Studies in monkeys may be next step in search for HIV cure

By Julie Steenhuysen

CHICAGO | Wed Oct 30, 2013 4:22pm EDT

CHICAGO (Reuters) - A powerful infusion of HIV-fighting antibodies beat back a potent form of the virus in monkeys and kept it at bay for weeks, U.S. government scientists and a team led by Harvard University found, offering a potential next step in the battle against human HIV.

The two studies, published on Wednesday in the journal Nature, involve the use of rare antibodies made by 10 percent to 20 percent of people with HIV that can neutralize a wide array of strains.

Such antibodies latch on to regions of the virus that are highly "conserved," meaning they are so critical to the virus that causes AIDS that they appear in nearly every HIV strain.

By attaching to the virus, they make it incapable of infecting other cells.

In the past decade, scientists have tried to make vaccines that could coax the body into making these same types of HIV-specific antibodies. But finding a way to make these complex antibodies has been challenging.

"These are the Ferraris of antibodies," said Dr Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, who led the larger of the two studies.

"Nobody, including ourselves, has been able to develop a vaccine that can generate immune responses that are even close."

In the studies, the teams instead tested these antibodies as a potential treatment for people infected with HIV. Both teams used rhesus monkeys with the Simian-human immunodeficiency virus, a monkey version of HIV.

Barouch's team studied the rare antibodies harvested from HIV-infected humans that were grown in large batches and could be infused at high doses. The team tested different combinations of antibodies in 35 infected monkeys.

The one that worked best was an antibody called PGT121.

"Basically, that antibody, given either alone or in combination, resulted in a dramatic effect," Barouch said.

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The antibodies reduced the virus to undetectable levels in 16 of 18 monkeys within seven days, and kept it there for one to three months. In three animals with the lowest viral load at the time of treatment, the virus did not resurface.

A smaller study by scientists at the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health, showed similar results.

Both teams say the approach should now be tested in people.

"All the data to date exist in the monkey model. We need to evaluate how these antibodies perform in humans infected with HIV," Barouch said.

His team did not test the antibody treatment in combination with antiretroviral treatments, the standard HIV drugs used by thousands of patients to control the virus.

But Barouch thinks such combinations would make sense because both treatments have different mechanisms of action.

While antiretroviral drugs only attack the machinery used by the HIV virus to make copies of itself, antibodies can directly attack free virus particles in the blood as well as in cells that are infected with the virus.

Barouch said researchers and drug companies are interested in the results, which could offer a next step toward a cure for the infection that causes AIDS.

In an interview on the Nature website, Dr Louis Picker of Oregon Health & Science University, who wrote a commentary on the research, said the study is "a baby step towards cure."

He said antiretroviral treatments, such as those made by Gilead Sciences and GlaxoSmithKline, reduce the ability of the HIV virus to replicate in the body by maybe 99.9 percent, but not 100 percent.

"This treatment on top of it may bring it to 100 percent," he said.

Still unclear is whether antibodies will also attack latent HIV cells that hide in the body and allow the virus to reappear when treatment stops.

"We haven't shown any cures," Barouch said. "However, we have shown the antibodies act not only on the virus in the bloodstream, but can also substantially reduce virus in tissues such as lymph nodes and the gut. Future research with these antibodies will help determine whether they might be part of a virus eradication or cure strategy."

(Reporting by Julie Steenhuysen; Editing by Xavier Briand)

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Current Hepatitis C Treatments Can't be Used by More Than Half of Patients

Provided by Infection Control Today

October 31, 2013

More than half of chronic hepatitis C patients studied in a new research project led by Henry Ford Hospital were not treated for the potentially fatal disease, either because they couldn't withstand current therapies or because they, or their doctors, were waiting for new treatments.

In a second, related study, Henry Ford researchers found that while the disease is not yet curable, there is a significant "lost opportunity" for hepatitis C patients to achieve the current best result of treatment.

Both studies are being presented at the annual meeting of the American Association for the Study of Liver Diseases being held in Washington, DC, Nov. 1-5.

Stuart C. Gordon, M.D., director of the Hepatology section at Henry Ford, and lead author of the first study, said it was launched because of a lack of information about the subject.

"Limited data exist concerning the clinical disposition of U.S. patients with chronic hepatitis C infection, including the reasons for lack of antiviral treatment," Dr. Gordon says. "Our goal was to add to that data."

The team collected electronic health records from four large American health systems of patients with confirmed chronic hepatitis C, a viral infection that progressively scars the liver and eventually destroys the organ and its vital functions.

Of these 4,271 patients diagnosed with the infection and still alive through the end of 2011, the median age was 57; 57 percent were male; 29 percent were black and 97 percent were insured.

• 543, or 12.7 percent, had previously achieved a sustained virologic response (SVR), meaning the hepatitis C virus was suppressed to the point that it could no longer be detected in their blood for six months after anti-viral treatment.

• 110, or 2.6 percent, were currently on anti-viral therapy.

• Of the remaining 3,618 patients, 12 percent had never been followed up within the health care system, despite clinical confirmation that they had chronic hepatitis C.

• The majority, 55 percent, were not being treated, either because of "absolute contraindications" to current therapy – meaning the risk of available treatment is too high – or because either the patient or physician were waiting for newer therapies.

• Another 12 percent of patients had chosen not to start treatment, despite a doctor's recommendation to do so.

"These results confirm that only a small proportion of chronic hepatitis C patients in American healthcare systems who were still being followed at the end of 2011 had achieved an SVR with available antiviral regimens," Gordon says. The second study sought to identify "lost opportunities" to treat hepatitis C patients and achieve SVR, now the closest thing to a "cure" for the disease.

"We looked at data regarding testing for chronic hep C, patient referral, patient visits and the start of treatment," explains Kimberly Ann Brown, MD, division head of gastroenterology at Henry Ford Hospital and lead author of the study's findings.

"In addition," Brown says, "we considered patient age, race, gender, income, marital status, psychiatric diagnoses and the number of comorbidities, or co-existing diseases."

The findings showed that of the 458 patients identified with a positive hepatitis C antibody, only 117 received confirmatory testing, were referred to a specialist and presented to the office for a visit. Of the 117 patients who came for the specialty visit, only 21, or 17.9 percent, were felt to be appropriate treatment candidates.

"This data speaks to the significant "lost opportunity" we have, not only in identifying patients with hepatitis C in our community, but also in providing them with appropriate treatment options," says Brown.

Source: Henry Ford Health System

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Studies of Experimental Hepatitis C Drug Show Promise for Preventing Recurrence in Liver Transplant

Provided by Infection Control Today

October 31, 2013

New drug therapies offer promise to some hepatitis C sufferers whose transplanted livers are threated by a recurrence of the disease, including some patients who have had no treatment options.

The encouraging findings are contained in two new studies by a collaboration of researchers across the U.S. – as well as in Spain and New Zealand – including Dilip Moonka, MD, medical director of Liver Transplant at Henry Ford Hospital. Both studies are being presented at the annual meeting of the American Association for the Study of Liver Disease being held in Washington, D.C., Nov. 1-5.

Both studies focused on the experimental anti-viral drug sofosbuvir, a direct-acting oral medication that may take the place of injectable interferon, which causes severe side effects in some patients.

The Food and Drug Administration is expected to decide in early December whether to approve its use for treating hepatitis C. Last week, the Antiviral Drugs Advisory Committee of the FDA voted unanimously in support of approval for sofosbuvir-based therapies for the treatment of chronic hepatitis C.

Chronic hepatitis C, which afflicts an estimated 3 million people in the U.S. alone, is a blood-borne viral disease that leads to scarring and deterioration of the liver. It is particularly insidious because patients usually don't develop symptoms until the scarring – or cirrhosis – is well underway.

Sofosbuvir, which belongs to a class of drugs known as nucleotide analogue polymerase inhibitors, acts at the molecular level by interfering with the RNA of the hepatitis C virus.

In the first newly released study, researchers tested it as an alternative to interferon, a naturally occurring protein that plays a role in fighting viral infections, but commonly produces a range of serious side effects.

The researchers used it in combination with ribavirin, which also inhibits the hepatitis C virus by interfering with its RNA to stem the replication of the virus and slow the progression of the disease. They sought to test the drug combination's effectiveness in preventing recurrence of hepatitis C in liver transplant recipients.

A total of 61 chronic hepatitis C patients with liver cancer were enrolled in the study and given both sofosbuvir and ribavirin daily for up to 48 weeks before liver transplant. All of the patients had well-compensated cirrhosis, meaning their bodies were still functioning without too much trouble despite liver scarring.

The researchers found that the new drug combination was both safe and effective in such patients and prevented post-transplant recurrence of the hepatitis C virus in more than 60 percent of them.

In the second newly released study, researchers focused on liver transplant recipients whose severe hepatitis C recurred after surgery and who either couldn't tolerate or didn't respond to approved antiviral therapies – leaving them with no other effective treatment options.

In such cases, experimental drugs can sometimes be tested under "compassionate use" protocols.

The researchers reported that as of April, 115 patients were approved for compassionate use of sofosbuvir combined with ribavirin and/or the antiviral drug peginterferon. At the time of their report, 63 had started treatment.

After several weeks of treatment and study, the researchers concluded that patients with severe recurrence of hepatitis C after receiving transplanted livers were able to tolerate the drug regimen, which produced strong antiviral effects.

Source

HCV in Spotlight at Liver Meeting

Meeting Coverage

Published: Oct 31, 2013 | Updated: Oct 31, 2013

By Michael Smith, North American Correspondent, MedPage Today

Hepatitis C will once again have center stage at the annual meeting of the American Association for the Study of Liver Diseases, which starts Friday in Washington, D.C.

The meeting begins just a week after an FDA advisory panel recommended approval of the first new direct-acting agents against the virus since 2011 -- simeprevir and sofosbuvir.

Meeting attendees will get the latest data on them -- data that is "highly anticipated," according to Gary Davis, MD, the association's secretary.

The standard therapy for hepatitis C (HCV) for many years was pegylated interferon-alfa and ribavirin -- the first an immune system booster and the second a general antiviral medication.

In 2011, the FDA approved two drugs that act against the viral protease enzyme -- telaprevir (Incivek) and boceprevir (Victrelis).

Since then, a suite of drugs has entered the pipeline, acting against various targets in the HCV genome. Among them are simeprevir (another protease inhibitor) and sofosbuvir, which is a nucleotide analog NS5B polymerase inhibitor.

Looked at together, the drugs in the pipeline hold out the promise of getting rid of interferon entirely -- a boon since the drug is regarded as both dangerous and difficult to take.

But, Davis noted, simeprevir was recommended for use in combination with interferon and ribavirin, while for some patients sofosbuvir was also recommended for use with the older drugs.

"People are waiting for interferon-free therapy," Davis told MedPage Today. Nonetheless, he added, simeprevir and sofosbuvir will "solve some of the problems we have" with HCV therapy.

Meanwhile, he said, some of the HCV medications in the pipeline have new data that will "wow" participants, although he was unable to give details in advance of the meeting.

Participants will also hear two important lectures, he said.

Nobel laureate Bruce Beutler, MD, of the University of Texas Southwestern Medical Center in Dallas, is slated to discuss genetic approaches to finding the cause of inherited diseases.

And Anthony Atala, MD, of Wake Forest School of Medicine in Winston-Salem, N.C., will discuss tissue engineering and its application to creating new organs, Davis said.

There will also be a "lot of activity" concerning fatty liver disease, Davis said. "This is becoming a huge problem and it's thought that 10% to 11 % of the U.S. population has this," he added.

Meeting participants will be able to hear talks and view posters on the mechanisms of fatty liver disease, as well as the roles played by diet and gut bacteria.

And a special lecture on drug toxicity -- delivered this year by William Lee, MD, also of University of Texas Southwestern Medical Center -- will focus on the common over-the-counter medication acetaminophen.

The meeting usually draws between 10,000 and 12,000 participants, Davis said.

Source

Gay Men Should Be Tested for Hepatitis C

Provided by The Huffington Post

Lawrence D. Mass, M.D.

Co-founder, GMHC; author, 'We Must Love One Another or Die: The Life and Legacies of Larry Kramer'

Posted: 10/30/2013 7:54 pm

Hepatitis C is the most common blood-borne infection in the U.S., and one of the most common worldwide. One in 50 Americans is infected. It accounts for more than 50 percent of all cases of end-stage liver disease and 50 percent of cases of liver cancer, and it is the reason for more than 50 percent of liver transplants. Yet it remains severely underdiagnosed. It's estimated that upwards of 75 percent of those infected remain untested and undiagnosed, as compared with 25 percent of those with HIV. More people now die from hepatitis C than from HIV.

Those of us who struggled through the early period of AIDS understand the meaning of "Silence = Death," the motto used by the AIDS activist organization ACT UP. So when hepatitis C began to emerge among MSM (men who have sex with men), the silence that ensued seemed eerily familiar. When I first started reporting on hepatitis C in gay men nearly a generation ago, the disease was already being called "the stealth epidemic," in part because of the typically long, silent progression of the disease in its chronic form, sometimes taking 20 to 30 years from acute infection to cirrhosis of the liver, but also because of the public silence about it. If people had the disease, they mostly didn't know it, and if they did have it and did know it, they didn't go public with it. Nor did those with the disease often seek treatment, which had the reputation of being prolonged, difficult and of mixed efficacy. Since the principal risk group for the disease was injection drug users, the public wasn't exactly clamoring to know more or be more involved. There was no megacelebrity out there to help galvanize public interest and support who would admit to having hep C the way that Magic Johnson came out as having HIV. How much has changed in the intervening years?

Despite newer and often highly effective treatments that are essentially curative, not much has changed in terms of public awareness and indifference. Hepatitis C remains a stealth disease. Public health officials have long resisted the call to sound the alarm for hep C as an STI (sexually transmitted infection), citing the weak transmissibility of hep C sexually. For years, they didn't even urge that the partners of those who were hep C-positive be tested. Granted that HCV hasn't shown itself to be nearly as transmissible sexually as HIV, I expressed my concerns about what seemed to be excessive cautiousness around testing recommendations -- in the gay press, for New York magazine as well as in a public health forum co-hosted by the CDC in Atlanta.^{1, 2} I argued that there needed to be greater awareness of and testing for hepatitis C as an STI, especially among MSM. As the call-out in New York put it, "Hepatitis C infections are spreading beyond high-risk groups, causing a few physicians to call for widespread testing. But the medical establishment is stalling. Sound familiar?"

Why was this so controversial? Why not just test everybody who might be at risk, even if that risk were "small"? The reason I was given by CDC epidemiologists and other public health officials was that urging everyone to get tested for hep C, even all MSM, could create unwarranted alarm and would be an unjustifiable expense in view of the relative minority of cases. Also, despite the increasing numbers of cases in gay men/MSM, those numbers remain "small," and it wasn't clear that other undisclosed risk factors such as injection drug use weren't responsible, since increased rates of sexual spread weren't being observed among heterosexuals.

So where do we stand with all this now? Amidst growing reports of new cases among clusters of gay men/MSM, especially in Europe, and growing numbers of cases in MSM generally, the latest review and recommendations from USPSTF (U.S. Preventive Services Task Force) from June 25, 2013, include the following:

The Task Force reviewed recent research studies on screening for and treatment of hepatitis C infection in adults. The final recommendation statement summarizes what the Task Force learned about the potential benefits and harms of screening: (1) Adults at high risk for hepatitis C infection should be screened for the infection. (2) Health care professionals should offer 1-time hepatitis C screening to adults born between 1945 and 1965.

And who are they designating as being at "high risk"?

The most important risk factor for hepatitis C infection is the use of injection drugs. Other risk factors include having had a blood transfusion before 1992, having multiple sex partners, and getting a tattoo with an unsterilized needle.

OK, so there, they've said it: "those having multiple sexual partners." But that recommendation is absent from their final, summary recommendations. There, they define those at "high risk" to be as follows:

People who use injection drugs now or have used them in the past. Having a blood transfusion before 1992 also puts a person at increased risk. Be screened only once. Some people with ongoing risk factors, such as injection drug users, need to be screened more than once.

There's no mention in these final recommendations of those having "multiple sexual partners," which would include the majority of gay men/MSM, apparently because they are more "at risk" than at "high risk." OK, but then why not designate MSM as "at risk," even if that risk is believed to be low? Clearly, public health advisories re hepatitis C testing for MSM remain unclear.

So where does all this leave us? When it comes to hepatitis C screening, gay men must once again be proactive. If you are a sexually active gay man/MSM, if you've had sex with multiple partners over time, get tested for hepatitis C. If your doctor or health care provider declines to offer the testing based on perceived low risk and unclear public health services recommendations, seek testing from another health care provider.

References:

1. Mass, Lawrence D., "C-Sick," New York, March 29, 1999.

2. "AIDS and Hepatitis C: Lessons from AIDS," from Emerging Illnesses and Society: Negotiating the Public Health Agenda, edited by Randall M. Packard et al., Johns Hopkins University Press, 2004.

Lawrence D. Mass, M.D., is a co-founder of Gay Men's Health Crisis and wrote the first published press reports on AIDS.

Source

United States to approve potent oral drugs for hepatitis C

Nature | News

Improved treatments offer hope for eradication of viral liver infection.

Sara Reardon

30 October 2013

Cocktails of new oral antiviral drugs to fight hepatitis C have aced clinical trials.

JAMES CAVALLINI/SCIENCE PHOTO LIBRARY

For decades, people with hepatitis C virus (HCV) have had to endure gruelling treatment regimens that include injections of the drug interferon, which can cause severe nausea and depression. But with the imminent approval of several highly effective oral antiviral drugs, and more on the way, researchers say that eradicating the infection worldwide is now a realistic goal.

Unlike previous HCV treatments, which sought to enhance the immune system with interferon and other drugs, the latest group of oral medications interferes with the virus’s ability to replicate and make proteins. A US Food and Drug Administration (FDA) board recommended two such drugs — simeprevir, made by Johnson & Johnson in New Brunswick, New Jersey, and sofosbuvir from Gilead Sciences in Foster City, California — for approval last week. When each is taken in combination with a drug called ribavirin, the treatment eliminates hepatitis C in around 80% of people.

“This is the first time in the history of humankind that we have a cure for a viral disease,” says pharmacologist Raymond Schinazi of Emory University in Atlanta, Georgia.

Findings from trials of different drug combinations are set to be released this week. A phase II study called COSMOS tested a combination of sofosbuvir and simeprevir in 197 people with HCV who had either not responded to interferon or who had advanced liver fibrosis caused by the virus. After 12 weeks of treatment, the drugs completely cleared the virus in more than 90% of participants.

Another study, led by physician Kazuaki Chayama at Hiroshima University in Japan, treated 220 people with a combination of daclatasvir and asunaprevir, two new drugs from Bristol-Myers Squibb in New York. The cocktail cured 85% of participants. Eric Hughes, lead global medical researcher at the company, says that it plans to submit the drugs for FDA approval in 2014.

Stopped short

Despite such encouraging results, larger studies of drug combinations involving multiple drug companies seem to be unlikely. Charlotte Edenius, vice-president of development at Medivir, a drug company in Stockholm that collaborated with Johnson & Johnson on the COSMOS study, says that Gilead and Johnson & Johnson do not plan to work together for a phase III trial. Similarly, a Bristol-Myers Squibb spokesperson says the company has no plans to collaborate with Gilead on larger trials of a combined sofosbuvir–daclatasvir therapy, despite a phase II trial completed earlier this year in which the drug pairing cured all 41 participants.

Even without phase III trials or FDA approval for this approach, David Thomas, a hepatitis C researcher at Johns Hopkins University in Baltimore, Maryland, expects that some physicians will begin prescribing such combinations 'off-label' for difficult-to-treat cases.

And, he says, the impressive cure rates achieved in clinical trials suggest that potent drug combinations could eradicate HCV worldwide — at least in theory. The virus does not have an animal reservoir, meaning that it is not harboured by other animals, and it is not easily spread between people, except through blood. Improved screening of blood supplies used for transfusions and better patient-screening techniques have already greatly cut transmission rates over the last 15 years. Emergence of drug-resistant virus strains could be a hurdle, adds Thomas, but they might be rare because the latest antiviral drugs are so potent in combination.

Price problem

Hepatologist Rajender Reddy at the University of Pennsylvania in Philadelphia sees a second stumbling block: getting such treatments to people who need them. Many of the roughly 170 million people worldwide who carry hepatitis C will not be able to afford the drugs, he says. There is also little incentive for drug companies to lower costs — unlike antiviral therapies for HIV, which must be taken for a patient's lifetime, HCV treatment is given for only 12 weeks.

Identifying HCV carriers is also challenging, because most people do not know that they have the disease until they develop severe cirrhosis or liver cancer — sometimes decades after being infected. Mandatory screening of at-risk populations such as the elderly and drug users would need to be a major part of an eradication effort, says virologist Charles Rice of Rockefeller University in New York. Crucial too is education to prevent people from contracting the disease in the first place. Even the most effective oral drugs do not raise a lasting immune response against the virus, and people can be reinfected.

That is why the search for a preventative HCV vaccine continues, with the most promising ones currently in phase II clinical trials. “Even if we have all the drugs we need — which is still an open question — it will be decades, if not a century, before it’s gone,” says Rice.

Journal name: Nature

DOI: doi:10.1038/nature.2013.14059

Source

Changes to Incivek (telaprevir) product labeling

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FDA approved changes to the Incivek (telaprevir) product labeling to include results from trial C211 (OPTIMIZE) to support a twice daily dosing regimen. In addition new contraindications were added for anticonvulsant medications (carbamazepine, phenobarbital and phenytoin) and other revisions to the section 7 Drug Interactions. Below is a summary of the changes

• Section 2: Dosage and Administration of telaprevir were updated throughout the label: from 750 mg three times a day to 1125 mg twice daily.
• The anticonvulsant medications carbamazepine, phenobarbital, and phenytoin were moved from the Drug Interaction section (Section 7, Table 5) to the Contraindications section (Section 4, Table 3)
• Section 6: Adverse Reactions was updated as follows:

Additional Data from Clinical Trials

In the analysis of an additional study (Trial C211), the safety profile of combination treatment with INCIVEK 1125 mg twice daily was similar to the safety profile for patients receiving combination treatment with INCIVEK 750 mg every 8 hours (q8h) [see Clinical Studies (14.2)]. No new safety findings were identified.

• The analgesic medications alfentanil and fentanyl were added in section 7 Drug Interactions Table 5 as potential drug interaction drugs when used with telaprevir. Specifically, careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when telaprevir is co-administered with alfentanil or fentanyl, including extended-release transdermal or transmucosal preparations of fentanyl.
• Section 12 Clinical Pharmacology was updated with information regarding the twice daily dosing regimen.

Telaprevir total exposure (AUC24h,ss) was similar regardless of whether the total daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125 mg twice daily.

Additionally the data from interaction trials with carbamazepine and phenytoin were included.

• Section 12.4 Microbiology was updated as follows:

In the C211 Phase 3 clinical trial, there were no differences in the types of emerging variants between subjects receiving telaprevir 1125 mg twice daily and subjects receiving telaprevir 750 mg every 8 hours. Similar proportions of subjects in both treatment groups had telaprevir-resistant variants at the time of failure.

• Section 12.5 Pharmacogenomics was updated to include the sustained virologic response rates at 12 weeks post treatment (SVR12) for the twice daily dosing regimen as follows:

In Trial C211, all subjects were prospectively tested for IL28B variants; there were no clinically relevant differences in SVR12 responses between q8h and twice-daily dosing within the genetic subgroups.

Trial	rs12979860 Genotype	SVR, n/N (%)	SVR, n/N (%)
C211 (treatment-naïve)		T12 Twice Daily/PR	T12 q8h/PR
	C/C	97/105 (92%)	92/106 (87%)
	C/T	139/206 (67%)	141/208 (68%)
	T/T	38/58 (66%)	37/57 (65%)

• Section 14 Clinical Studies was updated to include results from Trial C211 (OPTIMIZE)

Trial C211 was a randomized, open-label, Phase 3 trial conducted in treatment‑naïve subjects. Enrolled subjects received 12 weeks of either INCIVEK 750 mg every 8 hours [T12 (q8h)/PR] or INCIVEK 1125 mg twice daily [T12 (twice daily)/PR] in combination with peginterferon alfa‑2a and ribavirin. The trial was designed to compare twice-daily dosing [T12 (twice daily)/PR] versus q8h dosing [T12 (q8h)/PR] of INCIVEK. At week 12, INCIVEK dosing ended and subjects continued on peginterferon alfa‑2a and ribavirin treatment. The total treatment duration was determined based on the subjects’ individual on-treatment viral response. If a subject achieved undetectable HCV RNA < 25 IU/mL (target not detected) at week 4, the total treatment duration was 24 weeks. Otherwise, the total treatment duration was 48 weeks.

The 740 enrolled subjects had a median age of 51 years (range: 18 to 70); 60% of the subjects were male; 21% had a body mass index ≥ 30 kg/m²; 5% were Black; 2% were Asian; 85% had baseline HCV RNA levels ≥ 800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had HCV genotype 1a; and 43% had HCV genotype 1b.

Table 11 shows the response rates for the T12 (twice daily)/PR group and the T12 (q8h)/PR groups by treatment outcomes. The overall SVR rates were similar at 74% [T12 (twice daily)/PR; 274/369] and 73% [T12 (q8h)/PR; 270/371], respectively.

Table 11: Response Rates: Trial C211

Treatment outcome	T12 (twice daily)/PR N = 369% (n/N)	T12 (q8h)/PR N = 371% (n/N)
SVR	74% (274/369)	73% (270/371)
Undetectable HCV RNA (target not detected) at week 4a	69% (256/369)	67% (250/371)
SVR in subjects with undetectable HCV RNA (target not detected) at week 4	86% (221/256)	85% (213/250)
SVR in subjects who did not have undetectable HCV RNA at week 4	47% (53/113)	47% (57/121)
Outcome for Subjects without SVR	26% (95/369)	27% (101/371)
On‑treatment virologic failureb	10% (38/369)	10% (36/371)
Relapsec	8% (23/300)	6% (19/293)
Otherd	9% (34/369)	12% (46/371)

T12 (twice daily)/PR: INCIVEK 1125 mg twice daily for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks; T12 (q8h)/PR: INCIVEK 750 mg every 8 hours for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks

^{a   Subjects with planned total treatment duration of 24 weeks.}

^{b   On‑treatment‑virologic failure includes subjects who met a protocol‑defined virologic stopping rule and/or who had detectable HCV RNA at the time of their last dose of study drug and had viral breakthrough.}

^{c   Relapse was defined as having less than 25 IU/mL at the planned end of treatment followed by HCV RNA ≥ 25 IU/ml at the last observation within the SVR follow-up visit window.}

^{d   Other includes subjects with detectable HCV RNA at the planned end of treatment but who did not have viral breakthrough, and subjects with a missing SVR assessment during planned follow-up.}

SVR rates were similar for the T12 (twice daily)/PR and T12 (q8h)/PR groups across subgroups determined by sex, age, race, ethnicity, body mass index, HCV genotype subtype, IL28B genotype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups. 

• Fifty-four and 49 subjects in T12 (twice daily)/PR and T12 (q8h)/PR groups, respectively, had cirrhosis at baseline. The SVR rate in these subjects was 54% (29/54) in the T12 (twice daily)/PR group and 49% (24/49) in the T12 (q8h)/PR group. In the T12 (twice daily)/PR group, 52% (28/54) of subjects with cirrhosis achieved undetectable HCV RNA (target not detected) at week 4; their SVR rate was 68% (19/28). In the T12 (q8h)/PR group, 59% (29/49) achieved  undetectable HCV RNA (target not detected) at week 4; their SVR was 59% (17/29). The SVR rate for subjects assigned 48 weeks of treatment was 38% (10/26) in the T12 (twice daily)/PR group and 35% (7/20) in the T12 (q8h)/PR.

• Thirty-five subjects were Black/African Americans. The overall SVR among Black/African American subjects was 50% (10/20) in the T12 (twice daily)/PR group and 60% (9/15) in the T12 (q8h)/PR group. Among these subjects, 46% (16/35) were assigned to 24 weeks of treatment and of those 88% (14/16) achieved SVR.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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Gileads’ CEO Discusses Sofosbuvir During Q3 2013 Earnings Call

Gilead Sciences' CEO Discusses Q3 2013 Results - Earnings Call Transcript

Excerpt from page 4

“And finally, as all of you are aware, we had a successful FDA advisory committee last week. The panel [ph] voted unanimously in favor of approval of sofosbuvir with ribavirin for the treatment of genotype 2 and 3 hepatitis C infected patients and approval of [indiscernible] course of sofosbuvir pegylated interferon with ribavirin for the treatment of genotype 1 and 4 hepatitis C infected patients.

In addition, the majority of panel members were in favor of broadening the indication to improve genotype 1 treatment experienced patient in the label. [indiscernible] the use of sofosbuvir plus ribavirin in the pre-transplant setting quotations with ACC. At the advisory committee meeting, new data were presented from the VALENCE study which indicated that treatment-naïve and treatment experience genotype 3 hepatitis C infected patient was so faster by providing with 24 weeks with SVR rate of 84%.

We are naturally excited about bringing sofosbuvir to the market and we feel like panel members commented that this is a historic moment, for which every employee at Gilead is proud of. We look forward to working with FDA to complete the review of the sofosbuvir NDA and ultimately launch the product.

Meanwhile the clinical development program of the sofosbuvir [indiscernible] dose combination is also proceeding rapidly. Three phase 3 studies IN-1, IN-2 and IN-3 explore the utility of the fixed dose combination both treatment, naïve treatment experience genotype 1 hepatitis C infected patients, with and without ribavirin, therefore treatment durations of eight, 12 and 24 weeks, we anticipate having data from these studies that we have about towards the end of this year and into early next year as we are on track for NDA, MAA filings in the second quarter of 2014.

The development of sofosbuvir in combination with ribavirin for genotype 2 infected patients in Japan is progressing. The single-arm phase 3 study with 12 weeks treatment duration was fully enrolled in September and we are on track to submit the marketing application in Japan towards the middle of 2014. This is a significant opportunity as genotype 2 infected patients in Japan constitute over 25% of the total and sofosbuvir and ribavirin will be the first on oral interferon free option for these patients.

In addition, the phase 3 program after fixed dose combination of sofosbuvir/ledipasvir with and without ribavirin genotype 1 hepatitis C infected patients was initiated in September 2013 that we anticipate this study to be fully enrolled by the end of this year. This two-arm study in three [indiscernible] genotype 1 infected both treatment, naïve treatment experienced patients, randomized to a 12-week course of the fixed dose combination with and without ribavirin.

Finally, the potentially pan-genotypic interferon and ribavirin free regimen, the combination of sofosbuvir [indiscernible] GS-5816 is advancing to phase 2 development, two studies in treatment naïve and treatment experienced patients in various genotypes are fully enrolled, and depending on the emerging data, we should be in a position to initiate phase 3 studies in the second half of 2014.

More information on our programs will be presented at the annual AASLD meeting which will commence this week in Washington DC. Over 50 abstracts were submitted on Gilead's various liver disease programs and importantly, new data will be presented on the safety and efficacy of sofosbuvir,

Ribavirin in HIV core affected patient and in the post liver transplant setting.

In summary, very rapid progress has been made across all our therapeutic areas in all other programs. Our pipeline provides us with numerous opportunities with continued growth, both short-term and longer-term. We want to take this opportunity to thank all of our employees for their continued hard work and dedication.

So with that, we will now open the call for questions. Operator?”

Continue reading the full transcript here ……

The Rise and Fall of a Revolutionary Drug

Provided by The Motley Fool

By Brian Orelli | More Articles
October 29, 2013

One of the best drug launches in history has become one of the fastest run downs.

Approved in May 2011, Vertex Pharmaceuticals' (NASDAQ: VRTX ) hepatitis C drug Incivek hit $457 million in sales in its second full quarter on the market. Many drugs never hit $457 million in annual sales at their peak.

Less than two years later, sales are down to $86 million in the most recent quarter. You can't say I didn't warn you.

Ironically, what made Incivek so popular to begin with is also what caused the crash. Hepatitis C is a slowly developing disease, so there's a limited downside to patients waiting a few years to be treated if the virus isn't doing much damage to the liver yet.

Doctors could see that Incivek and Merck's (NYSE: MRK ) Victrelis were working well in clinical trials, so they cut back on the prescribing the standard of care at the time -- Roche's Pegasys or Merck's Pegintron with a generic called ribavirin -- because they only cured about half the patients and make many people feel like they have the flu.

Once Incivek was approved, the warehoused patients were prescribed Incivek, which had a little better data than Merck's Vicrelis, and sales skyrocketed.

Rinse and repeat
But then doctors heard about the next generation of drugs and started warehousing again. Doctors are going to prescribe Johnson & Johnson's (NYSE: JNJ ) simeprevir and Gilead Sciences' (NASDAQ: GILD ) sofosbuvir, which both look like they're going to get approved this year after getting unanimous endorsements from their respective advisory committees. The large number of drugs in clinical trials also siphoned off some patients.

Vertex has seen the writing on the walls, so the biotech is cutting 370 positions, about 15% of its workforce, to conserve cash while it ramps up its cystic fibrosis business. Vertex also has a next-generation hepatitis C drug, VX-135, but it'll take a few years to get approved -- if side effects don't kill it first -- so it doesn't make sense to keep the hepatitis C sales force on the payroll.

All those workers can find new homes at Johnson & Johnson or Gilead Sciences. At least until doctors start warehousing again.

These two biotechs should have longer legs
Like Vertex's revolutionary drugs for hepatitis and cystic fibrosis, Motley Fool analysts have found two drugmakers with a groundbreaking technology helping cancer patients. In the brand-new FREE report "2 Game-Changing Biotechs Revolutionizing the Way We Treat Cancer," find out about the new technology that big pharma is endorsing through partnerships, and the two companies that are set to profit from this emerging drug class. Click here to get your copy today.

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

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Gilead posts 17 pct profit rise, readies for HCV launch

UPDATE 2-Gilead posts 17 pct profit rise, readies for HCV launch

Tue Oct 29, 2013 6:18pm EDT

By Deena Beasley

Oct 29 (Reuters) - Biotechnology company Gilead Sciences Inc reported a 17 percent jump in quarterly net profit on Tuesday and raised its outlook for full-year sales as revenue and demand for its flagship HIV drugs exceeded Wall Street estimates.

Analysts expect the company's sales to surge even higher next year when Gilead plans to launch a new so-called HCV treatment for people infected with the liver-destroying hepatitis C virus.

Adjusting for one-time items, Gilead earned 52 cents a share in the third quarter, exceeding the average analyst estimate of 48 cents a share, according to Thomson Reuters I/B/E/S.

"They beat, ... driven by better product revenues and lower expenses," said RBC Capital Markets analyst Michael Yee. "It was also positive that they took up their product sales guidance."

Sales of HIV drug Atripla rose 4 percent to $899.7 million, while sales of an older product, Truvada, rose 1 percent to $813.7 million. Sales of newer HIV drug Complera more than doubled to $210.7 million, and the recently launched Stribild had sales of $144 million in the quarter.

Gilead is the world's largest maker of branded drugs to treat the human immunodeficiency virus, the cause of AIDS.

Quarterly revenue rose 15 percent to $2.78 billion, beating the $2.72 billion forecast by analysts.

For the full year, Gilead raised its estimate for net product sales to between $10.3 billion and $10.4 billion, from a previous range of $10.0 billion to $10.2 billion.

An advisory panel to the U.S. Food and Drug Administration last week voted to recommend that the agency approve Gilead's application for experimental HCV drug sofosbuvir to combat the hepatitis C virus. A final FDA decision is expected by early December.

Gilead estimates that over 4 million Americans are infected with hepatitis C, which causes deadly illnesses such as cirrhosis and liver cancer.

Wall Street analysts have forecast sofosbuvir sales of $1.85 billion next year alone, assuming a price of $85,000 per patient, according to ISI Group.

"We feel we've got a very strong value proposition with sofosbuvir," Kevin Young, head of commercial operations at Gilead, said on a conference call with analysts and investors.

Clinical trials of sofosbuvir in combination with other experimental oral Gilead drugs - a regimen that has not yet been submitted for regulatory approval - resulted in more than 95 percent of patients being cured.

Gilead's third-quarter net profit rose to $788.6 million, or 47 cents per share, from $675.5 million, or 43 cents per share, a year earlier. The number of shares outstanding rose in the latest quarter from the prior-year period.

Chief Financial Officer Robin Washington said those buybacks will continue next year.

Shares of Gilead, which have more than doubled over the past 12 months, were up 1 percent in after-hours Nasdaq trading at $70.25.

Source

Treatment of Chronic Hepatitis C: The Revolution!

Provided by NATAP

Reported by Jules Levin
EACs - European AIDS Conference - Oct 16-19 Brussels, Belgium

Heiner Wedemeyer
Hannover Medical School
Germany

from Jules: here is Dr Wedemeyer's slide presentation where he does a long review including vaccines, immune-based new therapies including Alisporivir, DAAs, direct acting activirals, new oral drugs, and reviews many of the reported studies from phase 2 & 3.

The FDA hearings on Oct 24/25 reviewed Simeprevir+PR for 24 weeks and Sofosbuvir +PR for 12 weeks, and as expected the panels voted unanimously to approve both 19-0 & 15-0. This is just the prelude to next year when the first 2 IFN-free regimens will be considered for approval by the FDA in the early part of 2014 & of course approval is expected, they are Gilead's Sofosbuvir+Ledipasvir & Abbvie's ABT450+ABT267+ABT333 both with and/or without RBV, phase 3 studies are ongoing, fully enrolled, phase 2 studied reported 95-100% SVR rates with 12 weeks therapy. FDA approval is expected around end of November & beginning of Decmber 2013. In phase 2 studies, Sofosbuvir+Simprevir has yielded 96% SVR rates in hard-to-treat null responders & patients with advanced disease, and Sofosbuvir+Daclatasvir has yielded 100% SVR rates in naives & patients who previously failed telaprevir or boceprevir. Earlier in research is Merck's 2nd generation drugs, MK8472, their NS5A & MK5172, their protease, phase 2 data will be reported at AASLD next week, phase 3 is planned. Boerhinger Ingelheim is studying a 3-drug oral combination for which they reported early results a few weeks ago with 90-100% SVR rates, which includes their protease Faldaprevir, their non-nuc & the Presidio NS5A. BMS is planning phase 3 now for their 3-drug IFN/Rbv free regimen which yielded a 94% SVR rate in phase 2. Vertex is studying their nucleotide in combination with other DAAs from other companies. Janssen istudying their own 3-drug oral combination, last week they announced acquisition of the GSK NS5A inhibitor to combine with their protease Simeprevir and their non-nuc. Roche is reporting results at this AASLD for their ANNAPR+URNA Study which looked at their 3-4 drug oral regimen which included their protease Danoprevir, Mericitabine, their nuc, and their non-nuc.

"All oral therapy will lead to a change in treatment paradigm"
"The number of treatable patients will dramatically increase! Interferon-Free"
"There is an association between SVR & all-cause mortality & liver-related mortality"

'New HCV oral IFN-free drug regimens will provide with 12-24 weeks convenient therapy an SVR is associated with reduced risk of progression to advanced liver disease, liver cancer and mortality
Will prevent HCV transmission and be cost-effective.....therapies will be once or twice daily, much less side effects than current IFN-based therapy Drug interactions will be an issue but we can deal with that'

Continue here to view complete slide presentation …..

Faldaprevir regimen is effective as first treatment for HCV genotype 1

10/29/13

By: SUSAN LONDON, Family Practice News Digital Network

SAN DIEGO – A regimen containing the oral investigational protease inhibitor faldaprevir is efficacious and safe as initial treatment for chronic hepatitis C virus genotype 1, a randomized phase III trial showed.

A team led by Dr. Christophe Moreno, a gastroenterologist at the Erasme Hospital, Université Libre de Bruxelles, Brussels, conducted the trial, known as STARTverso 1, among 652 patients in Europe and Japan.

More than three-fourths of patients given a faldaprevir-containing interferon-based regimen had achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), Dr. Moreno reported. This compared with only about half of patients given a placebo-containing regimen.

A low dose of faldaprevir worked just as well as a high one. In addition, most faldaprevir-treated patients met criteria for early treatment success and were therefore able to stop treatment after half the full duration.

The rate of serious adverse events was similarly low across treatment groups, and rates of most laboratory abnormalities were comparable.

"Faldaprevir is highly efficacious in European and Japanese patients infected with HCV [hepatitis C virus] genotype 1. Almost 90% of patients treated with faldaprevir were eligible for a shortened treatment duration of 24 weeks," Dr. Moreno commented. "Faldaprevir was well tolerated with few discontinuations due to adverse events at both dosages."

"Since this was primarily a European and Japanese study, there were no patients from this country [the United States], with African American ethnicity, which is one of the negative predictors of response," noted session comoderator Dr. Zobair N. Younossi, executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va.

"Do you think that that would change [the results], if you ran the trial in this country and had 20%-30% of patients with African American ethnicity?" he asked.

Two-thirds of the patients in the trial had HCV genotype 1b, Dr. Moreno replied. "As genotype 1a is more frequent in the U.S. and African Americans, we can suppose that maybe the results would be quite different.

"There is another trial, STARTverso 2, which is evaluating the efficacy of faldaprevir in patients from the U.S., Canada, and also other countries," he added.

The investigators enrolled in STARTverso 1 patients with treatment-naive HCV genotype 1and randomized them in 1:2:2 ratio to 24 weeks of pegylated interferon alfa-2a and ribavirin plus placebo for 24 weeks (arm 1), plus faldaprevir 120 mg once daily for 12 or 24 weeks depending on response (arm 2), or plus faldaprevir 240 mg once daily for 12 weeks (arm 3).

Patients meeting criteria for early treatment success (HCV RNA less than 25 IU/mL at week 4 and undetectable at week 8) in arms 2 and 3 stopped treatment at week 24. Patients who did not meet these criteria and all patients in arm 1 received interferon and ribavirin out to 48 weeks.

The main trial results showed that the rate of SVR12 was higher in both the high-dose faldaprevir group (80%) and the low-dose faldaprevir group (79%) than in the placebo group (52%, P less than .0001 for both comparisons).

Fully 87% of patients treated with low-dose faldaprevir and 89% treated with high-dose faldaprevir achieved early treatment success and therefore qualified for the shortened treatment duration of 24 weeks. Among these patients, 86% and 89%, respectively, achieved SVR12.

Just 1% of all patients treated with faldaprevir had a primary nonresponse. About 4%-10% of patients had a viral breakthrough, and 6%-15% had a relapse.

"Common baseline polymorphisms were not found to affect the efficacy of faldaprevir," Dr. Moreno commented. In particular, the drug worked equally well in the 23% of patients with genotype 1a who had the Q80K polymorphism, which has been found to reduce the efficacy of other protease inhibitors.

"The high dose of faldaprevir showed no benefit over the 120-mg dose in any subgroup analyzed," he added.

The rate of serious adverse events was 7% with both doses of faldaprevir and 6% with placebo. Moderate or worse gastrointestinal adverse effects were more common with faldaprevir (7%-12%) than with placebo (3%).

Rates of grade 3 or higher laboratory abnormalities were largely the same. The faldaprevir groups had a higher rate of hyperbilirubinemia (12%-53% vs. 1%); however, "bilirubin elevations were benign and transient," Dr. Moreno noted.

Compared with placebo, faldaprevir was not associated with an increase in the incidence of anemia, one of the leading adverse effects of first-generation protease inhibitors.

Dr. Moreno disclosed that he is a board member for Janssen, Gilead, MSD, and Bristol-Myers Squibb; is a consultant for Janssen and MSD; receives grants from Janssen, MSD, Roche, and Novartis; is on the speakers’ bureau for MSD, Janssen, and BMS; and receives travel support from Janssen, Gilead, MSD, and Novartis. The trial was sponsored by Boehringer Ingelheim Pharmaceuticals. Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

Source

Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients

J Hepatol. 2013 Nov;59(5):964-71. doi: 10.1016/j.jhep.2013.06.030. Epub 2013 Jul 10.

Scherzer TM, Stättermayer AF, Stauber R, Maieron A, Strasser M, Laferl H, Schwarzer R, Datz C, Rutter K, Beinhardt S, Steindl-Munda P, Hofer H, Ferenci P.

Department of Internal Medicine III, Medical University, Vienna, Austria.

Abstract

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1.

METHODS: Hemoglobin levels at baseline (Hb0) and the decline after 4weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9±11.1, male:185, female:123, BMI 25.3±3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180μg peginterferon-alpha 2a and ribavirin [1000-1200mg/d; females: mean (95% CI) 15.8mg/kg (15.4-16.2); males 14.3 (14.1-14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System.

RESULTS: 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8); p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1); p<0.001].

CONCLUSIONS: Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Age, GWAS, Gender, HCV, Hepatitis C virus, ITPA, RVR, Ribavirin-induced anemia, SNP, SVR, genome-wide association study, rapid virologic response, single nucleotide polymorphism, sustained virologic response

PMID: 23850877 [PubMed - in process]

Source

 

A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C

J Hepatol. 2013 Nov;59(5):926-33. doi: 10.1016/j.jhep.2013.06.019. Epub 2013 Jun 26.

Carrión JA, Gonzalez-Colominas E, García-Retortillo M, Cañete N, Cirera I, Coll S, Giménez MD, Márquez C, Martin-Escudero V, Castellví P, Navinés R, Castaño JR, Galeras JA, Salas E, Bory F, Martín-Santos R, Solà R.

Liver Section, Gastroenterology Department, Hospital del Mar, Universitat Autònoma de Barcelona, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain. Electronic address: 95565@parcdesalutmar.cat.

Abstract

BACKGROUND & AIMS: Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC.

METHODS: 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003-2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model.

RESULTS: Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes.

CONCLUSIONS: MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: 95% CI, 95% confidence interval, ALT, ANC, BOC, CHC, Cost-effectiveness, DAA, EOT, EPO, G-CSF, HADS, HBV, HCC, HCV, HIV, Hb, Hepatitis, ICER, MSP, NR, OR, PCR, PHQ, PLT, Programme, QALY, RBV, Response, SE, SVR, TVR, Treatment, ULN, absolute neutrophil count, alanine aminotransferase, boceprevir, chronic hepatitis C, direct-acting antivirals, end of treatment, erythropoietin, granulocyte colony-stimulating factor, haemoglobin, hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, hospital anxiety and depression scale, human immunodeficiency virus, incremental cost-effectiveness ratio, multidisciplinary support programme, non-responders, odds ratio, patient health questionnaires, pegIFN, pegylated interferon, polymerase chain reaction, potentially life threatening, quality-adjusted life year, ribavirin, standard error, sustained virological response, telaprevir, upper limit of normal

PMID: 23811030 [PubMed - in process]

Source

Doctors urge hepatitis C tests for boomers

October 29, 2013, 11:29 AM

By Matthew Heimer

Hepatitis C is a virus surrounded by a considerable stigma, with much of the general public associating infection with drug addiction and unsanitary living. But if a trend in the medical establishment continues to gain momentum, doctors will soon be telling millions of their otherwise healthy middle-aged patients to get tested for the disease, as Joseph Walker of The Wall Street Journal reports this week. (Walker discusses the phenomenon with Wendy Bounds of WSJLive in the clip below.)

About 3.2 million Americans carry the hepatitis C virus, or HCV, according to the Centers for Disease Control and Prevention, but the majority of them don’t know it; most don’t realize they’re carriers until the virus causes complications like liver cancer or cirrhosis, often decades after infection took place. The CDC estimates that HCV killed roughly 16,600 people in 2010. And this summer, the U.S. Preventive Services Task Force, a board that sets guidelines for medical practice, recommended that everybody born between 1945 and 1965 get screened for the disease at least once—an advisory that Walker estimates could affect as many as 60 million people.

Why single out the boomers? It’s partly a Me Generation issue: Intravenous drug users are among the highest-risk groups for infection, and boomers came of age during a time when experimentation with those drugs was relatively common. But the safety of the blood supply is a bigger factor: Blood donations weren’t routinely monitored and screened for many viruses before the early 1990s, and anyone who received a transfusion for any reason before then could potentially have been infected.

That task-force decision will mean some relief for boomers’ wallets. Testing can cost up to $200, not including follow-ups, but the fact that HCV screening has made the recommended list means that most private insurers are now required to cover the screening at no charge to the patient. (Medicare administrators say they’ll decide by next summer whether to cover screening.)

Still, as Walker reports, some doctors have misgivings about adding another blood test to older Americans’ medical to-do lists. HCV could be somewhat akin to prostate cancer as a midlife medical challenge: Since the majority of those infected won’t develop serious symptoms, many patients will have to decide whether to spend money, time and energy monitoring a condition that may never significantly affect them. (Then again, unlike prostate cancer, HCV can be transmitted from an infected person to someone else.)

On this front, at least, there’s some good news: Monitoring the liver for potential damage is now more likely to involve non-invasive procedures like blood tests, rather than more dangerous and complicated biopsies.

Source

Estrogen protects women with NASH from severe liver fibrosis

Provided by MedicalXpress

October 29, 2013

New research suggests that estrogen protects women with nonalcoholic steatohepatitis (NASH) from severe liver fibrosis. According to the study published online in Hepatology, a journal of the American Association for the Study of Liver Diseases, men are at higher risk of more severe fibrosis compared to women prior to menopause, but liver fibrosis severity is similar in men and post-menopausal women.

Non-alcoholic fatty liver disease (NAFLD) includes a range of liver disorders from simple fatty liver to inflammation, fibrosis, and cirrhosis. With the rapid rise in obesity, diabetes and metabolic syndrome, the prevalence of NAFLD—the result of insulin resistance—has also steadily increased. In fact, studies suggest that the NAFLD prevalence is 10% to 30%, making it the most common liver disease in the U.S.

"While most NAFLD patients have a mild disease known as fatty liver or hepatic steatosis, some patients present with NASH, which is more severe and increases overall mortality," explains Dr. Ayako Suzuki with the Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences in Little Rock, the lead author of the present study. "Our study aim was to investigate whether gender and menopause significantly impact fibrosis severity among adult patients with NAFLD."

The research team analyzed data from 541 adults with NASH who were seen at Duke University Liver Clinics and the Duke Metabolic and Weight Loss Surgery Program. The mean age of subjects was 48 years, with 35% of the group being men, 28% pre-menopausal women and 37% post-menopausal women.

Findings indicate that 22% of the cohort had advanced fibrosis. After adjusting for known predictors of fibrosis, the risk for greater fibrosis severity in post-menopausal women and men vs. pre-menopausal women was 1.4-fold and 1.6-fold, respectively. Furthermore, when dividing the cohort at age 50, which is the average age at menopause in the US, the risk for greater fibrosis severity in men vs. women before age 50 was 1.8-fold, while after the age 50 the risk was reduced to 1.2-fold.

"Our findings suggest a protective effect from estrogen against development of severe fibrosis," concludes Dr. Suzuki. "Further study of the impact of estrogen on fibrosis progression in NASH patients is needed." Explore further: Cardiovascular issues up mortality rates in patients with advanced fibrosis

More information: "Gender and Menopause Impact Severity of Fibrosis Among Patients with Nonalcoholic Steatohepatitis." Ju Dong Yang, Manal F Abdelmalek, Herbert Pang, Cynthia D Guy, Alastair D Smith, Anna Mae Diehl and Ayako Suzuki. Hepatology; (DOI: 10.1002/hep.26761) Published online: October 1, 2013.

Journal reference: Hepatology

Provided by Wiley

Source

Newly Approved Ultrasound Device Eliminates Risks and Pain of Liver Biopsy

DETROIT, Oct. 29, 2013 /PRNewswire/ -- Henry Ford Hospital is the first in Michigan to use a pioneering ultrasound device that can help patients with liver disease avoid invasive biopsies to manage their disorders.

FibroScan^® replaces repeated and sometimes painful liver biopsies for patients with chronic hepatitis C and B, fatty liver diseases and other hepatic disorders with a quick and painless procedure similar to the familiar ultrasound tests used to track pregnancy and diagnose internal diseases.

The device is based on a technology called transient elastography, which measures liver "stiffness" to assess disease and guide ongoing treatment.

"FibroScan^® is designed to measure liver fibrosis using a painless, non-invasive method of assessing many of the same conditions measured with biopsy," says Stuart Gordon, M.D., Director of Hepatology at Henry Ford Hospital. "It's an outpatient procedure taking less than 15 minutes."

At the annual meeting of the American Association for the Study of Liver Disease being held in Washington, DC, a multi-center study will be presented Monday, Nov. 4, which "confirms that (Fibroscan^®) very accurately assesses presence of cirrhosis in patients with chronic type B and C viral hepatitis."

Henry Ford Hospital was one of the seven U.S. institutions that conducted the study.

The patient feels only a slight vibration on the skin, the results are immediate and, because it does no harm, the procedure can be safely repeated as often as necessary.

About 150,000 people in the U.S. are diagnosed with chronic liver disease annually, about a fifth of them with cirrhosis, a scarring of the liver.

By one conservative estimate, more than 30,000 liver biopsies are performed in the U.S. each year, a number that led to medical discussions and calls for ways to make the procedure more "acceptable" to patients.

Cirrhosis and other diseases of the liver result from or cause hepatic fibrosis, in which fibrous scars develop as part of the liver's mechanism to heal its own damage.

Sometimes it's beneficial because the scar tissue surrounds and blocks off the cause of the damage. But often this scarring develops to the point that it interferes with liver function, as in cirrhosis.

For decades, a liver biopsy has been considered the "gold standard" for assessing liver disease. In most cases, the biopsy involves using a needle inserted through the skin and underlying tissue and into the liver to collect a sample of tissue. It's widely regarded as safe, but because it is invasive, it carries risks ranging from bleeding to rare instances of death. In addition, a proportion of liver biopsy patients complain of severe pain during the procedure.

Using FibroScan ^®, the skin in the area of the liver is first coated with a water-based gel. The doctor then passes an ultrasound sensor over the area to take 10 consecutive readings. The sensor produces vibrations that create a low-frequency seismic wave sent between the ribs and into the liver. The speed of the wave as it passes through the liver is used to determine the hardness or stiffness of the organ – the faster the wave, the harder the tissue.

The data collected during the readings are collected and analyzed in the console connected to the sensor, and provides immediate results on the presence and severity of liver fibrosis.

FibroScan^® is produced by Paris-based Echosens, entered the European market in 2003 and was already being used in more than 70 countries worldwide when it received approval by the U.S. Food and Drug Administration in April.

Note: To access Fibroscan^® a patient needs a physician referral. The cost is $200. Email: FIBROSCAN@hfhs.org.

SOURCE Henry Ford Hospital

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HIV -- Geneticists map human resistance to AIDS

Provided by Science Codex

Posted By News On October 29, 2013 - 4:30am

The key to future HIV treatment could be hidden right in our own genes. Everyone who becomes infected deploys defense strategies, and some even manage to hold the virus at bay without any therapy at all. This immune system struggle leaves its mark within the pathogen itself – genetic mutations that indicate how the virus reacted to its host's attacks. Scientists from EPFL and the Vaud university hospital center (UNIL-CHUV) retraced the entire chain of events in these battles, from the genome of the virus to the genome of the victim. They have created the first map of human HIV resistance. The goal of their research, which has been published in the journal eLife on the 29th of October, is to find new therapeutic targets and to enable individualized treatment strategies.

The human immune system is constantly developing strategies to fight HIV. Unfortunately, "the genome of the virus also changes rapidly, at a rate of millions of mutations a day," explains Jacques Fellay, co-author and EPFL researcher. In the majority of cases, the pathogen finds an effective strategy via this natural selection.

Sometimes the virus is faced with a tougher opponent. It resists, but its ability to replicate is compromised. "The virus survives but replicates more slowly, and thus its capacity for destruction is in some sense neutralized," says the scientist.

By studying strains of HIV that have been living in human hosts, the researchers can identify specific genetic mutations. These are like scars that each bear witness to a very specific attack launched by the immune system. What are the human genes involved in these defense strategies? And which, among all our genetic variations, predispose us to increased HIV resistance or, on the contrary, increased vulnerability? The scientists developed a method that allowed them to find answers to these questions.

A supercomputer, 1,071 patients and millions of combinations

To draw up the first map of human HIV resistance, the researchers had to analyze an enormous amount of data. They studied various strains of HIV from 1,071 seropositive individuals. They crossed more than 3,000 potential mutations in the viral genome with more than 6 million variations in the patients' genomes. Using supercomputers, they studied all these possible combinations and identified correspondence between patients.

"We had to study the virus before the patient had undergone treatment, which is far from easy," says Fellay. This meant they had to search in data banks established in the 1980s, before effective therapies were made available.

This novel, indirect method made it possible to obtain the most complete global overview to date of human genes and their implications in terms of HIV resistance. It allows us to not only better understand how we defend ourselves from attack but also how the virus adapts itself to our defense mechanisms. "We now have a true database that tells us which human genetic variation will induce which kind of mutation in the virus", explains Amalio Telenti, co-author and UNIL-CHUV researcher.

Therapies inspired by our own natural defense

This research has two major implications. New therapies could be developed based on studying humans' natural defenses, particularly those that result in a reduced replication of the virus. In addition, the scientists hope that by profiling the genome of HIV-infected individuals, it will be possible to develop individually targeted treatments that take into account the patients' genetic strengths and weaknesses.

Source: Ecole Polytechnique Fédérale de Lausanne

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FDA and Opioids: What's Going On Here?

Published: Oct 28, 2013 | Updated: Oct 29, 2013

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today; Kristina Fiore , Staff Writer, MedPage Today

Against the recommendation of its own advisors, the U.S. Food and Drug Administration approved a new high-dose narcotic painkiller, a drug that the FDA concedes has a high risk for abuse and one which was using a method that critics say may give the drug the appearance of greater efficacy.

Zohydro ER will be the first hydrocodone-only opioid, and it will come in doses packing five to 10 times more heroin-like narcotic than traditional hydrocodone products such as Vicodin that combine hydrocodone with over-the-counter pain relievers such as acetaminophen or ibuprofen.

Abuse Potential

Though the narcotic in Zohydro ER is designed to be released slowly over 12 hours, pleasure seekers will be able to crush it, chew it or mix it with alcohol to unleash its full punch at once. That abuse potential would have been blunted if the FDA required that the drug be formulated with abuse-prevention technology -- a process the FDA has publicly backed, but did not require in this case.

A November 2012 memo from the FDA's own staff warns that the drug will be abused more than traditional hydrocodone products. The memo compares what likely will occur with Zohydro to what happened with extended release oxycodone-containing opioids.

The most famous oxycodone product, OxyContin, for years was one of the most abused narcotics in America. In 2010, its maker, Purdue Pharma, reformulated its recipe to make it abuse resistant, a protection that Zohydro won't have.

In an email, FDA spokesperson Morgan Liscinsky said that while the agency supports a transition to abuse-deterrent opioids, "we do not believe it is appropriate or feasible at this time to require all products in the class to be abuse-deterrent.

"Rather, FDA will continue to take a product-by-product approach to regulatory decisions concerning the abuse-deterrent properties (or lack thereof) of opioid products."

Zohydro drugmaker Zogenix, based in San Diego, said in a statement to the Journal Sentinel/MedPage Today that it plans to develop an abuse-deterrent formulation of the drug and is "committed to advancing the program as rapidly as possible."

Liscinsky added that the FDA concluded that the benefits of Zohydro outweighed its risks and that data show it is safe and effective for round-the-clock use. Its label will have prominent warnings about abuse, she said. The label will urge prescribers to monitor patients for addiction or misuse.

"Prescribers now have a hydrocodone option for patients who require an extended-release opioid, which is important for several reasons," she said. "First, individual patients can respond differently to different opioids. Second, the benefits of opioids can wane as the patient becomes opioid-tolerant."

"While the current formulation of Zohydro ER does not have abuse-deterrent or tamper-proof features, we have started the development of an abuse-deterrent formulation and are committed to advancing the program as rapidly as possible," said a statement from Zogenix, the company that makes Zohydro.

But during the FDA advisory committee hearing last December, a company official said an abuse-deterrent formulation of the drug was only in early development and was "several years away from the market."

Friday's approval of Zohydro is the latest action by the agency, which recently has been the target of claims that it is too friendly toward the opioid industry. And it comes follows closely complaints that the FDA had not done enough over the years to curtail the booming overuse of opioids.

The U.S. already consumes 99% of the hydrocodone used in the world.

In 2010, Vicodin was the most prescribed medication in the U.S. with 131 million filled prescriptions. That same year, more than 16,000 people died of overdoses from narcotic painkillers, up from about 4,000 in 1999.

Vicodin comes in doses of 5, 7.5 and 10 mg of hydrocodone along with 300 mg of acetaminophen. Zohydro will come in six doses: 10, 15, 20, 30, 40 and 50 mg without any acetaminophen, which can cause liver damage in high amounts.

"If the FDA was really interested in protecting the public, they would have said, 'No thanks.... we have too many people dying of opioids in this country to justify approving Zohydro,'" said David Juurlink, MD, PhD, director of pharmacology and toxicology at the University of Toronto. "Minus the pesky acetaminophen, plus the crushability, it's a disaster in the making."

An FDA "Flip-Flop?"

On Thursday, after years of resisting the measure, the FDA finally moved to tighten restrictions on hydrocodone products. When the change occurs next year, hydrocodone products will have the same Schedule II restrictions as oxycodone products such as OxyContin.

However the day after the move, the agency reversed course, and approved Zohydro, despite the fact that its own advisory panel voted 11-2 in December not to approve the drug.

The Zohydro decision is "worrisome," U.S. Rep. Harold "Hal" Rogers (R-Ky.), said in a statement provided to the Journal Sentinel/MedPage Today. Kentucky has experienced substantial opioid abuse over the years.

"I am counting on the FDA to perform rigorous post-marketing studies and analysis to ensure this drug doesn't create another new wave of addiction," he said.

Rogers is chairman of the House Appropriations Committee and has co-hosted the National Rx Drug Abuse Summit.

"I am surprised," said Jeanmarie Perrone, MD, an associate professor of emergency medicine at the University of Pennsylvania and member of the FDA advisory panel who not to approve Zohydro.

Perrone said she was concerned about the safety of the drug and its lack of abuse resistance. At the advisory panel meeting, she also questioned its effectiveness.

The approval also suggests that the FDA is trying to help drug makers show that that opioids are safe and effective for treating long-term non cancer pain, said Lewis Nelson, MD, a New York emergency medicine specialist who has served as an FDA advisory panel member on opioid issues.

"I don't see any reason why the FDA should be helping pharma," said Nelson, also a medical toxicologist at NYU School of Medicine.

Enriched Data

The main research on Zohydro took place over a 12-week period. Experts say there is little rigorous research showing the drugs are beneficial when used for many months or years.

A Journal Sentinel/MedPage Today investigative report earlier this month documented how, for years, FDA officials and executives of companies that make pain drugs held annual private meetings at expensive hotels through an organization funded by the drug companies. The story was based on emails obtained through public records requests and provided to the Journal Sentinel/MedPage Today.

A topic at those meetings was a research approached called enriched enrollment, a technique that allows drug companies to weed out people who don't respond well to a drug or who can tolerate it before the actual clinical trial begins.

Zohydro clinical trials used the enriched enrollment methodology.

Experts say that approach makes it much more likely a drug will prove effective and possibly win FDA approval. It's also cheaper for drug companies to conduct such trials.

However, the approach has been described by critics as cheating because drugs tested that way are not likely to reflect what will happen when the drug gets on the market and is prescribed for large numbers of people.

Indeed, when the panel of FDA advisors voted against approving Zohydro last December, several of them expressed concerns about what would happen once the drug moved from the rarefied realm of clinical trials to the real world of everyday medicine, according to a transcript of the hearing.

"The question of what's effective is much greater than (the pain score of the test subjects) at the end of 12 weeks in a very limited, controlled experiment that somehow was a little bit better than a placebo group," panel member Judith Kramer, MD, a professor of medicine at Duke University, said at the meeting.

"...With treatment of chronic pain, are we really, in the long run, helping people, or are we creating an epidemic? This drug will almost certainly cause dependence in the people that are intended to take it," Kramer said.

Liscinsky, the FDA spokesperson said enriched enrollment follows the concept of personalized medicine in that it attempts to find those who a drug will be most effective in.

"Enrichment will not save a drug that is not safe of effective, but it will help find one that is," she said.

However, advisory panel members had a different view, according to a transcript of the meeting.

"I happen to live in the real world, and I would think that the (Zohydro) study population is very different than the real world population," said Alan Kaye, MD, PhD, a professor of anesthesia at Louisiana State University School of Medicine. "And as such, I certainly feel there would be quite a bit of morbidity and mortality that would result."

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