February 18, 2014

Achieving SVR reduces hep C treatment costs

Provided by Clinical Advisor

Jennifer Southall
February 17, 2014


Achieving SVR reduces hep C treatment costs

Patients with hepatitis C virus genotype-1 infection who had no detectable levels of the virus on blood tests, also known as sustained virological response, experienced a 13-fold reduction in treatment costs vs. those who did not achieve a response five years after treatment, according to researchers.

“We have shown important cost reductions arising from sustained virological response [SVR], which previous studies have either assumed or only observed on small numbers of patients,” William L. Irving, of the University of Nottingham in the United Kingdom and colleagues reported in the Journal of Viral Hepatitis.

For the study, researchers assessed health resource usage and costs associated with treatment outcomes in193 patients who received at least two months of treatment with pegylated interferon and ribavirin therapy for HCV genotype-1 infection.

Unit costs were derived from the National Health Service Payment by Results database and the British National Formulary. Average follow-up was 3.5 years for those who achieved SVR and 4.9 years for non-SVR patients.

There were no patients with SVR that experienced progression of liver disease state. Conversely, 7.4% of patients without SVR progressed from chronic hepatitis to cirrhosis, and 4.9% progressed from cirrhosis to decompensated liver disease.

During the five-year post-treatment observation period, researchers observed a 13-fold increase in costs among patients that failed to achieve SVR. This increased to 56-fold among those who were retreated.

“Achievement of a [SVR] has significant effects on health service usage and costs,” the researchers concluded. “This work provides real-life data for future cost-effectiveness analyses related to the treatment of chronic HCV infection.”


  1. Backx M. J Viral Hepat. 2014; 21, 208–215.


HCV Antivirals Race to Market

Provided by Gastroenterology and Endoscopy News

by Kate O'Rourke


Boston—Over the next five years, a whirlwind of new direct-acting antiviral agents (DAAs) for hepatitis C are expected to get the green light from the FDA. The recent approval of simeprevir (Olysio, Janssen) and sofosbuvir (Sovaldi, Gilead)–containing regimens is only the tip of the iceberg.

“There are multiple, oral, interferon [IFN]-free DAA regimens in late-stage clinical trials with high SVR [sustained virologic response] rates,” said Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology and professor of medicine at the Johns Hopkins School of Medicine, in Baltimore.

These include the Gilead-based regimen of sofosbuvir plus ledipasvir, with or without GS-9669; AbbVie’s ABT450/r plus ABT267 and ABT333; Boehringer Ingelheim’s faldaprevir plus deleobuvir, with or without PPI-668; Janssen’s simeprevir and samatasvir plus TMC647055/r; and Merck’s MK-8742 plus MK-5172. At press time, Bristol-Myers Squibb was in the process of submitting a regulatory filing for either daclatasvir plus asunaprevir, or this combination plus BMS 791325.

Three Mechanisms of Attack

The new hepatitis C virus (HCV) DAAs can be classified into three groups: protease inhibitors, such as simeprevir, with drug names ending in “previr”; polymerase inhibitors, such as sofosbuvir, with names ending in “buvir”; and NS5A inhibitors, such as daclatasvir, with names ending in “asvir.” All of the new agents target specific processes of the HCV life cycle.

Protease inhibitors prevent cleavage of HCV polypeptides into the mature viral proteins necessary for replication and tend to be genotype-specific. Polymerase inhibitors can be subclassified into nucleos(t)ide analogs and non-nucleos(t)ide analogs. Nucleos(t)ide analogs, which are pangenotypic, mimic the natural substrates of polymerase and inhibit the active site. Non-nucleos(t)ide inhibitors, aimed at HCV genotype 1, bind to several discrete sites outside of the polymerase active site, resulting in a conformational change, which in many cases, but not always, leads to loss of polymerase function. The NS5A inhibitors interfere with a membrane-associated phosphoprotein involved in HCV virion production. The treatment strategy involving these new agents is to include drugs that attack at least two different HCV targets in a single regimen.

“We are now going to get into an era of using combinations of direct-acting antivirals,” said Luis Balart, MD, chief of gastroenterology and hepatology at Tulane University School of Medicine, in New Orleans. “There will be two drugs, three in some cases, attacking the virus at different sites. By attacking the virus at two or three different sites, you prevent the resistance to agents that may lead to failure or cause patients to relapse.”

Robust Pipeline

At The Liver Meeting 2013, investigators presented data on numerous promising DAAs.


The LONESTAR trial evaluated an oral, fixed-dose combination tablet containing sofosbuvir and ledipasvir (SOF/LDV FDC). In this trial, 60 non-cirrhotic, treatment-naive patients with HCV genotype 1 infection were randomized to receive treatment with either SOF/LDV FDC for eight weeks, SOF/LDV FDC plus ribavirin for eight weeks or SOF/LDV FDC for 12 weeks. Additionally, 40 patients who had not achieved SVR after previous treatment with an HCV protease inhibitor regimen were randomized to receive 12 weeks of treatment with SOF/LDV FDC or SOF/LDV FDC plus ribavirin; 55% of these patients had compensated cirrhosis. Only two patients in the entire study experienced relapse (one patient was lost to follow-up), and the drugs were well tolerated.

The ELECTRON trial examined SOF/LDV FDC in 110 patients with HCV genotype 1 and included five cohorts. Prior null responders with stage F4 fibrosis received SOF/LDV FDC or SOF/LDV FDC plus ribavirin for 12 weeks. Prior null responders with F3/F4 disease received 12 weeks of SOF/LDV FDC plus ribavirin, with or without GS-9669, an NS5B non-nucleoside inhibitor. In the fifth cohort, treatment-naive patients without cirrhosis received SOF/LDV FDC plus ribavirin for six weeks. SVR rates at week 12 were 68% in treatment-naive patients and 70% in treatment-experienced patients with stage F4 fibrosis who received 12 weeks of SOF/LDV FDC. All other patients achieved SVR at week 12.

The National Institute of Allergy and Infectious Diseases SYNERGY trial tested SOF/LDV FDC alone for 12 weeks or in combination with GS-9451 or GS-9669 for six weeks in HCV genotype 1–infected patients; nearly 90% of patients in the trial were black. SVR at week 12 was 100% in patients who received only the fixed-dose tablet. Among patients who received combination treatment, SVR at week 4 was 90% at the time the data were reported, with one relapse. Efficacy was not reduced in patients with baseline NS5A resistance variants, and the regimens were well tolerated.

At press time, Gilead was finalizing regulatory filing for SOF/LDV FDC in HCV genotype 1 patients.

The PEARL-I trial tested 12 weeks of treatment with ABT-450/r, an HCV protease inhibitor dosed with ritonavir, plus ABT-267, an HCV NS5A inhibitor, in HCV genotype 1b, treatment-naive patients (n=42) and prior null responders (n=40) with stage F1 to F3 fibrosis. Roughly 95% of treatment-naive patients and 90% of null responders achieved SVR at week 12. There were no treatment discontinuations due to adverse events, and only one drug interruption because of grade 3 alanine aminotransferase elevation.

Researchers also presented results from a cohort of HCV genotype 1 patients treated in the AVIATOR trial with ABT450/r, ABT267 and ABT333 for 12 or 24 weeks, including 159 treatment-naive patients and 88 null responders. All 24 patients in the trial who required dose reductions achieved SVR at week 24. In the 223 patients who maintained full doses, 92.1% of treatment-naive patients and 94% of null responders achieved SVR at week 24.

The SOUND-C3 trial tested faldaprevir and deleobuvir plus ribavirin for 12 weeks in HCV genotype 1a (n=12) and 1b (n=20) patients. Although 10 of the 12 HCV genotype 1a patients failed therapy, 95% of patients with genotype 1b (19 of 20) achieved SVR at week 12. A Phase III trial in genotype 1b patients is under way.

In another trial of faldaprevir and deleobuvir, 12 weeks of treatment including PPI-668, with or without ribavirin, is being tested in 37 patients with HCV genotype 1a. At press time, all 13 patients who were evaluable at week 4 had achieved SVR. Only one patient discontinued therapy due to gastrointestinal symptoms.

The C-Worthy trial tested the NS5A inhibitor MK-5172 plus two doses of MK-8742, with (n=52) or without (n=13) ribavirin for 12 weeks. SVR rates at week 12 ranged from 89% to 100%. None of the patients discontinued treatment because of side effects. One patient who suffered a virologic relapse had HCV genotype 1a; he had an NS5A polymorphism in Y93N and a protease mutation in D168A/D, both of which were thought to play a role in the treatment failure.

Exciting Results, With Caveats

The list of DAA regimens in development outlined in this article is not even exhaustive. And although clinicians are enthusiastic about the new drugs, they also realize that increased options will bring challenges, especially because there are no clinical trials comparing one new DAA regimen with another. The activity of the new DAAs is being compared to historical data.

“What we are seeing are new Phase III trials that are going to be producing approved drugs that have never been compared with any other regimens,” said David Nelson, MD, vice president for research, University of Florida, Gainesville. “It is fantastic to move those drugs forward, but when we try to understand how those regimens will compare with each other in populations, it will be years before we have that type of data.”

Dr. Nelson pointed out that there are many new regimens for HCV genotype 1 that have similar SVR rates. He believes that most clinicians will make decisions based on data from Phase II and Phase IV studies, the cohort and case–control studies using drugs in special populations.

“We will have a lot of data like that and, of course, we will see a lot of case series and guidelines and opinions, based on a lower level of evidence. The highest standard of evidence will be limited, which will really challenge us to select the best regimen.”

Fred Poordad, MD, vice president of academic and clinical affairs at The Texas Liver Institute, San Antonio, said clinicians will need to scrutinize the drug combinations.

“In general, when you look at an antiviral drug, you need think about its resistance profile, whether it’s pan-genotypic, how potent it is, the adverse-event profile and the drug–drug interaction profile,” Dr. Poordad said.

For many of the new DAAs, clinicians will not be able to rely on traditional baseline predictors of response.

“From AVIATOR, we learned that some of our previously learned baseline predictors do not hold true. Things such as subtype, high viral load, degree of fibrosis excluding cirrhosis and IL28B[interleukin-28 B] status did not seem to affect the efficacy, even in this null-responder population,” Dr. Poordad noted. “I think the good news is that cirrhotics, even cirrhotic nulls, can achieve very high SVR rates with these oral agents. The caveat is the numbers are all small.”

Dr. Nelson agreed: “We, unfortunately, still see very small numbers of cirrhotics in most registration trials, so we need to be careful about extrapolating data on limited patients to broad real-world representation.”

Redefining Treatment Failures

According to Dr. Sulkowski, the new DAAs might change current notions about HCV resistance to these drugs. This concept is supported by a single patient in the LONESTAR trial who was treated for eight weeks with sofosbuvir plus ledipasvir and then relapsed after treatment. At the time of relapse, the patient’s viral quasi-species included variants with mutations conferring decreased susceptibility to both sofosbuvir and ledipasvir. The key features of this patient’s case, Dr. Sulkowski said, were the presence of the S282T mutation, which has been rarely seen in patients treated to date, and what happened next with retreatment: When clinicians initiated a second round of treatment with the same drugs, sofosbuvir and ledipisvir, plus the addition of ribavirin, the patient had robust and rapid viral suppression, and following a longer course of therapy (24 weeks), achieved SVR.

“Clearly, we need to learn more about retreatment of DAA failures, and that is one of our next challenges,” said Dr. Sulkowski. “This single case report may redefine how we think about treatment failures.”

DAAs a Homerun

What will definitely be redefined is the patient experience.

“The difference between these new DAA regimens and IFN and ribavirin is the difference between night and day,” said Dr. Balart. “The side-effect profile is so much better. These patients don’t get the systemic malaise, where they feel like they have the flu every day. We have had patients who have been sick from something else, such as an appendectomy, that had nothing to do with DAAs, and they were able to continue therapy.”

With the side-effect profile and the shortened treatment time, 12 weeks in the majority of studies, the new regimens are a homerun, according to Dr. Balart.

Which combinations ultimately get used in clinical practice will be influenced by which drugs get to market first.

“Whichever drugs are first to market always have an advantage, because physicians become familiar with them first,” Dr. Balart said. “However, given enough time, others will eventually catch up and become part of the available armamentarium, much like what has happened in the HIV treatment arena.”

Dr. Sulkowski has received consulting fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck & Co. and Vertex Pharmaceuticals. Dr. Balart has received research grant support from AbbVie, Bayer, Boehringer Ingelheim, Genentech, Genfit, GI Dynamics, Gilead, Janssen, Merck, Ocera, Salix Pharmaceuticals and Takeda Pharmaceutical; he has been involved with the advisory boards of AbbVie, Gilead, Janssen and Merck; and he has been on the speakers’ bureaus of Boehringer Ingelheim, Janssen, Merck and Salix. Dr. Poordad is a speaker for Gilead; he has received grant/research support from all of the companies mentioned in this article, except for AbbVie; and he is a consultant for Abbott, Achillion, Anadys, Inhibitex, Merck, Novartis, Pfizer, Pharmasset, Theravance and Tibotec. Dr. Nelson has received grant/research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech-Roche, Gilead, Merck and Vertex, and has served on the advisory committee/review panel for AbbVie, Gilead, Merck and Vertex.


Screening urged for Hepatitis C but drug costs are prohibitive

Provided by CMAJ

February 18, 2014


With new medications that cure over 90% of hepatitis C, experts are urging that screening recommendations expand to include all Canadians born between 1945 and 1975.

Photo Credit: Tetra Images/ThinkStock

Sergeant Lance Gibson contracted hepatitis C from a blood transfusion in 1981, but only received a diagnosis 28 years later.

“My liver was already in stage 5 liver disease,” explains Gibson. “So when I found out, it was already too late and I needed a transplant.”

As is typical of hepatitis C, he had no obvious symptoms of liver disease, which likely contributed to the delay in diagnosis.

With new medications that cure over 90% of hepatitis C, liver disease experts are urging that screening recommendations expand to include all Canadians born between 1945 and 1975. But there are two difficulties with this plan: Who will do all the screening? And who will pay for the new medications when the cost of a cure is $60 000?

The current practice of screening only those at high risk of exposure to hepatitis C, such as intravenous drug users or those exhibiting symptoms of the disease, is outdated, says Dr. Morris Sherman, chairman of the Liver Foundation. “The bigger concern is the far larger group of people who are not injection drug users, or at least not current injection drug users, and who did not acquire their disease recently, but acquired it many years ago.”

Hepatitis C is transmitted by contact with infected blood, including through shared needles or other illicit drug paraphernalia, contaminated sharp instruments, some higher-risk sexual behaviours and blood transfusions or organ transplants prior to 1992 in Canada.

Testing all Canadians born 1945–1975 would capture some 80% of individuals with the disease, Sherman estimates based on an analysis of Public Health Agency of Canada data. According to the agency, about 240 000 Canadians are infected with hepatitis C. The disease is linked to chronic liver disease and increased risk of liver cancer.

With the new medicines approved by Health Canada, hepatitis C is also “one of the very few, maybe the only, chronic viral disease that can be cured by medication,” says Sherman.

The United States has already adopted widespread screening of citizens born 1945–1965. The hope is that earlier diagnosis and treatment will make stories like Gibson’s rare.

However, not everyone is convinced that expanding screening recommendations is the right approach.

Alan Cassels, a drug policy researcher at the University of Victoria in British Columbia is one such critic. “I’ve seen numerous examples in the past of large-scale screening programs launched on populations without any adequate consideration to the downsides or the harms inflicted on the population.”

Cassels also questions whether there are more pecuniary motives behind the push for wider screening.

“We should focus our energy on the high-risk group, but then again, that’s not where the money is,” he says. “You can’t deny the market forces at play when it comes to screening.”

Although Health Canada has approved a medication to cure hepatitis C, provincial governments have yet to decide whether they will fund the drugs. That’s a big problem because the medicines are expensive.

Sovaldi (sofosbuvir), currently under review at the Canadian Agency for Drugs and Technologies in Health prior to potential approval by the provinces for drug formularies, is set at $650 per tablet in Canada. Sherman says that governments or insurance companies who opt to cover the drug will likely pay less. Until then, patients with hepatitis C can expect to pay about $60 000 out of pocket for the cure.

Meanwhile, it remains unclear how current numbers of liver specialists will be able to meet increased demand for screening.

“The short answer is, with difficulty,” says Sherman. “I think hepatologists are maxed out at the moment.” He notes that wait-times vary across the county, but are in the order of three to six months if not longer.

Sherman anticipates family doctors, as well as gastroenterologists and infectious diseases doctors, will play a greater role in the management of hepatitis C to meet the demand created by wider screening.

But Dr. Frank Martino, past president of the Ontario College of Family Physicians, says that family doctors are already stretched thin prioritizing the many messages and updates received from various specialists. When asked how he keeps up, he muses: “That’s the perennial question, isn’t it? Getting education out there is crucial.”

Sherman believes these obstacles can and will be overcome.

“Hepatitis C is an unprecedented situation for health care,” he argues. “I don’t know if there’s ever been a situation where there are so many people who require such expensive drugs that are so effective. And failure to provide these drugs is going to have a major impact on patient survival.”


— Michael Fralick, CMAJ


Treating HCV -- Is the Price Right?


Published: Feb 18, 2014

By Michael Smith, North American Correspondent, MedPage Today


New drugs on the horizon hold out the promise of being able to cure up to 90% of people with chronic hepatitis C (HCV). They are also promising to be expensive.

Eyebrows went up recently when Gilead Sciences announced the per-pill price for its new anti-HCV drug sofosbuvir (Sovaldi) would be $1,000. Over a 12-week treatment period, that amounts to $84,000 -- without counting the cost of other medications that would be used with sofosbuvir.

The other recently approved medication -- Janssen's simeprevir (Olysio) -- is being priced at $66,360 for a course of treatment, again without the cost of other medications.

But are those costs out of line for drugs that promise to cure a notoriously refractory illness in eight or nine cases out of 10? Especially when you consider that HCV is widespread, underdiagnosed, and leads in many cases to serious liver disease and death?

Short answer: No one really knows.

"There's a lot of sticker shock in medicine," according to Nancy Reau, MD, of the University of Chicago Medical Center.

But the price tag has to be weighed against the benefit, she and colleague Don Jensen, MD (also at Chicago) argued in a recent article in Hepatology that tried to parse the issue.

In the case of HCV, that's not a simple matter.

The CDC estimates that some three million Americans have chronic HCV, although most don't know it because it is usually without symptoms for many years.

But the disease has some serious consequences -- in the U.S., it is the leading cause of cirrhosis and liver cancer, the most common reason for liver transplantation, and it's estimated that 15,000 people die of HCV-related causes every year.

HCV treatment is measured with what's called the sustained virologic response, or SVR -- no detectable virus 24 weeks after the end of a course of treatment. A person whose treatment results in an SVR has less than a 1% chance of relapse, history shows, and to all intents and purposes is cured.

No Bargains

Cures have never been cheap or easy to come by. The earliest therapy was interferon-alfa for 24 weeks at a cost of less than $20,000 in today's dollars, Reau and Jensen noted.

The downside was that only 6% of patients achieved an SVR -- were cured. "That's an expensive therapy -- to treat 100 people to get six cures," Reau told MedPage Today.

But the odds of achieving SVR steadily improved: first with the use of 48 weeks of pegylated interferon, coupled with ribavirin, and then in 2011 with the addition of the first agents aimed directly at the virus -- the protease inhibitors (PIs) telaprevir and boceprevir.

However those therapies remain expensive and -- in real-world use -- not startlingly effective, according to Andrea Branch, PhD, of Mount Sinai Hospital in New York City.

Branch and her students looked back at 147 patients treated in their hospital with telaprevir, plus peginterferon and ribavirin, and asked how much a cure cost.

Bottom line? The median cost of treatment was $83,509 -- about 65% of that for telaprevir -- but only 44% of patients achieved an SVR, so that the per-cure cost was a whopping $188,859.

If the new drugs live up their promise of SVR rates in the range of 80% to 90%, Branch toldMedPage Today, it may well be that they will be cheaper to use -- on a per-cure basis -- than PI-based triple therapies.

"If these new drugs perform as expected and the costs are as expected, I think there will be an economic saving compared with previous triple therapy," she said.

Following the Numbers

Branch and her group will be monitoring outcomes with the new drugs and hope to have some real-world data in about 9 months, she said.

For an individual HCV patient, a cure can be quite literally priceless, Branch said -- the gift of life. But how do cost and benefit play out across the whole healthcare system?

On a broad scale, the equation is simple, Reau said: "People with hep C cost money."

For instance, one study found that the average annual health care cost for a patient with HCV was $24,176 -- but the expense rose markedly with advanced disease, reaching $59,995 among patients with end-stage liver disease.

"The only way to truly prevent that is to treat people before they declare themselves as someone who is going to get end-stage liver disease," she said.

A liver transplant, for instance, costs about $577,000, all in. A 12-week course of treatment that cured the HCV and prevented the need for transplant would be a good deal -- unless the therapy were horrendously expensive.

Even preventing some of the less serious complications would save money. A 2013 study among HCV patients found that curing them (with peginterferon and ribavirin) reduced annual medical costs by $2,648 on average, compared with patients treated but not cured.

On the other hand, those studies looked at patients already diagnosed with HCV and displaying at least some symptoms. What about the millions of hidden cases? What's the number needed to treat to prevent the serious consequences?

Boomer Disease

The CDC is urging all Americans born from 1945 through 1965 to get tested for HCV, arguing that they could then get treated with the new drugs, which the agency says would save lives and prevent many of the other consequences of the disease.

The cost-benefit implications of treating those people are not known, although Reau said it's likely they resemble the diagnosed cases in at least one way -- about a third will go on to have serious HCV-related disease.

Absent a cure, their HCV will be a drain on the healthcare system for years.

Traditionally, HCV treatment has been aimed at the sicker patients, largely because the therapy itself has had such unpleasant side effects that a relatively healthy person would be better off skipping it.

The downside of that practice has been that sicker people generally do less well on therapy, inflating the cost per cure, Branch said.

Indeed, many physicians have been "warehousing" relatively healthy patients, waiting to treat them until the less toxic direct-acting agents to win approval.

Another aspect of the cost issue is that prices aren't written in stone, Reau said, noting that four pharmaceutical companies have drugs in the pipeline. "It's hard to imagine that when there are four companies out there vying in the hep C space that some of that consumer drive won't affect prices," she said.

The drugs themselves are not expensive to make, according to a study presented at the 2013 meeting of the American Association for the Study of Liver Diseases.

Looking just at the chemistry, researchers led by Andrew Hill, PhD, of Liverpool University in England, estimated that, for example, the full 12-week course of sofosbuvir would cost about $136 to make.

Naturally, drug makers will want to recover the costs associated with the development program and make some money for their shareholders. For instance, among other costs Gilead paid $11.2 billion to buy the company that first created sofosbuvir.

There is pressure for Gilead to charge less for the drug in the developing world, and the company is reportedly in talks with Indian firms to make and market sofosbuvir at a fraction of the U.S. sticker price.

That pressure is likely to be placed on other manufacturers as well and, of course, there will be continuing pressure in the developed world to lower prices.

In the U.S., Reau and Jensen noted, the baby boomer generation is now old enough that much of the HCV treatment costs for that cohort will be borne by Medicare.

Moreover, a recent study in Alabama found that HCV prevalence appears to be higher among the uninsured and those on Medicaid than those with private insurance or Medicare.

In that context, widespread HCV treatment is likely to be "a financial burden on our health care system," but, Reau and Jensen argued, it will higher in the long run if people are not treated.


Also See: Sticker Shock and the Price of New Therapies for Hepatitis C: Is it worth it?