No Toxicity, Possible Cancer Benefit With Statins and HCC

Nick Mulcahy

May 08, 2013

In adults with hepatitis C virus (HCV) infection, statin use is associated with a significantly reduced risk for hepatocellular carcinoma (HCC), according to a large observational study from Taiwan.

"Statin use is a convenient and acceptable adjuvant strategy for preventing HCC in HCV-infected patients," conclude the authors, led by Yu-Tse Tsan, MD, from the National Taiwan University in Taipei.

The virus increases the risk of developing liver cancer 15- to 20-fold, they point out.

This is the first large population-based study to look at statin use and the risk for HCC, Dr. Tsan and colleagues note. Their results, from more than 260,000 HCV-infected patients, were published in April 20 in the Journal of Clinical Oncology.

Results from previous observational studies and randomized controlled trials of statins have been mixed on their protective effect for HCC, they say.

This is the first study to document a dose–response relation between statin use and the risk for HCC in HCV-infected patients. The authors found that, over a 12-month period, the greater the daily statin use, the greater the reduction in cancer risk.

When statin use was compared with no use, for an annual cumulative defined daily dose (cDDD) of 28 to 89, the adjusted hazard ratio was 0.66; for a cDDD of 90 to 180, it was 0.47; and for a cDDD above 180, it was 0.33.

The risks were calculated after controlling for a variety of confounders (age, sex, income, urbanization, liver cirrhosis, and diabetes) in 35,023 statin users and 225,841 nonusers.

In an accompanying editorial, Abby Siegel, MD, from the Columbia University Medical Center in New York City, praises the results as "compelling evidence" for an association between statin use and a significantly lower risk for HCC..

But she does not agree that statins are ready for this clinical use. "It is too soon to recommend off-label use of statins for HCC prevention," she writes.

"We need better insight into where in the spectrum of liver disease statins might work best and the appropriate duration of treatment," Dr. Siegel adds.

Liver Toxicity

The biggest contribution of this study might be the evidence that statins are not toxic in HCV-infected patients, Dr. Siegel notes.

"There was no increase in hepatotoxicity seen with use of statins in patients with underlying HCV, which has been a concern about using these agents in patients with liver disease," she writes. In fact, the adjusted hazard ratios for myotoxicity and drug-induced liver injury were nonsignificant (1.08 and 1.30, respectively) for patients with 90 days of regular statin use.

With these results, "we can feel more confident that statins do not cause harm in patients with liver disease," she says.

Dr. Siegel is impressed with 2 other aspects of this study. "The results were statin specific, and were not seen with other lipid-lowering agents," she writes. In addition, the follow-up in this observational study was "relatively long, at just over 10 years." This is important because no association has been found between statin use and reduced risk for HCC in HCV-infected patients in randomized controlled trials, she notes. The implication of her comments is that, although randomized controlled trials are the gold standard for clinical evidence, they are not usually very long and therefore could miss a treatment effect.

Dr. Siegel begins her criticism of the study in a predictable place — saying that observational studies are "susceptible to bias."

Most notably, she says, because the differences between the user and nonuser groups are seen so quickly (after a cDDD of just 28 to 89), "one might suspect that other nonbiologic factors are playing a role."

Clinical trials of statins in this setting are needed, Dr. Siegel concludes. But they would be expensive to conduct because of the large numbers of patients that would be required. As a possible solution, she proposes the use of surrogate markers to better determine just where in the continuum of liver disease (leading to liver cancer) statins have an effect.

The study authors and Dr. Siegel have disclosed no relevant financial relationships.

J Clin Oncol. 2013;31:1514-1521 and 1499-1501. Abstract, Editorial

Source

Incident Hepatitis C Virus Infection in Men Who Have Sex With Men: A Prospective Cohort Analysis, 1984-2011

Clin Infect Dis. 2013 Apr 22. [Epub ahead of print]

Witt MD, Seaberg EC, Darilay A, Young S, Badri S, Rinaldo CR, Jacobson LP, Detels R, Thio CL.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.

Abstract

Background. Prospective characterization of hepatitis C virus (HCV) transmission in both human immunodeficiency virus (HIV)-infected and -uninfected men who have sex with men (MSM) over the entire HIV epidemic has not been comprehensively conducted. Methods. To determine the trends in and risk factors associated with incident HCV in MSM since 1984, 5310 HCV antibody (anti-HCV)-negative MSM in the Multicenter AIDS Cohort Study were prospectively followed during 1984-2011 for anti-HCV seroconversion. Results. During 55 343 person-years (PYs) of follow-up, there were 115 incident HCV infections (incidence rate, 2.08/1000 PYs) scattered throughout the study period. In a multivariable analysis with time-varying covariates, older age (incidence rate ratio [IRR], 1.40/10 years, P < .001), enrollment in the later (2001-2003) recruitment period (IRR, 3.80, P = .001), HIV infection (IRR, 5.98, P < .001), drinking >13 alcoholic drinks per week (IRR, 1.68, P < .001), hepatitis B surface antigen positivity (IRR, 1.68, P < .001), syphilis (IRR, 2.95, P < .001), and unprotected receptive anal intercourse with >1 male partner (IRR, 3.37, P < .001) were independently associated with incident HCV. Among HIV-infected subjects, every 100 cell/mm³ increase in CD4 count was associated with a 7% (P = .002) decrease in the HCV incidence rate up to a CD4 count of 500 cells/mm³, whereas there was no association with highly active antiretroviral therapy. Conclusions. The spread of HCV among both HIV-infected and -uninfected MSM in the United States has been ongoing since the beginning of the HIV epidemic. In HIV-infected men with <500 CD4⁺ T cells, the HCV incidence rate was inversely proportional to CD4 T-cell count.

Source

Study suggests only half of Americans with hepatitis C receive complete testing for the virus / CDC Telebriefing on Hepatitis C testing

Press Release

Embargoed Until: Tuesday, May 7, 1:30 PM EDT 2013,
Contact: National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
NCHHSTPMediaTeam@cdc.gov; 404-639-8895

Study suggests only half of Americans with hepatitis C receive complete testing for the virus

CDC reinforces need for appropriate follow-up testing for current infection

Only half of Americans identified as ever having had hepatitis C received follow-up testing showing that they were still infected, according to a Centers for Disease Control and Prevention analysis of data from a multi-area study published today in the CDC report Vital Signs.

“Many people who test positive on an initial hepatitis C test are not receiving the necessary follow-up test to know if their body has cleared the virus or if they are still infected,” said CDC Director Tom Frieden, M.D., M.P.H. “Complete testing is critical to ensure that those who are infected receive the care and treatment for hepatitis C that they need in order to prevent liver cancer and other serious and potentially deadly health consequences.”

Testing for hepatitis C includes a blood test, called an antibody test, to determine if an individual has ever been infected with the virus. For people with a positive antibody test result, a follow-up test – called an RNA test – should be given to determine whether they are still infected so they can get needed care and treatment.

A small number of people with antibody-positive tests will have cleared the infection on their own, but most people with hepatitis C (about 80 percent) remain infected and can go on to develop significant health problems.

For the Vital Signs study, researchers looked at data from eight areas across the nation funded by CDC to conduct enhanced surveillance for hepatitis C virus infection. Of the hepatitis C cases reported in these areas (i.e., those cases with antibody-positive results), only 51 percent of the cases also included a follow-up (RNA) test result that identified current infection. Without follow-up testing, the other half are likely unaware if they are currently infected and therefore cannot get appropriate medical care.

Data included in this analysis also underscore the severe impact of hepatitis C among baby boomers. In the eight areas studied, 67 percent of all reported cases of current infection were among those born from 1945 through 1965. Deaths among people with hepatitis C also were more common among those born during these years (accounting for 72 percent of all reported deaths).

“Hepatitis C has few noticeable symptoms, and left undiagnosed it threatens the health of far too many Americans – especially baby boomers,” said John Ward, M.D., director of CDC’s Division of Viral Hepatitis. “Identifying those who are currently infected is important because new effective treatments can cure the infection better than ever before, as well as eliminate the risk of transmission to others.”

Overall, approximately 3 million Americans are infected with hepatitis C and up to 3 out of 4 do not know they are infected. The vast majority of those affected are baby boomers, or those born from 1945 through 1965. Left untreated, hepatitis C can cause serious liver damage, including liver cancer. Hepatitis C is a leading cause of liver cancer and the most common indication for liver transplants. In fact, liver cancer is the fastest-rising cause of cancer-related death in the United States. Deaths from hepatitis C have nearly doubled over the past decade, now accounting for more than 15,000 deaths each year.

In light of increasing evidence that many patients are not receiving the follow-up test, as well as recent changes in testing technologies and the availability of new effective treatments for hepatitis C, CDC is issuing updated guidance for health care providers on hepatitis C testing. These guidelines reinforce the recommended process for hepatitis C testing and underscore the importance of providers conducting follow-up RNA testing for all patients with a positive antibody test result in order to help ensure people infected with hepatitis C are properly tested and identified.

CDC recommends that everyone in the United States born from 1945 through 1965 be tested for hepatitis C. CDC also recommends that other populations at increased risk for hepatitis C get tested, including those who received blood transfusions or organ transplants before widespread screening of the blood supply began in 1992, or those who have ever injected drugs.

This Vital Signs coincides with Hepatitis Awareness Month and National Hepatitis Testing Day on May 19.

More information is available at www.cdc.gov/nchhstp/newsroom.

---

Press Briefing Transcript

 

CDC Telebriefing on Hepatitis C testing

May 7, 2013 1:30 pm E.T.

Audio recording [MP3, 4.01MB]

OPERATOR: Good afternoon and thank you all for standing by. This is the conference coordinator. All lines will be placed on listen only until we're ready for the question and answer session of today's call. This call is also being recorded. If you do have any objections, you may disconnect at this time. I would now like to introduce your first speaker, Mr. Tom Skinner. You may begin, sir. Thank you.

TOM SKINNER: Thank you, Lori. And thank you all for joining us today for another release of a CDC vital signs. This one is on the evaluation of Hepatitis C virus infection, testing and reporting. Eight US Cities 2005 to 2011. Today we're joined by the director of the CDC, Dr. Tom Frieden, who will provide some opening remarks. And then we'll turn the call over to Dr. John Ward who is the director of our division of viral hepatitis who will provide some further detail on the report. And then we will get to your questions. So without further ado, I’d like to turn the call over to CDC director tom Frieden.

TOM FRIEDEN: Good afternoon, everyone. Welcome and thanks very much for joining the call. Hepatitis C affects about 3 million Americans, about 3 million people infected. Most of the infected people in this country are baby boomers. Born between the years 1945 and 1965. The bottom line here is, if you were born between those years, get tested. And if you're positive, get follow-up testing. Before I head into details, really the take-home message from today's report is that you may not remember everything that happened in the '60s and '70s, but your liver does. And for that reason, everyone from 45 to 65 should be tested and should get complete testing. Once someone's infected with Hepatitis C, about four out of five, 80 percent, stay infected for life. The 3 million people today infected with Hepatitis C, about half will go on to have serious liver problems known as cirrhosis and about one-third may die from complications of their infection. That's one million people, potentially dying from Hepatitis C unless we effectively address it. Hepatitis C is the most common reason people need liver transplants. And it's the leading cause of liver cancer which is the fastest rising cause of cancer-related death in the U.S at CDC we estimate that if baby boomers get tested and if they're infected, get into care, we could prevent at least 100,000, about 120,000 deaths. Now, getting into some of the details of today's report, we were able to track Hepatitis C in eight US Sites, eight cities, from 2005 to 2011. And although many people were found to be positive, it appears that only about half had complete testing for the virus, meaning that following an initial test, they had follow-up testing. With Hepatitis C, you really need two stages of testing. The first test, a screen to see if you've ever been infected with the virus. And the second see whether you're still infected or whether you're one of the fortunate 20 percent that isn't still infected. Today's data show that even among young people who get tested positive, only about half had follow-up tests to see if they were still infected. That's what you need to get appropriate care and treatment. Right now there are better Hepatitis C treatments available than ever and there are more treatments coming in the coming year. So confirming that someone is more infected is more important than ever. Not everyone with Hepatitis C will need treatment, but everyone with Hepatitis C should be linked to care so that they can monitor how their liver is doing, determine when and if treatment is warranted, avoid things like excess alcohol which can damage their liver, and avoid medications that could also damage their liver as well as getting vaccinated against hepatitis b to protect their liver. Liver disease is something which is causing an increasing number of deaths, and many of those deaths could be prevented with the current treatments and with preventive actions that people can take if, but only if, they know that they're infected. Today CDC is also issuing updated guidance for doctors and other health care providers about how to test for Hepatitis C and how to provide follow-up. And Dr. Ward will provide more detail on that in his remarks. Before I turn the call over to Dr. Ward, I’ll be back with you for questions; I want to remind baby boomers to get tested for Hepatitis C. And if your screening test is positive, make sure you go back for a follow-up test. We have key messages in the vital signs for patients, for health care providers, for health care systems and for state and local governments, all of which can play an important role in reducing the risks that people will progress from Hepatitis C infection to severe liver disease, because it's possible to stop that progression. So, again, baby boomers may not remember everything we did in the '60s or '70s, but our liver does. Get tested to find out if you have the infection now, because if so, care and treatment really could save your life. Now, Dr. Ward?

DR JOHN WARD: Thanks, Tom and good afternoon, everyone. This is Dr. John Ward, the director of the division of hepatitis here at CDC. Today's report is based on an analysis of data from 2005 through 2011 reported by eight states in major cities across the country that received CDC funding to conduct enhanced surveillance for Hepatitis C. As Dr. Frieden just remarked, today's findings suggest that when people test positive for Hepatitis C ant bodies, the follow-up test is often not completed. The report found that among those individuals who received a positive antibody test, only half, 51 percent, also had a positive follow-up test reported to the health department that indicated that they were still infected. We already know there's a majority of those with Hepatitis C do not know that they're infected because they haven't been tested. These data suggest that even among individuals who have received that initial antibody test, as many as half do not know for sure if they still carry the virus. So what happened to the other half? They only had a positive antibody test? Some of these individuals may have cleared the infection on their own because we know that about 20 percent of persons who become infected with Hepatitis C will clear that infection on their own. So we believe that the larger portion of persons without a positive test, only a small proportion of those fall into this category. More importantly, we believe it's likely that most of these individuals are still infected with Hepatitis C but have not received that follow-up test necessary to confirm their infection and serve as a gateway to them receiving the care and appropriate treatment they need. Our findings add to other previous research which also has suggested that a substantial proportion of those with Hepatitis C antibodies, give us an idea of the gap between those who are and are not receiving the test and show us that we have a substantial challenge in front of us. Updated Hepatitis C testing guidance published today by CDC reinforces our current recommendations and underscores the importance of follow-up testing for everyone who tests positive for HCV antibodies. This reinforces CDC guidance published last year. We are hopeful that the percentage of cases reported RNA test results has already begun to increase since that time. We strongly urge all health care providers to implement Hepatitis C testing including the appropriate follow-up testing necessary to identify current infection with Hepatitis C.

TOM SKINNER: Lori, I believe that we're ready for questions. Could you please provide instructions for asking questions, please?

OPERATOR: Thank you, sir. We will now begin the question and answer session. If you would like to ask a question, please press star-one. You will be prompted to record your name. Press star-two to withdraw your request. One moment for the first question. Our first question comes from Michelle Meryl with the Hospital Employee Health Newsletter.

MICHELLE MERYL: Thank you very much for taking my question. So I had a question about health care workers. I know they're at risk for Hepatitis C, and they may be at risk for exposures from patients who have -- who are unknown -- it's unknown whether they have Hepatitis C. So I guess a couple-tiered question, will you have guidelines for management of health care workers with Hepatitis C as you do for hepatitis B? Are you recommending any special testing in a hospital setting, either of patients when they're admitted or of any kind of routine testing of health care workers who are involved in exposure-prone procedures?

TOM FRIEDEN: Dr. Ward, why don't you take that question?

DR. JOHN WARD: CDC has guidelines already for the management of health care workers with Hepatitis B, HIV and Hepatitis C. And so those are our current recommendations which stipulate the type of management that's indicated. The second part of that question regarding testing of patients as they come in, I think that really brings up the different settings or strategies that are -- could be brought to bear to put CDC's recommendations into implementation so that -- and so we have actually funded about 25 to 30 -- what we call demonstration sites to test out, what are the best ways to make testing available so that you reach the person's recommending and who can benefit from testing in a more efficient and effective way possible. So to your point, some hospitals that we're working with are beginning to implement routine screening in the emergency department. Some of them are experimenting with what's called physician reminders so that when someone checks into the clinic within this date of birth span, a reminder will pop up electronically, indicating that person is recommended for testing. And then there are various other strategies that health care providers are working with. But that's a critical piece. That to be effective, you have to have your policy put into operation, and that's why we're trying to develop best practices for and working with our partners around the country.

MICHELE MARILL: So if I could just follow up. So you're not going to update or change anything with regard to your recommendations specifically for health care workers?

JOHN WARD: That’s correct.

TOM SKINNER: Next question, Lori?

OPERATOR: Our next question comes from Robert Lowes with Medscape Medical News.

ROBERT LOWES: Yes, thanks for taking my call. I wanted to clarify something in the MMWR and in the press release, it says that of these 218,000 people, 49% just had the -- or tested positive on the antibody test. And then 50.8% were reported with a positive RNA test. Is it the case that the people that went beyond the antibody test, is it safe to construe that almost 51% went beyond getting the antibody test and then all of them turned out to be positive based on the RNA results? It's hard for me to put my head around how you're trying to express that. Because it sounds like that, you know, half the people, you know, tested positive in terms of the antibody test. But then the rest went on -- and of that group, half went on to get the RNA test, and they all were positive.

TOM FRIEDEN: Why don't we try to clarify that for you.

ROBERT LOWES: Yeah.

TOM FRIEDEN: And Dr. Ward can explain further. Among the universe of people who tested positive for the antibody, only 50%, only half, had any record reported to their health department that they had a follow-up test. So of those who were positive by antibody, only 50% had the recommended follow-up RNA reported. Dr. Ward, you want to say anything further?

JOHN WARD: No, I think that's -- I mean, I agree with that -- I don't know if there's a follow-up to that.

ROBERT LOWES: But in other words, the people who had the just antibody test, it really wasn't clear whether they harbored the virus because it just showed that at one point, they had the virus, but it did not show that they were -- they still had the virus, right?

TOM FRIEDEN: That’s right. What we know from many other studies is about 80% of them probably still did. So it's concerning that it looks like about half didn't have the follow-up testing since the great majority of them probably had continued infection and may not have gotten the required testing, or recommended testing, I should say.

JOHN WARD: I think, you know, both sides of this proportion really lead you to the same conclusion, and that is the testing for viremia is very important. You have to know -- the most important question to be answered by Hepatitis C testing is am I currently infected with this virus and have this condition? And that second test has to be conducted to answer that question.

TOM SKINNER: The next question, Lori?

OPERATOR: Our next -- as a reminder, if you would like to ask a question, please press star-one. You will be prompted to record your name. And our next question comes from Christopher Yi with Hartford Health.

CHRISTOPHER YI: Hi. We have a question here in regards to after the initial screening, how far after do you recommend a follow-up? Testing?

TOM FRIEDEN: Dr. Ward?

JOHN WARD: Well, I think we really -- we just recommended it be done. You know, at any time, obviously, the sooner, the better. But we don't put a time limit beyond which it's no longer helpful. This is a chronic infection that, you know, that lasts really essentially over the course of a lifetime once it's established. So that testing needs to happen. We would like for it to happen promptly. But we want it to happen in any case.

TOM SKINNER: Next question, Lori?

OPERATOR: Our next question comes from Liz Highleyman with hivandhepatitis.com.

LIZ HIGHLEYMAN: Yes, thank you for taking my question. I'd like to see if Dr. Frieden can clarify the percentages of people who turn out to be chronically infected with Hepatitis C who have -- who have gone on to develop cirrhosis, liver cancer and liver related early death. I know you gave a figure, but I didn't catch it.

TOM FRIEDEN: It’s about 37%. Is that correct, Dr. Ward?

JOHN WARD: About 37%, we estimate, will die of Hepatitis C related complications such as the ones the caller described over the course of a lifetime. And about -- we estimate of the 3 million Americans currently living with Hepatitis C now, about half will develop cirrhosis.

LIZ HIGHLEYMAN: Thank you.

TOM SKINNER: Next question, Lori?

OPERATOR: Sir, thank you. That was our last question. I'll turn the call back over to you.

TOM SKINNER: Dr. Frieden, would you like to close our call with some closing remarks, please?

TOM FRIEDEN: Sure. I would just first thank you all for being a part of this call. Remind us that 3 million people is a lot of people to have an infection which will seriously harm many of their health. That three out of four of them don't know they're infected. And even many of the people who have been tested don't appear to have gotten follow-up testing. So we have a lot more that we can do and need to do to make sure that we're protecting people as well as possible from serious illness and death from Hepatitis C, cirrhosis and liver cancer, in particular. So, again, if people born from '65 -- I’m sorry, from 1945 to 1965 may not remember everything that happened in the '60s and '70s, but their liver does. And so it's very important to get complete testing for Hepatitis C. For health care providers, it's very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care so they can avoid further liver damage, and if appropriate, get treated. And I want to thank you all very much for joining us.

TOM SKINNER: Thank you, Lori. And this concludes our call. If you have follow-up questions or need additional information on hepatitis or this particular Vital Signs, please call our hepatitis media office at 404-639-8895. Thanks again for joining us.

OPERATOR: Thank you. That does conclude today's conference call. Thank you all for joining. You may disconnect at this time.

Source

Aethlon Medical (AEMD) Note: An Update on the Clinical Status of the Aethlon Hemopurifier® in Hepatitis-C Care

SAN DIEGO, May 7, 2013 /PRNewswire/ -- Aethlon Medical, Inc. (OTCQB: AEMD), today released the following note authored by its Chairman and CEO, Jim Joyce .

Through the publication of CEO notes, I seek to provide shareholders and other interested parties with a level of corporate transparency often absent in the microcap marketplace. In recent notes, I reviewed various topics, including emerging opportunities in cancer and the expansion of our government contract program to create a sepsis therapeutic.

This note is specific to our most important near-term objective: the approval of a investigational device exemption (IDE) by the U.S. Food and Drug Administration (FDA) that would allow us to initiate clinical feasibility studies of Hepatitis-C (HCV) infected individuals receiving Hemopurifier® therapy. In this regard, FDA withheld clearance of our recently amended IDE based on a single information deficiency that was deemed a safety concern. Specifically, FDA has requested that we detail our training and monitoring procedures related to heparinization, which is the primary anticoagulant utilized in dialysis and other extracorporeal therapies, including our Hemopurifier®. We are assembling the requested information and expect to have our response back in the hands of FDA in the coming week. The approval of our IDE remains a critical step in our strategy to advance a first-in-class medical device to address a major-market infectious disease condition.

HCV is a blood-borne pathogen that affects upwards of 170 million persons, or 2-3% of the world's population. It is a leading cause of liver cirrhosis and transplant and there is no pre or post infection vaccine. The magnitude of the HCV therapeutic opportunity has spawned immense competition within the drug industry. According to citeline®, there are over 200 planned and ongoing Phase I-III trials of pipeline HCV drugs as of March 1, 2013. However, it should be noted that only ten companies are responsible for 83% (165/200) of the referenced HCV studies; Bristol-Myers Squibb, Gilead, Merck & Co., AbbVie, Boehringer Ingelheim, Johnson & Johnson, Roche, Vertex, Achillion and Novartis. A primary factor for this odd statistical imbalance is the reality that these organizations often acquire candidate therapies that demonstrate clinical promise.

As a medical device, we have an enduring opportunity as our Hemopurifier® is uniquely positioned as an adjuvant to either interferon-based standard of care (SOC) or emerging all-antiviral drug regimens. And, unlike adjunct drug strategies, the Hemopurifier® performs without adding drug toxicity. In studies conducted in India, a three-treatment Hemopurifier® protocol administered in combination with interferon-based SOC resulted in undetectable HCV levels in as little at seven days in hard to treat genotype-1 patients. The studies also documented the ability of the Hemopurifier® to capture as many as 300 billion copies of HCV during a single six-hour treatment. In addition to augmenting the early viral kinetic response to drug therapy, the Hemopurifier® is a candidate solution for viral rebound patients who traditionally are forced to discontinue therapy once HCV establishes resistance to their drug regimens. Such a solution would address a significant unmet medical need in HCV care.

In closing, we are confident that we can fulfill FDA's information request. In the interim, I remain grateful to loyal shareholders that support our cause and I salute the continued perseverance of my Aethlon teammates.

About Aethlon Medical

Aethlon Medical creates innovative medical devices that address unmet medical needs in cancer, infectious disease, and other life-threatening conditions. Our Aethlon ADAPT™ System is a revenue-stage technology platform that provides the basis for a new class of devices the rapid, yet selective removal of disease promoting particles from the entire circulatory system. At present, The Aethlon ADAPT™ product pipeline includes the Aethlon Hemopurifier® to address infectious disease and cancer, and a medical device being developed under a 5-year contract with Defense Advanced Research Projects Agency (DARPA) to reduce the incidence of sepsis in combat-injured soldiers. For more information, please visit www.aethlonmedical.com.

About The Aethlon Hemopurifier®

The Aethlon Hemopurifier® is a first-in-class medical device that selectively targets the rapid clearance of infectious viral pathogens and immunosuppressive proteins from the entire circulatory system. In the treatment of Hepatitis C virus (HCV), human studies have demonstrated that Hemopurifier® therapy may improve immediate, rapid and sustained virologic response rates when administered in the first few days of standard-of-care drug therapy. In addition to accelerating viral load depletion, post-treatment analysis of the Hemopurifier® has documented the capture of up to 300 billion HCV copies of HCV during a single six-hour treatment. Access to Hemopurifier® therapy is available on a compassionate-use basis through the Medanta Medicity Institute (Medicity), a leading center for medical tourism in India. The Medicity is offering treatment access to infected individuals who previously failed or subsequently relapsed standard-of-care drug regimens. The Hemopurifier® is also being offered as a salvage therapy to infected individuals who suffer a viral breakthrough during standard-of-care therapy. U.S. studies of the Hemopurifier® are currently pending approval of an IDE submitted to FDA.

The Aethlon Hemopurifier® and Cancer

In addition to the opportunity to address a broad-spectrum of infectious viral pathogens, the Hemopurifier® has been discovered to capture tumor-derived exosomes underlying several forms of cancer. Tumor-derived exosomes have recently emerged to be a vital therapeutic target in cancer care. These microvesicular particles suppress the immune response in cancer patients through apoptosis of immune cells and their quantity in circulation correlates directly with disease progression. Beyond possessing immunosuppressive properties, tumor-derived exosomes facilitate tumor growth, metastasis, and the development of drug resistance. By addressing this unmet medical need, the Hemopurifier® is positioned as an adjunct to improve established cancer treatment regimens.

Certain statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, that the FDA will not approve the initiation of the Company's clinical programs or provide market clearance of the company's products, future human studies whether revenue or non-revenue generating from either compassionate use or non-compassionate use of the Aethlon ADAPT™ system or the Aethlon Hemopurifier® as an adjunct therapy to improve patient responsiveness to established cancer or hepatitis C therapies or sepsis therapies or as a standalone cancer or hepatitis C therapy or standalone sepsis therapy, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings. The Company undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Contacts:

James A. Joyce
Chairman and CEO
858.459.7800 x301
jj@aethlonmedical.com

Jim Frakes
Chief Financial Officer
858.459.7800 x300
jfrakes@aethlonmedical.com

Marc Robins
877.276.2467
mr@aethlonmedical.com

SOURCE Aethlon Medical, Inc.

RELATED LINKS
http://www.aethlonmedical.com

Source

Chicago Boomers Face Silent Hepatitis C Virus Risk

MedSpring Immediate Care offers free screenings in May.

Austin, TX (PRWEB) May 07, 2013

Many baby boomers’ bodies may be harboring a silent killer: Hepatitis C. In fact, the federal Centers for Disease Control (CDC) recommends testing for anyone born between 1945 and 1965 as early diagnosis and treatment can help prevent liver damage, cirrhosis, liver cancer and other complications.

In recognition of Hepatitis Awareness month, MedSpring is offering baby boomers, those born between 1945-1965, free Hepatitis C screenings at any of its 14 centers in Chicago, Austin and Houston during the month of May. In addition, those born after 1965 with tattoos and body piercings are also eligible for free screenings.

The Hepatitis C virus is a contagious, blood-borne infection affecting the liver. Baby boomers may have contracted the disease numerous ways, including through a simple blood transfusion, injection drug use or an organ transplant performed prior to 1992. While baby boomers comprise only 27 percent of the U.S. population, the CDC estimates they account for 75 percent of the Hepatitis C cases and 73 percent of deaths related to the virus.

“This simple, one-time blood test can mean the difference between life-saving treatment and serious, even deadly, liver disease,” said Dr. Jon L. Belsher, M.D., MedSpring’s Chief Medical Officer. “The Hepatitis C virus is dangerous, especially to baby boomers, as it can go unnoticed for years with most people experiencing no symptoms.”

MedSpring centers will administer the complimentary blood test to the first 1000 eligible patients during regular center hours of 9am-9pm daily. For those patients requiring follow-up, MedSpring will provide complimentary consultation and referrals. Walk-ins are welcome, and appointments are also available. For more information, visit the Hepatitis C information page on MedSpring’s website.

MedSpring Immediate Care has three centers in Chicago, six in Austin, and five in Houston.

About MedSpring Immediate Care
MedSpring’s 14 Immediate Care centers focus on delivering quality care and exceptional service. For more information, including patient reviews and savings compared to an ER, please visit http://www.medspring.com or find us on Facebook and Twitter.

Source

A Small Percentage of Patients with Hepatitis C Receive Triple Therapy with Boceprevir or Telaprevir

Clin Gastroenterol Hepatol. 2013 Apr 16. pii: S1542-3565(13)00482-5. doi: 10.1016/j.cgh.2013.03.032. [Epub ahead of print]

Chen EY, Sclair SN, Czul F, Apica B, Dubin P, Martin P, Lee WM.

Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas, TX; Department of Medicine, Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL.

Abstract

BACKGROUND & AIMS: Protease inhibitor triple therapy for hepatitis C virus (HCV) infection (boceprevir or telaprevir with pegylated interferon and ribavirin) has been shown to increase rates of sustained virologic response in phase 3 trials. We investigated the proportion of patients who began therapy with this regimen in the 12 months following the Food and Drug Administration (FDA) approval of boceprevir and telaprevir in the US.

METHODS: We performed a retrospective cross-sectional study of 487 patients with HCV genotype 1 infection (396 did not receive triple therapy and 91 had begun triple therapy with boceprevir or telaprevir), seen at hepatology practices in Dallas and Miami from June 2011 through February 2012. The subjects were predominantly middle-aged, non-Hispanic white, and privately insured; 50% were treatment-naïve, and most had advanced fibrosis. We compared features of patients who initiated triple therapy with those who deferred it. Treated patients were followed to determine the discontinuation rate in the first 12 weeks of treatment.

RESULTS: Of patients assessed, only 18.7% began triple therapy-the same percentage as those receiving dual therapy (pegylated interferon and ribavirin) before boceprevir or telaprevir were approved for treatment of HCV infection in the US. Reasons for deferring treatment included relative contraindications (50.5%), patient choice (22.5%), and less-advanced liver disease (17.4%). Among treated patients, 15% discontinued prematurely because of serious adverse events. Based on multivariate analysis, factors associated with initiation of triple therapy included prior treatment relapse (odds ratio [OR] 4.6; 95% confidence interval [CI], 2.1-9.9) and liver fibrosis of stage 3 (OR, 9.1; 95% CI, 3.1-27) or stage 4 (OR, 9.0; 95% CI, 3.3-25) but not hepatic decompensation.

CONCLUSION: Only 18.7% of patients with HCV genotype 1 infection received triple therapy in the 12 months following FDA approval of boceprevir and telaprevir. This low percentage might result from concerns of side effects and recognition that more effective medications could be available in the future.

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

Source

Alcohol consumption as a cofactor for other liver diseases†‡

Clinical Liver Disease

Special Issue: Alcoholic Liver Disease

Volume 2, Issue 2, pages 72–75, April 2013

Jose Altamirano^*, Javier Michelena

Article first published online: 24 APR 2013

DOI: 10.1002/cld.197

Copyright © 2013 the American Association for the Study of Liver Diseases

^† CIBERehd is funded by Instituto de Salud Carlos III. Javier Michelena received “Formación del Profesorado Universitaro” grant from the Ministerio de Educación of the Spanish Goverment.

^‡ Potential conflict of interest: Nothing to report.

Abstract

Watch a video presentation of this article

Watch the interview with the author

Answer questions and earn CME

Alcohol has been shown to cause synergistic injury in combination with other chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis B and C, hemochromatosis, and autoimmune liver diseases. Abusive alcohol consumption rapidly accelerates the development of hepatic fibrosis and cirrhosis and also increases the risk of liver cancer and death from liver disease. The negative impact of alcohol consumption is dose- and time-dependent and varies depending on the underlying liver disease and may occur at much lower alcohol intake compared with an alcohol dose necessary to initiate alcoholic liver disease itself. There is not a clear “safe” limit for alcohol consumption in the setting of chronic liver disease. Thus, alcohol consumption should be avoided or at least limited in any patient with underlying liver disease.

Abusive alcohol intake is a major risk factor for chronic liver disease (CLD). In addition, alcohol consumption in the presence of other liver diseases may result in progression of the disease. Alcoholic liver disease is prevalent among patients with chronic hepatitis C (HCV) and B (HBV) virus infection, influences the progression of the disease and has a stimulation effect on viral replication.1, 2 Alcohol may negatively impact the course of NAFLD increasing the fibrosis rate in patients with non-alcoholic steatohepatitis3 and of hereditary hemochromatosis (HH).4 Finally, alcohol may interact with the metabolism of certain drugs5 and can also contribute to the development and worsening of some autoimmune liver diseases.6

Alcohol and Chronic Hepatitis C

Chronic HCV infection is the leading cause of advanced liver disease in the United States; an estimated 3.2 million people have active chronic HCV infection.7 Alcohol consumption is a common comorbidity in these patients, and multiple studies have shown that it may result in synergistic injury, with accelerated rates of fibrosis and the development of cirrhosis and liver cancer.8–11 Various mechanisms have been proposed, including: alcohol's effect on HCV viral replication, HCV-related cytotoxicity, hepatic oxidative stress, and immune modulation.

There is evidence that HCV RNA levels increase in concert with a more pronounced alcohol intake (Fig. 1a).12 Conversely, it has been shown that serum HCV RNA decreases with a reduction in alcohol intake (Fig. 1b).2 Alcohol consumption is also associated with HCV progression, and there is extensive evidence showing that chronic alcohol consumption leads to disease progression (Table 1). Even small doses of alcohol intake (below 30 g/day) can promote liver fibrogenesis.13 Thus, it appears that there is no “safe alcohol consumption” among patients with HCV infection. Chronic alcohol consumption in HCV-infected patients stimulates not only fibrogenesis but also hepatocarcinogenesis. Patients with chronic HCV infection who actively consume alcohol have a higher relative risk of hepatocellular carcinoma (HCC) compared with abstainers (54 versus 19, respectively).14 This risk also appears to be dose-dependent. In one study, alcohol consumption >80 g/day increased the risk for HCC significantly by a factor of 7.3 when compared with <40 g/day.11 Finally, there are data showing that alcoholics have inferior rates of response to HCV therapy.15 However, the question about a possible inhibitory effect of alcohol on therapy rather than patient noncompliance requires further research.

Figure 1. Impact of alcohol consumption and effect of alcohol reduction on serum HCV RNA levels. Abbreviations: HCV, hepatitis C virus; SRAC, self-reported alcohol consumption. (a) Adapted with permission from Hepatology.12 Copyright 1998, Wiley. (b) Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.

Table 1. Effect of Alcohol Consumption in the Progression of HCV Infection

Study	Alcohol Intake Evaluation	No. of Patients	Results
Roudot-Thoraval et al.33	Excessive alcohol intake defined as >5 drinks/day for women and 6 drinks/day for men for >1 year	6,664	Excessive alcohol intake was also associated with a higher risk of cirrhosis (34.9% versus 18.2%; P < 0.001).
Poynard et al.34	Abstinent/Moderate, <50 g/day; high, ≥50 g/day	2,235	Fibrosis rate progression increased from 0.125 to 0.167 in patients with consumption ≥50 g/day
Pessione et al.12	Weekly self-reported alcohol consumption	233	Significant correlation between self-reported alcohol consumption and serum HCV RNA levels (r = 0.26; P = 0.001)
Corrao et al.35	Lifetime daily alcohol intake	702	Alcohol intake + HCV infection multiplies the alcohol-associated risk of cirrhosis (odds ratio: 9.0 for 50 g/day, 26.1 for 100 g/day, 133 for >125 g/day)
Harris et al.36	Heavy drinking defined as >80 g/day	836	Heavy drinking exacerbates the risk for cirrhosis among patients with HCV infection (odds ratio: 7.8 versus 31.1 in HCV and HCV heavy drinkers, respectively)

Alcohol and Chronic Hepatitis B

The interaction of alcohol consumption with HBV infection has been studied less extensively. Alcohol stimulates carcinogenesis in patients with HBV. This effect was shown in the seminal study of Ohnishi et al.,16 in which patients with HBV infection and active alcohol consumption developed HCC approximately 10 years earlier than patients who did not drink at all. Additionally, a dose-dependent effect of alcohol consumption has been demonstrated. Patients with heavy alcohol consumption (>80g/day) had a significantly increased risk of HCC in HBV-related cirrhosis.17

Alcohol and NAFLD

NAFLD is increasingly recognized as the downstream hepatic consequence of the metabolic syndrome. Well-known risk factors for NAFLD include obesity (especially with increased waist circumference), insulin resistance, and hypertriglyceridemia. Small amounts of alcohol may improve peripheral insulin resistance that take place in NAFLD.18 In addition, some studies have shown a paradoxical association between modest alcohol consumption with a lesser degree of severity in NAFLD patients.19, 20 However, additional alcohol consumption worsens NAFLD at various stages of the disease, both in animals5 and in humans.21–23

There is evidence that the impact of alcohol consumption on the development of NALFD is dose-dependent. Studies from Europe have shown that alcohol consumption of more than 60 g/day increases the rate of fatty liver by echography to 46% compared with 16% in control subjects.24 Alcohol consumption has also shown an additive risk for NAFLD development in obese patients. In one study, individuals with a body mass index of more than 25 kg/m² had a further increase in fatty liver to >70%, and if both alcohol consumption and overweight were factors, steatosis was present in >90%.22

On the other hand, liver fibrosis in NAFLD also increases with alcohol consumption. Patients with high-risk alcohol consumption and obesity have an almost two-fold risk of developing cirrhosis21 (Fig. 2).

Figure 2. Obesity is a risk factor for alcoholic liver disease progression. Abbreviation: BMI, body mass index. Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.

Finally, recent evidence shows that even social drinking in patients with nonalcoholic steatohepatitis results in a significantly increased risk of HCC.25 This observation is in keeping with animal studies showing that alcohol administration is associated with deterioration of experimentally induced fatty liver disease in rodents and may also enhance the generation of carcinogenic DNA lesions.26

Alcohol Consumption and Hereditary Hemochromatosis

HH is an autosomal recessive gene disorder in which HFE gene mutations cause chronic intestinal hyperabsorption of iron, resulting in iron overload in various organs.27, 28 Iron overload is a negative prognostic factor for the development of liver disease.4 Alcohol consumption increases reactive oxygen species by producing H₂O₂, which leads to iron hyperabsorption and iron release due to a decrease in hepcidin. This leads to iron accumulation in the liver, resulting in increased toxicity (Fig. 3). One observational study showed that hemochromatosis subjects who drank >60 g/day of alcohol were approximately nine times more likely to develop cirrhosis than those who drank <60 g/day.29 Thus, patients diagnosed with HH should avoid alcohol consumption.

Figure 3. Iron overload due to alcoholic liver disease. Abbreviations: EtOH, ethanol; ROS, reactive oxygen species; TfR1, transferrin receptor 1.

Alcohol, Drug Interactions and Autoimmune Liver Diseases

Toxicity of various drugs may be increased by concomitant alcohol consumption. This is especially well known for methotrexate, paracetamol, and antituberculosis drugs. First, prolonged high-dose methotrexate intake results in stellate cell activation leading to zone 3 fibrosis, which is further enhanced by alcohol consumption, since alcohol by itself leads to an activation of stellate cells.30 Second, alcohol consumption induces cytochrome P450 2E, which is also responsible for the metabolism of various drugs (e.g., paracetamol and antituberculosis drugs such as isoniazid). An induction of CYP2E1 by alcohol results in enhanced metabolism of paracetamol with an increased generation of highly toxic intermediates that are not normally detoxified due to the decreased hepatic glutathione levels presented in alcoholic patients. Isoniazid toxicity depends on two factors: (1) the speed of isoniazid acetylation and (2) the speed of the metabolism of the intermediate acetylhydrazine by CYP2E1.31 Finally, it should be pointed out that vitamin A and beta-carotene taken in excess may also lead to hepatic fibrosis and cirrhosis.

The effect of alcohol consumption in patients with autoimmune liver diseases has not been studied extensively, though there is some clinical evidence in patients with primary biliary cirrhosis (PBC). In a study of 274 patients with untreated PBC, moderate alcohol consumption (30 g/day) was an independent predictor of advanced PBC stage.32 In these patients, moderate alcohol consumption was also significantly correlated with increased oxidative stress and steatosis on liver biopsies, which was thought to contribute to worsening of PBC stage.

Summary

Alcohol has been shown to cause synergistic injury in combination with other forms of CLD, particularly chronic HCV and HBV infection, NAFLD, HH, and autoimmune liver disease. Alcohol consumption, particularly in high doses, accelerates to liver fibrogenesis and the development of cirrhosis and also increases the risk of HCC and death from liver disease. Despite the effect of light alcohol consumption on decreasing insulin resistance and cardiovascular mortality, there does not seem to be a “safe” limit for alcohol consumption in the setting of combined CLD.

References

Source

HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort Study

7 May 2013, Vol 158, No. 9>

Original Research | 7 May 2013

Gregory D. Kirk, MD, MPH, PhD; Shruti H. Mehta, PhD, MPH; Jacquie Astemborski, MS; Noya Galai, PhD; Jonathan Washington, BA; Yvonne Higgins, PA; Ashwin Balagopal, MD; and David L. Thomas, MD, MPH

[+-] Article and Author Information

Ann Intern Med. 2013;158(9):658-666. doi:10.7326/0003-4819-158-9-201305070-00604

Background: Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.

Objective: To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.

Design: Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.

Setting: Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.

Participants: 1176 current and former injection drug users with antibodies to HCV.

Measurements: Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4⁺ lymphocyte count and HIV RNA levels.

Results: Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m², and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.

Limitation: The process of liver fibrosis began before the study in most persons.

Conclusion: In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.

Primary Funding Source: National Institute on Drug Abuse.

Source

Triple combination therapy for hepatitis C with telaprevir exhibits greater early antiviral activity than with boceprevir

Antivir Ther. 2013 May 3. doi: 10.3851/IMP2614. [Epub ahead of print]

Benito JM, Sánchez-Parra C, Maida I, Aguilera A, Rallón NI, Rick F, Labarga P, Fernández-Montero JV, Barreiro P, Soriano V.

Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.

Abstract

BACKGROUND: Achievement of early viral suppression is important in patients with chronic hepatitis C virus (HCV) infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far.

METHODS: All consecutive individuals that initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV-RNA (<25 IU/mL) at week 4 for TLV and at week 8 for BOC (4 weeks after lead-in).

RESULTS: A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, BMI, baseline HCV-RNA, HCV subtype 1a (45% vs 42%), IL28B-CC alleles (29% vs 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% vs 44%). Conversely, more patients on BOC than TLV had previously failed to peginterferon-ribavirin (82% vs 64%). RVR was achieved by 82% of patients on TLV vs 59% on BOC (p=0.001). Multivariate logistic regression analysis (OR [95% CI], p) confirmed that TLV use was the strongest predictor of RVR (3.54 [1.23-10.24], 0.02), being others HCV subtype 1b vs 1a (3.26 [1.17-9.09], 0.02) and low baseline HCV-RNA (0.41 [0.16-1.03], 0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR.

CONCLUSIONS: Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to-cure patients, such as those with high baseline HCV-RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV-RNA responses.

Source

Nonresponse to Interferon-α Based Treatment for Chronic Hepatitis C Infection Is Associated with Increased Hazard of Cirrhosis

PLoS One. 2013 Apr 25;8(4):e61568. doi: 10.1371/journal.pone.0061568. Print 2013.

Cozen ML, Ryan JC, Shen H, Lerrigo R, Yee RM, Sheen E, Wu R, Monto A.

Department of Medicine, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America.

Abstract

BACKGROUND: The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored.

METHODS AND FINDINGS: We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18-4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50-23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients.

CONCLUSION: These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.

Source

Free Full Text Article

Early HCV Response More Likely With Peg-Interferon Alpha-2a Than -2b

Reuters Health Information

May 03, 2013

By Will Boggs, MD

NEW YORK (Reuters Health) May 03 - Patients with hepatitis C virus (HCV) are more likely to have an early response to pegylated interferon alpha-2a than alpha-2b, a new meta-analysis has found.

"The Cochrane meta-analysis about sustained virological response and our meta-analysis taking into account rapid virological response and early virological response (show that) the efficacy of peg-a-2a is superior to peg-a-2b and thus it is the first choice in the management of hepatitis C," Dr. Manuel Romero-Gomez from Valme University Hospital in Seville, Spain, told Reuters Health by email.

Dr. Romero-Gomez and colleagues pooled data from eight randomized trials that compared peginterferon alpha-2a and alpha-2b in 4,566 patients.

A complete early virological response (EVR) was achieved by 53.3% of patients treated with peginterferon alpha-2a and 43.8% of those treated with alpha-2b (p=0.0028), the authors reported April 14 online in Alimentary Pharmacology & Therapeutics.

Results were similar in a sub-analysis of patients infected with HCV genotypes 1 and 4, but the difference fell short of statistical significance.

Crude rates of rapid virological response (RVR) were higher for peginterferon alpha-2a than alpha 2-b (25.0% vs 16.8%; p=0.0056), and results were also significantly better for alpha-2a in a sub-analysis of patients infected with HCV genotypes 1 and 4 (p=0.0048).

"RVR and EVR are crucial in the management of therapy in hepatitis C because they allow us to make decision about futility rules, saving cost and adverse events," Dr. Romero-Gomez said. "Using peg-a-2a we can treat more patients with double therapy if they reach RVR or add boceprevir/telaprevir in patients without RVR."

"We need more data to define which patients have to be treated with peg-a-2a or peg-a-2b," Dr. Romero-Gomez cautioned. "According to baseline characteristics, pega-a-2a seems to be better in very difficult-to-cure patients (genotype 1 with advanced fibrosis and metabolic derangements), but this point needs to be confirmed in further studies."

SOURCE: http://bit.ly/11lmZED

Aliment Pharmacol Ther 2013.

Source

Beta Blockers Ameliorate GI Permeability in Cirrhosis

Daniel M. Keller, PhD

May 02, 2013

AMSTERDAM, the Netherlands — Nonselective beta-blocker therapy improves gastrointestinal permeability and decreases intestinal bacterial translocation in patients with cirrhosis and esophageal varices, according to a new study.

These effects were associated with a reduction in the risk for variceal bleeding, and appear to be independent of a hemodynamic response, said Thomas Reiberger, MD, associate professor of hepatology at the Medical University of Vienna in Austria.

Dr. Reiberger presented the results here at the International Liver Congress 2013.

Infection and endotoxemia can impair liver function, increase portal pressure, and impair coagulation, which can result in variceal bleeding, he explained.

Antibiotic treatment is one way to reduce endotoxemia and bacterial translocation, but nonselective beta blockers might help by decreasing intestinal permeability.

Dr. Reiberger and colleagues tested this hypothesis in 50 cirrhotic patients with esophageal varices. Exclusion criteria were celiac disease, current infections, antibiotic or lactulose use in the previous 3 months, and consumption of > 6 g of alcohol per day.

Hepatic venous pressure gradient and other physical and laboratory parameters were measured at baseline and at 1 month, and intestinal permeability was assessed with sucrose, lactulose, and mannitol tests. Decompensation, bleeding, and death were assessed at 3-month follow-up.

The patients were predominantly men in their early to mid-50s (range, 18 to 75 years). Fewer patients with a lower hepatic venous pressure gradient (from 13 to 20 mm Hg) had large varices than those with a higher hepatic venous pressure gradient of more than 20 mm Hg (33% vs 66%; P = .002). There was also less portal hypertensive gastropathy with the lower hepatic venous pressure gradient (53% vs 97%; P = .015).

About 20% of patients had normal gastroduodenal and intestinal permeability, 18% had abnormal gastroduodenal permeability, 8% abnormal intestinal permeability, and 54% both abnormalities.

The higher hepatic venous pressure gradient was significantly associated with increased markers of gastroduodenal and intestinal permeability and of bacterial translocation before beta-blocker treatment, compared with lower hepatic venous pressure gradient. Portal pressure was linearly related to gastroduodenal permeability (P = .003) and intestinal permeability (P < .001).

Bacterial translocation was also associated with hepatic venous pressure gradient. Portal pressure was directly correlated with lipopolysaccharide-binding protein level (P < .001) and interleukin-6 level (P = .006).

Beta Blockers Reduce Pressure

"Not surprisingly, we found a decrease in portal pressure [21 mm Hg to 17 mm Hg; P < .05], but we also found a decrease in the sucrose/mannitol ratio and intestinal permeability index, indicating that beta blockers lead to an improvement of gastroduodenal and intestinal permeability," Dr. Reiberger reported. "Also, lipopolysaccharide-binding protein levels and interleukin-6 levels were significantly decreased with the nonselective beta-blocker therapy."

Fifty-one percent of patients had hemodynamic responses to the beta blockers. "Although there was a clear hint that the patients who were hemodynamic responders had better outcomes in these intestinal permeability tests...what's really striking is that the proportion of patients achieving a normal result on the sucrose, lactulose, mannitol tests after beta-blocker therapy is also really high in the nonresponders. That's why I conclude that it's independent of hemodynamic response," Dr. Reiberger explained. In addition, decreases in levels of lipopolysaccharide-binding protein and interleukin-6 were similar in responders and nonresponders.

There was a trend toward a higher risk for variceal bleeding in patients with abnormal gastroduodenal permeability than in those with normal gastroduodenal permeability (log-rank P = .066); the trend was similar for intestinal permeability. There was a significant correlation between higher interleukin-6 level and more variceal bleeding (log-rank P = .038). Intestinal permeability appeared to have no effect on survival.

After the presentation, an audience member asked Dr. Reiberger whether his team had looked at the different effects on the adrenergic system of propranolol and carvedilol. Dr. Reiberger noted that very few patients were on carvedilol but, from what he could see, there was no difference between them in terms of lipopolysaccharide-binding protein level, interleukin-6 level, or change in intestinal permeability.

Session moderator Isabelle Colle, MD, professor of hepatology and gastroenterology and head of the gastroenterology clinic at Gent University in Belgium, explained some of the mechanisms by which beta blockers exert their effects in this setting. By decreasing hepatic venous pressure gradient and portal pressure "the microcirculation in the intestine is better, so...you ameliorate the function of the barrier, which decreases permeability," she explained. In addition, patients with cirrhosis have slow intestinal transit times, which beta blockers speed up, "so you have fewer bacteria, you have less ammonia."

Dr. Reiberger suggested that beta blockers influence immunity because the sympathetic nervous system affects immune function.

Do all nonselective beta blockers have the same effects? A study of nonresponders to propranolol who were switched to carvedilol showed that "carvedilol had a better effect on the portal pressure than propranolol," Dr. Colle told Medscape Medical News. In the future, carvedilol will probably be better than propranolol, she noted.

Dr. Reiberger reports receiving research support from MSD, Roche, Phoenix, and Gilead. Dr. Colle has disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 84. Presented April 26, 2013.

Source

Vitamin D deficiency and vitamin D therapy in chronic hepatitis C

Annals of Hepatology

March-April, Vol. 12 No.2, 2013: 199-204

ORIGINAL ARTICLE

José M. Ladero,* María J. Torrejón,† Pilar Sánchez-Pobre,‡ Avelina Suárez,§ Francisca Cuenca,† Virginia de la Orden,|| María J. Devesa,† María Rodrigo,¶ Vicente Estrada,¶ Gustavo López-Alonso,† José A. Agúndez**

* Service of Gastroenterology, Hospital Clínico San Carlos, Department of Medicine, Medical School, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. † Clinical Laboratory Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. ‡ Service of Gastroenterology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. § Service of Clinical Microbiology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
|| Genomics Unit, Clinical Laboratory Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. ¶ Infectious Diseases Unit, Service of Internal Medicine, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. **Department of Pharmacology, University of Extremadura, Cáceres, Spain.

ABSTRACT

Background. Vitamin D has immunomodulatory properties, exerts an anti-hepatitis C virus (HCV) effect in vitro and improves response to interferon-based therapy in patients with chronic hepatitis C (CHC). Low serum levels of 25(OH) vitamin D [25(OH)D] are frequently found in CHC patients and seem to be related to more advanced stages of liver fibrosis. The study aims to establish the incidence of vitamin D deficiency in Spanish patients with CHC, its possible relation with features of liver damage and with the IL28B gene polymorphism, and the immediate effect of vitamin D therapy on CHC-related analytical variables. Materials and methods. Baseline serum 25(OH)D levels were measured in 108 consecutive CHC patients (60 men, age 54.3 ± 10.5 yrs). Results of transient elastography and of IL28B rs12979860C/T genotype were available in 89 and 95 patients, respectively. Forty one patients with insufficient levels of 25(OH)D received vitamin D supplements and were re-evaluated thereafter. Results. Deficiency of vitamin D (< 20 µg/dL) and suboptimal levels (20-30 µg/mL) were detected in 36.1% and 40.9% of patients, respectively. No relationships were found between 25(OH)D levels and biochemical liver tests, fibrosis stage and IL28B genotype. Vitamin D therapy normalized 25(OH)D levels in all treated patients, but did not modify significantly HCV-NA serum levels or biochemical tests. Conclusions. Vitamin D deficiency is common in Spanish patients with CHC but it is related neither to biochemical and virological variables nor with the fibrosis stage and IL28B polymorphism. Vitamin D therapy has no immediate effect on HCV-RNA serum levels.

Source

TACE, sorafenib improve survival among patients with infiltrative HCC

Mehta N. Clin Gastroenterol Hepatol. 2013;11:572-578.

May 7, 2013

Patients with infiltrative hepatocellular carcinoma experienced prolonged survival when treated with transarterial chemoembolization or sorafenib in a recent retrospective cohort study.

Researchers evaluated data from 155 patients with infiltrative hepatocellular carcinoma (iHCC) seen at the University of California, San Francisco Medical Center between 2002 and 2010. Participants had a median age of 60 years, MELD score of 13, maximum tumor diameter of 11.3 cm and alpha-fetoprotein level of 347 ng/mL.

Nearly all patients (95.5%) had died as of Sept. 2011. The survival rate was 63% of patients at 3 months, 30% at 6 months and 8% at 12 months, with a median survival of 4.0 months across the cohort. Median survival was longer among patients who underwent treatment, including transarterial chemoembolization (TACE, 6.0 months), sorafenib (7.5 months) or radiofrequency ablation with or without TACE (9.2 months), than patients who did not receive treatment (3 months).

Survival rates were significantly higher among patients treated with sorafenib (n=11, 73% at 6 and 36% at 12 months) and those who underwent transarterial chemoembolization (TACE, n=18, 45% and 17%) than participants who received no therapy (n=109, 17% and 2%) (P<.01 for all comparisons). No significant difference in survival was observed between those treated with sorafenib or TACE (P=.267).

Multivariate analysis indicated associations between mortality at 6 months and several factors, including: cirrhosis of Child-Pugh class B (HR=2.61, 1.36-4.8 vs. class A) or C (HR=6.12, 2.74-13.76 vs. class A); not having received sorafenib, radiofrequency ablation or transarterial chemoembolization (HR=2.79, 1.60-4.88); MELD score (HR=1.07, 1.03-1.12 per one-point increase); tumor size (HR=1.05, 1.01-1.10 per 1-cm increase) and an alfa-fetoprotein level above 1,000 ng/mL (HR=2.47, 1.56-3.84) (95% CI for all).

“iHCC is a radiographically distinct and advanced form of HCC,” the researchers wrote. “The majority of patients with iHCC have extensive tumor burden as well as macrovascular invasion. … The prognosis of patients who are diagnosed with iHCC is grim, with a median survival of only 4 months. Nonetheless, our results suggest that some patients may still derive survival benefit from liver-directed therapy and/or systemic therapy with sorafenib.”

Source

Only half of those with HCV complete confirmatory RNA test

May 7, 2013

Nearly 50% of people who have ever had hepatitis C virus have received a follow-up RNA test to confirm whether they are still infected, according to new research by the CDC.

“The majority of people who have HCV do not even know they have HCV,” John Ward, MD, director of the CDC’s Division of Viral Hepatitis, said during a media briefing. “People must complete the two-step testing process to accurately identify current infection, so that they can receive the treatment they need. These data give us an idea of the gap between those who are and those who are not receiving the second follow-up test, showing us that we have a substantial challenge in front of us.”

The researchers evaluated surveillance data from eight sites in the United States, obtained from 2005 to 2011. They compared the number of people with a positive HCV antibody test with the number of people with a positive HCV RNA test. They examined the numbers by birth cohort, surveillance site and number of deaths. They also calculated the rates of newly reported HCV infection in 2011.

There were 217,755 people with newly reported HCV, and among those, 107,209 (49.2%) only had a positive antibody test and 110,546 (50.8%) had a positive RNA test. In both groups, people born from 1945 to 1965 comprised most new infections. Across all of the sites, the rate of persons with newly reported HCV infection was 84.7 per 100,000 population.

“HCV affects about 3 million Americans, most of whom are baby boomers,” CDC Director Thomas Frieden, MD, MPH, said during the media briefing. “The bottom line is that if you were born from 1945 to 1965, get tested, and if that test is positive, have follow-up testing. You may not remember everything that happened in the ’60s and ’70s, but your liver does.”

According to Frieden, about half of the people infected with HCV will go on to have serious liver problems and about one-third may die of complications from their infections. HCV also is the leading cause of liver cancer, which is the fastest growing cause of cancer-related death in the United States, he said. If baby boomers are tested and receive care, about 120,000 deaths can be prevented.

The CDC recommends that testing for HCV begins with a rapid or laboratory-conducted assay for HCV antibody. A reactive result should be followed up with nucleic acid testing for HCV RNA.

For more information:

CDC. MMWR. 2013;62(early release):1-5.

CDC. MMWR. 2013;62(early release):1-4.

Source