TGIF Rewind: Big pharmaceuticals and the Hepatitis C drug trail dubbed a 'miracle cure'

Rewind: News and Views

Welcome to TGIF rewind, a look back at this weeks hepatitis C headlines with updates from around the web.

In The News

Big pharmaceuticals and the Hepatitis C drug trail dubbed a 'miracle cure'
What would you do if you had a potentially lethal illness, knew of a "miracle" cure which would most likely fix the problem in three months by taking one pill a day, but you couldn't afford to buy the medicine from the drug company which owned the patent? This is the position that "Patient Zero" found himself in. And he, with a doctor and a group of campaigning mates, found an answer – one that they believe costs up to 30 times less than the drug company might expect them to pay.

CDC
State Reporting Requirements for Viral Hepatitis

Check out new site w/ info on state reporting requirements for viral hepatitis

Drug and biotech industry trade groups give Martin Shkreli the boot

Former hedge fund manager Martin Shkreli has the Internet ablaze after hiking the price of the drug that's been on the market for decades. Here's what happened. (Gillian Brockell/The Washington Post)

Health Care Industry Mergers Side Effect of Affordable Care Act

Many are worried that the huge consolidations will dampen competition and push up health care prices over time...

One senator's push to fund hepatitis C treatment for veterans

Many veterans who fought to protect and defend our country are still fighting to get the support they need from the federal government...

Why people don't trust drug makers
Insurers and pharmacy benefit managers - not drug companies - are the ones who determine what patients pay for medications. Consider the controversy surrounding the hepatitis C drug Sovaldi. When the medicine came on the market, it quickly became ...

Rhode Island Medicaid Denied 65% of Hep C Treatment Requests in 2015
It's a move that, while saving the state millions of dollars, is keeping hundreds of sick patients from accessing a cure.

How Much Did Medicaid Programs Spend on Sovaldi in 2014?

Concern about drug costs has been particularly acute for state Medicaid programs, which face both limited budgets and high Hepatitis C prevalence among beneficiaries (higher than in the general population). And perhaps with good reason: In 2014, the ...

Sofosbuvir-velpatasvir combo effective in all HCV genotypes

By: MADHU RAJARAMAN, Internal Medicine News Digital Network

September 23, 2015 

A once-daily, fixed-dose combination of sofosbuvir (SOF) plus velpatasvir (VEL) had high success rates for the treatment of all six genotypes of hepatitis C virus, manufacturer Gilead Sciences reported.

In three of four phase III trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3), 1,035 HCV patients were given the drug combination for 12 weeks. In the fourth trial (ASTRAL-4), 267 HCV patients with decompensated cirrhosis were randomized to receive either the SOF/VEL combination for 12 weeks with or without ribavirin or 24 weeks of just SOF/VEL. The primary efficacy endpoint for all studies was a sustained virological response at 12 weeks, the company said in a statement.

The FDA has designated the SOF/VEL combination as “breakthrough therapy” status, granted to “investigational medicines that may offer major advances in treatment over existing options,” the statement said.Results showed that 98% of patients in the first three trials achieved the efficacy endpoint. In the ASTRAL-4 study, 94% of patients in the SOF/VEL plus ribavirin group achieved sustained virological response at 12 weeks. The rates of success in patients receiving the SOF/VEL combination for 12 or 24 weeks were 83% and 86%, respectively. The most common adverse effects were fatigue, nausea, and headache.

mrajaraman@frontlinemedcom.com

Press Release

Gilead Announces SVR12 Rates from Four Phase 3 Studies Evaluating Fixed-Dose Sofosbuvir/Velpatasvir (GS-5816) Pan-Genotypic

Two HCV Drugs to Be Discontinued

The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.

Rebetol is a nucleoside analogue indicated for chronic hepatitis C in combination with interferon alfa-2b (pegylated and nonpegylated), in patients ≥3 years of age with compensated liver disease. It is supplied as 200mg capsules in 56-, 70-, and 84-count bottles. The Rebetol discontinuation is effective February 1, 2016.

PegIntron is an antiviral indicated for treatment of chronic hepatitis C in patients with compensated liver disease. It is supplied as 50mcg/0.5mL, 80mcg/0.5mL, 120mcg/0.5mL, and 150mcg/0.5mL single-use vials and single-use pre-filled pens. No effective date is available for the PegIntron discontinuation.

For more information call (888) 463-6332 or visit FDA.gov.
Source
http://www.empr.com/safety-alerts-and-recalls/rebetol-pegintron-to-be-discontinued/article/440426/

Conatus Announces emricasan Phase 2 study reduces liver portal hypertension predominantly due to NASH or HCV

A player in J&J's hep C cocktail helps hustle a quick cure 

September 17, 2015 | By John Carroll
Gilead has already made a megablockbuster fortune out of its hepatitis C cure. But the race to cure patients faster (and probably cheaper) is still on. And Achillion today posted some new data from small studies that show its NS5A inhibitor odalasvir (or ACH-3102) could feature prominently in one of the new cocktail therapies now in development at Johnson & Johnson...

Around The Web

NATAP

Hepatitis C virus infection: a risk factor for Parkinson's disease
"In summary, our study not only demonstrated a significantly positive association between HCV infection and Parkinson's disease (PD) from a large population-based epidemiological study but also proved the dopaminergic neuronal toxicity by HCV in vitro at the molecular level through an increase in cytokines induced by HCV. Epidemiologically, we found that anti-HCV(+) patients had statistically significant increased risk of developing PD in the population-based study. 

Excluding people who use drugs or alcohol from access to hepatitis C treatments - Is this fair, given the available data? - EDITORIAL 

Revolutionary new drugs to cure hepatitis C virus (HCV) infection represent one of the most important breakthroughs in clinical medicine in recent decades. However, high pricing of these well-tolerated, highly efficacious all-oral regimens and high demand (actual or anticipated) has led many payers in the United States and other countries to exclude people who have recently used illicit drugs, injectable drugs or alcohol (with the definitions of "use" varying by jurisdiction) from access to these treatments

N Engl J Med 

Correspondence

Early Patterns of Sofosbuvir Utilization by State Medicaid Programs

N Engl J Med 2015; 373:1279-1281 September 24, 2015 

DOI: 10.1056/NEJMc1506108

To the Editor:

The cure rates associated with sofosbuvir, a new treatment for hepatitis C virus (HCV), have been remarkable.1 However, the high cost of the drug has raised concerns,2 particularly in regard to socioeconomically disadvantaged populations with a high prevalence of HCV infection, such as Medicaid beneficiaries. Demand for new HCV drugs in Medicaid populations drove historic surges in spending on drugs in 2014, the first full year during which sofosbuvir was available since its approval by the Federal Drug Administration (FDA) in late 2013.3 Given its recent introduction to the market, little is known about state-level utilization and spending patterns for sofosbuvir...

Healio 

NICE recommends software to diagnose, monitor liver fibrosis
“As well as meaning that people with chronic hepatitis B or C could avoid having invasive liver biopsies, the associated savings of more than £400 per person ...

Interferon-based therapy still common for HCV among veterans
In a retrospective study, researchers found that the uptake of direct-acting antivirals, specifically Victrelis and Incivek, increased among veterans with HCV over time…

Editorial

HCV Guidelines: A Living Breathing Document

The guidelines for hepatitis C have been updated twice in the month of August.

The first update incorporated the approval of daclatasvir (Daklinza, Bristol-Myers Squibb) in the United States and, based on that approval, modified treatment recommendations for most of the treatment groups..

Lucinda Porter
Hepatitis C: The Evolution of Treatment
Last week I discussed the history of hepatitis C. This week I focus on the evolution of hepatitis C treatment...

Healthy You

Green Tea Hidden Dangers: Teen Contracts Acute Hepatitis After Drinking Three Cups Per Day
A young woman has contracted hepatitis after drinking three cups of Chinese green tea per day.
Doctors have now warned of the hidden dangers of consuming too much of the herbal tea, which they believe was to blame for the teenager contracting acute hepatitis...

Over long term, diet and exercise are best to prevent diabetes

In a head-to-head comparison over 15 years, diet and exercise outperformed the drug metformin in preventing people at high risk for diabetes from developing the disease.

Metformin Link to Vitamin B12 Deficiency, Neuropathy, in Diabetes

Researchers link 4 years of metformin use to a net worsening of peripheral neuropathy in type 2 diabetes, even after accounting for improvements from HbA1c lowering.

Medscape Medical News, September 25, 2015 

Rethinking Drinking 

Explore calculators, interactive worksheets, and more that will help you take a look at your drinking habits and understand how they may affect your health...

Off Topic

Should Dr Oz, a Prominent Surgeon, Be Fired for Quackery?
Last spring, 10 physicians wrote to Columbia University, where Dr Mehmet Oz is employed, demanding his removal for promoting quack remedies on TV. Should he be? See what your colleagues think.

Scientists stop and search malware hidden in shortened URLs on Twitter
Intelligent system created to stop and search malware links
Engineering and Physical Sciences Research Council

Cyber-criminals are taking advantage of real-world events with high volumes of traffic on Twitter in order to post links to websites which contain malware.

To combat the threat, computer scientists have created an intelligent system to identify malicious links disguised in shortened urls on Twitter. They will test the system in the European Football Championships next summer. The research is co-funded by the Engineering and Physical Sciences Research Council (EPSRC) and the Economic and Social Research Council (ESRC).

In the recent study the Cardiff University team identified potential cyber-attacks within five seconds with up to 83% accuracy and within 30 seconds with up to 98% accuracy, when a user clicked on a URL posted on Twitter and malware began to infect the device.

The scientists collected tweets containing URLs during the 2015 Superbowl and cricket world cup finals, and monitored interactions between a website and a user's device to recognise the features of a malicious attack. Where changes were made to a user's machine such as new processes created, registry files modified or files tampered with, these showed a malicious attack.

The team subsequently used system activity such as bytes and packets exchanged between device and remote endpoint, processor use and network adapter status to train a machine classifier to recognise predictive signals that can distinguish between malicious and benign URLs.

Dr Pete Burnap, Director of the Social Data Science Lab at Cardiff University, and lead scientist on the research, said: "Unfortunately the high volume of traffic around large scale events creates a perfect environment for Cyber-criminals to launch surreptitious attacks. It is well known that people use online social networks such as Twitter to find information about an event.

"Attackers can hide links to malicious servers in a post masquerading as an attractive or informative piece of information about the event.

"URLs are always shortened on Twitter due to character limitations in posts, so it's incredibly difficult to know which are legitimate. Once infected the malware can turn your computer into a zombie computer and become part of a global network of machines used to hide information or route further attacks.

"In a 2013 report from Microsoft these 'drive-by downloads' were identified as one of the most active and commercial risks to Cyber security.

"At the moment many existing anti-virus solutions identify malware using known code signatures, which make it difficult to detect previous unseen attacks."

Professor Omer Rana, Principal investigator on the project which is also includes Royal Holloway, University of London, City University London, the University of Plymouth and Durham University said:

"We are trying to build systems that can help law enforcement authorities make decisions in a changing Cyber Security landscape. Social media adds a whole new dimension to network security risk. This work contributes to new insight into this and we hope to take this forward and develop a real-time system that can protect users as they search for information about real-world events using new forms of information sources.

"We have the European Football Championships coming up next summer, which will provide a huge spike in Twitter traffic and we expect to stress-test our system using this event."

Professor Philip Nelson, Chief Executive, EPSRC said: "Using social media is an integral part of modern life, vital to organisations, businesses and individuals. The UK needs to operate in a resilient and secure environment and this research will help combat these criminal Cyber-attacks."

Hope everyone has a wonderful weekend.

Tina

Conatus Announces emricasan Phase 2 study reduces liver portal hypertension predominantly due to NASH or HCV

Press Release

Conatus Announces Top-line Results From Multicenter Phase 2 Portal Hypertension Clinical Trial in Patients With Liver Cirrhosis

September 23, 2015 16:01 ET | Source: Conatus Pharmaceuticals

- Emricasan Significantly Lowered Portal Pressure in Patients With Severe Portal Hypertension -

- Conference Call and Webcast Presentation at 8:30 a.m. ET on Thursday, September 24 -

SAN DIEGO, Sept. 23, 2015 (GLOBE NEWSWIRE) -- Conatus Pharmaceuticals Inc. (NASDAQ:CNAT) today announced that the company's exploratory Phase 2 Portal Hypertension (PH) clinical trial of emricasan, a first-in-class, orally active pan-caspase inhibitor, met the following primary endpoints: a) a clinically meaningful and statistically significant change from baseline in hepatic venous pressure gradient (HVPG), a measurement of pressure in the portal vein, in patients with liver cirrhosis and severe portal hypertension (HVPG ≥12 mmHg); and b) a statistically significant change from baseline in cleaved Cytokeratin 18 (cCK18), a mechanism-specific biomarker of excessive cell death that contributes to chronic inflammation, in the total evaluable liver cirrhosis patient population.

The open-label PH trial was conducted at nine U.S. sites and enrolled 23 patients (22 evaluable) with portal hypertension and compensated liver cirrhosis that was predominantly due to nonalcoholic steatohepatitis (NASH) or hepatitis C virus (HCV), including patients with active HCV infection and patients who had a sustained viral response (SVR) to antiviral therapy. Portal hypertension, or elevated blood pressure in the major vein feeding into the liver, was confirmed by HVPG measurement >5 mmHg at baseline and measured again after treatment with 25 mg of emricasan orally twice daily for 28 days. Patients were divided according to the HVPG therapeutic threshold of 12 mmHg, which indicates more severe portal hypertension. Reducing the HVPG to below 12 mmHg or reducing HVPG by ≥10% or ≥20% has been strongly associated with clinical benefit in this patient population.

The HVPG endpoint was analyzed in: a) patients with baseline HVPG values ≥12 mmHg (N=12); b) patients with baseline HVPG values <12 mmHg (N=10); and c) all evaluable patients (N=22). HVPG measurement was standardized, and tracings were evaluated by a single expert reader not otherwise involved in the PH trial. HVPG decreased by a mean of 3.7 mmHg from the mean baseline of 20.6 mmHg in the higher baseline HVPG group (p<0.003), with 8 of 12 achieving a ≥10% decrease, 4 of 12 achieving a ≥20% decrease, and 2 of 12 achieving reductions below 12 mmHg. The changes from baseline HVPG were not statistically significant in the lower baseline HVPG group (+1.9 mmHg mean increase from mean baseline of 8.1 mmHg; p=0.12) or the total evaluable patient population (–1.1 mmHg from mean baseline of 15.2 mmHg; p=0.26). The cCK18 endpoint, analyzed in the total evaluable patient population, showed a statistically significant reduction (p<0.03) from baseline. Consistent with results from prior trials, emricasan was safe and well tolerated in the PH trial, with no dose-limiting toxicities and no drug-related serious adverse events. Detailed results are expected to be presented in a future scientific forum.

As liver cirrhosis progresses, portal pressure increases and hepatic function is eventually lost. Importantly, portal hypertension is largely responsible for events of hepatic decompensation including variceal bleeding, ascites, and encephalopathy, which contribute substantially to morbidity and mortality in these patients. By lowering elevated portal pressures, emricasan has the potential to decrease the risk of hepatic decompensation in liver cirrhosis patients over the short term, and may improve both liver function and structure over the long term through anti-inflammatory and anti-fibrotic effects.

David T. Hagerty, M.D., Executive Vice President of Clinical Development at Conatus, said, "We were excited to demonstrate that a drug candidate with the potential to achieve long-term resolution of fibrosis and cirrhosis also has the ability to induce a rapid and clinically meaningful reduction of severe portal hypertension. The reduction of portal pressure over a relatively short time frame in the patients with therapeutically relevant portal hypertension may reflect the initial impact of emricasan on the hyperdynamic circulation that is the predominant contributor to portal hypertension as cirrhosis progresses and/or a direct effect upon intrahepatic vasculature resistance. Future studies will be needed to assess the relative contribution of these mechanisms to the observed clinical effect. Decreasing HVPG has been identified by the FDA (U.S. Food and Drug Administration) as a validated, objective measure that may be acceptable as a surrogate endpoint for clinical trials of patients with liver cirrhosis. These results set the stage for future Phase 2b clinical trials in patients with cirrhosis and therapeutically relevant portal hypertension."

"These results demonstrate that emricasan can cause a clinically meaningful improvement in portal hypertension in the liver cirrhosis patients who need it most," said Conatus co-founder, President and Chief Executive Officer Steven J. Mento, Ph.D. "Specifically, patients with therapeutically relevant baseline portal hypertension showed meaningful decreases in HVPG. We believe the results from this trial establish the near-term effects of emricasan on portal hypertension. We are evaluating emricasan's potential longer-term effects on liver function and liver structure in our other two ongoing clinical trials: the Phase 2 Liver Cirrhosis (LC) trial and the Phase 2b post-transplant trial."

"Even though the number of patients in this trial was small," added Dr. Hagerty, "Conatus was encouraged by the consistency of responses in patients with portal hypertension and cirrhosis due primarily to NASH or HCV. These results further support our view that apoptosis and inflammation are important common mechanisms for progressive liver disease across multiple etiologies, and that treatment with emricasan is likely to provide both short- and long-term clinical benefits."

Conference Call/Webcast/Presentation

Conatus will host a conference call and webcast at 8:30 a.m. Eastern Time on Thursday, September 24, to discuss the top-line results and provide a mechanism-focused overview of liver cirrhosis and portal hypertension. To access the conference call, please dial 877-312-5857 (domestic) or 970-315-0455 (international) at least five minutes prior to the start time and refer to conference ID 45793794. An associated presentation and live and archived audio webcast of the call will be available in the Investor Center of the company's website at http://ir.conatuspharma.com/events.cfm.

About Emricasan Clinical Development

To date, emricasan has been studied in over 600 subjects in fifteen clinical trials across a broad range of liver disease etiologies and stages of progression. In multiple clinical trials, emricasan has demonstrated statistically significant, rapid and sustained reductions in elevated levels of key biomarkers of inflammation and apoptosis that are implicated in the severity and progression of liver disease. Importantly, these key biomarkers are known to be elevated and to have prognostic value in multiple hepatic indications that Conatus is currently pursuing. The company's ongoing Phase 2 LC trial is evaluating emricasan's potential medium-term effect on liver function using two other potential surrogate clinical endpoints – Model for End-Stage Liver Disease (MELD) score and Child-Pugh-Turcotte (CPT) status. The company also is evaluating emricasan's potential longer-term effects on liver structure in its ongoing Phase 2b clinical trial in post-orthotopic liver transplant (POLT) recipients who have reestablished liver fibrosis or cirrhosis post-transplant as a result of recurrent HCV infection and have successfully achieved a SVR following HCV antiviral therapy (POLT-HCV-SVR). The company currently is developing a strategy for initial registration of emricasan as a potential treatment for patients with liver cirrhosis.

About Conatus Pharmaceuticals

Conatus is a biotechnology company focused on the development and commercialization of novel medicines to treat liver disease. Conatus is developing its lead compound, emricasan, for the treatment of patients with chronic liver disease. Emricasan is a first-in-class, orally active pan-caspase inhibitor designed to reduce the activity of enzymes that mediate inflammation and apoptosis. Conatus believes that by reducing the activity of these enzymes, emricasan has the potential to interrupt the disease progression across the spectrum of liver disease. For additional information, please visit www.conatuspharma.com.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward looking statements, including statements regarding: presenting detailed results of the PH trial in a future scientific forum; emricasan's potential to decrease risk of hepatic decompensation; emricasan's potential to improve both liver function and structure through anti-inflammatory and anti-fibrotic effects; emricasan's potential to achieve long-term resolution of fibrosis and cirrhosis; emricasan's potential impact on hyperdynamic circulation and/or intrahepatic vasculature resistance; the acceptability of HVPG as a surrogate endpoint for clinical trials of patients with liver cirrhosis; whether the results from the PH trial establish the near-term effects of emricasan on portal hypertension or allow for future Phase 2b clinical trials in patients with cirrhosis and therapeutically relevant portal hypertension; emricasan's longer-term effects on liver function and liver structure; the importance of apoptosis as a common mechanism for progressive liver disease and that inhibiting apoptosis with emricasan is likely to be of both short- and long-term clinical benefit; the utility of MELD and CPT as potential surrogate clinical endpoints; the potential for emricasan to be a treatment for liver cirrhosis patients; and emricasan's potential to interrupt the disease progression across the spectrum of liver disease. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including: Conatus' ability to initiate and successfully complete current and future clinical trials; Conatus' ability to evaluate emricasan's potential medium-term and longer-term effects on liver function and liver structure in its other two ongoing clinical trials; Conatus' ability to develop a registration strategy and pathway for emricasan; Conatus' dependence on its ability to obtain regulatory approval for, and then successfully commercialize emricasan, which is Conatus' only drug candidate; Conatus' reliance on third parties to conduct its clinical trials, enroll subjects, manufacture its preclinical and clinical drug supplies and manufacture commercial supplies of emricasan, if approved; the potential that earlier clinical trials may not be predictive of future results; potential adverse side effects or other safety risks associated with emricasan that could delay or preclude its approval; results of future clinical trials of emricasan; the potential for competing products to limit the clinical trial enrollment opportunities for emricasan in certain indications; the uncertainty of the FDA's and other regulatory agencies' approval processes and other regulatory requirements; Conatus' ability to fully comply with numerous federal, state and local laws and regulatory requirements applicable to it; Conatus' limited operating history and its ability to operate successfully as a public company; Conatus' ability to obtain additional financing in order to complete the development and commercialization of emricasan; and those risks described in Conatus' prior press releases and in the periodic reports it files with the Securities and Exchange Commission. The events and circumstances reflected in Conatus' forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, Conatus does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.MEDIA: David Schull Russo Partners, LLC (858) 717-2310 INVESTORS: Alan Engbring Conatus Pharmaceuticals Inc. (858) 376-2637

Gilead Announces SVR12 Rates from Four Phase 3 Studies Evaluating Fixed-Dose Sofosbuvir/Velpatasvir (GS-5816) Pan-Genotypic

Gilead's new pan-genotype hep C combo scores stellar results in PhIII
September 21, 2015 | By John Carroll
Gilead has proved once again that it knows how to cure hepatitis C for a heavy concentration of patients, posting some stellar pangenotype data from a slate of four late-stage studies that combined its blockbuster Sovaldi with the experimental NS5A inhibitor velpatasvir. And the Big Biotech says it's ready to step up with new marketing applications with an eye to continuing its domination.

Press Release
Gilead Announces SVR12 Rates from Four Phase 3 Studies Evaluating a Once-Daily, Fixed-Dose Combination of Sofosbuvir (SOF) and Velpatasvir (VEL) (GS-5816) for the Treatment of All Six Hepatitis C Genotypes

If Approved, SOF/VEL Would be the First All-Oral Pan-Genotypic Single Tablet Regimen for Chronic HCV-

- U.S. NDA and European MAA Submissions Planned for Q4 2015 -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 21, 2015-- Gilead Sciences, Inc.(Nasdaq:GILD) today announced topline results from four international Phase 3 clinical studies (ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-4) evaluating a once-daily, fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF) with velpatasvir (VEL), an investigational pangenotypic NS5Ainhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.

In the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies, 1,035 patients with genotype 1-6 HCV infection received 12 weeks of SOF/VEL. Among these patients, 21 percent had compensated cirrhosis and 28 percent had failed prior treatments. The ASTRAL-4 study randomized 267 patients with decompensated cirrhosis (Child-Pugh class B) to receive 12 weeks of SOF/VEL with or without ribavirin (RBV), or 24 weeks of SOF/VEL. The primary endpoint for all studies was SVR12.

The intent-to-treat SVR12 rates observed in the ASTRAL studies are summarized in the table below. Complete results from all four studies will be presented at future scientific conferences.

Of the 1,035 patients treated with SOF/VEL for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 percent) achieved the primary efficacy endpoint of SVR12. Of the 20 patients who did not achieve SVR12, 13 patients (1.3 percent) experienced virologic failure and seven did not complete an SVR12 visit (e.g., lost to follow-up). Twelve of the 13 virologic failure patients relapsed (two genotype 1 HCV-infected patients and 10 genotype 3 HCV-infected patients). There was one patient with documented reinfection. No patients with genotype 2, 4, 5 or 6 HCV infection had virologic failure.

Patients treated with SOF/VEL for 12 weeks in these three studies had similar adverse events compared with placebo-treated patients in ASTRAL-1. Two patients (0.2 percent) treated with SOF/VEL for 12 weeks, one each in ASTRAL-1 and ASTRAL-2, discontinued treatment due to adverse events. The most common adverse events were headache, fatigue and nausea.

In ASTRAL-4, patients with Child-Pugh class B cirrhosis receiving SOF/VEL+RBV achieved higher SVR12 rates than patients receiving SOF/VEL for 12 or 24 weeks. Among genotype 1 and 3 patients treated with SOF/VEL+RBV for 12 weeks, the SVR12 rates were 96 percent and 85 percent, respectively.

The most common adverse events across all arms of ASTRAL-4 were fatigue, nausea and headache. Anemia, a common side effect associated with RBV, was reported in 31 percent of patients in the SOF/VEL+RBV arm and in 4 percent and 3 percent of patients treated with SOF/VEL for 12 or 24 weeks, respectively. Treatment emergent serious adverse events occurred in 18 percent of patients and nine patients died. The majority of serious adverse events and deaths were associated with advanced liver disease.

“The ASTRAL study results demonstrate that a 12-week course of therapy with the first fixed-dose combination of two pan-genotypic compounds can provide high cure rates for patients with all HCV genotypes,” said Norbert Bischofberger, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. “We are pleased to have now brought forward our second single tablet regimen for HCV infection that complements Harvoni, our first single tablet regimen approved specifically for patients with genotype 1 infection and which could eliminate the need for HCV genotype testing. We look forward to advancing the regulatory submissions for the SOF/VEL fixed-dose combination.”

The U.S. Food and Drug Administration has assigned the SOF/VEL fixed-dose combination a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options.

The SOF/VEL fixed-dose combination is an investigational product and its safety and efficacy have not yet been established.

About the ASTRAL Studies

The double-blind, placebo-controlled ASTRAL-1 trial enrolled 740 patients with chronic genotype 1, 2, 4, 5 or 6 HCV infection randomized to SOF/VEL or placebo for 12 weeks.

The open-label ASTRAL-2 study evaluated the use of SOF/VEL or SOF+RBV for 12 weeks in 266 genotype 2 HCV-infected patients.

The open-label ASTRAL-3 study evaluated the use of SOF/VEL for 12 weeks or SOF+RBV for 24 weeks in 552 genotype 3 HCV-infected patients.

The ASTRAL-1 study met its primary endpoint of statistical superiority to the pre-specified SVR12 goal of 85 percent (p<0.001). ASTRAL-2 and ASTRAL-3 also met their respective endpoints. In ASTRAL-2, the SVR12 rate among genotype 2 HCV-infected patients receiving SOF/VEL for 12 weeks was statistically superior to the SVR12 rate for patients receiving SOF+RBV for 12 weeks (p=0.018). In ASTRAL-3, the SVR12 rate among genotype 3 HCV-infected patients receiving SOF/VEL for 12 weeks was statistically superior to that of patients treated with SOF+RBV for 24 weeks (p<0.001).

The open-label ASTRAL-4 study evaluated the use of SOF/VEL with or without RBV for 12 weeks and SOF/VEL for 24 weeks in 267 HCV-infected patients with Child-Pugh class B cirrhosis, regardless of genotype.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that Gilead may be unable to file for U.S. regulatory approval of the SOF/VEL fixed-dose combination in the currently anticipated timelines. In addition, the FDA and other regulatory agencies may not approve the SOF/VEL fixed-dose combination, and any marketing approvals, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2015, as filed with theU.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full Prescribing Information for Sovaldi and Harvoni are available atwww.gilead.com.

Sovaldi and Harvoni are registered trademarks of Gilead Sciences, Inc. or its related companies.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

View source version on businesswire.com:
http://www.businesswire.com/news/home/20150921005402/en/

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Investors
Patrick O’Brien, 650-522-1936
or
Media
Cara Miller, 650-522-1616

Hepatitis C Weekend Review

Weekend Recap

Welcome to Weekend Reading, hope you are all enjoying the weekend!

For me Saturday is a great day to catch up on any HCV news or research I missed during the week. If you have the time click on today's topics for general information about hepatitis C, the cost of treatment, other health news, as well as interim study results using all-oral direct-acting antiviral therapy for the treatment of chronic hepatitis C.

Weekend recap provided by; Lucinda Porter, NATAP, Healio, HCV Advocate, Hepatitis Resource Center Blog, World Journal Of Hepatology, and The Body, along with media news and headlines from across the web.

Lucinda Porter 
What We Talk About When We Talk About Hepatitis C
Since 2007, more people have died every year from hepatitis C than from HIV. Fortunately, the latest hepatitis C medications can cure nearly everyone in a relatively quick, easy fashion. 

NATAP

Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment 

Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs.

Sofosbuvir plus Simeprevir Treatment of Recurrent Genotype 1 Hepatitis C after Liver Transplant

Patients with recurrent hepatitis C (HCV) infection post liver-transplant can be difficult to treat safely and effectively. A prior (COSMOS) study in non-transplant HCV patients, using sofosbuvir plus simeprevir, had high efficacy and tolerability in treating HCV genotype 1 patients, even prior non-responders to interferon therapy and those with cirrhosis. Our aim was to evaluate the efficacy of sofosbuvir and simeprevir in genotype 1 HCV post-liver transplant patients.

Harvoni in Advanced Liver Disease 

In this large-scale trial that evaluated the efficacy of all-oral direct-acting antiviral therapy in patients with HCV genotype 1 and decompensated cirrhosis, and post-transplant patients with cirrhosis, 12 or 24 weeks of treatment with ledipasvir-sofosbuvir and ribavirin resulted in high rates of response.

Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006-2010 

Incidence and mortality of many types of non-liver cancers were higher, and age at diagnosis and death younger, in patients with chronic HCV infection compared to the general population.

Healio

Odalasvir/Sovaldi yields 100% SVR in HCV genotype 1
Achillion announced additional interim results of its phase 2 pilot study of odalasvir in combination with Sovaldi, in which 100% of patients with hepatitis C virus…

September Issue of HCV Next
HCV Next provides an overview of current hepatitis C topics, as well as content on all forms of viral hepatitis, and other liver related disease.
Topic Highlights
Pediatric HCV: Small Patients, Big DecisionsHCV Guidelines: A Living Breathing Document
Caffeine Decreases Risk of Hepatic Fibrosis in Male HCV Patients
Liver Disease Expected to Increase in Switzerland Over Time
HCV may Increase Risk for Coronary Atherosclerosis in MSM
SVR Leads to Survival Benefit Among HCV Patients

HCV Advocate 

September Mid-Month Newsletter

by Alan Franciscus, Editor-in-Chief
This month’s column is about cirrhosis—the causes, how it develops, the tests to identify it, the symptoms of cirrhosis and effect of hepatitis C treatment on cirrhosis and the effect of cirrhosis on treatment.

Newly Diagnosed
Have you recently found out that you have hepatitis C? Being diagnosed with this brings up a lot of feelings and questions about hepatitis C. In this guide you will find information to help you find answers to your questions. This information is basic and assumes that you have very little knowledge about hepatitis C. Hopefully it reassures you. How can information about a disease be reassuring? We believe that once you get the facts, the future will look a little brighter.

Hepatitis Resource Center Blog
Hepatitis C-Salvage Study Grazoprevir and Elbasvir Plus Ribavirin: Final 24-week Follow-up Results
In the C-SALVAGE study, an interferon free combination of grazoprevir (an NS3/4A protease inhibitor) and elbasvir (an NS5A inhibitor) with ribavirin was used to treat patients with chronic HCV genotype 1 infection who had previously failed triple therapy with pegylated interferon and ribavirin plus an earlier-generation protease inhibitor.

Recent Posts
New HCV Peer-Reviewed PDFs For Free!
HCV Drug Costs: A Treatment Access Barrier
Tx Options for HCV GT 1 or 4 Non-responders
Two DAA regimen in cirrhotic HCV GT1b patients

World Journal Of Hepatology
Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments
The recently Food and Drug Administration approved direct-acting antiviral regimens for hepatitis C virus (HCV), ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, have demonstrated great efficacy, and thus far seem to have short treatment timelines and relatively benign side effect profiles. Depression has not emerged as a side effect of these treatments. With efficacious regimens that include no interferon-alpha and no ribavirin, there may no longer be a need for strong psychosocial assessment and monitoring built into the routine of HCV treatment. Good history-taking, strong pharmaceutical review, and reliable consultative relationships should be adequate for meeting psychosocial needs in HCV treatment

Assessing cardiovascular risk in hepatitis C: An unmet need.
Chronic hepatitis C is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Furthermore, hepatitis C virus seems to be an independent risk factor for cardiovascular diseases due to its association with insulin resistance, diabetes and steatosis. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after achieving the eradication of the virus.

Of Interest
Novel plan to curb drug costs seeks candidates' attention

The outcry gained momentum after the introduction last year of a $1,000-a-pill cure for hepatitis C. The 45-page plan seeks to rein in the overall cost of drugs ...

2015 Kelly Report: Health Disparities In America
History has shown us that the lack of access to healthcare, health insurance, and health providers has contributed to the gaps we observe in national health outcomes.

Big Pharma
Summary - Gilead Sciences at the Morgan Stanley Global Healthcare Conference
Gilead Provides An Update: Review And Analysis Of Wednesday's Q&A
Next-gen hep C combo plans clarified
Apparently we will have to wait until November, the month of the AASLD meeting, for details of the combo of Sovaldi with GS-5816 (sofosbuvir/velpatasvir), rather than this quarter. It appears that GILD is planning to go with this combo as a 12-week treatment for genotypes 2-6 in developed countries, and for all genotypes in regions where genotyping is not readily available..

Will The Next Hepatitis C Drugs Hit It Big?

Over the last two years, hepatitis C has produced the most epic drug launches in history. But as the fanfare dies down, investors face a key question: How much longer can this drug pipeline pop?

Healthy You And The Flu
Hepatitis C or No Hepatitis C, Get a Flu Shot
I have opinions on various issues, but when it comes to scientific proof, I don't waste my time arguing facts. The earth is round, and it travels around the sun. The only place where humans and dinosaurs coexisted was on the Flintstones. I just got my flu shot.

Things to know about the flu shot: Lots of options this year

WASHINGTON (AP) -- Give flu vaccine another chance: This year's version got a recipe change that should make it more effective after last winter's misery from a nasty surprise strain of virus....

Americans urged to get annual influenza vaccine

WASHINGTON, D.C. ― Everyone 6 months of age and older should receive an annual influenza vaccine, health officials advised at a press conference held by the National Foundation for Infectious Diseases.

In addition to flu vaccines, the panel also recommended pneumococcal vaccines for people aged 65 and older and for adults aged 19-64 with certain chronic health conditions, such as diabetes or heart disease.

Acetaminophen

Health Canada proposes new liver damage labeling for acetaminophen
Health Canada announced it is requesting input from clinicians and other healthcare professionals on proposed revisions to the labeling standard for nonprescription acetaminophen products, in an effort to encourage consumers to use them more safely, according to a press release from Health Canada.

Insulin Pens

Shake, shake, shake your NPH insulin pen before injecting
(Reuters Health) - A warning for people who use insulin pens: Not shaking your NPH insulin pen before injecting can result in wide variations in your insulin level and blood sugar control, researchers from Italy report.

Recall
California dairy recalls soft cheeses due to possible Listeria link
- California company Karoun Dairies has recalled a number of soft cheese products due to possible association with Listeria cases over five years in nine states, the U.S. Centers for Disease Control and Prevention said on Friday.

Awareness

Hepatitis C: Testing could save your life

If a simple blood test could improve your long-term health or possibly save your life, would you have it done? The answer for most people is a resounding “Yes.” Testing for hepatitis C which entails a basic blood draw and analysis, can be the difference between serious health complications later in life or a manageable — in some cases curable — condition.

In The News
Homeless Veteran Stand Down an infusion of hope for veterans in ...
Prescott Daily Courier-10 hours ago
Free haircuts, HIV and Hepatitis C screenings, pet care facilities, and three hot meals, were just a sample of what these in-need veterans were able to obtain on ...

Achillion Reports 100% SVR12 From Second Cohort of Patients in the Previously-Completed Six Week Phase 2 Trial Evaluating Odalasvir (ACH-3102) and Sofosbuvir for Genotype 1 HCV ("Proxy Study")

- 100% SVR12 reported for all patients treated for six- (n=18) or eight-weeks (n=12)
- Odalasvir (ACH-3102) is the subject of an exclusive, worldwide development and commercialization license granted to Janssen

FDA Grants Fast Track Designation to Can-Fite's CF102 in the Treatment of Liver Cancer
U.S. Food and Drug Administration (FDA) has granted the Company's drug candidate CF102 Fast Track designation as a second line treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer. CF102 had already received the FDA's Orphan Drug designation.

Clinical Thought - How I Use Resistance Testing to Guide Management of Patients With Chronic Hepatitis C

Recently, I have begun to hear many questions from colleagues and trainees regarding the use of resistance testing in the management of HCV-infected patients. To be honest, my answers to their questions are not always straightforward, as this is a rapidly evolving area of discussion in the field and I am confident that my opinion will evolve along with the data.

Study Shows Increase in Hepatitis C Rate Among Some HIV-Positive Men 
Researchers conducted an analysis of studies that spanned more than two decades and found that outbreaks of sexually transmitted hepatitis C is increasing among men who are HIV positive and have sex with other men

Redoing the Math: New York State Revises Its Estimate of People With HIV

The NYS Plan to End AIDS relies on increasing the number of HIV-positive people in the state who have an undetectable viral load, since being virally suppressed both improves their health and lowers the chance of HIV transmission to their partners.

Mathematical models estimate that to achieve the state's goal of only 750 new HIV infections per year, the percent of people virally suppressed will need to be over 80%. Since only an estimated 42% were virally suppressed in 2013, the state had a long way to go to achieve its goal.

But NYS recently lowered its estimate of the number of people with HIV in the state, which significantly increases the percent who are virally suppressed. Let's examine how that was done.

Feel Good Video

Sophia just wants to dance, but she found that difficult to do when she was diagnosed with scoliosis and was forced to wear a brace for 23 hours a day. Two years ago, a large tumor was found growing on her spinal cord, and she had major surgery at St. Jude Children's Research Hospital in Memphis to remove it. A year later, the tumor returned and Sophia underwent radiation and advanced proton therapy. Her physician at Willis Knighton Proton Therapy Center, Dr. Ben Wilkinson, promised Sophia he would learn the dance to Watch Me (Whip/Nae Nae) once radiation and therapy were complete. Dr. Wilkinson went one step further and surprised the 12-year-old with a flash mob from the staff. Now that's how you celebrate!

Whenever I watch videos like this I cry, do you?
See you all soon.
Tina

Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments

World J Hepatol 2015 September 8; 7(19): 2209-2213
World J Hepatol. 2015 September 8; 7(19): 2209-2213.
Published online 2015 September 8. doi: 10.4254/wjh.v7.i19.2209.
Copyright©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments
Paul J Rowan and Nizar Bhulani

Abstract
Chronic hepatitis C virus (HCV) is a global concern. With the 2014 Food and Drug Administration approvals of two direct-acting antiviral (DAA) regimens, ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, we may now be in the era of all-pill regimens for HCV. Until this development, interferon-alpha along with Ribavirin has remained part of the standard of care for HCV patients. That regimen necessitates psychosocial assessment of factors affecting treatment eligibility, including interferon-alpha-related depressive symptoms, confounding psychiatric conditions, and social aspects such as homelessness affecting treatment eligibility. These factors have delayed as much as 70% of otherwise eligible candidates from interferon-based treatment, and have required treating physicians to monitor psychiatric as well as medical side effects throughout treatment. All-pill DAA regimens with the efficaciousness that would preclude reliance upon interferon-alpha or ribavirin have been anticipated for years. Efficacy studies for these recently approved DAA regimens provide evidence to assess the degree that psychosocial assessment and monitoring will be required. With shorter treatment timelines, greatly reduced side effect profiles, and easier regimens, psychosocial contraindications are greatly reduced. However, current or recent psychiatric comorbidity, and drug-drug interactions with psychiatric drugs, will require some level of clinical attention. Evidence from these efficacy studies tentatively demonstrate that the era of needing significant psychosocial assessment and monitoring may be at an end, as long as a manageable handful of clinical issues are managed.

Keywords: Depression, Therapy, Psychiatry, Clinical, Direct-acting antivirals

Core tip: The recently Food and Drug Administration approved direct-acting antiviral regimens for hepatitis C virus (HCV), ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, have demonstrated great efficacy, and thus far seem to have short treatment timelines and relatively benign side effect profiles. Depression has not emerged as a side effect of these treatments. With efficacious regimens that include no interferon-alpha and no ribavirin, there may no longer be a need for strong psychosocial assessment and monitoring built into the routine of HCV treatment. Good history-taking, strong pharmaceutical review, and reliable consultative relationships should be adequate for meeting psychosocial needs in HCV treatment.

INTRODUCTION
Chronic hepatitis C Virus (HCV) is a global concern, with approximately 170 million people affected worldwide. It is the leading cause of liver cirrhosis in developed countries[1,2]. Of the 6 genotypes, genotype 1 is the most prevalent[3]. Interferon alpha was recognized as a successful treatment in the 1980s, but success rates were low. Since 1998, Interferon-alpha along with ribavirin has remained the standard of care for HCV infected patients, with success rates in genotype 1 only at approximately 40%, while success rates for genotypes 2 and 3 hover around 80%. Until recently, the only significant change to this regimen was the approval of pegylated interferon-alpha treatment, in 2001, making the regimen less challenging by reducing injections per week and boosting efficacy to some degree.

Due to side effects of this regimen, candidates must be assessed for eligibility. As much as 70% of otherwise eligible patients are not eligible to begin treatment due to contraindications[4,5]. A leading contraindication has been depression, since a leading side effect is the depression that may emerge or be exacerbated by interferon-alpha. Clinicians have also had to monitor other psychosocial issues, such as substance abuse. Some evidence suggests that treatment does not seem to work in active alcohol users[6], although some assessment have shown similarly successful outcomes regardless of current alcohol abuse[7]. Injection drug users have been perceived as at risk for insufficient adherence[8], and also at risk for re-infection[9], so this poses another area of psychosocial assessment. Clinically, a common practice has been to refer an otherwise eligible candidate for psychiatric care when any of these psychiatric conditions are present or have been recently active.

Another psychosocial concern is social stability: since treatment may take as long as 48 wk, a candidate must have stable housing and have means for refrigerating the interferon-alpha. Those with unstable housing or unstable income might need to have those issues addressed by social work before treatment can be initiated. For women of child-bearing age, the teratogenic risk of ribavirin requires attention to pregnancy risk. A recommended practice has been to assure mandatory birth control adherence for any woman of child-bearing age to be prescribed any extended regimen that includes ribavirin[10]. Thus, while the prevailing regimen promises good outcomes for many, psychosocial assessment and monitoring has been a necessary part of HCV treatment.

Major changes to this clinical picture began in 2011, with approval of the first direct-acting antivirals (DAA), boceprevir and teleprevir. While these drugs greatly boosted genotype-1 success rates and shortened treatment time by months, these successes were gained by augmenting an interferon-alpha and ribavirin regimen with these newer drugs. So, patients still faced the side effects and contraindications associated with interferon-alpha and with ribavirin.

With the 2014 Food and Drug Administration (FDA) approvals of the ledipasvir/sofosbuvir “Harvoni” regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir “Veikira Pak” regimen, and with more regimens under development, we may now be in the era of all-pill regimens for HCV. Compared to the prevailing standard of interferon-alpha-plus-ribavirin regimen that has prevailed since the 1990s, this advancement in HCV treatment is revolutionary for a few reasons: these new regimens have superior efficacy across genotypes; the treatment timeline is relatively brief; and patients no longer need to self-administer a medication by injection. Also, a further advancement seems to be the favorable side effect profile.

Clinics treating HCV patients have had to develop the capacity to provide the noted psychosocial assessment and monitoring. With the advent of these new regimens, it is worth reviewing their side effect profiles to consider the degree that psychosocial assessment and monitoring will continue to be part of HCV treatment. This requires examining how lengthy and complex any regimen is, the rates of discontinuation, the degree of psychiatric adverse events experienced by study enrollees, and whether any regimen medications have any psychosocial contraindications (e.g., homelessness, risk of pregnancy). This review draws upon previously published data, and no original data, so no institutional review board approval was needed, and no consenting of any participants was required; it is also noted that the authors have no conflicts of interest.

Ledipasvir-sofosbuvir regimen: Psychosocial aspects
The ledipasvir-sofosbuvir regimen, commercially available as Harvoni®, received FDA approval on October 10, 2014. The ION series of studies[11] established safety and efficacy for this regimen. ION-1 allowed individuals with mental illness to enroll, as long as the condition had been well-controlled for at least a year. Also, exclusion criteria included those with any psychiatric hospitalization, suicide attempt, or psychiatric disability period in the recent five years (ION-1 Study Protocol, 4.3 g). A positive drug screen, elevated AUDIT (excessive-alcohol screener) score, or drug abuse in the recent 12 mo were also exclusionary criteria. Therefore, enrollees could have a mental illness such as depression, but had to be free from recent complications of that condition. In the ION-1 study, there was no drop-out due to side effects (one enrolled participant dropped out after only one dose), and only 4 of the 431 participants receiving the ledipasvir-sofosbuvir regimen regimen were lost to follow-up: loss to follow-up can reflect any of many factors, including a passive refusal to continue a regimen due to side effects or a regimen that is too complex. This rate of loss to follow-up is much lower than interferon-based trials. In the initial study providing the superiority of pegylated interferon, by Fried et al[12], 677 participants were randomized and began treatment in the two pegylated interferon arms (one with ribavirin, one with placebo); of these, 145 (21.4%) experienced depression, and 28 (4.1%) discontinued treatment (20 refused to continue treatment at some point after beginning, and 8 had failure to return). About the same time, a similar efficacy study of pegylated interferon-alpha was conducted by Manns et al[13]. In this study, 30% of the 1025 patients in the two study arms receiving pegylated interferon-alpha experienced depression symptoms. In another analyses of these data[14], the researchers noted that 218 of 1010 (21.6%) patients receiving interferon-alpha sustained treatment for less than 80% of the planned treatment time span. Thus, depressive side effects and other aspects of interferon-based regimens have been challenging for patients to tolerate. For the ledipasvir-sofosbuvir regimen, low rates of discontinuation may also be due to the ease of compliance with the regimen: both medications are combined in one pill, taken orally once daily.

In the ION-1 trial, no psychiatric serious adverse events were reported among participants taking the ledipasvir-sofosbuvir regimen, although other serious adverse events, such as chest pain and pneumonia, occurred in a few of these patients. Thus, overall, there does not yet seem to be any notable risk of psychiatric symptomatology for the ledipasvir-sofosbuvir regimen, per study adverse event reporting or as might be suggested by drop-out/loss to follow-up or by adherence data. These study data indicate that, so far, psychiatric problems such as depressive symptoms do not seem to be a side effect of treatment, although it must be acknowledged that study criteria excluded those with current or recent psychiatric difficulty.

A related study, ION-3, was conducted to determine whether a more brief regimen, 8 wk vs 12 wk of ledipasvir-sofosbuvir, could be as efficacious[15]. This study, with a protocol largely parallel to ION-1, included 215 participants in the 8 wk ledipasvir-sofosbuvir arm and 216 in the 12 wk arm. Among these participants, the study’s Supplementary Materials indicate no psychiatric adverse events, and report very low rates of drop-out/loss-to-follow-up (4 of 431; 0.9%). So, again, the ledipasvir-sofosbuvir regimen seems very unlikely to produce psychiatric adverse events, or to have treatment discontinuation.

Is pregnancy risk a concern for the ledipasvir-sofosbuvir regimen, as for the interferon-alpha/ribavirin regimen? Thorough data, such as a randomized clinical trial with pregnant women, have not been conducted, and post-marketing surveillance is still young, so human data are limited. The FDA-approved medication insert data report that animal-model studies have failed to find any teratogenic effect when given to rats or rabbits at exposures that are 3 or more times greater than human doses. The status for pregnant women is currently Category B: animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Does the ledipasvir-sofosbuvir regimen have contraindications with any psychiatric medications, requiring close scrutiny in patients prescribed psychiatric medications? Prescribing information report no such noted conflicts, and neither of the two component medications have metabolism by cytochrome P450 genes, a common biological indicator of possible drug-drug difficulties for psychiatric medications. Post-marketing surveillance has been brief, but thus far contraindications for psychiatric medications have not been detected for this regimen.

Ombitasvir-paritaprevir-ritonavir and dasabuvir: Psychosocial aspects
Ombitasvir-paritaprevir-ritonavir plus dasabuvir is commercially available as Viekira Pak®, which is a once daily pill of ombitasvir-paritaprevir-ritonavir and a twice daily pill of dasabuvir[16]. Two related studies with similar protocols, PEARL-III and PEARL-IV[16], assessed the efficacy and adverse events of this regimen. Each studied the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen with or without ribavirin in randomized, placebo-controlled trials. PEARL-IV studied patients with genotype 1a, and PEARL-III studied those with genotype 1b. The placebo arms (no ribavirin) of each of these studies provide relevant data regarding possible psychosocial issues to be assessed and monitored in this no-interferon-alpha, no-ribavirin regimen.

Potential participants with current or recent alcohol or substance abuse (recent 6 mo) were excluded, but otherwise psychiatric comorbidity was not an exclusion. Together, in the placebo arms (no ribavirin), there were 414 participants who participated in 12 wk treatment. Aside from those discontinuing treatment due to virologic failure or to adverse events that had no psychosocial aspect, there were only 6 (1.4%) who did not complete treatment (consent withdrawn, lost to follow-up, or “other” reason). As noted earlier, reason for loss to follow-up cannot be ascertained, but it must be considered that psychiatric side effects or adverse events could be involved. These rates of non-completion are far lower than the rates, noted earlier, for interferon-alpha regimens.

The Supplementary Materials for PEARL-III and IV note adverse events, reported per Medical Dictionary for Regulatory Activities vocabulary. No distinctly psychiatric adverse events are noted except for “memory impairment”, reported by 14 (3.3%) of participants in the no-ribavirin arms of these studies.

So, the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen seems to be well-tolerated, with strong compliance and a very small burden of psychiatric side effects. Substance abuse may reasonably be a contraindication; more data are likely needed on the degree that those with current or recent psychiatric difficulties may need to be delayed from treatment, but this regimen seems to hold promise for those with psychiatric comorbidities.

There are two well-recognized psychosocial issues with this regimen: the inclusion of ritonavir is problematic for women of reproductive age, and there is a long list of drug-drug interactions between ritonavir and other medications, including several medications used for psychiatric indications. These challenges arise mainly because ritonavir inhibits the liver enzyme cytochrome P450-3A4[17], and so affects to some degree the pharmacokinetics of any drug affected by this enzyme. Extensive data exist regarding pharmacology of ritonavir because it has been recognized for years as part of efficacious human immunodeficiency virus (HIV) treatment[18]. Also, the University of California San Francisco “HIVInsite” website[19] has extensive data on HIV/AIDS drugs, including ritonavir, and is the source of some of the following observations regarding drug-drug interactions.

Ritonavir reduces the efficacy of hormone-based birth control[20,21]. The PEARL study protocols have required that women participating in the trials avoid pregnancy by using at least two forms of birth control, neither of which can be hormone-based. So, along with recognized evaluation for HCV treatment, providers will need to assess and monitor pregnancy risk, and pregnancy prophylaxis, for women of reproductive age.

Many of the ritonavir drug-drug interactions are with medications that have psychiatric indications, including carbamazepine (bipolar disorder), nefazodone (depression), and triazolam (insomnia). So, assessment and monitoring will require surveillance of psychiatric conditions and any medications for these. It is possible that patients taking triazolam for insomnia may not perceive themselves as having a “psychiatric” condition, so merely asking about “psychiatric” diagnoses or prescriptions may not reveal that a patient is using this drug; as is generally advisable, patients should be encouraged to report any and all prescription drugs, as well as over-the-counter drugs and any herbal or “alternative” remedies. Regarding herbal/alternative drugs, patients should avoid taking both ritonavir and John’s Wort[22], a fairly commonly utilized herbal remedy for depression. Ritonavir also has a drug-drug interaction with sildenafil, used for erectile dysfunction; use of both drugs can lead to pulmonary arterial hypotension, and there are drug-drug interactions with other drugs used for erectile dysfunction as well, including avanafil, tadalafil, and vardenafil. There is a fair amount of clinical folklore and evidence that sildenafil is misused for recreational purposes[23,24], so the clinical management of HCV treatment that includes ritonavir must assess and monitor the use of erectile dysfunction drugs, whether this use is legitimate use or recreational use.

In conclusion, clinical trial data indicate that these recently approved, all-pill, no-interferon-alpha/no ribavirin regimens are far more readily tolerated by patients generally, and do not seem to have notable psychiatric contraindications. Challenges of these regimens may be limited to examining drug-drug interactions, including the prescription of drugs for psychiatric indications or for birth control. None of these issues requires significant involvement of specialty mental health or social work professionals, although it is necessary to have these services readily available by consultation.

The type of psychosocial assessment and monitoring required for these regimens is typical in medical care delivery, and the adoption of the electronic medical record and e-prescribing can support the detection of potential drug-drug interactions. In many cases, precautions or alternative clinical management strategies can be determined for the duration of the 12 wk treatment, in consultation with a pharmacist, the prescriber overseeing the psychiatric condition, or both. So, with these recently FDA-approved DAA regimens for HCV, with no interferon-alpha and no ribavirin, treatment settings may no longer need to have strong psychosocial assessment and monitoring built into the routine of HCV treatment.

There are some further research issues to be assessed for these recently-approved DAA regimens. As clinical experience builds with all-pill DAA regimens, the experience of patients with well-controlled or poorly-controlled psychiatric comorbidity should be noted and reported. One or both of these regimens may be well-tolerated in patients with a range of psychiatric comorbidities. If the DAA regimens are well-tolerated by those with current or recent psychiatric comorbidities, this would greatly broaden the range of patients eligible to initiate therapy. Also, it would be valuable to investigate patient preferences for avoiding pregnancy for the duration of treatment. As evidence builds, we will be able to more firmly determine whether we have entered an era in which there is no longer any great need for psychosocial assessment and monitoring of patients undergoing HCV treatment.

Footnotes
P- Reviewer: Garcia-Elorriaga G, Isamu S S- Editor: Qiu S L- Editor: A E- Editor: Liu SQ
Conflict-of-interest statement: The authors have no conflicts of interest.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: July 5, 2015
First decision: July 31, 2015
Article in press: August 31, 2015

References
1.
GBD 2013 Mortality and Causes of Death Collaborators.Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117-171.[PubMed] [DOI]
2.
Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology. 2006;130:231-264; quiz 214-217.[PubMed] [DOI]
3.
European Association for the Study of the Liver.EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55:245-264.[PubMed] [DOI]
4.
Talal AH, LaFleur J, Hoop R, Pandya P, Martin P, Jacobson I, Han J, Korner EJ. Absolute and relative contraindications to pegylated-interferon or ribavirin in the US general patient population with chronic hepatitis C: results from a US database of over 45 000 HCV-infected, evaluated patients. Aliment Pharmacol Ther. 2013;37:473-481.[PubMed] [DOI]
5.
Rowan PJ, Tabasi S, Abdul-Latif M, Kunik ME, El-Serag HB. Psychosocial factors are the most common contraindications for antiviral therapy at initial evaluation in veterans with chronic hepatitis C. J Clin Gastroenterol. 2004;38:530-534.[PubMed] [DOI]
6.
Bhattacharya R, Shuhart MC. Hepatitis C and alcohol: interactions, outcomes, and implications. J Clin Gastroenterol. 2003;36:242-252.[PubMed]
7.
Bruggmann P, Dampz M, Gerlach T, Kravecz L, Falcato L. Treatment outcome in relation to alcohol consumption during hepatitis C therapy: an analysis of the Swiss Hepatitis C Cohort Study. Drug Alcohol Depend. 2010;110:167-171.[PubMed] [DOI]
8.
Aspinall EJ, Corson S, Doyle JS, Grebely J, Hutchinson SJ, Dore GJ, Goldberg DJ, Hellard ME. Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis. Clin Infect Dis. 2013;57 Suppl 2:S80-S89.[PubMed] [DOI]
9.
Micallef JM, Macdonald V, Jauncey M, Amin J, Rawlinson W, van Beek I, Kaldor JM, White PA, Dore GJ. High incidence of hepatitis C virus reinfection within a cohort of injecting drug users. J Viral Hepat. 2007;14:413-418.[PubMed] [DOI]
10.
Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med. 2006;355:2444-2451.[PubMed] [DOI]
11.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-1898.[PubMed] [DOI]
12.

Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.[PubMed] [DOI]
13.
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.[PubMed] [DOI]
14.
McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.[PubMed] [DOI]
15.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-1888.[PubMed] [DOI]
16.
Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, Tam E, Marinho RT, Tsai N, Nyberg A. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-1992.[PubMed] [DOI]
17.
Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53:4-9.[PubMed] [DOI]
18.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. [Accessed 2015 Jun 15]. .
19.
HIVInsite Gateway. [Accessed 2015 Jun 15]. .
20.

El-Ibiary SY, Cocohoba JM. Effects of HIV antiretrovirals on the pharmacokinetics of hormonal contraceptives. Eur J Contracept Reprod Health Care. 2008;13:123-132.[PubMed]
21.
Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, Leonard JM, Granneman GR. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol. 1998;46:111-116.[PubMed]
22.

Hafner V, Jäger M, Matthée AK, Ding R, Burhenne J, Haefeli WE, Mikus G. Effect of simultaneous induction and inhibition of CYP3A by St John's Wort and ritonavir on CYP3A activity. Clin Pharmacol Ther. 2010;87:191-196.[PubMed] [DOI]
23.
Smith KM, Romanelli F. Recreational use and misuse of phosphodiesterase 5 inhibitors. J Am Pharm Assoc (2003). 2005;45:63-72; quiz 73-75.[PubMed] [DOI]
24.
Apodaca TR, Moser NC. The use and abuse of prescription medication to facilitate or enhance sexual behavior among adolescents. Clin Pharmacol Ther. 2011;89:22-24.[PubMed] [DOI] 

Assessing cardiovascular risk in hepatitis C: An unmet need.

World J Hepatol 2015 September 8; 7(19): 2214-2219

Assessing cardiovascular risk in hepatitis C: An unmet need.
Javier Ampuero and Manuel Romero-Gómez.

Abstract

Chronic hepatitis C virus (HCV) is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Additionally, HCV seems to be an independent risk factor for cardiovascular diseases (CVD) due to its association with insulin resistance, diabetes and steatosis. HCV infection represents an initial step in the chronic inflammatory cascade, showing a direct role in altering glucose metabolism. After achieving sustained virological response, the incidence of insulin resistance and diabetes dramatically decrease. HCV core protein plays an essential role in promoting insulin resistance and oxidative stress. On the other hand, atherosclerosis is a common disease in which the artery wall thickens due to accumulation of fatty deposits. The main step in the formation of atherosclerotic plaques is the oxidation of low density lipoprotein particles, together with the increased production of proinflammatory markers [tumor necrosis factor-α, interleukin (IL)-6, IL-18 or C-reactive protein]. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after the eradication of the virus. Consequently, the number of studies evaluating this association is growing. Data derived from these studies have demonstrated the strong link between HCV infection and the atherogenic process, showing a higher risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, CVD-related mortality.

Keywords: Hepatitis C, Atherosclerosis, Coronary artery disease, Cardiovascular risk, Oxidative stress, Inflammation

Core tip: Chronic hepatitis C is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Furthermore, hepatitis C virus seems to be an independent risk factor for cardiovascular diseases due to its association with insulin resistance, diabetes and steatosis. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after achieving the eradication of the virus.

INTRODUCTION

Hepatitis C virus (HCV) infection is a global health problem that affects 170 million people worldwide. Hepatitis C is responsible for about 100000 deaths annually[¹]. Chronic hepatitis C is associated with significant morbidity and mortality, which result mainly from the progression towards cirrhosis and hepatocellular carcinoma[²]. Extrahepatic manifestations are well-known complications of HCV infection. Similar to non-alcoholic fatty liver disease[^3,4], HCV seems to be an independent risk factor for cardiovascular diseases (CVD) due to its association with insulin resistance, diabetes and steatosis[⁵]. However, our knowledge about this topic requires further studies. In fact, previous studies that assessed the association between HCV infection and CVD risk have been sometimes inconclusive[⁶]. In this review, our aim is to elucidate the role of HCV infection on the cardiovascular-related affectation.

HCV AND INFLAMMATION

HCV infection represents an initial step in the chronic proinflammatory cascade. It produces proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) alpha, leading to increased inflammation and liver fibrosis. In addition, HCV-related steatosis promotes increased expression of inflammatory markers. These molecules are able to inhibit the insulin signaling, causing insulin resistance and steatosis progression[⁷].

Insulin resistance

Several studies have established a direct role of HCV in altering the glucose metabolism, leading to insulin resistance and diabetes, especially in genotype 3[⁸]. This relationship could explain, at least in part, the impact of metabolic abnormalities on sustained virological response (SVR), regardless of other variables such as viral or IL28B genotypes. In fact, achieving SVR with antiviral therapy results in a dramatically decrease of the development of insulin resistance and the appearance of diabetes mellitus over time[⁹].

HCV core protein plays a fundamental role in the induction of insulin resistance. The PI3K/Akt pathway, whose phosphorylation is impaired upon insulin stimulation, is crucial for the inhibition of gluconeogenesis in the liver. HCV core protein is able to degrade the insulin receptor substrates (IRS) 1 and 2, by increasing the expression of TNFα and suppressing cytokine signalling-3, leading to defective downstream PI3K and Akt phosphorylation[¹⁰]. In fact, when viral clearance is obtained, the expression of IRS-1 and IRS-2 is restored and HOMA-IR index decreases, which indicates the independent role of HCV in insulin resistance[¹¹]. Furthermore, there are other non-structural proteins, like NS5A and NS5B, which also promote insulin resistance, enhancing TNFα and IL-6. The ability of these molecules to disturb insulin signaling is well recognized. IL-1β is other interesting molecule. It is produced by hepatic macrophages, and is related to liver inflammation and, ultimately, to disease progression[¹²]. Finally, the role of toll-like receptors is growing in importance. HCV infection activates these molecules, which are closely associated with proinflammatory cytokines, contributing to the vicious circle[¹³].

Oxidative stress

Oxidative stress is the other main pathway of HCV-mediated inflammation, as insulin resistance promotes fatty acid accumulation in the liver, resulting in increased β-oxidation and reactive oxygen species (ROS)[¹⁴]. On the one hand, mitochondrial fat oxidation upregulates nuclear factor κB (NF-κB). This latter activates the transcription of several proinflammatory genes and the production of proinflammatory cytokines[¹⁵]. On the other hand, ROS play an important role in fibrogenesis by proliferating hepatic stellate cells and collagen synthesis and by inducing tumor growth factor-β[¹⁶]. An imbalance between oxidant agents and antioxidant defenses is the final result of all these processes, causing oxidative damage to hepatocyte and altering the reparation of DNA.

ATHEROSCLEROSIS

Lipid oxidation

Atherosclerosis is a common disease in which the artery wall thickens due to the accumulation of fatty deposits, called atheromatous plaques. Cholesterol-rich low density lipoprotein (LDL) is the main atherogenic lipoprotein. LDL infiltrates into the endothelium and adheres to extracellular matrix components, resulting in accumulation in the vascular intima[¹⁷]. Interestingly, LDL particle size seems to facilitate the passing between the endothelial cells because small dense LDL represents a major component of an atherogenic lipoprotein phenotype[¹⁸].

The main step in the formation of atherosclerotic plaques is the oxidation of LDL particles, being the risk higher in the wall than in the bloodstream[¹⁹]. Monocytes penetrate into endothelium and are able to transform into macrophages. This latter kind of cells is able to phagocyte oxidized LDL (oxLDL) particles triggering a cascade of immune responses and producing an atherosclerotic plaque[²⁰]. During oxidation, LDL converts to oxLDL involving some enzymes (such as lipoprotein-associated phospholipase A2) with several consequences: (1) oxLDL activates T cells and macrophages, stimulating the production of foam cells; (2) oxLDL induces the expression of endothelial adhesion molecules and the stimulation of several growth factors; and (3) oxLDL affects nitric oxide releasing and vascular smooth muscles, contributing to impair the vascular contraction[²¹]. As a result, oxLDL is able to thicken the intima and enhance atherosclerosis.

Inflammation

Many markers, such as proinflammatory cytokines (TNFα, IL-6 and IL-18), C-reactive protein, and adhesion molecules, are increased in plasma in situation of chronic inflammation. C-reactive protein may promote inflammation and atherogenesis through effects on monocytes and endothelial cells[²²]. Regarding to proinflammatory cytokines, TNFα activates NF-κB after interacting with the vascular endothelium[²³]. On the other hand, there are other cells with the capacity of enhancing proinflammatory cytokines such as activated macrophages, Th1 lymphocytes, and foam cells. Furthermore, several receptors (i.e., CD-36 and toll-like receptors) located on the membrane of macrophages leads to uncontrolled phagocytosis of oxLDL[²⁴].

Diagnostic tests

Noninvasive and inexpensive tests to anticipate and facilitate the prediction of cardiovascular risk are growing in importance. Atherosclerosis can be detected by several methods, depending on the organ or tissue affected. Carotid intima-media thickness and the presence of carotid plaques serve as marker of subclinical atherosclerosis and can be measured by ultrasound. They are especially considered to be independent stroke predictors[²⁵] and related to cardiovascular events[²⁶]. Other tests have been developed with the same proposal. Coronary artery calcification, judged by computed tomography, is a good predictor of coronary heart disease[²⁷]. Brachial artery flow-mediated vasodilation is a test of endothelial dysfunction that is associated with early stages of atherosclerosis[²⁸]. Pulse-wave velocity seems to be the gold standard of arterial stiffness and an early indicator for atherosclerosis[²⁹]. Other methods, such as left ventricular hypertrophy (by electrocardiogram and echocardiogram)[³⁰] or peripheral arterial disease (PAD) (by ankle-brachial pressure index)[³¹], are not extended in clinical practice due to costs or specialized personal requirement.

BIOLOGICAL MECHANISMS LINKING HCV AND ATHEROSCLEROSIS

A large body of evidence shows that infective agents contribute to promote chronic inflammation which could be associated, ultimately, with atherosclerosis[³²]. Therefore, HCV infection has been widely assesed and biological mechanisms have been reported.

On the one hand, HCV infection seems to be associated with a higher risk of cardiovascular disease by indirect mechanisms. Firstly, HCV infection is strongly associated with metabolic abnormalities, including diabetes mellitus and liver steatosis, as well as metabolic syndrome. All of these risk factors are well-known predictors of cardiovascular disease[³³]. Secondly, HCV infection interrelates with the host immune response. As it is commented above, it is able to stimulate the production of proinflammatory cytokines[³⁴]. Thirdly, HCV infection comprises other extra-hepatic manifestations. In particular, cryoglobulinemia has been associated with higher prevalence of arterial hypertension and CVD compared to those patients without this entity[³⁵].

On the other hand, the HCV seems to be directly related to atherosclerosis. HCV RNA sequences have been investigated by highly sensitive reverse transcriptase-polymerase chain reaction in plaque tissues of patients who underwent to carotid revascularization, demonstrating the presence of genomic and antigenomic HCV RNA strands. Consequently, additionally to the role of HCV on the development of chronic inflammation due to insulin resistance and steatosis, HCV RNA sequences seems to play a local effect on the endothelium[³⁶].

IMPACT OF HCV-RELATED ATHEROSCLEROSIS

Coronary heart disease

Several studies have investigated the association between atherosclerosis and HCV infection, with conflicting results. In a systematic review, the majority of studies were of poor quality although revealed a tendency towards a higher risk of coronary heart disease (CHD) among patients with HCV infection. However, the studies showed heterogeneity in terms of methods and conclusions[³⁷]. Other studies have showed similar conclusions. Forde et al[³⁸] did not observe any difference in the incidence rates of CHD between HCV-infected and uninfected patients, as well as in terms of coronary revascularization procedures. Main limitation of studies showing no HCV-related effect on CHD is the inclusion of some patients who could have had spontaneously cleared HCV infection.

There are no many studies differentiating HCV antibody and RNA positivity, regarding to CHD events. In a very large study, authors found an increased risk of CHD in patients with HCV seropositivity, being an independent risk factor for CHD events. HCV seropositive patients had a higher incidence of CHD events compared with controls (4.9% vs 3.2%). Additionally, patients with detectable HCV-RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive (5.9% vs 4.7%). Therefore, there was an increased incidence of CHD events in patients with HCV seropositivity and the incidence was much higher in patients with detectable HCV-RNA compared with patients with remote infection who were only antibody positive[³⁹]. 

Electrocardiogram abnormalities are strongly associated with cardiovascular disease. HCV infection has been associated with increased risk to ischemic electrocardiogram when compared with non-HCV subjects, revealing a possible relationship between HCV seropositivity and ischemic electrocardiogram[⁴⁰]. Other study, performed by Butt et al[⁴¹], demonstrated that HCV-infected subjects had lower lipid levels and a lower prevalence of hypertension than those non-infected. Despite a favorable risk profile, HCV infection was associated with a higher risk of CHD after adjustment for traditional risk factors. In diabetic population, similar results have been obtained. Authors included three cohorts: patients who received pegylated interferon plus ribavirin (treated cohort), HCV-matched patients (untreated cohort) and diabetic patients without HCV infection (uninfected cohort). Main conclusion was that the incidences of ischemic stroke and CHD were all lower in HCV-infected patients treated with peginterferon and ribavirin, compared with infected individuals without antiviral treatment and diabetic patients without HCV infection. It is interesting to note that the risk of ischemic stroke and CHD were not attenuated in treated patients with PAD. This finding suggests that the pathogenic role of HCV can be limited at the early phase of atherosclerosis and that antiviral treatment could not reduce cardiovascular morbidity at an advanced stage[⁴²].

Carotid atherosclerosis

A large body of evidence has assessed the association between HCV infection and carotid atherosclerosis. First study was carried out by Ishizaka et al[⁴³], in which they evaluated the relationship between positivity for HCV and carotid-artery plaque and carotid intima-media thickening. After adjustment for cofounding risk factors, HCV seropositivity was found to be associated with an increased risk of carotid-artery plaque (OR = 1.92) and carotid intima-media thickening (OR = 2.85). A definite study was performed by Petta et al[⁴⁴] One-hundred-and-seventy-four consecutive biopsy-proven HCV genotype 1 patients were evaluated by anthropometric and metabolic measurements and other 174 patients used as controls. Authors found that patients with HCV genotype 1 had a higher prevalence of carotid atherosclerosis compared with a control population (carotid plaques: 42% vs 23%; IMT: 1.04 ± 0.21 vs 0.90 ± 0.16). However, no direct association was found between viral load and atherosclerosis. The novel finding was the independent association of the presence of carotid plaques with severe hepatic fibrosis, after adjustment for age. Authors concluded that severe fibrosis and the associated cascade of proinflammatory and profibrogenic pathways generated in the liver might promote carotid atherosclerosis at a much younger age[⁴⁴].

Peripheral artery disease

PAD is an under-diagnosed and under-treated disease. Some data suggest that HCV influences on the presence of PAD. In a retrospective cohort study, 7641 HCV-infected patients and 30564 matched controls were included. An excess risk of PAD development in HCV-infected patients was observed compared with non-HCV patients. The increased incidence of PAD in HCV-infected patients appeared since within first year. This study showed that gender had no effect on the risk of PAD development, but did aging. However, this study showed lack of evaluation of smoking, obesity or exercise[⁴⁵].

Cardiovascular mortality

Given that the HCV infection seems to be related to several atherogenic processes, many authors have evaluated its role on CVD-associated mortality similar to other viral infections[⁴⁶]. Guiltinan et al[⁴⁷] performed a retrospective study including HCV antibody-positive and HCV antibody-negative patients matched for age and gender. HCV infection was associated with a significant increase in overall mortality including significantly increased mortality from liver and cardiovascular causes. In the REVEAL cohort, including 1095 anti-HCV-positive and 760 detectable HCV RNA, was observed that those anti-HCV-positive patients showed a higher risk of CVD-related mortality compared with seronegative subjects[⁴⁸].

CONCLUSION

New direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection[⁴⁹]. Infected patients are going to live longer due to the eradication of the virus, so other HCV-related comorbidities have emerged. Specifically, cardiovascular disease is a major concern in this scenario. All the data provided in this review suggest a strong relationship between HCV infection and the atherogenic process, showing a high risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, CVD-related mortality. However, little is known about the precise mechanisms by which HCV enhances atherogenic processes. Therefore, we should be cautious when patients achieve SVR because maybe the cardiovascular risk remains after the virus eradication.

Footnotes

P- Reviewer: Balaban YH, Chiang TA, Desai ND S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

Conflict-of-interest statement: None.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: January 30, 2015

First decision: March 20, 2015

Article in press: August 31, 2015

References

1.

Hepatitis C. [Accessed 2014 Dec]. .

2.

Koike K. The oncogenic role of hepatitis C virus. Recent Results Cancer Res. 2014;193:97-111.[PubMed] [DOI]

3.

Ampuero J, Romero-Gómez M. [Influence of non-alcoholic fatty liver disease on cardiovascular disease]. Gastroenterol Hepatol. 2012;35:585-593.[PubMed] [DOI]

4.

Ampuero J, Gallego-Durán R, Romero-Gómez M. Association of NAFLD with subclinical atherosclerosis and coronary-artery disease: meta-analysis. Rev Esp Enferm Dig. 2015;107:10-16.[PubMed]

5.

Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol. 2014;61:S69-S78.[PubMed] [DOI]

6.

Ishizaka N, Ishizaka Y, Yamkado M. Atherosclerosis as a possible extrahepatic manifestation of chronic hepatitis C virus infection. Clin Med Insights Cardiol. 2014;8:1-5.[PubMed] [DOI]

7.

Ramírez Alvarado MM, Sánchez Roitz C. [Tumor necrosis factor-α, insulin resistance, the lipoprotein metabolism and obesity in humans]. Nutr Hosp. 2012;27:1751-1757.[PubMed] [DOI]

8.

Ampuero J, Romero-Gómez M, Reddy KR. Review article: HCV genotype 3 – the new treatment challenge. Aliment Pharmacol Ther. 2014;39:686-698.[PubMed] [DOI]

9.

Vespasiani-Gentilucci U, Gallo P, De Vincentis A, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol. 2014;20:2825-2838.[PubMed] [DOI]

10.

Adinolfi LE, Zampino R, Restivo L, Lonardo A, Guerrera B, Marrone A, Nascimbeni F, Florio A, Loria P. Chronic hepatitis C virus infection and atherosclerosis: clinical impact and mechanisms. World J Gastroenterol. 2014;20:3410-3417.[PubMed] [DOI]

11.

Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, Diago M, Alonso S, Planas R, Solá R, Pons JA, Salmerón J, Barcena R. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48:721-727.[PubMed] [DOI]

12.

Lapiński TW. The levels of IL-1beta, IL-4 and IL-6 in the serum and the liver tissue of chronic HCV-infected patients. Arch Immunol Ther Exp (Warsz). 2001;49:311-316.[PubMed]

13.

Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322-335.[PubMed] [DOI]

14.

Zampino R, Marrone A, Restivo L, Guerrera B, Sellitto A, Rinaldi L, Romano C, Adinolfi LE. Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol. 2013;5:528-540.[PubMed] [DOI]

15.

Sheikh MY, Choi J, Qadri I, Friedman JE, Sanyal AJ. Hepatitis C virus infection: molecular pathways to metabolic syndrome. Hepatology. 2008;47:2127-2133.[PubMed] [DOI]

16.

den Hartog GJ, Qi S, van Tilburg JH, Koek GH, Bast A. Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels: a new target in liver fibrosis. Eur J Pharmacol. 2014;724:140-144.[PubMed] [DOI]

17.

Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H. Atherosclerosis: process, indicators, risk factors and new hopes. Int J Prev Med. 2014;5:927-946.[PubMed]

18.

Diffenderfer MR, Schaefer EJ. The composition and metabolism of large and small LDL. Curr Opin Lipidol. 2014;25:221-226.[PubMed] [DOI]

19.

Hong D, Bai YP, Gao HC, Wang X, Li LF, Zhang GG, Hu CP. Ox-LDL induces endothelial cell apoptosis via the LOX-1-dependent endoplasmic reticulum stress pathway. Atherosclerosis. 2014;235:310-317.[PubMed] [DOI]

20.

Shentu TP, Singh DK, Oh MJ, Sun S, Sadaat L, Makino A, Mazzone T, Subbaiah PV, Cho M, Levitan I. The role of oxysterols in control of endothelial stiffness. J Lipid Res. 2012;53:1348-1358.[PubMed] [DOI]

21.

Chavakis E, Dernbach E, Hermann C, Mondorf UF, Zeiher AM, Dimmeler S. Oxidized LDL inhibits vascular endothelial growth factor-induced endothelial cell migration by an inhibitory effect on the Akt/endothelial nitric oxide synthase pathway. Circulation. 2001;103:2102-2107.[PubMed] [DOI]

22.

Salisbury D, Bronas U. Inflammation and immune system contribution to the etiology of atherosclerosis: mechanisms and methods of assessment. Nurs Res. 2014;63:375-385.[PubMed] [DOI]

23.

Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1:a000034.[PubMed] [DOI]

24.

Jain S, Khera R, Corrales-Medina VF, Townsend RR, Chirinos JA. “Inflammation and arterial stiffness in humans”. Atherosclerosis. 2014;237:381-390.[PubMed] [DOI]

25.

Hermann DM, Gronewold J, Lehmann N, Seidel UK, Möhlenkamp S, Weimar C, Kälsch H, Moebus S, Jöckel KH, Erbel R. Intima-media thickness predicts stroke risk in the Heinz Nixdorf Recall study in association with vascular risk factors, age and gender. Atherosclerosis. 2012;224:84-89.[PubMed] [DOI]

26.

Sillesen H, Muntendam P, Adourian A, Entrekin R, Garcia M, Falk E, Fuster V. Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage study. JACC Cardiovasc Imaging. 2012;5:681-689.[PubMed] [DOI]

27.

Bos D, Ikram MA, Elias-Smale SE, Krestin GP, Hofman A, Witteman JC, van der Lugt A, Vernooij MW. Calcification in major vessel beds relates to vascular brain disease. Arterioscler Thromb Vasc Biol. 2011;31:2331-2337.[PubMed] [DOI]

28.

Lind L. Flow-mediated vasodilation over five years in the general elderly population and its relation to cardiovascular risk factors. Atherosclerosis. 2014;237:666-670.[PubMed] [DOI]

29.

Bruno RM, Bianchini E, Faita F, Taddei S, Ghiadoni L. Intima media thickness, pulse wave velocity, and flow mediated dilation. Cardiovasc Ultrasound. 2014;12:34.[PubMed] [DOI]

30.

Taylor AJ, Rodriguez AE, Lee JC, Mathew SB, Cassimatis D, Gates D, Bindeman J, Feuerstein IM, Do SW, O’Malley PG. The relationship between subclinical atherosclerosis and electrocardiographic abnormalities as biomarkers of cardiovascular risk. Biomarkers. 2008;13:496-504.[PubMed] [DOI]

31.

Criqui MH, McClelland RL, McDermott MM, Allison MA, Blumenthal RS, Aboyans V, Ix JH, Burke GL, Liu K, Shea S. The ankle-brachial index and incident cardiovascular events in the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2010;56:1506-1512.[PubMed] [DOI]

32.

Sakurai-Komada N, Iso H, Koike KA, Ikeda A, Umesawa M, Ikehara S, Inoue M, Tsugane S. Association between Chlamydophila pneumoniae infection and risk of coronary heart disease for Japanese: the JPHC study. Atherosclerosis. 2014;233:338-342.[PubMed] [DOI]

33.

Haberka M, Gąsior Z. Carotid extra-media thickness in obesity and metabolic syndrome: a novel index of perivascular adipose tissue: extra-media thickness in obesity and metabolic syndrome. Atherosclerosis. 2015;239:169-177.[PubMed] [DOI]

34.

Perticone M, Maio R, Tassone EJ, Tripepi G, Di Cello S, Miceli S, Caroleo B, Sciacqua A, Licata A, Sesti G. Insulin-resistance HCV infection-related affects vascular stiffness in normotensives. Atherosclerosis. 2015;238:108-112.[PubMed] [DOI]

35.

Landau DA, Scerra S, Sene D, Resche-Rigon M, Saadoun D, Cacoub P. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy. J Rheumatol. 2010;37:615-621.[PubMed] [DOI]

36.

Boddi M, Abbate R, Chellini B, Giusti B, Solazzo V, Soft F, Pratesi G, Pratesi C, Gensini G, Zignego AL. HCV infection facilitates asymptomatic carotid atherosclerosis: preliminary report of HCV RNA localization in human carotid plaques. Dig Liver Dis. 2007;39 Suppl 1:S55-S60.[PubMed] [DOI]

37.

Roed T, Lebech AM, Kjaer A, Weis N. Hepatitis C virus infection and risk of coronary artery disease: a systematic review of the literature. Clin Physiol Funct Imaging. 2012;32:421-430.[PubMed] [DOI]

38.

Forde KA, Haynes K, Troxel AB, Trooskin S, Osterman MT, Kimmel SE, Lewis JD, Lo Re V. Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study. J Viral Hepat. 2012;19:271-277.[PubMed] [DOI]

39.

Pothineni NV, Delongchamp R, Vallurupalli S, Ding Z, Dai Y, Hagedorn CH, Mehta JL. Impact of hepatitis C seropositivity on the risk of coronary heart disease events. Am J Cardiol. 2014;114:1841-1845.[PubMed] [DOI]

40.

Lin MS, Guo SE, Chen MY, Huang TJ, Huang JC, Hu JH, Lin YS. The impact of hepatitis C infection on ischemic heart disease via ischemic electrocardiogram. Am J Med Sci. 2014;347:478-484.[PubMed] [DOI]

41.

Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49:225-232.[PubMed] [DOI]

42.

Hsu YC, Lin JT, Ho HJ, Kao YH, Huang YT, Hsiao NW, Wu MS, Liu YY, Wu CY. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology. 2014;59:1293-1302.[PubMed] [DOI]

43.

Ishizaka N, Ishizaka Y, Takahashi E, Tooda Ei, Hashimoto H, Nagai R, Yamakado M. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening. Lancet. 2002;359:133-135.[PubMed]

44.

Petta S, Torres D, Fazio G, Cammà C, Cabibi D, Di Marco V, Licata A, Marchesini G, Mazzola A, Parrinello G. Carotid atherosclerosis and chronic hepatitis C: a prospective study of risk associations. Hepatology. 2012;55:1317-1323.[PubMed] [DOI]

45.

Hsu YH, Muo CH, Liu CY, Tsai WC, Hsu CC, Sung FC, Kao CH. Hepatitis C virus infection increases the risk of developing peripheral arterial disease: a 9-year population-based cohort study. J Hepatol. 2015;62:519-525.[PubMed] [DOI]

46.

Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001;103:1064-1070.[PubMed]

47.

Guiltinan AM, Kaidarova Z, Custer B, Orland J, Strollo A, Cyrus S, Busch MP, Murphy EL. Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors. Am J Epidemiol. 2008;167:743-750.[PubMed] [DOI]

48.

Lee MH, Yang HI, Lu SN, Jen CL, You SL, Wang LY, Wang CH, Chen WJ, Chen CJ. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012;206:469-477.[PubMed] [DOI]

49.

Kohli A, Shaffer A, Sherman A, Kottilil S. Treatment of hepatitis C: a systematic review. JAMA. 2014;312:631-640.[PubMed] [DOI]