This presentation from pediatric infectious disease specialist Alexander Newman, MD, MSc, will get primary care providers up to date on oral and injectable pre-exposure prophylaxis for HIV, with reference tables to use in daily practice. Newman clarifies which meds have been shown effective for various populations and discusses how to ensure sensitive care for adolescents. He has answers to patients’ questions on safety, side effects and what happens if a dose is missed, and he lays out the testing protocols that must precede writing a prescription. Bonus: Learn about “on-demand” PrEP as well as DoxyPEP for preventing other STIs.
So this will be an introduction to PrEP or pre-exposure prophylaxis. Um, this is a, I, I realize it's actually a very dense presentation, so I might highlight some things on the slides, but kind of move through them, um, without diving into too much depth, um, uh, if it's just a little too much information, basically, but, uh, these slides will be available to you all, um, and I'm happy to take any questions, uh, at the end as well. All right, so, um, what we'll do is we'll go over what PrEP is, the different types of prep, um, and who to provide it for, an overview of prep practice, so how to prescribe it, how to monitor it, and what to do it in special situations, and then if time allows, um, which hopefully it will unless I ramble, and I apologize if I do, we'll also talk about a new therapy called Doxyep, um, which is actually kind of spearheaded here in San Francisco, um, at UCSF. So our first uh foray into PrEP. So what is it? So PrEP stands for pre-exposure prophylaxis. It is a prescribed medication for people without HIV to help prevent HIV and it's supposed to be given before the exposure occurs, and that's what makes it different than PEP or post-exposure prophylaxis, wherein we give medicine after an incident has occurred to prevent HIV. So this is always before it has occurred and to prevent against HIV. When taken as prescribed, the big take-home message here is that it's 99% effective as long as you're adhering to it, um, especially through HIV, uh, through sexual contact. The numbers aren't as strong for those who use IV drugs, um, however, they're still pretty remarkable. Throughout this talk, we'll talk about the three big uh prep medications, um, the first and oldest being oral intracetabine, Dadafovir, disaproxylfurate, also, also known as FTCTDF. For simplicity, I'm gonna call it Truvada, which is the um brand name given by Gilead who first made the medication, um, but know that it's also generic, but for simplicity's sake we'll call it Truvada from here on out. The next medication, um, often marketed as Nuprep is oral entrecetabine, uh, tenofovir alefenamide or FTCTF. That is not generic, also produced by Gilead and goes by the trade name Descobi. Again, given the similarities between the first two medications and their naming, uh, we'll call this one Descobi and the other one Truvada. And then finally, um, this one I might go back and forth with, I apologize, um, but we have one injectable medication now, and that's injectable cabotegravir. Um, uh, abbreviated is CB, also known as Apertude from Viv. Um, I actually stick to the generic name of this cabotegravir since it's pretty, um, uh, unique. So the first thing to know about PrEP is where it works and how it works. So, I'm very busy slide, I apologize, but again, just to remind you of the HIV life cycle and where these medications at. So the first thing that happens is binding or attachment followed by fusion of the HIV molecule with the cell membrane, reverse transcription of the uh viral RNA to DNA with its own packaged RNA transcriptase. Reverse RNA transcriptase, um, then integration into the host DNA genome where it then hijacks the cell machinery to produce its own copies using replication, assembly from the cell wall of the host cell, and then budding off and where our medications really take effect are those two red boxes there that's reverse transcription. And those two medications um are tenofovir and mtracytabine in those combination pills of Truvada and Descovy. Both of them are nucleoside reverse transcriptase inhibitor. They get incorporated into the um uh DNA molecule that's being made. And then terminate transcription and translation at that or transcription at that point, so it blocks further production of that DNA molecule preventing anything from being integrated. Um, cabotegravir is unique, it's what's known as an integrated strand transfer inhibitor, so it's an insti is how we often call it, um, and it prevents integration of that DNA, uh, that viral DNA genome into the host DNA so it can't hijack that machinery for reproduction or replication or reproduction. So there are two different sites, um, and where they act within the host or within the HIV life cycle. Um, here are all the big formative studies on, um, on PrEP and uh the different populations in which they were studied in. Um, MSM or men who have sex with men and trans women were grouped together. Um, we've had cisgender and heterosexual heterosexual men and women couples, um, and then just cis women alone. Um, kind of going through all of them, they kind of go by year by year in terms of, uh, you can see increasing efficacy because the studies got a little bit more well refined and, and adherence got a bit better, but the landmark one is called Iprex. It looked at Truvada versus placebo, initially only finding a 44% reduction in HIV infections, however, when they looked at the data, Uh, on those who had detectable drug levels that, uh, massively increased to greater than 90%. So really proved that, uh, while the intention to treat was only 44% efficacy when you actually looked at who took it was really efficacious. The proud study was next, it was open label, meaning they knew who was taking it. Um, it had a relative risk reduction of 86% in HIV acquisition. Ebrigay, um, looked at what we call on-demand dosing, which we'll touch on briefly, though it's not FDA approved, um, also found a really great reduction in HIV acquisition of 86%. And then the two newest ones, Discover trial, which looked at Descobi versus Truvada, um, Truvada then being the gold standard at that point, just to make sure that Descobi would still work for PrEP because it was a new formulation. It's a non-inferior study, meaning that it was just as efficacious in preventing HIV, uh, as opposed to the gold standard of Truvada, and then, uh, the HPTN 083 doesn't have a fun name, um, but it was Cabotegravir versus Truvada, also found to be non-inferior for MSM and trans women. Um, the studies aren't as, um, robust I would say for our uh sero discordant couples or cisgender men and women. Um, here sero discordant. Uh, means that one is HIV positive and one is HIV negative. Uh, Partners Prep was the first one though. It did look at, um, three different medications, tenofovir alone, Truvada, and placebo in these Sierra discordant couples. They actually had to stop early because in the interim analysis they found that it was highly efficacious and actually both the interventions. Arms 75% and 67% reduction versus placebo, um, which is great and then uh TDF2 again looked at tenofovir versus placebo also open label at that time found a 62% reduction, so not as strong, um, but we'll get into what it looked like with drug levels and adherence monitoring. And then finally for cis women not in a relationship um or any sort of sero discordant coupling, um, there were, uh, many that occurred around the time of IPRAX, so kind of happening, happening in tandem, um, that was FemPrep which again looked at Truvada versus placebo. It actually found very low adherence in these studies and so it ended early because of low efficacy. Um, the next study was voice actually very similar findings. They looked at actually several interventions Truvada, uh, tafovir alone, vaginal gel, and placebo. Again, adherence was so low during these studies that they found no efficacy. Um, the most recent one though, uh, was the life study which looked at cabotegovir versus Truvada. Again, at this point since Truvada showed so much efficacy in the, um, Partners Prep study, it was kind of rationalized that it would still work so long as adherence was strong, so it's now become the gold standard. Um, but cabotegravir, the new injectable prep, um, was analyzed against Truvada. Um, it was initially designed as a non-inferiority study and then actually found to be superior in preventing HIV as opposed to Truvada. So they're both great, um, but cabotegravir seems to be actually even better for our cisgender women. Again, looking at it outside of the intention to treat analysis and seeing who had detectable levels, who did pill counts, who was refilling the medication, had good adherence, you do see what should be expected, which is if you take the medication, you have a much um decreased risk of of HIV incidents. So, um, 75 to 90%, 63 to 78% prevention, and then 44% all the way up to 92%. That's that IPREX study which, which was pretty formative in this research. So ultimately, who is PrEP recommended for? Right now we recommend it for anyone, um, adolescent or young adult who is sexually active and at risk for contracting HIV just broad general statement. The other place I would really recommend considering it is if you have an adolescent or young adult in your practice who brings it up on their own and wants to start taking PrEP regardless of whether or not they identify any um HIV risk practices. So if they say they're not having sex, but I want to be on PrEP, they dig into it a little bit. But what we found too is that sometimes again our teens and young adults don't feel comfortable disclosing their um sexual practices or drug use with us. And so if they're asking about it, I would highly recommend um providing PrEP for them. Um, within the CDC they have a beautiful document on, on PrEP itself, and within that document is a supplement to help assess risk for MSM, uh, men who have sex with men and IV drug users specifically, so it's pretty generic. I pulled it up, um, just to kind of give you a rundown of what it looks like, um. Uh, but here we see that it's got it separated by age, practices, how many sexual partners. Ironically, they say that less than 18, there's no age risk there, though I would say, um, it's still a higher risk group. It's certainly higher risk than I would say are 41 to 48 year olds in terms of HIV incidence, but know that that young adult age of 18 to 28, probably 18 to 22, 23 for, for most of our outpatient providers is the highest risk category where we see the highest incidence of HIV. Um, similarly, if you have, um, a lot of male partners, the more partners that you have, regardless of condom use, um, increases your risk for contracting HIV. And then the two ones to draw your eye to is the type of sexual practices that are MSM or men who have sex with men are having. So if they are the receptive anal partner, so we call that a bottom, um, and they're not using a condom that is the highest risk for contracting HIV. Um, you can still get it if you are the insertive anal partner, the top, um, though if that's kind of moving your eyes to the bottom here, it's, it's more than 1 time for the bottom, it's, uh, 5 or more for the top where it increases the risk. There's a couple of studies that have looked at that. Either way, if they're not using condoms while having sex, I would say that's a big, um, trigger in my mind to consider prep. And then the other thing to dry your eyes to is how many partners are they having that are HIV positive, and I would have done this to say HIV unknown. So if they don't know their HIV status, I would just consider them positive and at that point increase their risk stratification. And finally, it doesn't occur too much in our teens and even some of our young adults, um, but certainly in the Bay Area we've seen a lot of use of methamphetamines, um, and know that, um, what we call what the, uh, community calls chem sex or methamphetamine use greatly increases the risk for HIV contraction as there's kind of riskier health or riskier sex taking practices during those periods. So ultimately this is supposed to be used if you have a score greater than 10, which ultimately if you've had one, if your, if your patient has had one. Um, a receptive anal sex partner, um, one time without a condom that already gets in the score of 10, and that should really trigger you to talk about prep. Simplifying it, ultimately, this is what the questions that I would generally ask, um, have they had sex in the last 6 months and um has it been with anyone with an unknown HIV status with inconsistent condom use, or do they have an HIV positive partner with either an unknown or detectable viral load? The important caveat to this, and that I really want to impress around all of our team. Um, and young adults, even those with HIV, is that if they get to undetectable, they cannot transmit the virus through sex, and so we call that undetectable equals untransmissible or U equals you. So really, so HIV positive partner is well controlled. Taking their medication, wildly adherent and undetectable, that's actually safe for them to to not use a condom if it's a monogamous uh monogamous relationship. However, again, it's just about talking it out and seeing if they want a backup method like prep in that situation. And then finally, if they're having sex and they've had um a new gonorrhea, chlamydia, or syphilis infection in the last 6 months, regardless of whether or not they say they're adherent with their condom usage, that should kind of clue you in to talk about PrEP. Any one STI infection last 6 months really greatly increases the risk of HIV contraction the following year. Um, and then a separate risk category again is that they're using injection drugs, um, that should also kind of make you talk about prep use. In terms of how we're doing with PrEP prescribing, so PrEP, uh, hit the scene at least for 18 and up way back in about 2013, 2014. Um, this graph looks at how we're doing in terms of targeting our prescriptions for those that qualify for PrEP. At this point in time, we think about 12 1.2 million people in the US, um, would, uh, meet high risk, uh, categories for needing PrEP. And while we're steadily increasing our prep prescription, it's kind of at a slower rate over the last 4 years or so, we've seen about at least a 10% increase in these prescriptions, but I think only those numbers might only get bigger um as the years go by, uh, and we could do a lot more to at least getting above 50, above 60, heck, above 80 would be wonderful. And with all things, um, there are some disparities in who PrEP is already provided to, so try to be cognizant of this when you're meeting your young, uh, your, um, youth, uh, your young adults and your teenagers. Um, what we've seen is that, uh, there is a gender disparity or cisgender men are offered it more than cisgender women, trans women, or trans men. Um, certainly white people are actually prescribed it far more often than non-white, uh, people who would, uh, qualify for PrEP at kind of alarmingly high rates. Um, the, the last estimate was that 78% of white people who would, uh, qualify for PrEP have been given that prescription versus only 11% of, um, black or African-American, um, folk or Hispanic or Latino folk. Um. And you know, whether that's just due to prescriber knowledge, patient knowledge, just healthcare, um, ability to, to access healthcare, it's, it's a very complicated interaction, but just know when you're meeting your teens and young adults to, to have this in mind. And then finally again, our, our young adults, our youth and young adults. At the lowest prescription rate of under 20% at this point, um, and while, uh, at least under 18 is estimated to be one of the lower incidence population, 18 to 22 is a very high risk population, and you should really be targeting those folks as well when talking about PrEP. All right, um, so we're gonna move on to prescribing prep. I'm gonna try and give you a lowdown of all the differences so that if you would like to have these conversations with your, uh, teens and young adults in your clinic, that you can be well informed and offer them all the same information to make a great Uh, uh, selection of which prep to choose if there are options for them. So first and foremost, this is kind of a table summary of differences of the three that are available. Know that um the uh men who have sex with men and trans women have the most options and that they can select from any of these three. cisgender women um can choose from Truvada and aptitude, um, and then cisgender men really have only been studied Truvada has only been studied in that population, so technically that's the only, um, FDA approval group, or sorry, cisgender men who have sex with women. Um, Truvada is kind of the only technical option for them. However, We can probably bend the rules a little bit, um. Um, in terms of the differences, so again, Truvada and Descovy are oral options. Um, the dosing regimen right now is approved by the FDA is a daily dose, and we recommend, uh, supplying a 90 day supply at each, uh, visit that you see them for. In terms of, uh, for Truvada, it since it was the first to market, it's actually the first that's now become, uh, generic and so cost-wise it's probably the most affordable with or without insurance or without supplemental insurance. Um, the other nice thing is it is the first to market. We have a lot more studies on a lot more safety data profiles, a lot more people that have been on it as opposed to the newer ones. So, um, if, if folks are kind of worried about, um, you know, taking the newest thing because they don't want to be quote unquote experimented on or anything like that, not that they would be. Um, that you can offer them some reassurance that this has now been over a decade in use. Um, in terms of providing exclusions, again, it's for everyone, um, however, it only goes down to 35 kg in terms of dosing. And then, um, we'll talk about the side effects later, but we do see an increase in creatinine for those on Truvada. So if they already have, um, a creatinine clearance of less than 60, they should not be provided provided Truvada as long as it's greater than 60, they can still take it safely. Um, for Descovy, again, oral, you know, take it daily, um, it is only brand named, um, made by Gilead. Gilead does offer a copay card, um, that they can apply for online or over the phone. Unfortunately, those on, um, government supplemented insurance, so things like Medi-Cal cannot qualify for Gilead, though Medi-Cal can pay for, um, a lot of the medication. It's not all of it though, and unfortunately I don't know the cost offhand. Um, the nice thing about it compared to Truvada, I will say is it is a much smaller pill, about 1/3 of the size, so if they are pill phobic, um, this one's much easier to swallow. Um, and again exclusions for, um, prescribing that 35 kg is the big one there. Um, it's really not approved for cis women in the sense that it hasn't been studied in cis women or trans men, um, and it's not for IV drug users that's not a group that it's been studied in. Um, similarly, it has a slight bump in creatinine clearance, uh, slight, sorry, sorry, slight decrease in creatinine clearance, slight increase in blood creatinine, um, but, uh, it's got a much lower value, so as long as it's greater than 30, you can still provide it for them. Um, for both of them, if they've missed, uh, for both Descovy and Truvada, if you've missed a dose, again, it's a 24 hour, uh, it's an every 24 hour pill. Um, so they have within the 12 hours of that missed dose to still take that dose and still resume their daily scheduling. So they're supposed to take it at 9 p.m. before 9 a.m. they realize they missed yesterday's dose, they can take it again and still resume their daily schedule. If it's after 9:00 a.m. in this example, they just skip it and go back to the next day's dose, and that's OK. Um, that'll differ greatly for Aperitude, which is why I bring it up. So Apertude or Cabutegravir, it's our first injectable. The nice thing about it is that it's given monthly to then bi-monthly after you get through the loading dose phase. Um, it is not available in generic. It's made by Viv. They also offer a copay card, also limited by government insurance though, um, but still should be moderately covered though that also, uh, they also needs to have a, um, in-office visit for the injection itself. So there are some charges with the actual administration. The nice thing about it is that it's discreet. There is no daily pill. They don't have to have a pill bottle at home, um, they just have to show up to their appointments. The big problem with this with Apertude is that it is long-lasting, so if they miss a dose, there's a very tight window of about 7 days, 7 to 10 days or so that they, they should be getting their doses on time. They miss that, they need to place an oral prep until their next dosing appointment, and then they have to restart the whole loading dose, um, uh, situation over with the every 28 days and then moving to every 8 weeks. Um, exclusions for that though, it has the most limited amount of side effects, which is really nice about our integrase inhibitors, I will say. Um, so the only prescribing exclusion is that, um, is that weight-based one, and I will say there is a weight limit in the sense that once you get above, I believe, uh, I can't remember the BMI is, I think it's above 150 kg though, um, they have an increased dosing regimen suggestion. Alright, side effect profile, always important to talk about these with your patients before prescribing prep. Um, uh, the two oral pills do have what we call an initiation or startup effect. Um, that just means within the first month, as I always say, as their body is kind of getting used to it, they might experience some changes to their body, but that should decrease with time. Truvada has headache, nausea, and upset stomach in about 10% of individuals, um, but again that, uh, goes away after the 1st 4 weeks or so of, of therapy. Um, the big one for Truvada is a reversible decrease in creatinine clearance, so increase in serum creatinine, so it's completely reversible. However, they already have underlying kidney issues and have a creatinine clearance less than 60. Truvada is not the medication for them. Um, we've also found that it has a reversible decrease in bone mineral density, not to the point where we see pathologic fractures or breaks, um, and DEXA scans can, we're the ones that kind of detect, but we don't recommend DEXA scans or or screening X-rays or anything like that. It's just. If you have a patient who already has low vitamin D, I'd put them on a supplement, or if they have a history of say rickets or something like, or some osteogenesis issue, then again, Truvada might not be for them, but it is completely reversible, which is important to tell folks. Um, uh, there are no metabolic effects that we know of for Truvada though. Descovy, again, it's kind of cousin in a sense, um, it's sort of effect is diarrhea, not so much the other effects though, which is nice. It had less of an impact on creatinine clearance, still has a mild one, still completely reversible. Again, we have a little bit more wiggle room where as long as their creatinine clearance is above 30, you can provide true uh Descovy. There are no musculoskeletal effects that we know of. Um, I will say it's often marketed as new or safer prep for that reason. I don't necessarily love that marketing, I'll say because both are quite, quite, quite safe and both are reversible once the medications are stopped. Um, Descovy has the added side effect of weight gain, about 2.2 kg on average, or about 5 pounds, not that significant, but important to tell folks about. Um, and then we have seen increased triglycerides, again, never to the point of needing to stop the medication. Um, one thing I will say is that the, as you can kind of infer with weight gain and increased triglycerides, we don't actually know if there's any cardiovascular effect long term as these, this is a newer medication, still being sussed out, but nothing, um, overt has come up from the initial data series. And then Apertude or cabatagravir, um, again, love my integrase inhibitors, they're wonderful because they have so many minimal side effects, as you can see here, the only side effect is that you can get injection site reactions. Everything else is very minimal or less than 1% of the time. So just warn them that um it's gonna hurt and also to say it out loud cause I've had a lot of um of my patients ask about injectable medication for their HIV. It is given in the glute, it's in the buttocks, um, and that's always in the buttocks. That's all we have for them right now. Sometimes in the thigh, I will say those are special circumstances, but um it's important to talk about that, make them prepared for that. All right, so you've kind of uh gone over now all the different forms of prep, you've discussed it with your patient, they've chosen it, you're ready to do the first visit and kind of um initiate prep therapy with them. It's a busy slide, I apologize. Um, but the first and most important thing to do, again, these are individuals who are at risk for acquiring HIV. So before providing them PrEP, which is either 2 medications or only 1 medication effective against HIV, um, as a reminder, I should have said this before, when we treat HIV it's 3 medications, so this is inefficient to treat HIV if they have it. It is really important to make sure they don't have HIV before starting PrEP. It's the really most important thing about the first visit. Um, and so you need to assess them for acute retroviral syndrome. Again, that indicates active HIV infection, active replication, high amount of viremia, or high amount of virus in their bloodstream. They'll generally present with flu-like symptoms, that wonderful generic catch-all that's just fever, achy body, um, headache, and then you'll also hopefully find, um, diffuse adenopathy, not just under the neck, under the armpits, and inguinal lymph nodes especially, um, the first. Uh, site that most HIV infections take place is in the GI tract again often because it's acquired through anal sex. So, um, during that visit, just make sure to do a very extensive lymph node exam, um, not, not just the neck, under armpits and the inguinal area as well. If they have those symptoms, send two HIV tests. The reason we do that is because we need two positives to confirm an HIV test, so you may as well just send both right off the bat. That's the HIV antigen antibody test, often called 4th gen or 5th gen HIV testing, um, as well as an RNA PCR or a viral load. Um, the reason you don't want to just send at least the HIV antigen antibody is that during the acute thyremic phase, those tests can sometimes be falsely negative because of a very short what we call window period where they'll be negative, but the RNA will be positive. Again, send both tests, we need 2 positives to confirm a diagnosis. Um, if you move past that, they don't have any of these symptoms, they're feeling great, um, they don't have HIV or at least they don't have acute retroviral syndrome. Um, these are the tests that we recommend sending at the initial visit. Um, so for everyone, again, they still need an HIV test. If they're on oral therapy, we recommend again just the 4th or 5th gen HIV antigen antibody testing that will often reflex to um a viral load if it's positive, um, but it's, it's still safe to use just the, the one with the kind of window period there. Um, because injectable therapy, you give it and then it's on board and in them for at least a month, um, this is the one where we really don't want to miss acute infections, so we do recommend sending an HIV one RNA, um, for those on injectables. So it's a little bit of difference between the orals and the injectables in terms of what kind of HIV test you're sending. Everyone should get an STI screening. Again, we're uh putting them on these medications because they're often at risk for acquiring a sexually transmitted infection. Um, and so you should make sure to send gonorrhea and chlamydia testing from every orifice. So that does mean talking about where they're having sex, oral sex, anal sex, and sort of. sex and then making sure you swab or send urine testing from all those sites. And then we also recommend an RPR. Um, there's a high coincidence rate of HIV acquisition with syphilis or at least, uh, syphilis is really coming back, guys, honestly in California. So it's really important to, to really do these RPR testings. Um, if they're taking oral prep, depending on the kind, uh, so for both of them we want to assess creatinine clearance, so send a BMP or you can just anonymously an isolated creatinine. We do want to send hepatitis B and C testing, honestly for everyone, cause that can be transmitted through sex, but importantly for um the oral preps because the medications in oral prep are actually effective against hepatitis B and to a lesser extent hepatitis C, and if you stop those medications, they can get a flare of either disease. And so knowing what their status is before starting it, um, is important, or at least sending the test before starting it is important, and you can just send those with the typical serologic testings for hepatitis B and C. Um, and then we also recommend a lipid profile for those who are taking, uh, Descovy only, so that's that FTCTAF, cause again it can cause hyperlipidemia. If, again, you've sent all these tests, um, and you've assessed them and they don't have acute retroviral syndrome, we do recommend sending them with a script, so long as you're going to get an HIV test result back within 48 hours or so. Where we find the biggest break is that, you know, we see the patient, we do the testing, we wait a bit, and then we call them and say, hey, we put the script through. Sometimes that script doesn't get picked up. And so having them have it in hand or just walking over to a nearby pharmacy to have it right after the visit, and then just saying, hey, I'm gonna call you with the results, you can start it um for oral prep, that's great. Right, so I'm gonna show kind of two back to back slides of what the follow-up will look like. Um, so for oral prep, um, I would say the CDC doesn't always recommend this. I like it for my teens and young adults, uh, cause pill adherence is, you know, can sometimes be questionable for our teens and young adults. So, um, one month after initiation, I like to just do a little video visit, um, and just check in with them and see how they're doing with the medication. The other thing I like to ask about is what side effects they're experiencing. Sometimes those will be the initiation effects that we talked about and so you should reassure them that those should go away as they continue to take the medication. Other times they might be experiencing something different, whether they've got a concomitant virus or something else has happened to them where they're experiencing some symptoms that might not at all be associated with oral prep. It's important to kind of suss that out and um reassure them that it might not be the oral prep, so they don't self-discontinue without telling you that. Um, and we'll kind of highlight through all this, but discussing risk reduction at every visit is really helpful, and that just means kind of adhering safer sex practices, um, you know, discussing with your partner what the HIV status is, um, all of those things. Um, every 3 months after you initiate prep oral prep, um, they should be coming back in for repeat HIV testing, as, as mentioned before, we'd like you to prescribe a 90 day supply, so they should be coming back in for a refill as well. Um, for, uh, you know, folks again assess how they're doing with condom adherence. If they mentioned that they haven't used condoms 100% of the time or even on oral prep, um, you should go ahead and repeat STI testing again through every orifice that they've had sex with. And then refill the script. Um, yeah, for every 6 months after you initiated it, um, this is where it's recommended for everyone that they repeat STI testing. It's not just optional. Um, I would just discuss with them how they're doing with the prep, do they want to continue on it? Uh, and then in this case, if they've had a creatinine clearance for that that's less calculated to less than 90 for both Descovy and Truvada, we recommend just repeating it at that time just to make sure it's still above 60 or above 30, um, and then it hasn't been impacted too greatly. Um, and then yearly, again, if they've had a normal creatinine clearance, you just repeat it yearly, um, just to again check in on it. And then for Tyscovy patients repeat triglycerides, just make sure they're not rising, um, too much, um, and they're not getting into the, uh, danger zone of being too high, um, and then again through all this discuss risk reduction. This is the same thing we kind of just talked about just in graphical format in case you like uh just kind of spot on a table of what test to send and where. Um, in this chart just to orient you MSM again stands for men who have sex with men, and TGW is transgender women. Um, and then PWID, uh, people who inject drugs. Um, very simple slide, uh, didn't know how to build it out, but I think this is a really powerful slide personally, um, in looking back at all these studies, there was a really great review that, uh, looked at how they assess drug levels as well as their incident rate of HIV and kind of just separated patients and pooled them all together from all these different studies to try to come up with a, um, baseline of how many, uh, pills you'd have to take a week to. impact HIV incidence and they really did find a nice little stepwise cutoff based on how many pills could be were either reportedly taken or could be sussed out based on drug levels. Again, baseline incidence rate would be 4.2 per 100 persons years, drops to half. They take less than or equal to two pills per week. Um, if they take 2 to 3, which kind of confuses me because they have less than or equal to 2, and then they have 2 to 3, so I guess it's around 2.5, um, it drops down significantly to 0.6, and then as long as you're taking 4 or more, uh, we're really happy about that, and they should have an instance risk of 0. And so I would say too, you know, it's always important to assess adherence with your patients, so long as they're taking 4 or more pills a week. Try not to, I really again try to lean in and say, hey, let's see what we can do to, to get that adherence up to 100%. However, it's not that they have to, um, you know, be too worried if they're taking, they've missed a pill here or there once a week or so. Um, they're still achieving adequate drug levels to provide protection against HIV. Like can we shoot for 100% for a little bit under that, I would still applaud them. I think that's still wonderful. Um, I'm gonna briefly touch on PrEP on demand. It is not FDA approved, um, and, uh, bluntly, I don't think it's great for teens, uh, cause it's not, uh, I mean, adherence is already hard, and then. Uh, doing an on-demand medication, I think will be even harder, um, but even so, just to make you aware in case you get asked about it by your, um, teens and young adults. So, um, first things first, it's the design for those who are having infrequent sex, so only every once in a while, um, where taking a daily medication might be overly burdensome and um not really impact on them because, you know, they're only having sex once or twice a year. Um, know that this study population that it was studied in was only adults, so greater than 18 years old, men who have sex with men. Um, so that is really only a population that truly could see any benefit from it, at least as far as we know from our studies. Um, it's not FDA approved, um, it was only studied for Truvada, so Descoy cannot be used for this and certainly not aptitude. Um, and the other big thing too is it's not for those with hepatitis B, as mentioned before, the components of Truvada can, um, uh, treat hepatitis B, and if you're taking it intermittently, you're gonna get flares of hepatitis B, which can lead to liver damage. Um, what it is though is that, um, you've got the Truvada pill between as long as it's 2 to 24 hours before they're having sex, they have to plan to have sex. I think it's already hard for teens. Um, they have to take 2 pills of Truvada, then, uh, 24 hours after those two pills, and as long as sex occurred in between there, they take another pill, just one, and then 48 hours after those two pills were taken, they take another pill, and then they can stop so long as they don't have another, and they don't have sex again, um, anytime soon. I think again this is hard just because again they have to remember these things. It's intermittent dosing, it's on demand, um, and they have to plan to have sex, which I don't know how often our our youth and teens are really doing. Um, the other thing to note too, and this is why it's not quite yet FDA approved, is when they looked at the data for how often those in the study were taking their on-demand prep, it really averaged out to 3 to 4 doses per week, which as I showed from the other slide is, is equivalent to taking it nearly every single day. Um, so is it really that different in this group that was studied because they clearly had a, a high amount of sex? It's, it's difficult to say. It's approved in other countries though, in Europe and in Australia especially, so, um, if other folks are hearing about it, um, I would just have a discussion with them and see if it's really right for them. Alright, moving on to injectable therapy. Um, so this looks a little bit different and it's often just because of how often the injections are given. Um, so one month after initiation, they do have to show up because they have to get their second loading dose to maintain adequate drug levels. Um, I would assess side effects at that point, um, and then repeat HIV testing as well, that's at HIV1 HIV RNA viral load. Um, and discuss risk reduction, and then every 2 months thereafter they're gonna be coming in for their for their Cabotec Revir dose and so at that point that's when you should be sending HIV testing. It's a little bit more frequent. Um, than those on oral prep, and that's only because that's when they're coming into your appointments, um, so that's when you should give it, uh, every 4 months, um, after the first or every 4 months after the initiation of Cabotegravir is when you should do an HR STI testing. So again, that's a little bit more than the 3 months that was optional, a little less than the 6 months that was, uh, recommended. Again, it's just because of the frequency of visits, and then yearly. Um, talk about whether or not they want to continue, uh, prep. Um, discontinuing this looks a little bit different than the other one. We'll talk about that because of how long the drug stays in the system, um, but it's really important to have these conversations frequently and make sure it's right for them. Again, this is a testing schedule if you like uh diagrams and tables better. All right, so the importance of risk reduction as I highlighted in every one of those little boxes. So, um, you might be thinking to yourself, you know, if I prescribe PrEP, um, and they're not using condoms, will they use it less because they now know that their, you know, their risk of HIV acquisition is, is minimal. And the answer is muddy at best, um. Early studies, um, when PrEP was kind of new on the scene is that they actually found an increased adherence rate for condoms and a decreased STI incidence. Um, part of that might be the McMalion effect. You're being observed, you're in study, um, you know that you're at risk for HIV because you keep getting counseling about it, so that's what led to that increase. As PrEP has become more at least widespread and as communities become more aware of how protective and efficacious it is, condom use has seemed to decrease. And STI incidence has risen with that, particularly among men, men who have sex with men. Um, so we find out later studies that that that effect kind of increases that they still might be at risk for gonorrhea, chlamydia, and syphilis. By no means am I suggesting that you should not provide them PrEP because of this risk. There's always a confounding effect to that now you're testing them maybe up to every 3 months for gonorrhea, chlamydia, and syphilis. So are we just picking up more cases because we're testing more? It's really hard to say. Um, but just know and just kind of um go over with them the importance of condoms still while using PrEP. It really should be talked about as a backup method for preventing HIV, not the primary method, um, though again, it is 99% effective. All right, so special situations. Um, really busy slide again, I apologize. This is just to reiterate though, um, that for positive testing we need at least 2 tests to confirm an HIV diagnosis. And so, um, while they're on oral prep or cabotrevir, um, if you get a positive test, so if it's an antigen antibody test for those on oral prep, um, we recommend sending off an HIV1 RNA assay with that or it should reflux to it. Um, if they're discordant and only one of them is positive. Uh, we recommend sending an HIV1 RNA assay again. Again, we want, we want two, positives here, and so this will be the tiebreaker. And so, um, if that second HIV1 RNA is positive at that point, they do have confirmed HIV. If it's negative, then they do not have HIV. So regardless of which one is positive in the first incidence, you got to use the tiebreaker, and if you got two positives, you're, you've got, you've got confirmed HIV. If you've got two negatives, you don't. Um, if both are positive right off the bat, that's confirmed HIV. Both are negative, then you're HIV negative. Um, so, um, certainly give us a call if there's discord results. Um, we actually field a lot of these calls and are happy to talk to you about them, um, but this is just kind of a general algorithm that we follow. And what to do. This is where it gets a little sticky because breakthroughs are actually exceedingly rare when uh patients are, are adherent. Um, and so for those on oral prep, um, if they've got a preliminary positive result and you're waiting for other ones, and your question is, what do I do? Do I stop the prep? Do I continue the prep? What do I do? All I will say, all of these recommendations are based on quote unquote expert opinion. So, someone in the field said this, and that's what we're doing now. Um. For those that, you know, kind of talk about intermittent dosing, whether they're doing 211, or they say, uh, you know, I missed like a handful of pills a week, so I'm only taking it 3 out of every 7 days or so. It's a complicated answer actually. Um, you can either hold it or continue it while awaiting results. There's no good answer here. Um, and it gets into some complicated, uh, um, testing that we often do, um, when we suspect resistance, which I can kind of hold towards the end, but know that that's not an easy answer, please call us about that. We'd be happy to talk about it with you and kind of assess it on a case by case basis. If you got no missed dosing though, the recommendation is still to continue PrEP and then to consider adding on a third medication, effectively at least giving them active HIV therapy at that point. Um, we'll talk about resistance while on PrEP when acquiring HIV. It's very rare, and so the reason and rationale for that is to give them effective HIV therapy if they're now HIV positive, um, because it's likely not resistant, but they need to be on treatment. But regardless, if they have a positive test while on PrEP and you want to talk about it, we'd be happy to field those calls. Um, simple answer for injectable prep is to please stop giving it, um, and to hold on giving them all medications until the results are known. Um, so at least that one has a simple answer, which is just, just stop. So kind of jumping right now to resistance while on PrEP, so these are kind of looking at every study that at least um reported that data as well as had data on the resistance profile. So again that formative study, the IPREX study, uh, well, first and foremost know that resistance is rare, uh, on those with with breakthrough HIV infections except for cabo tigervir which we'll get through. Um, for IPREX, um, they found that 2 out of the 48 of those that had breakthrough HIV infections that were while they were on PrEP, so again they looked back, make sure they hadn't missed a positive and somehow enrolled them on study. Um, but 2 out of the 48 had a resistance mutation, um, for, uh, uh, NRTIs, which is the class of medications that, uh, Truvada is. Um, so that's, uh, you know, 1 out of 25 or about 4%, 5%, uh, resistance rate, which is higher than the baseline rate of 1% within the general population, but, um, it's not so striking, um, that we've seen it, it's just slightly increased. Partners Prep had a had a bit more, it was 3 out of 21, but they found more um uh different uh resistance uh mutations than just the M184I mutation. Uh, it's harder to get an estimate than at that point, it's still above uh the general population. The slightly worrisome one, I would say, and we're still looking into why this is and what this means, um, but for cabotrevir, nearly 50%, um, so 4 out of 9 of the breakthrough infections had an integrase strand inhibitor resistance. So that's actually pretty huge. You're, you're talking about 50%, that's wildly bigger than what we see in the general population. I will draw you to the number though, only 9 breakthroughs, 9 out of, um, oh gosh, it's 200 to 300 individuals on cabotrevir. Um, so, uh, even more than that actually. I gotta go back on that, sorry about that. Um, but, uh, an increasingly small number had breakthrough, but those that did breakthrough had a resistance. Um, so that's where it's a little bit concerning. Uh, we're still looking into it. We still recommend, um, injectable prep for those that qualify, but the rate was higher than those that broke through while on, uh, the, the gold standard of Truvada. Take home Anders just so you know it's about 1:15. 0, thank you. To give you a time time stamp. Thank you. I appreciate it. I think I only have a few more slides, so, oh good, I'm doing pretty good on timing. Um, thank you for that though. All right, um, so stopping prep. Um, so it looks a little bit different for oral versus injectable, um, and the first thing I'm gonna draw you to is kind of this graph over here on this PrEP and HIV resistance, so when they're at the highest risk of resistance. So, um, this green zone is that they're doing great with their drug with their medication, they're taking it every day, um, they're at no risk for infection, at no risk for resistance. White here is that they're not taking any drug, they're at high risk for HIV but no risk for resistance. This kind of uh red zone is where they're either intermittently taking it or slowly pulling off of it, so they have detectable drug levels, not enough to prevent HIV acquisition, but enough to influence and select out. Um, HIV resistance mutations. So this is kind of the danger zone we're starting to talk about it or they're having decreased adherence. Um, for oral prep though, uh, that drug effect only lasts for about 7 to 10 days. So if they stop it, um, whether abruptly or after guidance and talking with you, know that that's a risky period for them to contract HIV and a higher risk period, um, for them to get resistant HIV because of the lowering drug levels. So it's really important to express them that they need to either be. Or use a condom every single time they're gonna have sex, uh, during that time period. I would say you should still talk about condom adherence from then on out with them, um, if they still haven't changed their risk profile, um, and you should continue to discuss HIV risk at follow-up appointments. Um, I would also say too if they're hep B positive and you did start them on, uh, daily Truvada, um, and daily or daily Descoy, it's important to monitor them for flares. So, um, monitor the liver enzymes for a few months after that. Injectable prep is, again, it's newer, so we don't have the best data on it quite yet as to how long this tail effect lasts. The estimates are months to years, right now, at least 6 months is the bare minimum of the tail effect. So it really lingers in the system for a while, and as again that uh drug load decreases the risk for acquisition of resistant HIV increases. And so if they want to stop injectable prep, and this might be a conversation to have with them at the first meeting, is that once they stop, they still have to take, An oral prep medication to prevent the acquisition of resistant HIV, um. And so, uh, you should start that within 2 months of the last cab dose, that's when they decide to stop, um, and, uh, I would say provide it for again up to 6 months or so and continue to discuss and reinforce barrier methods and abstinence perhaps during that time, um, and then I would say continue to meet with them at minimum every 3 months to, to test for HIV. So stopping cabo tiger beer is no small feat, I will say, um, but it is possible and it is something that you can discuss with your patient. Again, all this kind of goes to the wayside too if they're now in a steady monogamous relationship or have changed their risk taking behaviors where they're no longer at risk, um, uh, in terms of providing them prep, but it's a kind of case by case we're again happy to discuss those cases with you. Uh, the important thing to know is why I would still suggest talking about HIV with those that plan to stop. Um, it's just this, uh, lovely, uh, um, study here which found that, um, That HIV risk is still present in those that decide to stop and not take it anymore, um, as you can see, it's actually higher than those that were linked but not prescribed, um, and certainly not higher than those that were persistently on PrEP, so the risk still is present in the general population is an instance risk of 4, so it's still maybe a little bit less, maybe because they're linked to healthcare, but it's still there and kind of, uh, kind of goes up as opposed to those that were linked but never prescribed it, so. Um, still talk about HIV, still talk about it, still test for it, still reinforce, um, uh, risk modifying practices. All right, so in summary, it's one of our most effective PrEP is one of our most effective tools to prevent HIV infection, should be offered to teenagers and young adults, especially those at higher risk for acquiring HIV and certainly for those that just ask about PrEP and want to start it. There are disparities that exist, so it's important to kind of internalize those and make sure you're discussing it among all of your patients that will qualify. Um, it requires close follow-up and careful monitoring, but resistance in the event of breakthrough infection is exceedingly rare. Uh, and patients should continue on it even after stopping PrEP if they have not modified their risk-taking behaviors, and so you should still continue to talk to them about HIV. You can always put them back on PrEP or talk at least about, uh, risk modifying behaviors. And these are some useful prep resources for everyone. Again, I got most of these actually from the practice guidelines of the CDC. Um, please prep me as a national organization, looked at increasing prep. They've got so many great resources including posters, handouts, um, different, uh, walkthroughs for insurance. Um, it's really a great resource, um, and then I edit this at the end. I don't actually think it's on the slides. Um, we in infectious diseases actually do not provide prep. The reason for that is a kind of, uh, Uh breaks confidentiality if you're referring someone for it to an infectious diseases practice without an infection, um, and so all of our referrals should go through the teen clinic in Oakland if you'd like to have them seen within the UCSF system. Um, I believe adolescent medicine to over, uh, sorry, teen clinic in Oakland or the adolescent medicine. Um, clinic over in, uh, San Francisco as well. Again, these resources can be used for you to provide them in clinic if you feel comfortable, and we'd be happy to kind of guide you, um, as questions arise too if you'd like to implement them in the, in your clinic. Other thing I forgot to highlight, that's come up before too, uh, as we were talking about injectable prep, uh, as you can imagine, it's a lot of heavy lifting when they get the medication to, um, get appointments for injections to make sure to make sure your patients show up on time and uh within that window. Um, it is a kind of a high barrier to entry in terms of practices implementing it. It's one that we have not yet overcome in either the teen clinic or even in our infectious disease clinic. So we do not have injectable HIV medications at either site at this time, but locally in the Bay Area, there are several, several, uh, youth facing sites that do offer it, and so we're happy to connect you to that if that is what your patient, um, desires in terms of their HIV prevention practices. Perfect. Type in the Q&A and then I'm gonna briefly highlight a brand new tool in our arsenal to prevent, um, sexually acquired infections. Uh, first, well, I shouldn't say it's been spearheaded, I would say at UCSF. There have been several studies that occurred before that kind of influenced the studies at UCSF, but it's wonderful, and you might be hearing a lot more about it, especially from your young adults who it's approved approved in, um, and so what this is called is doxyep, kind of a busy slides Kaplan Meyer estimate over here on the right side. Um, but what doxyep is, is it's post-exposure prophylaxis, a little bit different. They're looking at doxyrep right now, but for now it's doxyep. What it is is it's doxycycline, 200 mg given once 24 hours to 72 hours um after having unprotected sex, and what we found is that it is really great at decreasing um acquisition of new sexually transmitted infections, and the one it's most effective against is chlamydia. Second most is gonorrhea and then uh syphilis, uh, well the uh infection rate was so small they couldn't make an estimate though theoretically we think it also prevents syphilis as well. So another tool, um, in, in prevention, um, here on the right here is this Kaplan-Meyer curve that looked that was kind of a landmark study, um. They had a prep cohort of people living with HIV cohort and either did standard care, which is again was not doxy uh doxepep or given doxepep, and then the cumulative probability of first STI diagnosis you can see cut down in nearly half, which is really great to see. So, um, fast facts for it is that we only have demonstrated efficacy in men who have sex with men or transgender women. I should say cisgender women were included in both in this study, um, but we did not find as high of an efficacy rate, um, or a significant one, and so they were dropped out. Um, the only population study is 18+, so we can't quite recommend it for our teens. I'm they're looking at that data right now, um, and so hopefully we'll have something to offer for our teens. Again, most effective in preventing chlamydia over gonorrhea, up to, you know, 88% reduction in chlamydia. Gonorrhea is 55%. which isn't, well, it's, it's pretty big I guess when the alternative is nothing, um, and then again syphilis, they didn't actually have that many syphilis infections to actually kind of compare the two rates, um, but, uh, the biologic plausibility states that it probably should be able to prevent, uh, syphilis as well. And so again, what you do is you provide oral doxycycline 200 mg. They take it once within 24 to 72 hours after condomless sex, and that's all they have to do, and that's where it's efficacious. Um, so it's recently CDC endorsed, they've got a task force, um, right now on it to provide, uh, generalized. Recommendations. Actually, I think they dropped uh two weeks ago, so I should update these slides. Um, uh, but, uh, just want to introduce the topic to you guys. Hopefully we'll have more information for you in the coming months to year. I'm hopeful that that timeline is, is tight.
