640] [Lawitz et al. 2013d]	SOF 400 mg/RBV/PEG 12 wk (n = 327)	1, 4, 5, 6; naïve (98% G1 or 4)	99	99	92	90 (G1a 92; G1b 82; G4 96)
POSITRON [ClinicalTrials.gov identifier: NCT01542788] [Jacobson et al. 2013]	SOF 400 mg/RBV (n = 207) or placebo (n = 71) 12 wk	2 & 3; naïve (IFN not an option)	99	100	83	78 (G2 93; G3 61)
FUSION [ClinicalTrials. gov identifier: NCT01604850] [Jacobson et al. 2013]	SOF 400 mg/RBV	2 & 3; previous treatment failure
	12 wk (n = 103) or		97	100	56	50 (G2 86; G3 30)
	16 wk (n = 98)		98	100	77	73 (G2 94; G3 62)

PEG, pegylated interferon alpha; RBV, ribavirin; SMV, simeprevir (TMC435); SOF, sofosbuvir (GS7977); DCV, daclatasvir; RGT, response guided therapy, EOT, end of therapy; SVR, sustained virological response.