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>>> good afternoon, everyone. i'm the deputy director forbehavioral and social science in the division of hiv/aidsprevention and it's my pleasure this afternoon to be able towelcome you on behalf of the division and on behalf of thenational center for hiv/aids, viral hepatitis, std and tbprevention. i want to thank you for beinghere today and thank you for being part of what i think isgoing to be an interesting and stimulating discussion.
i want to let you know inaddition to those of you here with us in the audience today,we're also being joined by people around the country andaround the world who are watching today's event via liveweb stream and are tweeting about it. as you know, this month marks 30years since the first cases of what later became known as aidswere reported in cdc's mmwr. today's session is one in aseries of lectures being conducted throughout the summerthat commemorate the unwavering
commitment of public healthofficials to the fight against hiv. this lecture series is designedto raise awareness about the importance successes that havebeen made over the past 30 years and to provide an opportunity toreflect on the hard won lessons that we have learned over thesemany difficult years. today we'll have a chance tohear from some of the public health leaders who have madecritically important contributions to the evolutionof hiv testing and the fight
against hiv. it would be hard to overstatethe importance of their contributions and thecontributions that hiv testing to public health, health careand the lives of people living with hiv and affected by hiv. in my mind, the availability ofhiv testing is clearly one of the top three criticalbreakthroughs since the hiv epidemic began. the availability of hiv testingmade it possible to screen blood
products and virtually eliminatehiv transmissions associated with infected blood products. hiv testing reduces riskbehavior among those who are living with hiv and it's acritical element in the prevention of mother to childtransmission. the importance of hiv testing isevidenced by the fact that after testing was approved by the fdain 1985 and scaled up along with other hiv prevention programs,we saw dramatic decrease in the number of new hiv infections inthis country.
now hiv testing is a criticalfirst step to improving the health of people living withhiv. people who don't know thatthey're infected, can't get the health care and services thatthey need. now, in this era of effectivehiv treatment, it's a little hard to think back and rememberwhat it was like in the early 1980s before hiv testing becameavailable. the fear that existed at thatpoint in time was sometimes overwhelming.
before we had hiv testing, youhad no way of knowing if you, someone you loved, or someoneyou had made love with had hiv until you became sick anddeveloped symptoms. testing gave people who were atrisk for hiv a way to take greater control of theirdestiny. to take steps to protectthemselves if they were negative and how to manage their ownhealth if they were positive. getting tested back in thosedays was not without controversy.
it was a time when we didn'thave not have effective treatments for hiv and therewere very real concerns about confidentiality and what mighthappen to those who tested positive. back then testing positive meantthat you had to face not only the possibility of an earlydeath but also the widespread stigma, discrimination andrejection by friends and family that were common back in thosedays. it's important that we don'tforget about the importance of
hiv testing on the lives ofpeople today who are worried about the risk of infection andare trying to reduce that risk as well as the impact that hivtesting has on the lives of those who were diagnosed withhiv. for those of us who have testedpositive, that testing event and that brief moment in time whenyou learn that you are living with hiv is one that stays withyou for a lifetime and it changes your life forever. fear, stigma, and discriminationhave not completely gone away,
but they've gotten better. fortunately we're now in a timewhen there's effective treatment and knowing your status andacting on that knowledge means that instead of facing death,people living with hiv are now facing the possibility of havinglong, healthy and productive lives. this change has truly beenmiraculous. now, i would like to turn thesession over to my colleague, dr. michelle owen.
dr. owen is the leader of thehiv incidents and diagnostics team in the laboratory branch ofcdc's division of hiv/aids aids prevention. her laboratory conducts researchto develop, evaluate and implement new diagnostictechnology and specific areas of research include evaluation anddevelopment of hiv diagnostics for detection of antibody,antigen and development of tests to determine recent fromlong-term infection and they are investigating new hiv testing toimprove diagnosis.
in addition to this research,dr. owen is also responsible for the oversight of cdc hiv clearreference laboratory which provides hiv diagnostic supportto public health laboratories, commercial labs and physicians. dr. owen has worked in researchat cdc since 1989 and from 1989 to 2003, her research was on hivand immunity. in 2004, she assumed the role ofdiagnostic activity lead in the laboratory branch. i'm going to stop there,michelle.
i'm going to let you take itfrom here. [ inaudible ]>> i'm going to doã±r brief introductions of the speakers. i'll introduce dr. cowen firstand let him speak. i will ask if you have questionsunless it's a real clarification question, if you can hold themuntil the end, please, because we have a lot of information toget through. we'll have about 30 minutes ofdiscussion so i certainly hope you'll you willall be able toget your
question in. dr. cowen has been working inthe field of retroviruses for quite a long time. he worked for nih and did a lotof work in his early career and then in 1993 he came to fda. welcome, dr. cowen, i thinkwe'll tell us about the successes with screening theblood supply. >> thank you, michelle. thanks to the organizers forincluding fda.
it really is an hahnonor to behere and i'm delighted to be the oneto represent the agency. i also want to point out thetitle of this session is "the evolution of hiv testing: then,now and beyond." given there are three speakers,i guess that means that i am then. i guess i'm the old stuff. dr. branson is the present anddr. cohen is the future. we'll see how this plays out.
having said that, i think it'salso very important for us to understand really where it isthat we've come from. and so i'm going to be talkingabout hiv screening as it first began and give you a bit of ahistory. i think that the history oftesting is best described on this slide right here, which isa graph. i usually start out with bulletsto say what i'm going to tell you, but i think this slidereally tells it all. i'll take you on a journey whichis going to beã‘i shown by this
little blood drop that's movingalong that's infected with hiv and we're starting with thefirst cases of hiv reported of course in 1981 which is whywe're here. and then the first case oftransfusion associated hiv reported in 1982 after whichhigh risk donor deferral was initiated. as a result of that deferral,then the peak was reached in 1982 and 1983 with the discoveryof hiv and there was a prosprogressiveimplementation.
i really could stop there. that's the message. instead i will go fill out my 15minutes with a bit more of the history. again, starting point here ifyou notice, these are cases of transfusion associated aidsreported to cdc by year and what you can see by 1983 there were ain some cases 700 transfusion transmissions that wereassociate ed -- of to give you other numbers, i'lldrop in other drops here.
12,000. 12,000 was the number of hivtransfusion transmitted infections in the early 1980s. 8,000 is the number of hivinfections that were transmitted in the early 1980s presumablythrough contaminated blood products such as factor 8 and1.1% represents the risk of transfusion. we had some very, very seriousthreats to the safety of the blood supply back in '83.
now, fda is responsible for thesafety of blood and regulates all aspect of blood safety andthere's an approach that we have called five layers of safetyincluding the donor eligibility including self-referral andscreening and filling out the donor questionnaire. second is laboratory testing anddeferral and then quarantine controls to prevent unit releasepending verification of donor suitability and investigationand correction when mistakes are made and follow-up inspectionsto make sure that the deviations
have been corrected and finallydonor deferral registry so people who are$ui9 are recognized and not allowed todonate. i'll focus on number two here. laboratory test and referral. i'll take you through a timeline. it's empty but will be full bythe time we get to the end of it. in 1983, we start with paperinstead of test.
the paper was recommendationsissued by public health service for deferral of at-risk denonorsfollowed in 1985 with fda approval of the first assayfollowed a couple years later by the first western blotrecognizing the screening test approved in 1985 was allowing --was identifying more people that were identifying people asinfected when they actually weren't so the mandate was tohave an additional more specific test to determine if the initialscreening test was a true positive or not and was thewestern blot approved in 1987.
this takes us to 1988 when thescreening was implemented there was a requirement of testing ofhiv and plasma donors. in 1990 and '91, the first testto detect hiv 2 recognizing that the existing test had sometrouble in detecting hiv 2. the test that were licensed wereeias detected hiv alone or combination test to detect bothhiv 1 and hiv 2 antibodies. this takes us to 1995. at that point fda wasrecommending the blood establishments implement donorscreening for hiv 1 antigen
using licensed test kits. at that time there were no teststhat were licensed. this was designed to haverecommendations in place so that when the first test was licensedin 1996, that could be implement implemented immediately. in 1997, the first hiv acid testwent forward for source plasma and in 1989 studies wereinitiated for the u.s. blood supply. these were investigatale alinvestigational
studies designed to collect datafor approval of a license application for these tests. while it would seem that theinvestigational studies may be trivial, they were not becausewhat happened was that all of the blood in the u.s. was beingtested under ind and so even though there was not a licensetest, the investigational test was used to screen all of theblood donors in the u.s. and therefore there was benefit tobe gained and i'll get to window period in just a few minutes.
in 2001 and 2002, then thestudies led to the submission of a license application and fda atthat time licensed the first test for pool plasma testing andfor blood donor screening. i tried to come up with somesort of graphic for this and i decided to do a visual pun andtherefore you see a kitty pool representing a mini pool. i tried. in 2003 fda licensed the firsttest to detect hiv 1 group o recognizing the diversity of hivin some cases proved to be
difficult for some tests to pickup and so group o was added to the test. so where did this actually getus? i'm going to talk now for aminute about window periods. with hiv antibody tests, thisshows you the connettics of antibody and first generationand second generation and third generation test. first generation test had awindow period of 65 days with second generation testimprovement in technology window
period was reduced to about 45days and with third generation test which are used to screenblood right now for hiv-1 antibodies and group 0, windowperiod is reduced to about 22 days. if we look at hiv p-24 antigen,the window period is reduced to 16 days and when you look at hivrna which is studied in plasma specimens it's reduced to 11days and if individual donor is used, that's reduced to sevendays. the window period is reduced sowe can identify people earlier
and earlier during the course ofinfection depending on the technology that's used. now, this goes according tobiology of the virus and response to the viral infection. how does this actually play outin terms of making a difference and that's shown in this slide. here you can see that at thebeginning in 1983 again the risk was 1/100 of a transfusiontransmitted infection of hiv. when the criteria were changed,the risk dropped and what i'm
showing is the risk of infectionper unit transfused. when hiv antibody screening wasgone, there was more of a drop and when p-24 began, there wasmore of a drop. you can see that theimplementation of testing has certainly made a tremendousdifference in the safety of the blood and interdicted a largenumber of infections that otherwise would have gottenthrough. just to put numbers on this fromthe graph, we are dropping from a risk of 140,000 or so now downto when mini pool is used to a
residual risk of 1 in 2 millionand individual a risk of 1 in 1.3 million. a lot of us deal with very largenumbers and so sometimes i'm not sure we really have a good feelfor what that actually means so i'm going to try to put this inperspective for you. if you would imagine a fullfootball stadium and that everyone in the stadiumrepresents someone that's been transfused. this is a photo of gillettefield where the patriots play.
this is in no way an endorsementof the fda for the patriots. imagine everyone in the stadiumis -- everyone in the stadium is transfusion recipient, the riskis going to be 1 in 45 sellouts. that's what 1 in 3 million is. that puts it in perspective howeffective this actually is. that's the residual risk. i also want to make a couplepoints here that i think often go overlooked and i call theseunderappreciated facts and the first one is available hivtesting technology is extremely
accurate.ã§ã³this is unlike tests for some other infectious agents. hiv test in general tend to havesensitivities that approach 100%. this is unheard of in thetesting arena. i think we overlook that a lot. when i speak with my colleaguesin the office at the centers for devices at fda who deal withmost of the diagnostics out there, we tell them we arelooking at numbers like this
approaching 100%, they areamazed at the sensitivity these tests can achieve. the other fact i want to makeyou aware of is even though hiv continues to mutate at a veryhigh rate, and there are numerous emerging variants, itdoesn't affect the virus. the technology is such that it'sbeen able to keep up with it. at the same time we don't wantto be complacent about this. we recognize there's always anopportunity for other variances to come into play that may notbe recognized by existing
testing and so there are activeresearch programs going on right now in fda labs to monitoremerging variance and impact of diversity on detection bycurrent and future tests. we kept up with hiv 2 and group0 and there's also n and p floating around out there aswell as circulating reforms. i want to let you know that manydonor screening tests that we licensed were given dual claimsfor diagnostic use recognizing that the clinical trials thatwere done were sufficient to support the use of these in adiagnostic setting so that led
to the first test used in thediagnostic setting. but we've also gone back theother way which is very interesting. we have recently in the pastyear or so approved the first hiv-1 combo test detecting bothhiv-1 antibody and p-24 antigen at the same time. there is value in giving alimited claim to that screening test. if you would encounter asituation when a traditional
blood donor screening tastemight be available, you can use a test like this as emergencydonor screening claim and we're in the process of working outrecommendations and guidelines for how tests like this can beused. this is the future we areplanning on giving more claims like this in the future. just to remind you where we arenow. i told you where we have comefrom. we're back in the present.
there's potential for reducingwindow period to seven days usually individual donor net. it's not being used widely fortechnical and efficiency and blood donor setting you have avery low prevalence of hiv infection and therefore most ofthose people will not be infected by hiv. it makes more sense to devoteresources to testing. individual nat is not the mostsufficient way to go. also the technology needs tocatch up a bit.
there are some systems out therethat can screen using individual donor nat but the high put ismore amenable to mini nat poll testing. the individual risk of hivtransmission in transfused blood is 1 in 2 million using minipull nat and 1 in 43 million for i.d. nat. there are new fda licensedapproved tools for blood screening for diagnostic forvery rapid testing and therapy monitoring.
that leads into what bernie isgoing to talk about and to bridge over what mike is goingto talk about and prove prevention and treatment aregained by having more people learn their hiv status. with that i would like toconclude by congratulating cdc for the extraordinary work theyhave done with extraordinary people and we at fda are proudto be a sister agency to you and look forward to more and evenbetter testing in the future. thank you very much.
[ applause ]>> thank you, elliott. unless there's specificclarification questions i think we're going to go ahead and moveon. the next speaker is dr. bernardbranson. assistant director forlaboratory diagnostics here at cdc. dr. branson has been involved incounseling testing for more than 20 years in the hiv field. he was the lead author on therevised recommendations for hiv
testing of adults, adolescents,pregnant women and health care setting. i think dr. branson is going togive you an overview of hiv diagnostic testing. >> thanks a lot, michelle. elliott talked a lot abouttests. what i would like to talk aboutis testing in addition to just tests because that's in part andparcel of some parallel development.
as elliott mentioned in 1985,fda licensed the first test and cdc did something that wasunprecedented at the time by establishing publicly fundedtesting sites. when the tests were licensed foruse in blood banks, there was real concern that people whowould like to find out hiv status would go to blood blanksin order to do it and they established alternative testsites for people who wanted an hiv test as an alternative togoing to blood banks and sent cdc staff out across the countryto different cities in order to
talk about the tests andrecommendations for testing and recommended testing based onrisks. introduction of unanimoustesting because of the stigma and discrimination that could beassociated with just seeking an hiv test at that point in time. importantly in 1985 theimplications and prognosis of a positive antibody test weren'tyet known. there was the san francisco citycohort established for looking at hepatitis infection andfollowed those people for hiv
and when this test first cameout, it was believed that 10% of people who tested positive wouldever go on to develop aids. they wanted to establish the hivtest and having symptoms of aids. in 1987, cdc conducted aconsultation about the role of virus antibody testing andprevention and control of aids and at that point in time theprocess that has been in place for many years of pre andpost-test counseling has been designed to explain hiv and howit could be prevented because
very people knew about that inthe country at the time they were seeking the test. you needed to explain the test,what the test result meant and as i pointed out, a big emphasisat the time was to explain that having hiv and a positive testdid not necessarily mean that you had aids and of coursecounseling was conducted pre- pre- and post-test to emphasizechanges. one of the conclusions from thisconference was that testing was adjuncted to eded eded tocounseling.
they needed to be provided withcounseling and there wasn't therapy so there wasn't much youcould do with a positive test result but could be an incentiveto change behavior. technology remained the same. there were standards for whathappened with testing across the country. there was real concern aboutfalse positive tests and as a result of that concern in 1989when cdc came out with recommendations for how tointerpret western blot, they
also recommended that nopositive test results be given out to an individual until thescreening test was repeat ededly reactive and a supplemental testhas been used to validate those test results. these were stringent standardsbefore giving out test results and one of the consequences ofthat is in the rest of the world people began introducing rapidtests and in the u.s. this recommendation precluded thatbecause you could not give a positive test result.
you could give a negative testresult and tell someone who had a positive test i can't tell youon the basis of the results but that really wasn't going to workand it virtually limited the market to the iea and westernblot in this country. as time went on, we startedlooking at what happened because you had to send a test to alaboratory and because it had to be confirmed before the resultscame back, we noticed that one of the problems with thisconventional testing is that since you had to return for yourtest result, many people never
did so. many people never received anhiv positive test result. from 1995 in red in std clinicshalf of people returned to receive their test results. that's in the hiv negativecolumn and even with outreach in order to talk to people and findpeople who tested positive about one-third to 40% of people whotested positive for hiv never received their positive testresults. we began to look at otheralternatives in order to help
improve this and one of theconclusions is that we needed to be able to use rapid test to beable to give people same-day test results and in 1998, thepublic health service recommendation was changed toprovide preliminary hiv positive test results before theconfirmatory results are available in situations wheretested persons benefit. this included clinics wherepeople went to seek their hiv test results and includedcircumstances like after a person had an occupationalexposure from a needle stick or
for a pregnant woman where youmight want to make a therapeutic decision immediately on thebasis of a preliminary positive test result. as a result of the change inthat recommendation, rapid tests came to the u.s. market andbetween 2002 and 2006, fda approved six different rapidtests for the united states. it was not only rapid tests thatwere important but the concept of another system of regulationfor testing in the country. they classify test on the abouta basis of how complicated there
are and what requirements thereare for monitoring and four of the rapid hiv tests approved bythe fda at least so far four of them have received waiverpictured on this slide and can be done at point of care and youcould provide result back to an individual relatively quicklyand they could be done by people who were not laboratoryprofessionals so that greatly expanded range of where testingcould happen in the country. by 2009, over 61% of all testingthat is conducted by health departments particularly amonghigh-risk persons were
clia-waived hiv rapid tests. through 2006, 2007, 2008,conventional tests in blue and rapid tests in purple. rapid tests overtook and becamethe major form of testing that was used. at the same time in cdc'sorganized publicly funded testing sites, while proportionof people tested, 1.4 million in 1989 to 2.1 million tests in2004, the percentage of people tested went up but peoplepositive went down.
high risk people were seekingpeople. 5% of those getting tested weretesting positive for hiv. by 2004, it was down to 1.2%. in recent years it's downto .75%. our publicly funded sites andour targeted testing based on risk was continuing to findinfected people but found fewer and fewer and that led to thechange in recommendations. following the pattern of thenumber of people ever tested, the national interview surveyasked people every year about
whether a person had ever beentested for hiv. in the pink line on the slidewhat you can see is that the number of people who say orpercentage of people who have ever been tested increased from1987 and 2002 to around 40% but then it stabilized. in 2002 the same proportion ofpeople every year said they had an hiv test. our progress had really stalledin terms of testing more people for hiv infection.
so in 2006 as a result of thisobservation and a result of observation that many people whowere going into health care settings had hiv infection butnever got diagnosed, cdc issued revised recommendations fortesting adults, adolescents and pregnant women and health caresettings. before they were based onfactors associated with risk for hiv so it was targeted testingand these recommendations called for routine voluntary hivscreening for all persons age 13 to 64 in health care settingswhere prevalence of undiagnosed
hiv was 1 in 1,000. they called for repeat hivscreening persons with known risk factors at least every yearand specifically int kated that inin health care settings, prevention standards should notnecessarily be required for people who were receiving an hivscreening test. this slide summarizes basicallywhat has happened over time with hiv, the number of peopleinfected and the proportion who found out their infection.
what you see in green areproportion of people infected with hiv and who know they areinfected with hiv. that number has increased sothat right now overall there are about 1.1 million people who areinfected with hiv in the united states. at least as of the end of 2008. in blue are the proportion ofpeople who have hiv infection and don't know it and linethat's going across the screen indicates what percentage ofpeople are unaware of their hiv
infection which decreased from90% back when the test first came out in 1986 to 20% in themost recent year for which we have an estimate back in 2008. people always focus on the factthat 20%ã±r of people don't know they're infected. i think the impressive featureis 80% of people do know that one other thing we see on thisslide is starting around 1996 when effective therapy becameavailable, the number of infected people in the countryhas continued to increase every
year because survival isincreasing for individuals and so we have made significantprogress in identifying people with infection and getting thosepeople onto effective treatment. there is a changing landscapeand i will talk a little bit about diagnostic tests recentlyapproved by the fda. originally there was eia thatwas done in large batchesã±r and followed by the western blot. more recently there areplatforms called random access assays and the new tests have adifferent principle.
in these two platforms oneapproved in 2006 and another in 2008, these are machines in usein hospitals and laboratories where they can store 30different kinds of tests. hiv, hepatitis b, hcg, which isa pregnancy test. you check which one you want. it can do one at a time or putin a specimen and get an immediate test result back inless than 60 minutes from one of these procedures. there's been the quantitativerna testing that can be used to
diagnose acute hiv infection inpeople before they develop hiv antibodies and also be used as aconfirmatory test who are hiv that was the first rna testapproved for diagnosis approved by the fda in 2006. previously there were tests usedfor monitoring and not for hiv diagnosis so this gave us anopportunity to identify people earlier in the course of an hivinfection. most recently as elliottmentioned, fourth combination assays have been approved.
they run a random accessplatform i mentioned so you can do one test at a time and youdon't have to match it. in this particular test that'sbeen fda approved you can get a result back in half an hour. one of the key ingredients thatmakes this combination test important is that while p-24antigen shows up early in the course of infection, it alsodisappears when antibody develops. if you only test for antigen,you'll find early infection.
if you test for antibody you'llfind for late infections but when you screen for both, youcan use a single test that's a lot more practical and a lotless expensive than testing with both an anti-testbody test andrna the western blot has been thelong stay of positivity and these are data actually frommichelle's laboratory looking at all of the fda approved testswith specimens identifying basically when 50% of thosespecimens end up turning positive compared with thewestern blot.
elliott showed you the graph ofdifferent tests. i'm going to show the specifictests so first test approved second generation in use until2007 picked up hiv infection two days after the western blotturned positive. the second generation test, thisbrand was rleb. picked up infection five or sixdays before the western blot turned positive. the rapid hiv test pick upinfection again between two and five days before western blotturns positive.
the other rapid test in thelaboratory pick up infection a little earlier. up to ten days before the timethe western blot turns positive. and then the third generationtest most wildly used for screening and two random accessplatforms that i mention pick up infection about two weeks beforethe western blot turns positive and if we use rna test it willpick up people nearly four weeks before the western blot turnspositive. so as you can see on this slidewhat's been happening is
sensitivity test has beenmarching so that infections detected earlier and earlier thefourth generation test we have a little less experience with butpicks up infection four to five days after rna picks up theinfection.ã‘i we're not able to detectinfection almost as soon as a person becomes infectious withnewest kinds of technologies. in summary i want to remind usthat 80% of people who are living with hiv in the unitedstates have been tested and are aware of their infection.
in order to continue thisprogress both targeted testing for persons with risk factorsand routine screening in health care setting remain necessary toidentify the infections that we have not yet diagnosed. the test that we have availableare really good. they detect infection earlierand produce results a lot more quickly so that people canreceive their results when they're in the health caresetting and finally hiv testing remains an essential feature asentry point for effective
treatment and prevention of hiv. thanks very much. [ applause ]>> thank you, bernie. we appreciate that. the next speaker is dr. mikecohen. he has a very distinguishedcareer. he's a professor of medicine,distinguished professor of medicine in microbiology andpublic health. hqãºã¡
the center for hiv backimmunology on the senior leadership group and chair ofprevention committee. welcome. >> thanks. good afternoon. i'm amazed that people are hereat 3:00 in the afternoon. government employees are underdifferent pressures than we are. i'll try to be brief andhopefully i'll have slides. i control the slides.
okay. we're going to go from adiscussion of detection to what do you do with information aboutdetection and go toward the future as much as possible inthis discussion. issues that i want to talk aboutare fact that people have to be linked to care. the test result isn't meaningfulif the person doesn't get the result or find their way intomedical care. they need access to appropriatetreatment whether in the united
states or somewhere else on theplanet. if we simply find and treat, wecan't deal with this problem with current technology becausefor every person we detect and treat me where from two to fournew infections occur. more people get infected. it's a big problem and one we'vebeen working 30 years on getting a grip on. i was asked to make an historicnote and antidotes are good and history is good.
what's important to recognize isin the '80s when some people in the room probably were not born,in the '80s, the disease held great fear and terribleprognosis and basically death. 100% of the people who acquiredthis diagnosis died and in 1985, i work at the university ofnorth carolina, 10% of all admissions were for hiv and sothat's a huge number. it's 1,000-bed hospital. at any point time at least 100people with hiv in the hospital. at least five deaths a week.
it was a pretty terrible time. people didn't really want toknow their status. especially because we hadnothing to offer other than modest management ofopportunistic infections. in 1989, frank graham and dennismackey wrote an editor al thatial thatattracted a lot of negative attention and they were forcingpeople to know their status and why because this was fraughtwith not much benefit but tremendous stigma worst realizedin ryan white who suffered
terribly through no fault of hisown as he acquired hiv from blood products in the early1980s. probably one of the biggestbiomedical events of the 20th century, azt and 30 more drugswere developed and this slide generated by cdc which is one ofthe most shown slides ever anywhere you see that as soon aswe had access to antiviral therapy, deaths plummeted and sothis became a totally different disease. most infectious disease centersin the united states developed
out-patient clinics to care forpatients with hiv. the attention of the communityof physicians involved in this moved to africa and other partsof the world where there was no access to this kind of therapy. the world for many years 1995 to2000, 2001, was divided into people who could get access topills and those who could not and would simply die. it was a very unpleasant time. we've moved away from that.
as this particular discussiontoday focusing mostly domestically, we need to beconcerned that 80% of the epidemic is outside of theunited states. i want to thank the organizersby the way and my friend for inviting me to be here today. that kind of brings us forward. now we have treatment. the treatment is going to beimportant. we'll talk about that.
and then we also have to dealwith prevention. prevention we have fouropportunities. most of our time has been spenton people who are hiv negative creating opportunities for themto remain negative. and this graph you see that wehave behavioral constructional activities that may take someonehiv negative to remain negative and activities for those thatare negative but may be higher risk. these are really important toolsfor people who are negative,
know they're negative, and areat substantial risk. but then we twisted aggressivelyto worry about people that are hiv detected. these people are rendered lesscontagious. probably the thing that'sattracted the greatest attention in recent times, for people whoknow they are infected, we only have a couple options. behavior change so peoples aremore responsible and use condoms and give their status.
the other thing we can do istreat everybody. in treating everybody, the ideawould be if the treatment is soã‘ieffective in personal health, maybe it renders people lesscontagious. this is an old idea. it's not brand new idea. most of us started working onthe idea as soon as azt was developed trying to demonstratethat drug would render people less contagious and tools thatwere used were trying to prove
that the drug led to fewer hivparticles in genital secretions. there was other studies done andthe observational studies looked at couples and they indicatedwhen they studied couples that when one partner in the -- whenone was positive and other was negative and the positive wasafforded therapy, the anticipated transmission eventsoccurred rarely. these observational studies wereconnected with the plausibility we thought existed that it wouldlead to reduced transmission events but we felt for a varietyof reasons that a trial was
necessary to understand themagnitude and durability of the benefit to therapy. the trial that was launched waslong and expensive trial called hiv prevention trial 052. this had a study that's shown onthe slide. half of the couples -- couplesare extremely well balanced. equal number of men and women. they are enrolled with highcount. median is 446.
people would not requiretherapy. half of the couples werefollowed and therapy was not offered for some period of time. therapy was delayed until suchtime it was more appropriate for personal health and the otherhalf of the couples volunteered to receive immediate therapy ata count higher than would be traditionally used for therapy. the purpose of therapy was nottheir own personal health although that was important.
it was to determine whether thattherapy would reduce the transmission probability totheir sexual partner. that study was supposed to go --the study was fully enrolled in may of 2010 and was supposed toend in may of 2015 or early 2016. on april 28th, a data safetymonitoring board indicated while the study could continue, thatthe results had to be made public and so this is a veryunusual event because the study is ongoing but the data safetymonitoring board felt the
results were so important to thehealth of the public that it was irresponsible or that theresponsibility of the sponsor was to make the results public. on the next slide i show you theresults that they were concerned about. over the period of 1.7 years,there were 39 infections observed. 39 transition events observed. now, the total is not reallyimportant.
what's important is the linkedcases where the virus could be linked from the infected personto their sexual partner. there were 28 of those. this linkage is not somethingyou can do at home. this is hard to do. a lot of sophisticatedtechnology. there were linked cases. there was only one linked casein someone receiving antiviral therapy whereas 27 linked casesoccurred in couples who no
therapy was provided. this led to a conclusion thatover this period of time there was a 96% prevention of hivtransition. now, we don't know whether thiswill go on forever but this is such strong prevention that itwas felt that the lickpublic neededto know the pills worked in this way. 97% were heterosexual couples. it doesn't lend itself to menhaving sex with men but to
understanding of heterosexualcouples. the one transmission case isinteresting. how is it possible one personwas able to transmit even though they received therapy. the answer will be revealedlater this summer when all will be told. all data related to the trialhas not been told to everybody and there will be an aidsinternational meeting that will have an online portion.
an hour and a half devoted tothis whole thing. then that one case will bedescribed in tremendous detail. something has to be kept insecret even from my friend, john. all right. so now this becomes theinfrastructure of a belief system. now we're concerned aboutprevention. we're trying to find infectedpeople and now we're in a
position to tell people who areinfected if you take your pills reliably, you'll become lessinfectious especially in a heterosexual relationship. while we speak, someone on theplanet a mathematical model is being modeled. there's plenty of opportunity. the assumptions provide theanswers. if i show you the next slidefrom a review article we wrote and you ask the question if youtreat everybody, can you stop
the epidemic? the green says treat everybodyand you stop the epidemic. these are models. the red is treat everybody andit will have no big effect. depending on your assumptions,you can have any answer you like when it comes to mathematicalmodeling. so we look at ecological studiesand we see two different kinds of points of view. we have investigators from sanfrancisco who told us they feel
enough a.r.t. was used in thosecommunities that they see reduced new cases of hiv orreduced incidents cases of hiv but mostly looking at newdiagnoses which is problematic and other countries say we usea.r.t. and we don't see a population benefit. i think what one can concludefrom all of this and this is a huge amount of information isit's a really interesting topic. treatment definitely reduces theprobability of transmission from one person to another and inorder to see that benefit at a
population level, we'll needmore information both observational information,modeling information and i like modeling a lot, i don't mean tobe negative, we have to know that the outcome depends on whatwe put in and we're going to need experiments and i'll get toexperiments in a second. so the experiments. having said all this, the horseis way out of the barn. the species wants to knowwhether treatment can serve as prevention and so there areseveral studies going on trying
to treat large groups of people,treat enough people to stop the transmission of hiv. there's one in uganda by britishand one in south africa and then the cdc and nih have separatecompetitions for very large sums of money that will be given outthis summer to use combination prevention using somecombination of behavioral, structure, circumcision andantiviral therapy to stop the spread of hiv. the combination trials are theway of the future.
this is beyond modelling. modeling says we have to doexperiments. the experiment -- these will becommunity randomized large scale experiments which will tell uswe can do this or we can't do it's going to be an excitingtime in the prevention field. now, this is -- i don't know ifi can go back. apparently not. that last slide was a picture ofnew york of the community that's going to participate in 065.
unfortunately as we try to usetreatment as prevention, there are inconvenient truths. acute infections come up a bunchof times already. i'll say a word about that in asecond. drug resistance is a big issue. if we treat more and more peoplewe can run into trouble with resistance and convert the epepidemic into more resistant viruses. this is acute infection.
this is a window of time whenpeople don't know they're infected. antibody is negative and asantibody becomes positive the process transpires. as virus grows to hugeconcentration the person is rendered very, very contagious. each viral particle during acuteinfection is considered to be 800 times more contagious thanviral particle from someone with chronic infection.
there are two social forces. so there is a lot of concernabout acute infection. the question is people areantibody negative during acute infection. hard to find. and even if we find thesepeople, what do we tell them? what do we tell them about theirsexual behavior and thudshould theybe treated? should we treat people duringacute infection?
there's no right answer to that. this is a graph from a paperpublished a few weeks ago that shows estimates of thecontribution of spread of hiv from people with acute infectionto other people. the lowest you get is 9%. generally speaking. highest you get is from ourstudy of 38%. you can even get higher thanthat. we argue that about one in threenew infections come from people
with acute infection. this kind of emphasizes thateven if we find all people with chronic infection, we still havea problem with acute infection. and then this is a studypublished giving all of the ideas that relate to should wetreat people with acute infection? we find people and we don't doany prevention activiststies or treat. treatmenttreatment, why do we want to
find them? we need to get our act straightabout this. lastly, an issue about reality. a lot of people are unaware oftheir status. some people are receivingmedical care. some are getting their pills. some are fully diagnosed and invery excellent care. not in care and engaged in careby this article by gardner. what's striking about thearticle, the numbers aren't
necessarily 100% correct, aboutyou they have voracity and there's another paper that saysthe same thing. if you look at the argument thatthis 1.1 million people are infected and you accept thatthere's 875,000 who know their diagnosis and look at the numbernot linked to care, it's a very large number not linked to careor let's say linked to care is 660,000. then you look at the number whoremain in care and are fully suppressed edsuppressed.
gardner argues it's only 200 to300,000. if we use treatment asprevention, how can this work if the denominator is 1.1 millionand number people benefiting in the richest country in the worldis only 300,000? how do we do this in africa andairborne asia? we need to be realistic. it's realism that helps us tosucceed. i'm going to end by saying this.
30 years later i've been workingon this problem my entire career. '80 i saw my first patient andit's now 2011. i'm not on the fast track. this has gone on a very longtime. what i can say 100% for sure isthis is a different problem than it was 30 years ago. this is a totally differentdisease and totally different problem and totally differentplanet.
there's no doubt that hivtreatment is amazing. it prolongs life and we're 100%sure that we can slow the transmission when we find peopleand offer them treatment. there's double benefit toknowing your status and being treated. the challenge for us is the laststatement. to assure that hiv detectionthat allows knowing your status leads to remarkable personal andpublic health benefits that are possible.
how do we as a human being takeall of this information and translate it into the mostmeaningful thing we can do for health of the individual andhealth of the public? thank you for listening. [ applause ]>> thank you. now we'll take questions. >> there's just a coupleobservations. first, a quote i'll use often inthat it's realism that helps to succeed.
thank you for that. i'll use that a lot. another sort of observation ihadn't noticed before is while deaths decreased after theadvent of hiv treatment, incidents stabilized at thatpoint and i hadn't noticed that before. that's the time it stabilized in'97 and '98 when we started stabilizing. but in terms of diagnostics andtesting in the role of acute
infection, i'm really struck bythe commitment we've had to keep the blood supply safe andtremendous expense to do pool nat testing for a safe bloodsupply. i'm curious what the importanceis of detecting acute infection for high-risk people and howmuch to commit to doing that? it's kind of a tough question. is it worth it as much as it isas blood supply and should we be going for it? >> i think both mike and i willtry to tackle that question
about acute infection. it's not always easy with bloodsupply. if you detect acute infectionyou don't transmit it and end of story. acute infection and mike and idon't always agree on the importance but in the beginningof the epidemic everyone has acute infection. and so obviously it was veryimportant to look for it. at current time what werecognize is that acute
infection and its importance isprobably related to how much of it is in whatever populationisã‘i experiencing it. in mmwr article on men havingsex with men that came out a couple weeks ago, what werecognize is that nearly 20% of the people who were infected butdidn't know it had the test within the last three to fourmonths and were told they were negative. and so i suspect that many ofthose people wouldn't have been
detected if we were looking foracute infection and because we know that's a high incidentgroup, it's probably very important to look for acuteinfection. on the other hand, first of all,if the person gets tested if they're infected, we want totell them they're infected so detecting acute infection wouldbe important. people who find out they are ininfected tend to change their behavior and are less likely totransmit and it makes a difference in terms of epidemicand the big question is whether
treating people with acuteinfection makes any difference and that is so far an unansweredquestions and maybe i'll turn it over to you at that point. >> those are really goodquestions to be honest. there's no right answer. the first thing about incidents,we have a lot of trouble -- michelle has worked for many,many years on better incidents assays. we have trouble understandingnew incidents.
it's often confused by peoplewho should not confuse it. true incident cases with he havea lot of trouble with. the incidents in the unitedstates has been estimated a lot of different ways at a lot ofdifferent numbers over the years. i would be hesitant and we'revery interested in reducing incidents in the united statesbut given how much trouble we have in measuring it, we have tobe very careful about declaring success or failure.
so what am i saying? when i look at the slide inthose numbers, i'm not 100% sure how much variability there isgiven our difficulty in detecting reality. in terms of -- we wouldn'tdisagree. it's very straightforward in asense. people with acute infections nodoubt they are very contagious. their contribution depends onhow many they are and how many sex partners they have and howlong they remain contagious.
people with chronic infectionuntreated will always overwhelm a number of people with acuteinfection but less efficient in their transmission. they'll have opportunity to havemore sexual episodes without a transition transpiring. they can create a very largeproblem. what happens as everybody wouldrecognize, everybody has acute infection at some point but mostis unrecognized. if you look at couples and italways takes three people when
we talk about sexualtransmission. you have a negative couple. they are minding their ownbusiness. a third person gets in therelationship. when that third person gets --that's exactly what happened. the third person -- hopefullynone of you are suffering that. our species is confounded bythree people being in a relationship together but don'tknow they're all in a relationship.
when a third person gets in arelationship and a transmission event occurs from the chronicperson to the unrecognizing partner, then the transmissionevent occurs very quickly to the next partner rendering 80% ofcouples in most places positive and that transmission eventoccurs in the first five months by all estimates it occursquickly. it emphasizes the importance ofacute infection. one argument with bernie. an article this week that has avery chronic epidemic and we
claim in that article that sayswe think a third of the cases even in epidemic are describedas acute infection. that has to do with theserelationships. these sexual relationships. it's a long winded answer. i apologize. lastly we don't know -- in termsof resources, i know of no one who could tell the right way toallocate resources because you can waste a lot of money tryingto find a few people with acute
infection or not. and the blood bankers spentestimated by the yale people in the beginning of the epidemicthat they spent $80 million in the last eight cases orsomething. very famous paper about what wasrequired to make the blood supply safe and it wasabsolutely required but it was terrifically expensive. is that true, elliott? the last eight cases or tencases?
>> i don't know. it's very expensive. >> do we have any questions outin cyberspace for the speakers? no questions. i have a couple of questions. actually, one just occurred tome off the top of my head and you were actually talking aboutwhen you talk about success of 052. it was great.
it was a very controlled studylike you said. you said you know people are ontherapy because you can look at them. i have a question that has to dowith testing but kind of a different testing question. how valuable do you think itwould be to have a test that could rapidly detect whether ornot someone is compliant with their therapy? so you could actually test --instead of just testing to see
if they are infected but are themeds present? >> i mean, 100% for sure a pointof care rapid test that shows spiral suppression is one of theholy grails of both treatment and prevention. it's extremely important. if it's not present, it meansthat the people are adherent and that they haven't acquireresistance. you get two things for one. a lot of people have beenworking on this for a long time.
this holy grail dip stick test. >> i'm saying not just hiv testbut a test that can tell you if the drug was present as well sobasically a test to measure compliance of actually takingdrugs. do you think it's useful? what do you think? >> i think i agree with mike. the more important thing in thestudy that ultimately what we want to look at is whether virusis undetectible in people.
if the drug is there but virusis detectible that doesn't help you answer the question and asmike was pointing out, not just this is holy grail but we'reclose. there are several prototypes ofpoint of care test that will look at whether people havedetectible virus and that will be the next game changer interms of monitoring therapy and helping to look for people withacute infection. >> this is jonathan with cdc. thank you for wonderfulpresentations.
one of the issues, mike, thatyou highlighted was the fact that technological innovationhas played a large role in the changes we've seen over the last30 years in the hiv epidemic but not enough. for example condoms prevent hivinfection but not everyone uses tests to detect hiv becameavailable but there are still one in five people in the unitedstates that have hiv and don't know they have and antiviraltherapy is successful at prolonging survival but noteveryone is accessing it or
taking it. i have a question regardingrapid antigen tests. the idea that we'll soon have inthe market available to people sometime in the next few years atest that will detect antigen as well as antibody very close tothe time of infection. my question for people on thepanel is once that technology is available, how do you thinkpeople would and should use that test to reduce transition andacquisition of hiv? >> a really good question.
i think if such a test becomesavailable, it's really important and it will filter -- first ofall, there are 36 million people with hiv infection living. they all had acute infection. the number of people that kindof present to a physician or health care provider with acuteinfection is small. but then whenever we do theseretrospective studies every single one says that 90% of thetime or 93% of the time when you really question the people, youcould figure out the day that
they acquired infection. they were sick. had a fever and rash and so onand so forth. i suspect that this is unknownto me. this is a suspicion. people actually are sick whenthey have acute hiv infection with a self-limited illness. i suspect if we have the testyou are describing and it's approved by elliott and it's ina physician's office, and i
think for higher risk patientsand for general patients it will be used pretty readily incombination with another event that will transpire. physicians will be aware there'sthis test they can use in a model-like illness. let me make sure you don't havethis thing. recognizing people have acuteinfection, we'll have to be aggressive then. that lends itself to the future.
there are two parts of thefuture. we'll treat people with acuteinfection. how strong we believe it's abenefit or not, it will happen anyhow for a whole bunch ofreasons. second, we're now into the cureaids window. this week or next week therewill be many, many millions of dollars, i think maybe $50million for a cure aids grant. that's going to really get a lotof attention. we're really going to try to dothis.
even if we don't cure aids, theway we approach the problem will be applied to people that makehiv disease more like cancer. remission if you will. that whole movement will favorwhat you just said. that is a test that doctors canuse. i better know this because thispatient has acute infection they'll go into the cure aidswindow. it's all kind of coming togetherover the next 20 or 30 years. this is not the fast track.
we've been in this 30 years. there's another 30 years atleast in front of us. >> i think i have differentperspective on the question that you're asking in that i thinkthat it is very unlikely if someone met a person they wantedto have sex with they would run to the doctor in order to get atest at that point in time. we had -- you are a doctor sothat's a different situation. on focus groups looking atconcept of self-testing several years ago and people wereinterested in doing that.
one of the recommendations wasthey should be sold in two packs. if you were going to do itbecause both partners need to be tested. but at that point when therewere only antibody tests available people were worriedabout the period and prospect for infection at that time. there currently is onemanufacturer that has applied for approval of home use orself-test for antibody only and
prospect you are raising of anantigen antibody test that would detect everyone infected earlyon would enlight peopleetghten people onwhat actions to take to protect themselves so assuming it couldbe done affordably, people could take control of their lives andopportunity for infection. >> one thing we didn't talkabout to add to what bernie said about home testing and much morebroad easy to use test, the preexposure deal we haven'ttalked about. those drugs we have the drugs.
we know that they work at somelevel. we know cdc is trying to developguidelines or recommendations but i think for sure whateverthose recommendations end up being, much more frequenttesting of people who choose to go that route will be essential. if you take those pills and youdon't test yourself or get tested very, very frequently,the chance you'll end up with resistant virus because very,very high. i think one of the issues aboutmuch better availability whether
antigen or antibody or antibodytests that if we're going to use preexposure effectively, testingwill be a big part of it. we really didn't get into that. do you agree with that? >> and just, elliott, from yourperspective, what level of sensitivity and negativepredicted value would you need or would fda need to see in anacute hiv infection test to actually even engage withdiscussions about it being available to the public?
>> are you talking about a homeuse test or are you talking about a professional use test? >> probably home use is wherethe complexities evolve most. >> for home use we've alreadyhad public meetings to talk about type of performance thatwe would expect. it was a very interestingdiscussion. obviously this is a verypolitically charged issue. we have people who are verypassionate on both sides of it. make home use available, don'tmake home use available.
the advisory committee has givenus the green light or recommended that fda couldactually proceed along these lines. having said that, we talked tothem about performance levels. currently the performanceacceptable performance levels for professional use rapid hivtest are 98% sensitive and 98% specific as lower bound of the95% confidence interval. taking the statistics out of theequation what that translates into is sensitivity 95% orgreater.
that's what we would expect fora professional use test be antibodies as they currentlyexist. now, when we got to home usesituation,ã‘i we had proposed thatthe levels be dropped top 95% as the lower bound. the reason for that was wedidn't want to put too heavy a burden on the manufacturers todo something which would be more realistic recognizing also thatwhen you take a professional use test and put it into the homeuse setting, you're going to see
a deterioration in performance. that was the rationale. there was interesting discussionas i mentioned with the advisory committee is one personsuggesting we drop it to 90% because of the perceived need tohave a test like this available but the committee decided that90% was too low. where we are right now is at 95%as lower bound. that's going to translate intohigher -- it will be about low 90s, something like that.
low 99s for sensitivity. the other interesting thing thatwe found out when we did a risk analysis is that when wecontacted our colleagues at cdc to ask who would be most likelyto use a test like this, the overwhelming majority of peoplewho would be using a home use test would be low-risk people. and so what that did was putemphasis on the test. if you have a slight drop-off onthe test, your positive predicted value just plummets.
it's looking like it has to bevery, very high. sensitivity should be high alsobut we're going to see a big impact on specificity. right now we're on record assaying 95% is the lower bound criteria you have to meet butwe'll work with our risk people so people understand what theimplications of that are. >> can i ask you a question? the problem i have for that andjohn may want to comment on this but the problem i have is if thetest is used like traditionally
it would be with low-riskpeople, i understand it exactly. if it becomes the prep test andit's used by gay men who are taking preexposure medicationsand there are 500,000, then 95% sounds to me like a terriblenumber because that sensitivity is way too low because you'llforce resistance and that will happen very quickly if they justtake it as prep. would you reconsider it? if the test is used, maybe youwould have to have two different kinds of tests.
>> with different indicationsperhaps. >> it would worry me. 95% doesn't sound right ifpeople are taking his and retesting themselves every monththat they're not hurting themselves by taking the pills. >> we should talk about thismore and be part of the general discussion i think. at the same time part of thatdiscussion might involve looking at having different intended useclaims.
>> interesting idea. thank you. >> good afternoon. my name is brittany hughes. i have a question from anindividual following the discussion via twitter. they want to know as far as hivtesting is concerned, can you speak about what support isavailable from the insurance industry for the public?
>> can you repeat the question? >> they want to know, can youspeak about what support is available from the insuranceindustry as far as i havehiv testingis concerned? >> the regulations for theinsurance industry in terms of providing support to people arestate by state and states have specific requirements indifferent places about what they require insurance companies todo and in most cases the insurance company will only dowhat is required for them in
terms of hiv testing. there are certain states thatbasically say you only provide hiv test result if the personrequests it. and in general they don't havestringent requirements for providing support to anindividual after they have been tested whether they testpositive or test negative as almost any other environment fortesting does provide. i think that again that's aquestion that we can't answer on a national level because eachstate makes its own decision
about what they requireinsurance companies to do. >> has there been any discussionon a national level about standards that were put in placefor hiv testing for the public? >> there's not been a discussionon a national level because we can issue a recommendation butwe can't set a standard or put in a regulation the way statescan. cdc long encouraged people toprovide results and support at the time of results to provideaccess to follow-up as a recommendation and certainlythat recommendation won't change
and that applies whether you'rean insurance company, a doctor or blood center doing thescreening across the board. >> thank you. >> hi. bernie, my question is for you. as you were talking aboutadvancements in the test, i wanted to know if we were tochange our testing algarrisms to what points would they stopchanges in state testing? >> thanks for asking thatquestion.
we've all been used to one wayof confirming testing which is with the western blot and weclearly know that now that the tests are a lot better that weneed to do something different than we have before. it was actually a questionmichelle promised she might ask is what would we do. >> read your mind. >> thanks for doing that. what cdc is in the process ofdoing is looking at alternatives
that will potentially do abetter job of confirming that we'll do less expensive job ofdoing confirmation and with faster turnaround time in mostcases. we have been in communicationwith a small number of states that have very specificrequirements in legislation. in other words, some statesinsisted you can only do western blot for confirmation andillinois just changed their legislation this year in orderto make it compatible with what cdc recommends.
part of our process is to,number one, recommend the algrit and then states take steps tomake sure regulations are consistent with the newestregulation that takes advantage of the best technology. >> do we have any otherquestions from the audience or cyberspace? it looks like we're right at ourtime at 3:30. if no one has any otherquestions, i want to thank all of the panelists and all of youfor attending.
[ applause ]i'm going to say one last thing as you're leaving. please don't forget this is alecture series. the next one will actually be onjuly 14th and it's going to be at morehouse and you can getmore information about that on the 30th anniversary
