Gene expression profiling of HCV genotype 3a initial liver fibrosis and cirrhosis patients using microarray

Published on: 2012-03-08

Hepatitis C virus (HCV) causes liver fibrosis that may lead to liver cirrhosis or hepatocellular carcinoma (HCC), and may partially depend on infecting viral genotype. HCV genotype 3a is being more common in Asian population, especially Pakistan; the detail mechanism of infection still needs to be explored.

In this study, we investigated and compared the gene expression profile between initial fibrosis stage and cirrhotic 3a genotype patients.

Methods: Gene expression profiling of human liver tissues was performed containing more than 22000 known genes. Using Oparray protocol, preparation and hybridization of slides was carried out and followed by scanning with GeneTAC integrator 4.0 software.

Normalization of the data was obtained using MIDAS software and Significant Microarray Analysis (SAM) was performed to obtain differentially expressed candidate genes.

Results: Out of 22000 genes studied, 219 differentially regulated genes found with P [less than or equal to] 0.05 between both groups; 107 among those were up-regulated and 112 were down-regulated. These genes were classified into 31 categories according to their biological functions.

The main categories included: apoptosis, immune response, cell signaling, kinase activity, lipid metabolism, protein metabolism, protein modulation, metabolism, vision, cell structure, cytoskeleton, nervous system, protein metabolism, protein modulation, signal transduction, transcriptional regulation and transport activity.

Conclusion: This is the first study on gene expression profiling in patients associated with genotype 3a using microarray analysis.These findings represent a broad portrait of genomic changes in early HCV associated fibrosis and cirrhosis.

We hope that identified genes in this study will help in future to act as prognostic and diagnostic markers to differentiate fibrotic patients from cirrhotic ones.

Author: Waqar AhmadBushra IjazSajida Hassan
Credits/Source: Journal of Translational Medicine 2012, 10:41

Source

CROI 2012: Early Data Show Drugs Effective in HCV Plus HIV

By Michael Smith, North American Correspondent, MedPage Today

Published: March 07, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

SEATTLE -- Two new drugs that directly target hepatitis C are effective in people also infected with HIV, researchers reported here.

Action Points

• These studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Explain that two different phase II trials found that sustained virologic response to hepatitis C virus (HCV) was achieved in more HCV/HIV coinfected patients treated with either boceprevir or telaprevir added to the cominbation of pegylated interferon plus ribavirin, as opposed to standard anti-HCV therapy alone.
• Note that results in both trials were comparable to treatment with these new drugs in patients infected with HCV alone, and the side effect profile was not different.

In separate phase II trials, the drugs -- telaprevir (Incivek) and boceprevir (Victrelis) -- each individually combined with standard hepatitis C therapy, showed about a 30% improvement in cure rates over standard therapy alone.

Despite the early stage of the research, the findings, reported at the annual Conference on Retroviruses and Opportunistic Infections, got an enthusiastic reception.

There's a clear "gap between the enthusiasm and the provisional nature of the data," commented David Thomas, MD, of Johns Hopkins University, who was not part of the studies but who chaired a press conference at which details were presented.

But he told MedPage Today there are two reasons for that: clinicians are feeling a sense of urgency about treating patients with HIV and hepatitis C, and "more substantive data" will not be available for a year and a half, when phase III trials begin to report.

"Cure matters," he said. "Here we are able to cure hepatitis C and we've never had that before in patients with HIV."

"There's 30% more people being cured," Thomas said. "That's a big deal."

Both drugs have been approved for treatment of hepatitis C in mono-infected patients, but not yet for people coinfected with HIV.

Both studies combined the novel drug with standard therapy – pegylated interferon and ribavirin -- and compared the results with standard therapy alone. Patients were allowed to keep taking their anti-retroviral medication. For this analysis, a cure was defined as a sustained virologic response – no detectable hepatitis C RNA -- 12 weeks after the end of treatment, the so-called SVR12.

For telaprevir, an intention-to-treat analysis of 60 patients showed that 74% of those in the telaprevir arm had an SVR12, compared with 45% of those on the standard therapy alone, according to Douglas Dieterich, MD, of Mt. Sinai School of Medicine in New York City.

He described the findings as a "huge leap forward" for treatment of coinfected people.

For boceprevir, the absolute numbers were not quite as robust, but the difference between the arms was similar, reported Mark Sulkowski, MD, of Johns Hopkins University School of Medicine.

In 98 patients, 60.7% of those taking boceprevir combined with standard therapy had an SVR12, compared with 26.5% of those getting standard therapy alone, Sulkowski reported.

In both studies, more than 80% of patients had hepatitis C RNA >800,000 IU/mL, and all had undetectable HIV levels before therapy for hepatitis C was added.

The differences between the arms in the two studies were 29% and 34.2%, respectively.

The findings are "shockingly comparable," Dieterich said.

Both Dieterich and Sulkowski suggested there is a pent-up desire to use the drugs in patients, even before phase III data are available and approval is forthcoming.

Until better data are available, "what should patients do?" asked Sulkowski. "These phase II trials, albeit small in size, demonstrate significant improvement over peginterferon and ribavirin."

"If you need to treat people, you need to treat people now," Dieterich said.

Both researchers said there is not a great deal of difference between outcomes for people with both viruses and those previously seen for patients with hepatitis C alone.

And although there are some interactions between the drugs and anti-retrovirals, there was little evidence that HIV might escape control. For instance, Sulkowski said, HIV viral breakthrough occurred in three of 64 patients on boceprevir and four of 34 on standard therapy alone.

Dieterich noted that the interferon part of the regimen "covers our back here" since it is itself a mild anti-retroviral. So, even if drug interactions lower the efficacy of the anti-retroviral medications, the interferon might pick up the slack.

"The real issue is going to come when we do away with interferon," as many clinicians hope can be done, he added.

The boceprevir study was supported by Merck. Sulkowski reported financial links with Merck and Vertex.

The telaprevir study was supported by Vertex. Dieterich reported financial links with Bristol Myers Squibb, Gilead, Idenix, Merck, Pharmasset, and Vertex.

Thomas reported financial links with Gilead and Merck.

Primary source: Conference on Retroviruses and Opportunistic Infections
Source reference:
Sulkowski M, et al "Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected patients: End of treatment (week-48) Interim results" CROI 2012; Abstract 47.

Additional source: Conference on Retroviruses and Opportunistic Infections
Source reference:
Dieterich D, et al "Telaprevir in combination with pegylated interferon-a-2a+RBV in HCV/HIV-co-infected patients: A 24-week treatment interim analysis" CROI 2012; Abstract 46.

Source

Also See:

1. CROI 2012: Results from Investigational Studies with VICTRELIS™ (boceprevir) Presented at the Conference on Retroviruses and Opportunistic Infections to Understand Potential Use in Patients Coinfected with Chronic Hepatitis C and HIV-1
2. CROI 2012: Data from Phase 2 Study of an INCIVEK® Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12)

CROI 2012: HCV PI Boceprevir Lowers Levels of Three Key HIV PIs

Provided by NATAP

19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle

Mark Mascolini

Boceprevir, the recently licensed HCV protease inhibitor (PI), lowered concentrations of three ritonavir-boosted HIV PIs--atazanavir, darunavir, and lopinavir--in a pharmacokinetic study that enrolled 39 healthy volunteers [1].

The FDA advises that "healthcare professionals who have started patients infected with both chronic HCV and HIV on Victrelis [boceprevir] and antiretroviral therapy containing a ritonavir-boosted protease inhibitor should closely monitor patients for HCV treatment response and for potential HCV and HIV virologic rebound" [2].

In a letter to healthcare professionals, the manufacturer cautioned that "these drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when coadministered [3]." The statement stressed that "Merck does not recommend the coadministration of Victrelis [boceprevir] and ritonavir-boosted HIV protease inhibitors."

Boceprevir and telaprevir, another HCV PI, won FDA approval in 2011 for use with pegylated interferon and ribavirin in adults with genotype 1 chronic HCV and compensated liver disease. Neither boceprevir nor telaprevir is licensed for use in people coinfected with HCV and HIV.

In work reported separately by NATAP, a placebo-controlled trial of boceprevir plus pegylated interferon and ribavirin for 100 people coinfected with genotype 1 HCV and HIV logged undetectable HCV RNA levels in 39 of 61 people (64%) randomized to boceprevir and 10 of 34 (29%) randomized to placebo at week 48 [4]. All study participants had an HIV load below 50 copies when the trial began.

The pharmacokinetic study involved 39 healthy volunteers between 19 and 55 years old [1]. No one had HIV infection, and none tested positive for hepatitis B surface antigen or HCV antibodies. Everyone took boceprevir at the standard dose of 800 mg three times daily on study days 1 to 6 then took no drugs for 4 days. On days 10 to 31 study participants took 300/100 mg of atazanavir/ritonavir once daily, 400/100 mg of lopinavir/ritonavir twice daily, or 600/100 mg of darunavir/ritonavir twice daily. On days 25 through 31, they also took the standard dose of boceprevir.

Taking boceprevir with an HIV PI lowered trough concentrations by an average 49% for atazanavir, 43% for lopinavir, and 59% for darunavir. Average area under the concentration-time curve (AUC) fell 35% for atazanavir, 34% for lopinavir, and 44% for darunavir. Respective average drops in peak concentrations were 25% for atazanavir, 30% for lopinavir, and 36% for darunavir.
Taking atazanavir with boceprevir did not alter boceprevir AUC. But lopinavir cut boceprevir AUC 45%, and darunavir lowered boceprevir AUC 32%.

The FDA also issued online guidance about these findings for patients and patient advocates [5]. The agency cautioned that HIV-positive people taking boceprevir with an HIV PI should not stop taking any of their drugs without first talking to their clinician.
In a separate study involving 24 healthy volunteers, boceprevir did not affect levels of the integrase inhibitor raltegravir [6].

References

1. Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 771LB.

2. US Food and Drug Administration. FDA drug safety communication: important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. February 8, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm291119.htm.

3. Reddy SSK. Merck & Co, Inc. Important drug warning. February 6, 2012. http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf.

4. Sulkowski M, Pol S, Cooper C, et al. Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected patients: end of treatment (week 48) interim results. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 47.

5. US Food and Drug Administration. Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitor drugs--drug interactions. For patients and patient advocates. http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm291389.htm.

6. de Kanter C, Blonk M, Colbers A, Fillekes Q, Schouwenberg B, Burger D. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase inhibitor raltegravir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 772LB.

Source

CROI 2012: Interferon-Free Hepatitis C Tx Hits Snag

By Michael Smith, North American Correspondent, MedPage Today

Published: March 07, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

SEATTLE -- Results in a hard-to-treat patient group have clouded the future of a closely watched agent that acts directly against hepatitis C.

Action Points

• This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Despite impressive results during treatment of hepatitis C virus with the investigational compound PSI-7977, all but one of the patients relapsed almost immediately after treatment stopped.
• The drug was being given in combination with ribavirin, one of the standard hepatitis C drugs, but without the other standby, pegylated interferon.

Despite impressive results during treatment with the compound dubbed PSI-7977, all but one of the patients relapsed almost immediately after treatment stopped, according to Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.

The drug was being given in combination with ribavirin, one of the standard hepatitis C drugs, but without the other standby, pegylated interferon, Gane told reporters at the annual Conference on Retroviruses and Opportunistic Infections.

Among researchers and clinicians, there has been intense interest in the compound, a nucleotide analog, because of the potential to eliminate interferon, whose side effects make treatment difficult for many patients.

"The holy grail is treating people without interferon," commented David Thomas, MD, of Johns Hopkins University in Baltimore, who was not part of the study but who chaired a press conference at which details were presented.

But he told MedPage Today the results being presented here are disappointing, especially since the drug appeared to be remarkably effective in patients with relatively easy-to-treat disease.

In earlier results from the phase II ELECTRON study, patients with genotypes 2 and 3 of the virus were completely cured after just 12 weeks of therapy with PSI-7977 combined with ribavirin, Gane noted.

But researchers were also testing the combination in 10 patients with genotype 1 hepatitis C who had previously not responded to standard therapy with ribavirin and interferon, and in 25 genotype 1 patients who had not yet been treated, Gane said.

The initial responses in both groups were similar to those seen in genotypes 2 and 3 -- a quick drop to undetectable levels of virus followed by complete suppression throughout the 12-week treatment period, Gane said.

But all but one of the so-called null responders relapsed, with hepatitis C levels rising sharply within days of stopping the drug, Gane reported. Data on the treatment-naïve patients is not complete yet and will be reported in the next few months, he added.

"It's still a drug we're excited about, but these data put some limits on its use," Thomas said.

"The drug was curing [patients with] genotypes 2 and 3 in 12 weeks with just ribavirin," he said, but that doesn't appear to be possible in the hardest-to-treat subgroup.

Now, he said, the researchers have to do "a lot of hard work" to figure how to overcome the obstacles.

Any new study in genotype 1 null responders will either be longer in duration, or will add another direct-acting agent, or both, Gane said. But the researchers and the drug's manufacturer haven't settled on what they'll do.

Gane said the researchers will offer the relapsed patients a rescue protocol with PSI-7977 and another medication, but, again, they haven't decided what that drug will be.

The study was supported by Giliad.

Gane reported financial links with Gilead, Janssen-Cilag, Novartis, Pharmasset, and Vertex.

Thomas reported financial links with Gilead and Merck.

Primary source: Conference on Retroviruses and Opportunistic Infections
Source reference:
Gane E, et al "100% rapid virologic response for PSI-7977 + ribavirin in genotype 1 null responders (ELECTRON): early viral decline similar to that observed in genotype 1 and genotype 2/3 treatment-naïve patients" CROI 2012; Abstract 54LB.

Source

Also See: CROI 2012: PSI-7977/ribavirin combo achieved rapid response in HCV genotype-1

CROI 2012: New Hepatitis C Drugs in Clinical Practice [VIDEO]

Published on Wednesday, 07 March 2012 00:00
Written by Gregory Fowler
Provided by HIVandHepatitis.com

New therapies are leading to a "huge sea change" in the way infectious disease doctors are thinking about hepatitis C, Douglas Dieterich suggested at a press conference at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this week in Seattle.

New therapies are leading to a "huge sea change" in the way infectious disease doctors are thinking about hepatitis C, Douglas Dieterich suggested at a press conference at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this week in Seattle.

Joining Dieterich on the panel, David Thomas drew similarities to the state of HIV treatment in the 1990s before the advent of HIV protease inhibitors and effective combination therapy.

Mark Sulkowski emphasized the need for guidelines for treating HIV/HCV coinfected patients, noting that new week 12 sustained virological response data presented at the meeting "truly are cutting-edge." The latest data, he said, allay concerns about post-treatment relapse, while Dieterich noted that worries about worse side effects among coinfected people have not been confirmed.

Finally, Edward Gane expressed optimism about seeing interferon-free regimens within the next 5 years.

3/7/12

Reference
Press conference. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 6, 2012.

Source

CROI 2012: PSI-7977/ribavirin combo achieved rapid response in HCV genotype-1

Posted on InfectiousDiseaseNews.com March 6, 2012

SEATTLE — An interferon-free, experimental nucleotide analogue, PSI-7977, plus ribavirin for 12 weeks achieved rapid on-treatment response in hepatitis C virus genotype-1 patients and was well tolerated in this population, according to presenter Edward Gane, MD.

Gane, a hepatologist at Auckland City Hospital in New Zealand and principal investigator for the ELECTRON study, presented findings from a phase 2, multi-arm study aiming to assess the uridine nucleotide analogue, PSI-7977, combined with ribavirin currently in phase 3 development.

“Results on genotype-2 and genotype-3 patients were presented at the Liver meeting last fall, which demonstrated 100% rapid virologic response rates with interferon-free PSI-7977 plus ribavirin,” Gane said during a press conference today. “Following these results, we enrolled additional patients who were genotype-1 treatment-naive and null responders.”

For the current study, Gane and colleagues assigned 400 mg PSI-7977 plus ribavirin to 10 null responders and 25 treatment-naive patients with HCV genotype-1. Researchers compared early on-treatment data with data from treatment-naive patients with HCV genotype-2 and genotype-3 included in the ELECTRON study.

“Treatment-naive patients just completed treatment,” Gane said. “Therefore, results will not be available until next quarter and will be presented at the Liver meeting in Europe.”

However, overall data, thus far, indicate that patients achieved rapid treatment response, and among all participants, HCV RNA remained undetectable at 4 weeks and throughout the treatment regimen.

Of the nine null patients who have reached the 4-week treatment time point, eight patients relapsed. The one responder was a young, white woman who had the IL28 gene, a favorable predictor for response to interferon-based treatment, according to Gane.

“The majority of null responders have relapsed post-treatment. Further treatment options in this very difficult to treat group will either be longer duration of PSI-7977 plus ribavirin or the addition of another direct-acting antiviral,” he said.

For more information:

• Gane E. #54LB. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle.

Disclosure: The researchers report no relevant financial disclosures.

Source

Study Shows Nurses are Exposed to Risks from Blood Exposure During Insertion and Removal of Peripheral IV Catheter

PRESS RELEASE

March 7, 2012, 8:30 a.m. EST

SANDY, Utah, March 7, 2012 /PRNewswire via COMTEX/ -- About one in two nurses experience blood exposure, other than from a needlestick, on their skin or in their eyes, nose or mouth at least once a month when inserting a peripheral intravenous (IV) catheter, according to a new study by the International Healthcare Worker Safety Center at the University of Virginia.[1] Exposure to blood carries the risk of infection from pathogens such as human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV) and MRSA.

Healthcare workers place more than 300 million short peripheral intravenous catheters (SPIVCs) every year in the United States alone[2]. The study shows nurses are at risk of exposure to blood pathogens in 128 of 100,000 IV catheter insertions. The more commonly recognized risk of exposure to bloodborne pathogens from a needlestick injury with non-safety catheters is 6.6 per 100,000 devices[1]. The Centers for Disease Control and Prevention (CDC) define at-risk blood exposure as "contact of mucous membrane (MME) or exposed skin (chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other body fluids that are potentially infectious."

Yet, the majority of such exposures go unreported. Of the total mucous membrane exposures (MMEs) sustained by respondents in this study, 69% were not reported. In comparison, the CDC's underreporting rate for sharps injuries is 57%.

Almost nine in 10 of those nurses who did not report the incident said they did not think the exposure was significant enough to report; more than one third said they were too busy, and 9% said they were concerned about others' perceptions.

"The use of safety IV catheters has helped reduce needlestick exposures. This study demonstrates the need to consider technology and precautions to reduce the risk of all sources of blood exposure," said Janine Jagger, Ph.D., MPH, lead author of the study and director of International Healthcare Workers Safety Center at the University of Virginia. The study looked at the practices of 379 nurses nationwide who place IV catheters. It was published in the December issue of Nursing 2011.

Study respondents also report a monthly average of 10 incidents of blood contact to gloves during IV insertions and say they unexpectedly come into contact with blood in a patient's room (on bed rails, bedside trays, or pump touchpads) an average of 3.55 times per month, or almost once a week. Pathogens in blood residue on these surfaces can be transferred to healthcare workers, housekeeping staff and visitors who might come in contact with these surfaces.

BD has recently launched its latest innovation in safety peripheral IV catheter technology designed to keep healthcare workers safe from needlestick injuries and blood exposure. In addition to proven needlestick protection, BD Insyte(TM) Autoguard(TM) BC with Blood Control Technology has also been proven to reduce the risk of blood exposure by 95 percent, compared to a non-blood control IV catheter, according to a recently published study[2]. This latest technology joins the BD Nexiva(TM) Closed IV Catheter System and broadens the choice clinicians have in selecting a safety IV catheter that offers protection from sharps and non-sharps blood exposure.

BD Medical, a segment of BD (Becton, Dickinson and Company) and the world's leading provider of IV catheters, sponsored this research through an unrestricted educational grant to the authors. For additional information on healthcare worker safety or Making Safety Safer(SM), visit www.bd.com/IAGBC and www.bd.com/bloodcontrol .

About BD

BD is a leading global medical technology company that develops, manufactures and sells medical devices, instrument systems and reagents. The Company is dedicated to improving people's health throughout the world. BD is focused on improving drug delivery, enhancing the quality and speed of diagnosing infectious diseases and cancers, and advancing research, discovery and production of new drugs and vaccines. BD's capabilities are instrumental in combating many of the world's most pressing diseases. Founded in 1897 and headquartered in Franklin Lakes, New Jersey, BD employs approximately 29,000 associates in more than 50 countries throughout the world. The Company serves healthcare institutions, life science researchers, clinical laboratories, the pharmaceutical industry and the general public. For more information, please visit www.bd.com .

[1] Jagger J, Perry J, Parker G, Komblatt Phillips E. Blood exposure risk during peripheral IV catheter insertion and removal. Nursing 2011. 2011;41(12):45-49.[2] Onia R, Eshun-Wilson I, Arce C, et al. Evaluation of a new safety peripheral IV catheter designed to reduce mucocutaneous blood exposure. Curr Med Res Opin. 2011;27(7):1339-1346.

Contact: Barbara Kalavik BD Public Relations (201) 847-4209  Barbara_Kalavik@bd.com 

SOURCE BD-Becton Dickinson

Source

Call your member of Congress today about the CDC Hepatitis C Screening Guidelines!

Dear Viral Hepatitis Advocate:

Congressman Hank Johnson, one of our strongest champions for viral hepatitis screening, care and treatment, is asking his colleagues to sign onto a letter to the CDC asking for the speedy release of new screening guidelines for the Hepatitis C virus. The proposed age-based screening guidelines will identify many more Americans with Hepatitis C and enable them to access care and treatment, thereby reducing deaths and health care costs.

We urge you to help Congressman Johnson by calling YOUR member of Congress today to ask him or her to sign on to the letter (below and attached). You can reach your Representative by calling the Capitol Switchboard at 1-202-224-3121 or google their website for a direct office number. Sign on to the letter closes on Thursday, COB, so please call today!

Here’s a sample call script:

“My name is ____________ , I live in (city, state), and I care about viral hepatitis. Hepatitis is a serious health problem in the U.S., in my District, and is a very important issue to me. I urge Representative _____________ to show leadership in the fight against hepatitis and liver cancer by signing Congressman Hank Johnson’s Congressional sign on letter to the CDC regarding hepatitis C screening guidelines.”

If there is time, tell them why this issue is important to you. You will probably only have time for 2-3 sentences. Members of Congress and their staff pay attention to their constituents. They need to hear how viral hepatitis affects you, the people you care for, your friends, family, and co-workers. Our lawmakers are unaware of viral hepatitis and how it impacts people in their Districts so they really need to hear from you!

Begin forwarded letter:

Dr. Thomas R. Frieden
Director
Centers for Disease Control and Prevention
1600 Clifton Road
Atlanta, GA 30333

RE: Release of Screening Guidelines for Hepatitis C

Dear Director Frieden:

We are writing to express our full support for the timely release of the Centers for Disease Control and Prevention’s (“CDC”) revised screening guidelines for the Hepatitis C virus (“HCV”). In particular, we urge the CDC to adopt new guidelines that would recommend a one-time screening for all Americans born between 1945 and 1965, the “baby boomer generation.” Existing risk-based screening is not effectively targeting a patient population where baby boomers account for 80 percent of all Americans infected with chronic HCV.[1]

HCV infection is the most common long-term blood-borne infection in the United States.[2] There are four million Americans currently infected with HCV, but 75% of these individuals are unaware of their condition.[3] Additionally, the incidences of chronic infection are disproportionately higher in minority populations. For example, HCV is twice as prevalent among African Americans as among Caucasians.[4]

Chronic HCV can result in long-term health problems, and is the leading cause of liver cancer and the most common reason for liver transplantation in the United States.[5] Despite new treatment options that can cure the disease, the mortality rate associated with HCV has now surpassed HIV/AIDS with 15, 106 deaths attributable to the virus in 2007 alone.[6] These are devastating numbers and that is why it is so important for the CDC to take action and release new age-based screening guidelines that will more effectively address this serious issue. Age-based screening may help to identify these HCV-infected patients prior to the onset of liver failure or liver cancer, allowing them to be adequately monitored and potentially treated.[7] Furthermore, by increasing efforts to detect HCV infection, screening may assist in reducing further transmission of the virus.

Recent studies offer evidence that this is sound public policy that will also save lives. An article in The Annals of Internal Medicine, authored by the CDC, provides a glimpse into the type of effect new guidelines could have. The article found that compared with the status quo, age-based screening would identify 808,580 additional cases of chronic HCV infection and, when followed by treatment, would reduce the number of deaths by 121,000. If implemented, this could be a transformative development given the study’s other finding that deaths from HCV are forecasted to increase to 35,000 annually by 2030.[8]

A similar peer-reviewed article on the cost-effectiveness of age-based screening was recently published in Hepatology. The study’s authors found that compared to the current strategy of risk-based screening, birth cohort screening followed by treatment reduced deaths by 78,000 compared to risk-based screening at a cost of $37,700 per quality-adjusted life year (QALY) gained. The study also found that birth cohort screening resulted in 84,000 fewer cases of cirrhosis, 46,000 fewer cases of liver cancer, and 10,000 fewer liver transplants.[9]

Deaths attributable to HCV are increasing, leading to a sense of urgency around the need to take action. We believe that the lessons from the HIV epidemic are applicable to combating HCV, that hepatitis C deaths can be prevented through promoting testing, early diagnosis & linkage to care. The CDC is to be commended for identifying the magnitude of the problem, but it is now imperative that it take further steps towards helping the millions of patients unaware of their condition to get screened and linked to care.

New CDC draft guidelines could offer an effective approach to reaching populations where the disease is most prevalent. We once again offer our full support for new HCV age-based screening guidelines, and urge the CDC to finalize their recommendations as soon as possible.

Sincerely,

Cc: The Honorable Kathleen Sebelius, Secretary, Department of Health and Human Services
Cc: Dr. Howard Koh, Assistant Secretary for Health, Department of Health and Human Services

Source

CROI 2012: Results from Investigational Studies with VICTRELIS™ (boceprevir) Presented at the Conference on Retroviruses and Opportunistic Infections to Understand Potential Use in Patients Coinfected with Chronic Hepatitis C and HIV-1

SEATTLE, March 6, 2012 – Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from two different investigational studies conducted to better understand the potential use of VICTRELIS^™ (boceprevir), the company’s oral HCV NS3/4A protease inhibitor, in treating patients coinfected with chronic hepatitis C virus (HCV) and HIV-1. These data are being presented for the first time today at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Results were presented from a 12-week post treatment interim analysis of a Phase IIb clinical study evaluating the investigational use of VICTRELIS in combination with peginterferon alfa-2b and ribavirin for the treatment of chronic HCV genotype 1 infection in adult patients coinfected with HIV-1 (n=100). In the study, a higher percentage of patients receiving VICTRELIS in combination with peginterferon alfa-2b and ribavirin had undetectable hepatitis C virus (HCV-RNA) 12 weeks after treatment ended (sustained virologic response-12¹ or SVR-12) than patients receiving peginterferon alfa-2b and ribavirin alone.

Additionally, Merck announced results as part of a late-breaker poster session [Poster #771] from a pharmacokinetic study evaluating drug interactions between VICTRELIS and ritonavir-boosted HIV protease inhibitors in 39 healthy volunteers. In this study, concomitant administration of VICTRELIS with ritonavir (Norvir^®) in combination with atazanavir (Reyataz^®) or darunavir (Prezista^®), or with lopinavir/ritonavir (Kaletra^®) resulted in reduced exposures of the HIV medicines and VICTRELIS. These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when co-administered. Merck does not recommend the co-administration of VICTRELIS and ritonavir-boosted HIV protease inhibitors.

"In light of the differing results in these data sets, Merck recognizes it is important to continue to study VICTRELIS in combination therapy in this difficult-to-treat patient population," said Eliav Barr, M.D., vice president, Project Leadership and Management, Infectious Diseases, Merck Research Laboratories. "Our collaborative studies with the French National Agency for Research on AIDS and Viral Hepatitis² (ANRS) and the AIDS Clinical Trial Group (ACTG), which is funded by the U.S. National Institute of Allergy and Infectious Diseases, will provide greater insight into the potential role of VICTRELIS in treating patients with chronic HCV genotype 1 infection who are coinfected with HIV-1."

Indications and usage for VICTRELIS
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (P/R), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to peginterferon alfa and ribavirin therapy.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alfa or ribavirin has not been established in patients coinfected with HIV and HCV.

Interim SVR-12 Results from Phase IIb HCV-HIV Coinfection Study
One hundred (100) adult patients with previously untreated HCV genotype 1 infection, on an optimized antiretroviral regimen and with stable HIV-1 disease (HIV-RNA less than 50 copies/mL; CD4 cell counts equal to or greater than 200 cells/mm³) were randomized into the study. Two patients randomized to the treatment arm receiving VICTRELIS in combination with peginterferon alfa-2b (P) and ribavirin (R) did not receive VICTRELIS. Thus, the interim analysis was based on 98 patients who received at least one dose of study drug: 64 patients in the arm receiving VICTRELIS plus PR, and 34 patients in the control arm receiving PR alone. All patients treated in the study received a 4-week lead-in with PR alone followed by VICTRELIS plus PR or placebo plus PR for 44 weeks, for a total treatment duration of 48 weeks. Preliminary 24-week on-treatment data from this study were presented at the Infectious Diseases Society of America annual meeting in October 2011. Final study completion will be at week 72, or 24 weeks after the end of all treatment.

The interim analysis showed that 60.7 percent (n=37/61) of patients receiving VICTRELIS in combination with PR achieved SVR-12 compared to 26.5 percent (n=9/34) of patients receiving PR alone, a treatment difference of 34.2 percent. Three (3) patients in the VICTRELIS plus PR arm had not reached 12 weeks post treatment and were excluded.

Three (3) patients in treatment arms receiving VICTRELIS plus PR and four (4) patients in the PR control arm experienced HIV breakthrough (HIV viral load greater than 50 copies/mL at two consecutive visits). Preliminary safety data for VICTRELIS in combination therapy in HCV/HIV-1 coinfected patients demonstrated a profile similar to that previously observed in patients with HCV mono-infection.

The most common clinical adverse events with a difference of equal to or greater than 10 percent for the treatment arm receiving VICTRELIS plus PR compared to the PR control arm, respectively, were: anemia (41 vs. 26 percent), pyrexia (fever) (36 vs. 21 percent), asthenia (weakness) (34 v. 24 percent), decreased appetite (34 vs.18 percent), diarrhea (28 v. 18 percent), dysgeusia (bad taste) (28 vs. 15 percent), vomiting (28 vs. 15 percent), flu-like illness (25 v. 38 percent) and neutropenia (19 vs. 6 percent). Serious clinical adverse events occurred in 17 percent and 21 percent of patients in the two treatment arms, respectively. Dose modification for any study drug due to a clinical adverse event occurred in 28 percent and 24 percent of patients, respectively, and study discontinuation due to a clinical adverse event occurred in 20 percent and 9 percent of patients, respectively.

About the Phase IIb coinfection study
The primary objective of this ongoing randomized, multicenter, double-blinded Phase IIb study is to compare the efficacy of 800 mg of VICTRELIS three times daily in combination with peginterferon alfa-2b (P) 1.5 mcg/kg weekly plus ribavirin (R) 600 to 1,400 mg/daily to therapy with PR alone in adult patients coinfected with chronic HCV genotype 1 and HIV-1. Patients were randomized in a 2:1 ratio to the treatment arm with VICTRELIS plus PR or the PR control arm, respectively. Patients were stratified by cirrhosis (yes/no) and baseline HCV-RNA (less than 800,000 IU/mL vs. equal to or greater than 800,000 IU/mL). The majority of patients were non-cirrhotic (95 percent), white (82 percent) and male (69 percent), with a median age of about 43 years. Most patients had high HCV-RNA (88 percent) at baseline and HCV genotype 1a infection (65 percent).

Antiretroviral regimens for HIV-1 that included non-nucleoside reverse transcriptase inhibitors (NNRTIs), or zidovudine, stavudine or didanosine were not permitted. Ritonavir-boosted HIV protease inhibitors could be included in antiretroviral regimens for HIV-1. Patients with detectable HCV-RNA and less than a 2 log HCV-RNA decline at treatment week 12 or detectable HCV-RNA at treatment week 24 were considered treatment failures and discontinued all HCV treatment.

Primary pharmacokinetic drug interaction study results
The study was a single-center, three-arm, open-label, drug-interaction study in 39 healthy adults. Patients received 800 mg of VICTRELIS three times daily on Days 1-6. Following a 4-day "washout" period, patients received either 300 mg of atazanavir/100 mg of ritonavir once daily, 400 mg of lopinavir/100mg of ritonavir twice daily, or 600 mg of darunavir/100 mg of ritonvair twice daily on Days 10-31. From Days 25-31, patients also received 800 mg of VICTRELIS three times daily. Blood samples were collected for the pharmacokinetic assessment of the HIV medicines and VICTRELIS.

In the study, co-administration of VICTRELIS reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59 percent, respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were observed in AUC and Cmax of atazanavir, lopinavirand darunavir. Co-administration of ritonavir-boosted atazanavir with VICTRELIS did not alter the exposure of VICTRELIS, but co-administration of VICTRELIS with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the exposure of VICTRELIS by 45 and 32 percent, respectively. These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when co-administered.

Important safety information about VICTRELIS
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia – The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia
(45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

# # #

¹ SVR-12, the primary endpoint of the interim analysis, is defined as achievement of undetectable HCV-RNA at the 12 week post-treatment visit.

² ANRS HC27 BOCEPREVIR pilot study; clinicaltrials.gov identifier: NCT01335529.

VICTRELIS^™ is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Norvir^®, Reyataz^®, Prezista^® and Kaletra^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

Source

CROI 2012: Telaprevir sustained high response rates in treatment-naive HIV patients

Posted on InfectiousDiseaseNews.com March 6, 2012

SEATTLE — Significantly higher response rates were observed with telaprevir combined with peginterferon alfa and ribavirin compared with placebo for the treatment of chronic hepatitis C virus genotype-1 infection in treatment-naive HIV patients.

Douglas T. Dieterich, MD, professor of medicine in the division of hepatology at Mount Sinai School of Medicine in New York, presented findings from a 24-week interim analysis of patients assigned telaprevir (Incivek, Vertex Pharmaceuticals).

“The numbers are impressive — 74% for treatment arm vs. 45% in the control arm,” Dieterich said during a press conference today. “This is a huge leap forward in treatment for HCV and HIV patients.”

Patients were grouped into the following treatment regimens:

• Part A: Patients received no concurrent antiretroviral therapy.
• Part B: Patients were on ART and also an efavirenz-based regimen or on an atazanavir plus ritonavir-based regimen.

Of the 62 patients included in the study, 44 reached week 24 of treatment and are, therefore, included in the current analysis. The mean age of the patients was 46 years; 88% male, and 27% black. Subtype 1a was confirmed in 68% and cirrhosis in 3.3%.

Although CD4 cell count percentage remained unchanged by week 24, absolute CD4 cell counts decreased overall.

At week 24, undetectable HCV RNA levels occurred in 86% of patients assigned treatment and no ART vs. 33% among those assigned placebo; in 75% of patients assigned to treatment who were also on an ART plus efavirenz-based regimen vs. 50% of those assigned placebo; and in 67% of patients assigned to treatment who were also on ART plus atazanavir/ritonavir-based regimen vs. 75% of those assigned placebo.

One patient in the efavirenz-based regimen group and one patient in the atazanavir/ritonavir group achieved HCV RNA breakthrough on telaprevir, according to the researchers.

Compared with placebo, 10% or more of patients assigned to treatment groups experienced vomiting, abdominal pain, nausea, dizziness, depression and pruritus. Both bilirubinemia and hyperbilirubinemia were more common among patients in the atazanavir/ritonavir group.

For more information:

• Dieterich D. #46. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle.

Disclosures: The researchers report no relevant financial disclosures.

Perspective

There is a lot of exciting work on hepatitis being presented at CROI. This is the first time that we will have data on cure rates in HIV/HCV coinfected persons treated with new protease inhibitors; a few first-ever in man releases of data.

Source

CROI 2012: Boceprevir regimen led to high rates of undetectable HCV RNA in HCV/HIV

Posted on InfectiousDiseaseNews.com March 6, 2012

SEATTLE — A boceprevir plus pegylated interferon and ribavirin combination resulted in significantly high rates of undetectable hepatitis C virus RNA at weeks 4, 8, 12, 24 and 48 in patients coinfected with hepatitis C virus genotype-1 and HIV.

“The [sustained virological response] 12 data being presented today is an endpoint that is currently being determined by regulatory authorities to represent a solid sustained virologic response metric,” Mark Sulkowski, MD, of Johns Hopkins University School of Medicine, said during the meeting. “Our data suggest that boceprevir plus pegylated interferon and ribavirin had a sustained virologic response rate of 60.7%, with three patients negative at 4 weeks.”

From November 2009 to December 2010, patients were randomly assigned in a 2:1 fashion to 1.5 mcg/week pegylated interferon plus 600 mg/day to 1,400 mg/day ribavirin and 800 mg boceprevir (Victrelis, Merck) three-times daily (n=64) or to placebo plus pegylated interferon and ribavirin (n=34). The median age of the patients was 43 years; 69% male, and 82% white.

Treatment duration was 44 weeks. Primary outcome measure was an achievement of SVR (undetectable plasma HCV RNA) by week 24 of treatment.

Overall, 61% of patients assigned to the boceprevir arm completed treatment vs. 32% of those assigned placebo by week 48. Compared with an undetectable HCV RNA rate of 29.4% in the placebo arm, the rate was 63.9% in the boceprevir arm.

Treatment failure occurred in 9% of those assigned boceprevir vs. 53% of those assigned placebo. Patients included in the boceprevir arm were more likely to experience adverse events, including a decreased appetite, anemia and neutropenia. HIV RNA virologic failure occurred in two patients in the placebo arm and in three patients in the boceprevir arm.

“Our data suggest that the boceprevir regimen was well tolerated in these patients with HCV/HIV coinfection,” Sulkowski said.

For more information:

• Sulkowski M. #47. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle.

Disclosure: The researchers report no relevant financial disclosures.

Source

Scientists Develop Better Test for Identifying Hepatitis Type

06/03/2012 20:22:00

Madison, Wisconsin - Hepatitis C virus (HCV) comes in many types and subtypes, and knowing these specifics helps determine how long a patient should be treated, doses and types of medication needed and how well the patient will do on treatment.

Scientists in the Molecular Diagnostics Laboratory at UW Hospital and Clinics are now providing doctors and patients much more information about virus type and subtype than before. No other hospital or laboratory in the country routinely offers this level of detail.

"We hope this new information will help clinicians make better judgments about the best course of treatment for each patient," says Dr. William Rehrauer, head of the Molecular Diagnostics Laboratory and assistant professor of pathology and laboratory medicine at UW School of Medicine and Public Health (SMPH).

Rehrauer and colleagues have developed a test that more accurately defines HCV type and subtype than before by looking at multiple locations on the viral genome instead of just one, as was done in the past.

In the process, the scientists also discovered, to their great surprise, a new type of hepatitis C virus never before seen in the United States. The strain, similar to one found in Russia, is probably very rare in North America, they say.

HCV is the most common chronic blood-borne disease in the United States, infecting approximately 3.2 million people. The World Health Organization estimates that 130 million to 170 million people worldwide carry the virus. The infection can cause several kinds of liver diseases, including cirrhosis and cancer.

The hepatitis C virus is divided into six or seven genotypes, or types, each defined by specific genetic information. Each type is further divided into many subtypes, with new types and subtypes being identified regularly. Type 1, subtype a (1a) is by far the most common form of hepatitis C virus in patients in the United States.

Genotype and subtype can significantly influence how, and even if, a patient will be treated.

"Patients with genotype1 do not respond all that well to standard therapies of alpha interferon or the combination of alpha interferon and ribavirin," says Dr. Robert Striker, a UW Hospital infectious disease specialist who sees many hepatitis C virus-infected patients.

The newest drugs have much better response rates but are expensive and produce side effects.

"They work well for genotype 1 viruses in general," says Striker. "While they do work for 1as, the effectiveness is not as high as for 1bs, where they work great."

Called protease inhibitors, the new drugs specifically target the area in the center of the virus genome called the protease, which is responsible for important steps in virus replication.

Genotype is determined by analyzing sequences in the viral genome. Laboratory technologists typically use commercially available tests that focus on a sequence at one end of the hepatitis C virus genome, referred to as 5 prime.

"The 5 prime tests don't provide much information on newly identified types and subtypes," says Striker, a professor of medical microbiology and immunology at the SMPH. "They don't tell you how the protease will respond to treatment."

Rehrauer and his team set out to provide additional sequence information that could be used to better guide treatment. Scientists in the Molecular Diagnostics Laboratory, a division of the hospital's clinical laboratories, are experts at doing this.

Dr. Molly Accola, who leads the efforts, scanned the scientific literature and viral sequence databases for an additional region to test. She found a good candidate at the opposite end of the HCV genome, called 3 prime, which could provide a distinguishing sequence that was better than 5 prime at identifying HCV genotype and subtype.

Accola developed a method to test 3 prime and validated it against the old test. She found that the combination of both regions was more effective at identifying hepatitis C virus types and subtypes than the historical 5 prime sequence alone. The lab began using the new test clinically about two years ago.

"Now, not only do we have a more informative region to test, we can add it to the old information," says Accola. "The combination is much richer in data."

With a molecular profile of the two ends of the genome in hand, Striker's team, which does genomic research on HCV, filled in the rest of the sequence.

Over a year, the scientists analyzed 133 samples with their two-site method and unexpectedly found one patient with type 2b genetic information in the 5 prime area and type 1a in the 3 prime area-a new kind of hepatitis C virus. Such a combined form of two related viruses--in this case a 2b/1a--is called a recombinant.

"HCV-infected patients are frequently exposed to multiple forms of the virus, but very few recombinants between two HCV genotyes have been found," says Rehrauer.

The place where 2b/1a combined--the cross-over point--was at the center of the genome, next to the hepatitis C virus protease where the new drugs work.

"While the 2b/1a recombinant finding was very interesting, the real value of testing the viral genome in two places, in my opinion, is that it lets us be more confident about the subtype determination," Striker says.

Over time, with new medications expected on the market in coming years, such details will matter more and more, he adds.

"The complexity of these viruses has not been appreciated," Striker says.

The recombinant work was published in the Virology Journal.

University of Wisconsin School of Medicine and Public Health

Source

More patients relapse in Gilead hepatitis C trial

By Deena Beasley

Tue Mar 6, 2012 5:17pm EST

(Reuters) - Two more patients in a 10-patient segment of a mid-stage trial testing Gilead Sciences Inc's experimental hepatitis C drug GS-7977 had the virus return within four weeks of treatment, researchers said on Tuesday.

The company, which recently paid nearly $11 billion to acquire the drug and its developer, Pharmasset, said last month that six out of 10 patients with a prior "null response" to standard hepatitis C therapy saw the virus return within four weeks of treatment with a combination of GS-7977 and the antiviral drug ribavirin.

The latest results from the mid-stage trial bring to eight the number of patients who have relapsed.

One patient has not reached the four-week point and the other showed a response to the drug, Dr. Edward Gane from New Zealand's Auckland City Hospital and the study's lead investigator said here at the Conference on Retroviruses and Opportunistic Infections.

The trial segment he updated involved patients infected with genotype 1 hepatitis C -- the most common, but also the most difficult to treat, subset of the disease.

"The majority of null responders have relapsed post treatment," Dr. Gane said, adding that such patients will likely need either a longer duration of therapy or combination treatment with other direct-acting antiviral agents.

He said the relapsed patients will be offered a "rescue protocol" in the form of another trial of GS-7977 in combination with a different experimental drug.

Shares of Gilead have dropped 18 percent since the company's announcement of the trial results, which suggested that an all-oral treatment for hepatitis C may be further away than many had hoped.

Dr. Gane said ongoing pivotal-stage trials of GS-7977 "should establish that interferon-free treatment is not a dream. It's a reality that should be here within the next five years."

Current hepatitis C drug regimens require injections of interferon, which causes severe flu-like symptoms and cannot be tolerated by some patients.

GS-7977 is designed to block an enzyme essential to the replication of the hepatitis C virus. It is one of a new class of treatments designed to be given without injections of interferon, which helps boost the body's immune system but can also cause debilitating flu-like side effects.

Gilead has said it expects to announce at the end of this month results from a mid-stage trial of GS-7977 in previously untreated hepatitis C patients.

Hepatitis C is a liver-destroying disease that affects some 170 million people worldwide. Untreated, it can lead to cirrhosis, liver cancer and the need for a liver transplant.

Source

Vertex, Merck hepatitis drugs work in HIV patients

By Deena Beasley

SEATTLE | Tue Mar 6, 2012 3:10pm EST

SEATTLE (Reuters) - Rival hepatitis C drugs from Merck & Co Inc and Vertex Pharmaceuticals Inc are effective in patients also infected with HIV, the virus that causes AIDS, according to data released on Tuesday.

The Vertex drug had the more impressive results, the data showed.

The results from midstage trials follow notification last month from U.S. regulators and Merck that use of the company's Victrelis drug in such "co-infected" patients could lessen the effectiveness of some medicines used to treat patients infected with the human immunodeficiency virus, or HIV.

Those findings involved "boosted" HIV protease inhibitors.

Both Victrelis, also known as boceprevir, and Vertex's Incivek, or telaprevir, are protease inhibitors designed to block an enzyme that the hepatitis C virus requires to replicate.

Since key HIV drugs are also protease inhibitors, which use the same pathway as the new hepatitis C drugs, there is a potential for drug interaction, said Dr. Douglas Dietrich, professor of medicine at New York's Mount Sinai School of Medicine and lead investigator on the Incivek trial.

He said 74 percent of trial patients treated with Incivek followed by the standard regimen of interferon and ribavirin were free of the hepatitis C virus, or HCV, 12 weeks after ending treatment, compared with 45 percent of patients given interferon and ribavirin alone.

There were no instances of a rebound of HIV for patients in the Incivek trial. Side effects seen more frequently with the drug were itching, headache, nausea, rash, fever and depression. No cases of severe rash were reported.

Merck's Phase II trial found that 60.7 percent of patients treated with Victrelis and the standard hepatitis C therapy were free of HCV 12 weeks after treatment, compared with 26.5 percent of patients treated only with interferon and ribavirin.

Three patients on Victrelis and four in the control group had an increase in HIV.

"These Phase II trials, albeit small in size, demonstrate significant improvement" over treatment with interferon and ribavirin alone, said Dr. Mark Sulkowski of Johns Hopkins University School of Medicine in Baltimore, the lead investigator on the Victrelis trial.

The trial results were reported in Seattle at the Conference on Retroviruses and Opportunistic Infections on Tuesday.

"The drugs that are used to treat HIV have certain metabolic effects," said Eliav Barr, Merck's vice president, infectious diseases. "You have to be careful not to mess with those drug levels."

Barr estimated that between 15 percent and 20 percent of U.S. HIV patients are also infected with HCV, a liver-destroying virus which has come to be a leading cause of death for HIV patients.

In the first half of this year, Merck plans to start a larger, pivotal trial of Victrelis in a broader range of HIV patients, with those results expected a couple of years later, Barr said. The company is also conducting a number of drug interaction studies.

Vertex said it is currently enrolling patients in a Phase III study of Incivek combination regimens in people also infected with HCV and HIV.

According to the U.S. Centers for Disease Control and Prevention, 1.2 million Americans have HIV, and one in five adults with HIV do not know they are infected.

Vertex said laboratory studies of Incivek and HIV protease inhibitors had found no harmful effects on antiviral activity when combined with HIV medicines Agenerase (amprenavir) from GlaxoSmithKline Plc, Prezista (darunavir) from Johnson & Johnson's Janssen unit and lopinavir. Slight antagonistic effects were observed on the antiviral activity of Reyataz (atazanavir) from Bristol-Myers Squibb Co.

Merck said last month that a study among healthy volunteers showed Victrelis as lessening the effect of a combination of HIV drug Norvir (ritonavir) from Abbott Laboratories Inc with one of three other anti-HIV pills: Reyataz, Prezista and Abbott's Kaletra (lopinavir/ritonavir).

In afternoon trading, Vertex shares were down 77 cents or 1.9 percent to $39.63 and Merck shares were down $1.04 or 2.7 percent to $37.41 As the broad market fell. Merck said earlier its first-quarter earnings would trail Wall Street estimates.

(Editing by Michele Gershberg and Gerald E. McCormick)

Source

Also See:

CROI 2012: Results from Investigational Studies with VICTRELIS™ (boceprevir) Presented at the Conference on Retroviruses and Opportunistic Infections to Understand Potential Use in Patients Coinfected with Chronic Hepatitis C and HIV-1

CROI 2012: Data from Phase 2 Study of an INCIVEK® Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12)

Biliary Atresia Linked to Food Allergy Post Liver Transplant

Kate Johnson

March 6, 2012 (Orlando, Florida) — The reason pediatric liver transplant patients have high rates of new-onset food allergy might be hidden in their indication for transplant, Japanese researchers reported here at the American Academy of Allergy, Asthma and Immunology 2012 Annual Meeting.

Patients who require transplantation for biliary atresia have higher rates of new-onset food allergy than patients with other indications for liver transplantation, said Tetsuo Shoda, MD, from the National Center for Child Health and Development in Tokyo, Japan.

In particular, those with a history of intestinal surgery had a 6-fold increase in new-onset food allergy, compared with those with no history, he explained.

The phenomenon of new-onset food allergy after transplantation is seen predominantly in liver recipients; its prevalence has been estimated to be between 10% and 20%, Dr. Shoda told Medscape Medical News.

Findings from previous studies have suggested that immunosuppressant medications such as tacrolimus increase intestinal permeability and trigger allergy, Dr. Shoda said. But this does not explain why new-onset food allergy is more common in liver recipients than in recipients of other organs.

He and his colleagues retrospectively reviewed the charts of 123 children who underwent living-donor liver transplantation at his institution from November 2005 to May 2010. Median age at the time of transplantation was 8 months.

Children received standard doses of tacrolimus and low-dose steroids for initial immunosuppression.

There was a 90% patient survival rate, and therefore 105 patients for analysis.

The indication for liver transplantation was biliary atresia in 44% of these patients, congenital metabolic disease in 25%, fulminant hepatic failure in 18%, liver cirrhosis in 5%, congenital absence of the portal vein in 3%, congenital hepatic fibrosis in 2%, and hepatic tumor in 1%.

Over a median of 10.5 months, 15 patients developed new-onset food allergy after liver transplantation, for a cumulative incidence of 14.3%. The majority of allergic reactions (86%) were urticaria or angioedema, but 47% were gastrointestinal symptoms.

The most common allergen was egg (53%), and 10 patients reacted to more than 2 food allergens. The median total immunoglobulin E level was 438.5 IU/mL.

There was a significant trend toward higher rates of food allergy in patients with biliary atresia than in those without (P = .012).

In the final analysis, the strongest risk factors for the development of new-onset food allergy were being younger than 12 months at the time of surgery (odds ratio [OR], 11.78; P = .003) and having a history of intestinal surgery (OR, 6.69; P = .009).

"Biliary atresia patients usually have had previous intra-abdominal surgeries, which might increase their risk for food problems, causing easier sensitization; after that, the tacrolimus is added," said Dr. Shoda.

Dr. Shoda has disclosed no relevant financial relationships.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2012 Annual Meeting: Abstract 131. Presented March 3, 2012.

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Hepatitis C Patients Relapse on Gilead’s Experimental Medicine in Study

By Ryan Flinn - Mar 6, 2012 11:46 AM ET

Gilead Sciences Inc. (GILD), which paid $10.8 billion to buy Pharmasset Inc. (VRUS) for its hepatitis C pill, said the number of patients who relapsed after they stopped taking the treatment has increased.

Eight of nine patients with the most-common form of the virus in the U.S. had a relapse within four weeks after stopping use of the medicine, GS-7977, and ribavirin, according to research presented today at the Conference on Retroviruses and Opportunistic Infections in Seattle. The patients in the study weren’t helped by prior therapies.

Gilead announced last month that six patients relapsed, sending shares down the most in 11 years. A longer duration or combination with other therapies may help these patients, said researcher Edward Gane, deputy director and hepatologist of the New Zealand Liver Transplant Unit at Auckland City Hospital.

“It’s clear the treatment options for this very difficult to treat group will either be longer duration of 7977 plus ribavirin, or alternatively, the addition of another direct acting antiviral,” Gane said at the meeting.

Last year, Pharmasset reported data on PSI-7977 showing that 40 patients with genotypes 2 and 3 who received the therapy were responsive after 12 weeks. About half the patients had been followed up to 24 weeks, and they were all cured.

Hepatitis C is a viral infection that can lead to swelling of the liver. As many as 170 million people globally carry the virus, which is transmitted through exposure to infected blood, and more than 350,000 die from related illnesses each year, according to the Geneva-based World Health Organization.

Gilead declined 1.4 percent to $45.59 at 11:41 a.m. New York time.

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

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

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One in Four U.S. HIV Patients Don't Stay in Care, Penn Study Shows

Baligh Yehia

Media Contact:Holly Auer | holly.auer@uphs.upenn.edu | 215-349-5659

March 5, 2012

Only about 75 percent of HIV/AIDS patients in the United States remain in care consistently, according to new research from the Perelman School of Medicine at the University of Pennsylvania published online this week in AIDS. The study of patients across the United States is the first to provide a comprehensive national estimate of HIV care retention and information about patients who are most likely to continue their treatment over time.
"Helping patients with HIV stay in care is a key way to reduce their chances of getting sick from their disease and prevent the spread of HIV in the community. Our findings show that too many patients are falling through the cracks," says the study's lead author, Baligh R. Yehia, MD, a fellow in the division of Infectious Disease and the Health Policy Research Program at Penn Medicine. "The benefits of keeping patients in care are clear both for patients and the community at large, and it may even result in decreased health care costs by preventing unnecessary hospitalization for an acute illness."

The researchers studied 17,425 adult patients cared for at 12 clinics within the HIV Research Network, a consortium that cares for HIV-infected patients across the nation, between 2001 and 2008. Just 42 percent of patients studied had what researchers defined as "no gap" in treatment — intervals of no more than six months in between outpatient visits — over the timeframe studied, while 31 percent had one or more seven- to 12-month gaps in care. Twenty-eight percent appeared to have gone without care for more than a year on one or more occasions. Since there is no gold standard on the best way to measure retention in care, the team used three different measures of retention to examine each patient’s visit record.

Click here to view the full release.

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Diet Can Cut Weight Tied to HIV Treatment

By Michael Smith, North American Correspondent, MedPage Today

Published: March 05, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

The right diet can prevent the weight gain, fat changes, and dyslipidemia associated with treatment for HIV, researchers reported.

In a prospective randomized trial, patients who followed a diet aimed at reducing total and low-density lipoprotein cholesterol avoided the changes often linked to highly active anti-retroviral therapy (HAART), according to Jorge Ribeiro, MD, SCD, and colleagues at the Hospital de Clínicas de Porto Alegre in Porto Alegre, Brazil.

After a year of follow-up, just 21% of those in the diet group had a lipid profile compatible with dyslipidemia, compared with 68% of the control group, Ribeiro and colleagues reported in the March 13 issue of the Journal of the American College of Cardiology.

The study is the first to try to isolate the effect of diet in people just starting HAART, the researchers said. Previous controlled studies, looking at diet and exercise together in people already on treatment, found little benefit, they noted.

"These findings indicate that nutritional intervention should be considered for all patients who start HAART," the researchers concluded.

Ribeiro and colleagues analyzed outcomes for 81 patients who started treatment from March 2004 to April 2006. All were asked about their current diet during assessment for the study, and after entry all were given dietary counseling.

Those in the diet group, however, were given more detailed instruction, including individualized diets with 25% of the total calories in lipids, 15% in proteins, and 60% in carbohydrates, including 30 g/day of fiber and 200 mg dietary cholesterol.

They also got nutritional guidance, based on the National Cholesterol Education Program, from a registered dietitian four times during the year-long trial.

Analysis showed:

• Nine of the 38 patients analyzed in the diet group had alterations in their lipid profile compatible with dyslipidemia, compared with 26 of the 43 in the control group.
• The diet reduced the percentage of calories from fat from 31% on average to 21%, but there was no change among controls.
• Total cholesterol was unchanged in the diet group, but rose from 151 to 190 mg/dL among controls.
• Similarly, low-density lipoprotein cholesterol levels were unchanged among those on the diet, but increased by a mean of 85 to 106 mg/dL among controls.
• Plasma triglycerides were reduced by diet from 135 to 101 mg/dL on average, but increased from 134 to 160 mg/dL among controls.
• Body mass index was stable in the diet group, but increased among those in the control group, from 23.2 to 26.2, by the end of the trial.
• All the differences were significant at P<0.001.

The researchers cautioned that the study did not have an exercise component, so the findings don't eliminate the possibility that a broader intervention might have different results.

The lipid changes that were observed are clinically relevant, according to James Stein, MD, of the University of Wisconsin School of Medicine and Public Health in Madison, Wisc.

The 15% difference between the groups in total cholesterol "would be expected" to yield a long-term reduction in the risk of cardiovascular disease of about 25% to 30%, Stein said in an accompanying editorial.

But he noted that all participants at the start of the study consumed markedly more total cholesterol than a typical American, which might have "accentuated the reductions" among those who started the diet.

Nonetheless, he argued, the findings are "an important addition to the literature and re-emphasize that dietary interventions can be as effective as low-dose statin therapy for preventing and treating dyslipidemia associated with HAART."

The study had support from the Brazilian National Council for Scientific and Technological Development, the Rio Grande do Sul Research Foundation, and the Fund for Incentive in Research of the Hospital de Clínicas de Porto Alegre.

The journal said the authors reported that they have no relevant relationships to disclose.

The journal said Stein reported being on data and safety monitoring committees for Abbott, Lilly, and Takeda.

Primary source: Journal of the American College of Cardiology
Source reference:
Lazzaretti RK, et al "Dietary intervention prevents dyslipidemia associated with highly active antiretroviral therapy in human immunodeficiency virus type 1–infected individuals: a randomized trial" J Am Coll Cardiol 2012; 59: 979–88.

Additional source: Journal of the American College of Cardiology
Source reference:
Stein JH "Nutritional therapy to prevent dyslipidemia in patients starting antiretroviral therapy for human immunodeficiency virus" J Am Coll Cardiol 2012; 59: 989-990.

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What Does Your State's HIV Disclosure Law Require?

By Andrew Chow, JD at FindLaw.com

Mon Mar 5, 2012 1:19am EST

A former pro wrestler's recent conviction for not telling his sexual partners he was HIV-positive raises questions about state HIV disclosure laws. How common are these laws, and what do they require?

A jury convicted Andre Davis, 29, who once wrestled under the name "Gangsta of Love," under Ohio's HIV disclosure law. Davis was sentenced to 32 years in prison.

Ohio is among at least 24 states that have enacted HIV disclosure laws, according to a 2008 study in The Journal of Law, Medicine & Ethics. Two broad types of laws exist, the study found:

State HIV disclosure laws can be classified as either "strict" or "flexible," according to the 2008 study. Strict laws, such as Ohio's, require people to disclose their HIV status to sexual partners prior to any type of sexual contact.

Under "strict" HIV disclosure laws, sexual contact includes intercourse, oral sex, and penetration by any object. Conviction usually does not require the emission of semen, or the infection of a victim.

Along with Ohio, laws in Arkansas, Michigan, and New Jersey also fall into the "strict" category, the study found.

Compare those laws with so-called flexible laws regarding HIV disclosure. California's law is the "least restrictive," the study found: For perpetrators to be convicted, they must engage in unprotected intercourse and infect their partner with HIV.

Under "flexible" disclosure laws, people who are HIV positive can legally use condoms and perform sex acts other than intercourse, without having to disclose their HIV status.

So which type of law is more effective? It's not clear, but either type is better than having no law, the study concluded. Flexible laws may actually produce a greater reduction in the risk of infection, because of the "safer sex" options available to HIV-positive sexual partners, the authors said.

Aside from the states mentioned above, others with HIV disclosure laws include Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kansas, Louisiana, Maryland, Missouri, Nevada, North Dakota, Oklahoma, South Carolina, South Dakota, Tennessee, Virginia, and Washington state.

Related Resources:

• Preventing HIV Transmission via HIV Exposure Laws: Applying Logic and Mathematical Modeling to Compare Statutory Approaches to Penalizing Undisclosed Exposure to HIV (The Journal of Law, Medicine & Ethics)
• Ex-Wrestler 'Gangsta of Love' Gets 32 Years for Having HIV Sex (FindLaw's Tarnished Twenty)
• HIV Disclosure Laws (eHow)
• State Criminal Laws (FindLaw)
• Browse Criminal Defense Lawyers by Location (FindLaw)

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Researchers Pursue Promising New Approach in the Treatment of Liver Cancer

Released:3/5/2012 1:40 PM EST
Embargo expired: 3/5/2012 3:00 PM EST
Source:Boston University College of Arts & Sciences

Newswise — Hepatocellular carcinoma (HCC), or primary cancer of the liver, is the fifth most common cancer worldwide. Despite the prevalence of this disease, until now there has been no effective, systemic treatment. Thanks to a team of researchers in Boston University’s Departments of Biology and Chemistry, and the Program in Molecular Biology, Cell Biology, and Biochemistry, that may be about to change.

The BU research team and collaborators recently discovered a promising new protein target for chemotherapy in the treatment of liver cancer—the transcription factor LSF. (Transcription factors are regulatory proteins that bind genomic DNA near the start of genes, either promoting or inhibiting the transcription or copying of the gene.) LSF is found in high levels in the tumor tissue of patients with liver cancer and has been demonstrated to promote the development of cancer (oncogenesis) in studies using laboratory rodents.

Central to their findings, the BU scientists identified small molecules that effectively inhibit LSF cellular activity, which in turn slows the growth of the cancer. In particular, one such molecule, called Factor Quinolinone Inhibitor 1 (FQI1), derived from a lead compound, was found to inhibit the ability of LSF to bind DNA both in extracts (in vitro, as determined by electrophoretic mobility shift assays), and in cells. Consistent with inhibiting LSF activity, FQI1 also eliminates the ability of LSF to turn up transcription. FQI1 also demonstrates antiproliferative activity, or the ability to prevent or retard the growth of cells. While FQI1 quickly causes cell death in LSF-overexpressing cells, including liver cancer cells, healthy cells are unaffected by the treatment. This phenomenon has been called oncogene addiction, where tumor cells are “addicted” to the activity of an oncogenic factor for their survival, but normal cells can do without it. This is very encouraging for use of such compounds clinically.

Quantitative analysis of FQI1 (based on a concordant structure-activity relationship of a panel of 23 quinolinones) strongly suggests that its growth inhibitory activity focuses on a single biological target or family. This focus, coupled with the striking correlation between the concentrations required for antiproliferative activity and for inhibition of LSF transactivation indicates that LSF is that specific biological target of FQI1.

Building on the in vitro trials, the researchers tested the efficacy of FQI1 in inhibiting liver cancer tumor growth by injecting HCC cell lines into rodent models. FQI1 was observed to significantly inhibit tumor growth with no observable side effects (general tissue cytotoxicity). These dramatic findings support the further development of LSF inhibitors as a promising new chemotherapy treatment for liver cancer.

The team’s findings have been published in the article (Antiproliferative small molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma) in the Proceedings of the National Academy of Science (PNAS) (www.pnas.org/lookup/suppl/doi:10.1073/pnas.1121601109). The co-principal investigators are Ulla Hansen, Professor of Biology, and Scott Schaus, Associate Professor of Chemistry, Boston University.

Contributing authors are Trevor J. Grant, Girish Barot, Hang Gyeong Chin, Sarah Woodson, Jennifer Sherman, and Tracy Meehan, Department of Biology, Boston University; Joshua A. Bishop, Lisa M. Christadore, and John Kavouris, Department of Chemistry, Center for Chemical Methodology and Library Development at Boston University; Sriharsa Pradhan, New England BioLabs, Inc., Ipswich, MA; Ayesha Siddiq, Rachel Gredler, Xue-Ning Shen, and Devanand Sarkar, Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA; Laura A. Briggs and William H. Andrews, Sierra Sciences, LLC, Reno, NV; and Kevin Fitzgerald, Alnylam Pharmaceuticals, Inc., Cambridge, MA.

About Boston University—Founded in 1839, Boston University is an internationally recognized private research university with more than 30,000 students participating in undergraduate, graduate, and professional programs. As Boston University’s largest academic division, the College and Graduate School of Arts & Sciences is the heart of the BU experience with a global reach that enhances the University’s reputation for teaching and research.

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