Clinical Education Initiative POST EXPOSURE PROPHYLAXIS. Speaker: Dr. Daniel Egan

Transcription

1 Clinical Education Initiative POST EXPOSURE PROPHYLAXIS Speaker: Dr. Daniel Egan 5/17/2016

2 [video transcript] 00:00:06 - Good morning everyone. So my name's Dan Egan, I am an emergency physician at the Mt. Sinai St. Luke's in Mt. Sinai Roosevelt. So we are gonna talk about post-exposure prophylaxis today, 00:00:21 so kind of just looking at what we've defined as objectives and what through CEI and the Department of Health we want to cover, specifically talk a little bit about the state guidelines, which have changed in the last couple of years. Talk about kind of what makes an exposure significant, how to evaluate the source patient, and then actually the nitty gritty details of postexposure prophylaxis and the challenges associated with it and what happens afterwards. So my understanding just so that we're all on the same page is that I have some physicians and nurses in the audience, is that right? - [Audience] Yes. - Okay. And the clinical practice setting is an outpatient, is it primary care or what kind of setting are we in? (audience members mumble) Okay, great. So a lot of my goal in talking about this is, as we'll get to, a lot of the difficulties encountered with PEP are in the linkage to care aspect of it and getting people to complete their therapy, and also just an awareness of people about PEP. So as we go through, feel free to stop me and interrupt me if you have questions. I can't, I'm in presenter mode here so I can't actually see your questions if you type them so just, since we're a small enough group, just let me know if you have any questions, and if you feel like there's going to be some background noise in your room if you could just mute your phone and then just come back on if you have a question. So, we will get started. 00:02:05 So I'd like to just start with some epidemiology and overview related to HIV, particularly within the New York City area. So does anybody have any idea of what this number represents? (student mumbles answer) Yeah, so this is the number of people in the United States who are currently HIV positive. This is a little bit of an estimate, with some statistic modeling, but this is the number that we have currently. 1

3 00:02:40 And then this number, this actually represents the number of new cases annually in the US, and the challenge in the public health world about this number is that we haven't made huge strides in the last, you know, 20, 30 years of this epidemic, so this number is decreasing a little bit but we haven't made significant strides in terms of decreasing numbers of new cases annually, and as many of you are probably aware, the governor has kind of started this campaign to end AIDS by 2020 in New York, meaning to get the number of new cases in New York state under 750 a year, so we have a lot of work to do and I think post-exposure prophylaxis directly contributes to our decreasing rates of new infection as we're gonna talk about, and then linking people to care. 00:03:32 So this number is directly relevant to what we all do working in this area, so this is, somewhere between 110,000 and 112,000 people, this is in New York City, so all five boroughs, who are positive. So if you think about that national number, we represent 10% of the nation's HIV burden. So, depending on where I give this talk or what audience it is sometimes people don't feel like this is terribly relevant, but in our world, HIV is extremely relevant and I'm sure that all of you see patients with HIV every day, and so we have a lot of people in New York City and so this concept of post-exposure prophylaxis is really important because not only do we have people that we know are positive but we have probably, we have significant numbers of people who are unaware. So understanding kind of how to initiate and how to complete postexposure prophylaxis is important. 00:04:26 This number is new. (audience background sound). I can't tell if you're asking me a question or if you're just talking, sorry. This number represents the number of people in the United States who are unaware that they're positive. 00:04:45 This is actually a very new calculation, so this was just published a couple weeks ago in MMWR. That number used to be 18.3%, and basically what they do is they, and you can see that this is basically a 2012 estimate, so they looked at people that are diagnosed in a, over a couple year period of time and then try to time when they were infected and for how long people did not know they were positive. So 14% of the US population who is HIV positive is not aware, and that's really, as you'll see, it's those people and people who are not in treatment that are the one's who are at highest risk of transmitting the infection, and the people who we need to worry about in terms of post-exposure prophylaxis. 00:05:34 This is what's going on in New York, so this is Department of Health data and you can see that, not surprisingly, the number of people who are living with HIV is increasing, which makes sense 2

4 because our treatment is really great. And the number of new HIV cases and diagnoses is decreasing a little bit, so we are making some progress in New York City, and this is kind of 00:05:58 just graphically showing that a little bit more. So, little by little we are kind of getting better and we're finding and preventing new infection about a 10% decrease annually in New York City. So we are making strides, it's not huge strides but we've certainly I think, as we have become better about getting more people tested routinely, about making people aware of post-exposure prophylaxis. Now we have pre-exposure prophylaxis for people in high-risk situations. We're making progress in terms of decreasing the incidence of new disease. 00:06:33 Not entirely sure what your population is in your clinic but this graph, which also mimics some national data, always makes me take pause, because it's really showing us that there's this kind of upsloping trend in younger people, particularly minority, ethnic minority men who have sex with men have this increasing rate of new infection even though the overall rates are going down. So we do have a lot of work to do in terms of getting our message out to younger men who have sex with men, particularly those who are minorities, of safe sex, of the awareness of post-exposure prophylaxis, etc. to try and decrease rates of new infection. 00:07:16 And this is actually just showing us new HIV diagnoses in the city kind of in a different graphic representation and the estimated kind of incidence annually. So you can see we diagnose a lot of people but we also think that even though we're just making the diagnosis, some of those people were infected before, so the number of, they think, new cases is also going down, not just people who are diagnosed. So again, all sort of the same message. 00:07:47 So, we have done, not we meaning me, but there have been huge strides made in terms of the treatment of HIV, so we've got now all sorts of wonderful medications that can really gain control and kind of recover some of the immune system once they're positive. And so the treatment has really made substantial strides. The flip side of that is that we haven't really done great things in terms of prevention, on a global, kind of national scale either to decrease those numbers and so this talk is one of the real kind of key methods of prevention of new infection and that's why we're focusing on it. 00:08:29 So we've got a number of different drugs which are highly effective at decreasing viral replication, and so using these drugs at different points in the virus's life cycle is how PEP can work. 3

5 00:08:45 And so, this is really why we're talking about this, so we don't have a vaccine at this point. We don't have a cure. But we do have this way to stop viral replication very early in its life cycle. In a way, that appears to be extremely effective at preventing new infections. 00:09:05 And this is kind of just graphically what we're talking about. So, the first thing that happens is on Day zero, so someone is exposed to HIV on one of the mucosal surfaces of their body. And so there's an exposure and we all know that it has to break through some barrier to get into, you know, underneath the mucosal surface. But in the first couple of days, we actually have this very narrow window of time when the virus is maintained locally. So it just kind of interacts with dendritic cells in the skin and the mucosa, it interacts with some local CD4 cells. It may just be taken to a very close lymph node, but the number of viral particles is not significant in terms of how ultimately people seroconvert and become HIV positive. So in that time period, if people are exposed to meds that prevent viral replication and prevent fusion with cells and integration into the DNA of the host, then we can potentially prevent someone from ever becoming HIV positive. But once we're past that little time window, basically it's game over. So once somebody has had significant replication and then the virus actually moves into the bloodstream, we're out of luck and we've missed our chance to prevent someone from actually becoming HIV positive. So really, one of the keys to this whole thing is that we have this very narrow window of time that we're gonna talk about, and New York state recommendations are that we think about post-exposure prophylaxis within 36 hours of an exposure. The CDC extends that to 72, although most of the animal data, which is where a lot of this comes from really doesn't support past 36 which is why New York state has kind of stuck with the 36 hour model, and it makes sense pathophysiologically when you look at kind of this graphic representation. 00:11:08 So, some of you may be wondering why an ER physician is talking to you about something HIV related, so, and this is just kind of how I got involved in this, so we in the ER probably take care of the most people who come in for PEP and so this is a case series out of Rhode Island, and this is before people even knew that much about PEP outside of the healthcare world. But they got a lot of visits for blood and bodily fluid exposure over a six year period of time, and you can see that three quarters of those were non health care workers, so people that had been either victims of sexual assault or had some kind of high risk sexual exposure. 00:11:45 And it's becoming increasingly common, these two papers are from Europe, but people all over the world are learning about PEP and are going to emergency departments when they have a high-risk exposure. 4

6 00:12:00 And where I work at Mt. Sinai St. Luke's Roosevelt, we actually have a huge population of people that come in specifically for non-occupational post-exposure prophylaxis which we call npep, and I think that's because, if you're familiar with where we're located, our Roosevelt site is in Hell's Kitchen and so there's a large MSM community who's coming to our hospital from Chelsea and the West Village. I take this opportunity to, sorry, just mention one thing and that we've looked at the people who come in for npep and the people who we diagnose as positive with our rapid testing program in the ED and it's a completely different population. So you can see here that the people who are coming into our department for post-exposure prophylaxis are mostly insured men, usually white men, who have, who are having sex with other men. And this is completely opposite our new HIV positive diagnoses, which, many of which come from our St. Luke's site which is serving a more kind of inner city, ethnic minority, people without access to care, more uninsured, more Medicaid, those are the people who are making up most of our new HIV positives and almost half, or half to two thirds of those people, when we make their first-time diagnosis in the ER, already have a CD4 count less than 208. So, this is just a plug for kind of what you're doing every day in terms of when you're working with your patients in primary care, internal medicine, particularly if you have people who are ethnic minorities who may not be aware, but just to inform people that this potential prevention method is available, because we're not seeing that same population coming into the emergency department looking for PEP, so we've got work to do in terms of disseminating the message of the availability of npep to people who are uninsured and are ethnic minorities. So that's just kind of the public health piece from that perspective. 00:14:09 And then after we start npep at the emergency department, it only really works if we have places to send people. So people who can continue this course of treatment which we're going to talk about, so that includes people who are in primary care practices and so if you are a practice that's comfortable administering HIV medicine to complete the course of 28 days, or if you're not, to have if your patients do start it in an emergency department somewhere and then they come to you for followup to have a protocol in place or at least a referring person to whom you can send your patients who's comfortable in finishing the course of post-exposure prophylaxis. And then many of hospitals, like for us we refer our patients who come in, if they don't have a provider, to our HIV centers at our hospitals. So, this linkage to care piece and kind of the collaboration between the emergency department and then the people, the providers who patients are following up with is critical in order for people to finish their course of treatment. 00:15:16 And this paper which was published pretty recently, in the last year, talks about the fact that only 54% of patients show up to their first visit after the emergency department for PEP, and then only 45% of patients complete their full course, so it's really easy to give someone their first dose in the emergency department and to give them their little starter pack. It's the 5

7 transition out of the emergency department into the primary care or HIV clinic or wherever they're following up, and getting them to actually stay on the meds for the full 28 days and to finish the course. And this data really just drives home the point that if we're losing half the people after their first dose to not complete the course then we need a little bit more intensive follow-up I think in terms of getting people to finish. Some of this, the variable that plays in there is that the older medications and some of the protocols that were used in the cohort that's looked at in this study and the side effect profile's a lot higher than the meds that are currently being used, and so there was a lot of noncompliance because of that in the past, which I think, you know, as New York state and HIV experts have redefined the meds in the protocol, one of the goals is that the experience of patients will not be as difficult in terms of the side effect profile. 00:16:52 Okay, so we're gonna do a little brain reset cause you've been listening to me chat nonstop for 16 minutes, so which of these fluids would not require someone to get post-exposure prophylaxis from a HIV positive person. Anybody? - Emesis. 00:17:14 - Yeah, great, so these are the fluids that are considered to be at risk, so these are the fluids that have had enough concent- (student makes noise) I'm sorry? Oh I thought that was a question. Okay so these are the fluids that have had enough virus isolated in them that would be considered to be innocuous, meaning that someone else could get infected as a result of it. And then importantly I think, particularly in occupational settings 00:17:43 or if someone calls you, these are the fluids that are considered to be non infectious. So, we see patients all the time who come in because they've been exposed, we see police officers who show up because a perpetrator spit in their face or, you know, a home attendant who comes in because they got urine on them from a patient and they're worried. So all of these things are not considered to be infectious with the caveat that any time there's visible blood in any secretion then all bets are off and that, you know, is then considered to be infectious. So it's important to kind of understand the fluids that are and are not infectious. 00:18:25 So we're going to divide the rest of the talk into two parts, so the first part we're gonna talk about is occupational exposures, so all of us that work in health care settings are obviously at 6

8 risk for needle sticks and injuries and exposures to bodily fluids, so we're going to talk a little bit about that. 00:18:44 These are some interesting numbers, so the National Institute for Occupational Safety and Health estimates that there's about 365,000 needle sticks annually in the United States. But many people don't report them, and I think that's partially because people either think it's not high risk or people think maybe they're going to get in trouble. So the message to this is that we want to create environments in health care settings where if people do have occupational exposures that they feel comfortable and safe to report them so they can get appropriate follow-up and care. And I remember being a med student in surgery and sticking myself and not telling anyone because I was so scared the attending was going to scream at me, so we, we're not all surgeons obviously but we also want to make sure that we have environments where people feel safe, because about one in 10 healthcare workers over the course of their career is gonna have a needle stick at some point. 00:19:47 We have data about what happens to health care workers who get exposed over the course of their career. 00:19:55 And so this is actually just a paper that was published awhile ago but there's ongoing collection of data, and the CDC follows health care workers who are exposed and/or convert to HIV positive status in the setting of something at work. And basically they collect a lot of demographic data which is voluntarily reported by hospitals but most places are taking part in reporting, and basically what they do is they collect a rift profile of what took place and speak to the provider's hospital or at least get an interview from people at the site, and they ultimately decide if an exposure is considered possible, where somebody maybe got it at work, but there's something else going on where they can't really say for sure, or a documented clear case where somebody seroconverted after an exposure at their job. 00:20:52 And the most recent data published is from 2010 and this is basically since 1981, the numbers of health care workers in the United States who have acquired HIV in the work setting, and you can see the documented cases are the ones that are definitive, and so there have been 57 cases in that time period. There are a lot of possible cases 00:21:15 and the possible things are because more than 90% of those people had very clear non occupational risks that in discovery were found to be probably higher risk than the exposure that they had at work, but in the ones that were definitive, most of them were percutaneous, so needle sticks or injuries with sharp objects, as opposed to mucocutaneous like a blood splash 7

9 to the eye. And really, I think the key is that in 55 out of the 57 cases that were definitive, you can see that many, and this is because information was available at the source, 70% of those source patients had AIDS, so there's definitely something related to the stage of disease and the person who's the source, which causes more infection. It's very very clear, which I'm going to tell you some more data later, that people who are not treated or have poorly controlled viral loads are much much more infectious. 00:22:25 This I think to me is one of the most compelling pieces of information that PEP works in an occupational setting. So in 1996 the CDC and OSHA basically recommended that PEP become the standard for health care workers who have needle stick injuries or exposures to bodily fluid, and since that time there have been only three cases of health care acquired HIV, and you can see from this graph that the last two cases occurred in :22:56 And what's, the three cases in which it happened, two of them the health care workers declined post-exposure prophylaxis and one of them was considered a case of PEP failure because the patient had advanced disease and a multi-drug resistant strain of HIV. But, we haven't had any since 1999, so I think that people in health care settings are quick to get seen and treated and we're good about starting people on post-exposure prophylaxis and employee health systems are good about getting people to complete their 28 days, so you know although this is not randomized data or a prospective trial, I think it's really, it's pretty convincing that it seems like this is working since it became the standard. 00:23:45 So people always want to know in the occupational setting what exactly is the risk. So does anybody know what the quoted percent risk is for someone who has a percutaneous needle stick? So I can just answer for you, 0.3%, so three in 1000, and the mucocutaneous exposure is actually much lower, it's quoted at about 0.1% although you can see depending on what you read rates that are quoted as low as 0.03%. So when someone asks me what's the chance of me getting HIV from a needle stick because they're trying to make a decision as to whether they want to enter into this 28 day course of medication, this is the number that we quote, 00:24:34 but it's important to know that this number is really just an average, so there have been 20 prospective case series from around the world, so these are not, it's not just from the US because we haven't had that many people, and you can see here that they basically just took all of these cases together and found out the rates of seroconversion and kind of just averaged them and found out the percent, so this is where these numbers come from. So there are a lot of other factors that weigh into whether a needle stick exposure is going to be infectious. 8

10 00:25:11 Just to point out the difference, which is why Hep B vaccination is so important, so the Hepatitis B virus, you can see the risk of exposure is orders of magnitude higher than the 0.3% of HIV. And Hep C, although much less than Hepatitis B, still is a much more significant risk than HIV, and we're not getting into, so Hep B obviously we have a vaccine, so hopefully all health care workers are fully vaccinated and immune. Hepatitis C, don't have a vaccine, but we have good data that shows that people who are exposed to patients with Hep C, as soon as they start showing levels of virus in their blood if they do become, if they, you know, are seroconverting, if they- (background audience noise) I can't understand what you're saying, I'm sorry if you're asking a question. So the Hep C prophylaxis, basically we know that if someone starts taking interferon or some of these other anti-hep C medications shortly after exposure that it shows we do really well with eradicating the virus and not having someone ever become a chronic Hep C carrier. So important to also consider that in terms of the evaluation of somebody after they've been exposed. 00:26:42 So this is the only paper that we have basically looking at the effectiveness of post-exposure prophylaxis in the health care setting, and you can see that it was published a very very long time ago, and we're never gonna see another trial like this because we know that it's very effective and so nobody's ever going to agree to allow any kind of randomized control data. So what this was was an international trial from around the world and basically looked at people, healthcare workers specifically, who ultimately became HIV positive after a needle stick versus those who did not, and try to identify what were the things that made it more likely that someone would become HIV positive after a needle stick. 00:27:26 And you can see the numbers here, so there were 33 case patients for healthcare workers who became HIV positive compared to 679 who ultimately did not. 00:27:37 And so basically they did a whole lot of analysis of the situation and did a logistic regression to try and find out what was considered to be more risk. And these are the four things that carried the higher risk in terms of becoming HIV positive, so an injury that was deep, so not just a superficial scratch. If the device with which the person was stuck had blood on it. If it was a procedure that had involved cannulating an artery or vein, cause then in theory there's going to a hollow bore needle as well as a reservoir for blood to sequester and then viral particles to be present. And then I think this last piece which is consistent as well with the US data in a terminal illness in the source patient, so meaning there's a much higher viral load and quantity of virus per volume of blood. But I think the piece here which is really interesting is that post- 9

11 exposure use of zidovudine, so AZT, one of the earlier meds, was associated with a very very low protective odds ratio. 00:28:46 So to put that in different words, basically giving someone AZT after they were exposed to an HIV patient was associated with an 81% reduction in risk. So this was a single medicine given and we know now based on what we're kind of extrapolating from the treatment of HIV and using multiple drugs to treat HIV that giving three drugs is better than giving one in terms of controlling the virus and decreasing replication when people are infected, and so that has become the standard with post-exposure prophylaxis as well. And so the effectiveness of a single agent was 81% we think, we don't know cause we're not going to see this again, and that the effectiveness of giving three drugs is, you know, in the high 90s. So when people ask me well how effective is it to take a course of post-exposure prophylaxis, I usually tell them exactly that, I say well we know it's at least 80% effective and that's with just one medicine but we're giving three so we know that it's probably even more than 81%. 00:30:00 So like I said, we're never going to see better studies because of that, no IRB is ever going to approve a trial with someone in a control group without getting the treatment because it would be, at this point considered unethical. So one of the things to,i think important to know in decreasing the risk not only for, PEP but in terms of what to do at the time of an exposure so that people are aware, 00:30:28 So I think people get a needle stick and one of their first instincts is to do something like this where they kind of squeeze their finger and bleed their finger. This is not advised, so the, if you remember way back in the beginning that first slide that I showed about what happens in the first couple of days infection there's this HIV fusing with CD4 cells and dendritic cells and so we want to do nothing that's going to increase the amount of inflammation in the area because with inflammation comes white cells and therefore CD4 cells and so there's more cells that the virus can infect. And they think that by jarring the area around a wound with aggressive squeezing and stuff you're kind of inducing a inflammatory response. This is not recommended, and similarly avoiding agents that are going to be very toxic to that area and induce an inflammatory response, so not to use betadine or these scrub brushes that are going to be really aggressive, you know, rubbing alcohol or something. People really feel the urge, and I get it cause they're nervous, of doing a lot to the area to try an get it as clean as possible, and bleach, I mean people have done all sorts of things, and really the recommendation is to just strictly wash it with soap and water and just kind of clean the area and then the most important thing is to go get your first dose of post-exposure prophylaxis. So this is good just from an educational point of view 10

12 00:31:56 if you're dealing with people who have a needle stick. So like I said, washing it and avoiding squeezing and these things and then trying to gather as much information as you can about the source person and the type of exposure so that you can make an adequate assessment of risk, and if you're in a place where you start the first dose you can start it or decide that you're going to refer them to an emergency room or somewhere else where they can get their first dose. And all of the data that we have from animal studies really shows that the time to the initiation of the first dose is really critical, and getting that first dose in early is one of the most important factors in terms of preventing infection, so kind of the advice is that, you know at least get them to a place where they can get that first dose fast and then we can do follow-up investigation later to get more details, but not to waste a lot of time trying to get more information, trying to get testing, trying to get all these other things and delaying that first dose of medication. So first dose in and then getting more information later. 00:33:03 In terms of the source person, so it's recommended obviously that that person have a rapid HIV test, and depending on the testing technology that you use, they have different sensitivities, so if you are using a fourth generation HIV test which is a combination looking at antibodies as well as the P24 antigen, you probably have the window for a positive test down to somewhere around two and a half to three weeks. The third generation tests, which are just the antibody tests, are more in the three to four week range. So one of the things that's important is to identify whether a person has any risk factors for acute HIV, meaning the source person, so to take a good risk assessment, to see if they've had any unsafe exposures in the last couple of weeks, and if they have symptoms of acute HIV, which include fever and sore throat, lymphadenopathy or a rash, kind of GI systems. And that information, the two of those pieces of information together are going to help a person decide whether they want to complete a course of post-exposure prophylaxis for 28 days. If you do work in, if you are ever in a hospital setting, just so you know, the New York state laws, you actually can test an unconscious or person without capacity source patient without their consent, so that's, that was a new kind of change to the law a couple of years ago where you always needed consent in the past. So the way the law reads now is if the person is a source of exposure to a health care worker, if they are awake they have to give consent, but if they are not able to give consent because they're either in a coma or they were a trauma or cardiac arrest or something and someone gets injured, we can test them without consent, but it has to be fully anonymous test and not documented in their record, which is a little bit of a loophole in the law, and hospitals need to develop protocols that they can test people without it having a medical record number associated with it, but most places have actually established protocols for that. 00:35:20 Some special situations, so if you are encountering these and you are seeing patients in followup from an emergency department after starting PEP, pregnancy doesn't actually change a whole lot. Really just the Efavirenz is the one medication which has some pregnancy-related 11

13 teratogen effect, so it's avoided and it's not in any of the regimens. And then if you, if the source person is known to be positive and we know the medications that they're on, it's recommended that there's a discussion with an HIV specialist in terms with which meds to continue for the course of their treatment. There's differing feelings on, as to whether someone should take the same medications as the person who was the source patient or if they should take different ones, so if someone is on meds and they're well-controlled and they're undetectable, we obviously know that those medications work against their strain of virus. The flip side to that argument is if they do have any little amount of virus circulating is it one that's potentially resistant to the one that they're taking and that's why it's still circulating. Many people will just use the degree of disease control of the source person, if we know it, to make a determination as to what meds the person's gonna get, but the New York state guidelines, you know, just recommend using the standard ones. 00:36:43 This is definitely a number to write down and a number to have access to. This is the PEP line, so this is a 24/7 available consultation line for providers for basically questions related to HIV, to post-exposure prophylaxis, to pre-exposure prophylaxis, to Hepatitis C, to STI management, diagnosis, and treatment. If you call this number you actually will get an infectious disease expert 24 hours a day, so an attending physician to help guide you through the management of someone related to any of these topics if you're unsure. So it's a really amazing resource, it's through CEI and the department of Health AIDS Institute that gives people kind of direct access to an expert if you're not sure, so worth writing this number down and keeping it handy in case you do have somebody who you're not sure about whether or not their risk is significant and if they need anything. 00:37:47 So now we're just going to talk about the other scenario which is non-occupational, which really incorporates victims of sexual assault and those who have consensual sexual exposures who, either because they didn't at the time use a condom or maybe they were a little bit intoxicated and made some decisions or, regardless of the etiology they were exposed in a consensual method. 00:38:10 So, it's a little bit different than a needle stick and so there's some differing data, although ultimately a lot of this comes down to the same thing that it's very effective. So we're going to look a little bit at some animal data 00:38:22 and then the perinatal data. So this is one of the first studies that looked at using AZT again in maternal-child transmission, 12

14 00:38:33 and you can see that this is a randomized, double-blind, placebo controlled trial, so kind of the highest standard we have in medicine in terms of clinical trials, but again, we're never going to see that again because we know that it's effective and you can see that the treatment arms were either placebo or giving AZT to mom before she gave birth, during labor, and then for six weeks to the infant after. And the transmission reduction from just that one drug you can see went down from 25% to 8%, so that's a 17.7, I'm sorry a 17.2% reduction in risk or a number needed to treat which I think is a really easy way to think about things so if you had to treat basically six patients in order to prevent one HIV transmission, and that in medicine is amazing. Most of the things that we do, the numbers in the industry are significantly higher than that, you know, even giving somebody aspirin for mortality in MI is in the 20s, so this is a really effective treatment that we learned from there. 00:39:39 And similarly another perinatal study here showed that if you, this was helpful in terms of defining when people needed to start, but they started, in one of the a, you know there are multiple different arms in this trial, but one of them they delayed giving the AZT to the infant until 48 hours of birth, where they had about a 9% seroconversion, but if they waited past day three that number would double, so it appears that there is that very time-sensitive window when we have an opportunity to prevent transmission. 00:40:13 And similar to the graph that I showed you for the occupational acquired HIV, this graph kind of shows a similar thing with what's going on with perinatally acquired HIV around the United States. You can see that that graph is approaching zero, 00:40:28 and New York kind of shows the same thing, we have almost no cases in New York City, there's always going to be something because people sometimes arrive precipitously in labor, deliver, and we don't have information about their HIV status and the full protocol of mom getting it before delivery, mom getting it during delivery and then the baby doesn't always happen because they're not aware that they're pregnant they're just kind of giving birth suddenly. 00:40:57 And then this is the animal data which really is what has driven home the fact that this works. So, these are the Macaques, these are the Simian animals infected with Simian Immunodeficiency Virus and they're infected through their mucosa either rectally or vaginally with basically the HIV equivalent, and then either given tenofovir which is one that we use in essentially all of our PEP and PrEP regimens now because of the animal data, or not given anything, and they're given it for 28 days. And every single macaque that was given tenofovir within 24 hours of their exposure was protected against SIV. And then this is where that 36 hour thing comes in, if the treatment delay was 48 to 72 hours people started to become 13

15 infected. And then the other thing was that it's not only how soon after an exposure but how long do you take the meds for, so when the animals were only given the meds for 10 days, 50% of them still ultimately seroconverted, and if they only took it for three days none of them were protected. So, it appears to me multi-factorial and not just the full regimen but starting it quickly, and both of those things need to happen in order for this to be successful. 00:42:20 So the risk assessment here is a little different obviously than a needle stick or a mucosal exposure in the occupational setting because there's a lot of different factors that go in to the type of sexual exposure that give us information about risk. 00:42:38 This is a nice kind of estimation of the type of exposure and what the risk is to the exposed person and when I'm seeing a patient, I often times will bring this information to the bedside and have a conversation with them about what their risk is from kind of just global averages, and I think it helps them decide if they're willing to take that chance or not. And you can see that the range is anywhere from one in 150 up to one in 2000, and so that's a very wide range and some people are comfortable with a risk of one in 2,000 and some people are not and so it's a very patient-dependent decision. I think it's helpful for people to kind of have a sense of how big the exposure is in terms of their risk of acquiring HIV. 00:43:28 Similarly we know that there are other things that increase risk, so uncircumcised men are more likely to acquire HIV and transmit because there's more dendritic cells in the foreskin, and so dendritic cells have more HIV present and/or acquire HIV easier. And then, ulcerations on the genitals basically already have breached the mucosal barrier, so if there's something else going on that has an ulceration they're going to be at higher risk. 00:43:58 We also know that the presence of an STI at the same time, because that basically is something that's creating an inflammatory state, so all of those inflammatory cells that HIV's gonna infect are present. And then traumatic exposures or anything where there's blood. And lastly, which I think is probably by far the most important, it's what the viral load of the source person is and how sick they are because clearly there's some information related to that. 00:44:29 So in my mind this is probably one of the most incredible studies that we've seen in the last couple years about HIV transmission. So this was presented at CROI meeting, so the international meeting on retroviruses in The manuscript has not come out yet because the study is ongoing, but it's called the partner study, and basically they have a cohort of patients enrolled in their group in couples, and one of the persons in the couple is HIV negative and one is HIV positive, and they basically follow and log their sexual acts. And in this prelim 14

16 data that they presented they had over 30,000 condom-less sexual acts between a positive and negative person where the positive person has an undetectable viral load and there were zero cases of HIV transmission. And you can see that the mix there is about 60% heterosexual contact and 38% homosexual contact. So this, coupled with the fact that no one has published a case report of a person with an undetectable viral load transmitting virus to someone else is really really important, so we haven't gotten to a place where we're saying not to give postexposure prophylaxis to someone who's undetectable. But I think this is another piece of really important information in terms of preventing new infections because if we get people in treatment and get them undetectable in their viral loads, they're likely probably non infectious but if we don't want to use that word yet cause we're not 100% sure, then they're extremely extremely low risk in terms of transmitting a virus to someone else. 00:46:17 So just in terms of non occupational post-exposure prophylaxis, some people get worried about this, using this as a source of prevention and just not practicing safe sex, so people can probably argue back and forth about that, but it's clearly a method of prevention and it's very clear that just using condoms alone is not working in terms of eliminating the disease. There's mixed data about whether using, getting a course of npep causes people to change their sexual behavior. And you know the last thing I just want to say is that if you do have patients who are frequent PEP users or are frequently taking part in high risk behavior, then perhaps they should be considered for pre-exposure prophylaxis and referred to a specialist who's comfortable prescribing pre-exposure prophylaxis. 00:47:07 The last part is we're just gonna kind of go through the guidelines, so these are all accessible, hivguidelines.org is a fantastic website from the state that really goes through all of the resources and the guidelines related to HIV and hepatitis, prophylaxis and treatment. So, particularly with PEP we're talking about exposure within 36 hours, like I mentioned earlier, although the CDC does say that you can extend up to 72 hours and New York state basically says if you have a high-risk exposure and you're within 72 hours you can consider administering it as well. 00:47:47 The nice thing is that the regimen has become the same for everybody, so basically it's a three drug regimen, so it's Truvada, which is Emtricitabine, Which I always have trouble saying, and tenofovir combination plus Isentress or Dolutegravir, and so basically these are taking a combination of reverse transcriptase inhibitors as well as integrase inhibitors to get the virus at different stages in its life cycle to try and stop replication. And then the alternative regimen is listed below there, so you can see that zidovudine, which was the original one that was studied and so therefore was in a lot of the regimens until the last couple years is no longer part of this because it carried with it such a huge side effect profile, particularly GI symptoms, and also had 15

17 a lot of drug interactions, so it's gone from the regimens and these are the current drugs that are recommended for 28 days. 00:48:49 And what typically happens is that the state recommends a three to five day supply, so most people do four, given to patients in the ED so that will get them through, and actually give them the meds not just give them the prescription, that will get them through to a follow-up appointment with a provider on weekends and holidays. And in the cases of sexual assault the recommendation is that the supply is seven days, and this is because, I think there are some thoughts that these patients may take a little bit longer to go to follow-up, there's obviously a lot of psychosocial things going on at the time of a visit for sexual assault and so giving them a longer supply they have a little bit more time to get into follow-up. 00:49:29 This is the information that we obtained and if you were to start PEP in your practice this is the information that's recommended for these patients who have been exposed at the time of exposure. So you can see it's really just gathering baseline data so that we have renal function, we have liver function, we have their hepatitis vaccination history, and then evaluating them for STIs and syphilis based on what the exposure was, and then documenting baseline HIV status, so that we know that they're negative as they enter in to this post-exposure prophylaxis course of treatment. 00:50:11 So the side effects stuff, you know, we don't have great long-term information yet on compliance and things with these newer regimens, but like I mentioned before, there was that paper that was published last year which showed that about half of people don't complete it. And it's, you know, some of these meds are not easy and as people are initially taking them is when a lot of patients who are HIV positive talk about having the most side effects with headaches and fatigue and nausea, vomiting, cramps. And those things get better as you're on them for a longer period of time, but obviously these patients are only taking them for a short period of time. So we will often give patients a prescription for anti-emetic to help with the nausea, and then really just encourage follow-up with providers and just trying to get them through this 28 day course of treatment. 00:51:03 If the information, I would just say that if you have the information about the source patient, so it's a known partner, something like that, I think it's worth just speaking with either their provider or an HIV specialist because there is a lot of drug resistance out there as you probably know, the virus replicates and mutates a lot, doesn't have a great kind of proof-reading system in its replication process, and so there's, at the time of diagnosis there's a lot of resistance, even in New York City, and so that may change some of the drugs that are recommended if we have 16

18 that information available. So either yourself and a colleague that is really kind of in tune with HIV stuff or the PEP line, all of which are available to help with this. 00:51:48 And then the linkage to care is the piece that's really the tricky part for us, so we can refer but we can't really force people to go and we also can't make them finish their treatment, so, you know hopefully, patients show up, kind of either you have some place you know you're going to send them or you have a protocol in place. Employee Health Services in hospital centers is where patients will follow-up for their non, sorry, for their occupational exposure, and then in the period of the weeks they're gonna be with you kind of talking about risk reduction behavior and monitoring for signs of acute seroconversion. 00:52:26 This is basically what the state says is the, these are the things that should happen over the course of four weeks, and ultimately 12 weeks after someone is exposed. So coming in to see you at baseline and then having weekly check-ins to talk about compliance, to talk about side effects, to talk about any symptoms of seroconversion, rechecking their laboratory testing on week two, and then on week four, again having some repeat labs and then an HIV test. Most of the testing technology that we have is going to pick up a positive test by week four, but the guidelines call for a repeat HIV test at week 12 after their exposure. If you were instead of doing just a regular HIV test if you were doing a viral load, you know, in theory finding the virus before someone actually seroconverts, by week four the viral load should absolutely be positive if they've been exposed. But the guidelines call for a standard HIV test at week four and then a standard HIV test at week :53:36 So that kind of is a ton of information, so hopefully you've learned some things or been reminded of things which, that the, there's a narrow window of opportunity, but in looking at what's going on in the US, both from an occupational and non occupational standpoint, it appears that this is really effective. New York state supports PEP up to 36 hours after an exposure and the data that we have really show that probably does work and it's probably the best data we're gonna have because we're not gonna really see randomized controlled trials, but we do have really good evidence that lets us know that this is an effective treatment. 00:54:18 Here's that number for the CEI Line, the PEP line, to get clinical inquiries for all of these different things, and if you would like these for your, you can go to the website and there's downloadable things but you can also order them through the contacts that helped set up this training session for you. 00:54:40 And just a reminder, hivguidelines.org and the CEI training website for what we do. PEP411 is a 17

19 little bit out of date, but if you have patients who just want to learn a little bit, this was designed a couple years ago, so the regimens are not exactly right but the information and sort of the patient-friendly presentation using mostly ethnic minorities in the videos is helpful for people to just kind of see and learn a little bit about PEP. 00:55:10 So if anybody has any questions I would be happy to try and answer them, and if not then I guess we're gonna be done. - Hi, this is Dr. Resnick speaking. - Hi. - I have a couple of questions. -Sure My first question is that how long that needle stick or needle is infected, for example if needles fell down is not in the sharp container and somebody accidentally stuck him or herself. For how long it is infective? - Yeah, so, great question. Unclear exactly how long the virus will survive, but it's not long, it's probably, it's a short number of hours. It's not like some of these other viruses, like, for instance MERS which can live outside the body for a very long time, so it's probably a couple of hours and so if you know how long it's been, if it's been outside the body for days and days and we're sure, then it's likely not infectious, but it's tricky and so I think we, the scenario that we see all the time are either housekeeping people in hotels or sanitation workers who come in and they've been stuck by a needle which we presume has been outside, you know, the blood has been outside the body for a very long time, but we still just don't take the chance and we typically just still start them on post-exposure, but it's not a very survivable virus outside of the body. - And my second question is what if the patient refused to be tested for HIV and refused to provide any further information about his personal life? - You're talking about, like a source person? - Source person, yes. - Yeah, so the way that the law reads currently we don't have any recourse, so you can't, people are still protected for their own decision making, so this was a big step in terms of the 2012 iterations of the, or iterations of the law allowing us to test without consent if they were unconscious or were not able to give consent. But as you saw, it still is an anonymous test that's not in the record, but if someone is awake and refusing we really can't do anything. There are some ethical questions, so you can test for hepatitis seralities without consent. You can look at 18