FDA Panel Recommends First Drug for HIV Prevention

Truvada (emtricitabine/tenofovir disoproxil fumarate)

From Medscape Medical News

Janis C. Kelly

May 11, 2012 — The US Food and Drug Administration's (FDA's) Antiviral Drugs Advisory Committee has strongly backed approval of the first-ever drug for the prevention of sexually acquired HIV-1 infection.

In a marathon 12-hour session, the panel recommended approval of a supplemental indication for Truvada (emtricitabine/tenofovir disoproxil fumarate) for preexposure prophylaxis (PrEP) in:

• HIV-uninfected men who have sex with men,
• HIV-uninfected partners in serodiscordant couples, and
• other individuals (such as sex workers) who are at risk of acquiring HIV through sexual activity.

The panel also urged the agency to "put some teeth into" Gilead's proposed risk evaluation and mitigation strategy (REMS) because of concerns that healthy people taking Truvada for HIV prevention will be harmed if they become infected with HIV and do not change from single-drug PrEP prophylaxis to a 3-drug combination antiretroviral treatment regimen, that continuing single-drug Truvada after HIV infection will lead to development of Truvada-resistant viral strains, and that taking the PrEP regimen increases the risk for adverse effects, particularly kidney damage.

The hearing occurred against the background of growing concern that the number of new HIV infections in the United States has remained at about 50,000 per year for the past decade. Most (75%) new HIV infections are in men. Black men have the highest incidence of new HIV overall: Incidence is 8 times higher in blacks and 3 times higher in Hispanics/Latinos than in whites.

The main driver of HIV transmission in the United States is unprotected anal sex between men who have sex with men (MSM), who represent about 2% of the population older than 13 years but account for from 56% to 61% of new HIV infections annually. The number of new HIV infections among 13- to 29-year-old MSM increased 38% from 2006 to 2009, largely because of a 48% increase among young black MSM, according to the FDA background document. Proponents of the Truvada PrEP approach hope that the daily pill will be "another tool in the toolbox" for reducing the continuing spread of HIV.

In support of the requested new indication, Gilead Science presented data from the Preexposure Prophylaxis Initiative (iPrEx) trial, which found that MSM participants who took Truvada daily had a 44% reduction in HIV incidence over the course of 1.2 years of follow-up compared with placebo. The study participants also received monthly HIV testing, free condoms, treatment for other sexually transmitted diseases, and routine counseling and were paid for participation in the study. Even with this supportive structure, nearly half of the study participants had no detectable level of Truvada when tested, suggesting that they were not taking the drug regularly.

Results of the iPrEx study were published online November 23, 2010, in the New England Journal of Medicine. Several speakers during the public comments part of the committee meeting reported that Truvada is already being seen as a "medical condom" (in the words of AIDS Healthcare Foundation's Whitney Engeran-Cordova) and might be taken intermittently or as a "party drug," leading to rapid development of Truvada-resistant HIV.

The resistance problem is one reason the FDA took the unusual step of asking that Gilead design a REMS, something that typically happens only when there are concerns about drug toxicity. The proposed REMS includes mailings to about 200,000 healthcare providers; a medication guide for uninfected individuals; voluntary training for primary care prescribers, infectious disease specialists, emergency medicine physicians, obstetrician-gynecologists, and addiction specialists on the importance of strict adherence to daily dosing and of regular monitoring of HIV serostatus; a prescriber safety brochure; an individual safety brochure; and a "TRUVADA for PrEP" wallet card for the patient. The REMS does not require participation by either physician or patient in the education program before making Truvada available.

The REMS plan also does not require a negative HIV test ("documentation of safe use condition") for a patient to receive each 30-day supply of Truvada, which sparked considerable criticism from the panel.

The possibility of "behavioral compensation" (reduced condom use by a patient who assumes protection from the pill) was dismissed by Gilead speakers but remained a concern for several panelists, who noted that condoms, used correctly, are more than 90% effective at preventing HIV infection.

Panelist and speakers also questioned whether the 44% protection seen in the clinical trial would also occur in "real-world" settings, as it requires daily use by a healthy person of a drug that costs $13,000 per year and carries some risk for adverse effects.

The committee voted 19 to 3 in favor of Truvada PrEP for HIV-uninfected MSM, 19 to 2 (1 abstention) in favor of Truvada PrEP for HIV-uninfected partners of those with HIV, and 12 to 8 (2 abstentions) in favor of Truvada PrEP for others at risk of acquiring HIV through sexual activity. The panel also favored monthly HIV testing and regular monitoring of renal function for those taking Truvada PrEP.

The panel ran out of time before full consideration of the proposed REMS, of postmarketing studies that should be required, and on whether current evidence makes the conduct of placebo-controlled trials of primary HIV prevention unethical.

The FDA is expected to make a final decision on the Truvada prophylaxis indication by June 15. It is already approved as part of combination therapy for treatment of HIV infection.

FDA Antiviral Drugs Advisory Committee Meeting. Silver Spring, Maryland. May 10, 2012.

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Guest Commentary: Baby boomers and hepatitis C in Colorado

Posted: 05/11/2012 01:00:00 AM MDT

By Nancy Steinfurth denverpost.com

Colorado's "baby boom" generation faces a ticking health care time bomb — and employers have the opportunity this year to help protect the health of their workers and potentially cut their company's health care costs at the same time.

The challenge that employers and baby boom employees alike face is that many Americans born between 1946 and 1964 have the hepatitis C virus (HCV) and don't know it. A quick blood test and a fast diagnosis results in a far more rapid and less expensive course of treatment. These proactive steps not only save lives but in turn help reduce costs and throw a lasso on soaring insurance premiums.

If it were as simple as all that, we know companies would be clamoring to raise workers' awareness. Unfortunately, myth and misinformation about HCV have left millions of Americans blissfully unaware that a serious and life-threatening disease may be brewing inside them — and by the time symptoms are noticeable, it can often be too late.

That's why exploding the myths surrounding HCV are so critical and having the imprimatur of company leaders in businesses large and small in this fight can make a massive difference.

Let's tackle the biggest myth head on. A number of baby boomers go untested because they assume that the only way to have contracted hep C is through intravenous drug use. Wrong. Many Americans — including many veterans — who had transfusions or blood products prior to 1992 were infected with HCV before donated blood was accurately and adequately screened for the disease. Other risk factors include tattooing in unsafe settings and having been on long-term dialysis.

These myths have consequences. Statistics show that more two-thirds of Americans with HCV are baby boomers and 75 percent of those with the disease are living their lives unaware.

Ignorance is not bliss.

Hepatitis C is a contagious liver disease prevalent — and widely undiagnosed — among baby boomers, with experts estimating that two-thirds of those with hep c were born in the baby boom years of 1946 to 1964. In raw numbers, of the 102 million Americans age48 to 66, an estimated 1.3 million are infected with hepatitis C virus but remain undiagnosed. Hepatitis C ranges in severity from a mild illness lasting a few weeks to a serious, lifelong illness that attacks the liver. It results from infection with the hepatitis C virus, which is spread through contact with the blood of an infected person.

The facts are that symptoms of hep C may not appear for 20 years or more and the later that the disease is diagnosed, the more difficult — and expensive — it is to treat.

That's why a federal strategy released in recent days recommends placing a priority on screening Americans by age, moving beyond the less effective method of screening by so-called "risk group." A new national study showed that screening all American baby boomers could save 48,000 lives.

Instead of allowing this status quo to continue, common-sense tells us to focus on the age group that faces the most dire challenges. That's the message we at Hep C Connection, a statewide organization that educates the general public about hepatitis C and provides resources and support for those affected by the virus, are sharing with employers throughout Colorado.

By focusing on this critical age group in every workplace, employers could literally save lives. Studies show that by raising awareness, employers could help ten times more baby boomers to get tested and three times as many men and women being diagnosed and getting early treatment.

At Hep C Connection, we provide free testing in the metro-Denver area and we connect patients with testing locations in other parts of Colorado which, in most cases, provide the screening free of charge.

The prevention of serious, life-threatening conditions as a result of the early screening is huge with, for example, an estimated 28,000 prevented cases of liver cancer and 6,000 liver transplants being avoided.

In addition to the benefit to lives saved and diseases prevented, the cost of treating these and other serious conditions is very high. For employers, this means the savings of billions of dollars in employee health care costs — and health insurance premiums — going forward.

That is perhaps the most important, common-sense reason for business owners and executives to raise awareness among their baby boomer employees. But there is a bottom-line, dollars-and-sense reason as well. National studies show that age-based testing would save billions of dollars, including more than $4 billion in savings from the prevention of advanced live disease.

Coloradans living longer lives and employers lowering health care costs. By sounding the hep C alarm to baby boomers across our state, businesses can do well by doing good.

Nancy Steinfurth is excutive director of Hep C Connection, a statewide organization that educates the general public about hepatitis C and provides resources and support for those affected by the virus. (www.hepc-connection.org).

EDITOR'S NOTE: This is an online-only column and has not been edited

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Fatty Acids in Fish May Lower Liver Cancer Risk

^{© Suprijono Suharjoto/Fotolia.com}

Researchers found that fish that are rich in n-3 polyunsaturated fatty acids help lower risk of hepatocellular carcinoma.

By: MARY ANN MOON, Family Practice News Digital Network

The consumption of fish rich in n-3 polyunsaturated fatty acids was inversely related to the risk of developing hepatocellular carcinoma in a population-based study of Japanese adults, Dr. Norie Sawada and colleagues reported in the June issue of Gastroenterology.

In addition, higher intake of several individual n-3 polyunsaturated fatty acids (PUFAs) – particularly eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid – also correlated with lower hepatocellular carcinoma (HCC) risk.

The associations were dose dependent for intake of n-3 PUFA-rich fish and for intake of individual fatty acids, said Dr. Sawada of the National Cancer Center, Tokyo, and associates.

Dietary n-3 PUFAs, also called omega-3 PUFAs, have long been thought to lower the risk of developing several cancers, but few studies have examined a potential protective effect against liver cancer in particular. One recent prospective study in the United States showed an inverse association between consumption of "white meat," including fish, and liver cancer, but other studies have found no such correlation.

Dr. Sawada and colleagues examined the issue by analyzing data from a large cohort study launched in the 1990s and supervised by the Japanese department of public health. The investigators analyzed detailed dietary data from 90,296 adults who were aged 40-69 years at baseline and were followed for an average of 11 years.

The study subjects completed questionnaires regarding their usual intake of 138 food items during the previous year, using standard portions or units of consumption. Nineteen items on the questionnaire asked about dietary fish and shellfish, which in Japan includes salted fish; dried fish; canned tuna, salmon, or trout; and bonito, tuna, cod, sea bream, mackerel, sardine, mackerel pike, roe, eel, squid, octopus, prawn, clam, crab, vivipara, as well as various fish pastes.

The investigators used the subjects’ responses to calculate daily fish consumption. They also calculated daily intake of all n-3 PUFAS combined, and intake of four individual fatty acids. They separately calculated the consumption of fish rich in n-3 PUFAs, namely salmon, trout, sea bream, mackerel, sardine, mackerel pike, and eel.

Blood samples that had been taken during general health check-ups were screened for hepatitis C antibodies and hepatitis B surface antigen to determine whether the subjects were carrying hepatitis C or B.

A total of 398 cases of incident HCC developed during follow-up (Gastroenterology 2012 Feb. 20 [doi:10.1053/j.gastro.2012.02.018]).

Total fish consumption showed a weak inverse association with risk of HCC, with a multivariable hazard ratio of .64 for highest vs. lowest quintile (95% confidence interval, 0.41 to 1.02, P for trend = .07). The association reached statistical significance when the analysis was confined to fish rich in n-3 PUFAs with a HR of 0.64 (95% CI, .42 to .96, P for trend = .04).

Strong, dose-dependent inverse associations also were found between HCC risk and dietary intake of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid.

These results did not change substantially when the data were adjusted to account for subject age, sex, smoking status, and body mass index. The findings also persisted across several subgroups of patients such as alcohol drinkers and coffee drinkers.

The inverse association between consumption of fish high in n-3 PUFAs and HCC risk also was strong in the subgroups of patients positive for hepatitis B or hepatitis C.

The reasons underlying this protective effect against liver cancer are not yet known. It is likely that the anti-inflammatory properties of polyunsaturated fatty acids play a role, "given that HCC is an inflammation-related cancer which has a background of chronic inflammation triggered by exposure to hepatitis virus infection or toxic compounds such as ethanol," Dr. Sawada and associates said.

This study was somewhat limited in that it was necessary to estimate the consumption of fish and individual fatty acids rather than measuring these amounts directly. Also, the dietary data were based on subjects’ self-report at only a single time point.

The study was supported by the National Cancer Center Research and Development Fund and the Ministry of Health, Labor, and Welfare of Japan, both in Tokyo. The authors reported no financial conflicts of interest.

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OraSure HIV Test Has Risks of False Results, FDA Says

By Anna Edney - May 11, 2012 3:30 PM ET

People who use what could be the first completely at-home HIV test under development by OraSure Technologies Inc. (OSUR) risk receiving false results, U.S. regulators said in a report.

Outside advisers to the Food and Drug Administration should weigh whether the benefits of the kit are greater than the potential risk of false negative and false positive results, agency staff said in the report today ahead of a May 15 advisory panel meeting. Regulators are considering approval of the OraQuick In-Home HIV Test, which would be sold without a prescription and provide users with their HIV status at home in a similar fashion to pregnancy tests.

“There is considerable personal and public health value in informing infected, but otherwise untested, persons of their true positive HIV status,” FDA staff wrote. “However, this benefit is offset in some measure by HIV-positive individuals who receive an incorrect message that they are not infected.”

OraSure fell 14 percent to $9.65 at 3:15 p.m. New Yorktime, the largest intraday decline in two years.

About 1.2 million people in the U.S. have HIV, the virus that causes AIDS, and 20 percent of those people are unaware they are infected, according to the Centers for Disease Control and Prevention. The test made by Bethlehem, Pennsylvania-based OraSure would be the first of its kind. Other kits, such as Home Access Health Corp.’s Express HIV Test System, require users to anonymously send blood samples to a laboratory for testing.

Clinical Trial Findings

A clinical trial of OraSure’s test identified 100 previously undiagnosed people infected with HIV of 5,800 patients who used the product, according to the company. OraSure markets the only FDA-approved rapid HIV test that detects HIV antibodies in oral fluid and provides results in a clinic or doctor’s office within 20 minutes.

OraQuick would produce one false negative result for every 13 true positive tests, FDA staff said. That would total an estimated 3,800 people with HIV who falsely test negative each year, according to the report. In addition, the test would produce one false positive result for every 3,750 true negative tests resulting in 1,100 people a year who aren’t infected believing they are, the report said.

The false negatives reported were higher than what the FDA considers a “minimum acceptable performance” while the false positives were lower.

‘Confident’ in Test

“We are very confident in the efficacy, safety and performance of the OraQuick In-Home HIV Test, which has been proven to have a calculated accuracy of 99 percent in extensive self-test clinical studies,” Ron Ticho, a spokesman, said in an e-mail.

OraQuick would identify 9,087 previously undiagnosed HIV-positive individuals for each 1 million who use the test, Ticho said.

OraSure doesn’t have an estimate for when the FDA may decide on the home-results test, said Susan Brophy, of Golin Harris, who is a spokeswoman for the company.

The FDA cleared the Home Access test in 1996. Results can be obtained the day a sample arrives at a laboratory and retrieved anonymously using a pin number, according to theHoffman Estates, Illinois-based company. The FDA stresses the benefit of having medical professionals help users interpret the results and understand treatment options on its website.

The FDA staff expressed concern that people who may have gotten tested professionally would turn to the “less sensitive, but more private,” alternative. No studies have been done to test the potential impact, according to the report.

“Counseling, which uses both printed material and telephone interaction, provides the user with an interpretation of the test result,” the FDA said on its website about the Home Access test system.

Counseling also can provide information on preventing transmission of the disease for people who are infected and on treatment options and doctor referrals, the FDA said.

More than 16,000 people with AIDS were estimated to have died in 2008, the CDC said.

To contact the reporter on this story: Anna Edney in Washington at aedney@bloomberg.net.

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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Thomas Jefferson University Hospital Creates Comprehensive Hepatitis C Center

New Center Tailored to Treat Rising Population for “Silent Killer”

Philadelphia, PA (PRWEB) May 11, 2012

Thomas Jefferson University Hospital recently opened its new Jefferson Hepatitis C Center, one of only a few comprehensive, multidisciplinary centers dedicated to the study of hepatitis C virus and hepatic disease in the Pennsylvania, New Jersey and Delaware tri-state area.

According to the Centers for Disease Control and Prevention (CDC), 3.2 million Americans are infected with chronic hepatitis C – a virus that affects the liver. It is spread primarily by exposure to blood that is infected with hepatitis C. Left untreated, hepatitis C can cause cirrhosis, liver cancer and liver failure, and is also the leading indication for liver transplant in the US. Baby boomers, anyone born between 1945 and 1965, are the largest patient population according to the CDC, accounting for as much as two-thirds of hepatitis C infections.

“The Jefferson Hepatitis C Center aims to offer a coordinated approach to treatment for patients with hepatitis C by some of the area’s most experienced hepatologists,” says Jonathan Fenkel, M.D., director of the Center.

If liver damage cannot be controlled, Jefferson is home to the longest continuously active liver transplantation program in the Philadelphia area.

While two million people in the US suffer from Hepatitis C, an additional 1-2 million are undiagnosed, putting them at risk for devastating long-term effects. The virus is often called the “silent killer” because it can produce no symptoms and can go undetected for decades.

The Jefferson Hepatitis C Center offers patients:

• A tailored program to meet individual needs
• A twice-weekly outpatient hepatitis C treatment clinic
• A multidisciplinary monthly HIV/hepatitis C coinfection clinic
• An active clinical trials program
• Expert consultations for referring physicians and patients including a detailed plan highlighting potential drug interactions and treatment considerations

In addition to Dr. Fenkel and Jefferson’s three experienced hepatologists, the Hepatitis C multidisciplinary team includes close collaboration with pathologists, infectious disease specialists, psychiatrists, radiologists, clinical pharmacists, and diagnostic laboratories; all of whom are highly experienced in the testing and evaluation of Hepatitis C and other liver conditions.

“At the Jefferson Hepatitis C Center, we are working to find effective treatment options for those chronically infected with hepatitis C,” says Dr. Fenkel. “Until recently, few medications were able to successfully treat this infection. But now, we are at the dawn of a new era. Patients have access to new, FDA-approved medications that make treatment successful for nearly four out of five patients. Also, even better medications are still being studied and patients will have access to these ongoing and future clinical trials.”

Thomas Jefferson University Hospitals (TJUH) are dedicated to excellence in patient care and education. It is consistently ranked by U.S. News & World Report among the nation's top hospitals. It has over 950 licensed acute care beds with major programs in a wide range of clinical specialties. TJUH is one of the few hospitals in the U.S. that is both a Level 1 Trauma Center and a federally-designated regional spinal cord injury center. TJUH patient care facilities include: Jefferson Hospital, Jefferson Hospital for Neuroscience, and Methodist Hospital in South Philadelphia. Additional out-patient sites are located throughout Pennsylvania and New Jersey. TJUH is a part of Jefferson Health System and a partner of Thomas Jefferson University.

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FDA Advisory Committee Supports Approval of Gilead’s Once-Daily Quad Single Tablet Regimen for HIV

– Final FDA Decision On The Quad Anticipated Late Summer –

FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 11, 2012-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) has voted 13 to 1 in support of approval of the Quad, a complete single tablet regimen of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate, for the treatment of HIV-1 infection in treatment-naïve adults.

The recommendations of the Advisory Committee are not binding, but will be considered by FDA as the agency completes its review of Gilead’s New Drug Application (NDA) of the Quad. Gilead submitted the NDA on October 27, 2011 and FDA has set a target action date under the Prescription Drug User Fee Act (PDUFA) of August 27, 2012. Applications for marketing approval of the Quad are also pending in Australia, Canada and the European Union.

“With new government guidelines recommending that people diagnosed with HIV begin treatment early, it is important that we continue to simplify and improve HIV therapy,” said Andrew Cheng, MD, PhD, Senior Vice President, HIV Therapeutics and Development Operations, Gilead Sciences. “The Quad is the latest example of Gilead’s ongoing efforts to develop highly effective and well tolerated single tablet regimens for people living with HIV.”

The Quad NDA is supported by the positive results from two pivotal Phase 3 studies in which Quad met its primary objective of non-inferiority as compared to Atripla^® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (Study 102) and to a regimen containing ritonavir-boosted atazanavir plus Truvada^® (Study 103). The NDA is also supported by Chemistry, Manufacturing and Controls (CMC) information on the individual components of the Quad and the co-formulated single tablet regimen.

In all studies, the Quad was well tolerated and most adverse events were mild to moderate. The most common adverse events observed were nausea, diarrhea, upper respiratory track infection and headache. Overall, there have been nearly 9 million patient years of experience with tenofovir-containing regimens.

About the Quad

The Quad contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg, a “boosting” agent that enables elvitegravir once-daily dosing; and Truvada (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg).

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Unlike other classes, 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. Cobicistat acts only as a pharmacoenhancer and has no antiviral activity. In addition to studying the agent as part of the Quad, Gilead is also examining cobicistat’s potential in boosting commercially available HIV protease inhibitors.

The Quad, elvitegravir and cobicistat are investigational products and their safety and efficacy have not yet been established.

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 FDA and other regulatory agencies may not approve the Quad and that any marketing approvals, if granted, may have significant limitations on their use. Further, even if approved, Gilead may not be able to successfully commercialize the Quad, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. 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, 2012, 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.

U.S. full prescribing information for Atripla is available at www.Atripla.com.
U.S. full prescribing information for Truvada is available at www.Truvada.com.

Truvada is a 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 or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000 .

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Susan Hubbard, 650-522-5715 (Investors)
Erin Rau, 650-522-5635 (Media)

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