Could new hepatitis C drugs bust state budgets?

Michael Ollove, Pew/Stateline staff writer12:24 p.m. EST March 3, 2014

Two new drugs have been approved to help millions of Americans who suffer from hepatitis C, but both are extremely expensive.(Photo: USA TODAY photo)

Two new medications to treat the deadly epidemic of hepatitis C promise millions of Americans a better chance of a cure, shorter periods of treatment and fewer side effects than older drugs. They also threaten to bust state budgets and raise private insurance rates.

The new hepatitis C medications present a dilemma for Medicaid and other insurers, who must balance the cost against the huge number of people who could benefit from the treatment. A course of treatment costs between $84,000 and $168,000 -- or $1,000 to $2,000 per pill.

More people now die of hepatitis C than HIV/AIDS, according to the U.S. Centers for Disease Control and Prevention (CDC).The infectious disease can lead to scarring of the liver, cirrhosis, liver cancer, liver failure and death. For some sufferers, the only option for survival is a liver transplant.

The new drugs — simeprevir (sold as Olysio by Janssen Therapeutics, a division of Johnson & Johnson) and sofosbuvir (marketed as Sovaldi by Gilead Sciences) — could stamp out the disease, which afflicts an estimated 3.2 million to 5.2 million Americans. In clinical trials, the new drugs, which have already reached the market, have reached cure rates as high as 95%. Patients take them by pill, usually every day for 12 weeks, and they have mild side effects.

Until now, the drug of choice for treating hepatitis C was interferon. But patients typically must be injected with interferon for nearly a year, and it can have severe side effects including flu-like symptoms, fatigue, anemia, and depression. It also isn't all that effective, with a 45% cure rate for those with hepatitis C, genotype 1, the most common strain.

The Food and Drug Administration (FDA) approved the two medications late last year, after states had already completed their Medicaid budgets. It was no secret that the drugs were coming—patients were eagerly awaiting their approval. It wasn't clear, however, just how expensive they would be. By comparison, treatment with interferon or other drugs costs $15,000 to $20,000. Many patients have declined those treatments in anticipation of simeprevir and sofosbuvir hitting the market.

"I don't recall any other situation in which we've had very effective, very expensive drugs come out for an important condition with such a large patient population potentially eligible for treatment," said Steven Pearson, president of the Institute for Clinical & Economic Review. ICER is convening the California Technology Assessment Forum of scholars, policymakers and insurers later this month in San Francisco to consider the clinical and policy ramifications of the new hepatitis C drugs.

The potential cost of treating even a fraction of those with the disease is nothing short of astronomical.

ICER's preliminary study estimates that in California alone, treating just half of all those with chronic hepatitis C with the new medications would cost an additional $18 billion this year, compared to what is being spent now. Because the prevalence of hepatitis C is about two times higher among Medicaid beneficiaries than the general population, a disproportionate share of the financial burden of these drugs could fall on the states and the federal government, which jointly finance Medicaid.

"If you do back-of-the envelope calculations, it's clear budgets couldn't take on the potential of every eligible patient," said Pearson.

One of the drugmakers, Janssen, defended the pricetag. "We think the price reflects the value that Olysio brings to patients, medical providers and health care systems," spokesman Craig Stoltz said.

More specialty meds coming

Matt Salo, executive director of the National Association of State Medicaid Directors, said it's likely the new hepatitis C medications will be part of a new wave of extremely expensive, complex, and finely tuned "specialty" medications that will create continuing dilemmas for the health care system.

"I don't know that public policy has yet come up with how we are going to deal with this," Salo said. "If a cure comes out for lupus and it costs $300,000 a year, at what point do we say, 'We can't do this for everybody?' Those are big policy questions we're going to have to start to grapple with."

In the case of the new hepatitis C medications, the grappling starts in earnest at ICER's San Francisco conference. The group may issue recommendations on which privately insured and Medicaid patients should be approved for the new medications first. For example, it could advise that only those patients showing signs of cirrhosis should receive the new drugs, and that the remainder could use the old medications or wait for the next generation of hepatitis C drugs to reach the market, presumably at lower cost.

If there is rationing of the new drugs, it won't be an easy sell to patients, many of whom have lived with liver disease for years and some of whom could not tolerate the old treatments.

"Are you going to say to patients, 'We understand you have a viral infection and there's a cure, but because you are in a mild stage, we don't think you need treatment now?'" said Mark Sulkowski, an infectious disease specialist and professor of medicine at Johns Hopkins School of Medicine.

The high cost of the drugs also raises concerns over how they will be dispensed. Does it make sense to hand over to patients a bottle of pills worth at least $84,000? Will there be a black market for the drugs? And what happens if a patient stops taking the medications before the end of treatment? Should they get to resume another full course of treatment?

Hepatitis C on the rise

No one yet knows how strong demand for the new drugs will actually be. But the number of eligible patients could soar. Asymptomatic until advanced stages, hepatitis C can go undetected for years, often decades, and it is estimated that least half of the people with the disease do not know they have it. Today, it is often spread by blood-to-blood contact associated with intravenous drug use. But in the past, people often contracted it through blood transfusions and transplants.

Last year, the CDC and the U.S. Preventive Services Task Force both came out with a new recommendation that all baby boomers – everyone born between 1945 and 1965 — be screened for hepatitis C. For unknown reasons, researchers have found a greater prevalence of hepatitis C in that population than others. Additional screening will only increase demand for treatment.

State Medicaid agencies are just now beginning to react to the implications of the two new medicines. The majority of Medicaid beneficiaries are in managed care plans, but those managed care plans set their capitation rates (the amount Medicaid pays managed care plans per patient in a year) for 2014 before the FDA approval of simeprevir and sofosbuvir. Now, some of those plans are asking their state Medicaid agencies for a carve-out or "pass-through" for these drugs, meaning that the Medicaid agencies would bear the costs of those drugs above the capitations. The states could also try to negotiate with the manufacturers for a better price.

"This is going to fall on taxpayers because we think it will fall disproportionally on those in Medicaid," said J. Mario Molina, chief executive of Molina Healthcare Inc., a Medicaid managed care plan with 2.1 million beneficiaries in California.The potential costs of these drugs could overwhelm the Medicaid agencies, forcing them to turn to their legislatures for additional money.

Mike Wofford, chief of pharmacy policy with the California Department of Health Care Services, said it is possible his agency would have to ask the legislature for help. "If a budget breaker comes along we have to figure out how to pay for it," he said. But he also noted that it's too soon to know if events are heading in that direction because of uncertainty over demand. Already, though, California Medicaid is requiring that patients obtain prior authorization if they want the new hepatitis C drugs.

Private insurers also are grappling with the implications of the new drugs. Susan Pisano, a spokesperson for America's Health Insurance Plans, said "There's always the potential that a high level of new costs to the system can have an impact on premiums."

Drug companies currently are free to set prices based on market demand, but Pisano suggested that drug pricing deserves more scrutiny, particularly since more specialty drugs are in the pipeline, including new treatments for hepatitis C. "Heretofore there's been great focus on insurance but little focus on what the pharmaceutical companies are charging," she said.

Gilead Sciences, maker of Solvaldi, said the drug represents a significant advance over other treatments. Spokeswoman Michele Rest said Medicaid agencies are eligible for "deep discounts."

The two drugmakers are not likely to have the market to themselves for long. A new generation of hepatitis C drugs is expected to win approval later this year. That increased competition could drive down prices. Or, if the drugs are deemed even more effective, it could lead to more sticker shock.

Stateline is a nonpartisan, nonprofit news service of the Pew Charitable Trusts that provides daily reporting and analysis on trends in state policy.

Source

There’s a Life-Saving Hepatitis C Drug. But You May Not Be Able To Afford It.

Provided by Kaiser Health News

By Julie Appleby
KHN Staff Writer
Mar 03, 2014

This KHN story was produced in collaboration with The Daily Beast

There's a new drug regimen being touted as a potential cure for a dangerous liver virus that causes hepatitis C.  But it costs $84,000 -- or $1,000 a pill. And that price tag is prompting outrage from some consumers and a scramble by insurers to figure out which patients should get the drug —and who pays for it.

Called Sovaldi, the drug is made by California-based Gilead Sciences Inc. and is the latest in handful of new treatments for hepatitis C, a chronic infection that afflicts at least 3 million Americans and is a leading cause of liver failure. It was approved by the U.S. Food & Drug Administration in December.

"Everyone is still scrambling to figure out how to handle this," said J. Mario Molina, president and CEO of Molina Healthcare, one of the nation's largest Medicaid managed care companies, which is seeking emergency guidelines from the 11 states in which it operates.  "It's far superior to anything we've had to treat hepatitis C.  The problem is it's extraordinarily expensive."

Medicaid programs may be particularly hard hit because they are likely to cover a higher proportion of patients with the virus and cannot raise premiums like commercial insurers, Molina said. Medicaid managed care firms like his are paid a set amount per member per month by the state to cover all their medical costs.

If left untreated, hepatitis C causes liver damage over the course of decades. The U.S. Preventive Services Task Force recommends that all baby boomers be tested for the blood-borne virus, which often goes undiagnosed because it produces few symptoms. It is spread mainly by intravenous drug use, but many people were unknowingly infected by poorly sterilized medical equipment and blood transfusions before widespread screening of the blood supply began in 1992.  Some may also been infected through tattoos and piercings with contaminated needles.

Big Gains Over Current Drugs

With a success rate of better than 90 percent, Sovaldi is seen as a vast improvement over older treatments, some of which helped only half of patients. Those older drugs cost about $25,000 per treatment, while some newer products approved in 2011 have prices closer to Sovaldi, but have more side effects or are more complex to administer.

A typical course of treatment with Sovaldi goes 12 weeks and costs $84,000, but some patients may need to take the drug for twice as long. Guidelines also suggest that for some patients, Sovaldi be used with other drugs, such as interferon and ribavirin, adding to the cost.

Molina said he has asked state Medicaid directors for guidance on how to proceed with its 2.1 million beneficiaries. In the meantime, he said his firm will not cover the drug, which he says could add $300 million to $400 million to its costs this year.  He wants states to cover the drug outside its contracts with his company because the costs were not built into rates negotiated for this year.

"Whether we pay for it or the state pays for it, it will be a huge expense,” he said. “California spends $3,500 per person a year in the Medicaid program. You could cover an awful lot of people for $84,000."

A Molina spokeswoman said the company is not required to cover the drug since it was approved after its managed care contracts were negotiated. “In the meantime, we are continuing to cover the same medically necessary hepatitis C treatments that were available prior to December 2013,” said the spokeswoman, Sunny Yu.

In traditional Medicaid, states must cover FDA-approved drugs marketed by companies that have negotiated rebates with the federal Medicaid drug rebate program. Gilead participates in that program, a spokeswoman said.

But states have flexibility to manage their Medicaid drug costs by using preferred drug lists and requiring prior authorizations for some treatments. In addition, enrollees covered under the health law’s expanded Medicaid program may have access to a narrower selection of drugs in some cases, depending on how the state has set up its program.

Limiting How Many Are Eligible

Private insurers, meanwhile, are developing their own criteria for which patients are eligible for the drug, said Steven Pearson, who is organizing a public forum in San Francisco on March 10 to help patients, doctors, insurers and policymakers compare Sovaldi’s cost and effectiveness with other treatments.

Some insurers are limiting it to patients who have tried the older drugs, but failed to get satisfactory results. Others will provide it to those in the middle stages of liver damage, but not to those who show little or no signs of damage, said Pearson, who heads the Institute for Clinical and Economic Review, a nonprofit organization that helps groups evaluate the effectiveness of different medical interventions.

A report prepared for the San Francisco forum estimates that if every patient in California with advanced liver damage were treated, the cost would be $6.3 billion.

Gilead says its price is justified because of the drug’s effectiveness. Those who take it can head off chronic problems, such as liver disease or the need for an eventual liver transplant.

“Gilead believes that the price of Sovaldi is fair based on the value it represents to a larger number of patients, including many of those with no current options,” said Michele Rest, a company spokeswoman. “The cost of the entire … regimen of 12 weeks of Sovaldi with interferon and ribavirin is consistent with and, in many cases, actually less than the cost of the previous … regimens – with shorter duration of therapy, increased tolerability, and higher efficacy. “

She said the company has financial aid programs to assist patients who are uninsured, underinsured or who need assistance to help pay for the medicine, but declined to say how many were enrolled.

‘What Is The Proper Cost?’

In 2011, Gilead paid $11 billion to buy Pharmasset, the company that developed the drug, while it was still in final stage testing. Analysts have estimated that the drug will reap billions in annual sales.

Molina says Gilead is entitled to a return, but questions whether taxpayers should be paying so much of its acquisition costs.

"It is estimated that half the patients who get this will be covered by government programs," Molina said. "If they overpaid for the company they acquired, why should the government have to bail them out?"

Similar questions are being raised by the AIDS Healthcare Foundation, a Los Angeles-based advocacy and health care group, which is urging state Medicaid directors to bargain hard for rebates on the drug’s cost.

“The pricing of Sovaldi is being driven by Gilead's desire to recoup its investment in Pharmasset, and assumes it can accomplish this by charging Medicaid and other taxpayer-funded programs whatever it wants," President Michael Weinstein wrote in letters to state Medicaid directors.

Medicaid managed care nonprofit CareSource, headquartered in Dayton, Ohio, says it is already covering the drug, mainly for members who have had bad reactions to the older treatments.

"It's a great medication for the members, but we are concerned about the cost," said Chief Medical Officer Craig Thiele.

While there was some discussion about waiting to see if other drugs to treat hepatits C might be approved, Thiele said CareSource didn't want to delay.

He noted that the questions raised by Sovaldi may apply to many new pharmaceuticals, including potential hepatitis C treatments.

"What concerns me is this may be a trend, a wave of expensive medications," he said.

Matt Salo, executive director of the National Association of Medicaid Directors, said many state officials share those concerns.

"The broader question is what is the proper cost of life-saving pharmaceuticals?" he said. "This is not an isolated incident ... this is a trend that is going to get worse before it gets better."

Source

Costly hepatitis drug Sovaldi rattles industry

Provided by The Washington Post

By Sandhya Somashekhar, Saturday, March 1, 2:32 PM

When the Food and Drug Administration approved a medication called Sovaldi in December, it was hailed as a breakthrough in the fight against hepatitis C, a blood-borne disease that affects 3.2 million Americans and kills more people in the U.S. annually than AIDS.

Then California-based Gilead Sciences, the manufacturer, announced the price: $84,000 for a 12-week course, more than what many cancer treatments cost in a year.

The hefty price tag has rattled patient advocacy groups and insurance companies, who say most costly new treatments coming on the market are targeted for a smaller patient population. Putting such a premium on a drug that could help so many will be crushing, they say.

At least one prescription drug plan is encouraging doctors to delay prescribing Sovaldi for patients who can wait. One insurer has said it risks bankruptcy if it’s required to cover the drug for everyone who needs it this year. Advocates say Gilead has taken corporate greed to new levels.

The drug has also prompted a new round of hand-wringing over a larger issue: the escalating cost of specialty drugs, which are designed to treat chronic illnesses such as rheumatoid arthritis and multiple sclerosis and sometimes require special handling.

While these therapies are delivering body blows to some of the world’s most pernicious diseases, they also are testing the limits of what society is willing to pay for sought-after treatments or cures.

“The advancements that are coming in medicine are going to be stunning and amazing, both in terms of the kinds of things we can treat that we never could and what their cost is going to be,” said Matt Salo, executive director of the National Association of Medicaid Directors. “We’re going to need to think as a country about how do we value health and health care.”

In the past, treating hepatitis C was not always successful and involved lengthy treatment with injectable drugs that had significant side effects. By contrast, Sovaldi promises to cure nearly all sufferers with a once-daily pill that has far fewer side effects.

The Centers for Disease Control and Prevention has called hepatitis C an undeclared public-health crisis, affecting as much as 2 percent of the adult U.S. population and killing 1,500 Americans a year. It is caused by a virus and is typically transmitted through blood contact, such as dirty syringes.

Many people contracted the disease through blood transfusions before routine testing of donated blood for hepatitis C began in 1992.

The disease can go undetected for years and can eventually lead to cancer or cirrhosis of the liver. It is particularly prevalent among baby boomers. Federal health authorities recommend that everyone born between 1945 and 1965 be tested for the disease.

Ronni Marks, 60, of New York City contracted the disease from one of the many blood transfusions she underwent since childhood. After two unsuccessful treatments in the past that caused debilitating side effects, she began a course of Sovaldi and two other drugs this year.

“Hopefully these are the wonder drugs they say they are,” she said.

When a friend asked Marks for a photo of the slim, yellow pill — a single dose costs $1,000 — she snapped a picture of it on a blue background. “She said that it looked like it was taken on a Tiffany’s box,” Marks said. “I joked that it should have been, considering the price.”

In a statement to The Washington Post, Gilead said the price is fair because it is a significant improvement from previous treatments and it is not more expensive than the old treatment. It said it has had a good response from insurance companies agreeing to cover the drug. Gilead added that it offers a generous assistance program to help low-income people get the drug at a low cost.

The fact that Sovaldi actually cures hepatitis C gives it an advantage over other types of therapies, allowing the company to price it higher, said Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development, an independent nonprofit research group at Tufts University.

“It is legitimately a big deal,” he said.

He noted that several other companies also are developing therapies for hepatitis C and that Gilead wants to lock in an aggressive price before it faces tougher competition.

Still, the price has provoked an outcry from the insurance industry, as well as from state Medicaid directors who say taxpayers will have to shoulder much of the cost of the drug because many with hepatitis C get their health care from the government through Medicare, Medicaid and the prison system.

Molina Healthcare, a company that operates Medicaid ­managed-care plans for 11 states, has told state officials it cannot bear the cost of covering the drug. The company, which gets a flat fee from states for each Medicaid recipient, negotiated its 2014 rates before the FDA approved Sovaldi. It is asking states to pay for the drug separately and is deciding whether to cover the drug at all.

“We can’t absorb this kind of a hit,” said chief executive J. Mario Molina.“It would cause us and other health plans to potentially become insolvent.”

Express Scripts, the nation’s largest prescription drug benefit manager, has said it is encouraging some doctors in its networks to delay prescribing Sovaldi for hepatitis C patients who can safely wait. It is the first time the company, which helps employers keep down the prescription drug costs for their employee health plans, has asked doctors to avoid a drug because of the cost.

The company hopes that when rival hepatitis C drugs hit the market, the increased competition will drive down costs.

“We have a public health crisis that’s been identified in hepatitis C. We now have a drug that is wonderful in its promise,” said Karen Ignagni, president of America’s Health Insurance Plans. “But the pricing of this drug for a public health crisis doesn’t match the situation.”

Lena H. Sun contributed to this story.

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Does the Latest HCV Breakthrough Therapy Spell Trouble for Gilead Sciences, Inc.?

Provided by The Motley Fool

By Cory Renauer | More Articles
February 26, 2014 | Comments (9)

Gilead Sciences (NASDAQ: GILD ) was the first to submit its highly anticipated hepatitis C virus (HCV) combination therapy to the FDA. Recently, Bristol-Myers Squibb (NYSE: BMY ) earned a Breakthrough Therapy designation for its dual regimen, likely to compete with Gilead's. AbbVie (NYSE: ABBV ) , and Merck (NYSE: MRK ) are also developing combination HCV treatments of their own, both with breakthrough designations.

Gilead's combo carries an enormous price tag, but America's largest pharmacy benefit manager Express Scripts (NASDAQ: ESRX ) has voiced its intent to curtail the pharmaceutical industry's pricing power. Here's a look at the competing therapies, and the expedited regulatory pathway that could result in several of them reaching the market at roughly the same time.

About the Breakthrough Therapy designation
The FDA has implemented expedited pathways in the past, but I don't think any has been as well defined as the Breakthrough Therapy designation. Implemented in 2012, the designation is reserved for targeted therapies that hit significant efficacy marks in early or mid-stage clinical trials. The nature of the condition must also be serious enough that patients are clearly willing to trade safety for speed, like HCV.

Without an expedited pathway, HCV therapies would likely need to provide data on the percent of patients surviving for several years after dosing. With the designation the FDA will work with the drug makers to define acceptable, shorter-term endpoints that should warrant approval. Of course, early approvals remain contingent on longer safety trials also designed in partnership with the agency. In the meantime, patients with unmet needs gain access to lifesaving new treatments.

Clash of the combos
From Gilead's perspective, the designation can erode the lead its HCV therapy had on its competitors. Gilead's Sovaldi as a single agent may have beat competitors to the US market in December last year, and last month in the EU, but it's the combination therapies that seem to have doctors warehousing patients by the thousands.

Fellow Foolish author Brian Orelli raised an important point recently. As a single agent, Sovaldi pills must be taken with pegylated interferon injections to be effective for genotype 1 (GT1) patients. Interferon injections produce very uncomfortable side effects. Sovaldi's first year on the market flying solo may be one of the most successful launches ever, but there are potentially millions of HCV patients that can wait for interferon and ribavirin free combination therapies. And that's where the trouble lies for Gilead in the years ahead.

In order to see a return on the $11 billion spent acquiring Sovaldi, Gilead has priced the single-agent therapy at $84,000 for a 12 week regimen in the US. If Express Scripts, America's largest pharmacy benefit manager, has its way, the combo will be far less expensive. During an interview with Bloomberg late last year, Express Scripts' Chief Medical Officer Steven Miller said his company would, "identify which drugs can be pitted against each other and make some really tough formulary decisions." Others may compete with Gilead on price, and the HCV combo field is getting more crowded each month.

A Breakthrough Therapy breakdown
AbbVie, Merck, and Bristol-Myers all have Breakthrough Therapy designated, HCV combinations in development. In a recent post I highlighted some data that makes AbbVie's and Merck's cocktails seem just as effective as Gilead's combination pill.

Since then Gilead has filed a New Drug Application with the FDA for the once-daily fixed-dose combination of ledipasvir and sofosbuvir for the treatment of GT1 HCV. On February 24, the FDA granted a Breakthrough Therapy designation to Bristol-Myers' daclatasvir and asunaprevir combination therapy for genotype 1b HCV patients. This is the second Breakthrough designation granted to Bristol-Myers' HCV combos.

While AbbVie and Gilead are widely expected to compete in order to remain on the Express Scripts formulary, Bristol-Myers' two drug combo was designated for the GT1b indication. Generally GT1b is more prevalent in Europe, so Gilead and AbbVie might not be competing with Bristol-Myers for a place on the Express Scripts formulary. At least not for a majority of GT1 patients.

Merck's two-pill HCV combination received its breakthrough designation last October for GT1 HCV. The company has remained quiet about the combo since reporting interim data at the American Association for the Study of Liver Diseases Meeting last November. During the latest earnings call, Merck's management mentioned its HCV program only in passing. The company's R&D head, Roger Perlmutter responsed to a direct question regarding the regimen by stating that data so far was not yet ideal. I'll keep my eyes open for more from the company. For now it doesn't seem that Merck is willing to enter the ring with AbbVie, Gilead, and Bristol-Myers just yet.

Final take
There may be three other HCV combination therapies in development with breakthrough designations, but for now it seems Gilead needs to concern itself with just one, AbbVie's. We can nitpick over the data, but the opinion that matters is that of major payers, like Express Scripts.

The late stage data from AbbVie and Gilead are outstanding, and Merck doesn't seem like it's willing to compete with them. If Bristol-Myers' combo's designation will only support an early approval for GT1b patients specifically, that should leave the majority of the US market to Gilead, and AbbVie. So far, it seems the only clear winner from that fight will be the payers.

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Cory Renauer has no position in any stocks mentioned. The Motley Fool recommends Express Scripts and Gilead Sciences. The Motley Fool owns shares of Express Scripts. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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New Therapies and Screening for Hepatitis C Are Changing Treatment Landscape

Provided by PharmTech

Feb 27, 2014

The American Journal of Managed Care (AJMC) recently convened an expert panel that analyzed the implications of recommendations by the US Preventive Services Task Force that all Americans born between 1946 and 1964 be screened for the hepatitis C virus (HCV). Widespread screening, along with new therapies that move patients from a chronic condition to a cure, is changing the landscape in treatment of hepatitis C, said the AJMC panel, according to a press release.

An estimated 3.2 million people have HCV, but the vast majority are unaware they have it, the AJMC noted in the press release. HCV gained steam in the early 1980s, before blood products were routinely screened for its presence. Screening people for HCV would allow candidates for treatment to rid themselves of the disease early, before complications become difficult and expensive to treat. Targeting the baby-boomer generation before most of them retire would allow those found to be carrying the virus to obtain treatment under commercial insurers, rather than Medicare. The cost of treatment to cure HCV, which may be possible in 90 to 94% of cases with new therapies, must be weighed against the cost of caring for what was once an expensive, long-term chronic condition, noted one of the panelists.

New therapies are available, with others in development. FDA recently granted breakthrough therapy designation to Bristol Myers-Squibb’s (BMS) investigational DCV Dual Regimen (daclatasvir and asunaprevir) for use as a combination therapy in the treatment of genotype 1b chronic hepatitis C infection, BMS announced in a press release. The designation is based on data from the company’s ongoing Phase III clinical trial program evaluating the all-oral combination regimen of DCV, an investigational NS5A replication complex inhibitor, and ASV, an investigational NS3 protease inhibitor, without ribavirin. BMS also recently announced that the European Medicines Agency validated the company’s marketing authorization application for the use of daclatasvir for the treatment of adults with HCV with compensated liver disease, including genotypes 1, 2, 3, and 4. The application seeks the approval of daclatasvir for use in combination with other agents for the treatment of chronic hepatitis C and will be reviewed under an accelerated regulatory review.

Source: American Journal of Managed Care

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CDC Foundation and Lilly to Address Unsafe Injection Practices in U.S. Healthcare Settings

Partnership Expands the Centers for Disease Control and Prevention's Work With Healthcare-Associated Infections

BY MARKETWIRED

FEBRUARY 26, 2014 11:40 AM EST

ATLANTA, GA--(Marketwired - February 26, 2014) - More than 150,000 patients have been notified of potential exposure to hepatitis and HIV due to unsafe injection practices in U.S. healthcare settings since 2001. According to the Centers for Disease Control and Prevention (CDC), medical injections are an overlooked source of infections and outbreaks. To better protect patients from this ongoing problem, the CDC Foundation's partnership with Eli Lilly and Company will support and expand CDC's Safe Injection Practices Coalition -- a group of public health, medical and industry organizations collaborating to raise awareness among patients and health care providers about safe injection practices.

"The combined educational resources and subject matter expertise from CDC and the Safe Injection Practices Coalition are critical to expanding patients' and health care providers' knowledge of safe injection practices," said Charles Stokes, president and CEO of the CDC Foundation. "We are grateful to CDC and the Safe Injection Practices Coalition for advancing this work and to Lilly for its partnership in this important coalition."

The partnership will extend the reach of Safe Injection Practices Coalition's One & Only Campaign, an injection safety awareness campaign that has produced and distributed educational and multimedia tools for health care providers and patients. Lilly's partnership will support the expansion of the coalition's activities, resources and tools for provider training and education, as well as patient empowerment. Funding will also support dissemination of safe injection messages using social media (follow us @InjectionSafety), YouTube, electronic continuing medical education, advertising and print materials for providers and patients.

"Findings from CDC-led research and outbreak investigations indicate that many health care providers are not following safe injection procedures," said Joe Perz, Dr.P.H., M.A., epidemiologist and team leader in the Division of Healthcare Quality Promotion at CDC. "To protect patients, all health care providers should review CDC's safe injection practice guidelines with their staff and colleagues."

Through this three-year partnership with Lilly, the Safe Injection Practices Coalition will:

• Expand the One & Only Campaign to new audiences such as individual and group-owned physician practices;
• Educate health care providers through new and enhanced training and communication materials to address emerging issues;
• Improve the Safe Injection Practices Coalition website and social media platforms to share resources and toolkits with new audiences; and
• Engage new and existing Safe Injection Practices Coalition partners.

"Lilly is committed to helping health care providers help their patients, through life-changing medicines and improving understanding and management of disease," said Alex Azar, president of Lilly USA. "We're honored to support CDC and health professionals across the country in this important initiative to advance patient safety and public health."

About the Safe Injection Practices Coalition
The Safe Injection Practices Coalition is a partnership of healthcare-related organizations, patient advocacy organizations, industry partners and other public health partners, led by the Centers for Disease Control and Prevention (CDC). The CDC Foundation is the convening partner of the coalition, formed to promote safe injection practices in all U.S. healthcare settings. The coalition has developed the One & Only Campaign -- a public health education and awareness campaign -- aimed at both health care providers and patients to advance and promote safe injection practices. For more information, visit www.oneandonlycampaign.org.

About the CDC Foundation
Established by Congress, the CDC Foundation helps the U.S. Centers for Disease Control and Prevention (CDC) do more, faster, by forging public-private partnerships to support CDC's work 24/7 to save lives and protect people from health and safety threats. The CDC Foundation currently manages more than 200 CDC-led programs in the United States and in 58 countries around the world. Since 1995 the CDC Foundation has launched more than 700 programs and raised $400 million to advance the life-saving work of CDC. For more information, visit www.cdcfoundation.org.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. The company was founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today Lilly remains true to that mission in all its work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit www.lilly.com and http://newsroom.lilly.com/social-channels.

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Hepatitis C virus infection and insulin resistance

World J Diabetes. 2014 February 15; 5(1): 52-58.

Published online 2014 February 15. doi: 10.4239/wjd.v5.i1.52.

Copyright ©2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Sandip K Bose and Ranjit Ray.

Sandip K Bose, Ranjit Ray, Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO 63104, United States

Ranjit Ray, Division of Infectious Diseases, Allergy and Immunology, Edward A Doisy Research Center, St. Louis, MO 63104, United States

Ranjit Ray, Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104, United States

Author contributions: Bose SK performed literature search and wrote the initial draft of the paper; Ray R edited the paper and made additional changes as needed.

Supported by The National Institutes of Health, NO. DK080812

Correspondence to: Ranjit Ray, PhD, Division of Infectious Diseases, Allergy and Immunology, Edward A Doisy Research Center, 1100 S. Grand Blvd., 8^th Floor, St. Louis, MO 63104, United States. rayr@slu.edu

Telephone: +1-314- 9779034 Fax: +1-314-7713816

Received November 9, 2013; Revised December 20, 2013; Accepted January 13, 2014;

Abstract

Approximately 170 million people worldwide are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and is the primary cause for liver transplantation in the western world. Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of type II diabetes. Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. Various mechanisms have been proposed in regard to HCV mediated insulin resistance, involving up regulation of inflammatory cytokines, like tumor necrosis factor-α, phosphorylation of insulin-receptor substrate-1, Akt, up-regulation of gluconeogenic genes like glucose 6 phosphatase, phosphoenolpyruvate carboxykinase 2, and accumulation of lipid droplets. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.

Keywords: Hepatitis C virus, Insulin resistance, Insulin receptor substrate 1, Protein kinase B, mammalian target of rapamycin/S6K1, Suppressor of cytokine signaling 3, Glucose transporter-4, Lipid metabolism, Anti-viral therapy

Core tip: Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection and often leads to development of type II diabetes. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, hepatocellular carcinoma and resistance to anti-viral treatment. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways.

INTRODUCTION

Hepatitis C virus (HCV) contains a positive sense single stranded RNA genome and belongs to the family Flaviviridae and genus Hepacivirus[¹]. HCV genome, 9.6 kb in length, is composed of a 5’ non-translated region (NTR), a long open reading frame (ORF) encoding a polyprotein and a 3’ NTR. The ORF encodes a polyprotein of about 3000 amino acids that is translated via an internal ribosome entry site at the 5’ NTR. The polyprotein is then cleaved by both cellular and viral proteases into at least 10 different proteins[¹]. These include three structural proteins namely, core and two envelope glycoproteins (E1 and E2). In addition, a protein called F or ARFP can be produced from a frame-shift of the core protein[²]. An ion channel protein p7 is formed by cleavage of E2[³]. Non structural proteins of HCV include NS2, NS3, NS4A, NS4B, NS5A, and NS5B.

The primary host cell for HCV is hepatocytes but replication may also occur in other cell types, such as peripheral blood mononuclear cells, as well as in B and T cell lines[^4,5]. HCV is a major cause of acute and chronic liver disease worldwide. More than 170 million people are currently infected with HCV[⁶]. Currently HCV vaccine is not available. Acute infection is usually asymptomatic, making early diagnosis difficult. Approximately 70% of acutely infected individuals fail to clear the virus and become chronically infected[⁷]. Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and is the primary cause for liver transplantation in the western world. The sustained antiviral response rate in treatment of chronic HCV infection with interferon (IFN)-α with ribavirin is limited (about 30%-40%)[^8,9]. Boceprevir and telaprevir protease inhibitors, have been shown to exhibit significantly higher rates of sustained virologic response (SVR) against HCV genotype 1 (about 65%-75%) as compared with peginterferon-ribavirin alone[^10,11]. However, use of these antiviral agents display higher incidence of adverse events, such as rash, gastrointestinal disorders, and anemia.

Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment[¹²]. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. The aim of this review is to summarize the currently available information on how chronic HCV infection interferes with insulin signaling pathways resulting in insulin resistance.

GLUCOSE UPTAKE AND INSULIN RESISTANCE

Glucose is a key metabolite essential for the production of energy (mostly ATP) which is required by cells. There are several mechanisms underlying increased glucose production. These include production of free glucose by increased glycogenolysis in the liver, increased gluconeogenesis, activation of forkhead box transcription factor (FoxO1) and improper insulin-glucagon hormonal balance, which stimulates increased glucose production[¹³]. Several factors contribute to elevated gluconeogenesis in diabetes, namely (1) increased supply of glucogenic precursors to the liver (glycerol, amino acids, free fatty acids), (2) increased lipid content, (3) increased cytokines and adipokines, and (4) decreased insulin receptor (IR) signaling in hepatocytes[¹³]. Glucose uptake into cells is regulated by the action of specific hormones, namely insulin and glucagon. Insulin is a peptide hormone secreted by the β-cells of the pancreatic islets of langerhans and maintains normal blood glucose levels by facilitating cellular glucose uptake, regulating carbohydrate, lipid and protein metabolism and promoting cell division and growth through its mitogenic effects[¹⁴]. The ability of insulin to stimulate glucose uptake into tissues is central to the maintenance of whole-body glucose homeostasis[¹⁵]. Type II diabetes mellitus (T2DM), occurs when the production of insulin is not sufficient to overcome a difficulty the body has in properly using insulin. This difficulty is called insulin resistance, resulting in increased glucose levels. Both forms of diabetes can pose an increased risk of major lifelong complications. In the case of insulin resistance, this includes a fivefold increased risk of coronary vascular disease, diabetic retinopathy and neuropathy[^16-19]. Fatty liver is relatively common in overweight and obese persons with T2DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers[²⁰].

Glucose transporter-4 (GLUT-4) was shown to be the major isoform responsible for enhanced glucose uptake into muscle and adipose tissues following the secretion of insulin into the bloodstream[^21,22]. The process of glucose uptake by cells requires a series of events to take place in a timely manner. It involves the binding of insulin to the IR resulting in subsequent phosphorylation and activation of IR substrate 1 and 2 (IRS-1/IRS-2), central molecules of the insulin signaling cascade[^23,24]. This in turn activates protein kinase B (AKT) by phosphorylation of Ser⁴⁷³ and Thr³⁰⁸ residues. Activated AKT causes the translocation of GLUT-4 from intracellular compartments to the cell surface where it is required for glucose uptake[²⁵]. Any change in the signaling is likely to induce insulin resistance which is associated with a number of pathophysiological changes including glucose intolerance, obesity, dyslipidemia and hypertension. Insulin resistance is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin, but the cells in the body become resistant to insulin and are unable to use it as effectively, resulting in an attenuated biological response, leading to hyperglycemia[²⁶]. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance[²⁷]. During the course of insulin resistance several inflammatory cytokines and lipid metabolites, like free fatty acids, interrupt with the normal insulin signaling and promote T2DM.

CHRONIC HCV INFECTION AND INSULIN RESISTANCE

Epidemiological studies suggest that patients with chronic HCV infection have a significantly increased prevalence of T2DM as compared to hepatitis B virus infected patients[^28-30]. Both insulin resistance and diabetes can adversely affect the course of chronic hepatitis C (CHC), leading to enhanced steatohepatitis and liver fibrosis[^30-32]. Insulin resistance, associated with type 2 diabetes, can promote fatty liver, and excessive hepatic accumulation of fat may promote insulin resistance and therefore contribute to the pathogenesis of the metabolic syndrome[³³]. Insulin resistance is a critical component of type 2 diabetes mellitus pathogenesis. Several mechanisms are likely to be involved in the pathogenesis of HCV-related insulin resistance[³⁴]. Several cellular lesions have been associated with insulin resistance, but the precise mechanism by which HCV induces insulin resistance remains elusive with numerous viewpoints and opinions[³⁰].

Impairment of IRS-1 and IRS-2 expression has been observed in the liver of patients with chronic HCV infection, as well as in HCV core transgenic mice, and from in vitro cell culture system[^35-38]. HCV mediates dysfunction of the insulin signaling pathways via several distinct mechanisms, such as upregulating the expression of suppressors of cytokine signaling 3 expression[³⁵], down regulation of peroxisome proliferator-activated receptors gamma (PPARγ)[³⁶], activation of mammalian target of rapamycin (mTOR)/S6K1 pathway[³⁸], and increased tumor necrosis factor-α (TNF-α) secretion[³⁹].

MODULATION OF IR SUBSTRATE BY HCV

HCV modulates insulin signaling and IRS-1 via multiple mechanisms which have been presented in Figure 1. Ser/Thr phosphorylation of IRS-1 inhibits its association with the IR, which in turn inhibits tyrosine phosphorylation of IRS-1, required for its activation, and promotes degradation. Upregulation of serine phosphorylation of IRS-1 is a key negative feedback mechanism under physiological conditions to prevent the action of insulin. In an insulin-resistant state, an imbalance occurs between positive IRS-1 Tyr-phosphorylation and negative Ser-phosphorylation of IRS-1[⁴⁰]. HCV core protein expression in hepatocytes upregulates Ser³¹² phosphorylation status of IRS-1 and modulates downstream Akt activity by inhibiting Thr³⁰⁸ phosphorylation[³⁷]. Ser³¹² and Ser¹¹⁰¹ phosphorylation of IRS-1 inhibits its association with the IR and stimulates degradation. HCV core protein induces insulin resistance by increasing Ser³¹² and Ser ¹¹⁰¹ phosphorylation, marking its for degradation via the activated mTOR/S6K1 pathway[³⁸], and subsequently blocking Tyr- phosphorylation of IRS-1 and Thr³⁰⁸ phosphorylation of Akt for the inhibition of glucose uptake. Activation of mTOR signaling also plays a key role in modulating IRS-1 activity. HCV genotype 2a infection significantly downregulates the expression of TSC1/TSC2, which in turn results in activation of downstream mTOR and S6K1[³⁸]. Phosphorylation of IRS-1 at Ser¹¹⁰¹ via the mTOR-S6K1 pathway may release IRS-1 from intracellular complexes, thereby enabling its degradation[⁴¹]. HCV significantly increases Ser¹¹⁰¹ phosphorylation of IRS-1, which enables its degradation[³⁸].

Figure 1 Schematic showing the interference of Hepatitis C virus in the insulin signaling pathway. Hepatitis C virus (HCV) core protein is known to up regulate Ser³¹² phosphorylation of insulin receptor substrate (IRS)-1 leading to degradation of IRS-1, the key molecule involved in propagation of insulin signal downstream from the insulin receptor (IR). HCV infection is also known to down regulate TSC1/TSC2 complex, resulting in subsequent upregulation of mTOR/S6K1 which leads to Ser¹¹⁰¹ phosphorylation of IRS-1 and its subsequent degradation. A role of HCV mediated upregulation of SOCS3 and tumor necrosis factor-α (TNF-α) has also been proposed which leads to degradation and blocking of IRS-1 function. HCV also upregulates glucose 6 phosphatase (G6P), phosphoenolpyruvate carboxykinase 2 (PCK2) leading to increased glucose production, and down regulates glucose transporter (GLUT)-4, GLUT-2, leading to decreased glucose uptake by hepatocytes. Overall, these alterations lead to insulin resistance. mTOR: Mammalian target of rapamycin.

A decrease in expression of IRS-1 and IRS-2, in patients with HCV infection has also been reported[³⁵]. Down-regulation of IRS-1 and IRS-2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells[³⁵]. HCV core up-regulated suppressor of cytokine signaling 3 (SOCS3) and caused ubiquitination of IRS-1 and IRS-2. HCV core-induced down-regulation of IRS-1 and IRS-2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells, indicating the important role played by SOCS3 in mediating down regulation of IRS-1[³⁵]. There have been reports that HCV genotypes might play an important role in deciding the pathway by which it impairs insulin signaling. It has been shown that the core protein of HCV genotype 3a promoted IRS-1 degradation through the downregulation of PPARγ and by upregulating the SOCS7, the core protein of genotype 1b activated the mTOR[³⁶].

TNF-α, released in an excess may promote phosphorylation of serine residues of IRS-1 eventually leading to the downregulation of downstream insulin signaling molecule Akt. HCV core protein increases the expression level of TNF-α and promotes insulin resistance[⁴²].

IMPAIRED LIPID AND GLUCOSE METABOLISM BY HCV

Insulin resistance is strongly influenced by abnormalities in lipid metabolism. Any dysfunction of the lipid metabolism triggers lipotoxicity through the production of free fatty acids thereby promoting insulin resistance[⁴³]. HCV core protein down-regulates microsomal triglyceride transfer protein, an enzyme that mediates lipid translocation to the endoplasmic reticulum membrane and decreases the assembly of very low density lipoproteins[⁴⁴]. It has been observed that HCV promotes fatty acid synthesis by the upregulation of lipogenic gene sterol regulatory element binding protein 1c which promotes the transcriptional activation of other lipogenic genes like acetyl CoA carboxylase, ATP citrate lyase, hydroxymethylglutaryl CoA reductase[⁴⁵].

HCV infection promotes the expression of gluconeogenic genes namely, glucose 6 phosphatase (G6P) and phosphoenolpyruvate carboxykinase 2 (PCK2) resulting in increased glucose production and enhanced insulin resistance[^46,38]. HCV also down regulates the expression of GLUT4, which is necessary for uptake of glucose. This results in a decreased glucose uptake and increased plasma glucose, leading to development of insulin resistance[³⁸].

A schematic showing how HCV interferes with insulin signaling pathway, leading to insulin resistance is presented in (Figure 1). HCV modulates functioning of IRS-1 via multiple mechanisms, including up regulation of Ser³¹² or Ser¹¹⁰¹ phosphorylation which leads to degradation of IRS-1. HCV also upregulates SOCS3 and down regulates TSC1/TSC2 leading to blocking of insulin signaling. HCV infection leads to increased gluconeogenesis via up regulation of G6P and PCK2. GLUT-4, and GLUT-2 expression is also down regulated by HCV leading to decreased glucose uptake. Overall, all these alterations by HCV leads to development of insulin resistance.

INSULIN RESISTANCE AND LIVER DISEASE PROGRESSION

The metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia[⁴⁷]. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer, including the risk of developing HCC. IR is induced by HCV-4 irrespective of severity of liver disease. IR starts early in infection and facilitates progression of hepatic fibrosis and HCC development[⁴⁷]. HCC patients showed higher IR frequency, and moderate to high viral load associated with high HOMA-IR in CHC and HCC[⁴⁷]. Insulin resistance associates with a higher risk of HCC in cirrhotic HIV/HCV-co-infected patients also[⁴⁸]. There are many causes of HCC, and nonalcoholic fatty liver disease (NASH) is emerging as a leading risk factor owing to the epidemic of obesity and T2DM. The mechanisms leading to HCC in obesity and T2DM likely involve interactions between several signaling pathways, many of which are modulated by HCV infection, and also include oxidative stress, inflammation, oncogenes, adiponectins, and insulin resistance associated with visceral adiposity and diabetes[⁴⁹].

Insulin resistance and subsequent hyperinsulinemia are highly associated with fatty liver disease and is an important risk factor for the progression of fibrosis in CHC[^50,51]. From metabolic aspect, HCV infection resembles NASH in numerous features, such as the presence of steatosis, serum dyslipidemia, and oxidative stress in the liver[⁵²]. On the other hand, there are noticeable differences between hepatitis C and NASH, in the fact that HCV modulates cellular gene expression and intracellular signal transduction pathways, while such details have not been noted for NASH. HCV core protein expression leads to the development of progressive hepatic steatosis and HCC in transgenic mice[⁵³]. Hepatic steatosis is known to occur at a high rate (40%-86%) in chronic HCV patients, and a close relationship between steatosis and intrahepatic core protein expression has been noted[⁵⁴]. Insulin resistance is a prominent mechanism linking steatosis and fibrogenesis although this link is complex and not properly understood.

CLINICAL IMPLICATIONS OF HCV-MEDIATED INSULIN RESISTANCE

Several epidemiological, clinical and experimental data show that HCV plays a direct role in perturbing glucose metabolism, leading to both insulin resistance and diabetes[^28-30]. Curing HCV results in the amelioration of insulin resistance and decreased incidence of diabetes after the end of therapy[^55,56]. In the only trial that used the antidiabetic metformin[⁵⁷], only a marginal, nonsignificant increase of the SVR rate was observed, despite an increased virological response after 4 wk of triple therapy. The data reported in a study using different schedules containing the antiglycaemic PPAR-γ agonist pioglitazone[⁵⁸] are discouraging. Overall, the administration of insulin sensitizers together with the standard of care has not only failed to improve the virological response to therapy, but has also fallen short of providing much useful insight into the mechanisms linking reduced response to insulin resistance[⁵⁹]. Early sulfonylureas although useful in lowering blood glucose level, were associated with significant off-target effects, and the biguanide phenformin was discontinued due to adverse events[⁶⁰]. Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment of diabetes during HCV infection.

THERAPEUTIC APPROACHES AND FUTURE GOALS

Treatment for HCV induced insulin resistance is highly linked with anti-viral treatment. Treatment of chronic HCV infection has 2 goals. The first is to achieve SVR (i.e., sustained eradication of HCV, which is defined as the persistent absence of HCV RNA in serum 6 mo or more after completing antiviral treatment). The second goal is to prevent progression to cirrhosis, HCC, and decompensated liver disease requiring liver transplantation. The treatment of HCV has evolved over the years. Current treatment options include combination therapy consisting of ribavirin and pegylated IFN. Protease inhibitors are emerging as a third feature of combination therapy. The sustained antiviral response rate in treatment of chronic HCV infection with IFN-α and ribavirin is limited (about 30%-40%)[^8,9]. Boceprevir and telaprevir protease inhibitors have been shown to exhibit significantly higher rates of SVR against HCV genotype 1 (65%-75%) as compared with peginterferon-ribavirin alone[^10,11]. More recently, sofosbuvir has also been used for treatment along with ribavirin, with significant increased SVR[⁶¹]. However, use of these antiviral agents display higher incidence of adverse events, such as rash, gastrointestinal disorders, and anemia. Thus, development of therapies with less side effects is desirable.

The prevalence of HCV antibodies in the type 2 diabetic population ranges between 1.78% and 12.1%[⁶²]. Several cross-sectional studies have found a higher prevalence of HCV antibodies in type 2 diabetic patients than expected in the general population[^62,63]. Early phase and total insulin secretion are determined using oral glucose tolerance testing (OGTT), Insulin sensitivity was measured directly by steady-state plasma glucose concentration during insulin suppression test. Fasting plasma glucose ≥ 126 mg/dL or 2-h plasma glucose > 200 mg/dL during OGTT are generally used as criteria for diagnosis of diabetes[⁶⁴]. Well controlled DM was defined when the HbA1c level was < 7%. Agents used in diabetic therapy include the following: sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, Meglitinide derivativesetc[⁶⁰]. Although effective in reducing blood glucose levels, early sulfonylureas were associated with significant off-target effects, and the biguanide phenformin was discontinued due to adverse events[⁶⁰]. Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment. However, many patients require additional glucose control treatment with an agent that has a complementary mechanism of action like metformin. Some common drugs used for treatment of T2DM available in the market include metformin oral, actos oral, Byetta subQ, Januvia oral, etc.

Another possible way of reversing insulin resistance would be via targeting the signaling components in the insulin signaling pathway modulated by HCV. For instance, we have shown that HCV up regulates phospho-S6K1, which stimulates degradation of IRS-1[³⁸]. Thus, targeting phospho-S6K1 would be a target against HCV induced insulin resistance. These studies have not been done yet, so at this time it will be difficult to comment on the predictive outcome on reversal of insulin resistance. Use of specific inhibitors of SOCS-3, which may become useful to correct resistance to both insulin and IFN-α, are not available for clinical use. Alternatively, one may envision inhibiting TNF-α by administering infliximab or similar agents. IR also results from uncontrolled diet and life style. Regulation of weight, diet, and life style management will also be key in managing IR.

ACKNOWLEDGMENTS

We thank and Lin Cowick for preparation of the manuscript.

Footnotes

P- Reviewers: Efanov AM, Teeter JG, Traub M, Vestergaard ET S- Editor: Zhai HH L- Editor: A E- Editor: Liu SQ

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