PRE-EXPOSURE PROPHYLAXIS (COMBINED JUNE 2015)

Transcription

1 Clinical Education Initiative PRE-EXPOSURE PROPHYLAXIS (COMBINED JUNE 2015) Antonia Urbina, MD Jeffrey Kwong, NP, MPH Mathew Rodriguez 6/18/2015

2 Pre-Exposure Prophylaxis (Combined June 2015) [video transcript] Dr. Urbina: I'm going to try to give you the nuts and bolts of pre-exposure prophylaxis. So, hopefully by the end of this seminar that you would feel comfortable relaying this information back to your clinics. 00:00:25 These are my disclosures. 00:00:29 Our learning objectives today are gonna be to discuss the New York State and CDC Guidelines for Pre- Exposure Prophylaxis, describe selection of candidates for PrEP. You know, PrEP is really gonna be for those individuals that are at risk for HIV infection, for people that are consistently using condoms, or those that are at lower risk, then no, PrEP is not indicated, so we're gonna go over some of those criteria. Discuss the management of the patient on PrEP, discuss PrEP therapy and side effects. Now again, really overall, the safety of PrEP has been established in the clinical trials, but we are gonna go over some of the mild start up side effects that can occur, discuss the actual challenges associated with PrEP, and discuss follow up care including labs, PrEP, and counseling. 00:01:25 All right, so the FDA, on July 16, 2012, the FDA approved the use of tenofovir, 300 milligrams plus emtricitabine, 200 milligrams. And you know these two pills are co-formulated into one tablet called Truvada for HIV in PrEP, again, in adults who are at risk for becoming HIV infected. And the dosage is one tablet with or without food daily. So really, the big issue with PrEP is daily adherence. You really do need to take it daily to have maximal efficacy. I'm gonna talk about some of it when you onboard patients is that you really need to have them take it at least one tablet daily for a week, for it to reach steady state levels, and for it to be protective. So it's not like you can take one tablet and expect it to work. Daily dosing, one week. All right, and sometimes that can be a challenge for some of the patients, right? Because during that ramp up period, you really want to make sure that they're taking steps to not acquire HIV infection. There were four trials that found PrEP to be effective for preventing HIV infection when taken as prescribed. So again, adherence, adherence, adherence. So a lot of face these issues with patients with already HIV infection, but also patients that are diabetic, antihypertensives, taking their medications when they should take them. There were two trials, the FEM-PrEP and the VOICE trials, and these were PrEP trials in females, where they did not show a benefit. I'm gonna go over this a little bit, but the likely reason for this was due to poor adherence. But that's an important finding as well, because what were the reasons that drove women, mainly in African countries, not to take these medications? Was it stigma, disclosure, barriers to taking medications? So all of these issues are extremely important, but the main reason was poor adherence in females in these two trials. But all trials found PrEP to be safe. So that's something important that we can impart to our patients is that really the PrEP trials found Truvada to be safe. 1

3 00:03:54 All right, so the big sentinel trial was the iprex Trial, and it was published in the New England Journal of Medicine. And the author was Grant, Robert Grant and his team, and it was titled Pre-exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. And I want to go over this trial in a little detail, because all of the other PrEP trials had a similar design. 00:04:24 So the iprex Trial was a phase three, double-blind, randomized, placebo-controlled trial that occurred at 11 sites in six countries. It enrolled adult HIV-negative, men who have sex with men, or transgender women in the US, Peru, Ecuador, Brazil, Thailand, and South Africa. Now there were two study arms, one of them was the active arm, where Tenofovir/emtricitabine, or Truvada was given orally once a day. And the other, the patients were given a dummy pill, or an actual placebo, and their primary outcome was the prevention of HIV infection. 00:05:08 So the inclusion criteria for these study subjects, they had to be male sex at birth, at least 18 years of age. So that's something that we need to discuss. PrEP for persons less than 18 years of age is something that we can't do without parental consent. But I think it's an at-risk population, so we really should be having that conversation. So patients had to be HIV seronegative, they had to be at risk for HIV acquisition, so primarily men who have sex with men, condomless anal sex, and their labs at inclusion had to be normal. That was a complete blood count, a basic metabolic panel, and liver function tests. So exclusion criterias were any serious or active illness, such as diabetes, tuberculosis, or cancer. So that's important, so this trial excluded those persons, but when we start to really scale up PrEP in the real world, what does it mean for patients that are methamphetamine abusers, that are dehydrated, that are active crack cocaine users, and that are concomitantly started on PrEP. So I think we don't have that data, so I just wanted to highlight what patients were excluded. Active substance use, nephrotoxic agents, and any pathological bone fractures. So those were the patients that were excluded. 00:06:43 In the iprex Study they had study visits every four weeks after enrollment. So these patients were highly monitored and screened, and at each visit they were given comprehensive package of prevention services, such as risk reduction counseling, distribution of condoms, the diagnosis and treatment of sexually transmitted infections as well. And all of this is important when you do prescribe PrEP, because all of these really add to the efficacy. And then at each visit, also, they did rapid testing for HIV antibodies. 00:07:22 So here's the graph, all right. So on the horizontal axis we have time from initiation of study, and on the vertical axis, we have the probability of acquiring HIV infection. In the red we have the placebo arm. And in the blue we have the active arm, or the Truvada arm. So what you'll see is that the two curves start to split, meaning that there was a higher probability of HIV infection in the arm that was given placebo, versus active drug. And at the end of the trial, what they found was a 44% reduction in risks in those 2

4 that were given active drug. Now remember, both of these arms also received all of those comprehensive preventive services, distribution of condoms, treatment and screening of STD's. So what they found was a 44% reduction, and this was highly statistically significant. With a confidence interval of between 15 and 63%, meaning that the efficacy could have been low as 15%, or as high as 63%. So when I first saw this, I was like ah, 44%, I mean, would I really hang my hat on that, and feel comfortable with that 44% drop in HIV acquisition? So I was still on the fence with it, but what I'm gonna show you is data that shows that if you then looked at the patients that had detectable drug levels, that's when we started to see that 90 plus efficacy rates. So again, the big thing with PrEP is adherence, having detectable drug levels in order to really be effective. 00:09:11 So let's talk a little bit about safety and tolerability. So tenofovir/emtricitabine was well tolerated, nausea did occur at 2%, versus less than 1% in the placebo arm, and also there was more weight loss. So greater than 5% weight loss, it was 2% in the Truvada arm versus 1% in the placebo arm. So these were more common in the active arm, but there were no differences in severe grade three, or life threatening grade four laboratory abnormalities between these two groups. And importantly, there was no drugresistant virus found in the 100 participants infected after enrollment. So far we're not seeing drug resistance in patients who when they start PrEP are HIV negative. Where we do see resistance in people that have undetected, or undiagnosed HIV, and then are started on PrEP, because PrEP is just two medications. For people with established HIV, you need to treat with at least three. So PrEP is effective for prevention, but for someone with established infection it would have to be Truvada plus something else. That's why when you onboard patients with PrEP, you have to make sure that not only are they not HIV-positive, but they're not in the early stages of HIV infection, what's called acute HIV infection. That's when they have a positive viral load and a negative antibody. So we're gonna go over that a little bit more when we describe how to onboard patients. 00:11:06 So risk compensation, what is risk compensation? Risk compensation is if patients know that an intervention is going to be effective, or reduce their risk for acquisition of HIV, are they gonna change behaviors then? Meaning are they going to have more episodes of condomless sex? So in the iprex trial, what they showed here again, on the horizontal axis we have weeks since randomization, and on the vertical axis we have acts of receptive intercourse within the last 12 weeks. What we found is that in both of these arms, the occurrences of receptive anal sex between the two arms were the same. So there was not risk compensation in this trial that occurred. My experience so far in prescribing PrEP is that whatever behaviors are there before they start PrEP kind of continue after. So if they're using condoms before PrEP, they tend to continue to use them after. If they're mixing it up and sometimes using condoms, and other times using not, they tend to continue with that behavior. Again, I think really counseling our patients is important, because to really maximize efficacy, we want to combine all of our prevention services. But again, at least in the iprex, and in others, they did not show evidence of risk compensation. 3

5 00:12:32 So now going back to efficacy, so what we see here in the iprex is HIV by group and drug detection. If we look in the arm that was given placebo, no drug, there were 64 infections, and there was no drug detected. What we would expect, right? These patients were not given active drug. Now if you start to divide up the group that was given Truvada, and if you looked at those that had drug detectable levels versus not, of those where there were no detection of drug levels, there were 33 infections. Meaning they weren't taking the medication. And there were only three infections in those where they were able to detect drug levels. So now if you look at the rates of efficacy, just based on those that had detectable drug levels, it's a 92% reduction in risk. So that's something I said wow, that to me has legs, that to me sounds like a public health intervention that can really start to bend the curve for new HIV infections. So now with the other PrEP trials, and I'm gonna go over these. We're gonna start to do the same analysis, so I'm gonna give you what the results showed for all patients who entered into the trial, whether they took the drug or not, and then show you the analysis on the far right of efficacy based on those that had detectable drug levels. 00:14:18 So the first trial is the Partners PrEP trial, and that looked at heterosexual couples, serodiscordant couples, either the male or the female in that relationship was positive, and the other one was negative, and that looked about 4,800 patients. They had two arms, one was just Tenofovir, and the other one was the approved medication for PrEP, Truvada. So you'll see that the efficacy there was 67%, just for Tenofovir, and 75% for Truvada. But again, if we do the analysis, based on efficacy by those that had detectable drug levels, you'll see 86% and 90% efficacy. What I want to point out is that in the partners PrEP trial, 40% of those individuals were women. And even though it was not powered to look at differences between the genders, the efficacy rates between the genders was about the same, so the numerical values were similar. I found that to be very reassuring that at least in 40% of this population that were female, that PrEP seemed to be, one, safe in women, and also efficacious in women.now the Tenofovir 2 Study looked at heterosexual men and women, about 1,200, and there all comers, they showed 62% efficacy, but again, if we looked at those that just had detectable drug levels, it was 85%. In these two studies combined, in the Tenofovir 2 Study, about half of the participants were women. So if you look at the Partners PrEP and the Tenofovir 2 Study, about 3,000 women enrolled. So I think that's good data to support that PrEP can be equally effective in both men and women. Although there are some differences that we are going to talk about a little bit. Now there were two disappointingly trials where PrEP was not shown to be efficacious in women, and they were the FEM PrEP and the VOICE trials. They were found to be futile. Again, what was really driving this was the women were not taking the medications. And again, I think that's also important to analyze why and what kind of drove them not to take the medications. Because I think that's an important part of the study. And then the last trial, which I think is very important, is the Thai IVDU trial, Intravenous Drug Users, and they enrolled about 2,000 Thai patients, and they showed 49% efficacy, but again, if you looked at those that took the medications, 74%. So again, I think we have a sense of the different populations where PrEP can be efficacious. 4

6 00:17:25 So on May 14, 2014, the CDC released clinical practice guidelines for PrEP. They provide clear criteria for determining a person's HIV risk and indications for PrEP use. They require that patients receive HIV testing to confirm their negative status before starting PrEP. Again, PrEP is only for individuals that are HIV negative. You want to make sure that they're not in the early stages of HIV infection, and we really want to underscore the importance of counseling about adherence, and HIV risk reduction, including encouraging condom use for additional protection. PrEP is highly efficacious against protecting for HIV, but it does not protect against other bacterial sexually transmitted infections or hepatitis C. 00:18:22 The PrEP guidelines recommend regular monitoring of HIV infection status, side effects, adherence, and sexual or injection risk behaviors. PrEP is not writing for a month with 11 refills. As part of the CDC guidelines, they also include a provider supplement, which has additional materials and tools for when to prescribe PrEP, so I encourage everyone to take a look at that. And they also recommend that PrEP be considered for people who are HIV-negative, and at substantial risk for HIV. So how does the CDC define substantial risk? So for sexual transmission, all right, and this definition really requires interpretation on the part of the primary care provider. 00:19:17 But what they're saying is that this includes anyone who is in an ongoing relationship with an HIV positive partner, so serodiscordant couples. So that's one criterion for persons that may want to consider for starting on PrEP. It also includes anyone who is not in a mutually monogamous relationship with a partner, who recently tested HIV negative. So again, mutually monogamous relationship with a negative partner. And is a gay or bisexual man who has had anal sex without a condom, or been diagnosed with an STD in the past six months. Or is a heterosexual man or women who does not regularly use condoms during sex with partners of unknown HIV status, who are at substantial risk for HIV infection. So for example, if your partner is someone who injects drugs or is bisexual. That's how the CDC defines risk for sexual transmission. 00:20:29 Now for people who inject drugs, this includes those who have injected illicit drugs in the past six months, and who have shared injection equipment, or been in drug treatment for injection drug use in the past six months. Again, we show the Thai data efficacy, safety, tolerability, in that population. And providers should also discuss PrEP with HIV discordant couples during conception and pregnancy as one of the several options to protect the HIV negative partner. What the guidances all say is that you want to make sure the HIV-positive partner is on antiretroviral therapy, has an undetectable viral load, so that you're minimizing risk that way, but then that the HIV-negative partner starts on PrEP during times of conception. So there's also guidance about how to do that. And PrEP is only, again, for people who are at ongoing substantial risk for HIV infection. If a person has an isolated exposure risk, then that's where post exposure prophylaxis should be offered. So those are for people who present after a single high-risk event or potential high risk exposure. PEP, or post exposure prophylaxis, should be given, ideally, within 36 hours after the exposure, and it needs to be given for one month, or 28 days, following the exposure. 5

7 PEP is an emergency. PrEP you have more time to onboard the patient, make sure their baseline labs are normal, that they're HIV-negative. But again, isolated exposures, you want to consider post exposure prophylaxis. 00:22:21 So now here in New York State, on January 14, 2014, the New York State Department of Health published their guidance for the use of PrEP to prevent HIV transmission. You can view these guidelines at So again, what's the candidacy for PrEP, now with the New York State Guidelines? 00:22:43 PrEP is indicated for individuals who have a documented negative HIV test and are at ongoing high risk for HIV infection. The negative HIV test results need to be confirmed as close to initiation of PrEP as possible. So, this is something where you are gonna really have to speak with your patients about their latest exposure. So, really PrEP is getting comfortable about talking about sex, drugs, and rock and roll with your patients, because it is important to illicit this information, to really know are they at risk for being recently exposed with HIV. Because if they are then, I may want to draw, in addition to the antibody test, a viral load test, to rule out very early infection. We know acute HIV infection is a positive viral load with a negative antibody, that dates the infection to within that first couple of weeks. So, I would say, if there's been a recent exposure, if they have signs or symptoms of acute HIV infection, or if you're nervous, in addition to the antibody, get that viral load before you start PrEP. And PrEP is not meant to be used as a lifelong intervention, but rather as a method of increasing prevention during highrisk episodes or periods. 00:24:12 Providers need to obtain a thorough sexual and drug use history and regularly discuss risk taking behaviors, and we have to get away from terms like do you engage in high-risk sex. Because what does that mean to the individual, right? So, I asked a patient once, you know, do you engage in high-risk sex? And they told me that for them, high risk meant having sex on a plane with a pilot. That's high risk, right? Because the plane could crash. So again, I think you have to be more specific and objective. Do you have sex? Okay, if yes, do you have sex with men, women, or both? Do you have insertive or receptive sex? Do you have anal sex? Do you use condoms? The term that I like, I think the CDC has kind of coined it a lot is do you engage in condomless sex? Or do you find it difficult to always use condoms? But again, move away from these terms that are kind of stigmatizing or judgmental. And then you do want to encourage safer sex practices and safer injection techniques. So, you really want to have this as part of your armamentarium when you do dispense PrEP as well. Condoms are still very effective for prevention not just of HIV, but other bacterial STIs. All right, and individuals who do not have continued risk should be educated about non-occupational post exposure prophylaxis. So, for those patients that are always consistently using condoms, they're in a monogamous relationship with a negative partner, let's just say that for some reason they have an isolated exposure outside of their relationship, maybe PEP rather than PrEP is a better intervention. The New York State Department of Health also has guidance for who's a good candidate for PrEP, so we'll go over this. 6

8 00:26:19 Men who have sex with men who engage in unprotected anal intercourse, number one. Stimulant drug use, especially methamphetamines, but I would say not just methamphetamines, right? Cocaine use, also alcohol. So, any disinhibiting drug can also lead to higher rates of HIV acquisition. Individuals who are in a sero-discordant sexual relationship, especially during attempts to conceive. Individuals with greater than or equal to one ano-genital sexually transmitted infection per year. That should be the red flag. An ano-genital STI, gonorrhea, chlamydia, or syphilis. Rectal STIs are the strongest predictor for incident or new HIV infection. Someone has a rectal STI, red flag for PrEP. Transgender individuals, we know that they have high prevalence for HIV within that community. Individuals who have been prescribed non-occupational PEP with continued high-risk behavior, or multiple courses. Again, so patients that present with PEP, or PEPers, you might want to consider making them PrEPers. Intravenous drug use, but also transgender individuals or those that inject hormones, be it anabolics, or transgender hormones, estrogens, and then individuals that engage in transactional sex. 00:28:03 There are different risk scores that we can use to screen patients. This is one developed by the CDC. So, it's a risk score for men who have sex with men, and it's basically a series of seven questions. They ask about age, they ask about how many men have you had sex with in the last six months? How many times did you have receptive anal sex? How many of your male sex partners were HIV-positive? In the last six months, how many times did you have insertive anal sex? In the last six months, have you used methamphetamines, such as crystal or speed? And in the last six months, have you used amyl nitrate, also called poppers, during sex? All of these, you add up the score. If an individual has a score of 10 or greater, you definitely want to evaluate for PrEP. If their score is nine or less, then you may want to consider other prevention strategies. So again, this is a screening tool that you could distribute in your waiting rooms, or you could do in the exam room as well, to get the conversation started. 00:29:25 What are the contraindications to PrEP? There are not many. Again, the data showed it to be safe, efficacious if taken as prescribed, but the lack of readiness, and or ability to adhere, that would be my biggest barrier to starting PrEP. If you take it the way you're not supposed to take it, or if you take it intermittently and you think you're protected, you won't be. And if you think that you can take it intermittently and be fully protected, then individuals can be at risk, or under the perception that they are protected. The other big risk is that if you continue with PrEP, and you do sero convert, remember it's only two medications, it's not enough to fully suppress the virus. What you can do is that you can breed resistance to the Truvada. So, not only will that compromise your own ability to treat the HIV infection, but that's also a now drug-resistant strain that can potentially be transmitted. So, that's why patients have to come in frequently to get HIV tested. So, the other psycho-social is efficacy of PrEP is really dependent on adherence to ensure that these plasma drug levels reach that protective level. And again, it takes about a week to reach the protective levels in the blood, another two weeks for rectal tissue, and then three weeks for vaginal tissue. But the standard convention among treaters of PrEP is give me at least a week. So, how about the medical contraindications? Well, documented HIV infection, if they're already HIV positive, you're not gonna prescribe PrEP. It's inadequate therapy to fully suppress 7

9 the virus. Now drug-resistant HIV has been identified in patients with undetected HIV who received Tenofovir/emtricitabine Truvada for PrEP. So again, those initial periods where you onboard the patients, you really have to do your due diligence to make sure that they are in fact truly HIV-negative. And then the other medical contraindication is kidney dysfunction. Specifically, patients that have an actual creatinine clearance less than 60 ml's per minute. 00:31:56 The New York State also clearly states that although consistent condom use is a critical part of a prevention plan for all persons prescribed PrEP, lack of use of barrier protection is not a contraindication to PrEP. Meaning if patients were consistently always using condoms, they wouldn't need PrEP. So again, inconsistent condom use is actually a strong indicator, for me, where I think PrEP would be efficacious. And again, I think any individual that seeks PrEP, I'm quite impressed that they're really taking their sexual health in their own hands. That they really want to take steps to really prevent HIV infection, I think that type of behavior should really be encouraged and applauded. 00:32:47 What are some of the other important considerations to consider for PrEP for the practicing provider? Well does the patient have chronic active hepatitis C? Both Tenofovir and emtricitabine, not only do they have anti HIV activity, but they have anti Hepatitis B activity. So, although not FDA-approved for treatment of Hepatitis C, Truvada may be used to treat Hepatitis B. What you have to be concerned about is if the patient should interrupt therapy, if they have chronic active Hep B, they may have a flare when you stop the medication. So, that would just be something that you would have to monitor, and maybe treat with another anti Hepatitis B medication. Importantly, patients before you start them on PrEP should be screened to assess their immunity against Hepatitis A and B. If they're not immune, vaccinate them. So, it's a great opportunity to do that. Now is the patient pregnant or attempting to conceive? You want to discuss the known risk and benefits, providers need to report to the antiretroviral pregnancy registry, any HIV-negative women who starts on Truvada. Truvada is a category B medication. So far, animal data does not show any teratogenicity. There are not very well-controlled trials in HIVnegative women, but if their risk for acquiring HIV during their pregnancy is, to me, significant, I would prescribe PrEP. Have that conversation with the patient, and talk about some of the maybe potential side effects, not just to themselves, but to the infant. But again, Tenofovir-based regimens are being increasingly used for HIV-positive women who are pregnant. So again, the very few transmissions that we had across New York State, mother to child transmission occurred because the mother acquired HIV during her pregnancy. Now, is the patient taking other nephrotoxic drugs? Kidney toxic drugs that can interact with Truvada? You want to obtain a thorough medication history, especially drugs like chronic non-steroidal anti-inflammatory drugs that we know can stress the kidney. Again, so a thorough medication history, really try to minimize other nephrotoxic drugs that are given at the same time. And does the patient have any evidence of any bone loss disease, osteopenia, osteomalacia, osteoporosis? Not that you can't prescribe it, but you wanna discuss the risk of bone loss, especially in those with other risk factors, and possibly also check Vitamin D levels, calcium supplementations, or if they're hypogonadal. So again, we're gonna talk about some of those potential side effects, but Truvada, in 8

10 some cases, can cause acute kidney injury, and it also does lead to small, but actual significant losses in bone mineral density. 00:36:07 All right, so the New York State also came up with their pre-prescription assessment checklist. So first, is the patient in acute HIV infection? Are they presented with a febrile, flu-like illness? Rash, lymphadenopathy, meningeal symptoms? In the context of potentially risky behavior in the last six weeks? Whoa, that should be the red flag, and maybe I want to draw that viral load in addition to the antibody test. Their medication lists. Substance use and mental health screening, I think it's important because those are predictors of adherence. Knowledge about PrEP, so why is the patient coming to you? Ask them, what are your feelings about PrEP? How do you feel it works? And health literacy, if you're handing them pamphlets or materials, can they comprehend the written material? And really importantly, again, the readiness and willingness to adhere to PrEP. Now PrEP really equals primary care. I think there can be different models that you can set up, but I think it's best to envelop and accept that patient as part of your practice. So, I do really think that PrEP equals primary care. So, if the patient doesn't have a PCP, you may now take on the ownership of that. Partner information, determine the status of their partner. If their status is unknown, get them in, get them tested. If their partner is positive, even to further minimize risk, they should be on antiretroviral therapy. Their viral loads should be undetectable. Domestic violence screen, I think that's really important. Truvada is an HIV medication. What if someone were to unknowingly run into a bottle of Truvada and it wasn't disclosed that they were on it for PrEP? Are they gonna assume that individual was HIV-positive? So again, a lot of those things. What is their relationship like at home? Are they gonna have issues with disclosing that they're on PrEP, to either family members, spouse, significant others? Housing status is important. We know that really stable housing equals good adherence. And the means to pay for PrEP. So, we know that most insurances cover it, Medicaid will cover it, we know that New York State is now rolling out their PrEP app insurance. But for commercially insured patients, sure, they'll cover the costs of the medication and the visits, but how about the copays and the coinsurances? Those can really add up. Now there is the Gilead Patient Assistant Program that can assist, but you do need to meet a certain income threshold. So again, it can be costly to some individuals. And then for the reproductive plans for women. Again, I think we should discuss this at all, what are their plans for becoming pregnant or not? Okay, I think sometimes having a script is important, so the New York State Guidance has this preprescription education, and I think it's great just to read it. 00:39:17 The pill Truvada has two drugs in it that are commonly used to treat HIV in persons who are HIVpositive. When taken daily by people who are HIV-negative, they can block HIV from infecting the body. The pill needs to be taken every day in order for the body to build up sufficient drug levels to block HIV. It cannot be expected to work if it is only taken just before or just after sex. And PrEP reduces, but does not eliminate HIV transmission risks. You still need to use condoms if you are taking PrEP, because PrEP does not protect against other sexually transmitted diseases. Okay, more patient education. So how does PrEP work? 9

11 00:40:08 Explain how PrEP works in language that is easy to understand. As just stated, explain how PrEP works as part of a comprehensive prevention plan. If you say it more as a plan for wellness, you know what I mean? Not like, this is something you should take because I don't want you to get HIV, but this is really part of sexual wellness and health. I think it's a great way to start communicating with patients. Now the limitations of PrEP. Efficacy is really dependent on adherence, it reduces, but does not completely eliminate the risk of HIV infection, and it does not protect against other STI's. Gonorrhea, chlamydia, syphilis, hepatitis C, lymphogranuloma venereum, LGV, it does not protect against any of those. And PrEP use, dosing needs to be a daily adherence. And again, you need sequential dosing for at least a week to reach those steady state levels. Two weeks in the rectal tissue, three weeks in the vaginal tissue. And you want to reinforce condom use in periods following missed doses. Generally, the convention is a week to onboard, daily dosing, and then if a patient has been off for more than five days, the levels start to drop below protection. So again, it's about a week, and then about five days is the tail when the drug levels will start to drop. That's important, remember patients are gonna have to come in every three months for HIV testing and refills. Take that into account, and part of the education is that if you find yourself running out of medications, I would say more than five days, or even say three days, then really take those extra steps to make sure you are protecting yourself, condoms. All right, and then the common side effects we spoke about it s headache, abdominal pain, weight loss, mild, typically just for the first couple of days. The majority of these resolve definitely by the first month. And you can give standard measures like antidiarrheals, anti-gas, anti-emetics, if indicated to alleviate these symptoms, but I find that I haven't had to do that. 00:42:32 The long-term safety of PrEP. So, there has been 24-month follow up data in HIV negatives showing the clinical safety of oral Tenofovir in HIV negative persons. There is a bone mineral density loss, but it's about half of what we see with HIV-positive patients that are on a Tenofovir-based regimen. But still, about a 1% drop. And the baseline tests that you need to schedule. You need to explain that tests have to be taken before prescribing PrEP. So, they're not gonna get that medication on that first visit because you're gonna have to do the baseline screening test, which we're gonna go over. Explain the importance of follow up monitoring, including HIV testing at least every three months. So, they're gonna get to know you, your system, your clinic quite well. And the criteria for discontinuing. Any positive HIV test result, PrEP needs to be stopped immediately. You don't want to keep that drug pressure on, those drug levels on with virus that's replicating. That's how you develop resistance. You know, in patients with HIV, if they don't take their medications, they don't develop resistance. If they take them all the time, their viral loads are undetectable. It's those patients that only take it 40 to 70% of the time, their drug levels go like this, and they have virus that replicates. That's how you breed mutations. So, you want the patients to stop the medication immediately. If they should develop renal disease, and you can monitor that through the blood test, and if they're not adherent to their medications or to their appointments as well. Or if they have change in their risk behavior where PrEP is no longer needed. So as humans, we evolve, we change, we mature, so that PrEP may be only for periods where they're most at risk. I never like to promote anything as lifelong, right? Let's just start it now. I think it's gonna really be a good prevention tool for you now, and then let's see how it goes. But again, at some points persons may not 10

12 need PrEP. And then use of medication for unattended purposes, diversion of Truvada. These HIV medications are expensive. They do have street values. So, if you feel that they're diverting their medication, would also be another indication. 00:45:05 All right, so symptoms of acute HIV infection. You want to alert patients to these if anytime during PrEP they should have fever, rash, lymphadenopathy, meningeal symptoms, gastrointestinal symptoms, to alert you, maybe signs of acute HIV infection. And for women, again, the benefits. The women who are either pregnant, or who want to become pregnant, it can decrease their risk of acute HIV infection, which is women who acquire HIV during pregnancy, are very likely to transmit in the womb, in utero. So again, for those women at risk. And if the benefit outweighs the risks, which are minimal, then PrEP could be indicated. And then any potential toxicity. Data suggests that Truvada does not increase the risk of birth defects, category B, however not enough data to exclude the possibility of harm. 00:46:09 How do we prescribe PrEP? So, first thing you want to do is get the HIV test. Ideally, you want a third or fourth generation, the more sensitive, the one that can detect HIV earlier. But hey, if you feel they're in acute HIV infection, recent exposure, or you're nervous about exposure, in addition get the viral load test, because that's really gonna then be able to effectively rule out early and chronic HIV infection. You want to get that basic metabolic panel. Mainly to look at the creatinine and the creatinine clearance. Again, if it's less than 60, then this patient cannot be started on Truvada. Urinalysis, you want to identify any pre-existing kidney disease, so a lot of proteinuria, a lot of sugar. Serology for hepatitis A, B, and C. Again, you want to screen for sexually transmitted infections, gonorrhea, chlamydia, and you want to do three site testing, or wherever there's been exposure. Pharyngeal, urethral, urine, and rectal. The majority of STIs that are asymptomatic are pharyngeal and rectal. Most urethral STIs are symptomatic and patients will experience symptoms. So again, rectal and pharyngeal, especially rectal. You also want to screen for syphilis. And important in those patients, you want to consider vaccinations for human papillomavirus, young men, young women, up to the age of 26. And meningococcal vaccines for MSM. So, start to get these preventive measures in there. Again, PrEP equals primary care. And pregnancy tests for any female of childbearing age. 00:48:07 So again, PrEP is not one month with 11 refills. The first prescription should only be for 30 days. So again, you're gonna do your screening test, you're gonna do HIV, maybe viral load, you're gonna say, "Hey, I need you to continue to protect yourself, use condoms. I'm gonna see you back in a week, and at that point we're gonna review your blood test and I'm gonna give you your first prescription of Truvada, just 30 days." After that 30 day visit, you're gonna assess adherence, tolerability, commitment, and then you're gonna write them for 60 days. Now at that time, you can check kidney function, creatinine, creatinine clearance, if you feel a person may be at an increased risk for some acute kidney injury, and that means somebody that has borderline renal function, they're of older age, black race, hypertension, or diabetes. You don't have to at that second visit, but again, if they're at increased risk. So again, one month. Then at that one month, you're gonna write them for two months, and then that will bring you 11

13 to three months. And then it's basically rinse and repeat. So again, 30 days, check and make sure they're adherent, committed, prevention package there, and then you're gonna write them for two months, and that will bring them to the three-month period. After that three-month visit, prescriptions can be given for 90 days, provided that the patient is adherent, and then the patient should return for threemonth visits for HIV testing and other assessments. But that's how you do it. So, you got the baseline, the follow up in about a week or two, the 30 day prescription, the two-month, and then three months hence after. 00:50:05 All right, so just kind of rounding up here. The New York State Department of Health gives this menu of services that should be done. So, at each visit, you should assess adherence. Provide risk reduction counseling in the way or manner that resonates most with that patient. And really utilizes that emotional intelligence and that connection where you can impart, really, wellness, sexual health, prevention. You want to offer condoms, distribute condoms, and then manage side effects. So, the laboratory testing, HIV testing, again, you want to use third and fourth generation tests, and that's gonna be done every three months. And whenever you feel that they may be in acute HIV infection or have symptoms, you also want to do an RNA viral load test. STD screening, you want to ask them at every visit about STI symptoms. The STI screenings that they recommend are the nucleic acid amplification testing, if your labs are approved for that, for gonorrhea and chlamydia, based on the site of exposure. Don't forget the pharynx and don't forget the rectum. Again, any STI can enhance acquisition of HIV, especially the ulcerative STIs. And then you also want to do RPR testing, or syphilis testing. So, for STI testing, you want to do that at least every six months, even if the patient is asymptomatic. Otherwise, you would only do screening and treatment if they were symptomatic. Asymptomatic, you're gonna do it twice a year. HIV testing, every three months. STI screening at least every six months, or twice a year. Hepatitis C screening, so you want to do it at baseline, and then you want to do it annually for persons that inject drugs, or MSM, men who have sex with men, or for those with multiple sexual partners. And then for renal function, after that basic metabolic panel, what they recommend is just doing a serum creatinine and a calculated creatinine clearance. You want to do it at baseline, you want to do it at three months, and then after that it's just going to be every six months. And then the urinalysis is just done annually, and then pregnancy testing every three months. Again, you'll get used to this menu of services, but we know that the tests that are done every three months are gonna be HIV testing, pregnancy testing. The ones that are going to be done twice a year is going to be the STI screening for those that are asymptomatic, and the renal function screening. The annual tests are the urinalysis and the hepatitis C. 00:53:07 All right, so discontinuation of PrEP immediately if the patient receives a positive HIV test result. There's a big risk of resistance if the patient is maintained on Tenofovir and emtricitabine only. You also want to obtain a genotypic assay and refer and link the patient to HIV care. Or if you're an expert in HIV care, you can continue to manage this patient. Discontinuation of tenofovir/emtricitabine in patients with chronic active hepatitis B, as explained, can cause a flare, so you do want to monitor them with liver function tests. You also want to discontinue if they should develop renal disease, non-adherence to 12

14 medication or appointments after attempts to improve. You do need to explain that tail, and that if they don't take the medications daily that they are again at risk for HIV acquisition. And then using medications for purposes other than those intended. And then if they should reduce their risk behaviors to the extent that PrEP is no longer needed. 00:54:12 All right, so to summarize, PrEP is now part of the evidence-based interventions to prevent HIV transmission, another tool in our prevention tool box. And although the overall number of new HIV infections is decreasing in New York State, we do know that in some populations, especially young men who have sex with men, they continue to increase, especially in young black and Hispanic men. And PrEP may be an effective option to really augment behavior change in these high-risk individuals. So with that, I will end there. Hopefully you got the kind of nuts and bolts for PrEP, how to dispense it, how to monitor patients, so I will open it up now to questions. 00:55:00 So let me just say one thing before we do, so that is my there, and if you do have any clinical questions regarding PrEP, you can call the CEI line at , or you can visit us at So now I'm gonna open it up to the audience for any questions. 00:55:30 All right, so the question is, there's a newer formulation of Tenofovir called TAF, so tenofovir/alafenamide. The data so far shows that this drug causes less bone mineral density issues, and less effects on tubular function, or kidney dysfunction. The one issue with that one is it's a bit of a different compound. It accumulates more intracellularly, so it goes right where it needs to go and less in the bloodstream or the plasma, and that's how it has its effect, but we don't know if it's the same protective effect with those difference in its pharmacokinetics. Gilead is doing those trials, I think, first in primates and animal models to see, but it maybe something that may be. But for now, I wouldn't interchange the two, because we don't really know if it's the same level of protection based on those differences. 00:56:31 So, the question is with the Gilead Patient Assistance Program, does that work for patients with commercial insurance, in addition to other insurances? And yes it does, if they meet that income threshold, below the income threshold, regardless of their insurance status. 00:56:48 Great questions, okay, question number three out of four, is so New York State is doing this prep app insurance, that's gonna be rolled out. We just started enrolling patients at Mount Sinai last week. It's like an insurance, like ADAP, it's very specific for PrEP. So, with regard to your questions, it does cover for the screening of STI's and treatment, three sides so pharyngeal, urine, rectal, and treatment, and it covers for hepatitis A, hepatitis B, and meningococcus, not HPV. 13

15 00:57:30 So, the question is the viral load test, are we gonna be using it more frequently with patients with PrEP? Yes, I think we are. Now that's good and bad. The viral load is not a screening test for HIV, it's really a screening test for acute HIV infection. So, it's best used in patients that have signs or symptoms of acute HIV infection. But also when it's used at patients that have just been exposed... So, generally viral loads will become detectable about 10 days after infection. So, for example, if a patient comes to you and says three days ago I had-- I'm gonna use the term though I told you not to use it, high-risk sex, or condomless sex, three days ago, a viral load isn't gonna tell you anything about acute HIV infection because it's too recent the exposure. So you kind of, I like to say, it has to be at least, I say, 10 days for that viral load to pick it up, maybe you can get away with seven. Also, if you start to just routinely screen with viral loads in lower risk populations, you may start getting some false positives. We'll start getting some of those. So, somebody in acute HIV infection should have viral loads in the tens of thousands, but what if you get one that's 500 or 200? Is that a false positive or is it that eclipse period? So, we are gonna have to work through that, and there's gonna be a learning curve for that. So, I really would reserve the viral load for when you really feel that it's gonna be clinically significant or impactful on whether you decide to prescribe Truvada. 00:59:12 The question is right, so a patient on PrEP, they are having condomless sex, they are not symptomatic, and they're coming to you for that three-month visit. Yeah, I feel confident enough with the efficacy of PrEP, because that's what it's there for, just to do an antibody test during that time. So, I would just say the viral loads are just for that onboarding, that's kind of where I'm most anxious about it, because the worst thing to do would be to start somebody in acute or early infection just on Truvada, but subsequent to that, if they are adherent, asymptomatic, then a negative antibody test there, I would feel comfortable dispensing the next 90-day supply. 00:59:53 Again, the question is how about for those patients that want to take Truvada instead of condoms? How do you start that conversation? I mean, I think in that patient PrEP can be a really effective tool, in terms of really preventing HIV acquisition, but I think it's also a great opportunity to have a dialogue with that patient. Again, PrEP, a contraindication for PrEP is I'm not in consistent condom use, right? So again, but I think for that patient, there are so many other things you can start having conversations about. So, prevention of other STD's, and to also let them know that although I'm prescribing PrEP, it's not 100% effective. It doesn't completely eliminate your risk. So there are really things that you're gonna have to do in conjunction with PrEP to really maximize this effect, but I do think it's meeting patients who where they're at, at that moment, and PrEP may be the start, but then you may be able to layer in other things. But I wouldn't let their lack of condom use to be a barrier to a provider starting. I think it's a great point, I think the fact that they've come to you and disclosed such personal information, I think is very promising. 14

16 01:01:16 The question is is there any data to show that there's a difference in efficacy based on age, race, or gender? Yeah, so far no. So far in the trials where they have been able to look at differences in kind of gender and age, there has not been shown to be any differences. But a lot of these studies were not powered to really detect subtle differences. So, I think now there are a lot of real-world studies that are looking at differences in age, patients with comorbid conditions like hypertension or diabetes, substance users. And in the real world, what does that mean? But to date, no on big differences. Yeah, just a good point is that I think individuals who are older can meet criteria for PrEP. I know people don't think about that, but the majority of older adults who acquire HIV are heterosexual. So yeah, I think that's another population, in addition to the IVDU, where you really want to consider at least having a conversation about PrEP. 01:02:25 Right, so the question was is there really any data to look at trans men and efficacy in PrEP in that population? No, there really aren't. So, I think that's a big gap, in terms of knowledge. Because we don't really know. What we do know is that in trans individuals that adherence is lower. So, what are the factors that are driving that? But again, we don't really have a lot of data or information about that. 01:02:56 Right, so the question was is there data about intermittent use? So, at the recent CROI conference they presented data on the IPERGAY study. The IPERGAY was a French cohort, French and Canadian, MSM, and they gave them event-driven PrEP. So, it was basically two pills of Truvada, 2 to 12 hours before the event, and then one pill the day after, and then followed by another pill. So basically, four pills around one exposure. And they had to stop the study because it did show efficacy. So, 86% reduction in risk. I mean, you know, very good. The issue with that one is that both the CDC and the New York State Department of Health really recommend daily dosing. One, that was just one study. The other thing is that on average, the individuals in that study were having one sex act a week, or 16 pills a month, what it averaged was they were taking four pills a week. So, it was almost like they were doing daily dosing, and we know from the IPREX data, the rollover data, that if patients take it at least four pills a week, that the efficacy is very good. So again, I have a little bit of caution with the IPERGAY. But I do think that if I had an individual where they had very isolated exposures, they were concerned about daily dosing, I do have some data to inform me, in terms of the schedule that I would advise the patient. I would also be cautious with using that protocol in women. We know Tenofovir has better penetration into rectal tissue, and that vaginal tissue, less penetration. The pharmacokinetics are a little different. So, I would have caution with the intermittent event driven for women. For men, again, I would prefer recommend daily dosing until there's more data to kind of support it. But again, if those patients have very isolated exposures, they say I don't want to do daily dosing, at least I have this IPERGAY study to inform me. Thank you very much, enjoy the rest of the conference. [audience applauding] 15