Rapid Progress and Effective Cures Usher New Era for Hepatitis C

Released:5/29/2013 4:55 PM EDT
Source Newsroom:Saint Louis University Medical Center

Adrian Di Bisceglie, M.D., chair of internal medicine and co-director of the Liver Center at Saint Louis University, urges baby boomers to learn about the risk factors for hepatitis C and talk with their physicians about screening for the virus.

Newswise — In 1989, researchers first identified the hepatitis C virus, a health threat that had been worrying doctors as they noticed patients with unexplained liver damage occurring after receiving blood transfusions. The discovery of the potentially debilitating and deadly virus sparked several decades of productive research. Researchers made unusually rapid progress, in medical research terms, and developed therapies that had success in eliminating the virus, at least in some patients. Then, in 2011, two new drugs were brought to market that changed the landscape in a dramatic way, offering a cure for many more who suffer from a chronic form of the illness.

Currently, we estimate that 4 million people in the U.S. are infected with the virus, and at least 10,000 people in this country will die from its complications each year. Symptoms of hepatitis C can be quite variable and often only develop at the most advanced stages of liver disease, years after the virus was contracted. For this reason, it is believed that roughly 60 percent of those who have the virus are unaware of it. Patients who have a chronic infection can develop inflammation of the liver, leading to fibrosis and cirrhosis, as well as other complications that may result in liver cancer and death.

While hepatitis C is sometimes compared to HIV, and, indeed both are blood-borne, the viruses behave differently. For example, hepatitis C is not frequently spread through sexual contact. It is more likely to be transmitted from a needle stick, blood transfusion or organ transplant received before 1992, recreational drug use, or from mother to infant.

(In fact, reducing hepatitis C transmission by blood donation has been a success story of its own. In the mid-1960’s, approximately one in 10 transfusions was associated with hepatitis, initially referred to as non-A, non-B hepatitis, but now known as hepatitis C. Now, thanks to an all-volunteer blood donor system, as well as questionnaires that weed out donations from those with high risk behavior, and the routine testing of donated blood for various biomarkers of hepatitis, the risk is virtually nonexistent at one in five million.)

Today, we see hepatitis C patients from all walks of life. We see captains of industry who may have contracted the virus in their youth and healthcare workers who received accidental needle sticks on the job or even young people who acquired it from their mothers at birth. Because they may only begin to show symptoms decades later, it’s often impossible to pinpoint the exact way the virus was contracted.

However, there is an inexpensive and accurate blood test for hepatitis C. Liver disease specialists advocate that those at risk ask their doctor to be tested. In particular, the CDC now recommends that all baby boomers -- those born between 1945 and 1965 -- be screened. Doctors also urge those with risk factors such as a blood transfusion prior to 1992, a history of injection drug use and abnormal liver enzymes counts be tested.

With parallel clinical trials successfully concluding in recent years, two effective new drugs, Merck’s boceprevir and Vertex’s telaprevir, were FDA approved in 2011 to treat the virus. Added to the existing treatment regimen of peginterferon and ribavirin, these new medicines can cure nearly 80 percent of those with the disease.

Though the new treatments still require the use of peginterferon, which frequently causes taxing side effects, we’ve turned a corner. The new drugs lower the average treatment time from 1 year to 6 months. More antiviral drugs against hepatitis C are in the pipeline, and their use may eventually eliminate the need for interferon altogether.

But, right now, we can tell patients with hepatitis C that treatment time is expected to be much less than a year, is far more likely to cure them, and is likely to add years to their lives. The opportunity to halt progressive liver damage is a chance to save those with the virus from debilitating fatigue, cancer and death.

Physicians now can recommend testing to patients with the knowledge that we have effective medicines to treat the virus if we find it. These new medicines are revolutionizing the care of those with hepatitis C. It’s critical that those at risk be screened so the illness can be treated.

Adrian Di Bisceglie, M.D. is chair of the department of internal medicine and co-director of the Liver Center at Saint Louis University. He also served as Liver Diseases Section Chief at the National Institutes of Health where he supervised research in viral hepatitis and was among the first to use interferon when the illness simply was known as non-A, non-B hepatitis. Throughout the search for a cure for hepatitis C, Di Bisceglie led numerous research studies and recently co-authored a New England Journal of Medicine paper on the successful telaprevir clinical trial.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

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War on drugs 'driving hepatitis C pandemic'

Hepatitis C virus can lead to fatal liver disease

29 May 2013 Last updated at 19:44 ET

The global war on drugs is fuelling a hepatitis C pandemic causing millions of needless infections, the Global Commission on Drug Policy has warned.

Repressive drug law enforcement is driving high rates of infection among injecting drug users, it said.

Resources need to be redirected into treatment and prevention.

The Commission estimated that of 16 million people worldwide who inject drugs, 10 million are living with hepatitis C.

This puts them at risk of fatal and debilitating liver disease.

The Global Commission called on governments to decriminalise drug use and provide schemes, such as those which give access to sterile needles, to halt the spread of the disease.

"The war on drugs is a war on common sense.”

End Quote Ruth Dreifuss Global Commission on Drug Policy

The group, which includes seven former presidents, ex-UN chief Kofi Annan and other world leaders, has previously linked the "failed" war on drugs with the spread of HIV.

In its latest report it says in some countries with the harshest drug policies more than 90% of people who inject drugs are living with hepatitis C.

Eastern Europe and Central Asia have seen the fastest spread of infection and the highest number of infections has been reported in China, the Russian Federation and the USA.

Strongly enforced policies criminalising drug use force users away from public health services and locking up vast numbers of injecting users perpetuates the spread of the infection, the Commission warned in the latest report.

Hidden epidemic

Hepatitis C is highly infectious and around a quarter of those with chronic infection will develop fatal liver disease.

But the disease can go undetected for several years with no or few symptoms and many people are completely unaware they are infected.

Governments "must immediately redirect resources away from the 'war on drugs' and into public health approaches that maximise hepatitis C prevention and care", the report recommended.

Hepatitis C

• Hepatitis C is most commonly spread through blood-to-blood contact
• It is three times more prevalent than HIV among injecting drug users
• Initially it can cause no or very mild symptoms such as fever, nausea and fatigue
• In 80% of those infected the infection becomes chronic and the virus remains in the body long-term
• A quarter of those with chronic infection will develop potentially fatal liver disease
• Many people do not know they are infected until they get advanced liver disease

"Hepatitis C has to be one of the most grossly miscalculated diseases by governments on the planet," said commissioner Michel Kazatchkine, who is also the UN secretary-general's special envoy on HIV/AIDS in Eastern Europe and Central Asia.

"It is a disgrace that barely a handful of countries can actually show significant declines in new infections of hepatitis C among people who inject drugs."

The report highlighted Scotland's national Hepatitis C Action Plan as an example of best practice.

Launched in 2006, the strategy has led to a four-to-six-fold increase in the provision of sterile injecting equipment and an increase in the number of people, mainly in drug services and prisons, being tested for the infection.

The provisions put in place, which also include an eight-fold increase in the number of prisoners receiving treatment for hepatitis C, have led to falling rates of infection.

The Commission also highlights the potential for dramatic savings to countries' health and welfare budgets in the long term from preventing cases of liver disease.

"The war on drugs is a war on common sense," said commissioner Ruth Dreifuss, who is also the former president of Switzerland.

"Repressive drug policies are ineffective, violate basic human rights, generate violence and expose individuals and communities to unnecessary risks.

"The hepatitis C epidemic, totally preventable and curable, is yet another proof that the drug policy status quo has failed us all miserably."

The World Hepatitis Alliance said: "It is incomprehensible that hepatitis C, along with hepatitis B, is so consistently ignored.

"If you compare rates of hepatitis C in drug users in countries with good harm reduction and more enlightened drug policies with those in countries without, it is clear that regarding drug use exclusively as a criminal justice issue is a health disaster. Hepatitis C, its prevention, care and treatment must be addressed and must be addressed as the health issue it is."

A UK government spokesperson said: "This government is committed to breaking the vicious cycle of addiction and drug usage remains at its lowest level since records began.

"The best protection from drugs is not to take them in the first place, but we must ensure good healthcare is available for those who want to treat their addiction - and we are seeing a rise in the numbers of users exiting treatment programmes free of drugs."

Source

Dual IBD, metabolic syndrome diagnoses linked to NAFLD

Provided by Healio

May 28, 2013

ORLANDO, Fla. — A combination of inflammatory bowel disease and metabolic syndrome increased the risk for developing nonalcoholic fatty liver disease, according to data presented at Digestive Disease Week.

Using data collected from the University of Pennsylvania electronic health care record, researchers performed a retrospective chart review of 10,863 patients with NAFLD seen between 1997 and 2011. IBD was present in 297 cases, with a dual diagnosis of IBD and NAFLD in 37 patients, including 11 with ulcerative colitis and 26 with Crohn’s disease.

Patients with any three of the following characteristics were considered to have metabolic syndrome (MetS): BMI greater than 30 kg/m2, diabetes/insulin resistance, hypertension or hyperlipidemia. Liver biopsy or BARD fibrosis score was used to determine NAFLD severity, while IBD severity was indicated via Montreal classification and physician global assessment.

“Intestinal inflammation and bacterial translocation have been implicated in the pathogenesis of NAFLD,” the researchers wrote. “It is unknown, however, whether the combination of obesity and chronic intestinal inflammation in IBD patients increases NAFLD risk or severity.”

Among the 37 patients with dual IBD/NAFLD diagnoses, the mean BMI was 31 kg/m2 . At NAFLD diagnosis, the mean C-reactive protein (CRP) was 30.7, 35% of participants had MetS, and 62.2% had severe IBD. Eighty-one percent of this subset had BARD scores between 2 and 4. Patients with MetS had significantly greater estimated NAFLD severity compared with those without MetS (P=.048). Bilirubin levels were significantly higher among MetS patients (0.9 compared with 0.5; P=.004), but alanine aminotransferase, aspartate aminotransferase, CRP and erythrocyte sedimentation rate levels did not differ according to MetS presence.

“Patients with more severe IBD tend to have a higher risk of progression to NAFLD,” researcher Arpan Patel, MD, a resident at the University of Pennsylvania, told Healio.com. “Patients who carry a dual diagnosis [of metabolic syndrome] have higher BARD scores, which correlate to worsening NAFLD severity. If you have a patient with IBD, and they have metabolic syndrome, you should be worried about NAFLD in that patient.”

Disclosure: Researcher Gary R. Lichtenstein, MD, reported numerous financial disclosures.

For more information:

Carr RM. Mo1261: Metabolic Syndrome and IBD Severity May Increase Risk of NAFLD. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla.

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Achillion Nominates ACH-3422 as Nucleotide for the Treatment of Chronic HCV

May 30, 2013

— Advancement of ACH-3422 Complements Achillion's Portfolio of 2^nd Generation Protease and NS5A Inhibitors Providing the Opportunity to Optimize Treatment Duration and Outcomes for All HCV Patients —

— Conference Call and Webcast to be Hosted Today at 12:00pm EDT —

NEW HAVEN, Conn., May 30, 2013 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced the nomination of the preclinical compound, ACH-3422, a novel small molecule nucleotide prodrug of a uridine analog designed to inhibit HCV NS5B polymerase. This compound will be advanced as a development candidate for the treatment of chronic hepatitis C (HCV) viral infection. Achillion plans to complete regulatory submissions during the first quarter of 2014, with first-in-human studies anticipated in the first half of 2014, followed by combination development in the second half of 2014.

"Our research and discovery team has always maintained the highest standards for developing proprietary best-in-class compounds, and this has led to the nomination of ACH-3422, which we are now advancing toward the clinic," commented Milind Deshpande, Ph.D., President and Chief Executive Officer. "The addition of ACH-3422 gives Achillion a portfolio of assets that also includes a 2^nd generation protease inhibitor, sovaprevir, and a 2^nd generation NS5A inhibitor, ACH-3102, which together provide Achillion the opportunity to potentially optimize treatment outcomes and duration of therapy across all HCV patients."

Dr. Deshpande further commented, "Along with the nomination of this candidate, we continue our efforts to accelerate the development time-lines for our all-oral, interferon-free combination of sovaprevir and ACH-3102, our protease and NS5A inhibitors, as a regimen for the treatment of HCV. Beginning in the third quarter of 2013, we expect to begin to report interim results from the ongoing -007 clinical trial of these agents for the treatment of HCV genotype 1 treatment-naïve patients."

Preclinical profile of ACH-3422

ACH-3422 is a small-molecule, nucleotide prodrug inhibitor of HCV NS5B polymerase. In vitro, ACH-3422 has demonstrated excellent potency, with activity demonstrated across all genotypes of HCV and an EC₅₀ of approximately 50 to 65 nanomolar against genotype 1 HCV. To date, Achillion has completed 14-day safety studies in animals, where no significant findings were noted at the highest dose tested. ACH-3422 appears to have high oral bioavailability, rapid uptake and conversion of the prodrug into the monophosphate within the liver, and a pharmacokinetic profile supportive of once-daily dosing. Manufacturing and IND-enabling studies have been initiated, with the expectation of submitting an IND to the FDA in the first quarter of 2014.

Conference Call

The Company will host a conference call and simultaneous webcast on Thursday, May 30, 2013 at 12:00 p.m. Eastern time. To participate in the conference call, please dial (877) 266-0482 begin_of_the_skype_highlighting (877) 266-0482 end_of_the_skype_highlighting in the U.S. or (631) 291-4567 for international callers. A live audio webcast of the call will be accessible at www.achillion.com, under the News Center section of the website. Please connect to Achillion's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

A replay of the webcast will be available on www.achillion.com. Alternatively, a replay of the conference call will be available starting at 9:00 p.m. Eastern time on May 28, 2013, through 11:59 p.m. Eastern time on June 5, 2013 by dialing (855) 859-2056 or (404) 537-3406. The replay passcode is 87685598.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including more than 5 million people in the United States, making HCV more than twice as widespread as HIV. Three-fourths of the global HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

For additional information on Achillion's ongoing clinical trial please visit: http://clinicaltrials.gov

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's discovery, clinical development, and commercial teams have advanced multiple novel product candidates with proven mechanisms of action into studies and toward the market. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000 begin_of_the_skype_highlighting 1-203-624-7000 end_of_the_skype_highlighting.

Forward-Looking Statements

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 important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the expected potency, bioavailability, pharmacokinetic and other characteristics of development candidate ACH-3422; Achillion's expectations regarding timing for the commencement, completion and reporting of results of its clinical trials of ACH-3422, ACH-3102 in combination with ribavirin and sovaprevir in combination with ACH-3102. We may use words such as "expect," "anticipate," "project," "intend," "plan," "believe," "seek," " estimate," and "may" and similar expressions to identify such forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: successfully advance ACH-3422 into clinical trials; replicate in later clinical trials positive results found in preclinical and earlier stage clinical trials of sovaprevir, ACH-3102, ACH-3422 and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2012 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.

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Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies

Gastroenterology
Volume 144, Issue 7 , Pages 1450-1455.e2, June 2013

Jianmeng Chen, Jeffry Florian, Wendy Carter, Russell D. Fleischer, Thomas S. Hammerstrom, Pravin R. Jadhav, Wen Zeng, Jeffrey Murray, Debra Birnkrant,

Received 18 December 2012; accepted 27 February 2013. published online 07 March 2013.

Absrtact

Background & Aims

Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development.

Methods

We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals.

Results

The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection.

Conclusions

SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.

Keywords: Therapy, Outcome, Effectiveness, Quantification

Abbreviations used in this paper: AIMS, Antiviral Information Management System, CHC, chronic hepatitis C, DAA, direct-acting antiviral, HCV, hepatitis C virus, NPV, negative predictive value, PPV, positive predictive value, SVR, sustained virologic response

Author names in bold designate shared co-first authorship.

Conflicts of interest This authors disclose the following: Jadhav Pravin was employed by Merck after completion of this study. The remaining authors disclose no conflicts.

Funding This project was supported by funding through a critical path grant and in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and Center for Drug Evaluation and Research.

PII: S0016-5085(13)00288-6

doi:10.1053/j.gastro.2013.02.039

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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European Commission Approves Stribild®, a New Single Tablet Regimen for the Treatment of HIV-1 Infection

FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 28, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorization for Stribild^®(elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg), a single tablet regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild. This approval allows for the marketing of Stribild in all 27 countries of the European Union.

“Single tablet regimens make it easier for HIV patients to take their treatment consistently every day, which may improve their health outcomes,” said Jürgen Rockstroh, MD, Professor of Medicine, University of Bonn, Germany and a lead investigator for one of the Stribild pivotal studies. “Stribild is a highly effective and well tolerated HIV treatment regimen, and is an important addition to the growing arsenal of simplified therapies in Europe.”

This approval is supported by 48-week data from two pivotal Phase 3 studies in which Stribild met its primary objective of non-inferiority compared to Atripla^® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg) (Study 102) and to a regimen containing ritonavir-boosted atazanavir plus Truvada^®(emtricitabine/tenofovir disoproxil (as fumarate)) (Study 103).

“We look forward to making Stribild available to HIV-treating physicians and their patients throughout the European Union as quickly as possible,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences.

Stribild is also approved in the United States, Canada, Australia, South Korea, Japan and Turkey.

Stribild is the third single tablet HIV regimen developed by Gilead to become available in Europe. The first, Atripla, was approved in the European Union in 2007 and is marketed by Gilead in partnership with Bristol-Myers Squibb and Merck & Co. The second, Eviplera^®▼ (emtricitabine/rilpivirine/tenofovir disoproxil (as fumarate) 245 mg)), is marketed by Gilead and Janssen R&D Ireland and received European marketing authorization in November 2011.

About Stribild

Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil (as fumarate) 245 mg.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights.

Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body.

Marketing applications for elvitegravir and cobicistat as standalone agents are currently under review in the European Union. In the United States, on April 29, 2013, Gilead announced it had received Complete Response Letters from the U.S. Food and Drug Administration (FDA) on its New Drug Applications for elvitegravir and cobicistat as standalone agents. The company is working to address the questions raised in FDA’s letters as quickly as possible.

Elvitegravir and cobicistat as standalone agents are investigational products and their safety and efficacy have not yet been established.

EU Important Product Information About Stribild

Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. Lactic acidosis has a high mortality and patients at increased risk should be followed closely.

Stribild should not be taken with any of the following due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild:

• alpha 1-adrenoreceptor antagonists: alfuzosin
• antiarrhythmics: amiodarone, quinidine
• anticonvulsants: carbamazepine, phenobarbital, phenytoin
• antimycobacterials: rifampicin
• ergot derivatives: dihydroergotamine, ergometrine, ergotamine
• gastrointestinal motility agents: cisapride
• herbal products: St. John’s wort (Hypericum perforatum)
• HMG Co-A reductase inhibitors: lovastatin, simvastatin
• neuroleptics: pimozide
• PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension
• sedatives/hypnotics: orally administered midazolam, triazolam

As a fixed combination, Stribild should not be administered concomitantly with other medicinal products containing tenofovir disoproxil (as fumarate), lamivudine or adefovir dipivoxil used for the treatment of hepatitis B virus infection.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil (as fumarate).

Patients who have previously discontinued treatment with tenofovir disoproxil (as fumarate) due to renal toxicity should not be treated with Stribild.

Patients should have creatinine clearance calculated and urine glucose and urine protein determined prior to initiating Stribild therapy.

Stribild should not be initiated in patients with creatinine clearance below 70 mL/min. It is recommended that Stribild is not initiated in patients with creatinine clearance < 90 mL/min unless, after review of the available treatment options, it is considered that Stribild is the preferred treatment for the individual patient.

Creatinine clearance, serum phosphate, urine glucose and urine protein should be monitored every four weeks during the first year and then every three months. More frequent monitoring of renal function should be considered in patients at risk for renal impairment.

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Patients who experience a confirmed increase in serum creatinine of greater than 26.5 μmol/L (0.3 mg/dL) from baseline should be closely monitored for renal safety.

Renal function should be re-evaluated within one week if serum phosphate is < 0.48 mmol/L (1.5 mg/dL) or creatinine clearance decreases to < 70 mL/min during Stribild therapy.

If creatinine clearance is confirmed as < 50 mL/min or serum phosphate decreases to < 0.32 mmol/L (1.0 mg/dL) then Stribild should be discontinued.

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil (as fumarate) and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil (as fumarate) without cobicistat.

Stribild should be avoided with concurrent or recent use of a nephrotoxic medicinal product due to the increased risk of renal adverse reactions (with the tenofovir disoproxil (as fumarate) component of Stribild).

Bone abnormalities (infrequently leading to fractures) may be associated with proximal renal tubulopathy and appropriate consultation should be obtained if suspected.

Stribild has not been studied in patients with severe hepatic impairment (CPT Score C).

Discontinuation of Stribild therapy in patients co-infected with HIV and hepatitis B virus (HBV) may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Stribild should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post treatment exacerbation of hepatitis may lead to hepatic decompensation.

Immune Reactivation Syndrome has been reported in patients treated with combination therapy, including the components of Stribild.

Combination therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown.

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 worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

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 physicians in Europe may not see advantages of Stribild over other HIV therapies and may therefore be reluctant to prescribe the product. In addition, pending marketing applications for elvitegravir and cobicistat as standalone agents in the United States and Europe may not be approved or approvals may be delayed, including due to Gilead’s inability to address the questions raised in FDA’s complete response letters. Further, any marketing approvals, if granted, may have significant limitations on their 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 March 31, 2013, as filed with the U.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.

EU Summary of Product Characteristics for Atripla, Eviplera, Stribild and Truvada are available at
http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp

Eviplera, Stribild and Truvada are registered trademarks of Gilead Sciences, Inc.
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

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.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Investors:
Patrick O’Brien, 650-522-1936
or
Media:
Stephen Head, +44 (208) 587-2359 (Europe)
Erin Rau, 650-522-5635 (U.S.)
www.gilead.com

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NGOs thanked for efforts to help patients cope with Hepatitis C

By Rayan Sheety
May 28, 2013

Dubai: “Globally, majority of Hepatitis C victims struggle with the disease due to unsafe healthcare,” said Charles Gore, the president of the World Hepatitis Alliance.

The Emirates Medical Association (EMA) hosted a charity-appreciation benefit on Monday at the Palace Hotel in the Downtown area.

The event acknowledged charities like Red Crescent, Zakat Fund and 30 other NGOs for their contribution towards generating awareness about Hepatitis C and providing support for patients who have contracted the disease and are not financially equipped to acquire treatment.

The benefit started with a speech by Dr Yousif Al Serkal, after which a video was previewed showcasing the many efforts carried out by the 30 NGOs.

After the video, Gore gave a presentation about general statistics regarding Hepatitis C and the role of NGOs in helping patients cope with a disease that has the same mortality rate as HIV if contracted with Hepatitis B.

“The problem with Hepatitis C is that it has a low priority in most countries,” said Gore. He outlined a cycle which stated that a lack of awareness about Hepatitis C leads to low priority which in turn leads to lack of funding. This all contributes to a lack of proper data, action and awareness.

Through this cycle he introduced the concept of World Hepatitis Day, going on to say, “Every country, every government should have activities for World Hepatitis Day.” He further stated that World Hepatitis Day is “designed to be an overwhelming framework in which countries can do whatever is appropriate for them.”

Activities on World Hepatitis Day include raising awareness through multiple platforms like screening events, Radio/TV interviews and press conferences as well as free vaccinations and sporting events and so on and so forth.

Gore went on to talk about the roles NGOs can play in the lives of Hepatitis C patients besides financially supporting them.

“Aside from funding, NGOs can provide reliable information so patients know there is somewhere to go to find help,” said Gore, further stating that hepatitis patients need support because of stigma and discrimination that is thrown their way by people who do not fully understand the disease.

He also said, “I came to understand that representation and advocacy are as important as support,” before concluding his presentation by thanking the members of the NGOs for their “tremendous” efforts.

The benefit was concluded with the presenting of awards to various present members of the 30 NGOs that participated in the Hepatitis C campaign and the presenting of the final award to Gore himself.

Source

Chronic hepatitis C virus (HCV) disease burden and cost in the United States

Hepatology

Early View (Online Version of Record published before inclusion in an issue)

Viral Hepatitis

Homie Razavi^1,*, Antoine C. ElKhoury², Elamin Elbasha², Chris Estes¹, Ken Pasini¹, Thierry Poynard³, Ritesh Kumar²

Article first published online: 6 MAY 2013

DOI: 10.1002/hep.26218

Copyright © 2013 American Association for the Study of Liver Diseases

Abstract

Hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. A better understanding of HCV disease progression and the associated cost can help the medical community manage HCV and develop treatment strategies in light of the emergence of several potent anti-HCV therapies. A system dynamic model with 36 cohorts was used to provide maximum flexibility and improved forecasting. New infections incidence of 16,020 (95% confidence interval, 13,510-19,510) was estimated in 2010. HCV viremic prevalence peaked in 1994 at 3.3 (2.8-4.0) million, but it is expected to decline by two-thirds by 2030. The prevalence of more advanced liver disease, however, is expected to increase, as well as the total cost associated with chronic HCV infection. Today, the total cost is estimated at $6.5 ($4.3-$8.4) billion and it will peak in 2024 at $9.1 ($6.4-$13.3) billion. The lifetime cost of an individual infected with HCV in 2011 was estimated at $64,490. However, this cost is significantly higher among individuals with a longer life expectancy. Conclusion: This analysis demonstrates that US HCV prevalence is in decline due to a lower incidence of infections. However, the prevalence of advanced liver disease will continue to increase as well as the corresponding healthcare costs. Lifetime healthcare costs for an HCV-infected person are significantly higher than for noninfected persons. In addition, it is possible to substantially reduce HCV infection through active management. (HEPATOLOGY 2012)

According to estimates from the National Health and Nutrition Examination Survey (NHANES), 1.6% of the US population was infected with the hepatitis C virus (HCV) in 1999-2002.[1] In a recent study, over 15,000 deaths were attributed to chronic hepatitis C virus (HCV) infection in 2007,[2] already exceeding earlier estimates.[3] HCV infection is associated with chronic, progressive liver disease. Chronic hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma (HCC),[4, 5] which are major indications for liver transplantation.[6] A better understanding of HCV disease progression and the associated baseline cost, which excludes the cost of antiviral treatment, can help the medical community manage HCV and develop treatment strategies in light of the emergence of several potent anti-HCV therapies.

Historically, researchers have studied HCV disease progression and cost using Markov models.[3, 7] In these models, a homogenous cohort of HCV-infected individuals are introduced, and the model is used to track their progression and cost over time. A recent study[15] varied the age at infection, gender, and disease duration over time using six cohorts to estimate future disease burden. However, in a previous analysis[16] it was found that the predictability of the HCV epidemiology model is very sensitive to the number of age and gender cohorts used, due to the large difference in new infections' incidence and mortality across cohorts. Thus, we set out to create a disease progression and cost model that was more refined than those used in previous studies.

The present study represents an improvement over previous work. A total of 36 cohorts composed of 17 5-year age cohorts and one age cohort for 85+ was used for each gender. A system dynamic model was developed to provide maximum flexibility in changing inputs (incidence rate, age at infection, background mortality, transplantation rate, treatment rate, and cost) over time. Finally, more recent healthcare cost data[17] were used to estimate the HCV cost burden as compared to previous studies that relied on older data.[18]

The goal of this study is to describe the future disease and cost burden of HCV infection in the United States using a systems approach, assuming there is no incremental increase in treatment as the result of the new therapies.

Materials and Methods

A system dynamic modeling framework was used to construct the model in Microsoft Excel (Redmond, WA) to quantify the HCV-infected population, the disease progression, and the associated cost from 1950-2030. Uncertainty and sensitivity analyses were completed using Crystal Ball, an Excel add-in by Oracle. Beta-PERT distributions were used to model uncertainty associated with all inputs. Sensitivity analysis was used to identify the uncertainties that had the largest impact on the peak cost in 2025. Monte-Carlo simulation was used to determine the 95% confidence interval (CI) for cost and prevalence. When historical data were available, nonlinear polynomial extrapolation of historical data was used for future assumptions in 2012-2030. The Excel optimization add-in, Solver, was used to calibrate the model using reported National Health and Nutrition Examination Survey (NHANES) prevalence data[1] as described below:

Populations in a given health state (incident HCV, cured, F1, F2, etc.) were handled as stocks, while annual transitions from one health state to another were treated as flows with an associated rate/probability (see Supporting Appendix A, Fig. 1). Historical data reporting the number and indications for liver transplantations from 1988 to 2010 were used to estimate the number of transplantations attributable to chronic HCV infection.[6] Trended transplantation rates from 1988-2011 were used for 1971-1987 and 2011-2030.

The populations were tracked by age cohorts and gender. Five-year age cohorts were used through age 84, and those aged 85 and older were treated as one cohort. Each year, one-fifth of the population in each age group, except for 85 and older, was moved to the next age cohort to simulate aging, after accounting for mortality.

The model started in 1950 to track the prevalent population from the time of infection and forecasted the sequelae populations to 2030. The impact of individuals infected with HCV prior to 1950 was expected to be small and within the margin of error of our analysis. Prevalence of chronic HCV in any given year was calculated by the sum of viremic incidence of new infections (incidence) minus mortality and cured cases, up to that year, as shown below.

Annual background mortality rates by age and gender[19] were adjusted for incremental increase in mortality due to injection drug use (IDU) and transfusion.[16] These rates were applied to all populations. For individuals with decompensated cirrhosis (diuretic sensitive and refractory ascites, variceal hemorrhage, and hepatic encephalopathy), HCC, and those who required a liver transplantation, a separate mortality rate was also applied for liver-related deaths,[8, 10, 20] as shown in Supporting Appendix A, Tables 1, 2.

The number of cured patients in 2002-2007 was estimated using published data for the number of treated patients[21] and an average sustained viral response (SVR) of 34%, as shown in Supporting Appendix B, Table 1. The number of cured patients prior to 2002 was ignored. The number of patients cured in 2008-2030 was extrapolated using 2002-2007 data. The objective of this analysis was to estimate the HCV disease progression and the associated cost in the US when there was no incremental increase in treatment as the result of the new therapies. The launch of direct-acting antivirals in 2011, the increased number of treated patients, and the higher SVR of new therapies were not incorporated in this model. The impact and cost of new therapies were specifically excluded in order to establish a baseline for future comparisons. This, however, will lead to higher projections of advanced liver diseases and poor outcomes as compared to the real world.

With known annual mortality and cured population, annual incidence was calculated using a constant multiplied by the relative incidence. Relative incidence was calculated from the literature data[15] by dividing each year's incidence by the 1950 incidence to result in a relative incidence of 1 in 1950, as shown in Supporting Appendix C, Table 1. Incidence in the US peaked in 1989 when it was 11.5 times higher than incidence in 1950. Solver was used to find the constant that resulted in a prevalence of 3.2 (95% CI, 2.7-3.9) million in 2000.[1]

The annual incidence was distributed among different age and gender cohorts using distributions reported by the Centers for Disease Control and Prevention (CDC)[22] from 1992-2007. Incidence distribution from 2007 was used for 2008-2030 based on the assumption that the future risk factors will remain the same. In 1967-1991, the incidence distribution by age and gender was changed every 5 years and the rates within each 5-year period (e.g., 1967-1971) were extrapolated linearly by age cohort and gender. The distribution was kept constant prior to 1966 based on the assumption that the risk factors remained the same. Solver was used to calculate the annual age and gender distributions, which minimized the difference between the forecasted prevalence age and gender distribution in 2000 and those reported by NHANES.[1]

Since the objective of this study was to determine healthcare costs associated with HCV infection, incremental costs derived from a matched cohort study were used. The cost by sequelae data came from previously published work by McAdam-Marx et al.[17] The healthcare costs among chronic HCV individuals in F0-F3 stages were adjusted for the proportion not under care (see Supporting Appendix D). The 1950-2010 costs were inflation-adjusted using the Medical Care Services component of the Consumer Price Index.[26] The 2011 annual medical inflation rate of 3.06% (2.88%-5.33%) was used to estimate future costs in 2012-2030.

The lifetime cost of an HCV-infected individual by age and gender was calculated by introducing 1,000 viremic incident cases in 2011 and using the model to track the progression of these cases and the annual cost over time. The annual healthcare costs for all sequelae and all years were summed and divided by 1,000 to calculate the individual cost. The average cost was calculated by distributing 1,000 new viremic incident cases using 2010 incidence age and gender distribution.[27]

Results

The annual background and liver-related mortality are shown in Supporting Appendix E. Background mortality is forecasted to peak at 39,935 in 2022 as the HCV population ages, while liver-related deaths peak at 29,695 in 2019 as the number of deaths from decompensated cirrhosis reach their maximum.

Relative incidence and estimated incidence are shown in Supporting Appendix C, Table 1. The constant multiplier for incidence was estimated at 23,790 (20,070-28,990), resulting in a prevalence of 3.2 (2.7-3.9) million in the year 2000.[1] Incidence values represent acute cases, and 82% (55%-85%)[28] of these cases progressed to chronic HCV with a METAVIR score of F0, as shown in Supporting Appendix A, Table 1. Incidence for all sequelae is shown in Fig. 1.

Figure 1. HCV sequelae incidence: US 1950-2030.

Peak viremic prevalence of chronic HCV infection was reached in 1994 with 3.3 (2.8-4.0) million infected individuals (Fig. 2). While the overall prevalence has been declining since, the prevalence of more advanced liver diseases has been increasing. The prevalent population with compensated cirrhosis is projected to peak in 2015 at 626,500 cases, while the population with decompensated cirrhosis will peak in 2019 with 107,400 cases. The number of individuals with HCC, caused by HCV infection, will increase to 23,800 cases in 2018 before starting to decline.

Figure 2. HCV sequelae and total prevalence (millions): US 1950-2030.

In 2011, the total healthcare cost associated with HCV infection was $6.5 ($4.3-$8.2) billion. Total cost is expected to peak in 2024 at $9.1 billion ($6.4-$13.3 billion), as shown in Fig. 4. The majority of peak cost will be attributable to more advanced liver diseases—decompensated cirrhosis (46%), compensated cirrhosis (20%), and HCC (16%). The maximum cost associated with mild to moderate fibrosis (F0-F3) occurred in 2007 at nearly $780 million. The cost associated with compensated cirrhosis is expected to peak in 2022 at $1.9 billion, while the peak cost for decompensated cirrhosis and HCC is predicted to occur in 2025, with annual costs in excess of $4.2 billion and $1.4 billion, respectively (Fig. 3).

Figure 3. Projected HCV sequelae cost: US 1950-2030.

Figure 4. Total prevalence and healthcare costs with 95% CIs.

The lifetime cost of an individual infected in 2011 was estimated at $64,490 ($46,780-$73,190) in 2011 dollars. When medical inflation was applied, the lifetime cost increased to $205,760 ($154,890-$486,890). The lifetime cost estimate varies widely by age and gender due to life expectancy. As shown in Table 1, costs for HCV infections among younger individuals and females will be higher than among the elderly and males.

Table 1. Lifetime Cost by Age, HCV Infection, and Gender (in 2011 Dollars)

Age	Male	Female
Average - all ages & genders* $64,490 ($46,780 - $73,190) *Using 2011 incidence age and gender distribution. All values in 2011 dollars with no inflation adjustment.
0-4	$116,600	$147,130
5-9	$105,960	$138,360
10-14	$94,810	$128,440
15-19	$83,430	$117,590
20-24	$76,550	$108,260
25-29	$70,000	$98,040
30-34	$62,950	$87,680
35-39	$57,030	$77,550
40-44	$51,610	$67,880
45-49	$47,180	$59,030
50-54	$35,940	$46,560
55-59	$26,310	$35,510
60-64	$18,540	$26,200
65-69	$12,660	$18,750
70-74	$8,530	$13,170
75-79	$5,630	$9,010
80-84	$3,770	$6,150
85+	$2,680

Discussion

The predictive value of a model can be confirmed by comparing its forecasts with real-world observations. The model was calibrated using HCV prevalence by age and gender in the year 2000, as reported by NHANES.[1] The incidence was back-calculated and the model was used to fit reported prevalence in 2000. Total prevalence in other years, prevalence and incidence by sequelae, and mortality were calculated. A 2010 incidence of 16,020 (13,510-19,510) was forecasted versus the reported incidence of 17,000.[29] The wide CI for incidence was driven by the large uncertainty in reported prevalence.[1] According to the study by Davis et al.,[15] HCV incidence peaked in 1989 when it was 11.5 times higher than the incidence in 1950. This corresponded to a peak incidence of 274,000 in a single year. A 2010 prevalence of 2.5 (2.1-3.2) million cases was estimated, matching the most recent NHANES data that showed 2.5 million cases in the 2009-2010.[30] In comparison, Davis et al.[15] reported an HCV prevalence of about 3.3 million in the same period.

Our analysis predicted that HCV prevalence in the US peaked in 1994 at 3.3 million viremic cases. The overall prevalence is declining, and the 2030 prevalence is expected to be one-third of the peak prevalence. Incidence has dropped significantly since its peak in 1989 due to the implementation of HCV antibody screening of the blood supply in 1992, with full implementation of universal donation screening for viral RNA through nucleic acid testing (NAT) in 1999,[31, 32] and to a decline in IDU.[33] However, disease burden continues to grow. The dichotomy of HCV is that, while the overall number of infections is projected to decline, the number of individuals experiencing advanced liver diseases, liver related deaths, and healthcare costs are expected to increase. This was a key insight provided by this analysis.

A recent study by the CDC[2] reported an increased recorded mortality rate in the US HCV-infected population in 1999-2007. Consistent with this study, we forecast that mortality will continue to increase and peak in 2020 (Supporting Appendix E). After 2020, the decline in the number of HCV infections will outweigh the increase in background mortality, and liver-related deaths and the number of deaths will decrease. Mortality is projected to peak at ∼69,440 deaths, with 29,650 deaths attributable to liver disease, including over 9,000 attributed to HCC in 2020.

As shown in Fig. 1, the incidence of more advanced liver diseases will continue to increase, with incidence of decompensated cirrhosis and HCC peaking in 2016-2017. However, not all infected individuals progress to the next stage, and the peak incidence is lower at each consecutive sequelae. The total prevalent population of each sequela is shown in Fig. 2. Over 50% of the HCV prevalent population resides in F0-F3 stage of the disease at any point in time. However, by 2030 compensated cirrhosis cases will account for 37% of all prevalent cases. The HCV compensated cirrhosis population is projected to peak in 2015, while the decompensated cirrhosis population will peak in 2019. A smaller portion of the HCV-infected population will go on to have HCC, but the size of this population does not grow substantially beyond 24,000 due to the very high mortality rate in this population.

A key observation was that peak healthcare costs lag peak prevalence by almost three decades. This is due to the time required for infected cases to progress to more advanced forms of liver disease, which are more expensive to treat.

Sensitivity analysis identified the key drivers of variance in peak healthcare cost. The incidence uncertainty (20,070-28,990), calculated from the uncertainty in NHANES 2000 prevalence, accounted for 52% of the variance in peak cost. Higher incidence led to more prevalent cases and higher cost. Uncertainty in the annual cost of diuretic sensitive ascites ($2,525-$29,860)[17, 18] accounted for 15% of the total variance. Finally, uncertainty in persistence (32%-80%)[34, 35] accounted for 13% of the variance. Higher persistence resulted in higher SVR and a greater number of cured patients, which in turn resulted in lower healthcare costs. This highlights the importance of SVR on future costs. In this study, the treatment cost was specifically excluded, and yet the SVR of historically treated cases still turned out to be important. The treated population had to be included in the disease progression portion of the model since it affected the size of prevalent populations. In 2002-2011, we estimated that 322,700 individuals were cured. If persistence in the real world were the same as observed in clinical trials (80%),[35] the average SVR would be 46%, resulting in 430,000 cured cases in 2002-2011. This would result in a decrease of $1 billion dollars in peak healthcare costs.

Patients experiencing decompensated cirrhosis accounted for the majority of future costs. In 2011, it accounted for 40% of total costs, and by 2030 it accounted for 47%. This was followed by compensated cirrhosis (22% of 2011 and 19% of 2030 total cost) and HCC (15% of 2011 and 16% of 2030 total cost). The prevalence of decompensated cirrhosis was 20% of compensated cirrhosis, but the annual cost was 12 times higher.[17]

The average lifetime cost of a patient was estimated at $64,490 as compared to a recent study that reported an average cost of $19,660 per patient in 2002-2010 alone.[17] The analysis of cost by age at infection demonstrates a link between life expectancy and healthcare cost. Individuals infected in the 1950s were expected to have lower lifetime costs due to lower life expectancy (and lower medical costs), while newly HCV-infected individuals are expected to cost the healthcare systems more due to the longer life expectancy. This highlights the continued importance of prevention as a means of managing future healthcare expenditure.

The effects of new therapies were excluded from our model. However, if the number of treated patients is doubled and kept constant at 126,000 per year in 2012-2030 and the average SVR is increased to 70%, the 2030 prevalent population is projected to be fewer than 100,000 cases. This illustrates that it is possible to substantially reduce HCV infection in the US through active management.

There were a number of limitations in this study that impact the accuracy of our base projections. There is strong evidence that progression transition rates change with age and gender. A single transition rate was used for all ages and genders. This led to a higher incidence/prevalence in early years and among females, as well as higher liver-related mortality among the younger age groups. However, the CIs in our study did capture uncertainty in the above assumptions.

The model does not explicitly account for alcohol consumption and metabolic syndrome. Frequent heavy intake of alcohol significantly increases fibrosis progression,[36, 37] and accelerated disease progression has been associated with metabolic syndrome.[38, 39] The model implicitly takes these factors into account, as the transition probabilities and sequelae cost incorporate some level of alcohol consumption and metabolic syndrome. If an increasing proportion of the prevalent population experiences heavy alcohol intake or metabolic syndrome, progression to advanced liver disease, and the associated costs, will likely increase.

The model does not take into account the persistent risk of fibrosis progression and liver cancer in virologically cured patients. Observational studies have demonstrated that most patients who achieve SVR experience stabilization or regression of fibrosis. After SVR, episodes of cirrhosis decompensation are extremely rare, and instances of HCC are likely to be small in number and not greatly impact overall disease burden or costs.[40]

A limitation of prevalence measures used in this analysis is that high prevalence populations may be undersampled through the NHANES.[41] In particular, undersampling of veterans, prisoners, and the homeless would result in underestimation of the current prevalence, future disease, and cost burden. In addition, while IDU has declined from a peak in the 1970s, there is some evidence of a recent increase in IDU among middle-aged adults, potentially leading to a higher incidence of HCV.[33] In all cases, the sequelae prevalence and the healthcare costs will be higher than the estimated base value.

A further limitation is that the model does not consider recent recommendations[42] to implement birth cohort screening for HCV. Such screening could reduce the future incidence of advanced liver disease and associated costs, when infected individuals identified through screening receive appropriate treatment and achieve SVR.[43]

Treatment of HCV prior to 2002 was also ignored. The first pegylated interferon was launched in August of 2001, and the number of patients treated with pegylated interferons was small in that year. Prior to that launch, patients were treated with nonpegylated interferon. The number of individuals cured prior to 2001 was small, and their exclusion did not have a material impact on the outcome of the model.

The rate of SVR used in the model was derived from studies of treatment-naïve patients; however, average SVR is lower in treatment-experienced patients. Because the majority of treated patients are naïve, it is unlikely that the use of a single rate for SVR substantially impacted estimates of treated and cured patients beyond our CIs.

A final limitation is that the future cost of liver transplants is based on the assumption that transplantation will remain at the same rate as today. All other sequelae costs were determined as the result of the disease progression. The number of liver transplants, however, is determined by the clinical guidelines and availability of donors. Thus, the future costs associated with liver transplants could be higher if transplantation rates increase.

In conclusion, our analysis demonstrated that overall HCV prevalence in the US is in decline due to lower incidence. However, the prevalence of advanced liver disease will continue to increase, as will the corresponding healthcare costs. Lifetime healthcare costs for an HCV-infected person are significantly higher than for noninfected persons, and the expected cost is higher among populations with a higher life expectancy. Finally, it is possible to substantially reduce HCV infection in the US through active management.

Acknowledgments

We thank Steven Wiersma of the World Health Organization (WHO) and Charles Gore of the World Hepatitis Alliance, who challenged us to develop a robust cost burden model for HCV. The authors also thank Scott Holmberg of the Centers for Disease Control and Prevention (CDC). His explanations of how to interpret the data published by CDC and feedback on our forecasts were critical in calibrating this model. In addition, we thank Greg Armstrong of CDC for proposing the methodology used to estimate incidence when prevalence, mortality, and cured populations are known. He developed this methodology and shared it with us as a way of estimating incidence. We thank Regina Klein of the Center for Disease Analysis (CDA) for the background research and Kim Murphy of CDA for developing the custom Excel codes to run the model. Finally, we thank Carrie McAdam-Marx of the University of Utah for explaining the methodology used by her group to calculate the incremental cost of HCV sequelae.

References

Supporting Information

Source