March 7, 2012

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

31530

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

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

PR-Logo-Newswire

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

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

logo_Merck_no_be_well

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).

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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.

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