November 18, 2010

Why so many antibodies fail to protect against HIV infection

November 18, 2010

DURHAM, NC — Researchers have been stymied for years over the fact that people infected with the AIDS virus do indeed produce antibodies in response to the pathogen — antibodies that turn out to be ineffective in blocking infection.

Now, scientists at Duke University Medical Center can explain why: Some of the earliest and most abundant antibodies available to fight HIV can’t actually “see” the virus until after it’s already invaded a healthy cell.

The scientists based their conclusion on the results of a series of crystallography and biochemical experiments that revealed the specific molecular structures different types of antibodies need to have in place in order for them to mount an effective defense.

Previous research had shown that two of the most robust antibodies against HIV — antibodies called 2F5 and 4E10 — target a specific part of the outer coating of the virus called the MPER region of gp41. The antibodies, which operate in a lock and key relationship, are able to latch on to the virus as it reveals this vulnerable part of its structure, referred to as an “Achilles heel” of the AIDS virus.

“What our studies revealed, however, is that the virus actually creates two versions of this ‘Achilles heel,’ says Barton Haynes, MD, director of the Duke Human Vaccine Institute (DHVI) and the senior author of the study appearing online in Nature Structural & Molecular Biology. “One version is for these rarer, broadly-neutralizing antibodies, and the other is for the more abundant, first-responding antibodies that won’t be able to do much good because the Achilles heel isn’t detectable to them until the virus has already gained entry.”

Nathan Nicely, PhD, the lead author of the study and a member of the DHVI, designed and conducted most of the crystallography studies. “This structure has been difficult to obtain, but now that we have it, it has been instrumental in our understanding why this non-neutralizing antibody interacts with the HIV-1 outer coat.”

Haynes says the findings are important because they distinguish what parts of the virus an antibody needs to recognize from those parts that are decoys. “We are homing in on a better understanding of what the immune system needs to do in order to mount an effective defense against HIV.”

The study was funded by a Collaboration for AIDS Vaccine Discovery Grant from the Bill & Melinda Gates Foundation.

Colleagues who contributed to the study include S. Moses Dennison, Leonard Spicer, Richard Scearce, Garnett Kelsoe, Yoshihiro Ueda, Haiyan Chen, Hua-Xin Liao, and S. Munir Alam, all from Duke.

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Clin Transplant. 2010 Nov 16. doi: 10.1111/j.1399-0012.2010.01349.x. [Epub ahead of print]

Han SH, Reddy KR, Keeffe EB, Soldevila-Pico C, Gish R, Chung RT, Degertekin B, Lok A; the NIH HBV OLT Study Group.

David Geffen School of Medicine at UCLA, Los Angeles, CA University of Pennsylvania, Philadelphia, PA Stanford University, Stanford, CA University of Florida Gainesville, Gainesville, FL California Pacific Medical Center, San Francisco, CA Massachusetts General Hospital, Boston, MA University of Michigan, Ann Arbor, MI, USA.

Abstract

Han SH, Reddy KR, Keeffe EB, Soldevila-Pico C, Gish R, Chung RT, Degertekin B, Lok ASF. Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV-OLT study.
Clin Transplant 2010: Doi: 10.1111/j.1399-0012.2010.01349.x.
© 2010 John Wiley & Sons A/S. ABSTRACT: Background:  Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV-related HCC is increasing, while the number of patients listed for HBV-related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long-term outcome of patients transplanted for HBV-related HCC in the National Institutes of Health (NIH) HBV OLT Study Group. Results:  Ninety-eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV-related HCC. With a mean follow-up of 36.5 months post-OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre-OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre-OLT in predicting HCC recurrence. Serum alpha-fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p = 0.003). HCC recurrence was significantly associated with decreased post-OLT survival. Conclusion:  HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence.

© 2010 John Wiley & Sons A/S.

PMID: 21077950 [PubMed - as supplied by publisher]

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A Promising First Step for Combination Oral Therapy Against HCV

In a short-term study, use of a protease inhibitor and a polymerase inhibitor together rapidly lowered HCV RNA levels.

Oral hepatitis C virus (HCV) protease inhibitors are expected to be approved in 2011. Adding these agents to standard HCV treatment (peginterferon plus ribavirin) improves the likelihood of sustained virologic response, but the interferon component must be given subcutaneously and has substantial side effects. In the industry-funded INFORM-1 study, researchers explored whether an interferon-free regimen containing two new oral anti-HCV agents — the protease inhibitor danoprevir, plus the nucleoside polymerase inhibitor RG7128 — could successfully suppress HCV replication.

Patients with chronic HCV genotype 1 infection but not cirrhosis or HIV infection were randomly assigned to receive placebo (n=14) or one of six different doses of danoprevir plus RG7128 (n=74) for 13 days. Treatment was directly observed in a clinical research unit.

At day 14, patients who received danoprevir plus RG7128 had marked declines in HCV RNA, with the median reduction ranging from 3.7 to 5.2 log10 IU/mL in the different dose groups; some patients achieved undetectable HCV RNA levels. At the highest doses tested, reductions in viral load were similar between patients who were treatment naive and those who had not responded to previous standard-of-care treatment. No phenotypic drug resistance was detected, although one patient with viral rebound did have a clone containing a danoprevir-resistance mutation.

Comment: This study shows that a combination of two oral investigational agents effectively suppresses HCV replication, at least in the short term. There has been an explosion of new direct-acting anti-HCV agents, and promising trial results were reported for many of them at the Liver Meeting this month in Boston. If longer-term studies show that combination therapy with new oral agents can eliminate viral replication, we may be able to cure HCV with pills alone. As an editorialist notes, we are "on the eve of a new era in HCV treatment."

Rajesh T. Gandhi, MD

Published in Journal Watch Infectious Diseases November 17, 2010

Citation(s):

Gane EJ et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010 Oct 30; 376:1467.
Medline abstract (Free)

Thomas DL. Curing hepatitis C with pills: A step toward global control. Lancet 2010 Oct 30; 376:1441.
Medline abstract (Free)

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Published on: 2010-11-17

Chronic HCV infection combined with occult hepatitis B infection has been associated with liver enzymes flare, advanced hepatic fibrosis and cirrhosis, poor response to standard interferon-alpha, and increased risk of HCC. This study aimed to elucidate the prevalence of occult hepatitis B infection in Egyptian chronic HCV patients, and to clarify its role in non-response of those patients to pegylated interferon/ribavirin therapy.

This study enrolled 155 consecutive chronic HCV patients under pegylated interferon/ribavirin therapy. All patients were exposed to clinical assessment, biochemical, histological and virological examinations.

HBV parameters (HBV DNA, anti-HBc, anti-HBs) and patients'response status to the combination therapy were determined.

Results: In this study, occult hepatitis B infection occurs in 3.9% of Egyptian chronic HCV patients; tends to affect younger age patients, associated with higher base line HCV viral load, less hepatic fibrosis than monoinfected patients. This occult hepatitis B infection is not a statistically significant cause of non-response to pegylated interferon/ribavirin therapy.

Anti-HBs was not associated with any biochemical, histological or virological abnormalities in those patients, contrary to low response rate to therapy and higher HCV viral load that was observed with anti-HBc.

Conclusions: Detection of HBV DNA in HBsAg negative chronic HCV patients plays a non significant role in non-response of Egyptian patients to pegylated interferon/ribavirin therapy.

Author: Mohamed EmaraNahla El-GammalLamiaa MohamedMaged Bahgat

Credits/Source: Virology Journal 2010, 7:324

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Medivir Gains as Early Study Shows Drug Kills Hepatitis C Virus

By Frances Schwartzkopff - Nov 18, 2010 7:20 AM ET

Medivir AB, the drugmaker competing to develop a new hepatitis C medicine, rose the most in four months in Stockholm trading after its drug reduced the virus to undetectable levels in patients who failed earlier treatment.

After 24 weeks, 86 percent of patients who had only partially responded to earlier treatment had undetectable virus levels after taking TMC435 alongside standard care, the Huddinge, Sweden-based company said in a study published today. That compared with undetectable levels in 19 percent of patients receiving a placebo. Shares rose as much as 9.2 percent.

Medivir is developing TMC435 with Tibotec Pharmaceuticals. The drugmaker, a unit of New Brunswick, New Jersey-based Johnson & Johnson, also is working simultaneously with Vertex Pharmaceuticals Inc. on a new hepatitis C drug.

Vertex, based in Cambridge, Massachusetts, plans to seek U.S. approval for its medicine, Telaprevir, by the end of the year.

Medivir, which still needs to conduct the last trial needed to seek regulatory approval, said 78 percent of patients who didn’t respond at all to initial treatment had undetectable virus levels after taking TMC435, almost twice as many as those who received a placebo.

The medication also led to undetectable virus levels in 94 percent of patients who had relapsed after receiving earlier care. That compared with 83 percent of patients taking a placebo. 462 patients participated in the 48-week study, with results taken half way through.

Medivir rose 8.5 kronor, or 6.8 percent, to 133.5 kronor at 12:54 p.m. local time. The advance gave the drugmaker a market value of 3.5 billion kronor ($511 million), its highest since December 2000.

To contact the reporter responsible for this story: Frances Schwartzkopff at fschwartzko1@bloomberg.net

To contact the editor responsible for this story: Angela Cullen at acullen8@bloomberg.net

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Hepatologist Bruce Bacon Honored for Distinguished Service

November 18, 2010
Carrie Bebermeyer
314.977.8015
bebermcl@slu.edu

ST. LOUIS - Bruce R. Bacon, M.D., professor of internal medicine in the division of gastroenterology and hepatology at Saint Louis University, received the American Association for the Study of Liver Diseases (AASLD) Distinguished Service Award at the 61st annual meeting of the AASLD. This is an honor given to an individual for his or her ongoing service to those with liver disease.

Bacon holds the James F. King, M.D., endowed chair in gastroenterology at SLU and served as the director of the division of gastroenterology and hepatology at the Saint Louis University School of Medicine from June 15, 1990 to June 1, 2010.

"The AASLD's distinguished service award is a fitting honor for Bruce, who has dedicated his life to helping patients," said Adrian M. Di Bisceglie, M.D., chair of internal medicine at SLU. "Through patient care, basic and clinical research and medical and public education, few have done more to advance the field of hepatology."

Bacon received his undergraduate education at the College of Wooster and his medical degree at Case Western Reserve University. He completed his internal medicine residency and training in gastroenterology at Cleveland Metropolitan General hospital and the city hospital of Cleveland before joining the faculty of Case Western.

A leader in the field, Bacon served as an advisor to and grants reviewer for the National Institutes of Health, president of the AASLD, chairman of the gastroenterology board and the transplant hepatology board for the American Board of Internal Medicine and, most recently, a member of the Digestive Diseases Research Council. He has also been an associate editor for major medical journals, including Gastroenterology and the American Journal of Gastroenterology and is a regular reviewer for prestigious medical journals such as The New England Journal of Medicine.

Bacon was named a National Institutes of Health Research fellow, receiving a postdoctoral research fellowship from the American Liver Foundation and an NIH New Investigator Research Award among other achievements. He also helped to establish the Missouri chapter of the American Liver Foundation and received their Outstanding Chapter Leadership award and was chairman of the Patient and Professional Education Committee for that organization.

Among Bacon's biggest achievements is his contribution to the discovery of the HFE gene, the gene associated with hereditary hemochromatosis, a disorder that interferes with the body's ability to absorb iron. He received the Marcel Simon Award for best research in hemochromatosis by a young investigator for his studies on the mechanism of iron toxicity given by the BioIron Society.

In 1999, he helped to found the Saint Louis University Liver Center, which has earned an international reputation for patient care, basic and clinical research and medical and public education.

His supporters formed an organization to help him and Saint Louis University. Among this group are a few who stand out for their contributions to this worthwhile cause - Joan Lipic, Julia Spears, Sue Barlett, and of course, his patient Naomi Judd who continues to support the Friend's organization with her power as a country star to help the foundation exceed expectations in funding research for the SLU Liver Center. The Friends of the Saint Louis University Liver Center has now raised about $2 million to support research at SLU.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

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Organ procurement air transportation displays poor safety record

Public release date: 18-Nov-2010
Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

Industry-wide standards needed to improve security of transplant teams

The transplant community was largely unaware of sub-standard transportation practices for donor organs until a number of fatal air crashes took the lives of transplant personnel, calling attention to procurement aviation safety. A new report highlighting the need for improved safety measures in organ procurement travel appears in the December issue of Liver Transplantation, a peer-reviewed journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).

In the U.S., the Organ Procurement and Transplantation Network (OPTN) is responsible for maintaining the national transplant waiting list which currently has more than 72,000 patients on the active wait list and only 8,477 donors. Given the scarcity of donor organs the need to quickly expedite their recovery and delivery to intended transplant patients is apparent. Many times procurement by air transport is necessary and at times dangerous due to nonstandard practices as John Renz, M.D., Ph.D., from the University of Chicago points out in his report.

Dr. Renz evaluated fatal and non-fatal procurement air accidents in the U.S. which were reported to the National Transportation Safety Board (NTSB). He found in one incident, a surgeon who was not licensed to fly at night attempted to do so and crashed on take-off, killing himself and a physician's assistant. Other accidents involved pilot error such as runway overrun, mismanagement of an abnormal flight control situation, and lack of flight crew coordination. "No accident was associated with the processes of procurement," said Dr. Renz. "It was the tolerance of dangerous operational practices, not found in commercial airline service, which contributed to the incidents."

A prior study by Englesbe and Merion calculated that the procurement air travel fatality rate is 1000 times higher than commercial aircraft, speculating the "riskiest job in medicine" belongs to transplant surgeons involved in procurement transport. In his editorial also published in this month's issue, Dr. Robert Merion, Professor of Surgery at the University of Michigan Health Systems and President of Arbor Research Collaborative for Health, adds, "We need better data on organ procurement travel and a commitment to zero tolerance policy for procurement-related travel accidents." Dr. Merion, who lost four colleagues in a 2007 procurement flight crash which also claimed the lives of the two pilots, suggests the outcome of each procurement flight or ground transport be reported to the OPTN.

In his report, Dr. Renz also presents measures to create a "culture of safety" among those involved with organ transportation. He cites the use of quality aircraft, two-pilot crews, and aviation safety consultants as methods to improve safety. "Mandating turbine-powered, fixed wing aircraft, operated by reference to instruments under commercial flight regulations, to airports with continuous radar surveillance by two qualified pilots would ensure a level of competence and safety we expect with scheduled airline service," concluded Dr. Renz.

While both the study and editorial stress a need for procurement travel standards, the two doctors disagree on feasibility and cost of implementation. The authors do agree that further evaluation is necessary and should ultimately result in national procurement transportation standards that will ensure the safety of those involved in the travel and continued service for transplantation patients awaiting donor organs.

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This study is published in Liver Transplantation. Media wishing to receive a PDF of this article may contact healthnews@wiley.com .

Full citation: "How Can We Improve Procurement Air Travel Safety?" John F. Renz. Liver Transplantation; Published Online: September 21, 2010 (DOI: 10.1002/lt.22191); Print Issue Date: December 2010. http://onlinelibrary.wiley.com/doi/10.1002/lt.22191/abstract

Editorial. "Physician, heal thyself; but don't fly thyself." Robert Merion. Liver Transplantation; Published Online: November 16, 2010 (DOI: 10.1002/lt.22219); Print Issue Date: December 2010. http://onlinelibrary.wiley.com/doi/10.1002/lt.22219/abstract

About the Journal

Liver Transplantation is published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society . Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AALSD and the ILTS, Liver Transplantation. delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit Liver Transplantation.

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