FDA Workshop
Behavior-Based Donor Deferrals in the NAT Era
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
FDA WORKSHOP ON BEHAVIOR-BASED DONOR DEFERRALS IN THE NAT ERA
Wednesday, March 8, 2006
8:00 a.m.
Lister Hill Auditorium
National Institutes of Health
Bethesda, Maryland
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CONTENTS
Welcoming Remarks
Jesse Goodman, M.D., M.P.H., CBER
Introduction to the Workshop on Behavior-Based
Donor Deferrals in the NAT Era,
Jay S. Epstein, M.D., OBRR/CBER
I. Behavioral Risks for Transfusion-Transmitted Diseases and HCT/Ps
Current Policy and Social Dimensions:
Eve Lackritz, M.D., CDC Moderator
Design and Efficiency of Current FDA
Recommendations for Blood Donor Deferral,
Alan Williams, Ph.D., OBRR/CBER
FDA's Current Recommendations on Behavior-Based
HCT/P Donor Deferrals,
Melissa Greenwald, M.D.
Behavioral Risk Exclusions in Other Countries,
Cees van der Poel, M.D., Ph.D.
Social Dimensions of Current Deferral Policies,
Ronald Bayer, Ph.D.
Prevalence and Incidence of Known and Potential
Transfusion-Transmissible Infections in Relation to
Behavioral Risks:
Matthew McKenna, M.D., M.P.H.,CDC, Moderator
Transmission of HIV by Blood Transfusion,
Matthew McKenna, M.D., M.P.H., CDC
Transmission of HBV and HCV by Blood Transfusion,
Ian Williams, Ph.D., M.S., CDC
Transmission of HTLV I & II by Blood Transfusion,
Edward L. Murphy, M.D., M.P.H., UCSF and BSRI
Transmission of HHV-8 by Blood Transfusion,
Sheila Dollard, Ph.D., CDC
II. Assessing the Risks from Transfusion
Indira Hewlett, Ph.D., OBRR/CBER Moderator
Residual Risk of Disease Transmission by
Transfusion: Causes and Components,
Michael Busch, M.D., Ph.D., BSRI
Inventory Management Errors in Whole Because
Release,
Sharon O'Callaghan, MT (ASCP), OCBQ/CBER
Quantitative Models for Transfusion Risks
Associated with Selected Behavioral Categories
a. Point Estimates of Transfusion Risks from
Quantitative Models of Deferral Policy
Changes,
Andrew I. Dayton, M.D., Ph.D., OBRR/CBER
b. Probabilistic Modeling of Uncertainties
Associated with Transfusion Risks,
Steve Anderson, M.D., M.P.P. OBE/CBER
Promise and Challenge in Behavioral
Questionnaire Design,
Kristen Miller, Ph.D.
III. Potential Alternatives for Donor Screening and
Testing,
Jay S. Epstein, M.D., OBRR/CBER, Moderator
A Blueprint for Decreased Reliance on
Behavior-Based Deferrals,
Celso Bianco, M.D.
Behavioral Risks and Emerging Infections: Is there
a Pattern?
Roger Dodd, Ph.D.
Closing Remarks, Jay S. Epstein, M.D., OBRR/CBER
PROCEEDINGS
DR. DAYTON: Welcome. Thank you all for getting up so early to join us. This is the FDA Workshop on Behavior-Based Donor Deferrals in the NAT Era. I don't think we need more of an introduction than that. Our CBER Center Director, Jesse Goodman, is going to open the workshop with some welcoming comments. Jesse?
Welcoming Remarks
DR. GOODMAN: Well, I would like to welcome everybody and also thank you for your participation and interest and input because this is really what this is about--discussion and input.
Just a few very brief comments, some of which will be echoed by Dr. Epstein, but I think that many of the people in the room here have a lot to feel very positive about. Whether you are a donor, a part of the government or part of the blood community, blood recipient community, there has been such a dramatic change and improvement in the safety of the blood supply, particularly from the viral pathogens we are all so aware of in the last 20 years or so. I remember very palpably, having been involved in the care of HIV and hemophilia patients at UCLA when this was all happening, just the terrible toll of that situation, some of which still continues but it is because of a lot of people working together, despite really challenging issues and because of the application and development of new technology that we really are in such a better place.
So, I think we should start with that as a congratulatory note. In addition, some methods continue to improve. We refine our ways in which we screen donors and we improve testing. Now, I think, as I will get to in a second, that is not a reason for complacency. In fact, that is a reason to tell us what we can achieve and why we should try to continue to achieve that because we should not take safe blood supply for granted.
One of the reasons for this discussion is to consider how and whether improved testing may change any approaches practically to how we manage blood safety. Of course, one issue in recent years that contributes to this openness to think about this issue is the general introduction of nucleic acid testing and screening which, as people know, has really tremendously improved the safety margin for viral pathogens, and also is a platform that allowed us to face new emerging pathogens--West Nile virus.
As I said, I think today for FDA we are here to be primarily in a listening mode but also to share our current information, models, some of the scientific basis for where we have been. I want to emphasize that this is not a decisional meeting or process at this time. It is also not intended to be a debate. We can say quite openly that we don't have a preferred or predetermined outcome. I want to say that personally I know many of us and we have spent a lot of time dealing with blood availability challenges as well as having blood and plasma products available to benefit people. You know, personally I am a donor, except that I am currently excluded because of travel. I have to talk to our staff about that.
But we do appreciate the desire to donate. I think this is a very important and socially valuable thing in a society where we really need to value those kinds of contributions highly, and we appreciate the interest in making sound policy.
Sometimes there can be some emotional issues in this but, you know, I want to assure everybody that our policies and our considerations of this are based on the science, the protection of the recipient and also feasibility, what can be done. So, we have to look at all of those things.
We do particularly have a primary responsibility to the safety of the blood supply and to the health of recipients. I was thinking about this actually, you know, coming over here and I realize that that, in fact, is a common goal. It is not that readily apparent but why does somebody want to donate? Well, their desire is to give life, to make a recipient healthy. So, we really have to keep in mind the ways in which the donor community, the recipient community and the blood community have common goals.
It is also important to keep in mind that we have a complex system. It has managed to make these accomplishments in safety from contributions from a lot of people, and that starts with the donor, goes to the recipient and includes the healthcare provider and includes the blood community, whether blood banks and systems or transfusion, and it certainly includes the contributions of technology, diagnostic testing, etc. It includes the contributions of our surveillance system and our colleagues at CDC. So, as we look at information we want to hear from all these groups, and as we look at possible approaches we always want to hear from all these groups.
The final thing I wanted to say is, as I started with, there will always be new and emerging threats to the blood supply. You know, one that is mentioned and is on the program because it relates to one particular behavioral deferral, potentially to geographic deferrals, is the HHV-8 issue. In that case there are science gaps, etc., to be discussed. But, you know, we are obviously all facing a great concern about things like TSE and other future threats to the blood supply.
So, I think we should also be very forward looking and focused not just on the issue of the moment but what are the tools in the long-run that will help protect us against future threats. This is sort of consistent with FDA's scientific initiative, the Critical Path initiative, which is to have, for example on a policy and guidance end, our practices be as robust as possible to face not just the issues of today but the issues of the future.
But also there are probably scientific opportunities there and, again, some of these opportunities in the blood area are not always the focus of huge, large-scale investments. I think we should identify and prioritize what are some of the things we can accomplish scientifically and work with our colleagues in industry, NIH and CDC to get there. Examples there are better testing, abilities to move pathogens in and out of our testing systems, ability to detect multiple pathogens, processes to inactivate and assure the safety of the products themselves. There has been a lot of work on these but it is all in very early stages; then, finally, improvements in the products themselves, you know, the move towards recombinant products in certain areas, exploration of synthetic products, etc.
So, I try to keep the big picture in mind even though I focus here today on where are we with donor deferrals? How does the testing and changes in testing affect that? And, you know, what are your creative ideas and what is your input? So, with that in mind, I just again thank you. We are really going to listen to this input. We will try to identify if there are scientific needs, what those are and we will try to move forward in that kind of collaborative spirit. So, I thank you very much. I apologize in advance for having to head off to a flu meeting in Canada, but I will be very engaged in hearing what comes out of this meeting. So, thanks very much, everybody.
[Applause]
DR. DAYTON: Thanks very much, Jesse. Now let me introduce Jay Epstein who is going to give the introduction to the workshop. Jay?
Introduction to the Workshop on Behavior-Based Donor Deferrals in the NAT Era
DR. EPSTEIN: Good morning and welcome. It is my pleasure and privilege to provide a little bit of background and then a quick overview of the program for this meeting.
The FDA general strategy for assuring safety of the blood supply is based on five overlapping layers of safeguards. Our concept over the decades has been to optimize each safety layer as if independent.
What are these safety layers? Well, first, as you know, we engage in screening and deferral based on risk factors. These can be geographical, behavioral and medical. We go about this through a process of donor education, which is followed by self deferral, and then we have a health historian perform an interview and if these factors are elicited then, likewise, there is deferral.
The second tier, of course we focus on a great deal, which is the laboratory testing. We test, as you know, for HIV-1 and 2, hepatitis B, hepatitis C, HTLV-I and II, West Nile virus and syphilis variably under regulations and in compliance with guidance.
Additionally, we utilize deferral registries so that deferred donors are identified and use of their blood is prevented, should it be inadvertently collected.
Additionally, and we are going to focus a lot on this in the present workshop, we have as part of the current good manufacturing process quarantine controls which are intended to prevent the release of a unit pending the complete verification of donor suitability, including behavioral and medical screening as well as testing.
Lastly, a little appreciated layer is, again under CGMP, the requirement to investigate and correct any deviations that could affect the quality of the product.
Now, these strategies have been very highly successful at reducing the major transfusion-transmitted disease risks over the last one and a half to two decades. I think the point, which I will illuminate further in the next slide, is that these advancements which are on a log scale represent a combination of effects, both from behavioral exclusion and also testing, although it is without a doubt that testing plays a very dramatic role.
In fact, our current risks are now so low that they cannot be measured directly and, hence, we rely on models to estimate the current residual risk, that is to say the risk after all the safeguards have been followed. That becomes important because in today's workshop you are going to hear a lot about model building in order to estimate risk and this is how we need to go about it.
Those are numbers from the current literature and risk per million donations, ranging from 1 in 2 million for HIV/HCV; a little bit higher, 1.5 per million for HTLV; and then the highest residual risk of a major transmissible disease is still from hepatitis B and if you assume 14 million collections and about 1.7 units per collection yielding 23 million components, you can estimate that this is the number of contaminated components that may be entering the blood system each year. Now, this is not adjusted for rate of transmissibility or the disease attack rate, it is just the potential rate of exposures to potentially contaminated units.
But looking a little bit more closely at the role that has been played by behavioral exclusion, this is just an example for viral hepatitis. In the 1970s there was concomitant
introduction of labeling of paid versus volunteer donation for blood for transfusion, which was at the same time as the first generation of the test
for HBsAg, and the combined effect was a very dramatic, approximately 90 percent, reduction. We have never completely teased out how much of this
was due solely to the change in labeling which eliminated paid donation, but we do know from the antecedent literature that paid donation was highly
associated with transmission of hepatitis.
These are percents here, this is as high as 30 percent in the 1960s, per transfusion episode which might have involved multiple units of exposure per episode. Again, another example here was when we introduced the high risk exclusions for HIV based on certain categories of risk, we had a further reduction in the hepatitis B risk and it was because of the convergent epidemiology of HIV and HBV. So, the point here is that these two strategies have at various times worked well in tandem
What I am going to describe next is the general paradigm of the way the oversight system responds to an emerging threat. What happens when an emerging pathogen threatens the safety of the blood supply? Well, generally the first step is that we introduce deferral criteria which are based on epidemiologically determined risk factors and those can be medical, geographic or behavior-related exposures. Where feasible, tests are then developed but we generally maintain the deferrals as an overlapping safeguard. The reasons for that will become clear later because risk is a result not only of screening out detectable positives but also avoiding the collection in the first place because they are then a threat for inadvertent release from the quarantine inventory.
Of course, there is also the benefit of reducing the number of window period cases if you can eliminate persons with recent infection through screening. Then over time test sensitivity and specificity generally improve. This is because of competition in the marketplace, as well as the upward vector of science and technology. But, again, risk-based deferrals are usually retained as an overlapping safeguard, especially when data are lacking on the relative safety contribution of risk-based versus test-based deferrals. This is an area where we generally are weak. It is the unusual case where information is brought forward that can actually tell us over time what the relative contributions are of the risk-based deferrals and testing.
Over time the expansion of risk-based and test-based deferrals has certainly added to blood safety, and we showed that in earlier slides. But we also recognize that it has added considerably to complexity. As the number of risk-based deferral criteria has increased, it has been asked whether the blood questionnaire is as effective as it should be and whether simplification would enhance its value. Additionally, the question has arisen whether testing has become so effective that some risk-based deferrals no longer provide a significant added safety value. We do understand the argument that, whereas we measure testing as an added benefit to risk deferral initially, we ought to be flexible enough intellectually to look at it the other way later and say, well, what does behavioral exclusion add to testing were the sequence reversed. So, we understand that.
Now, at the same time these very same safety strategies have sometimes raised social issues, particularly focusing on donor selection. FDA is aware that some current donor selection criteria have been perceived by some individuals as possibly based on prejudice or on past needs rather than on current science. It is our hope that this forum will clarify the rationale for current deferrals and also provide an opportunity for scientific input and discussion into current donor policies.
We further recognize that the blood system depends on the trust, generosity and good will of donors, and we very much appreciate the altruism and the intended social contribution of all who seek to donate. I think that Dr. Goodman stated this very well in opening the workshop. However, while we consider the donor's perspective very carefully and seriously and, indeed, this is part of the reason for the workshop today, FDA's primary responsibility is to the safety of the blood supply and those who will receive blood and blood products.
So, we come then to the structure of the workshop. It is important to state that we are not here to make policy today. We are here to listen. We are here to gather information and, hopefully, to have a critical review of the current science which underlies our present policies.
That said, the public discussion of the scientific basis for the use of behavior-based donor deferral criteria to prevent transfusion-transmitted infectious diseases is our primary charge, and to consider whether the blood safety advancements from introduction of nucleic acid based tests, NAT, or other methods would permit changes to these deferrals without compromise to blood safety. So, that is our charge and I hope everyone will keep it in mind as the day goes on.
I don't think I turned up the lights and the slide is still a little bit dim. Maybe that is a signal! Okay, let me quickly then review the structure of the workshop. It is organized in your agenda in three segments. In the first segment we will have a review of the current behavior-based deferrals. We will review FDA's policies for blood and also touch on our policies for cell and tissue product donations. We will review the effectiveness of donor screening procedures. We will get some international balance by hearing about deferral policies in Europe. We will discuss the social dimensions of the issue and we will have a discussion, disease agent by disease agent, on the association of transfusion/transmissible disease risks with specific behaviors that we call high risk behaviors. We will then have a panel, and the panel will include the presenters but also that will be an opportunity for participation by all of those assembled, and the focus will be on the question what behaviors are associated with risks of transfusion-transmitted disease--of course, infectious disease is what we are talking about--and how do these risks compare amongst cohort groups with these behaviors?
In the second segment of the agenda we will assess the risk of the transfusion transmissible infectious diseases. We will hear presentations on current estimates of risk for these infections; on inventory errors as a source of the residual risk; risk estimates for certain candidate modified deferrals; and a critique of the value of donor questionnaires. Again we will have a panel of the discussants and the audience on the question how do behavior-based deferrals contribute to blood safety when donors additionally are tested by nucleic acid tests?
Then, in the final segment of the agenda we will have a discussion on potential alternatives for blood donor screening and testing, and we will critically review two things, first, an overview of alternatives that might be considered as well as a framework for thinking about them, and then a specific focus on how these behavioral risk factors ought to be considered in relation to emerging infectious diseases. Once again, we will convene a panel. The panels keep getting bigger and bigger, incidentally. This panel will focus on considering the implications of the quantitative risk models which will have been presented earlier, and then try to draw attention to the need for additional scientific data where it would help us to resolve whatever may appear to be the most critical questions.
In closing, let me just say that I am very pleased with today's turnout. I am glad that this subject has drawn in so many participants, and just to reiterate, FDA values everyone's contribution to this workshop and we look forward to a lively and enlightening day of presentations and discussions. Thank you very much.
[Applause]
DR. DAYTON: Thank you, Jay. I will introduce Eve Lackritz who is going to moderate the next session.
I. Behavioral Risks for Transfusion-Transmitted Diseases and HCT/P
Current Policy and Social Dimension, Eve Lackritz, M.D., CDC, Moderator
DR. LACKRITZ: Good morning, everybody. This is a very optimistic schedule that we have to keep time on. We are going to have a number of presentations that are all timed differently so I will have to ask each presenter to keep track of the time. We will have questions. We might have time for maybe one burning question but otherwise questions will be left for the open discussion.
Our first speaker is going to be Dr. Alan Williams who is going to present on the design and efficiency of current FDA recommendations for blood donor deferral.
Design and Efficiency of Current FDA Recommendations for Blood Donor Deferral
DR. WILLIAMS: Thank you, Eve, and good morning, everyone. What I am going to do is build somewhat on the introduction that Dr. Epstein presented and give a few more characteristics about the donor eligibility policy development process; present some of the behavioral deferrals that are the subject of discussion today; and then, in kind of a combination of things, introduce some of the studies that help assess what the efficacy is of the current deferrals, and at the same time introduce some of the modes of survey data collection that gave rise to some of those data and how they all provide data that contribute to the understanding of the process, but don't necessarily mean that you can take data from one mode of study and compare it directly with a different mode of study. You need to keep in mind that sometimes you get different answers.
Clearly, one of the most important reasons for providing accurate donor qualification is related to the layer of safety that is involved with determining donor eligibility before the testing process. Obviously, it is critical to maximize blood safety, particularly in relation to known agents where there is a laboratory screen in place because of considerations related to testing window periods that may be present, albeit a very small opportunity for testing errors, release errors and staff protection.
Similarly, it is important to provide mechanisms to ensure safety against known or unknown agents for which no laboratory screen currently exists. In some instances donor screening by epidemiologic criteria may be the sole protection in place. There may be a threat that is recognized and only partially characterized scientifically, and vCJD would be an example in this category. But there also might be a threat that is completely unrecognized but the contribution to safety may be possible through eligibility or ineligibility of individuals whose behavior has heightened exposure to a certain type of agent or certain agent that is transmitted in a parenteral manner. So, deferral for instance of individuals who might have a high rate of parenteral exposure may provide a measure of safety even though an agent may be unknown. I would use here as an example injecting drug users who have a high rate of needle sharing with other individuals who had a high rate of needle sharing and that provides an amplification effect leading to high rates of exposure of parenteral agents.
It is important to have accurate donorqualification to minimize donor loss. In other words, the questions need to be as sensitive and specific as possible so that donors who truly are eligible remain eligible. It is important to minimize negative operational impact because a question that doesn't obtain its desired goal may result in something like donation information transmission which then could result in recall of products or other operational impacts.
I think one that doesn't get a lot of attention but I think is important to stress is that frequently component preparation and other production aspects of the collected blood unit take place before the testing results are fully available. So, the safer the blood is coming in the door and through the processing process, it helps to minimize staff exposures to infectious donations even though universal precautions are in place certainly in the blood collection centers.
There are various stages of donor qualification. One of the oldest ones is the exclusion of defined risk populations or provisions for labeling. For instance, donors, in fact, can be paid for blood donations; it is just that the label needs to reflect that fact. Prisoners are excluded because of high risk particularly of injecting drug use. There is self-deferral prior to the appearance for donation. I put this bolded because, in fact, this appears to be the major source of self-deferral. The donors who recognize they are not eligible through educational materials or conversations with staff at the time they make an appointment just don't appear at the blood center, appropriately, and this is really the place where most of the deferral takes place. Donors can defer on site if they see educational materials prior to their interview. They can be deferred by staff during an interview. It could be a self-administered interview followed up by staff contact or a face to face interview. In reality, for some of the major risk factors that we are speaking about today, deferral at that point of the screening process is really fairly rare. Most of it takes place before that time.
You will hear of some data today about post-donation information which comes after the donor has donated a unit of blood. This can come from a donor calling back to say they really didn't feel that healthy that day or they are ill now. It can come from third-party information and it can come from subsequent donation history in which a donor reveals a factor that makes them ineligible that they should have admitted earlier.
I put together five principles for consideration of regulatory aspects of donor eligibility. The first is to ensure consistency and a risk/benefit balance to any potential policies, including the determination or modeling, if necessary, of sensitivity, specificity and predictive value wherever possible. It is important to consider that safety really is context dependent. As all of you are aware, it includes the continued availability of medically necessary products. So, eligibility criteria that had a major impact on availability of critical products would certainly not be appropriate.
The second principle is to strive for science-driven policy but recognize the need to act in the interest of public health when scientific answers are not fully available. That is, to take prudent measures if appropriate. This would be equated to the institution of deferrals for travel to countries with high levels of BSE that were put in place in fact before there was recognition of transfusion transmissibility of the agent.
A third principle that I think is an important one to keep in mind for today's discussion is to ensure that any changes in existing regulatory policy can be shown, within reason, to result in improved or at least equivalent safety of the blood supply for the recipients.
The fourth principle is vetting and public airing of proposed policy within FDA, within HHS, within the public and involved blood collection community, and other industry and provide opportunity for public comment.
Finally, to help provide liaison support to organized industry efforts to define voluntary standards because not all of the standards, obviously, are regulatory and we do liaison actively with AABB, PPTA and other standard-setting organizations.
To move to some of the wording associated with some of the current deferrals, and all of these except the last one are based in guidance issued by FDA in April of 1992, entitled Revised Recommendations for the Prevention of Human Immunodeficiency Virus Transfusion in Blood and Blood Products. The wording cited here is the wording that was put together by a task force responsible for development of a donor history questionnaire on behalf of the blood community, and this questionnaire is available on the AABB web site and is now in widespread use throughout the country for standardized donor screening.
Criteria organized by time frame in the past 12 months--has the donor had sexual contact with anyone who has HIV AIDS or has had a positive test for the HIV AIDS virus; had sexual contact with a prostitute or anyone else who takes money or drugs or payment for sex; had sexual contact with anyone who ever used needles to take drugs, and parenthetically, or steroids or anything not prescribed by their doctor? Steroids in this instance is actually an industry standard incorporated into the same question.
In the past 12 months, has the donor had sexual contact with anyone who has hemophilia or has used clotting factor concentrates? For females, has the donor had sexual contact with a male who has ever had sexual contact with another male in the past 12 months?
Since 1977, which was the first AIDS clinical case recognition in the U.S., from 1977 to the present, has the donor received money, drugs or other payment for sex from 1977 to the present? Have you--referring to males, had sexual contact with another male even once?
The so-called indefinite deferrals--has the donor ever used needles to take drugs, steroids or anything not prescribed by a doctor? Has the donor had sexual contact with anyone who was born in or lived in Africa? The last question is due to potential exposure to group O HIV, and stems from a 1996 interim recommendation related to HIV group O infections, published in December, 1996.
Now I would like to move a little bit to some thoughts about assessing the efficacy of donor deferrals. I wanted to introduce, first of all, what are some of the sources of data. Actually, the blood collection environment and donors in particular are really rich sources of epidemiologic information. There have been many, many observations and publications related to donor prevalence and incidence in the donor population. There is information related to rates of deferral, rates of post-donation information reported back to blood centers, and other operational measures.
Related to efficacy, for at least 15 years now there have been active programs to interview donors found to be positive for infectious disease markers, particularly hepatitis and HIV, to determine what their risks were that resulted in that infection. Then, starting in the early to mid '90s, there were some anonymous mail surveys which actually got at risks in donors who did not have infection to determine sort of what the risk burden was in the current donor pool, the rich sources of information in the donor pool.
The general population--there are certainly data available, but the data available to actually compare with the donor population is somewhat limited. There are marker prevalence studies. Many of these are in defined subgroups or risk subgroups. There are limited behavioral risk surveys. Some of them are AIDS-related risk factors like condom use. But if you try to find a general population to look at something like sexual contact of a woman with an IV drug user or male sex with another male, it is really very difficult to come by any general population information.
I just wanted to note here that there is a special category which is donors who appear to a blood center for the first time. They are a very crude representation of the general population but they do represent the incoming general population which has been exposed to the educational materials from the blood center, has been screened one time at the blood center and not, for the most part, tested by the test results. So, it is a unique source of comparison with the general population and the impact of the donor screening.
So, these are all different modes of data collection. There can be comparisons made between data from different sources. They may not be rigorous and often aren't, but it does make use of the only available data, and I think you are going to see a fair amount of those comparisons today so perhaps keep that in mind.
So, just an example of data reflecting reduction of infectious disease marker prevalence in accepted donors, donors compared with the general population. There were studies from CDC which showed that there were 0.47 percent confirmed HIV-positive in the donor aged general population around the 1994 time frame, '93, '94 time frame. At that same time frame there was the RED survey data around 1995 showing 0.03 percent confirmed HIV-positive in first time donors.
So, reflecting back to what I mentioned about first time donors, one can estimate roughly about a 93.6 percent reduction in HIV seroprevalence that is, for the most part, related to the donor eligibility education and screening.
There can also be determinations made relatd to infectious disease marker prevalence over time. This is now I think a classic diagram from Mike Busch, published in 1992, showing from a combination of observations, including HIV look-back studies in donors in the San Francisco area, a 90 percent reduction of post-transfusion HIV-1 transmission in that area prior to the implementation of specific testing. One can see in estimated exposure recipients up to the '80s, again the first AIDS case and then, at the peak of the curve, recognition of high risk groups, initiation of donor deferral, progressive impact of different at risk individuals and then, by 1985 when HIV screening was implemented, a large portion of the risk of blood supply had, in fact, been removed by behavioral screening.
An additional thought on where there is no test data involved is comparing risks in accepted donors. Studies out of University of Chicago in 1994 showed a 4.1 percent prevalence of MSM in the past 5 years in the male general population. We had a similar risk from the RED study. The anonymous male survey showed a 0.6 percent risk in accepted male donors so, again, a crude correlation but about an 86 percent reduction related to risk as opposed to markers.
Then, similarly, for injecting drug use 3.9 percent since 1978 in the general population--this was from the pilot Dallas household survey--versus about 0.5 percent IDU ever among accepted donors, again about an 86 percent or 87 percent reduction.
So, some of those are the positive aspects of efficacy of deferral but I think there still are some developmental research areas. The first would be observations about false-negative behavioral screening. The first point is that interviews of accepted seropositive donors frequently identified behavioral risk that should have prevented donation. These studies are important to monitor the risk exposures that resulted in the donor's infection and also to rule out unusual modes of infection transmission, and CDC supported quite a few studies in the '90s to help look at these factors.
These are data showing comparison between data from interview studies. These are in-person interviews of donors found to be HIV seropositive. A study was in place for at least a decade, and I think a little bit longer, showing in males in the late 1980s the risks for male contact with other males, heterosexual contact with a known at risk partner and a fairly sizeable component of no reported risk, and a smaller component of injecting drug use. That proportion changed a little bit by 1997 so that males who have sexual contact with other males was down to about 40 percent, and I think some later data, up through year 2000 shows that MSM constitutes--without separating by gender--about 23 percent of the total risk associated with HIV seropositive in interviewed donors.
Similarly, for females, as you might expect, the largest category of exposure is heterosexual contact with an unknown at risk individual and a large component of no reported risk. Similarly, again looking at risk rather than markers, surveys of accepted unselected donors also identify behavioral risks and identify the behavioral risk burden in the donor pool. This donor pool potentially contributes to incident infection, which is important because it includes potential for window period cases.
This is the first anonymous male survey done by the RED study, published in 1997. I won't go through all of these, they are in your handouts, but it documented in the overall donors who responded to the survey risk factors that, in fact, should have resulted in deferral prior to donation.
Since 1977 MSM deferral criteria was defined as 0.6 percent; IDU ever 0.5 percent; and overall cumulatively 1.9 percent of donors who reported one or more risks known as deferrable risks that should have prevented the donation, about 242,000 donors a year at that time.
REDS did a similar study methodologically in 1998, and there was a recent publication in Transfusion that provides some of these data. Although there are a couple of potential explanations, interestingly, the male respondents who reported MSM since 1997 had just about doubled. Now, whether this is measurement error whether it is a true increase in that donor population, or whether it is due to the fact that there is five years additional time to develop that group of donors needs to be worked out. The observation is that the reports increased two-fold, from 0.6 to 1.2 percent.
One of the real values of surveys like this is not quite as much the estimate of overall prevalence because, you know, there is a certain lack of validation of those data, but that the survey method itself is reproducible over time and I think one of its real values is the ability to stratify against other factors.
Some factors found in correlation with these donors were other deferrable risks, including injecting drug use, receiving money or drugs for sex, self-reported HIV test seeking--not a deferral but an interesting observation. These were higher in all subgroups reporting MSM contact since 1977.
There was some distinction made between MSM who had had activity within the last five years versus those who had abstained from MSM activity for the last five years. Reactive screening tests were correlated with the group with recent activity but not with the group that had abstained for five years.
Another observation related to this paper is that 92 males out of the 25,000 respondents reported MSM activity in the past year. That is 0.36 percent. This subgroup of male donors was higher for all other transfusion-transmitted behavioral risks for HIV test seeking, for other test markers and for numbers of lifetime sex partners compared to other males who responded to the survey.
The HIV window period is known to be considerably less than one year so what this translates to is that there are approximately 16,000 individuals, extrapolating from the survey data, with MSM activity in the past year. These donors may have a variety of reasons for proceeding with blood donation, but I think one can't argue the fact that this is a source of incident HIV entering the blood supply and, in fact, when these donors were interviewed, you know, the MSM risk came out. So, this is the risk pool; this is the risk burden for a certain proportion of HIV. So, I think it is important that improved behavioral science continue to identify and interdict blood donation by overtly high risk donors, and this really should be treated as a priority.
I am going to end with a few thoughts about some behavioral science perspectives and some of the research things that are going on which I think are really quite interesting and progressive. Information about personal behaviors is inherently difficult to collect, and there are a number of reasons for this. There is the phenomenon of social acceptability of the information. If you are sitting across from an interviewer you may be hesitant to give them your full life story in terms of your risk history. Right response rates in surveys tend to be low and there is frequently missing data in certain data elements and inconsistencies frequently occur.
I would point out that regulated blood establishments are a special case because of the training involved. Often I think, you know, there, you know, there is much better quality medical history in the blood center that in some other settings, including research, but still it is the nature of the behavioral data collection that it is not entirely reproducible. People tend to avoid careful reading. This is a known phenomenon so that, you know, often the educational materia was there but the donors just don't read to the end and get the full message.
It is known that there is improvement in quality with serial data collections or serial donations. Many of the donors are repeat and you actually see evidence of improved education in deferral as donors repeat more frequently.
Donors frequently form their own basis for risk assessment. This can be related to denial of a certain risk or lack of respect for the policy that is in place. There can also be external factors which prevent appropriate self-deferral. This can be some sort of perceived or actual secondary gain from donation--peer pressure and environment, including privacy; comprehension of the question; and the fact that some of the questions themselves, trying to meet scientific criteria, actually end up being quite complex for the lay individual to understand.
There are some very useful areas of applied research that have taken place and continue. The AABD uniform donor history task force has been working close to a decade now on improving a streamlined donor questionnaire, which includes the use of capture and interval questions, improved educational materials and, importantly, cognitive validation to the extent possible to see how well people understand the questions that are actually being administered to the donors.
Also, following on some of the behavioral work related to the AIDS epidemic, the use of computer assisted self-interview, particularly when there is an audio component through head phones, has scientifically been shown to produce a better interview process because it is private. You don't need literacy. It is standardized. It can have multiple languages. It can have visual aids and the respondent often can control the speed of the interview. This is now making its way into blood establishments. Several centers are now using this process and finding that the donors like it; the staff like it; and I think the evidence points to a better interview process.
So, in conclusion, FDA considerations of donor deferral are grounded on several well-defined principles that are science-based but also consider the context of risk and the inevitable scientific uncertainties.
Second, based upon limited data from donor screening situations, we estimate that there is about 85-99 percent sensitivity of current blood donor screening procedures in their ability to determine donor eligibility.
Finally, further behavioral research in this area remains critical, in particular methods that will support the identification and interdiction of donation of overtly high risk donors who fail to self-defer. Thank you very much.
[Applause]
DR. LACKRITZ: Could the projectionist come down now to correct the projector? Alan, do you want to stay there and answer questions while we are getting that fixed--if we get that fixed?
[No response]
For our next speaker we have a replacement. It is going to be Melissa Greenwald who will be presenting on FDA's current recommendations on behavior-based HCT/P donor deferrals.
FDA's Current Recommendations on Behavior-Based HCT/P Donor Deferrals
DR. GREENWALD: Good morning. Dr. Solomon sends her apologies. She is very sorry she couldn't make it today but I will be here to talk to you about FDA's current recommendations for behavior-based HCT/P donor deferrals.
Why are we discussing these today? HCT/Ps are human cells, tissues or cellular or tissue-based products and you see why we call them HCT/Ps. We have two different donor types. We have cadaveric donors, what we call cadaveric donors who are not heart-beating donors and, obviously, we can't do testing and follow-up on those donors. We also have living donors. If the donor is available we do have the opportunity to do testing and follow-up so we are interested in looking at various options such as testing the donor, quarantining products, re-testing and release.
Obviously though, any changes to blood donor suitability policies may well affect HCT/P donor policies, and there are some differences between the blood donor and HCT/P donor deferral policies based on behavioral risks.
I will go through a brief history of the regulation of human tissue for transplantation. Back in 1985 CDC made some recommendations to test for HIV-1 in organ, tissue and semen donors. Then there was really a sentinel publication in 1992 where there was a report in the New England Journal of Medicine of transfusions of HIV-1. That transmission came from a serum-negative organ in a tissue donor. Of course, we all know that testing was a bit different back then. There were four organ recipients and three fresh-frozen bone recipients who ended up developing HIV from transplantation.
As a result of this, the Public Health Service formed a working group which was comprised of individuals from both the Public Health Service as well as external consultants. The result of this working group was that there were CDC guidelines for preventing transmission of HIV through transplantation of human tissues and organs that was published in MMWR in 1994.
So, I will take a little bit of a look at those 1994 CDC guidelines. They directly apply to donation and transplantation of human organs and solid tissues, but also serve as a general guide for human breast milk and semen. The publication itself listed some factors that were considered in developing those guidelines. There are differences between organ donors and tissue donors, heart-beating versus non-heart-beating donors. There are differences in time constraints and variability. Organs must be transplanted much sooner than corneas, which must be transplanted much sooner than bone, for instance. Bone can be stored in freezers for years before being used.
There are differences in risk transmission. Vascularized organs are much better vectors for transmission of infectious agents than avascular tissues. This limited availability of organs and the risk/benefit ratio at transplantation to the recipient is different. We call organ transplantations generally a life-saving procedure, whereas tissue transplantation is generally considered to be life-enhancing. Despite the fact that these factors were recognized, it really was too complex to stratify the behavioral exclusionary criteria.
We will go through what those precise exclusion criteria were: Men who have had sex with men in the preceding five years; persons who report non-medical intravenous, intramuscular or subcutaneous injection of drugs in the preceding five years; persons with hemophilia or related clotting disorders who have received human-derived clotting factor concentrates; men and women who have engaged in sex in exchange for money or drugs in the preceding five years.
Persons who have had sex in the preceding 12 months with any person described in the previous slide or with any person known or suspected to have HIV infection; persons who have been exposed in the preceding 12 months to known or suspected HIV-infected blood through percutaneous inoculation or through contact with an open wound, non-intact skin, or mucous membrane; inmates of correctional facilities; and children 18 months or younger born to mothers who either have or are at risk for HIV or who breast fed in the previous 12 months.
Finally, we move on to the FDA regulation of HCT/Ps. As a result of the transmission, FDA published an interim rule in 1993. This was really just the beginning of trying to get a standardized regulation to approach screening and testing of donors, HCT/P donors.
The interim rule had similar requirements to screen and test donors for HIV-1 and 2, hepatitis B and hepatitis C, and also had a few requirements for written procedures, records and inspections. That interim rule was finalized in 1997, and there was a guidance that was published along with that rule. That guidance describes the behavioral deferrals for HIV, hepatitis B and hepatitis C, and those were based on the 1994 CDC guidelines criteria. It also described clinical evidence of HIV, hepatitis B and hepatitis C, as well as physical evidence of HIV and viral hepatitis.
Then, in 1997 we also published a proposed approach to regulation of human cellular- and tissue-based products. So, this was FDA's sort of announcement to the world that we were going to be taking a broader scope to the regulation. In 2001 the final rule was finalized and 2004 was a busy year for us. The donor eligibility final rule was finalized. That has requirements for screening and testing for HIV-1 and 2, hepatitis B and hepatitis C, syphilis, and also some other infectious agents for specific tissue types. It also has requirements for screening for TSEs, including CJD and variant CJD.
Along with that donor eligibility rule came the donor eligibility draft guidance which is in the process of being finalized. In that guidance FDA announced its intention to add West Nile virus, SARS, vaccinia and sepsis to the list of relevant communicable disease agents or diseases. At that time we gave recommendations on how to screen for those agents. The current good tissue practice rule was also finalized in 2004, which provides for manufacturing controls to try to improve the safety of cells and tissues as well.
In the process of writing and revising the rules, there was consultation amongst the Public Health Service in June of 2000. The purpose of that consultation was to look at whether or not the 1994 CDC guidelines should be revised. In other words, should the behavioral deferrals be changed. This meeting was a closed meeting that involved members of the Public Health Service as well as invited members of the public. There was a review of the incidence and prevalence data that was available at that time in high risk groups.
Looking at that data, they tried to make a determination of how much benefit might be gained by having an increased donor pool versus how much additional risk you might be taking on to release an infectious product if the deferral criteria were changed. The conclusion of that consultation was that more studies are needed and the current data really did not support the identification of safe subsets of groups that were at risk.
Our draft donor eligibility guidance that was published in 2004 basically really retained the 1997 deferrals which, of course, was based on the 1994 CDC guidelines. There were some changes from the 1997 guidance, and these are just some of the changes. We didn't want to bore you with too many of them: Sex or other close contact in the preceding 12 months with any person having clinically active hepatitis. Really, that used to be any person having hepatitis at all, viral hepatitis. Persons who have had a past diagnosis of clinical, symptomatic viral hepatitis after age 11, unless the evidence from time of illness documents that hepatitis was identified as hepatitis A virus. Previously, that last part of the sentence about hepatitis A was not included. Also, it included exclusions for CJD, variant CJD, West Nile virus, SARS, vaccinia, sepsis and xenotransplantation. It is our current thinking that the final guidance will clarify for everyone that we consider HIV-1 group O to be part of HIV-1 and that, just as is done in the blood industry, donors should either be screened or tested for group O.
Now, the donor eligibility rule does allow limited uses of HCT/Ps from ineligible donors. If donors are ineligible based on behavioral risks, clinical or physical evidence or even reactive test results, under some circumstances those donors may still be able to donate. Those would be allogeneic use in first-degree or second-degree blood relatives; directed donors of reproductive cells or tissues; documented urgent medical need, which is when there is no comparable cell or tissue available to the recipient and that recipient would be likely to suffer death or serious morbidity. Really, that is mostly related to HLA-matched hematopoietic stem cells. It does require special labeling and physician notification if otherwise ineligible donors are used as donors.
So, there was a study that was published in August of 2004 in the New England Journal of Medicine, which has been really the only large study that has been published, looking at the incidence and prevalence of HIV, hepatitis B, hepatitis C and HTLV among U.S. tissue donors. The study involved a little over 11,000 donors, between 2000 and 2002, involving five tissue banks. They looked at confirmed positive test results and determined the marker prevalence rate. They used that information then to estimate the incidence rate and the probability of viremia for HIV, hepatitis B, hepatitis C and HTLV among those tissue donors. Of course, these are deceased tissue donors. The conclusion was that the prevalence and incidence rates are lower among tissue donors than in the general population but, in fact, higher than in first-time blood donors. This data chart is from that study. Really it is just so you can look at it and see where the tissue donors kind of fall out between first-time blood donors and the general population. I am going to end with just a little bit of background about the rationale behind the HCT/P behavioral deferrals. One would expect more reliable answers to the donor history questionnaire if questions pertain to the recent past, such as the past five years, as opposed to all the way back to 1977. This is especially important because many times with tissue donors we are talking to the next of kin; we are not really talking to the donors themselves.
There is limited availability of certain cells and tissues. HLA-matched cells are needed, and there are size restrictions for pediatric tissues like heart valves. Finally, there are differences in risks of viral transmission due to more extensive processing of some types of tissues. Some examples of processing include removal of blood and viable cells by extensive washing, use of alcohol, hydrogen peroxide and irradiation, and other proprietary methods for viral clearance.
So, if you would like some additional information, Ruth's e-mail address is on there but, actually, it is pretty easy to find because if you substitute my name, melissa.greenwald into the same e-mail address you will find me as well. Thank you very much, and have a great day.
[Applause]
DR. LACKRITZ: Thank you. Our next speaker is going to be Dr. Cees van der Poel who will be speaking on behavioral risk exclusions in other countries outside the United States.
Behavioral Risk Exclusions in Other Countries
DR. VAN DER POEL: Ladies and gentlemen, thank you very much for inviting me here today. I am going to present the discussions we had in Europe about behavioral risk exclusion, and the main focus of those discussions at the moment were related to MSM behavior. Now, we are, and I am aware of the fact that, of course, there are more risk behaviors than MSM but the problem was that we had to address this issue first because it was put on the agenda in Europe. We will proceed afterwards to go to the other risk behaviors in more detail this coming year, I hope.
Now, I am not completely speaking on my own behalf; I am speaking on behalf of the European Blood Alliance which is an alliance of blood establishments, of blood operators, if you like, from non-profit institutions in Europe. Since the board of that blood alliance asked me to come up with advice, we got scientists from different countries in a small working group together and tried to assess the issues.
Now, the background was to report strictly on MSM deferral and provide background information to the EBA board, the board of directors of the blood establishments in Europe. The questions from the MSM interest groups were actually raised to political levels that were different in different countries. It was raised, for instance, in The Netherlands to our parliament where the parliament asked questions of the minister and the minister answered those questions. In Belgium the minister just had discussions with the blood establishments, and in Italy the minister went out in the open by saying that blood bankers were nuts.
[Laughter]
So, the tendency and the atmosphere was completely different in different countries. One of the main issues that politicians have to face in being responsible for public health and being responsible for blood safety is the discriminatory effects of the measures. So, that is why we addressed that aspect as well. Also, we tried to assess whether a change from permanent deferral to temporary deferral, for instance for 12 months, would be fruitful.
We thought we would have to take into account the residual risk of HIV transmission to recipients of blood and we had to take into account the present practice and regulations in Europe. We looked at the task from different aspects. First we were going to survey the epidemiological data from public health surveys where we would be looking at the prevalence and incidence of HIV in MSM and other infections that would be prevalent or incident in MSM like hepatitis B, syphilis or recently lymphogranuloma venereum. Then we would look at the epidemiological data from the blood establishments and what is the relative contribution of MSM to donors who are positive for HIV and other infections; the positions taken by governmental authorities; the European regulations which are laid down in a directive in 2004/33/EC; and to address some compliance and public address issues.
Now, first the epidemiological data from France, as reported by G. Follea, in France MSM is about 27 percent of the new HIV infections in 2003-2004, whereas only 4 percent of the general population has a history of MSM. The 4 percent, by the way, is quite similar to what I just heard from the FDA as a background figure in the general population of MSM behavior. And, 51 percent of HIV in MSM is recent, within 6 months; 78 percent of MSM have multiple partners during the last 6 months; and in MSM stable relations, 63 percent have other partners.
If we look in the past, from 1997-2004 there was an increase in unprotected anal intercourse by about 70 percent; syphilis by about 20 percent; gonorrhea by about 35 percent--increase, that is. Cases of hepatitis C have occurred, which is usually not sexually transmitted, by anal intercourse among MSM.
So, that is a trend that you will see in different countries in Europe where the impression is that the fairly effective treatment of AIDS in the last years has generated more freedom to experiment with new partners, and there is more promiscuity at the moment than there was in the past. Of course, this needs to be further studied in detail.
Now, the epidemiological data from Germany, as reported by Kurt Roth [?] and the data that were provided to him by the German authorities, in Germany MSM is 40 percent of new HIV since 2001 and MSM as a relative proportion of HIV-positive cases, new HIV-positive cases, went up from 37 percent to 46 percent from 2001 to 2004. MSM went from 30 percent to 40-50 percent in new HIV cases and since 2001 there is about a 30 percent increase in new HIV cases among MSM in 6 metropolitan areas. MSM at present is 70 percent of the new syphilis cases in Germany and there have been small outbreaks of lymphogranuloma venereum in 2003 and 2004.
In The Netherlands the picture is not very different. MSM here consists of about 49 percent of new HIV cases in 2003-2004. Whereas about 37 percent of new HIV is heterosexual, increase of MSM as a main risk factor has occurred between 2003 and 2004. In anonymous screening programs in STD clinics the HIV prevalence in MSM is increasing. It used to be about 10-11 percent and it is now up to 20-30 percent, and it is predominantly in the older age groups which is a fact that we do not understand completely, but it seems that in The Netherlands at least the incidence in older MSMs is higher than in young MSMs.
HIV prevalence in the general population is comparable to the data you have just seen from the FDA. It is about 0.06 in rural areas to 0.2 percent in the cities. Cohort studies of HIV incidence in new cases per annum in MSM increased from 1-2 percent to 3-6 percent between 1991 and 2002. The entry criteria of the cohorts did not change but, of course, a cohort is a cohort and may not be totally representative of the whole population or the whole group that you are trying to address. But we have a long-standing tradition of large cohort studies with MSMs in Amsterdam, for instance, and that is an ongoing program.
The non-Dutch HIV is becoming more important but it is presently decreasing and I will show you the slides later on. It is about 17 percent of the HIV cases in The Netherlands. In recently HIV-infected MSM, 70 percent had sexually transmitted disease also, and sexually transmitted disease in MSM increased by 16 percent during 2004 and we had primarily in the Rotterdam lymphogranuloma outbreaks in HIV-positive MSMs, but it is now in other parts of the country as well.
Here is a slide which shows you from our public health department new HIV diagnoses by year, gender and here you see the blue line, which is the absolute numbers of HIV diagnosis and you see that there is a dip. This was the encouraging period where we thought that the public address and safe sex propaganda would decrease the incidence, but here it is up again.
Here are the heterosexual males and the heterosexual females. So, it is about 1,000 new cases in 2004, half of which are from MSM, and if you add these two heterosexuals up you have about half of them. But, interestingly, the female heterosexual, apart from the intravenous drug use, is predominantly import from countries south of the Sahara, in Africa, and there is a decrease here.
Here are the figures so you see that MSM is about 49 percent--this is in 2004--49 percent of the total new HIV diagnoses. Heterosexual contact is about 40 percent, evenly spread between male and female. Then, here you see that intravenous drug use is low, and that is low because of our preventative measures, we hope, on needle exchange programs. Blood products--those are partners of hemophilia patients and incidental cases. Mother to child transmission, needle stick injury and not known but, of course, this is usually a percentage of 10 that you don't know.
Infectious syphilis from 2000-2004 by sex and sexual preference, you can see that there is an increase of syphilis cases in MSMs. The red bars is women and the blue bars are heterosexual men.
The risk factors in acute hepatitis B--this is another program. Hepatitis B is a notifiable disease in The Netherlands, and you see that in 2001, the blue proportion, is the proportion acquired by MSM and here it is getting larger. This is the heterosexual transmission of hepatitis B, and this is the unknown. The yellow bars are sexually unknown and the very slight green bar here is intravenous drug users.
Now, the epidemiological data from public health in U.K.--this picture is slightly different from The Netherlands and Germany and France. MSM is only 32 percent of new HIV cases in 2004, whereas 64 percent of the new HIV cases are heterosexual. We have no denominator for the extent of MSM behavior in the general population in the U.K. but we estimate that maybe it will be the same as in France, The Netherlands and America.
From 1996-2003 there is a 16 percent increase of HIV in MSM, mainly acquired in the U.K., but the incidence in MSM is about 4.5 percent in London, 2.5 percent outside London after a dip in 1999. So, it is the same profile that we have. The incidence is increasing and we are talking about an incidence of about 1/100 or 2/100.
In 2003, 22 percent of gonorrhea and 56 percent of syphilis was in MSM and between 200-2004 there was an increase of unprotected anal intercourse by 40-50 percent. They had outbreaks of lymphogranuloma in MSM also in the U.K., but there is a 400 percent, 4-fold, increase of HIV by heterosexual contact in Africa south of the Sahara. So, this will be a new project for the working party of EBA to look at how we are going to address this.
The Health Protection agency, which is the public health agency in the U.K., looked at all these figures as well and declared, from a governmental point of view, that there is considerable HIV import by heterosexual contact in Africa, but the group most at risk in the U.K. is still the MSM.
Data from Belgium--in Belgium there were syphilis outbreaks in Antwerp from MSM. There was an 86 percent increase in active syphilis in the last quarter of 2003, about 80 percent of which is in MSM, and co-infection of HIV with syphilis is at 51 percent, of which 58 percent is MSM.
So, now we come to the effects of those public health data on the blood donors. In France, the HIV incidence in the donors is about 3.0 to 1.0 per 105 donor-years so it is about 1-3 per 100,000 donor-years, which is more or less stable over the period of '98 to 2004. From 1992-2004 there is an increase of HIV-positive male donors as a proportion among the HIV-positive donors. So, in 2004 41 percent of HIV-positive donors is MSM, and the proportion of recent infections within 6 months rose from 10 percent to 44 percent.
Germany and The Netherlands--in Germany they had about 100 HIV cases in the donors and about 30 percent of them had an interview for risk factors. Of those who answered the interviews or who were interviewed, 40 percent were MSMs.
In The Netherlands we have an ongoing program which started in 1995 voluntarily and had about 77 percent compliance, but it is now mandatory that every donor who is counseled for a confirmed positive infection is extensively interviewed with a five-page questionnaire, and it turns out that the donors are very much in favor of that because they want to know themselves. This program is now ongoing with ongoing epidemiological monitoring. We found that HIV in new donors, 20 percent of those is MSM, but in repeat donors, and that is our main concern because of seroconversions with potential infection to the recipient, about 30 percent is MSM. Hepatitis B in new donors is only 3 percent in MSM, but in repeat donors it is about 14 percent.
If you look at the prevalence of HIV, for instance, in The Netherlands in new donors it is about 1-2 per 100,000. It has been higher in the past, as you see, and we estimate that the prevalence in the general population is about one log higher. So, the data that were shown previously from the FDA--the impression that your donor selection up front reduces the risk that you get an infected donor in the house as a new donor is about a one log reduction. You see that over the last years this was pretty stable.
What is worrying though is the incidence. The incidence is quite low. We were fairly happy here at the end of the '90s where we had about 0.2 per 100,000 donor-years but then, in 2002, we had a national discussion on whether MSMs could donate again and it went up and we have to see what happens next.
HIV in blood donors in the U.K., period 1995-2004, HIV in new donors, 21 percent was in MSMs and in 42 percent was acquired heterosexually in Africa. So, that is really a problem and that is reflecting what goes on in the general population but it is in new donors. Whereas, in repeat donors HIV cases, 45 percent of those were from MSMs and only 29 percent were heterosexually acquired abroad. So, probably in our deferral or our communication method there is something that has to be looked at.
HIV in donors with an applicable deferral criterium is 64 percent in MSM; 8 percent in intravenous drug users; and 26 percent heterosexual in Africa. So, the problem in the U.K. is the reason that the European Blood Alliance is going to look at this in the coming year. HIV in repeat donors seroconversion has been stable with a similar figure as you see in the other countries.
Now we come to the modeling studies. As Jay very clearly said and is true, the safety of blood is so high at the moment and the incidences are so low that we cannot measure easily the differences in safety and we have to make model studies. Fortunately, we have one of the authors of the models, Kate Soldan, on our panel se we critically looked at all these models and I think that not only for this infection but also for other infections the modeling studies are becoming more and more important and this is a trade that we will have to learn as the blood banking community in the future.
In the Soldan study there was a suggestion to deselect--they call it deselect; that means to unselect the present permanent deferral for MSMs for the last 12 months versus all. So, if they would go from permanent deferral to 12-month deferral, the risk to recipients would increase by 60 percent in that paper. If they would not select at all for MSM behavior they would have 500 percent increase. But there is new unpublished data from Kate which says that the unsafety, if you like, of increasing risk is less than previously published.
But there is a problem. There are two uncertainties in the model, the uncertainty of compliance that is not measured so that was an estimate, and the discussion was if we would not be so strict for homosexual men, then maybe they would comply better with our questionnaire. But the problem in this model is that compliance with the questionnaire is already assumed at 97 percent. So, statistically, if you would hoist it up to 100 percent it doesn't matter in the outcome of the model, and it is also not likely also.
Uncertainty of HIV incidence in MSM who do not practice for 12 months which, actually we felt in the working party, was the most crucial point where we have no data, and I can come to that later. There is no data to base the estimates or the assumptions on to say, okay, if people say they had MSM behavior but not for the last 12 months, what is the safety of that in terms of HIV or other infections?
The German model is going to be addressed later on at this meeting so I will be short about it. The risk incremental is on the same order of magnitude as the present risk, but current MSM deferral is five times more effective than the deferral of female contact with contact to MSM. The limitation of that study is that it was in one center, and there is also uncertainty on the data that you use for non-recent MSM behavior.
The Sanchez study, which is very well known here in the United States, is an anonymous study and they suggested that the cutoff would be five years rather than 12 months. So, we will have to continue those discussions I think.
Now we come to the regulatory part. There is a recent new directive in the European Union, and that directive is under a treaty and the treaty says that all laws in the European Community, the 25 countries, will have to comply with that. So, if something is in the directive in the European Commission, then it means that all the laws of these member states will have to be changed in order to comply with that.
Article 2.1 says that persons whose sexual behavior puts them at high risk of acquiring severe infectious disease that can be transmitted by blood is permanent deferral. There are also statements on other sorts of risks but there was no discussion within EBA that MSM behavior is to be considered as sexual behavior with a high risk of acquiring HIV which, by the way, is a severe infectious disease. So, based on these three criteria, the directive has to apply and we have to permanently defer.
Now we look at governmental political positions. France is not likely to change. They have this in their guidelines from the EFS. Germany has the Richtlinien and Bundesartztekamme, the guideline from the medical profession. They are not likely to change. The Netherlands has discussed this on the parliamentary level and the minister of health has said to the parliament that he is not going to change in light of the European directive. In the U.K. there is a national committee and they have an annual review, and although it is quite thoroughly discussed there is no change in policy yet. In Belgium, where it was discussed between the minister and the establishment, there is no change after discussions.
Now, the public address issue, we feel that the present safety is based on self-deferral for at least a big part because you can see that in the difference of prevalence in new donors versus prevalence in the general population, and that goes up for one log and you see that figure coming back in many studies. Apparently, that is because we communicate quite massively that some people should not donate. So, those communications are apparently effective to a certain extent but there is room for improvement. We have to inform the donors anyway. That is also in the European regulations. So, maybe we could look at how we inform donors on this issue if we would want to change or whether we would not want to change.
Uncertainty of safety, if deferral would change in modeling studies, it is our conclusion that they indicate some loss of safety but that the extent of the loss of safety is uncertain. But we feel in Europe that the equality in deferral where you would argue you are permanently deferring a group of people, X, while you are temporarily deferring a group of people, Y, would seem unfair. That discussion, we feel, is not fruitful because we feel that there is no right to donate. So, we would only go based on the analysis of the safety and supply, for that matter, for the recipient. We would not go on a sort of equality and right to donate.
The committee on equal rights in The Netherlands translated the European requirements on equal treatment in Dutch law, and I can give you that paper because it is translated in English, if you want. It firstly discussed in 1998 several cases of discrimination of the blood banking community against MSMs but also against people from Africa, etc. The point here is that in the European laws direct and indirect discrimination is forbidden, and indirect discrimination is when you discriminate in practice when you do not intend to discriminate but the effect of your act is discriminatory. So, the concept of indirect discrimination is in conformity with the definition of the EC directive on equal treatment on the grounds of race or ethnic origin.
This committee looked at that and I think it took one and a half years to come out with a verdict. There were actually four cases which were discussed, four cases of MSMs against four blood banks. They claim that the Equal Treatment Act forbids discrimination on sexual orientation, age and ethnicity in offering goods or services, and MSM behavior is a manifestation of sexual orientation and, therefore, the blood banks are discriminatory.
The verdict of that committee which is, by the way, much longer and much more nuanced, is that in the case where there is no direct discrimination the purpose of the donor selection was not to discriminate but to prevent transmission of HIV and other infections. Homosexual men are disproportionately affected by the selection. That is true. But there is an indirect discriminatory distinction, however objectively justified and not disproportional, in the interest of the recipient's blood. That is the bottom line, the interest of the recipients of blood.
In summary, the public health surveys show MSM is at high risk of HIV and a considerable proportion of MSM is in positive donors where we have to look carefully at seroconversions rate and outcome. This is still a big proportion.
Risk of MSM--no practice for 12 months is not established but should be established. Recipient risk increases, however the extent is unknown. And, MSM is at increased risk of sexually transmitted diseases and emerging known and unknown infections. HIV incidence in repeat donors is directly linked to blood safety, but is presently low and stable despite increasing frequencies in the public health data. Any HIV transmission in The Netherlands and in Europe is to be reported to the European competent authorities, as is every seroconversion with a look-back.
So, the conclusion of the European Blood Alliance was to not change the present policy of permanent deferral. The reason for this deferral, such as summarized in this report, should be publicly communicated, preferably in collaboration with MSM representative groups. That is now done in Belgium and we are going to do that in Holland.
G. Follea looked at the questionnaire and what the practice is at the moment, and 15 of 15 country questionnaires have the same policy at the moment. And, further studies could be envisioned to assess the safety of multiple infections of a low risk group. So, this is the the formal position of the EBA. I could elaborate a little bit more as a person and as a scientist.
My question, or the question in Holland is would the gay community really be helped by deferral of 12 months? I have discussed this many times with their representation groups and we discussed this often in recent times again. They feel that it is highly disputable whether that would help them. That would mean that they would have to communicate that you would not have sex for a year, which in Amsterdam terms is quite a laughable position.
[Laughter]
And it is reflected on the negative side in Australia where they are merging all the blood banks in Australia into one Red Cross system. There was no uniformity about this deferral so they made it uniform for 12 months deferral, temporary deferral. But now they are sued in Australia for being discriminatory, and that is what the gay people told me, they said, well, not being able to donate if you have sex for one year we feel is discriminatory, but what we feel is that we have now gained acceptance in Holland and many other countries to be able to marry, and we have a stable relationship, and so why could you not focus on a totally different point of view as a subset of safe MSM donors, the monogamous donors? So, from their point of view, the discussion is not so much on temporary versus permanent but more the appreciation of their relationship, if you like.
Now, we have in Amsterdam cohort studies. That is a separate foundation which does very large studies not only on MSM but also anybody with a risk who wants to enter these studies is entered, and we have discussed this with the scientists from this group whom you may know, and there is a subset in the cohort with a safer profile. The problem is that we don't yet know what that profile is but we feel that it could be elaborated. So, we think that we should extend this cohort, not to draw these people to the blood banks but to the municipal health services and get a cohort where we would say that there are people with a safe risk profile but MSM monogamous behavior for instance or no MSM during the last year.
So, we would not only test them for HIV but anonymously test them for anything that is sexually transmitted, anything. Why? That is because if we only measured HIV we probably would not have the power to do this study in reasonable terms. We will do the same set of tests, extra tests on a cohort of new donors, a representative cohort of new donors entering the donor population in Holland.
We are just doing the arithmetic on the power and duration of the study. The problem is, of course, if we would get enough people participating and, problem number two, is the duration. But we feel that even if it would take us three years to solve this, the gay people are in favor of that because we have had the problem now for 25 years so two years or three years extra to make a good solution is acceptable.
Why I come to that conclusion is that there is a subset, for instance if you look at the hepatitis B, acute hepatitis B, in MSMs there were 6 cases in 2004 in people with a steady partner and 82 in people with a casual partner. So, we will have to look at that subset of people who are less at risk.
Also, what we are going to do with the EBA, as I announced earlier, is to look at the import of HIV from countries with high prevalence. I shared with you the differences in epidemiology of HIV in Europe and you see that this part of Europe is especially of concern but that is introduced by intravenous drug use and prostitution for intravenous drug use, whereas in Belgium, here and in England there is import of HIV from sub-Saharan Africa and here you see that this, in yellow, is all the same with about the same prevalence. Thank you.
[Applause]
DR. LACKRITZ: Our last speaker of our first session will be Dr. Ronald Bayer, from Columbia University, speaking on social dimensions of current deferral policies.
Social Dimensions of Current Deferral Policies
DR. BAYER: I guess it is time for a different perspective. By way of background, I have been dealing with this issue since 1982, since before the HIV test was discovered when the New York Blood Center was trying to develop deferral policies. I have come back to it periodically and I find my own perspective on this issue shifting, in part because of my understanding of the shifting science.
It is 23 years since the U.S. Public Health Service first addressed the threat to the blood supply posed by the then emergent AIDS epidemic. Almost a year before the identification of HIV, which was in 1984, then called HTLV-III or LAV, and two years before the licensure of the antibody test, the pressure largely from the hemophilia-related community began to mount to exclude high risk donors from the list of eligible donors. Among those thought of as posing a risk, of course, at that point in the epidemic were gay men. From the vantage point of just a few years, resistance to such exclusionary measures would seem utterly misguided.
Gay organizations, first beginning to struggle with the implications of the new threat to the survival of gay men, were concerned that an explicit bar to donation by men who had sex with men would only serve to bolster stigmatization and homophobia. Banning men who had sex with men from the donor pool would exclude them from one of the great acts of altruism in contemporary society so carefully mapped by Richard Titmus.
Recall also that discussion of such restrictions and bans occurred at a time when half the states in the United States still criminalized sex between men, consenting adults, and that in 1985 the Supreme Court of the United States in Bowers versus Hardwick would uphold Georgia's sodomy statute, dismissing claims that gay adult men had a right to have sex as vacuous.
Typical of the resistance to exclusions were comments like these, "a ban on gay donors would be a return to the bad old days when a recurrently scapegoated minority could be sweepingly stigmatized for the taint of bad blood. A ban will pit victim against victim and serve only to divert attention from the vital medical and ethical concerns that lie at the heart of this health crisis."
But gay men and those who spoke on their behalf were not the only opponents of the imposing donor restrictions. Some of the most knowledgeable and experienced blood bankers, concerned about the adequacy of the blood supply, also expressed doubts about what they felt would precipitate action in the face of inadequate data. The director of Yale,s Blood Center, Joseph Bove, was joined by Aaron Kelber of the New York Blood Center in issuing warnings. "We are," said Bove, "contemplating all those wide-ranging measures because one baby got AIDS through transfusion."
Against such voices of restraint were those who saw an emerging crisis that asserted and required immediate action. The remarks of CDC's Donald Francis, memorialized in the book "And the Ban Played On," reflected the sense of alarm. "How many cases will it take?" he demanded of those who were reluctant to take precautionary steps. And Jim Curran at the CDC warned, "the thing is people are dying. The medical problem is more important than the civil rights issue." Curran's expression of concern was echoed by some physicians within the gay community. "We must," said one doctor, "spread the word among gay men to avoid blood and plasma donation until more is known. Gay men cannot, even with the best of intentions, add to morbidity and mortality."
It was in this context of this dispute which captured in some way claims and concerns that would animate and punctuate debates over the next decades that the Public Health Service issued its first formal recommendations on March 4, 1983: Sexually active homosexual and bisexual men with multiple partners should refrain from blood donation. These were, of course, exclusions that were modest in comparison to those that would later be imposed excluding any man who had sex with any man since 1977.
Much, of course, has changed since the imposition of restrictions based on interviews or questionnaires about risk behavior. Increasingly sophisticated specific and sensitive blood tests have been relied upon. The first antibody test, employed in mid 1985 with its problematic window period, has been replaced by subsequent tests and now NAT. Such tests all but closed the so-called window of undetectable infection. With such tests in place, debate resurfaced repeatedly over the role and necessity of restricting men who have sex with men even once from donating blood.
At the heart of that debate are a series of empirical questions, but they are empirical questions with profound moral significance. More than three decades ago the National Research Council made a clear conceptual distinction between the process of risk assessment, which it asserted entailed an essentially empirical analysis and risk management which involved political judgments about the acceptability of risk. But strikingly, according to the NRC, even risk assessment involved irreducible elements of value judgment given the uncertainties involved. How conservative was one to be at each step of the assessment was in part a policy choice, not a choice dictated by science in and of itself. Hence, to portray the response to risk in public policy as a matter of science alone was to mask the matters at stake. The question of acceptable risk was, and has remained, essentially a moral question.
When the federal government began to address the issue of protecting the rights of those with disabilities, the Supreme Court in the landmark case, called Arline versus Nassau County, determined that discriminating against those with infectious disease, in this case tuberculosis, could only be justified if such individuals posed a significant risk. To do otherwise, stated the court, would be to yield to society's accumulative myths and fears, and the court articulated a four-part test including the duration of risk, the severity of risk and the probability that a transmissible agent would be communicated. Ultimately, that four-part test was incorporated into the Americans with Disabilities Act.
At bottom, the Supreme Court's and congressional determination was an embrace of the proposition that in facing the question of acceptable and unacceptable risk the accumulated prejudice of society should not serve as a foundation for public policy.
Let me suggest to you that this whole discussion around HIV was reflected in a quite bitter dispute about whether or not people with HIV infection--clinicians--should be allowed to continue to practice medicine. Remarkably, in that context those who said people with HIV should not be allowed to practice medicine said no risk at all is tolerable. The risk they were talking about was a theoretical risk or the risk that came from one dental practice in Florida where five patients had been infected by one dentist, the only documented case in the United States of transmission from a healthcare worker to patients, and that was the only evidence. There was a theoretical risk certainly, but it was a theoretical risk not substantiated by any demonstrable evidence.
It should be clear now where I am trying to take you. There is no right, as we have heard over and over again today, to donate blood if, in so doing, one places potential recipients at risk. No principle of equity or respect for persons could justify the imposition of such burdens on those in need of blood. That much is obvious, but how much risk is tolerable in blood donation? What price should one be willing to pay for achieving greater levels of security? Are there some risks that are so vanishingly remote, maybe detectable in models, that the imposition of costs in dollar terms or in terms of discrimination that they would require would be either an irrational expenditure or an unfair burden?
In 1989, Harvey Feinberg, then dean of the Harvard School of Public Health but now president of the Institute of Medicine and an expert on risk analysis, said to a conference on the nation's blood supply that, quote, a simple-minded focus on safety is no longer an appropriate approach for those concerned with sensible uses of the blood supply. With very high levels of security already achieved incremental improvements would come at very high costs and would produce only marginal benefits. Today, said Feinberg, the harder kind of question is how can we define and attain a desirable balance among the goals of safety and adequate blood supply and our ethical responsibility to society, to the patient and to the donor?
It was those issues that surfaced when just more than five years ago the FDA addressed the issue of its ban on blood donation from men who had sex with men within the prior 23 years. An advisory committee upheld the restriction, but just barely by a 7-6 vote. It was not surprising that gay spokesmen would state HIV is a disease that affects the African American community disproportionately. More telling was the fact that the American Association of Blood Banks, which opposed the extant policy, said by way of explanation, that the longest window we know to detect virus is a year. The science is there.
It is that issue that we now address today. There are two questions we need to confront: Are the risks associated with permitting donation from men who have had sex with men ever at any point during the last 29 years or, for that matter, in the last five years, greater than we are willing to tolerate in blood donation generally?
Secondly, is the risk aversion policy we embrace applied in a way that entails an invidious discrimination? Does it reflect our accumulated prejudices whether conscious or unconscious?
In preparing for today's talk, I looked at the current exclusionary policies with regard to behavior and was troubled more than I was comforted. Current restrictions based on sexual or other risk behaviors include, as Alan Williams pointed out earlier, anyone who has had a tattoo in the last 12 months, unless applied by a state-regulated entity with sterile needle and non-reused ink;
Anyone who has had an ear or body piercing in the last 12 months, quote, unless the ear or body piercing has been done using single dose equipment;
Anyone who in the past 12 months has had sexual contact with a person with hepatitis;
Anyone who in the past 12 months has had or been tested for syphilis or gonorrhea;
Anyone who has had sex with a prostitute or anyone who takes money for drugs or payment for sex;
Anyone who in the past 12 months has had sexual contact with anyone who has ever used needles to take drugs or steroids, or anything not prescribed by their doctor;
Any female donor who in the past 12 months has had sex with a man who has had sex with another man;
Anyone, man or woman, who in the past 12 months has had sexual contact with a member of the opposite sex who has AIDS or has tested positive for HIV;
Then, men who have had sex with men since 1977, no matter how monogamous their relationship is classed, such men are linked with prostitutes, sex workers and drug users. Given the current testing technology, there is clearly a public health rationale for jettisoning the 29-year exclusion for men who have had sex with men. But why stop at five years? Why not three years or two years? The logic of shifting from a 29-year exclusion, since 1977, to a five-year exclusion is hard to uncover. Why not three years or two years? Indeed, it is hard to understand, given the goal of safety and the commitment to precaution that is embedded in public health practice, why anything more than a one-year exclusion is justified.
Officials may believe that to make such a radical move would be political suicide, but to claim that the evidence or the ethical premises of medicine and public health require an exclusion more exacting than that which prevails for women who have had sex with a man with AIDS is difficult to understand, and I am afraid it may confuse the dictates of convention with the requirements of science or ethics. What we cannot do as a result of this discussion is take refuge in science when, in fact, what we are responding to is political pressure. Thank you.
[Applause]
DR. LACKRITZ: Thank you. We will now take a 15-minute coffee break so we will see you back here at 10:20.
[Brief recess]
DR. DAYTON: Let me bring the second half of the session to order. I have to warn everyone that there is no food and drink allowed in the auditorium--not anyone in particular, mind you and, as we said, the penalty is permanent deferral!
The second part of this over-arching session is on the prevalence and incidence of known and potential transfusion-transmissible infections in relation to behavioral risks. Mat McKenna is not only going to moderate this session but he is going to give the first talk in it on the transmission of HIV by blood transfusion.
Prevalence and Incidence of Known and Potential
Transmission-Transmissible Infections in Relation
to Behavioral Risks
Matthew McKenna M.D., M.P.H., CDC Moderator
Transfusion of HIV by Blood Transfusion
DR. MCKENNA:
Thanks, Andy. Good morning. I think just as a quick orientation, this session is really going to be devoted very much to presenting the overall epidemiology of the various pathogens and viruses that are of interest to protection in blood transfusion processes, not so much focused on transmission of these particular viruses. The talk I am going to be giving in expressing that epidemiology is focused on the incidence and prevalence of HIV by behavioral risk factors in the United States or the current status and, of course, that has implications, as we all know for transfusion risk.
The topics I will be covering are listed above. For most of the presentation I will just be presenting population-based case surveillance data collected by state and local health departments that is forwarded to CDC according to existing public health reporting laws. I will refer briefly to a few cross-sectional cohort studies that have looked at the prevalence and incidence of HIV in certain specific populations. Of course, these are studies where individuals have generally consented to participate or are in selected populations where there may be anonymous testing so their generalizability is not quite the same as the surveillance data.
I will also discuss some information on the population distribution of behavioral risk factors in the U.S. and focus somewhat on the implications for understanding HIV infection incidence. Another piece embedded in this is presenting data on population-based information regarding trends and testing for HIV and the CDC estimates for overall levels of diagnosed versus undiagnosed infection in the country.
All the data I will be presenting will be from published sources, or sources that have been presented in public or scientific meetings, or data that is imminently to be published.
The challenge we face--it hasn't been discussed very much but the challenge we face in sort of talking about the incidence of infection, of course, is that our case surveillance system in the U.S. focuses on diagnosed cases, sort of the right-hand side of the events that we actually measure in depiction of the spectrum of HIV infection. However, with population-based information and certain assumptions and a lot of background information about the natural history of HIV infection, it is pretty reasonable to be able to infer back to the issues of most interest, which are the behavioral risks for HIV infection and the undiagnosed population in the U.S.
To further clarify the assumptions behind such estimation procedures, I think it is useful to think metaphorically about the progression of HIV and how the surveillance data can be used to provide a complete picture of the epidemic. All the numbers here, by the way, are broad estimates for prevalence and incidence of HIV infection as well as the clinical events.
But overall, if we think of the health status of persons infected with HIV as pots in a sense; they sit in the different health states in pots and transitions from one health state to the other are spigots that represent the flow from one to the other, then the flow through each of the spigots represents a rate determined by two things: the incidence and, in the case of flowing from the highest pot to the second pot, the level of testing. In a sense, testing opens and closes the valve on the spigot and the incidence rate increases or decreases the pressure on that particular spigot. We then can directly measure most of what is depicted here and infer the actual incidence rate as long as we assume that there are no major changes in how open the valve is.
The most important determinant, of course as I have alluded to, is the HIV testing trends, particularly in the most recent past. However, in terms of overall population testing in the U.S., this data source is the most comprehensive, which is from the national health interview survey and shows that really throughout the latter part of the 1990s both the overall prevalence of lifetime history of being tested for HIV as well as being tested for HIV in the most recent year has remained fairly stable in the general population.
Now, this, of course, doesn't tell us very much about testing in very high risk populations. Indeed, if we were to be successful, as CDC's most recent initiative in advancing HIV prevention really tries to augment testing in high risk populations, we could see very small, if any, risk or change in HIV testing in the general population and, yet, see an increase in the number of new diagnoses. But generally the evidence that such a change has occurred is pretty limited.
Just to also give people some background in terms of the national data I will be presenting, it is from the national HIV reporting system but currently only 33 states have quality data that can be used to analyze trends in that system, and those states are depicted above in yellow for the data.
The two lines here depict the trends in the number, which is the top line, the yellow line, and the rates of HIV diagnoses occurring in the 33 areas during the period 2001-2004. Just parenthetically here, we saw a map earlier from Europe showing the highest rates to the lower rates with gradation and groupings. The U.S. rate, which has generally been a little bit above 20 per 100,000 would equate to above 200 per million in the slide we showed before from Europe, which is among the highest rates in the European arena. EAPC here stands for the estimated annual percent change, which is just an expression of the percent change per year of each of these parameters. Just to easily think about it, it is pretty much what your mutual fund company quotes to you about increases or decreases on an annual basis for your investments; it is the same sort of idea.
Generally the basic message is that there has been very little change. Neither one of these estimated annual percent changes are statistically significant when compared to zero. So, for us with a mission of prevention, the stability here is very disconcerting.
When the number of cases per year diagnosed in the U.S. is looked at by behavioral risk we get a slightly different picture. Except for trends amongst men who have sex with men, the trends for all other risk groups have been statistically significant in a downward direction. Some of these, particularly the pink line which is high risk heterosexuals and the yellow line, men who have sex with men in the injection drug using population, are a bit more modest and we think could be due to artifacts in the HIV reporting system in the U.S. However, the rates in the green line, the decreases among injection drug users, is almost 10 percent per year and has been part of a longer-term trend we see in a variety of other data sources that we are convinced is really quite reflective of decreasing incidence in that population.
However, as I have talked about, are there data to support the assumption that trends in incidence of HIV diagnoses is an indicator of incidence of HIV infection? Sort of during the '90s when we didn't have as high quality and as comprehensive HIV diagnosis reporting, we were having to thrash around quite a bit. This is data from a meta-analysis that was done by Quan at CDC where he took 74 studies either from cohort information or from studies that were using the serological testing algorithm for recent HIV seroconversion, which is utilization of an assay which allows us to estimate incidence on a cross-sectional basis--he took those 74 studies and meta-analyzed them in a sense.
What you see is these two black lines from about 1982 to 1998. This line, here, represents trends among men who have sex with men and this is the line for injection drug users. In an earlier period of time from the data I was showing you, it very much reflects what we see now, decreases and then stabilization, decreases in the late 1980s and incidence rates of HIV in these two risk groups, and then stabilization among men who have sex with men throughout the 1990s and continuing decreases in injection drug users.
It is also worthwhile noting the absolute rates here. Amongst men who have sex with men the general infection rates were about 3 percent per year, and in injection drug users it was getting below 1 percent per year into the 0.5 percent per year range.
We have more recent data from anonymous counseling and testing centers in Louisiana and Texas, where we use the serological testing algorithm assay to estimate incidence in persons who were getting tested for HIV for other reasons, shows amongst men who have sex with men--despite this blip that we think is just part of the inherent variability in these sorts of studies--a stable rate between 2-3 percent per year amongst men who have sex with men and rates in the 0.5 percent per year range in other persons, both females and males.
This number is almost quite disconcerting to me when we go to national meetings and we see poster after poster and presentation after presentation of these sorts of data from clinic-bases surveys. These are high risk populations, of course. These are people who are being tested for HIV or attending clinics that have counseling and testing services, and these rates are probably a bit high but the number is almost always the same, between 2.5 to 3 percent, no matter what populations are looked at. There are some in San Francisco and others who are seeing somewhat slower rates in their STD clinics but for the most part this is what is seen around the country--very consistent with what Quan found in his meta-analysis.
In terms of prevalence, these are data that got quite a bit of publicity and I thought they were worth reviewing, not so much for their representativeness but just to clarify where they came from and what they mean. They were published in the MMWR back in June of the past year, and they represent data from the national HIV behavioral surveillance program in five cities where HIV testing was done, in addition to surveys of men who have sex with men who were attending venues frequented by persons who engage in that behavior.
The most notable piece that was highly publicized, very highly publicized out of this was, of course, that there were a little over 1,700 men that were surveyed at these venues and 25 percent of them were HIV-infected and almost half, 48 percent, of them were not aware that they were infected. One of the strongest predictors, of course, of awareness was the age. The older they were, there was decreasing unawareness of their infection.
But the issue about the data I just showed you is to please understand that these are very high risk populations. It is not population-based; it is not a household survey. These are persons attending venues where we know individuals are going to be at very high risk. But in terms of understanding prevalence of undiagnosed in the population, we return again to the case surveillance information. I just want to go once again through some of the assumptions and methods used to see what is really a diagnosed population, though very population-based; whether it is truly representative of all those being diagnosed and how we infer these other pieces of information.
That calculation method for estimating overall HIV incidence has been around since the 1990s, and is mostly used for AIDS cases to estimate that. Today, with more comprehensive HIV, we can use HIV detection, differentiating between persons diagnosed with HIV/not AIDS and AIDS, as well as well as the CD4 distribution, to understand the trajectory of CD4s over the length of an HIV infection to make some estimate among those diagnosed inferring back to the incidence rate in the past. That gives us very good information about cumulative historical incidence and allows us to come up with reasonable prevalence rates, and really is still highly precise for more recent periods of time in terms of calculating incidence.
But this sort of methodology is the data from which I will be presenting where the data over the next few slides was derived and has been presented in a national meeting by Glynn and Rhodes.
Overall, we estimate that for total HIV prevalence in the U.S. the number of persons infected by the end of 2003 was about 1,039,000 to 1,185,000. Amongst those, 42 percent were HIV without AIDS, 34 percent with AIDS and about 24-27 percent with undiagnosed infection.
When looked at by risk group in the terminology we are currently using, transmission category, about half or 45 percent of those infections were in men who have sex with men; 27 percent in persons identified as having high risk heterosexual contact; and 22 percent in injection drug users.
Now, though we know among those infected about 25 percent are undiagnosed, is there much difference amongst these various risk groups in that proportion? Our estimates are that there is not very much difference. This is looking at a slightly different sort of number but, luckily, with algebra we can get to the other one. This is what was actually presented at the meeting but it is the distribution amongst the diagnosed and diagnosed by risk factor.
What it really shows is that amongst men who have sex with men we estimate that the proportion with undiagnosed infections is about the same as it is in the rest. The injection drug users actually have a lower rate among the infected and heterosexuals have a slightly higher rate. But in general there is not much variability, between 23-28 percent we estimate amongst all the risk groups are all the infections--the individual infected who is unaware of the infection.
Now, in terms of distributions of risk behaviors, we have heard from our European colleagues about their estimates of the size of the MSM population. Data we just released in September of this year from the National Center for Health Statistics from a national survey of family growth--the national survey of family growth is a long-standing survey, population-based household survey that traditionally has interviewed 15-44 year-old women in the United States. In this most recent cycle going through 2002, they also interviewed men in what is right now the most detailed sexual history we have. From that, 6 percent of the men ages 15-44 reported a lifetime history of sex with another man, and about half of those reported such activity in the last 12 months.
Another study by Catania, which is a fairly population-based phone survey amongst men from zip codes enriched and known to have high levels of men who have sex with men residing there, found that 90 percent of urban MSM reported that they had engaged in MSM behavior in the previous 5 years. So, when we are talking about some of these deferrals and what the opportunities are for opening up and making available more donorship, figures about this are about the best we have in terms of what the volume is or how many persons would be donating on a population basis.
In terms of estimating the IDU population, Friedman has recently estimated, in a '96 large MSA, the rate and prevalence of injection drug use between 19-173 per 10,000 persons. If you extrapolated that across all of them, it would be about 1.6 million persons. However, they also estimate that lifetime injection drug use--because those were just for the last 12 months--is about 2.5 times that size, which would give you somewhere in the neighborhood of about 4 million persons who have some lifetime history of injection drug use.
The estimation of the high risk heterosexual and coming up with what that looks like is probably, we almost think, methodologically impossible at CDC. In terms of the surveillance data I have been showing, it is just impossible in terms of behaviors. At CDC we do require that for a person to be classified into that category in the surveillance data as a diagnosed individual, they have to report or someone needs to record or document that men have had sex with men or sex with an IUD drug user or persons from other high risk groups, persons with hemophilia or persons who are HIV-infected.
Also, in a very interesting study, a cohort study out of Baltimore, where Strathdee looked at risk of new HIV infection in injection drug users and found that for men it was mostly related to their injection drug use behavior, whether they shared needles recently, did not take precautions in harm reduction, but amongst females, actually their sexual practices and whether they had sex with men who had sex with men or other unprotected sexual activities was a stronger determinant of their risk.
What this has left our national HIV behavioral surveillance system with in trying to identify high risk heterosexual populations is not really being able to default to any information from the individual about their own heterosexual practices. In fact, from the NSFG, the median lifetime partners for males was 5.6 partners per man and 3.3 lifetime partners in that age group I was talking about earlier, which in some of the surveys and some of the classification systems would put half of the population into the high risk heterosexual category.
For our behavioral surveillance program, what we have defaulted to is basically anyone who engages in heterosexual sex who is either residing in or reports to us contact with a social network in a geographic area where there is a very high HIV infection or diagnosis rate. They need to have HIV present in a prior assessment of exposure to HIV, or engage in behaviors with a population with very high risk of HIV needs to be there. Behavior itself in terms of heterosexual practices is very difficult and doesn't seem to be a very accurate differentiator for high risk heterosexual sex.
So, limitations of the data, as I have talked about in terms of using the case data, it is modeled from national surveys. The models are assumption laden and imprecise, especially for very detailed subgroup analyses, which I know people here would like us to talk about. Also, at CDC we really are now focused much more on what are the next steps we need to take to decrease the rates of transmission in the general population. Therefore, we tend to focus on defining, identifying and understanding high risk groups and do very little study or investigation into low risk populations.
As has been discussed, it is very resource intensive to collect enough--particularly numerator information--numbers of infections in low risk populations, to make that efficient from a resource and expenditure standpoint. As I said, the public efforts focus on high risk populations.
Then, just some thoughts about risk among the donating population, and people with more experience in this have talked a little bit about it. What is the association of risk in the donating population, both in terms of self-deferral but also in knowing their own infections? I have already indicated that older age persons who are at risk, if they are infected, are m