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FDA approves new melanoma drug - (Need to do some research with the HP. Maybe the HP can bring costs down!)
August 17, 2011, 5:24 pm
Fast F.D.A. Approval of Melanoma Drug
By DUFF WILSON
Updated: The Food and Drug Administration approved an expensive new melanoma drug much faster than expected, giving a boost not only to that drug but also to other experimental products that may offer gene-based personalized medicine.
The F.D.A. approved vemurafenib, with the brand name Zelboraf, to treat patients with metastatic melanoma who have a certain genetic mutation called BRAF V600E. The drug inhibits the cancer-spreading action of that particular gene, which is held in about 50 percent of people who have metastatic melanoma.
The F.D.A. also approved a test for the genetic mutation.
Roche Holding said the drug would be available in about two weeks at a price of $9,400 a month. The drug will be sold by Genentech of San Francisco, a subsidiary of Roche of Switzerland, and Daiichi Sankyo of Japan.
Roche sought approval in May under an expedited review process for drugs that may offer major advances. The F.D.A. was expected to act by Oct. 28. Its approval came more than two months early — a vote of confidence by an agency that has been accused of failing to act promptly on some other drugs.
The fast action may portend well for crizotinib, a proposed lung cancer drug from Pfizer shown to be effective in the estimated 3 to 5 percent of non-small cell lung cancer patients whose tumors have a certain gene. That, too, was submitted with a diagnostic gene test. It is still under review.
In March, the F.D.A. approved another new drug for late-stage melanoma, called Yervoy, from Bristol-Myers Squibb. It acts on the immune system. Bristol-Myers Squibb charges $120,000 for a course of treatment.
Clinical trial results on the two drugs were released at the annual meeting of the American Society of Clinical Oncology, to the acclaim of skin cancer doctors.
“This has been an important year for patients with late-stage melanoma,” Dr. Richard Pazdur, director of the F.D.A. Office of Oncology Drug Products, said in a press release on Wednesday.
But it is far from a cure.
“The F.D.A.’s quick action on this drug approval is important because it gives melanoma patients a new way to fight this deadly disease,” Timothy J. Turnham, executive director of the Melanoma Research Foundation, said in a statement. But many patients become resistant, he added, and the drug prolongs lives only months on average, pointing to the need for further research.
Side effects of Zelboraf may include joint pain, rash, hair loss, fatigue, nausea, skin sensitivity when exposed to the sun, and another skin-related cancer that can be managed with surgery.
Melanoma is the deadliest skin cancer. About 8,700 people died of it in the United States last year and 68,000 were newly diagnosed, according to the National Cancer Institute.
An earlier version of this post misstated the monthly cost of the melanoma drug. It is expected to be $9,400 a month, not $9,800.
http://prescriptions.blogs.nytimes.com/2011/08/17/fast-f-d-a-approval-of-melanoma-drug/
Proposed draft constitution for a society dealing with “Exosomes, Microvesicles and beyond”
July 22nd, 2011 § 1 Comment
Hello Exosome and Microvesicles friends.
There has been a lot of discussion since the IWE in Paris in January to establish a true society for this rapidly growing field. Margareta Sjöstrand has helped us draft a constitution for this Society, based on the constitution of other large Academic Associations. It may seem complicated, but it isn’t really. Thanks to Clotilde Thery and Douglas Taylor for giving early feedback.
This draft Constitution will be also made available to a larger community, beyond the FB-colleagues, but that will come in a few weeks. Please feel free to comment, or send me an e-mail with any suggestions you may have (jan.lotvall@gu.se). Or comment on the dedicated facebook page: http://www.facebook.com/groups/171229582921487
PLEASE NOTE THAT THE NAME OF THE SOCIETY IS PROVISIONAL (we have to figure out the nomenclature first )
The Draft Constitution of the World Exosomes and Microvesicles Society:
Constitution of the World Exosomes and Microvesicles Society (WEMS):
(or should it be “International Microvesicles and Exosomes Society (IMES)”
ARTICLE 1: NAME, SEAT, AND INCORPORATION
(a) The name of the association shall be the “World Exosomes and Microvesicles Society “
hereinafter referred to as the “Society”or “WEMS.”.
(b) The Society is an association pursuant to Swedish Law.
(c) The official headquarter (seat) of the Academy is in Gothenburg, Sweden. The address of the office of the Society will be determined by a resolution of the Executive Committee of the Society.
(d) The Society is an international organization of individual persons, constituted as an association. The Society has no commercial aims and is not for profit.
(e) The Society may be moved elsewhere in Sweden or the world, as determined by the General Assembly.
ARTICLE 2: AIMS
The Society shall be a non-profit organization aimed at:
• promoting basic, translational and clinical research within the field of Exosomes and Microvesicles;
• collecting, assessing and disseminating scientific information of Exosomes and Microvesicle research;
• being a scientific reference body for other scientific, health and political organizations;
• encouraging and providing training and continuous education within the field of Exosomes and Microvesicles.
ARTICLE 3: LANGUAGES
English shall be the official language of the Constitution and By-Laws, and of any document or activity where more than one language is used.
ARTICLE 4: MEMBERSHIP (MEMBERS WITH VOTING RIGHTS)
Members of the Society with voting rights:
Individual members: individual members who are scientifically or clinically interested in Exosome and/or Microvesicle Research shall be eligible to join the Society as Individual Members.
ARTICLE 5: EXECUTIVE COMMITTEE
The Society Executive Committee of the society shall consist of:
• The President
• The Secretary General
• The Treasurer
•The Past President• Six members at large
The term of office shall be two years commencing and finishing at an annual WEMS Congress. The position of a member of the Executive Committee is an honorary one and no remuneration shall be paid to any member of the Executive Committee, provided that each member of the Executive Committee is entitled to the reimbursement of his/her actual costs and out-of-pocket expenses which he incurred in this function. If a member of the Executive Committee renders special services to the Association, he may be entitled to an equitable remuneration.Eligibility for re-election: The President is not re-eligible for the same post. It is not possible to hold the position of Secretary General or Treasures in total for more than two terms (four years in total).No individual may serve for a total of more than four terms in the executive committee unless they are elected as president. No individual can serve for more than two terms as Member-at-Large.
The Executive Committee shall hold a meeting at least once every year. The Executive Committee shall define detailed rules dealing with relevant activities of the Society, such as congress organization, editorial activity and the composition and function of subsidiary bodies. It shall examine applications for membership, and shall have the power to accept or reject these applications. It shall propose the place of the Annual Meeting.
The presence of at least five members of the Executive Committee is required for decisions.
The President, the Secretary-General and the Treasurer, together with the past President, constitute the Board of Officers aimed at conducting the day-to-day business of the Academy and all business delegated to this Board by the Executive Committee. An administrative assistant may be delegated limited responsibilities.
The Secretary-General is responsible for:
(a) notifying all members of the date, place and agenda of the General Assembly at least one month before the meeting
(b) notifying the members of the Executive Committee of the date and place of any meeting at least one month before the meeting
(c) making a yearly report to the General Assembly of all activities of the Society;
(d) keeping records of the Executive Committee and General Assembly meetings.
(e) acting as deputy chair of the Executive Committee
The Treasurer is responsible for:
(a) keeping a register of all members and affiliates
(b) receiving all fees of individual members
(c) paying all expenses approved by the President or the Executive Committee
(d) presenting a yearly balance certified by professional auditors and making a report to the General Assembly of the financial status of the Academy.
ARTICLE 6: GENERAL ASSEMBLY
The General Assembly shall be the governing body of the Society. All members regardless of their voting right are entitled to receive an invitation for the General Assembly and to participate and speak in the General Assembly. Only members with voting rights are entitled to vote in the General Assembly.
The General Assembly shall elect the members of the Executive Committee from among individual members of the Society and approve or disapprove of any external and internal audit.
The General Assembly shall meet every year. At any meeting of the General Assembly, the President, the Secretary-General and the Treasurer shall submit a report of all their activities since the last General Assembly, to be approved by a majority vote.
ARTICLE 7: ADMISSION AND ELECTIONS
• Individual Members: A formal application is to be sent to the Treasurer, and shall be approved by Board-of-Officers.
• Members of the Executive Committee: Any individual member can propose a candidate for a member-at-large position. Proposals must be sent to the Secretary-General at least three months before the General Assembly. The executive committee shall prepare a slate of nominations, taking into account geographic and professional affiliations, and shall propose this to the General Assembly. A simple majority vote of the members of the General Assembly is required to confirm the election of the proposed slate of candidates. In the event that a slate of nominations is rejected, the executive committee shall consult the membership and propose an alternative slate for approval either at an extraordinary general assembly or by a secure ballot. In this event, a postal or web-based ballot may be used, at the discretion of the executive committee.
• The President, Treasurer and Secretary-General shall be nominated by the Executive Committee from among the eligible officers, and shall be elected by the General Assembly. The nomination requires the approval of the general assembly, one year before taking up their terms. Once nominated and approved, the president-elect, treasurer-elect and secretary-general elect shall continue to serve in their existing capacity on the executive committee.
ARTICLE 8: DELEGATION OF POWERS
a) The Executive Committee may set up an executive office to serve the Society.
b) The Executive Committee may enact by-laws or regulations by which certain powers vested in the Executive Committee, the Board of Officers or an Officer of the Academy are delegated temporarily or permanently to third persons – namely to the executive office staff.
c) The Executive Committee and/or the Board of Officers may also appoint attorneys who will represent the Academy in the matters described in the respective power of attorney.
ARTICLE 9: AUDITORS
a) The Executive Committee shall appoint a renowned auditing company as Auditors of the Society for a term of one financial year. Reappointment is possible. The Auditors will audit the books and the financial statements of the Society pursuant to the appropriate professional standards to be agreed on with the Board of Officers and submit their report for the financial year expired to the Executive Committee.
b) The Executive Committee shall submit the report of the Auditors together with the balance sheet, the lost and profit statement and the report of the treasurer for the last financial year of the Society to the General Assembly for approval.
d) The Society may also appoint internal auditors, constituting of up to two members of the Society, as decided by the General Assembly. The internal auditors cannot be members of the Executive Committee.
ARTICLE 10: MEMBERSHIP FEES
Each individual member shall pay annual fees as decided by the Executive Committee. Individuals that fail to pay their dues, will be excluded as members of the Society, and will lose their voting rights.
ARTICLE 11: DISSOLUTION
The Society may be dissolved by a resolution of the General Assembly. The Society will then be liquidated by its Executive Committee or by other liquidators appointed by the General Assembly. The General Assembly will designate another tax-exempt institution with similar purposes to which any net assets of the Association remaining after the payment of all debts shall be transferred. Any distribution of assets of the Association to its members is not possible.
ARTICLE 12: AMENDMENT OF THE CONSTITUTION
The Constitution may be amended by a simple majority vote of the General Assembly or by a simple majority of those participating in a postal and/or web based vote.
Proposals to change the Constitution should be notified to the Secretary at least three months before the General Assembly.
Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production. (Very technical - only posted the summary)
Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z.
SourceJ Immunol. 2011 Jul 15;187(2):676-83. Epub 2011 Jun 15.
Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production.
Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z.
Source
Department of Pharmacology, Radiology and Oncology, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, United Kingdom.
Abstract
In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment.
PMID: 21677139 [PubMed - in process]
Department of Pharmacology, Radiology and Oncology, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, United Kingdom.
Abstract
Extracellular adenosine is elevated in cancer tissue, and it negatively regulates local immune responses. Adenosine production from extracellular ATP has attracted attention as a mechanism of regulatory T cell-mediated immune regulation. In this study, we examined whether small vesicles secreted by cancer cells, called exosomes, contribute to extracellular adenosine production and hence modulate immune effector cells indirectly. We found exosomes from diverse cancer cell types exhibit potent ATP- and 5'AMP-phosphohydrolytic activity, partly attributed to exosomally expressed CD39 and CD73, respectively. Comparable levels of activity were seen with exosomes from pleural effusions of mesothelioma patients. In such fluids, exosomes accounted for 20% of the total ATP-hydrolytic activity. Exosomes can perform both hydrolytic steps sequentially to form adenosine from ATP. This exosome-generated adenosine can trigger a cAMP response in adenosine A(2A) receptor-positive but not A(2A) receptor-negative cells. Similarly, significantly elevated cAMP was also triggered in Jurkat cells by adding exosomes with ATP but not by adding exosomes or ATP alone. A proportion of healthy donor T cells constitutively express CD39 and/or CD73. Activation of T cells by CD3/CD28 cross-linking could be inhibited by exogenously added 5'AMP in a CD73-dependent manner. However, 5'AMP converted to adenosine by exosomes inhibits T cell activation independently of T cell CD73 expression. This T cell inhibition was mediated through the adenosine A(2A) receptor. In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment.
PMID: 21677139 [PubMed - in process]
Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production.
Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z.
Source
Department of Pharmacology, Radiology and Oncology, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, United Kingdom.
Abstract
Extracellular adenosine is elevated in cancer tissue, and it negatively regulates local immune responses. Adenosine production from extracellular ATP has attracted attention as a mechanism of regulatory T cell-mediated immune regulation. In this study, we examined whether small vesicles secreted by cancer cells, called exosomes, contribute to extracellular adenosine production and hence modulate immune effector cells indirectly. We found exosomes from diverse cancer cell types exhibit potent ATP- and 5'AMP-phosphohydrolytic activity, partly attributed to exosomally expressed CD39 and CD73, respectively. Comparable levels of activity were seen with exosomes from pleural effusions of mesothelioma patients. In such fluids, exosomes accounted for 20% of the total ATP-hydrolytic activity. Exosomes can perform both hydrolytic steps sequentially to form adenosine from ATP. This exosome-generated adenosine can trigger a cAMP response in adenosine A(2A) receptor-positive but not A(2A) receptor-negative cells. Similarly, significantly elevated cAMP was also triggered in Jurkat cells by adding exosomes with ATP but not by adding exosomes or ATP alone. A proportion of healthy donor T cells constitutively express CD39 and/or CD73. Activation of T cells by CD3/CD28 cross-linking could be inhibited by exogenously added 5'AMP in a CD73-dependent manner. However, 5'AMP converted to adenosine by exosomes inhibits T cell activation independently of T cell CD73 expression. This T cell inhibition was mediated through the adenosine A(2A) receptor. In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment.
PMID: 21677139 [PubMed - in process]
Hope this involves AEMD also!
1ST ANNOUNCEMENT: Conference on Exosomes & Microvesicles, Lake Buena Vista, Florida, October 15-17, 2011
University of Louisville, 19th July 2011: The organizing committee under the chairmanship of Professor Douglas Taylor are pleased to announce a Conference & Exhibition on exosomes and microvesicles to be held from the 15th to 17th October at the Wyndham Lake Buena Vista Resort, Florida.
This exciting conference is designed to bring together researchers in the rapidly growing field of exosomes and microvesicles. Attendees are encouraged to come to Florida in October to share their latest research with colleagues in this exploding field.
The scientific organizing committee under the chairmanship of Professor Douglas Taylor of the University of Louisville is seeking papers covering a range of topics:
- Basic cell biology/biochemistry of vesicle biogenesis
- Vesicle purification/characterization/analysis/composition
- Use of vesicles in clinical applications
- Vesicle functions in normal physiological processes
- Role of vesicles in human disease
- Recent developments and remaining challenges
Commenting on the meeting, Professor Taylor said “New analysis techniques are emerging which cast doubts upon some of the old definitions that we use. They also show that the standard preparation methods do not result in pure exosomes, but a mixture of exosomes and microvesicles, which the current dogma tells us should have very different properties. The conference is sure to be the venue for some exciting and heated debates.”
Researchers are encouraged to submit abstracts for both oral and poster contributions via the conference web site. The submission deadline is 15thAugust, 2011. The Conference website (http://www.exosomeandmicrovesicle.org) also allows registration for the meeting for both delegates and exhibitors.
For further information, please NetDyaLog Limited:
Jezz Leckenby
T +44 (0) 1799 521881
M +44 (0) 7843 012997
NetDyaLog website www.netdyalog.com
jezz@netdyalog.com
Exosomes: secreted vesicles and intercellular communications
Clotilde Théry
Institut Curie, INSERM U932, Paris, France
Corresponding author
F1000 Biol Reports2011, 3:15 (doi: 10.3410/B3-15)
Published: 01 Jul 2011
© 2011 Faculty of 1000 Ltd
The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/3/15
An adapted version of this article has been published in The Scientist magazine: http://the-scientist.com/2011/07/01/exosome-explosion/
Abstract
Exosomes are small membrane vesicles of endocytic origin secreted by most cell types, and are thought to play important roles in intercellular communications. Although exosomes were originally described in 1983, interest in these vesicles has really increased dramatically in the last 3 years, after the finding that they contain mRNA and microRNA. This discovery sparked renewed interest for the general field of membrane vesicles involved in intercellular communications, and research on these structures has grown exponentially over the last few years, probing their composition and function, as well as their potential value as biomarkers.
Introduction
Secreted vesicles known as exosomes were first discovered nearly 30 years ago. But, considered little more than cellular garbage cans acting to discard unwanted molecular components, exosomes remained little studied for the next 10 years. Over the past few years, however, evidence has begun to accumulate that the vesicles are like signaling payloads containing cell-specific collections of proteins, lipids, and genetic material that are transported to other cells where they alter function and physiology. The findings have reignited interest in exosomes, but also more generally in all secreted vesicles, whether they can be called exosomes or not, and the topic has now blossomed into a full-fledged field of research—that of vesicle-modulated cell-cell communication.
Two years ago, I began receiving daily emails regarding my articles on exosomes, requesting reprints, details on exosome-related protocols, and advice on the purification and characterization of the vesicles. Having worked in this area for more than 10 years, I thought I knew all the other researchers working on the subject, but the requests were coming in from groups I hadn't heard of before. The flood of inquiries made me realize that the field had been growing, attracting the attention of more and more researchers in a relatively short period of time.
A quick glance at the literature confirmed the trend: while fewer than 20 PubMed-referenced papers using the word “exosomes” were published in early 2003, and just over 60 in 2007, nearly 350 exosome studies have been published in the last 3 years alone. The idea thus came to me and to Graça Raposo, who discovered exosomes from immune antigen-presenting cells in 1996, to organize an International Workshop on Exosomes (IWE). Although a meeting organized by the late Rose Johnstone, who participated in the first description of exosomes in 1983, had drawn 25 scientists to Montreal, Canada, in 2005 [1], the new meeting, which took place this January at our home institution, the Curie Institute in Paris, attracted nearly 10 times as many attendees. There, researchers discussed their recent findings on exosomes, and on other types of secreted membrane vesicles, in fields ranging from immunology to neurobiology and tumor biology, as well as potential clinical applications, such as biomarkers or as therapeutic tools.
In pluricellular organisms, cells communicate with each other via extracellular molecules such as nucleotides, lipids, short peptides, or proteins. These molecules are released extracellularly by cells and bind to receptors on other cells, thus inducing intracellular signaling and modification of the intracellular physiological state of the recipient cells. But, in addition to these single molecules, eukaryotic cells also release in their extracellular environment complex structures called membrane vesicles, which contain numerous proteins, lipids, and even nucleic acids, and can affect the cells that encounter these structures in much more complex ways. Although known to exist for several decades (for instance, in blood, where they are generally called “microparticles”, or in seminal fluid, where they are called “prostasomes” [2]), membrane vesicles have long been thought of as mere cell debris, signs of cell death, or structures very specific to a unique organ. The phenomenon of exosomes and their wider involvement in intercellular signaling began to emerge from this picture in the last decade.
Exosomes represent a specific subtype of secreted membrane vesicles (reviewed in [3]). Exosomes are formed in endosomal compartments called multivesicular endosomes, containing internal vesicles that package and store molecules in membrane-bound structures. Endosomes are generally considered to function as an intermediate compartment between the plasma membrane, where endocytosis of extracellular molecules takes place, and compartments (lysosomes), where these molecules are released and degraded. However, about 25 years ago, the groups of Philip Stahl [4] in the United States and Rose Johnstone in Canada [5] described, using very elegant pulse-chase and electron microscopy experiments, that in reticulocytes undergoing maturation into red blood cells, multivesicular late endosomes could fuse back with the plasma membrane (instead of with lysosomes), and release their contents, including numerous small vesicles, extracellularly. In 1987, the term “exosomes” was proposed to define these extracellularly released intra-endosomal vesicles [6].
Exosomes remained all but forgotten for the next 10 years until Raposo, while working with the group of Hans Geuze in Holland in 1996 [7], showed that Epstein–Barr virus (EBV)-transformed B-lymphocytes secreted exosomes that bore molecules essential for the adaptive immune response: major histocompatibility class (MHC) II dimers bound to antigenic peptides. These exosomes were also shown to present the MHC–peptide complexes to specific T cells, suggesting that they could play a role in adaptive immune responses. Two years later, the groups of Raposo, Amigorena, and Zitvogel [8] demonstrated that dendritic cells (the immune cells that initiate adaptive immune responses by presenting MHC–peptide complexes to naïve T cells) also secrete exosomes bearing functional MHC–peptide complexes, which could promote induction of antitumor immune responses in mice in vivo. These results provided the basis for the hypothesis that exosomes could play an active role in intercellular communication, at least in the immune system, and prompted the very first attempt at using them in the clinic, as a new type of anticancer therapy in humans. (After phase I trials held between 1999 and 2002, a phase II trial is currently ongoing at the Gustave Roussy Institute (with participation of the Curie Institute) in France [9].)
The first major advance of subsequent years was linked to the development of large-scale protein analysis techniques, which allowed us to demonstrate that exosomes represent a specific subcellular compartment, rather than random cell debris. Proteomic analyses of exosome composition were first performed on exosomes secreted by dendritic cells [10,11], and then on exosomes from numerous other different cell types, which are compiled in the ExoCarta compendium [12]. These studies showed that exosomes did not contain a random array of the intracellular proteins, but a specific set of a few protein families, essentially coming from the plasma membrane, endocytic pathway, and the cytosol, with very limited amounts of proteins from other intracellular compartments (e.g., nucleus, endoplasmic reticulum, and Golgi apparatus), which made them clearly different from membrane vesicles released by apoptotic cells. These results established that exosomes are actively secreted by live cells, and confirmed their intra-endosomal origin. In parallel, studies of exosomes purified in vitro from tissue cultures (of immune cells but also epithelial and tumor cells), started showing that exosomes secreted by one cell could be captured by another cell and transfer information to the latter. The information transferred could include antigens or MHC–peptide complexes for increasing the range of antigen-presenting cells and the efficiency of induction of immune responses [13-15], or in some cases negative signals leading to death of the target cell [16]. These observations provide the basis of the nowadays popular idea that exosomes represent a new type of intercellular messenger.
The second real breakthrough in this field came in 2007, with the convincing description by the group of Jan Lötvall in Sweden of the presence of mRNA and microRNA (miRNA) inside these vesicles [17]. In addition, the authors showed, at least in vitro using large amounts of concentrated exosomes, that some mRNA present in exosomes could be translated into proteins in target cells, suggesting that exosomes can transfer genetic information. This discovery, and the concomitant development of research on miRNAs, sparked the recent exponential increase in the numbers of papers on exosomes.
In January 2011, oral and poster presentations at the IWE 2011 covered all the currently explored fields of exosome research spanning immunology and cell biology, their use as biomarkers, and their relationship to tumors. This led to very open and constructive discussions. My four major conclusions from this meeting are that: (a) exosomes are not the only secreted membrane vesicles that could act as intercellular messengers, and efforts should be dedicated to combine and compare data obtained on these different vesicles; (b) the next few years should show us whether RNA and miRNA in circulating vesicles (exosomes or others) will prove to be useful biomarkers of various diseases, providing new diagnostic or prognostic tools; (c) although they were originally described in cells of the immune system, exosomes are now known to be secreted by many different cell types, and a large amount of recent data highlight their possible functions as messengers during development of tumors, in some functions of stem cells, in the nervous system, or during interactions of pathogens with their host; (d) although the last 3 decades have expanded our knowledge of exosomes considerably, there is still no definite evidence for their physiological functions in vivo, and demonstrating such functions remains a major challenge of this field.
Exosomes and other secreted membrane vesicles
The term “exosomes” should be used to define secreted membrane vesicles that form inside intracellular multivesicular compartments and that are released upon fusion of these compartments with the plasma membrane (Figure 1). Because of this intracellular origin, exosomes are similar in size to internal vesicles of multivesicular compartments; that is, around 100 nm in diameter. Exosomes are commonly purified on the basis of size by serial steps of centrifugation, with a final 100,000 g ultracentrifugation to pellet exosomes; however, this purification is not absolute. Some cells also release other types of membrane vesicles, which can, for instance, directly bud off the plasma membrane towards the outside of the cell. The size of such vesicles is not as strictly determined as that of exosomes, and they can be anywhere between 50–1,000 nm in diameter. Various terms have been used for these vesicles, such as “ectosomes” [18], “shed vesicles”, or “microvesicles”, but this latter term has also been used more widely for any type of vesicle, whether intra- or extracellular, and regardless of its intracellular origin. The release of large plasma membrane-derived vesicles is quickly induced after stimuli such as fresh fetal calf serum on tumor cells [19], complement deposition, or increasing intracellular Ca2+ in neutrophils [20]. Vesicles can be separated by size using ultracentrifugation at different speeds, with the larger vesicles pelleting at lower speed than the smaller ones. But similarly sized vesicles of different intracellular origins (i.e., exosomes and small plasma membrane-derived vesicles) will not be separated by this method. Flotation of vesicles on sucrose gradients can allow some separation of vesicles with different densities, but this separation is not complete. Thus, adequate means to distinguish the different types of vesicles secreted by a cell are still lacking.
Figure 1.
Exosome basics
Proteomic studies of microvesicles or ectosomes have not, so far, been as extensive as for exosomes, but they are underway and they will help to understand the specificity of their secretion. Like exosomes, membrane microvesicles and ectosomes contain various active molecules, such as cytokines, growth factor receptors, and RNAs, and also metalloproteases (which have not been described in exosomes), but since studies comparing exosomes and other vesicles released by the same cells are only beginning now, understanding the functional specificity of each type of vesicle should become possible in the next few years.
RNA and miRNA in secreted membrane vesicles
Since the identification of RNA in exosomes in 2007 and development of high-throughput techniques for nucleic acid analyses, there have been an ever increasing number of studies reporting sequences of the RNA in exosomes. Such studies show that not all messenger RNAs present in a cell end up in exosomes, and there is apparently specific targeting of some mRNA sequences into the released vesicles [17]. These last observations refute the idea that mRNA in exosomes results from a random contamination of secreted vesicles by mRNA released extracellularly by dying cells. However, it is still unclear from the few published studies whether one can (as for exosomal proteins) find a set of exosomal mRNA that would be consistently targeted to exosomes in any cell type, possibly in addition to cell type-specific mRNA sequences. Understanding the mechanisms of mRNA targeting to these vesicles should open the way to understanding the function of RNA delivery to secreted vesicles. Of note, mRNA has also been described in microvesicles (or mixed exosome/microvesicle preparations) released by tumors or embryonic stem cells [21-23], and some ongoing studies are now comparing sequences of RNA targeted to either exosomes or larger vesicles, and determining whether there is a distinct targeting to each of them.
The situation is even more complicated for miRNA: even though they have also been observed in various exosome preparations, the heterogeneity of techniques used to identify the miRNA sequences do not allow one to conclude whether there is specific targeting of miRNA to secreted vesicles. In addition, although extracellular release of miRNA can be decreased by some drugs, the literature still describes heterogeneous results concerning the respective contribution of free (or protein-associated) miRNA, as compared to miRNA encapsulated in exosomes or other secreted membrane vesicles.
Despite the uncertainties about the nature of mRNA and miRNA-carrying vesicles, the biopharma industry has put a lot of effort into studying the use of secreted vesicles—especially their mRNA and miRNA content—as biomarkers in clinics. This is easier than it might seem to be because their encapsulation into membrane vesicles protects extracellular RNAs from degradation, and allows efficient recovery from biological fluids, such as plasma, urine, milk, sperm, or saliva. Work in several different laboratories to compare RNA (as well as protein) sequences in vesicles isolated from normal and cancer cell lines, for instance, and from biological fluids of patients (cancer or other diseases) is ongoing. It is still too early to propose new biomarkers (either for diagnosis, prognosis, or predictive response to therapies) from these studies, but given the current effort put in this direction, the next few years should allow us to decide whether such markers exist and are useful.
Proposed functions of exosomes
Once secreted, membrane vesicles interact with surrounding cells: many fluorescence microscopy studies show capture of these vesicles and accumulation in internal endocytic or phagocytic compartments, especially in phagocytic cells such as macrophages, but one must keep in mind that vesicles smaller than 200 nm in diameter cannot be detected by confocal microscopy techniques, and only electron microscopy allows detailed visualization of exosomes. Hence, the way individual vesicles interact with recipient cells is still not known, and has been proposed to involve binding at the cell surface via specific receptors, internalization by endocytosis or micropinocytosis, and/or fusion with plasma membrane or with the limiting membrane of internal compartments. Evidence that fusion does occur in certain cases comes from a recent study showing diffusion of exosomal lipids in the membrane of recipient cells [24]: this observation explains how exosomes could release their internal content (e.g., RNA) into the cytosol of recipient cells.
Exosomes induce physiological changes in recipient cells upon interaction. Because the original description of exosomes was in immune cells, there is a vast amount of data on the immunological effects of exosomes, and these vary strongly depending on the physiological state of the cells which secrete them (see [9] for references). For instance, mature dendritic cells secrete exosomes that carry antigens or MHC–peptide complexes, and induce antigen-specific immune responses by other dendritic cells (especially in the context of anticancer therapies); conversely, exosomes secreted by dendritic cells subjected to immunosuppressive treatments, or modified to express immunosuppressive cytokines, can instead promote tolerogenic immune responses, which could make them useful as a treatment for autoimmune diseases. In a third example, macrophages infected with procaryotic mycobacteria release exosomes that, depending on the mycobacteria strain, bear antigens and promote immune responses (nonpathogenic strain), or inhibit macrophage activation and cytokine secretion, thus dampening immune response (pathogenic strain).
Although exosomes secreted by tumor cells carry antigens from the secreting tumors and can be captured and used to present tumor antigens by dendritic cells, they also bear various immunosuppressive molecules, which can inactivate T lymphocytes or natural killer cells, or promote the differentiation of regulatory T lymphocytes or myeloid cells (which suppress immune responses). The net result of these contradictory effects in vivo is not yet established, and although several groups defend the hypothesis that tumors secrete exosomes to promote their growth by inhibiting antitumor immune responses, or by promoting angiogenesis or migration outside the tumor bed to form metastases, this has not been proved. Still, it has been suggested that depletion of membrane vesicles from the blood circulation of patients could be used as an anticancer treatment [25], but I would be cautious in using such approaches in the absence of proper understanding of what tumor-derived exosomes or other membrane vesicles do in vivo. An alternative explanation is that membrane vesicles of tumor origin in the circulation of cancer patients could simply be the result of tumor expansion, rather than a sign of active involvement of these vesicles in tumor progression.
Other tissues or cells secrete exosomes bearing immunosuppressive molecules: placenta-derived vesicles, which bear ligands for natural killer lymphocytes, are found in pregnant women's blood circulation, and extensive analyses of components of these vesicles are underway to identify their role in the mother's tolerance to the fetus. Depending on the state of the host, exosomes (or vesicles) present in their bronchoalveolar fluid can bear tolerizing molecules (e.g., in mice tolerized for an allergen) or, conversely, increase proinflammatory cytokine secretion by airway epithelial cells (in asthmatic human patients). Secretion of exosomes by eukaryotic parasites (Leishmania major) or pathogens (such as fungi) has also been recently described. It is thought to contribute to tolerance of the host for the parasite by dampening immune response or, conversely, to contribute pathologic inflammatory reactions of the host to the pathogen.
In addition to the immune system, exosomes probably affect other physiological functions. Exosomes are secreted by neural, epithelial, muscle, and stem cells, and their range of proposed functions is extensive. Exosomes from mesenchymal stem cells contribute to tissue repair of host cardiac tissue, and, conversely, lung tissue can release exosomes (or possibly other vesicles) that modify stem cells to promote differentiation of the lung tissue into lung epithelial cells [26,27]. Exosomes also contribute to communication within the nervous system. Exosomes are secreted by neurons, oligodendroglial cells, and microglia, and exosomes from each source can affect other neural cells [28-30]. Exosomes are involved in the formation/transfer of pathogenic proteins (such as prions and amyloid deposits) [31,32]. No doubt other functions will appear in the coming years!
Physiological functions of exosomes
Despite the amount of data on what exosomes (and other secreted membrane vesicles) can do in vitro, or in vivo when injected into animals, all data discussed above were obtained with vesicles purified and concentrated in vitro from cell culture supernatants or from biological fluids, so it is not clear whether these processes occur under physiological conditions. The main problem is that the efficiency of the purification and quantification procedures is unknown. It is likely that ultracentrifugation does not allow 100% recovery of the vesicles secreted at any given time, and that part of the secreted vesicles are even inaccessible to purification because they are recaptured by cells rather than released in the culture medium or fluid, so it is very difficult to know whether the amounts of membrane vesicles used to observe the effects described above correspond to physiological amounts secreted in vivo, or not. Indeed, there remains a nagging question in the exosome field as to whether they actually have any physiological functions in vivo.
Answering this question requires tools to inhibit or increase exosome secretion specifically, without affecting secretion of other membrane vesicles, or affecting general secretion of proteins or lipid mediators. Several groups are currently trying to identify such tools, especially by deciphering the molecular mechanisms involved in formation of intracellular vesicles of multivesicular compartments, and in the fusion of these compartments with the plasma membrane. Several molecules have been shown to affect exosome secretion, although in the absence of means to visualize and quantify actual fusion of multivesicular endosomes with the plasma membrane in real time, it is still difficult to know whether they are involved specifically in this final step, or at another stage of the endocytic pathway. A consensus has not yet been reached on the molecular mechanisms involved. Indeed, depending on the cell types, different molecules have been described in the biogenesis and secretion of exosomes: Rab11 in erythroleukemia cell lines [33], Rab27 in Hela cells [34], and Rab35 and neutral sphingomyelinase in oligodendroglial cells [35,36]. It remains to be determined whether these discrepancies are due to different machineries used in different cell types, and/or whether the secreted vesicles analyzed in the different studies come from different intracellular compartments (along the endocytic pathway, or even outside this pathway). Recent studies showing that internal vesicles of multivesicular endosomes can, in some circumstances, form without the help of the ESCRT (endosomal sorting complex required for transport) machinery (described as being responsible for segregation of molecules into internal vesicles of late endosomes in yeast) suggest that, indeed, more types of multivesicular compartments than initially thought may coexist in the same cells, and may possibly lead to different types of exosomes. In any case, targeting one or the other of these molecules to affect exosome secretion will require careful evaluation of the consequences (in terms of exosomes, but also other secretions) in each different model system analyzed. Other approaches to address the physiological functions of exosomes in vivo, proposed during the meeting in Paris, include generating exosomes with modified expression of a given functional protein and analyzing their functional outcome, or containing bacterial enzymes to identify target cells via measurement of the enzymatic activity. Using these approaches in genetically modified mice will be the next step for this challenging field.
Finally, similar cell biology studies on the generation of other secreted membrane vesicles are also underway, and hopefully will allow proper discrimination of the roles as messengers of the different types of vesicles.
Conclusion
With the amazing expansion of the number of published studies on exosomes in the last 3 years, it is clear that research on secreted membrane vesicles and their roles as intercellular messengers is now a very exciting field, with new ideas, hypotheses, and questions coming up faster than answers! The IWE in Paris allowed most of the long-term exosome and vesicle aficionados, as well as many of the newcomers, to meet, exchange ideas freely, and to point out current problems with technologies, definitions, and characterization. The meeting ended with the decision to prolong this very productive workshop by setting up future yearly meetings, virtual spaces to record exchanges and discussions (such as a website and/or a Facebook page), and a scientific society dedicated to exosomes and secreted membrane vesicles. Some of these are already underway, with the next IWE tentatively scheduled for April 2012, a Facebook page already up and running [37], a website for comparison of protein and RNA composition of exosomes already set up [38], and the rest hopefully coming soon. We strongly encourage the readers of this article to check these web links [37,38] to follow the next steps of this emerging scientific world.
Abbreviations
IWE, International Workshop on Exosomes; MHC, major histocompatibility class; miRNA, microRNA.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
CT apologizes to all the IWE participants whose work she could not clearly cite in this short article, and thanks INSERM, Institut Curie, Fondation de France, Institut National du Cancer (INCa), and Agence Nationale de la Recherche (ANR) for support of her research.
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Treatment of HIV/HCV Coinfected People with Compensated Liver Cirrhosis (Think HP!)
http://www.hivandhepatitis.com/coinfection/coinfection-hiv-hep/hiv-hcv-coinfection/3151-treatment-of-hivhcv-coinfected-people-with-compensated-liver-cirrhosis
FDA Updates Dosing of Pegasys plus Ribavirin for Hepatitis C Patients with Kidney Impairment
http://www.hivandhepatitis.com/hepatitis-c/hepatitis-c-topics/hcv-treatment/534-hcv-drug-advisories-hcv-drug-advisories/3149-fda-updates-dosing-of-pegasys-plus-ribavirin-for-hepatitis-c-patients-with-kidney-impairment
ADAP Waiting List Exceeds 9000 for the First Time
http://www.hivandhepatitis.com/hiv-policy-advocacy/336-hiv-adap-hiv-adap/3147-adap-waiting-list-exceeds-9000-for-first-time
IAS 2011: Poor CD4 Cell Recovery after Starting HIV Treatment Should Be a Cause For Concern (Another subgroup which should benefit from the HP)
http://www.hivandhepatitis.com/hiv-aids/hiv-aids-topics/hiv-disease-progression/3133-ias-2011-poor-cd4-cell-recovery-after-starting-hiv-treatment-should-be-a-cause-for-concern
The President’s FY 2012 Budget and Implementation of the National HIV/AIDS Strategy
Having emerged from the worst recession in generations, the President has put forward a plan to rebuild our economy and win the future by out-innovating, out-educating, and out-building our global competitors and creating the jobs and industries of tomorrow. But we cannot rebuild our economy and win the future if we pass on a mountain of debt to our children and grandchildren. We must restore fiscal responsibility, and reform our government to make it more effective, efficient, and open to the American people. The President’s 2012 Budget is a responsible approach that puts the nation on a path to live within our means so we can invest in our future—by cutting wasteful spending and making tough choices on some things we cannot afford, while keeping the investments we need to grow the economy and create jobs. It targets scarce federal resources to the areas critical to winning the future: education, innovation, clean energy, and infrastructure. And it proposes to reform how Washington does business, putting more federal funding up for competition, cutting waste, and reorganizing government so that it better serves the American people.
Even as we meet these challenges, other pressing issues must be addressed. In July 2010, President Obama fulfilled a pledge to the American people by releasing the nation’s first comprehensive plan to fight the domestic HIV/AIDS epidemic. HIV remains a serious public health threat to the United States: More than 56,000 people become infected with HIV in the US each year and there are more than 1.1 million
Americans living with HIV. Developed following a robust public input process with the engagement of community members, advocacy groups, scientists and Federal officials, the National HIV/AIDS Strategy for the United States is organized to achieve three key goals: reduce the number of new HIV infections, increase access to care for people living with HIV/AIDS, and reduce HIV-related health disparities.
In releasing the Strategy, the Administration also issued a Federal Implementation Plan outlining initial critical actions to be taken by Federal agencies in 2010 and 2011. The President also directed lead Federal agencies to develop plans for operationalizing their efforts to implement the strategy, improve coordination across agencies, and report on progress toward achieving key metrics. Implementing the National HIV/AIDS Strategy: An Overview of Agency Operational Plans, a report that describes critical steps being taken by the Federal government to achieve the goals of the Strategy, and the individual plans themselves, can be found at www.AIDS.gov.
To address HIV/AIDS in the United States and implement the National HIV/AIDS Strategy, the Budget:
Maintains the Strong Federal Commitment to Fighting HIV/AIDS in the United States. Within a constrained budget environment, the Administration maintains or increases domestic HIV/AIDS funding for HHS, HUD, VA, and DOJ. The Budget includes increases in discretionary, domestic HIV/AIDS funding for HHS (+$219 million) and VA (+$173 million) above FY 2010, while maintaining HIV/AIDS funding levels for HUD and DOJ. In addition to programs with dedicated HIV funding, the Budget will support a government-wide response to the HIV epidemic that includes: the enforcement of civil rights laws by the Department of Justice; the protection of workers from discrimination and the promotion of employment
opportunities for people living with HIV by the Department of Labor and the Equal Employment Opportunity Commission (EEOC); the provision of health care to service members and their dependents by the Department of Defense; and the provision of income supports to workers with disabilities, retirees and their dependents through the Social Security Administration.
Provides Strategic New Investments. The Budget increases total Federal domestic discretionary HIV/AIDS funding by $382 million through targeted increases for critical research, innovative HIV prevention
activities and grant programs that support increased access to critical HIV health care services. The Budget:
••Increases Funding for the Ryan White HIV/AIDS Program to Bolster the AIDS Drug Assistance Program (ADAP) and Increase Funding for Early Intervention and Primary Care Services Through the Part C Program. The President’s Budget will increase funding for the Ryan White HIV/AIDS Program by $88 million over FY 2010, for a total funding level of $2.4 billion. In response to the growing crisis of waiting lists for access to State ADAP programs, the Budget increases funding for AIDS drug assistance programs by $80 million over FY 2010 ($105 million above the FY 2010 enacted level, prior to the transfer of $25 million in emergency funds), for a total request of $940 million in FY 2012. Within this total, the Budget includes $60 million for a supplemental grants program to assist State AIDS drug assistance programs that have waiting lists and/or have implemented restrictive cost-containment measures. Additionally, in recognition of the need to maintain access to critical early intervention and primary care services for people living with HIV/AIDS, the Budget proposes a $5 million increase in funding for the Part C program over FY 2010.
••Increases Funding for HIV Prevention Efforts at the Centers for Disease Control and Prevention (CDC). The Budget will support critical investments in CDC to prevent new HIV infections. A total funding level of $858 million represents an increase of $58 million above 2010, of which $30 million is allocated from the Prevention and Public Health Fund. The Budget also transfers $40 million from the Chronic Disease Prevention and Health Promotion Program at CDC for school health programming to the National Center for HIV, STD, Viral Hepatitis and TB Prevention to achieve closer coordination of CDC’s HIV and STD prevention programs.
••Increases Funding for Cutting Edge HIV/AIDS Research. The Budget includes an estimated $2.7 billion for domestic NIH HIV/AIDS research, an increase of approximately $70 million over FY 2010, to support research priorities that will establish the scientific foundation to achieve the goals of the President’s National HIV/AIDS Strategy. Key prevention research includes vaccines and microbicides, as well as the use of treatment strategies as a method to prevent new infections.
A critical new area of prevention research is the study of treatment strategies as a method to prevent new HIV infections. Examples of such strategies that NIH is currently investigating include: Pre-exposure prophylaxis (PrEP), the long-term use of treatment regimens for high-risk uninfected individuals to prevent HIV acquisition; and “Test and Treat,” a study to determine whether a community-wide testing program with immediate treatment can decrease the overall rate of new HIV infections in that community.
••Increases funding for HIV/AIDS Treatment, Care, and Prevention Services for our Nation’s Veterans (VA). The President’s Budget includes $950 million in FY 2012, an increase of +$173 million above FY 2010 (+$70 million above FY 2011 enacted) for the Department of Veterans
Affairs HIV/AIDS program. With this increase, VA will intensify HIV screening efforts for all veterans,
expand HIV testing and educational efforts, and continue to provide improved access to comprehensive clinical care, including lifesaving HIV medications, and mental health services. These resources will help VA remain a leader among health care organizations in responding to the challenges posed by the HIV/AIDS epidemic and implementing the initiatives put forth in the National HIV/AIDS Strategy.
Re-Prioritizes Current Commitments to Achieve the Goals of the National HIV/AIDS Strategy. Through the Budget, the Administration is committed to ensuring that all Federal resources are reprioritized
to have the maximum impact at lowering the number of new HIV infections in the US, increasing access to care for people living with HIV, and reducing HIV-related health disparities.
••Authorizes the Secretary of HHS to Transfer 1% of HIV Program Funding to Support Innovative, Cross Agency Collaboration. The Budget will transfer 1% of all HIV/AIDS program spending at HHS to the Office of the Secretary for new, collaborative efforts to achieve the goals of the National HIV/AIDS Strategy. This will establish a pool of approximately $60 million, to be administered by the Assistant Secretary of Health, who will work with HHS operating divisions to identify and maximize opportunities for establishing new collaborative activities within communities most impacted by the HIV/AIDS epidemic.
••Develops a New, More Effective Approach for Critical Minority HIV/AIDS Initiative (MAI) Funds. Responding to the HIV epidemic in minority communities is a critical imperative for the US. This is done through all programs and agencies operating HIV programs, but is enhanced by dedicated funding provided through the Minority HIV/AIDS Initiative. To ensure that MAI grant funds (~$54 million) are having the biggest impact at reducing the disproportionate impact of HIV in minority communities and are responsive to the highest risk populations identified
in the National HIV/AIDS Strategy, the HHS Assistant Secretary for Health will centralize the administration of these funds and develop a strategic approach for using these funds to compliment other public and private efforts. Priority consideration will go to funding a small number of demonstration programs and previously evaluated and scientifically demonstrated high impact activities.
••Shifts Prevention Resources from Low to High Impact Activities. CDC will redirect approximately
$51 million from less effective and efficient programs to programs that are aligned with the goals of the Strategy. This will be achieved by placing greater emphasis on effective interventions for people living with HIV (including linkage and maintenance to medical care), adherence to antiretroviral treatment, and interventions to reduce transmission risk, placing greater emphasis on effective, community-level, structural, and single-session interventions and public health strategies. CDC will de-emphasize intensive individuals and small group interventions for at-risk populations that are difficult to take to scale.
••Adopts New Funding Formulas to Allocate HIV Prevention and Housing Funds Based on HIV/AIDS Cases. In FY 2012, HUD’s Housing Opportunities for People with AIDS (HOPWA) program and CDC’s HIV prevention health departments program plans to implement new funding algorithms based on living HIV/AIDS cases. During FY 2011, HUD will submit a legislative
proposal to effect this change. CDC has already initiated this process through previous and ongoing open, transparent sessions that solicit stakeholder feedback about essential decision points. CDC anticipates implementing allocations based on the new funding formula will take
place over a three-year period (FY 2012-2014) to minimize disruption to grantee activities and to allow for planning. These adjustments are being made to ensure that Federal funding allocations
are made using the most current and complete data available of incident and prevalent HIV/AIDS cases.
••Expands Investments in a Program to Use the Highest Prevalence Jurisdictions as Models of Innovation. HHS is focusing significant attention on using the 12 highest prevalence local jurisdictions responsible for 44% of living AIDS cases to test and evaluate new approaches to integrate planning, monitoring, and delivering HIV prevention and care services. This is anchored by the CDC’s Enhanced Comprehensive HIV Prevention Planning (ECHPP) program. First funded with $11.6 million of Prevention and Public Health Funds in FY 2010 and continued in FY 2011 at the same level of core health department funding ($11.6 million), the Budget will maintain these investments with the core program in FY 2012 and increase program funding by $10 million with funding from the Prevention and Public Health Fund for a total FY 2012 funding level of $21.6 million.
••Funds Evidence-Based Approaches to Integrating HIV Prevention and Care in Mental Health and Substance Abuse Programs. The Budget includes $178 million for SAMHSA to continue its support of evidence-based prevention interventions and behavioral health services and treatment for people at risk for or living with HIV/AIDS who have co-occurring mental and/or substance use disorders. SAMHSA will also continue to support the goals of the National HIV/AIDS Strategy though collaborations with other Federal agencies to 1) improve the coordination of behavioral health resources and services for racial and ethnic minorities at risk for or living with HIV/AIDS living in the 12 cities most impacted by HIV/AIDS; 2) develop a behavioral health and HIV/AIDS webpage and related materials that will be located on AIDS.Gov and disseminated through the use of social marketing; 3) assess HIV testing capacity and frequency in SAMHSA funded drug-treatment centers; 4) address the needs of people living with HIV/AIDS who are homeless; 5) address prejudice and discrimination related to HIV/AIDS; and 6) develop self-directed and wellness-centered approaches to behavioral health care for people living with HIV/AIDS.
••Supports Housing Assistance for People Living with HIV/AIDS. The Budget provides $335 million for the Department of Housing and Urban Development’s Housing Opportunities for Persons with AIDS program, which will continue to addresses the housing needs of persons with HIV/AIDS by providing tenant-based rental assistance, operating subsidies for permanent and transitional housing facilities, and homeless prevention activities.
Total U.S. Government-wide HIV/AIDS Spending: $28.3 billionTotal U.S. Government-wide Domestic HIV/AIDS Spending: $21.4 billion Total USG Domestic Discretionary HIV/AIDS Spending: $7.7 billion Total USG Domestic Mandatory HIV/AIDS Spending: $13.7 billionTotal U.S. Government-wide Domestic and Global Discretionary HIV/AIDS Spending: $14.6 billion
Observing National HIV/AIDS and Aging Awareness Day in an Aging Epidemic
By Deborah Parham Hopson, PhD, MSPH, RN, RADM, USPHS, Associate Administrator for HIV/AIDS, HIV/AIDS Bureau (HAB), Health Resources and Services Administration (HRSA)
Dr. Deborah Parham Hopson
Four years ago, the nation began its observance of National HIV/AIDS and Aging Awareness Day (September 18). The fact that we get to observe this day reflects a sharp contrast to where we were when CDC reported the first cases of AIDS 30 years ago. Once a death sentence, HIV disease has evolved into a chronic disease if caught early and properly managed—an accomplishment made possible thanks to improved care delivery and treatment advances.
HIV and Aging
People living with HIV are not, however, immune to the myriad of age-related health conditions. This means health care providers must become evermore comprehensive in their care offerings. And this demand is only growing: in 2008, 44% of the Ryan White Program’s clients were 45-64 years of age (a 15% increase since 2002).
To assist our Program’s providers in caring for this population we have taken a number of steps:
Added “older adults” as one of our population-specific fact sheets (PDF 233KB)
Offered a training (PDF 4.3MB) on HIV and aging at the Ryan White 2010 All Grantee Meeting
Issued The Graying of HIV (PDF 295KB) HRSA CAREAction newsletter to look at emerging client needs and provider strategies
Highlighted the story of Darlene—a 56-year-old HIV-positive patient—as part of our Living History support videos
Our AIDS Education and Training Center launched an “Over 50” section to increase the depth of our training resources while our TARGET Center continues to add technical assistance materials specific to this population
Our grantees are working tirelessly to add new services and specialties for their aging patients, whether in-house under the umbrellas of their one-stop-shops, creating clinic days for specialists to visit on site, or forging new community partnerships with providers adept at addressing age-related conditions. One such provider is Bronx-Lebanon Hospital Center, whose story we featured in our biennial progress report (PDF 17MB). Our providers recognize that older people are more often using social media and are a part of the trend of looking for health information online (PDF, 1.1MB).
New HIV Diagnoses
While the aging of HIV patients represents a phenomenal milestone in treatment and a testament to the level of care coordination among our frontline providers, a new trend has also emerged in recent years: older people newly diagnosed. Some older people underestimate their risk for contracting HIV. We also know that late diagnoses at any age are associated with poorer health outcomes and more rapid disease progression. To increase prevention, testing, and early engagement efforts, we are collaborating with our federal partners as part of the National HIV/AIDS Strategy.
In this way we can create the strongest safety net of all: one where we can reduce HIV infections as well as offer world-class, truly comprehensive wraparound services to those in need – including our aging population. As you plan to mark National HIV/AIDS and Aging Awareness Day and continue frontline service every day, I encourage you to reach out to HRSA and to the Ryan White Programs in your area to stay abreast of new resources and emerging trends.
http://blog.aids.gov/2011/08/observing-national-hivaids-and-aging-awareness-day-in-an-aging-epidemic.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+aids%2Fgov+%28Blog.AIDS.gov%29&utm_content=Yahoo%21+Mail
Medical tourism: A faraway health fix (Scroll to the bottom of the article and read the comments on India!)
http://www.chicagotribune.com/health/sc-health-0803-medical-tourism-20110803,0,4286362,full.story
Medical tourism: A faraway health fix (Scroll to the bottom of the article and read the comments on India!)
http://www.chicagotribune.com/health/sc-health-0803-medical-tourism-20110803,0,4286362,full.story
Prevention the key in new push on HIV/AIDS - (Although this article is about HIV prevention it speaks about the state of HIV/AIDS in this country - the HP may play a significant role in cutting costs down of current SOC, may fasten the decrease in viral load as it would work over a few days, help for patients with comorbidities like HCV, kidney disease etc.,)
http://articles.cnn.com/2011-08-04/opinion/mermin.aids.prevention_1_routine-hiv-hiv-prevention-hiv-testing?_s=PM:OPINION
Rising cost of health benefits unlikely to slow soon - (The HP can make a significant dent on multiple fronts to decrease health care costs)
http://www.jsonline.com/business/126814748.html
Encouraging News on the Scientific Front; Moving It Forward to Policy and Programs (with the HP things can only get better in the fight against HIV - ANESRI)
Posted: 29 Jul 2011 03:48 PM PDT
By Eric Goosby, Ambassador, U.S. Global AIDS Coordinator (Cross-posted from State Department Blog)
In last week’s post, I previewed the International AIDS Conference in Rome. This week I’d like to offer some brief reflections on the activity there, and what it means for our PEPFAR programs.
For those of us who have been working in this field for some time — which in my case is about 30 years — the mood in Rome was positive, with a palpable sense of encouragement. This was largely fueled by two things: new evidence of the long-term benefits of antiretroviral treatment efforts to date, and new scientific breakthroughs regarding the benefits of treatment for prevention. These developments are transforming the way we think about AIDS.
HIV/AIDS has had a devastating impact on life expectancy in many African countries, and in turn on their economic and social development. As an editorial in the Annals of Internal medicine recently noted: “Political debate centers on whether, especially given the current global economic downturn, money designated for HIV treatment in Africa would be better spent in [other] areas… But often forgotten in these debates is the unique nature of AIDS as a killer of young adults, of those on whom the very survival of societies depends.”
That’s why a new study published in the Annals of Internal Medicine last week is so encouraging. The study examined the long-term impact of the growing availability of treatment with antiretroviral drugs (ARVs) on life expectancy in patients of a Uganda NGO. The authors found that treatment “increased life expectancy to nearly normal levels,” noting that this finding “underscores the fact that HIV diagnosis in resource-limited settings is no longer a death sentence.”
We have long known that treatment is a life-saver; the impact of this on the lifespan of the individual on treatment — and ultimately on society — is now increasingly clear. Also becoming clear are the dramatic prevention benefits of treatment — saving not only the lives of the people taking the medicines, but the lives of their partners as well.
Data presented in Rome demonstrated the definitive prevention benefits of treatment. HIV-positive individuals who were part of HIV-discordant couples were randomly assigned to either early treatment or treatment that was delayed until they had clinically declined. Among couples where the infected partners received early treatment, transmission to the uninfected partner was reduced by at least 96 percent. This was an extraordinarily powerful result. It is consistent with the well-established fact that with ARVs, HIV-positive pregnant women can nearly eliminate the risk of passing HIV on to their newborns.
In addition to the preventive effect of treatment, two studies demonstrated the impact of oral antiretroviral pre-exposure prophylaxis (PreP) on transmission. One was a Gates Foundation-funded study among HIV-discordant heterosexual couples in Kenya and Uganda, and another was supported by the U.S. Centers for Disease Control and Prevention among heterosexual men and women in Botswana. Both found over 60% fewer new infections among those taking PreP.
These new data add to our knowledge base from studies on topical PrEP among women (a 39% reduction in new infections) and oral PrEP among MSM (a 44% reduction). Taken as a whole, the evidence base for the preventive effect of antiretroviral treatment is now unequivocal. ARV-based tools could be critical for the many people in HIV-discordant relationships and for others who are otherwise at high risk of infection.
Clearly there will be implications of these findings for PEPFAR, and it is important to prepare our programs to incorporate this new research in a careful but rapid way. Many in Rome expressed the view that the U.S. must play a leadership role in this effort, and we are doing so.
Our task is to translate new science into policy to inform programs. To do this, we are working with the World Health Organization and others as they develop normative guidance for the potential use of these tools. We are also supporting critical implementation science research needed for future scale-up of related programs.
Earlier this year, PEPFAR established a distinguished external Scientific Advisory Board. We are working closely with its members to assess the key issues around scale-up of these tools. Some of the big issues we will face include: increasing testing; supporting overburdened providers and health systems; ensuring linkages to care; prioritizing resources; and targeting the right populations. We are fortunate that in recent years we have had the experience of translating research on male circumcision into programs, providing us with valuable lessons as we move forward.
It is apparent that this is an extraordinary moment in the global AIDS fight, and particularly for PEPFAR — a moment in which a path toward an HIV-free generation is becoming clear. Just as America’s support has been essential in so many of the breakthroughs to date, both in terms of scientific research and program implementation, we will continue to be a global leader in this next stage of the fight.
Federal Leads Review Progress at One-Year Anniversary
By Ronald Valdiserri, M.D., M.P.H., Deputy Assistant Secretary for Health, Infectious Diseases, U.S. Department of Health and Human Services (Relevant to AEMD in Bold at the bottom)
Dr. Ronald Valdiserri
On the eve of the first anniversary of the National HIV/AIDS Strategy (NHAS), representatives of the six federal agencies tasked by the President with lead responsibility for implementing NHAS gathered for one of our regular meetings and shared updates on implementation progress. Chairing the meeting, the Assistant Secretary for Health, Dr. Howard Koh, praised the participants for the progress being made within and across Departments and for the personal dedication of each of these representatives to bringing the Strategy to life not only within their respective agencies, but also across the nation.
During the meeting, the agency representatives each highlighted some of the significant recent activities underway in pursuit of the Strategy’s goals. These included:
Department of Housing and Urban Development – Among the several activities underway at HUD, according to Mr. David Vos, Director of the Office of HIV/AIDS Housing, are preparations for an upcoming roundtable for faith- and community-based organizations in the mid-Atlantic area that will focus on successful collaborations to provide housing and supportive services to low-income households with a person living with HIV and AIDS, and will to promote understanding to combat stigma and discrimination. HUD is also conducting cross-training with the Health Resources and Services Administration’s Ryan White program project officers at HHS to ensure all share a solid and common knowledge base about HIV/AIDS programs in other departments.
Department of Justice – The DOJ’s Civil Rights Division has developed a subsite within ADA.gov to address civil rights issues related to HIV/AIDS, including the ability to file a discrimination claim online. The office is also preparing an update to its “bench book” for judges regarding HIV/AIDS and civil rights law, according to Ms. Allison Nichol, Chief of the Disability Rights Section of the Department’s Civil Rights Division. CAPT Chris Bina, Pharm.D., reported that the Department’s Federal Bureau of Prisons continues to offer universal HIV testing to all inmates sentenced to a federal facility. The Bureau also recently updated and released its National HIV Practice Guidelines and is preparing a seminar for the system’s healthcare providers about them. CAPT Bina also noted that the Bureau is sharing its best practices regarding both healthcare for inmates with HIV and facilitating linkages to care for HIV positive ex-offenders re-entering the community with their colleagues who administer state and local jails, where the majority of the nation’s prisoners are incarcerated.
Department of Labor – A recent DOL-convened roundtable explored how to improve employment opportunities and outcomes and reduce stigma and discrimination for people living with HIV/AIDS, reported Mr. Dylan Orr, Special Assistant/Advisor to the Assistant Secretary for Disability Employment Policy. In an effort to better coordinate related federal efforts, many of the other lead federal agencies were involved in the roundtable (including the Departments of Justice, Housing and Urban Development, and Health and Human Services, and the Social Security Administration) as well as the Equal Opportunity Commission, the Department of Education, the White House Office of National AIDS Policy, and a number of HIV/AIDS service providers, employers, disability employment advocates, and members of the HIV/AIDS community. On another front, DOL’s Office of Federal Contract Compliance Programs (OFCCP) has launched a system for prioritizing and fast-tracking investigations of employment discrimination complaints based on HIV/AIDS status. OFCCP has also developed public education materials on employment rights under Section 503 of the Rehabilitation Act of 1973 and the Americans with Disabilities Act with emphasis on HIV/AIDS employment discrimination. These materials have been distributed to OFCCP’s field offices and will also be distributed to stakeholders and community groups.
Department of Veterans Affairs – VA’s Dr. Maggie Czarnogorski, Deputy Director, Clinical Public Health Program, reported the Department’s ongoing effort to increase HIV testing among veterans. Based on recently analyzed data, the VA had a 140 percent increase in HIV tests from 2009 to 2010 with over 350,000 tests conducted in 2010. To continue these expanded testing activities, VA has provided grants to 20 VA facilities to expand HIV laboratory testing and is offering an electronic clinical prompt that reminds providers to offer an HIV test, integrating HIV testing into more than 20 Stand Downs for homeless veterans, and capturing and sharing best practices related to HIV testing throughout its network. It is also supporting and working closely with 10 women veterans health programs and preparing to launch a social marketing campaign to promote HIV testing among veterans later this year.
Social Security Administration – The SSA is working to expedite claims identifying HIV/AIDS as the primary qualification, according to Mr. David Rust, Deputy Commissioner for Retirement and Disability Policy. The agency’s entry for HIV/AIDS in the listing of impairments is being updated after over a year of work that included consultations with the community and the Institute of Medicine. Mr. Rust also observed that SSA is working with the Department of Labor on employment opportunities for beneficiaries through its “Ticket to Work” program.
Department of Health and Human Services – Mr. Michael Evanson of the HRSA’s HIV/AIDS Bureau reported on the agency’s recent update to policies governing the use of Ryan White HIV/AIDS Program funds for housing referral services and short-term or emergency housing needs. He concurred with HUD’s David Vos that HHS and HUD will need to work together to help all grantees understand the new policy and what is allowed and required. I also noted that other HHS agencies and offices will be highlighting examples and reflections on their NHAS implementation progress via blog posts and on their web sites.
We also shared with our colleagues from across the government that simultaneous to implementing the NHAS, HHS is also working to implement the recently released Action Plan for the Prevention, Care and Treatment of Viral Hepatitis. This new effort is significant for our federal partners since up to 30 percent of persons living with HIV are co-infected with hepatitis and both infections share commonalities around transmission, so our efforts on either will impact both.
Several of the participants observed that another measure of progress in this first year of collectively pursuing the Strategy’s goals has been the continuation of these regular cross-departmental conversations. Each of our quarterly meetings has offered opportunities for cross-pollinating ideas and engaging in both collaborative and complementary efforts aligned with the Strategy. As each of the lead federal agencies presses forward with its own efforts to implement the National HIV/AIDS Strategy, we will all continue to identify and leverage cross-agency collaborative opportunities that are as yet untapped to ensure better coordination of efforts at all levels and, most importantly, improved outcomes.
Pipeline Report Shows Good Prospects for People with HIV, HCV, and TB
Experimental HIV Drugs Published on Friday, 29 July 2011 00:00 Written by Press Release
An updated summary of experimental therapies for HIV, hepatitis C virus (HCV), and tuberculosis, produced by treatment advocates with i-Base and TAG, shows rapid progress in therapies for HCV and steady progress in the area of HIV.
Below is an edited excerpt from a recent i-Base/TAG press release describing the new report.
2011 Pipeline Report Shows that Medical Prospects for People With HIV, Hepatitis C, and Tuberculosis Have Never Been Better
Analysis reveals a golden age of antiretroviral drug development, rapid uptake of innovator compounds, and rapid return on investment Rapid evolution of HIV and Hepatitis C Virus (HCV) therapies promises continuing progress, while a renaissance in TB drug, diagnostic, and vaccine development is underway New York/London/Rome -- July 15, 2011 -- The new drug, diagnostic, and vaccine pipeline has never looked more promising for people with HIV, hepatitis C virus (HCV), and tuberculosis (TB), according to a report released today by Treatment Action Group (TAG) and HIV i-Base (click link to download).
As the writers of the report reveal, the prospects for dramatic -- and in some cases revolutionary -- changes in prevention and treatment for the three diseases in the next decade are extremely good.
For a second year now, TAG and i-Base have collaborated to produce the Pipeline Report. This year, Jonathan Berger from SECTION27 in South Africa contributed a new chapter on patent laws and antiretroviral licensing policies.
As the report makes clear, medically, the prospect for people with HIV, HCV, and TB to live long and healthy lives -- and in the cases of HCV and TB, to be cured rapidly with safe, effective, oral combination therapy -- has never been better.
A golden age of antiviral drug development
To assess the state of the HIV treatment development process, the authors went back over all the drugs TAG reported as entering phase II or beyond since 2003. “The past decade has indeed been a golden age of antiretroviral drug development,” commented Polly Clayden of i-Base and Mark Harrington of TAG. Of 29 new chemical entities approved by the U.S. Food and Drug Administration (FDA) to treat HIV infection since 1986, the report finds almost half (14/29) were approved in the years since 2003. Thirty-four drugs and fixed dose-combinations (FDCs) are FDA-approved for sale in the United States; a further 131 drugs and FDCs (including adult and pediatric formulations) are tentatively approved under the FDA’s generic registration program to facilitate global access through programs such as the President’s Emergency Program for AIDS Relief (PEPFAR).
The success rate for new antiretroviral drugs and FDCs that entered phase II or further trials since 2003 is a whopping 30.4% (14/46), according to the TAG/i-Base analysis. Expected approvals this year for the integrase inhibitor, elvitegravir, the pharmacokinetic booster cobicistat, and the two FDCs rilpivirine/FTC/TDF and elvitegravir/cobicistat/FTC/TDF (Quad) -- would bring the success rate to 39.1% (18/46).
The success rate also demonstrates the rapidity in which new drugs and combinations are incorporated into the standard of HIV care in developed countries showing that investors will enjoy a substantial return on their investment -- the HIV drug market is estimated at $13 billion a year currently, though only 19.4% -- or 6.6 of 34 million -- of the world's HIV positive persons are on treatment.
Globally, 34 million people are living with HIV infection, an estimated two billion with latent Mycobacterium TB infection, and up to 130 million with chronic HCV infection. At least 1.8 million people died from AIDS in 2009, one quarter of them from TB, which alone killed 1.7 million people. There is neither global nor national surveillance for HCV-related illness and death, but more than 300,000 people die from HCV complications each year, and HCV mortality will continue to increase in the coming decade.
HIV infection can be controlled with lifelong triple-combination antiretroviral therapy. Latent TB infection can be treated with six to nine months of isoniazid (INH) or 12 weeks of once-weekly rifapentine and INH. Active TB disease, if drug-susceptible, can be cured in 95% of cases with four drugs in six months, while drug-resistant forms of the disease can be cured up to 70% of the time if multidrug-resistant, or just 30% if extensively drug-resistant, with unpleasant combinations that can take up to two years to work, if they work at all. HCV is now curable in up to 75% of infected people with genotype 1 (predominant in major pharmaceutical markets) who have access to -- and can tolerate -- today’s standard of care: triple therapy with pegylated interferon, ribavirin, and an HCV protease inhibitor.
Decades of high-quality research, increased investment, and growing and targeted community-based activism have set the scene for the possibility -- for the first time since HIV/AIDS emerged in 1981 -- to make dramatic reductions in new HIV infections worldwide, while saving the lives of as many of the 34 million currently infected who can access therapy. Treatment is continually improving, with modern combinations dramatically less toxic, more tolerable, and easier to take than the first generation ART combinations of the 1990s.
The authors warn that despite buoyant medical prospects, "the world’s activists and political leaders face a crisis in which the former must persuade the latter to redirect billions of dollars from unproductive wars into life-saving health research and access programs, at home and internationally.”
The report highlights the most pressing priorities for research, access and activism for HIV, HCV and TB, emphasizing opportunities for cross-cutting integration of efforts. And the authors stress, “Activists, scientists, implementers, and political leaders are obliged to exert their utmost efforts to accelerate scientific progress and save as many lives as possible in spite of the challenges we face.”
The report is released on the eve of the 6th International AIDS Conference on HIV pathogenesis, treatment and prevention in Rome, Italy, and is available on-line at:
www.treatmentactiongroup.org
www.i-base.info
About HIV i-BASE
HIV i-Base is a London based HIV treatment activist organization. HIV i-Base works in the UK and internationally to ensure that people living with HIV are actively engaged in their own treatment and medical care and are included in policy discussions about HIV treatment recommendations and access. www.i-base.info
About TAG
Treatment Action Group (TAG) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. www.treatmentactiongroup.org
7/29/11
Source
i-Base and TAG. 2011 Pipeline Report shows that medical prospects for people with HIV, hepatitis C, and tuberculosis have never been better. Press release. July 15, 2011.
Back Hepatitis B 10 Million Injection Drug Users May Have Hepatitis B or C
Hepatitis B
10 Million Injection Drug Users May Have Hepatitis B or C
Written by Liz Highleyman
Prevalence of hepatitis C antibodies in injecting drug users (Source: The Lancet)
Approximately 10 million injection drug users (IDUs) worldwide might be infected with hepatitis C virus (HCV), and more than 1 million may be living with hepatitis B, according to a meta-analysis of data from over 70 countries published in the July 28, 2011, advance online edition of The Lancet.
Sharing needles and other equipment for injecting drugs is an major risk factor for transmission of viral hepatitis and HIV, but detailed estimates of the extent of the problem are not available.
Paul Nelson from the National Drug and Alcohol Research Centre at the University of New South Wales in Sydney, Australia, and colleagues therefore set out to estimate national, regional, and global prevalence and population sizes for IDUs with hepatitis B and C.
The researchers performed a systematic search of peer-reviewed databases (Medline, Embase, and PsycINFO), "grey literature" (reports by government agencies, industry, etc.), conference abstracts, and online resources relating to hepatitis B virus (HBV) and hepatitis C virus (HCV) in IDUs.
Out of 4386 peer-reviewed and 1019 grey literature sources, they reviewed 1125 sources in full. The collected information about HCV antibody (anti-HCV) status, indicating infection with HCV, which typically results in chronic infection; HBV core antibody (anti-HBc) status, which indicates either past HBV infection -- which usually results in spontaneous clearance -- or vaccination; and HBV surface antigen (HBsAg) status, which indicates current infection.
They then calculated prevalence estimates and combined these with IDU population sizes (mainly derived from the Reference Group to the United Nations on HIV and Injecting Drug Use) to calculate the approximate number of IDUs who are HBV or HCV positive.
Results
Hepatitis B:
The researchers identified eligible reports on anti-HBc status in 43 countries and HBsAg status in 59 countries, representing 65% and 73%, respectively, of all IDUs. Again, anti-HBc prevalence rates varied widely, from 4.2% in Slovenia to 85.0% in Mexico. HBsAg status, or current infection, varied both across and within countries (for example, 3.5%-20.0% in the U.S. and 3.7%-30.9% in Iran. Prevalence estimates suggested 5%-10% of IDUs in 21 countries and more than 10% in 10 countries are HBsAg positive. Overall, 6.4 million IDUs might be anti-HBc positive (range 2.3-9.7 million) and 1.2 million (range 0.3-2.7 million) might be HBsAg positive or currently infected. The largest populations were in east Asia and southeast Asia (0.3 million) -- where HBV is endemic and many were presumably infected as children -- and in eastern Europe (0.3 million). Hepatitis C:
The researchers located eligible reports on anti-HCV prevalence among IDUs in 77 countries, representing 82% of all IDUs. Prevalence of anti-HCV positivity varied greatly among countries, ranging from 9.8% to 97.4%. Prevalence estimates suggested 60%-80% of IDUs had HCV in 25 countries and more than 80% did so in 12 countries. Overall, about 10.0 million IDUs worldwide (range 6.0-15.2 million) might be anti-HCV positive. The largest populations of HCV positive IDUs were in China (1.6 million; 67.0%), the U.S. (1.5 million; 73.4%), and Russia (1.3 million; 72.5%). The number of IDUs thought to have HCV is about 3.5 times larger than the 2.8 million (range 0.8-6.2 million) estimated to be living with HIV. "More IDUs have anti-HCV than HIV infection, and viral hepatitis poses a key challenge to public health," the study authors concluded.
They explained in their discussion that reported IDU population size estimates reflect the number of current or recent users of injection drugs, not people who have ever used them, so the total number of cases of hepatitis B or C attributable to injection drug use would be higher.
"Efforts to prevent, treat, and reduce harms related to liver disease in IDUs are essential -- especially in situations in which HIV has successfully been prevented or managed -- because the large numbers of IDUs infected with HCV and significant morbidity resulting from this infection mean that the health and economic costs of HCV transmitted by injecting drug use might be as high as (or higher than) those of HIV," they wrote.
"Evidence about the effect of needle and syringe programs and provision of other injection equipment on prevention of HCV infection is scarce, but reduction of risk is paramount, particularly during the period of initiation to injecting when incidence of HCV is highest," they continued. "[The] potential role of HCV treatment in the prevention of HCV transmission in IDU populations warrants further investigation," but high cost and side effect remain as barriers.
Turning to hepatitis B, Nelson and colleagues noted that "ecause of the high rate of chronic HCV infection in IDUs, HBV infection is particularly likely to show HBV and HCV coinfection, which is associated with more rapid progression of liver disease and attendant mortality."
"Vaccination against HBV must be prioritized for all susceptible IDUs, especially those already infected with HCV," they wrote. "A substantial reduction in the burden of HBV infection in IDUs is expected in countries with universal infant vaccination programs, once these individuals reach the age at which acquisition of HBV through injecting drug use is most common."
"Correctional facilities provide one opportunity to vaccinate, treat, and reduce the transmission of viral hepatitis in a population with high rates of injecting drug use, HBV, and HCV, many of whom cycle in and out of the community," they suggested.
Investigator affiliations: National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia; Victorian Infectious Diseases Reference Laboratory, North Melbourne, VIC, Australia; College of Nursing, New York University, New York, NY; Beth Israel Medical Center, New York, NY; Centre for Population Health, Burnet Institute, Melbourne, VIC, Australia; Centre for Health Policy, Programs and Economics, School of Population Health, University of Melbourne, Melbourne, VIC, Australia.
7/29/11
Reference
PK Nelson, BM Mathers, B Cowie, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. The Lancet (free full text). July 28, 2011 (Epub ahead of print).
Another R03 - (so many grants, it gets confusing. Trying hard not to repost. Sorry in case I do! Aethlon should be eligible for some of this)
http://grants.nih.gov/grants/guide/pa-files/PA-11-276.html
Another R01 for HIV
http://grants.nih.gov/grants/guide/pa-files/PA-11-275.html
Another R21 for HIV -
http://grants.nih.gov/grants/guide/pa-files/PA-11-273.html
R21 - Gov Grant for HIV
http://grants.nih.gov/grants/guide/pa-files/PA-11-277.html
R34 - clinical trials for HIV grant
http://grants.nih.gov/grants/guide/pa-files/PAR-11-278.html
Ro1 Gov Grant for HIV -
http://grants.nih.gov/grants/guide/pa-files/PA-11-271.html
PURPOSE
The Division of AIDS Research (DAR) at the National Institute of Mental Health (NIMH) issues this announcement to outline priority areas for innovative research. This Funding Opportunity Announcement (FOA) encourages research designed to increase the impact of effective HIV/AIDS-related interventions for prevention and treatment. This FOA is informed by priority areas from the National HIV/AIDS Strategy, the NIH Office of AIDS Research (OAR) Plan for HIV/AIDS Related Research, as well as the NIMH Strategic Plan (Objective 4): To strengthen the public health impact of NIMH-supported research. That is, through research, evaluation, and collaboration, to develop the capacity of NIMH to help close the gap between the development of new, research-tested interventions and their widespread use by those most in need.
The two overarching goals of this FOA are to encourage projects that will:
Improve the uptake of efficacious interventions. Broad research areas to advance include, but are not limited to: Dissemination research, research syntheses to inform policy, evaluations of optimal intervention financing and cost-effectiveness, and research to strengthen health systems and address personnel training and expertise.
Conduct research to inform and enhance the effectiveness and efficiency of interventions, in order to maximize community impact. Broad research areas to advance include, but are not limited to: Implementation science and operations research, testing combination approaches to HIV-related interventions, comparative effectiveness research, and analysis of the impact of policy changes on public health outcomes.
BACKGROUND
Many interventions are available in the continuum of HIV prevention, HIV-testing, and HIV care (e.g., HIV treatment adherence). To maximize public health impact, significant progress is needed to deliver interventions more efficiently and effectively, transfer interventions from one setting or population to another, and to make better-informed choices between competing interventions. This implementation gap is impeding the success in prevention, care, and treatment programs in both the numbers of persons reached and the effect on health outcomes. Advances are urgently needed to reduce these unknowns and increase the public health impact of HIV/AIDS prevention, treatment, and care services.
R03 Gov. Grant for AIDS
http://grants.nih.gov/grants/guide/pa-files/PA-11-272.html
The Division of AIDS Research (DAR) at the National Institute of Mental Health (NIMH) issues this Funding Opportunity Announcement (FOA) to outline priority areas for innovative research. This FOA encourages research designed to increase the impact of effective HIV/AIDS-related interventions for prevention and treatment. This FOA is informed by priority areas from the National HIV/AIDS Strategy, the NIH Office of AIDS Research (OAR) Plan for HIV/AIDS Related Research, as well as the NIMH Strategic Plan (Objective 4): To strengthen the public health impact of NIMH-supported research. That is, through research, evaluation, and collaboration, to develop the capacity of NIMH to help close the gap between the development of new, research-tested interventions and their widespread use by those most in need.
The two overarching goals of this FOA are to encourageprojects that will: 1) improve the uptake of efficacious interventions and 2) conduct research to inform and enhance the effectiveness and efficiency of interventions, in order to maximize community impact.
R21 Gov. Grant -
http://grants.nih.gov/grants/guide/pa-files/PA-11-261.html
The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
July 28 Is World Hepatitis Day
Details Category: Hepatitis B Published on Wednesday, 26 January 2011 00:00 Written by Liz Highleyman
HBV © Russell Kightley
Thursday, July 28, is World Hepatitis Day, an opportunity to raise awareness about life-threatening viral hepatitis. Over years or decades hepatitis B and C can progress to severe liver disease including cirrhosis and liver cancer. Viral hepatitis is a leading indication for liver transplants worldwide.
Hepatitis B virus (HBV) is endemic in several regions of the world, with an estimated 100 million carriers in Southeast Asia alone. Several nucleoside/nucleotide analogs are available to treat chronic hepatitis B, but therapy does not always produce a cure. Fortunately, effective vaccines are available, leading to dramatic decreases in incidence.
Hepatitis C virus (HCV) is also common worldwide and cannot yet be prevented with a vaccine. Development of direct-acting antiviral agents has ushered in a new treatment paradigm, but these drugs still must be used with pegylated interferon/ribavirin. The first of the new agents -- boceprevir and telaprevir -- were approved in the U.S. in May.
World Hepatitis Day Events
The World Health Organization (WHO) is recognizing World Hepatitis Day for the first time in 2011.
In the U.S., President Obama's administration will recognize World Hepatitis Day by hosting the first White House meeting focused on the hepatitis B and C epidemics.
The San Francisco Hepatitis C Task Force will launch its first public education and outreach campaign, distributing educational materials at Muni and BART stations (Castro, 16th & Mission, Montgomery, and Embarcadero) during morning and afternoon commute hours.
Experts say a majority of people living with hepatitis B and C do not know their status. World Hepatitis Day offers and opportunity to raise awareness and encourage testing.
For more information see:
World Health Organization: http://www.who.int/csr/disease/hepatitis/world_hepatitis_day/en/index.html
World Hepatitis Alliance: http://www.worldhepatitisalliance.org/Home.aspx
7/26/11
http://www.hivandhepatitis.com/hiv-aids/hiv-aids-topics/hiv-prevention/3100-ias-2011-hiv-prevention-a-womens-revolution-video
(Hopefully the HP would someday be in the algorithm for early treatment of both HIV and HCV)
The 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011) held last week in Rome heralded remarkable data showing that early HIV treatment and pre-exposure prophylaxis (PrEP) can dramatically reduce the risk of HIV transmission.
But biomedical prevention methods will only work if people have access to them, and many women worldwide do not have access due to lack of economic resources or the right of self-determination.
A coalition of women at IAS 2011 held a press conference to demand sexual self-determination for women, calling for a women's revolution to take full advantage of the advances in prevention science. "Women need sexual rights, not just reproductive rights," said Louise Binder of the International Community of Women Living with HIV/AIDS.
Louise Binder, IAS 2011, Rome Italy, July 19, 2011:
Global Coalition of Women Call for HIV Prevention Revolution for Women and Girls
Demand that leaders, including Pope and Holy See, endorse and act on women's HIV prevention tools ad sexual rights
Rome -- July 19, 2011 -- At the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention in Rome, a global coalition of women representing international, national and local communities of people living with HIV/AIDS, HIV non-governmental organizations, and researchers identified recent developments as components of a potential HIV prevention revolution. They called on the Vatican to support and endorse the HIV prevention revolution which can benefit both women and men worldwide and is informed by a rapidly growing body of scientific evidence including new ARV-based prevention strategies as well as proven technologies like male and female condoms and male circumcision.
“Women and girls bear the heaviest burden of the epidemic worldwide. Until we have a full range of protection and treatment options, we will never end this pandemic,” said Louise Binder of the International Community of Women Living with HIV/AIDS. “Every day we withhold protection methods and treatment from women and girls, millions are infected, become sick, and die. There is now real hope that we can reverse this using new and proven tools -- but only if women’s voices and priorities are heard, and not silenced by forces like the Pope and the Holy See. We therefore call on the Pope to remove the obstacles he has placed in the past and bless the prevention revolution for women.”
During the conference data have been presented by leading HIV researchers on ARV based prevention in HIV positive and negative people. These data provide unprecedented hope in the form of women-controlled strategies for women and girls who are both HIV positive and those who are HIV negative when added to comprehensive programs including male circumcision, male and female condoms and other proven prevention.
“We have evidence-based research at this conference that female-initiated HIV prevention is possible in the form of topical and oral pre-exposure prophylaxis for HIV negative women and treatment initiation regardless of CD4 cell count for HIV positive women. These findings are hugely hopeful and, with sufficient commitment, can contribute to a prevention revolution. We must have commitment and leadership to acting on these data so that we can finally stop this epidemic in its tracks,” said Dr. Elizabeth Bukusi, a leading prevention researcher at the Kenya Medical Research Institute.
The Holy See explicitly opposed the expansion language protecting and ensuring the rights of women and girls in the recently adopted 2011 Political Declaration on HIV/AIDS. “In Africa, the numbers of women infected and affected are staggering. Countless women’s lives will be saved in my country and around the world if donors, implementers and religious leaders -- including the Pope -- make implementation of the new prevention science, in the context of sexual rights, their top priority,” said Mariliza Amony Marko Toban, a young AIDS activist from Southern Sudan.
Advocates emphasized that the data can be most effectively harnessed and the prevention revolution achieved only in the context of programs and implementation research that embrace and implement full sexual health and rights for women and girls.
“As women and girls, we know our epidemic and we must be a part of constructing, implementing, and evaluating interventions that impact our lives. One thing that we know is that offering women choices that include bio-medical interventions is a key to saving our lives,” said Ebony Johnson, ATHENA network and member of the AVAC ROAR cadre of US-based prevention research advocates. “We also know that in order for us to optimize the impact of new prevention technologies, we need progressive policies, laws, affirmation of rights and support from religious leaders to bring a legal and social shift in the harmful gender norms and social driver that keep women and girls vulnerable. This need is real and the time is now!”
7/26/11
Source
ATHENA, AVAC, et al. Global Coalition of Women Call for HIV Prevention Revolution for Women and Girls. Press release. July 19, 2011.
Liver cancer and non-hodgkin lymphoma in hepatitis C virus-infected patients: results from the danvir cohort study
International Journal of Cancer, 07/25/2011
Omland LH et al.– Hepatocellular carcinoma (HCC)–risk is increased substantially in hepatitis C virus (HCV)–infected patients compared to the general population. Chronic as opposed to cleared HCV–infection increases the risk of HCC and perhaps non–Hodgkin lymphoma (NHL).
Transformational Medical Technologies Initiative
(TMTI)
The objective of the TMTI is to develop broad-spectrum therapeutic
countermeasures to mitigate the effects of exposure to the Warfighter from
emerging or genetically-engineered biological threats. The TMTI strategy is to
accelerate the development of new medicines by establishing alliances with
academia and the pharmaceutical and bio-technology industries. Through this
alliance, applicable drug candidates will be identified and incorporated into the
program. Proactive technology scanning and directed development through
targeted solicitations will be initiated to broaden the scope of therapies for
consideration.
JOINT PROJECT Transformational Medical Technologies Initiative | Medical | Biological Therapeutics
CONTRACTOR(S)/GOVERNMENT PERFORMERS
U.S. Army U.S. Navy U.S. Air Force U.S. Marine Corps U.S. Coast Guard National Guard U.S. Army Reserve U.S. SOCOM
Homeland Defense DoD Other Agencies Academia Foreign Military
NSN: Unavailable
USER(S)
IN DEVELOPMENT
SCHEDULE FY09 FY10 FY11
Contract #1-6 (HFV) Phase I trials
Contract #1-4 (IBF) Phase I trials
MS B Decision (Hemorrhagic Fever Viruses)
Contract #1-2 Phase II Pivotal Animal Studies
JPM CB Medical Systems (JPM-CBMS)
Centrally manages and employs government and commercial best
pharmaceutical development practices to oversee the Joint Vaccine Acquisition
Program (JVAP) and Medical Identification and Treatment Systems. The JPMCBMS
remains the vanguard in rapidly providing safe, effective, and affordable
CBRN MCMs to the Warfighter. This is accomplished by the JPM-CBMS’ expertise
in U.S. Food and Drug Administration (FDA) regulatory compliance, product
development, full lifecycle management, and partnering with other governmental agencies and nations.
Transformational Medical Technologies
About TMT
Transformational Medical Technologies (TMT) is a Department of Defense (DOD) program that was created to revolutionize protection for the Warfighter against biological threats. TMT accelerates the development and manufacture of broad-spectrum countermeasures by fostering the discovery of novel medical technologies, employing nontraditional scientific approaches, and streamlining drug development and DOD acquisition management practices.
TMT is "transformational" in two ways:
It fosters novel, adaptable countermeasures that protect against multiple emerging and genetically engineered biological threats. It uses a management approach modeled on commercial pharmaceutical organizations and novel within DOD—integrating the management of product generation through science and technology (S&T) research and advanced development (AD) activities into a single program office (PO) under federal acquisition regulation guidelines. Through TMT, DOD partners with the pharmaceutical and biotechnology industries, academia, and other government agencies to meet program goals. Integrating S&T concept development with AD activities minimizes challenges related to product transitions, and the sole PO maintains a start-to-finish view of the development process while managing a dynamic product portfolio and coordinating performer activities to ensure timely product delivery.
Mission & Vision
Mission
Protect the Warfighter from emerging and genetically engineered biological threats by providing a novel response capability from identification of pathogens to the development of medical countermeasures
Vision
To protect the Warfighter and the Nation from biothreats
Last updated: 7/15/2010 1:54:55 PM
Another BAA to consider :
https://www.fbo.gov/index?s=opportunity&mode=form&id=4dd0fc45188361a41203ddd3cfa5c5a8&tab=core&_cview=0
Solicitation Number:
BAA-CBMS-07-01
Notice Type:
Presolicitation
Synopsis:
Added: Jul 21, 2011 1:45 pm
GENERAL INFORMATION
Notice Type:
Presolicitation
Posted Date:
July 21, 2011
Response Date:
March 31, 2012
Archiving Policy:
Automatic, on specified date
Archive Date:
May 30, 2012
Original Set Aside:
N/A
Set Aside:
N/A
Classification Code:
A -- Research & Development
Medical Chemical, Biological, Radiological and Nuclear (CBRN) countermeasures are an integral part of the U.S. Department of Defense (DoD) Chemical Biological Defense Program (CBDP) System of Systems approach that serves as the foundation and strength of the CBDP. The Joint Program Executive Office for Chemical and Biological Defense (JPEO-CBD) is organized into eight Joint Project Management Offices, each responsible for specific commodity areas. The Chemical Biological Medical Systems Joint Project Management Office (CBMS JPMO) consists of the Joint Vaccine Acquisition Program (JVAP), Medical Identification and Treatment Systems (MITS), and Biosurveillance (BSV) Joint Product Management Offices (JPMOs). The medical CBRN countermeasures developed by the CBMS JPMO directly support the current, near-term, and far-term challenges by providing the capability to prevent, diagnose and treat the effects of chemical, radiological and biological warfare agents. The JVAP JPMO provides biological protection by ensuring Warfighters' immune systems are primed to protect them from selected threats. The MITS JPMO is responsible for the advanced development of U.S. Food and Drug Administration (FDA)-approved/licensed/cleared products for prophylaxis, treatment and diagnosis of CBRN agent exposure. The TMTI JPMO is developing and evaluating novel processes to accelerate the development and approval of medical CBRN countermeasures by leveraging lifecycle bioinformatics, enabling technologies, and other emerging technologies. General information on JPEO-CBD and subordinate JPMOs can be obtained from the JPEO-CBD website at http://www.jpeocbd.osd.mil/. This Broad Agency Announcement (BAA) is intended to solicit pre-proposals for: 1) those parts of development not related to the development of a specific system or hardware procurement in accordance with (i) the Federal Acquisition Regulation (FAR) 35.016 (a) and (ii) DoD Grant Regulations (DoDGARs) subject to section 2374 of Title 10 United State Code and 2) the development of prototypes in accordance with Section 845 of Public Law (P.L.) 103-160. Specific areas of interest are described in the Areas of Interest attachment. As to any resultant procurement contracts, this BAA is issued under the provisions of the Competition in Contracting Act of 1984 (P.L. 98-369), as implemented in the FAR at accordance. This Announcement provides a general description of CBMS JPMO's project areas, including specific areas of interest, general information, evaluation and selection criteria, and proposal preparation instructions. All Attachments that are required with the submission of a full proposal are described in the Mandatory Proposal Forms section of this announcement. Proposals are sought from all eligible sources, including educational institutions, nonprofit organizations, and private industry. Generally, this announcement is continuously open; preliminary proposals (preproposals) may be submitted and will be evaluated at any time throughout the year. The availability of funds may limit the ability of the U.S. Government to make awards in specific areas, nevertheless preproposals are sought under this BAA announcement for all areas of interest described in the Areas of Interest. This announcement of the U.S. Government's current interests will be posted on the Grants.gov web portal (http://www.grants.gov/), the Federal Business Opportunity website (http://www.fedbizopps.gov), the JPEO-CBD website (http://www.jpeocbd.osd.mil/ For the complete BAA documents, select current opportunities from the left side menu, then select Chemical Biological Medical Systems. From time to time, this BAA may be amended with announcements or calls for proposals. Additionally, the application process may be amended as other electronic application processes are implemented. All amendments to this BAA will be announced on the JPEO-CBD website, the Grants.gov web portal, and the Federal Business Opportunity website. To facilitate communication on both scientific and administrative matters relating to this BAA, a single email address may be used for all communication with CBMS JPMO. Please send all technical and administrative questions and inquiries to cbmsbaa@amedd.army.mil. Potential applicants are encouraged to discuss their proposal ideas with the CBMS technical staff. In addition to the address above, potential applicants may discuss their ideas with the Technical Contacts listed at the end of each area of interest. Administrative questions concerning the preparation of preproposals or proposals should be addressed to U.S. Army Contracting Command, Natick Contracting Division-Ft. Detrick, Grants Officer. They should be emailed to cbmsbaa@amedd.army.mil, faxed to 301-619-5069, ATTN: BAA 07-01, or mailed to the following address: Chemical Biological Medical Systems ATTN: BAA 07-01 64 Thomas Johnson Dr. Frederick, MD 21702. The Catalog of Federal Domestic Assistance (CFDA) can be accessed online at http://www.cfda.gov. The online CFDA provides access to a database of all Federal programs available to the grant community, including state, local and tribal Governments, academia and research institutions, commercial firms and not-for-profits. Included on the web site are contact information for the office that administers each program, instructions on how to apply for assistance, and several proposal writing guides. The CFDA number for this announcement is 12.360.
Additional Info:
JPEO-CBD Current Business Opportunities for CBMS
Contracting Office Address:
ACC-APG SCRT - Natick (SPS), ATTN: AMSRD-ACC-N, Natick Contracting Division (R and BaseOPS), Building 1, Kansas Street, Natick, MA 01760-5011
Place of Performance:
ACC-APG SCRT - Natick (SPS) ATTN: AMSRD-ACC-N, Natick Contracting Division (R and BaseOPS), Building 1, Kansas Street Natick MA
01760-5011
US
Point of Contact(s):
Sandra OConnell, 301-619-2895
ACC-APG SCRT - Natick (SPS)
http://www.absoluteastronomy.com/topics/Hepatitis_C_virus
(Read the bottom in Bold)
Structure
The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedralTruncated icosahedron
In geometry, the truncated icosahedron is an Archimedean solid, one of thirteen convex isogonal nonprismatic solids whose faces are two or more types of regular polygon.It has 12 regular pentagonal faces, 20 regular hexagonal faces, 60 vertices and 90 edges....
protective shell of proteinProtein
Proteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
, and further encased in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s, E1 and E2, are embedded in the lipid envelope.
Genome
Hepatitis C virus has a positive sense single-stranded RNARNA
Ribonucleic acid is a biologically important type of molecule that consists of a long chain of nucleotide units. Each nucleotide consists of a nitrogenous base, a ribose sugar, and a phosphate...
genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA....
. The genome consists of a single open reading frameOpen reading frame
In molecular genetics, an open reading frame is a DNA sequence that contains a start codon and a stop codon in the same reading frame. ORF is supposed to be a gene which encodes a protein, but in some cases encoded protein for ORFs are not known...
that is 9600 nucleotideNucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides play central roles in metabolism...
bases long. This single open reading frame is translated to produce a single protein product, which is then further processed to produce smaller active proteins.
At the 5' and 3' ends of the RNA are the UTR, that are not translated into proteins but are important to translation and replication of the viral RNA. The 5' UTR has a ribosomeRibosome
Ribosomes are the components of cells that make proteins from all amino acids. One of the central tenets of biology, often referred to as the "central dogma," is that DNA is used to make RNA, which, in turn, is used to make protein. The DNA sequence in genes is copied into a messenger RNA ....
binding site (IRES - Internal ribosome entry siteInternal ribosome entry site
An internal ribosome entry site, abbreviated IRES, is a nucleotide sequence that allows for translation initiation in the middle of a messenger RNA sequence as part of the greater process of protein synthesis...
) that starts the translation of a very long protein containing about 3,000 amino acids. This large pre-protein is later cut by cellular and viral proteaseProtease
A protease breaks down proteins. A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein.-Standard:Proteases are classified into six broad groups:* Serine...
s into the 10 smaller proteins that allow viral replication within the host cell, or assemble into the mature viral particles.
Structural proteins made by the hepatitis C virus include E1E1 (HCV)
E1 is a viral structural protein found in hepatitis C....
and E2E2 (HCV)
E2 is a viral structural protein found in hepatitis C amongst other viruses, including HPV....
; nonstructural proteins include NS2NS2 (HCV)
NS2 is a viral protein found in hepatitis C....
, NS3, NS4NS4 (HCV)
NS4 is a viral protein found in hepatitis C....
, NS4A, NS4B, NS5NS5 (HCV)
NS5 is a viral protein found in hepatitis C....
, NS5A, and NS5B.
Replication
Replication of HCV involves several steps. The virus replicates mainly in the hepatocyteHepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s of the liver, where it is estimated that daily each infected cell produces approximately fifty virions (virus particles) with a calculated total of one trillion virions generated. The virus may also replicate in peripheral blood mononuclear cells, potentially accounting for the high levels of immunological disorderImmunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and disease; malfunctions of the immune system in immunological disorders ; the...
s found in chronically-infected HCV patients. HCV has a wide variety of genotypeGenotype
The genotype is the genetic constitution of a cell, an organism, or an individual usually with reference to a specific character under consideration. For instance, the human albino gene has two recessive alleles, recessive a and recessive a...
s and mutates rapidly due to a high error rate on the part of the virus' RNA-dependent RNA polymeraseRNA-dependent RNA polymerase
RNA-dependent RNA polymerase , , or RNA replicase, is an enzyme that catalyzes the replication of RNA from an RNA template...
. The mutation rate produces so many variants of the virus it is considered a quasispeciesQuasispecies model
The quasispecies model is a description of the process of the Darwinian evolution of certain self-replicating entities within the framework of physical chemistry...
rather than a conventional virus species. Entry into host cells occur through complex interactions between virions and cell-surface molecules CD81CD81
CD81 molecule, also known as CD81 , is a protein which in humans is encoded by the CD81 gene...
, LDL receptorLDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles. The receptor also recognizes the apoE protein found...
, SR-BISCARB1
Scavenger receptor class B member 1 also known as SR-BI is a protein that in humans is encoded by the SCARB1 gene. SR-BI functions as a receptor for high-density lipoprotein....
, DC-SIGNDC-SIGN
DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene....
, Claudin-1CLDN1
Claudin-1 is a protein that in humans is encoded by the CLDN1 gene. It belongs to the group of claudins.-Interactions:CLDN1 has been shown to interact with CLDN5 and CLDN3.-Further reading:...
, and OccludinOccludin
Occludin is a protein that in humans is encoded by the OCLN gene.Occludin is a 65-kDa integral plasma-membrane protein located specifically at tight junctions described for the first time in 1993 by Shoichiro Tsukita...
.
Once inside the hepatocyte, HCV takes over portions of the intracellular machinery to replicate. The HCV genome is translated to produce a single protein of around 3011 amino acids. The polyprotein is then proteolytically processed by viral and cellular proteases to produce three structural (virion-associated) and seven nonstructural (NS) proteins. Alternatively, a frameshift may occur in the Core region to produce an Alternate Reading Frame Protein (ARFP). HCV encodes two proteases, the NS2 cysteine autoprotease and the NS3-4A serine protease. The NS proteins then recruit the viral genome into an RNA replication complex, which is associated with rearranged cytoplasmic membranes. RNA replication takes places via the viral RNA-dependent RNA polymeraseRNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
NS5B, which produces a negative-strand RNA intermediate. The negative strand RNA then serves as a template for the production of new positive-strand viral genomes. Nascent genomes can then be translated, further replicated, or packaged within new virus particles. New virus particles are thought to bud into the secretory pathway and are released at the cell surface.
Diagnosis
Diagnosis of HCV can occur via DNA analysis of the 5'-noncoding region (5'-NCR). However results vary according to the HCV genotype and viral loadViral load
Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid. For example, it can be given in RNA copies per milliliter of blood plasma...
. Non-western HCV genotypes have not been studied as much. In 2009 it was shown that the 3'-X-tail element of the HCV genome is highly conserved across genotypes. It could be tested for $US8.70 within a couple of hours and could also be a valuable tool for screening of blood suppliesBlood donation
A blood donation occurs when a healthy person voluntarily has blood drawn and used for transfusions or made into medications by a process called fractionation....
.
Genotypes
Based on genetic differences between HCV isolates, the hepatitis C virus species is classified into six genotypes (1-6) with several subtypes within each genotype (represented by letters). Subtypes are further broken down into quasispecies based on their genetic diversity. The preponderance and distribution of HCV genotypes varies globally. For example, in North AmericaNorth America
North America is the northern continent of the Americas, situated in the Earth's northern hemisphere and in the western hemisphere...
, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In EuropeEurope
Europe is one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally divided from Asia to its east by the water divide of the Ural Mountains, the Ural River, the Caspian Sea, the Caucasus region and the Black Sea to the southeast...
, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in AfricaAfrica
Africa is the world's second-largest and second most-populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
. Genotype is clinically important in determining potential response to interferonInterferon
Interferons are proteins made and released by lymphocytes in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong...
-based therapy and the required duration of such therapy. Genotypes 1 and 4 are less responsive to interferonInterferon
Interferons are proteins made and released by lymphocytes in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong...
-based treatment than are the other genotypes (2, 3, 5 and 6).
Duration of standard interferon-based therapy for genotypes 1 and 4 is 48 weeks, whereas treatment for genotypes 2 and 3 is completed in 24 weeks.
Infection with one genotype does not confer immunity against others, and concurrent infection with two strains is possible. In most of these cases, one of the strains removes the other from the host in a short time. This finding opens the door to replace strains non-responsive to medication with others easier to treat.
Vaccination
Unlike hepatitis A and B, there is currently no vaccineVaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
to prevent hepatitis C infection.
In a 2006 study, 60 patients received four different doses of an experimental hepatitis C vaccine. All the patients produced antibodies that the researchers believe could protect them from the virus. Nevertheless, as of 2008 vaccines are still being tested.
Current research
Current research is focused on small-molecule inhibitors of the viral proteaseProtease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
(with drugs such as Telaprevir and BoceprevirBoceprevir
Boceprevir is a protease inhibitor being studied as a treatment for hepatitis C.It was being developed by Schering-Plough and has since been absorbed into the Merck's new pipeline since its acquired Schering in 2009...
, both currently in phase III clinical trials) and RNA polymeraseRNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
, and other nonstructural genes. The study of HCV has been hampered by the narrow host range of HCV. The use of repliconsReplicon (genetics)
A replicon is a DNA molecule or RNA molecule, or a region of DNA or RNA, that replicates from a single origin of replication.For most prokaryotic chromosomes, the replicon is the entire chromosome...
has been successful but these have only been recently discovered. HCV, as with most all RNARNA
Ribonucleic acid is a biologically important type of molecule that consists of a long chain of nucleotide units. Each nucleotide consists of a nitrogenous base, a ribose sugar, and a phosphate...
viruses, exists as a viral quasispeciesViral quasispecies
A viral quasispecies is a group of viruses related by a similar mutation or mutations, competing within a highly mutagenic environment. The theory predicts that a viral quasispecies at a low but evolutionarily neutral and highly connected region in the fitness landscape will outcompete a...
, making it very difficult to isolate a single strain or receptor type for study.
For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirinRibavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...
, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature , showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.
Reduction of circulating virus through blood filtration (DFPP and LAP) in combination with the standard-of-care drug therapy has shown promising results with increasing cure rates of standard-of-care therapies.
It has been shown that simple physical reduction in circulating HCV using a one week pretreatment of the patients blood using a Double-filtration plasmapheresis (DFPP) technique, increased the cure rate for treatment-naïve type 1 HCV patients from 50% (controls) to 78% (treated). Viral load was decreased by an average of 26% during the one week pretreatment.
Using lectin affinity plasmapheresis (LAP) further reduces circulating viral load in patients. Using LAP the viral load was decreased on average 41% A more detailed analysis using normalized data to correct for any variations in initial viral load gave an average 29% per treatment viral load reduction in 5 HCV-positive dialysis patients. The latter data indicate that continuous application of LAP could bring HCV viral load to undetectable levels in 4.1 days. Compared to DFPP, the LAP approach has the advantage that no plasma losses are incurred. In addition hemopurification can be carried out for extended periods of time analogous to continuous renal replacement therapy for the treatment of acute kidney failure, making the process much more effective. Calculations based on these data predict that continuous hemopurification would substantially increase the rate of viral load reduction (approx. 14-fold) and therefore increase the cure rate for HCV standard-of-care drug therapies without adding additional drugs and their associated side effects.
Currently Medanta, The Medicity Institute (Medicity) has approved a treatment program for using (LAP) in treating chronic HCV in combination with standard-of-care drug therapy.See also
Hepatitis C virus stem-loop VIIHepatitis C virus stem-loop VII
Hepatitis C virus stem-loop VII is a regulatory element found in the coding region of the RNA-dependent RNA polymerase gene, NS5B. The structure is important for colony formation, though its exact function and mechanism are unknown ....
Hepatitis C virus 3'X elementHepatitis C virus 3'X element
The Hepatitis C virus 3'X element is an RNA element which contains three stem-loop structures that are essential for replication.-References:* [1] * [2] * [3]...
Hepatitis C virus (HCV) cis-acting replication element (CRE)Hepatitis C virus (HCV) cis-acting replication element (CRE)
The Hepatitis C virus cis-acting replication element is an RNA element which is found in the coding region of the RNA-dependent RNA polymerase NS5B. Mutations in this family have been found to cause a blockage in RNA replication and it is thought that both the primary sequence and the structure...
External links
Academic articles about the HCV six genotypes
HCV Sequence and Immunology Databases at Los Alamos National Laboratory
Virus Pathogen Database and Analysis Resource (ViPR): Flaviviridae
The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.
GVK Biosciences (GVK BIO) is Asia's leading Discovery Research and Development organization. GVK BIO provides a broad spectrum of services, stand-alone and integrated, across the R&D value chain. GVK BIO's diverse portfolio of more than 100 customers includes Big Pharma, Agri & Life-sciences companies, leading biotechs and academic institutions. Spread across five locations in India and headquartered in Hyderabad, GVK BIO assists clients accelerate their research. Additional information can be accessed at www.gvkbio.com.
CTRI Number CTRI/2010/091/001114 [Registered on: 02/12/2010]
Last Modified On:
Post Graduate Thesis
Type of Trial
Type of Study
Study Design Other
Public Title of Study A Pilot Study Using the Aethlon Hemopurifier® in the Treatment of Chronic HCV Infection in Combination with Standard of Care Drug Therapy
Scientific Title of Study A Pilot Study Using the Aethlon Hemopurifier® in the Treatment of Chronic HCV Infection in Combination with Standard of Care Drug Therapy
Secondary IDs if Any Secondary ID Identifier
AEMD?HCV?2010 v1.1 Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Name Dr Vijay Kher
Address Deptt of Nephrology & Renal Transplant Medicine
Medanta- The Medicity
Gurgaon
HARYANA
122001
India
Phone 0124-(Erased)
Fax 0124-(erased)
Email vijay.kher@(erased by ANESRI)
Details of Contact Person
Scientific Query Name Dr Vijay Kher
Address Deptt of Nephrology & Renal Transplant Medicine
Medanta- The Medicity
Gurgaon
HARYANA
122001
India
Phone
Fax
Email vijay.kher@
Details of Contact Person
Public Query Name Anuj Sarin
Address Qualtran LLC
Spazedge Business Park, Suite # 347, Tower B Sector 47 Main Sohna Road
Gurgaon
HARYANA
122002
India
Phone +91-98
Fax +91-
Email anuj@
Source of Monetary or Material Support Aethlon Medical, Inc. 8910 University Center Lane, Suite 660 San Diego, CA 92122
Primary Sponsor Name Aethlon Medical, Inc. 8910 University Center Lane, Suite 660 San Diego, CA 92122
Address
Type of Sponsor
Details of Secondary Sponsor Name Address
Qualtran LLC Suite No 347, Tower B Spazedge Business Park Main Sohna Road, Gurgaon Haryana (India) 122002
Countries of Recruitment India
Sites of Study No of Sites = 1
Contact Person Name of Site Site Address Phone/Fax/Email
Dr Vijay Kher Medanta-The Medicity Sector-38,-122002
Gurgaon
HARYANA 0124-
0124-
vijay.kher@
Details of Ethics Committee No of Ethics Committees= 1
Name of Committee Approval Status
Medanta Independent Ethics Committee Approved
Regulatory Clearance Status from DCGI Status
Not Applicable
Health Condition / Problems Studied Health Type Condition
Hepatitis C Virus (HCV) Genotype 1
Intervention / Comparator Agent Type Name Details
Intervention Hemopurifier Device subjects will receive up to Two-6 hour Hemopurifier® treatments for up to three days in combination with standard of care drug therapy, followed by drug therapy alone for up to 47-additional weeks.
Comparator Agent Standard Care According to Investigator discretions
Inclusion Criteria Age From
Age To
Gender
Details Inclusion Criteria ?Males and females 18 years of age and older ?Not on Pegasys-ribavirin or equivalent currently or within past 28 days ?Have received no other investigational drugs within 28-days before entry into study ?Have recovered from the toxicity of any prior systemic therapy ?Study subjects must be willing to submit to temporary vascular access catheterization through the subclavian, jugular or femoral vein. Catheter must be demonstrated to provide adequate blood flow 300 ml/min) during the course of the studies. ?Ability to tolerate blood volume losses of up to 150 ml per week. ?Stable clinical condition, including stable hematocrit. ?Karnofsky score ≥ 60 ?Must have the following minimum hematologic, biochemical, and serologic criteria documented at least 28-days prior to entry into study: oHemoglobin values of 8 gm/dL for males and females oPlatelet count > 100,000/mm3 oBilirubin < 4 mg/dL oAlbumin stable and within normal limits ?Men and women of child-bearing potential must be practicing barrier or oral contraception, for the duration of the study, or documented as surgically sterile or one year post-menopausal ?If female, be non-nursing, non-pregnant and have a negative serum or urine pregnancy test within two weeks of starting study. ?The subject must be informed of the investigational nature of this study and written informed consent obtained prior to enrollment in this study.
ExclusionCriteria Details Exclusion Criteria ?Clinically significant infection, other than HCV, defined as any acute viral, bacterial, or fungal infection, which requires specific therapy (Anti-infectious therapy must have been completed at least 14-days before entry into study). ?Received any investigational agent(s) within 28-days of entry into study ?Any known pre-existing medical condition that could interfere with the subject's participation in the protocol, including serious psychiatric disorders, CNS trauma or active seizure disorders requiring medication, poorly controlled diabetes mellitus, significant cardiovascular dysfunction within the past 6 months (e.g., angina, congestive heart failure, recent myocardial infarction, severe hypotension, or significant arrhythmia) ?Subjects with ECG showing clinically significant abnormalities ?Need for frequent blood transfusions. ?Recent History of bleeding or bleeding disorders requiring the restriction in use of anti-coagulants during study treatments. ?Active immunologically mediated disease (e.g., inflammatory bowel disease [Crohn's disease, ulcerative colitis], rheumatoid arthritis, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, autoimmune or inherited hemolytic anemia, scleroderma, severe psoriasis). ?Any medical condition requiring, or likely to require during the course of the study, chronic systemic administration of steroids or other immunoregulatory medications ?Substance abuse, such as alcohol (~80 gm/day), IV drugs, and inhaled drugs (If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 months. Subjects receiving methadone within the past year are also excluded.) ?Any cancer requiring systemic chemotherapy ?Any other condition that, in the opinion of the Principal Investigators, would make the subject unsuitable for enrollment, or could interfere with the subject participating in and completing the protocol
Method of Generating Random Sequence Random Number Table
Method of Concealment Not Applicable
Blinding/Masking Not Applicable
Primary Outcome Outcome TimePoints
?Decreases in circulating HCV (qPCR) viral load of ≥50% by the end Hemopurifier treatments when compared to viral load prior to initiation of therapy. ?Undetectable HCV viral load in less than 30 days or greater than 100 fold drop in HCV viral load in three months after initiation of drug therapy.
Secondary Outcome Outcome TimePoints
?SVR as indicated by undetectable HCV viral load measured six months after the completion of drug therapy ?Acceptable Incidence of unanticipated adverse device events throughout and following experimental treatment ?Incidence and occurrence of adverse events during the course of study or follow up assessments. ?Clinically acceptable changes in hematology or blood chemistry during treatment ?Undetectable levels of GNA or insignificant increases in soluble silica in the blood ?SVR as indicated by undetectable HCV viral load measured six months after the completion of drug therapy. ?Acceptable Incidence of unanticipated adverse device events throughout and following experimental treatment. ?Incidence and occurrence of adverse events during the course of study or follow up assessments. ?Clinically acceptable changes in hematology or blood chemistry during treatment
Target Sample Size Total Sample Size="30"
Sample Size from India=""
Phase of Trial N/A
Date of First Enrollment (India) No Date Specified
Date of First Enrollment (Global) 10/12/2010
Estimated Duration of Trial Years="1"
Months="0"
Days="0"
Recruitment Status of Trial (Global) Open to Recruitment
Recruitment Status of Trial (India)
Publication Details
Brief Summary This will be a pilot, randomized, single site, controlled efficacy and safety study in which control subjects will receive drug therapy only and study subjects will receive up to Two-6 hour Hemopurifier® treatments per day for up to three days in combination with standard of care drug therapy, followed by drug therapy alone for up to 47-additional weeks. Control patients will be enrolled from the general population of HCV patients scheduled to receive SOC drug therapy. Experimental subjects enrolled from this same population will receive a venous catheter capable of providing ~300 ml/min blood flow. Control subjects will not receive a catheter. Intermittent dialysis machines are recommended to control blood flow in this experimental treatment phase of the study. The Hemopurifier® treatment will consist of two-6 hour treatments per day separated by 6-hour rest periods as an in-patient procedure for up to 3 days within the first week. If more aggressive treatment is warranted, each Hemopurifier® treatment can be extended up to 24 hours for a maximum of three days (physician?s discretion). During the first week, laboratory tests and quantitative viral load determinations will be performed before and after each Hemopurifier® treatment. Follow up evaluations of each of the study subjects will then be conducted at days 7, 30, 90, and 6, 12, 18 months after the final Hemopurifier® treatment. Drug therapy will be continued for up to 48-weeks following the Hemopurifier® treatment. Study subjects will then be tested for HCV viral load 6 months after cessation of drug therapy to determine maintenance of a sustained viral response (SVR).
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