[00:06:42]

Why PrEP Is Within Your Scope of Practice

So why is PrEP within the scope of your practice? Since many of you have been trained in family medicine, this is something that might be not so much news to you, but perhaps the persons who trained you may be. Most persons who train in internal medicine, or certainly in infectious diseases, have heard this story before about how important PrEP is as a way to try to prevent HIV.

Because how soon is it going to be until we get an HIV vaccine? Anyone want to give a guess? Dr. Sattar, what do you think?

Speaker: Well, 5 or 10 years.

Dr. Hardy: Yep. And how much progress have we made in the past 40 years? Not much, zero really. So, in the absence of a vaccine, PrEP is really the best way to offer our patients a way to prevent them from becoming HIV-positive with pharmacologic measures. Vaccines have just eluded us tremendously. So, in the world of prevention, this is really the only way to go.

[00:07:46]

Pre-Exposure Prophylaxis Works!

Pre-exposure prophylaxis works, and this is something that you probably heard already. We don't need to prove that to anyone. But basically, PrEP is the use of antiretroviral medications, the same one we use to treat HIV, to give to persons who are at risk for acquiring HIV through sex or through injection drug use.

And that second part, injection drug use, is important to remember. Not all PrEP has been studied in injection drug users, but some has. And it has been shown to be effective. And so, this is an indication by the FDA and by the CDC.

So, taking it consistently, PrEP reduces the risk of acquiring HIV by over 99% in persons who are having sex and about 74% of persons who are injecting drugs. So, it's still good.

PrEP is recommended for adults and adolescents who are at least 35 kg or 77 lb or at risk for acquiring HIV. And you'll see that this has really been simplified. Initially, when PrEP came out, we had to quantify how many partners, how many risk factors, how many STDs in the past 6 months.

The CDC has really simplified this to say if you're weighing more than 77 lb and you are at risk for acquiring HIV through sex or drug use, you're indicated for PrEP.

[00:09:01]

Who Can (and Should) Provide PrEP? You!

So, who should and can provide PrEP? Well, basically everyone who has a license to prescribe medications in the U.S. should do this, including pharmacists, actually, as well. Are there any pharmacists in here? I don't think there are today. But pharmacists in California can in fact provide PrEP by simply asking at a county where they work, and they can actually do it. They can even give injections too. So primary care providers, STI clinic providers, HIV care providers, substance use disorder providers. It's really a very long list now, especially in California.

So this is, I think, a very important background as to why PrEP should be rolled out very nicely.

[00:09:39]

Universal PrEP: Recommended by Multiple Guidelines

So universal PrEP has been recommended by multiple guidelines so that all sexually active adults and adolescents should be informed about PrEP. So the indication for being informed about PrEP is what? You have sex. You have sex. Answer to that question is yes.

The next response is, have you heard about PrEP? So, CDC guidelines also recommend this for persons who inject drugs. But right now, we only have one agent that has been shown to actually prove that it works, but still available.

[00:10:08]

Current PrEP Uptake

So current PrEP uptake. This is the part that's a bit disappointing. When was PrEP first put out on the market in the United States? Close. 2012. PrEP was first licensed by the FDA in 2012. That was over 13 years ago, summer of 2012. And how good are we doing in terms of rolling out PrEP around the United States even? Let's look.

[00:10:33]

PrEP-to-Need Ratio in US as of 2023

So the PrEP-to-need ratio that has been coined by the CDC as of 2023, just 2 years ago, how many persons would be at risk for HIV and how many actually are getting it are shown on these 2 graphs. PrEP uptake is very unequal for one thing. You see that, for example, among persons who are White there at the bottom, the number of new cases of HIV in 2022, the year before, was there at 24%. And how many persons who are white have been given PrEP? 64%. That situation has reversed for persons of color, particularly among persons who are African American or Black.

39% of new cases in 2022 of HIV occurred in persons who are African American or Black, but only 14% of persons who are at risk, you know, African American, have been put on PrEP. And very similar numbers for persons who are Hispanic Latino as well. So that's an important situation.

The graph to the right actually makes this even more very visible, is that since PrEP was first licensed in 2012, there on the left-hand of that graph through 2023, you see how that how that line is growing among persons who are White, but it stayed really almost flat into the persons who are of color. So, this is really, we're not getting it where it needs to be. And I don't need to tell you guys who work at this Ryan Schrader clinic, that this is something that's very, very important that we're missing.

[00:11:54]

Need for PrEP Is Much Greater Than Population it Reaches

So, as this slide demonstrated, the need for PrEP, the PrEP-to-need ratio is not in our favor at all. The CDC now recommends that approximately 2.254 million people in the United States are at risk for HIV. When I first did this about 5 years ago, that number was 1.3 million. So, it has grown dramatically as well. And these persons who have at least a 1% risk of getting HIV per year are men who have sex with men, people who have heterosexual sex, and people who inject drugs. And that includes a lot of people. That includes a lot of people across the board.

But when we look at this nice little graph here to the left, we see what the PrEP-to-need ratio is. The population receiving PrEP is that little dark green at the bottom there, about 366,000 people. That's how many of the CDC estimates are receiving PrEP or at least been offered PrEP in the United States. But the need there is again 2.25 million. So, it's about 17%.

We have not really progressed very far on this since PrEP became available in 2012.

[00:13:02]

Why Might We Need Long-Acting HIV Prevention?

So why might we need long-acting HIV prevention? This is something that, hopefully, since we now have 2 long-acting agents on the market and available, will really probably change some of that PrEP-to-need ratio.

It's really pretty simple, just like for treatment. Daily oral PrEP is effective, but it's not worked equally well for all populations. And that may be why it hasn't been offered so much. Because taking a pill every day when you don't have a medical problem, it can be very challenging.

Long-acting options may help, of course, with unwanted or unplanned sex acts, alcohol or drug use when one's judgment may be impaired. Surely stigma challenges this because the fact finding tablets in someone's purse or medicine cabinet or in possession could be stigmatizing in terms of people getting confused, whether they have HIV, or just trying to prevent it.

Travel to try to keep the pills with you when you're moving around. And of course, choice is really important as well. So, thank God we have some other options besides daily pills as well.

[00:14:06]

PrEP Regimen Options: Something for Everyone

So PrEP regimen options, and this is something that has grown recently and will continue to grow hopefully for the future. And we call this something for everyone, because I think we've really gotten to the point now where we have offer people different things. And we don't no longer say that one is the best. It is about what is the best regimen for that person.

[00:14:26]

What Is the Ideal PrEP Regimen?

And this is where the individualization really can come out very nicely. Certainly, either a daily oral medication with FTC/TAF or FTC/tenofovir, both have been proven to work in high-risk populations. Cabotegravir as well has been proven to work, dose once every 2 months. And now lenacapavir through a subcutaneous injection after 2 oral doses every 6 months, has been proven to work as well. So, we have some really good options out there.

Why aren't we using them more?

[00:14:54]

Evidence Supporting PrEP Use

Here's a nice table that really summarizes the evidence supporting PrEP use. And as you move from the left to the right across from daily tenofovir/FTC, on-demand tenofovir/FTC, daily FTC/TAF, every 2 months cabotegravir, or every 6 months lenacapavir, basically in the order in which these medications were licensed or these protocols were shown, you see that the green checks are where things have been proven to work.

You see the red Xs are it's not—there's some holes going across the board there. So, for example, in terms of receptive vaginal or neovaginal sex, certainly TAF, I'm sorry, FTC/tenofovir has been shown to work there from several large studies, but on-demand FTC/tenofovir, no, has not been shown to work in a person who was born with a vagina. Or daily FTC/TAF has been shown to work there either.

It has been studied. No, I mean, tenofovir has not been studied in this group, or TAF has not been studied in that group well, but it is something that needs to be very carefully evaluated. It has been studied, but it has not shown good results, I'll put it that way. We'll get to that in just a second.

And as we go down the list there, certainly injection drug use, as we see 1 green check and 4 red Xs, the only drug that has been really shown to work in persons who inject drug is tenofovir/FTC. And that was actually a study that was done in Bangkok, Thailand. The response rate took about 2 and a half years to actually be seen. It was a slower sort of response in terms of protection, but it did provide a 74% response compared to placebo.

Pregnant women, we certainly have 3 agents now, both daily tenofovir/FTC, as well as both of our injectable medications, have now been recommended to be used in pregnant women or those who are nursing and also initiating with a double dose.

This is something that has been now recommended because it actually gets the levels of tenofovir up faster. And that's one of the reasons in the on-demand PrEP that they use 2 doses of tenofovir/FTC upfront before sex and then 1 more dose 24 hours later if sex did occur and another dose 48 hours later if sex did occur. But in order to try to get the levels up even more quickly, they're now recommending that the person who wants to get protected perhaps faster take a double dose with any kind of tenofovir/FTC to begin with.

And then low creatinine certainly can't be used with the tenofovir regimens. They can be used with all the others. And of course, osteopenia, osteoporosis are problems with tenofovir as well.

[00:17:36]

Daily Oral FTC/TDF vs FTC/TAF for PrEP

So, kind of moving on from there, we know that tenofovir/FTC and tenofovir/TAF have been used very successfully in men who have sex with men and transgender women. A large study called the DISCOVER study proved that. It was done in the U.S. and Europe. The heterosexual men and women, there's about a 99% good response with FTC/tenofovir. Unknown in heterosexual men and women for FTC/TAF, just not been studied there, is for tenofovir. And people who inject drugs, like I said, there's about a 74-84% protection, but unknown with FTC/TAF.

So, our 2 oral agents are not equivalent in terms of where they've been studied. Could we make an extrapolation and say, well, FTC/tenofovir works, we can then assume FTC/TAF would work too? That's a great question. And there really needs to be studies for that to understand, because the biggest difference between FTC/tenofovir and FTC/TAF is what? Pharmacokinetics. Pharmacokinetics and pharmacodynamics.

How the medication gets across the—is benefited to get across the GI tract to begin with, and also how it is benefited to get inside the cell, the pharmacokinetics, FTC/TAF as well. So, making an assumption based upon another similar drug that has different pharmacokinetics and pharmacodynamics would be a bit risky, would be a bit risky. So in the study that was seen, there was, in the DISCOVER study, in which gay and bisexual men and transgender women were studied with tenofovir and TAF, there was incremental changes in lab markers of bone metabolism and renal function, in which those lab markers did in fact look better in persons who were receiving FTC/TAF compared to FTC/tenofovir.

But there was no difference in clinically relevant adverse events. I think that's something that's a very important thing to point out, is that in PrEP, it has not been comprehensively proven that TAF is better. Because if for one thing, PrEP is usually taken over long periods of time, I'm sorry, over periods of time off and on, it's not continuous therapy like it is in treatment.

And so even the DISCOVER study did not prove that PrEP with TAF was better. The laboratory markers estimated that, but the real outcomes with clinically significant adverse events would. How about you have a patient, though, that wants to be on oral medication, but has a creatinine clearance less than 60? In that kind of situation, TAF would probably be great, because you can give it safely in that situation. But if that person is a woman, you may have some questions to deal with that. But hopefully, we think we have other options. But I think that's an important thing to understand.

The other thing we have to recognize is that there are several generic versions of FTC now, where there is no generic version for FTC/TAF, which is something that, again, will oftentimes influence how our payers will cover these options.

[00:20:45]

On-Demand Oral FTC/TDF PrEP for HIV Prevention in Men Who Have Sex With Men

On-demand PrEP was something that was developed in France, Canada, and also France, through 2 large studies, the IPERGAY study, which compared the 2-1-1 on-demand dosing with placebo. And in that study, there was in fact demonstration, there was an 86% protection with the on-demand PrEP. So, we know it works, at least among gay and bisexual men and transgender women. It has not been studied in any other population comprehensively to really understand whether that may work.

So, for right now, on-demand PrEP or the 2-1-1 follow-up has only been proven to work in gay and bisexual men and who are having rectal sex and transgender women who are having rectal sex as well. We know nothing about this regimen in vaginal sex. And can we make extrapolations from one sexual act to the other? Probably not, because of the mucosa that's found in each part of those bodies is different, is different. And so that is something we've got to be, I think, aware of in terms of how we use these different options.

It's also important to recommend that on-demand PrEP has not been used in the face of HBV coinfection. So, when HPV is coinfected, what effect that would have on again, off again sort of treatment with drugs that are hepatitis B-active would be problematic. And also, vaginal exposure, as we mentioned before.

[00:22:10]

Q2M Injectable CAB vs Daily Oral FTC/TDF for PrEP

Every 2-month injectable cabotegravir versus daily oral tenofovir/FTC was studied in gay, bisexual men and transgender women in the study called HPTN 083, and also in cisgender women primarily having heterosexual sex in HPTN 084.

Both of these demonstrated that the injectable medication given every 2 months was, in fact, superior to oral daily tenofovir/FTC. There were safety concerns, of course, in which there were the fact that, again, what they actually found, there were similar rates of renal adverse events between the 2 groups. So again, we did not see that there was much of a difference of using a long-acting injectable versus daily oral tenofovir/FTC, probably because the use of these medications are, in fact, very safe most of the time.

There was weight gain, actually, in both CAB arms among the men and transgender women, as well as in the cisgender women that occurred in the first year, but actually kind of got decreased over time. So, in this situation, we're not talking about TAF, we're talking about FTC/tenofovir, in which weight loss has oftentimes been associated with that drug. And with cabotegravir, the cabotegravir actually made the weight go up a bit.

So, this is something that's still sort of, I think, not really understanding it greatly, but there's not been a huge outcry about unwanted weight with cabotegravir so far.

[00:23:37]

PURPOSE 1 and 2: PrEP LEN vs FTC/TDF or FTC/TAF

The PURPOSE 1 and PURPOSE 2 studies were the big studies that came out this summer, and these were the 2 first of a series of studies in which lenacapavir dosed as 2 oral doses on day 1 and day 2, and an injectable dose on day 1 was compared to both FTC/tenofovir and FTC/TAF among cisgender women.

In PURPOSE 1, this was a study in which women entirely in sub-Saharan Africa, who were between the ages of 16 and 25, adolescent and young women at a high risk for HIV infection, were given the randomized, I should say, 2:2:1, meaning twice as many with lenacapavir, twice as many with FTC/TAF, and half as many with FTC/tenofovir.

You see that there's a background rate here of infection, which they did because at this point it was really difficult to understand what the current rate of HIV infection was in this population of women. So, for 9 months before the study even started, they actually were testing women and seeing what the background incidence of new HIV infections were in these countries in sub-Saharan Africa, and that's how they established the background of 2.41. Then they continued on with the study and enrolled the women in these 3 different options. What we found at the first analysis of this study, at about 9 months mean follow-up, meaning the women had gotten 2 injections of lenacapavir, there were zero infections out of about 2,000 women.

But in the FTC and the FTC/tenofovir arms, look at the rate of protection. Those 95% competence arms entirely overlap. So, does that mean that FTC/TAF and FTC/tenofovir don't work in women? How do we counter that with information we have in other parts of our PrEP study armamentarium? What do you think? Why didn't these medications work in women, whereas, lenacapavir dose, as we just mentioned, every 6 months injections did?

Speaker: Nothing works in women.

Dr. Hardy: Pretty much. Same sort of situation done by both blood and hair analysis demonstrated there were very low levels of either one of these medications in the women.

This was the first time that TAF was studied in women, and to my eye there's no good proof here that TAF works in women. Of course that doesn't mean biologically it doesn't work, it just means that the women didn't take it for whatever reason. But that's a very important part of the whole idea of how medications are given is adherence.

You notice that down there, and there was of course, an ongoing analysis because the first analysis was done when 50% of the women had reached 1 year, which meant that the other 50% had not reached 1 year. So, when that in fact was done, when all the women had reached 1 year of follow-up, the zero unfortunately did not persist because there actually were 2 new incident HIV infections in the lenacapavir arm. So unfortunately, we can no longer say that lenacapavir has a perfect record.

There actually were 2 infections that occurred as the study continued to be followed up. Pretty much what we would expect from any kind of biological protection, nothing is 100%. I think it's kind of crazy to think it might be.

In the men's study, which was a similar study in terms of design and involved not only cisgender men who are obsessed with men, transgender men, transgender women and non-binary persons, it really expanded this into other areas of gender identity, as it was just a comparison between lenacapavir and FTC/tenofovir. TAF had already been proven to work in this group, so they didn't study it again. But again, what you see here is that the incidence rate was in fact lower with LEN than it was with either the background that was done before or with the tenofovir/FTC, which is, I think, really important information.

There were 2 infections that occurred during that first follow-up period of 50% of patients reaching a year, and 1 more infection that occurred after that. So basically, there were 2 in the women's study and 3 in the men's study, which again is still an incredibly great response in terms of protections. But I think it's important that everyone look at this and understand that probably nothing is 100%. Nothing is 100%, even if you inject it every 6 months. So, I think that's an important criteria to keep in mind as we look at these down the line.

[00:28:06]

Lenacapavir Dosing and Interactions

The thing that is a little bit new and different that I think we need to pay attention to with lenacapavir is dosing.

We kind of get high up on the fact that this is 1 injection every 6 months. In reality, in practicality, it's not. It is in fact 2 oral doses on day 1 and day 2, and actually 2 1.5 ml injections every 6 months.

Why is that important? Because about 60% of patients who have gotten lenacapavir injections have formed nodules, nodules that are on the size of somewhere between 1-1.5 cm in size, and they persist for approximately 9 months. These nodules kind of hang around for a while. They're always in twos because that's how the medication is injected, usually in the abdomen. It has been an infrequent to rare reason that someone stopped taking lenacapavir. Only about 4 people in the women's study actually did that happen.

But it is important to note that this is something that is occurring and is being watched over time. It is not simply just 6 months, 1 injection every 6 months. It's 2 orals and then 2 injections every 6 months, which is important, I think, to really understand what the commitment to this is really all about. There is no renal or hepatic adjustment needed, which is very important.

The other thing I think is important is to realize that lenacapavir is both a substrate and an inhibitor, a substrate of P-gp, UGT1A1, and CYP3A liver enzyme systems. So, remember all those times we had to be concerned about how medications interact with one another? This is the same kind of situation, except in this situation, the medication is going to last for 6 months at a level that could be interacting. So it's going to be important to really understand what else the patient is taking in addition to the lenacapavir, because we've got a long-active medication here, and think about what's going on, not just for the next 2 or 3 weeks, but also what's going on for the next 6 months in terms of that patient's other concomitant medications.

There has been some recommendations in the FDA package information that says that if lenacapavir is in fact inducing the CYP3A and dropping the level of lenacapavir, then the response is just increase the dose of lenacapavir. The practicality of that may or may not be so easy because of the fact that getting more lenacapavir to do that may not always be such an easy thing to get insurance to pay for, because right now the drug costs around $28,000 per year or about $14,000 for 2 injections every 6 months. At least that's the wholesale cost. We'll see what it really looks like in the future.

So, there is a need to look at other medications that are metabolized by the P-gp, UGT1A1, and CYP3A inhibitors, the systems, I should say.

[00:30:59]

Mitigating Injection-Site Pain and Postinjection Recommendations

We've also learned a whole new area of what's called mitigating injection site pain and postinjection recommendations. For those of you who actually started using cabotegravir, you'll notice that the number 1 side effect that I've seen has been postinjection pain. Because that medication regimen includes, for treatment it's 2 injections, for prophylaxis it's just 1 injection, but it's a fairly heavy amount of medication going into someone's gluteal muscle between 2-3 ml. I think that's not a small injection. It is a big muscle, but it's not a small injection. And injection site pain is a very common, I would say probably at least 60-70% of people complain of it. It usually lasts for 1-4 days. Then we find ways to try to ask the patient to decrease that, because that's the main reason that they say they don't like it, by using ice before or after the injection just to reduce inflammation, topical analgesics, oral analgesics like ibuprofen or aspirin. Needle removal needs to be carefully done. And if you read the package insert for this, it's an injection, inject, and then pull out halfway, move like a Z-track, and then pull it out the other way. That's to try to make sure the medication does not leak out the exit route of the needle, because that can sometimes happen. The same thing can happen with lenacapavir, too, with the 1.5 ml injections that again needs to be carefully learned how to do this.

Leakage, and then, of course, putting a Band-Aid over it, is something we do all the time anywhere after an injection, but this is something I think is really important, because in terms of really asking patients, what's your biggest complaint? For patients who are getting a CAB, it's going to be injection site reactions. For persons getting lenacapavir, it's going to be that and perhaps nodule formation, which some of these mitigating sort of things may in fact help.

[00:32:52]

Individualizing Cases PrEP:

So individualizing PrEP for different kind of cases.

[00:32:58]

Key Barriers by Principal Population

The key barriers in principal populations, of course, like, for example, let's take adolescents. Adolescents have been studied, they were studied as a separate trial in both the cabotegravir and all, and because they were already involved in the lenacapavir studies that went down to the age of 16, adolescents have been studied concomitantly.

But of course, some of that is the barrier may be dissatisfaction with the medical team or lack of support for young people. That's something that oftentimes adolescents are difficult. I don't need to tell you guys who've dealt with kids before that trying to get them to do something regularly could be tough.

Racial and ethnic minority groups, we've already seen how these groups in the United States have pretty much been overlooked. Cisgender women, less studies and less information about all of our options we mentioned already.

Transgender individuals, we've seen this happen, we've seen that included in studies pretty nicely all the way across. But of course, drug-drug interactions with gender-affirming hormones are really an important thing to keep an eye on because this has been probably the one reason that many people in the transgender community have been concerned about taking PrEP.

And people who inject drugs, again, we have one medication that's been studied, but there is a study going on now in injection drug users with lenacapavir, which we'll see results with, probably, I think, next year or so, and other studies will hopefully be coming out as well. You know, what we oftentimes do in the field, when I say in the field, in the treatment of medicine, we give people an injectable medication called cabotegravir, which has really not been studied in injection drug users. But there's kind of an overlap here between injection drug users and sex, because oftentimes the 2 things go together. Using to this is sexual transmission, not so much injection drug use. It's really difficult oftentimes to tease those 2 apart in all situations as well.

[00:34:44]

Case 1: Cisgender Woman

So, first case. 26-year-old cisgender woman taking tenofovir/FTC for PrEP. Her male partner is living with HIV and has imperfect adherence with his ART regimen. She's interested in conceiving and is curious about her PrEP options while trying to conceive, which she's asking. She's also busy with a job and another child at home and is unsure.

[00:35:06]

Poll 2: Your best advice regarding her PrEP is:

So, your best advice regarding her PrEP is:

Continue her daily oral FTC/tenofovir;

Continue her daily or switch her to daily oral FTC/TAF;

Switch her to long-acting CAB;

Switch her to long-acting LEN.

Any of these options are good; or

Would you stop PrEP during pregnancy and breastfeeding.

Which one of those would you choose?

So, continue the oral FTC/TAF, and that probably has the clearest recommendation and the most data behind it in terms of safety and efficacy. We also have to acknowledge that it is now something that has been recommended by our guidelines for LA CAB because there were women, you know, what happened in the CAB study for women and also in the lenacapavir study is that when women became pregnant, they were exited from the study. And in the second part of the extension of the long-acting CAB, they did not exit women who were pregnant. They allowed them to get pregnant. There were about 325 pregnancies that occurred in that group. So, there's now data that has been generated to show that the outcomes are very good compared to women who had never received CAB. And the levels of the medications in the baby, in the mother's milk, has been low. So, there's not a whole lot of information there.

The same thing was actually even done better in the initial study were kept in the study from the very beginning. They were not exited at all.

So, the other answers you put on LA CAB for C or for D would be based upon your patient's ability to take a daily pill during her pregnancy. So those are, I think, again, showing what her options may be.

The one thing we probably would not give with her is to give her FTC/TAF because that is something in which not only has it not been studied in women, but it hasn't been studied in pregnant women either, in which pharmacokinetics do change the way medication is metabolized.

[00:37:24]

PrEP in Pregnancy and Breastfeeding

So, PrEP and pregnancy and breastfeeding.

We know that pregnancy is associated by itself with an increased risk of HIV acquisition. Women can become infected during pregnancy, and that's happened more than once, which is why it is recommended that women be tested again for HIV in the third trimester, not just the first trimester of their pregnancy or before they get pregnant. And of course, there's safety concerns for pregnancy that affects fertility and other barriers to PrEP uptake as well.

So, things to be concerned about are really important there.

[00:37:55]

FTC/TDF PrEP in Pregnancy and Breastfeeding

FTC/tenofovir is recommended for PrEP and has been for quite some time because there's been good data that has shown that this has worked. It is widely used in persons with HIV, including pregnant women. There's no link to teratogenicity and the antiretroviral pregnancy registry, kind of our best way of actually being able to follow this in the real world. And data from lactation studies in women who are HIV-positive, there's limited drug exposure and there's been no differences in pregnancy or prenatal outcomes in 5 completed studies. So, we feel very comfortable with continuing FTC/tenofovir. A lot of good data to actually support that.

[00:38:30]

FTC/TDF in Pregnancy: DART Study

In the FTC/tenofovir study, the DART study, if you look at one of these of 182 infants, there was either no in 62 of them, 20% to 89%, or 111 over 90% in utero exposure. So, lots of babies did in fact have exposure, just no for FTC.

The 12-month mortality rate was 5%, similar to the 2-4% that has been seen in this area of the world where we studied. And there was no increase in congenital, renal or growth malformations from in utero tenofovir exposure. So that kind of makes us feel good.

The weight for age after birth for the first 5 years actually showed very similar between babies that were exposed and babies that were not exposed. And the same thing in terms of height for age in terms of growth. So that, I think, makes us feel pretty comfortable about that. And it really, I think, underpins why tenofovir/FTC is used the most in women who are pregnant or who want to get pregnant.

[00:39:28]

LA CAB in Pregnancy: CAB Concentrations

LA CAB in pregnancy, as I mentioned, we have some limited clinical data, but some good pharmacokinetic data in which women who were receiving long-acting cabotegravir did in fact have pharmacokinetics, and there was really no significant difference in the composite pregnancy or in the composite pregnancy poor outcomes data. The pharmacokinetics showed that it was really no different in terms of how fast it left the woman's body.

Although what you can see there is that the half-life in the pregnant women for cabotegravir was about 52.8 days versus 60.3 days in women who did not receive cabotegravir or who were not, I should say, were not pregnant. So pregnancy did have an effect on how fast the cabotegravir was probably being metabolized, because you can see the graphs there are not—the lines are not entirely the same, probably a little faster in the face of cabotegravir in pregnancy because of the fact that we know a lot of levels get decreased, often as because of the volume of distribution in pregnancy increases, and that'd be part of the reason why that's going on.

[00:40:40]

LA CAB in Pregnancy: HPTN 084 OLE Adverse Events

So when we looked, as I mentioned, in the open-label extension study of HPTN 084 in which women were randomized to get either long-acting cabotegravir or tenofovir initially, in terms of looking at 3 groups of women, those who got active CAB at the time they were analyzed, prior CAB or no CAB, looking at grade 2 adverse events, pregnancy-related grade 2 adverse events, the ranges for how these events occurred was really not different between the ones who got active CAB and were continued in their pregnancy or those who didn't ever get CAB at all.

So, I think this, of these 325 pregnancies in which it was outcome reported, has given some credence to why guideline panels are now saying you don't have to stop the CAB if a woman gets pregnant. There is safety enough to say that it's not going to harm the outcome of the baby, at least from what we got so far. Whether a formal study is going to be done like what was done before with other medications would be great, but if that ever gets done, that's going to be something that would be really helpful. Those are very nice.

[00:41:45]

LA CAB in Pregnancy: HPTN 084 OLE Pregnancy Outcomes

Pregnancy outcomes here again have shown full-term birth, pre-term birth, stillbirth, or in utero fetal death, spontaneous abortion, or composite pregnancy outcomes. What we're seeing here between the no CAB and the red bars, prior CAB or active CAB in the light blue and then darker kind of teal color, is that there's not a whole lot of difference.

This again was a study that was not set up to look at this. It was data that was put together after the fact when they changed the fact that women could stay in the study if they became pregnant on CAB. But it really shows something that I think is reassuring, and this is why the guidelines responded to this.

I think the one thing that kind of surprised me was the spontaneous abortion at less than 20 weeks. The thing that's over that area there, that says this represents participants in countries with and without legal abortion status. Why is that important?

Because if a woman got an abortion and it was illegal to get in her country, she could say it was spontaneous to keep herself safe. That's why they think that some of the numbers for abortion were so high in this study because not all countries where these women were studied, a lot of abortions to occur.

[00:43:00]

LEN in Pregnancy: PURPOSE 1 Sub study

So, LEN and pregnancy in the PURPOSE 1 study, the women's study, this gender women's study. Again, there were women who became pregnant and stayed in the study, 193 in the CAB arm and the FTC/TAF arm, 218 and the FTC/tenofovir, 98.

So there actually were quite a few pregnancies that occurred during this period of time. And as we see looking at some data about pregnancy outcomes, in terms of the proportion of patients that were completed, those that were unknown, live births were really not significantly different across the board. Stillbirths were not different across the board in the 3 different medications.

And we know that the FTC/tenofovir is the preferred one already. Induced abortion or spontaneous miscarriages. Again, no real differences among these fairly not huge number of women being studied, but at least to kind of give us some good feelings.

I think in a situation for us to be able to know that a woman does get pregnant and she's on lenacapavir, she's going to be safe. And why is that important? Because lenacapavir, just like cabotegravir, is going to last a long time. You can't stop it if a woman is pregnant. We now need to know that it is in fact going to be safe, we're not going to hurt the baby.

[00:44:12]

Conclusions: Breastfeeding/Pregnancy and PrEP

So, conclusions.

FTC/tenofovir, there's extensive data from many years of experience with HIV treatment and PREP and safety data from numerous studies and guideline recommendations. Both long-acting CAP and long-acting lenacapavir, early analyses are reassuring, but there will need to be, of course, ongoing surveillance to critically, and confirm safety in pregnancy and also breastfeeding. And this is where the whole thing comes back to what's called shared decision-making. That if this actually occurs in one of your patients, you need to go back and talk to your patients and use the data we've just reviewed in terms of talking to the woman about what might actually be the best for her.

[00:44:50]

Evidence Supporting PrEP Use

So back to our graph here, or our table, we can see that there are some holes for on-demand PREP for pregnancy and breastfeeding, holes for daily TAF, but 2 checks for long-acting medications. So, I think that's something that has actually happened much more quickly with these long-acting options than it has been with other options in the past.

[00:45:12]

Posttest 1: If following FDA indications, which HIV PrEP options should you recommend for cisgender women?

So, our first posttest question. If following FDA indications, which HIV PREP options should you recommend for cisgender women?

FTC/tenofovir only;

FTC/tenofovir CAB or LEN;

FTC/tenofovir, FTC/TAF, CAB or LEN; or

FTC/tenofovir, FTC/TAF, CAB LEN, or on-demand FTC/tenofovir.

Make your choice now.

Yay. So, B is what I think everyone's going to be, you know, pick, and they did 100%, which is great. Basically, no TAF. Basically, no TAF. One thing to remember. Got that answer.

[00:46:08]

Case 2: Transgender Woman

So, our next case, transgender woman. 22-year-old transgender woman is interested in PREP, but is concerned about interactions with her gender-affirming hormone therapy. Her hormone therapy consists of estradiol valerate, 20 mg delivered by IM injection every 2 weeks, and spironolactone, 100 mg/day. She also has had buttock implants 4 years ago, which is again, a potentially complicating situation.

[00:46:37]

Poll 3: Based on her concerns, your best advice regarding her PrEP is:

So based on her concerns, your best advice regarding her PREP is:

Start daily oral FTC/tenofovir;

Start event-driven base 2-1-1 FTC/TAF;

Start daily oral FTC/TAF;

Start long-acting CAB; or

Long-acting LEN

What would you do? This is where options are nice to know. Hopefully, if you can base it on scientific evidence and data, even better.

Great. So, most people would start on oral tenofovir/FTC because we know that there has been the most experience with that, especially in terms of gender-affirming hormone therapy. There's been multiple studies done from around the world, which have demonstrated that there is no influence of either one of those drugs on lowering estradiol. There is a slight effect of the estradiol perhaps lowering some of the tenofovir levels, but those are serum tenofovir, not intracellular tenofovir, and that may not be so important. But if you chose C, oral daily TAF, that would actually work fine too because transgender women have been shown to be successfully protected with this.

I'm going to assume that—I don't know of a particular study that's used TAF versus tenofovir, but since the actually is the same drug once it is put into the body, in cells, in blood, tenofovir by itself, it's probably safe to do it with—assume whatever will occur with hormones will occur the same with TAF. And of course, start LEN, that could be a possibility as well. But you could also start long-acting CAB because it worked there as well, because this woman has actually several different options for treatment.

[00:48:28]

Prevalence of HIV and PrEP Use in Transgender Women in the United States

So the prevalence of HIV and PrEP use in transgender women in the United States, it's important to point out, and this was something that I became acutely aware of when I worked in Washington, D.C., which I learned was the transgender capital of the United States, and our clinic had over 2,000 transgender patients, is that transgender women are 34 times more likely to be living with HIV than the general population. So, this is a huge, huge important fact I think for people to know. And most of these transgender women are Black or Latina.

So the prevalence of HIV among transgender women is estimated to be at least 14%, sometimes as high as 40%, depending upon which group of transgender women you're looking at. So, this is a very important target population of making sure that they know about PrEP.

In the 2019-2020 National HIV Behavioral Survey of Seven Studies, high PrEP awareness was known in terms of HIV-negative transgender women, 827 of them, 82-96% had heard of PrEP, but only 17-46% were actually on PrEP.

So the message is out there. The knowledge has been delivered, but the action on that has not actually happened. And I think that's something that we really need to be very careful about, about reversing, because it is something that's a really difficult situation.

[00:49:50]

FTC/TDF in Transgender Individuals: ImPrEPT Consort

Here's one of those studies that actually demonstrated, the ImPrEPT study that actually looked at gender-affirming hormones at baseline, and then stable estrogen levels in transgender women, and 12 weeks later after FTC/tenofovir was added. And there is really no difference there at all.

When you looked at transgender men in terms of their testosterone levels, again, the baseline level versus the week 12 level was a little bit lower, but probably not significantly different because of those big, wide arms up and down. So, I think this, again, is something that we can probably feel pretty good that tenofovir and FTC, primarily the tenofovir diphosphate, has very little effect on at least estrogens and testosterone that are given as gender-affirming hormones.

[00:50:44]

FTC/TAF in Transgender Individuals: DISCOVER Nested Sub study

The FTC/TAF in transgender individuals was studied in small numbers of patients in the DISCOVER study. Remember, this was a study that enrolled about 5% of the patients that were enrolled overall in the 5,000-patient study were transgender women, and about 10% of those were involved in a sub study that looked at hormone levels. In the transgender women, their tenofovir levels were really no different than their FTC levels.

So, in this case, it was a situation they were looking at the effect of the hormones on the drugs that were being used to prevent HIV infection. And this was something that didn't probably answer all the questions that transgender women would want to know, is because the opposite in terms of what effect the tenofovir has on their estradiol levels was not done.

[00:51:38]

Oral Contraceptives and Oral CAB

So oral contraceptives and oral CAB, at least with this, there's some data, and we can't always use oral contraceptive levels as a marker for estradiol that is being given for gender-affirming hormones, but at least with these 2 medications, ethinyl estradiol and levonorgestrel, the difference between levels given with or without CAB seem to be pretty much the same, almost overlapping.

So at least there is some effect that we kind of hope that this actually will be okay, although I think a study in people who are actually taking the hormones really needs to be done separately.

[00:52:13]

Feminizing Hormones and LA CAB: HPTN 083 Secondary Analysis

Feminizing hormones and long-acting CAB in the HPTN 083 secondary analysis, again, looking at the levels here in women, 30 women who did, and 23 who did not take gender-affirming hormones and were given CAB injections, you see there's really no difference in the affirming therapy reported in these fairly small number of women who were involved in this. And this is looking at the right pharmacokinetics, I think, because this is actually looking at the gender-affirming estradiol.

But the CAB concentrations were nominally higher in the transgender women who reported using hormones, than those who did not. So, this actually was, I think, kind of a helpful thing as well.

[00:53:02]

Conclusions: Gender-Affirming Hormone Therapy and PrEP

So, conclusions. Gender-affirming hormones and PrEP in general, the gender-affirming hormones do not interact with HPV medications. There's reassuring evidence with both tenofovir/FTC and tenofovir/TAF.

There's some early information about CAB and gender-affirming hormones with something that's similar, and the data with this and LEN is pending. There were a lot of transgender women that were involved in the Purpose 2 study, and since that study just basically wrapped up this past summer, we expect to see a lot more information coming out over the next several months.

[00:53:35]

Evidence Supporting PrEP Use

So, evidence supporting PrEP use, when we look at receptive anal intercourse, all PrEP options are in fact being studied and are recommended. Receptive vaginal intercourse, all options except on-demand and TAF.

Really important to point those 2 out.

[00:53:52]

Posttest 2: What would you recommend for a transgender person who is considering HIV PrEP but is concerned about interactions with GAHT?

So, what would you recommend for a transgender person who's considering HIV PrEP but is concerned about interactions with gender-affirming hormones?

Offer daily oral PrEP with long-acting cabotegravir or oral PrEP or long-acting cabotegravir because they do not lower levels;

Offer daily oral PrEP or long-acting cabotegravir but with hormone level adjustments;

Avoid daily oral PrEP because it lowers hormone levels; or

Avoid long-acting cabotegravir because it lowers levels.

Which one of those would you pick?

Great. So, you know, again, I think we got data that actually shows that drug-drug interactions between oral PrEP, tenofovir, or TAF and long-acting CAB are good options. We're still waiting for that same information about lead.

[00:55:00]

PrEP Implementation

So PrEP implementation. This is part of the presentation, which I think most of you feel pretty comfortable with already.

[00:55:07]

HIV Monitoring While on PrEP

We know that HIV monitoring while on PrEP has now been changed. Initially, the CDC and the IAS-USA recommended that in order to avoid missing cases while persons are on these PrEP options, that they should in fact have an additional HIV RNA test done.

What the CDC did is to recommend, and so does the IAS-USA, both antigen antibody and HIV RNA at baseline. So, at baseline, everyone gets the same thing across the board. But the CDC and the IAS-USA have differed now in terms of what's happening during follow-up.

Right now, the CDC still recommends that the HIV RNA be done with both FTC/TAF and cabotegravir. They just put out recommendations this September that said that for lenacapavir, it only seems like you need to do 4th generation every 6 months, every 6 months. Different schedule there.

IAS-USA has actually dropped the HIV RNA for everyone across the board. And while I mentioned those new CDC guidelines that came out with lenacapavir in September, I know the person at the CDC who's actually working on this, Rupa Patel, who will actually put out new recommendations changing the ones that were out there already, eliminating the HIV RNAs from follow-up for both of these, for the oral and for the CAB as well. So that will change in the future because there's been good data that show that it did not occur very often in terms of missed seroconversion with tenefovir/FTC or TAF, and also that the HIV RNA added very little to discovering new HIV infections in both CAB studies.

[00:56:52]

Expanding PrEP Uptake

Expanding PrEP uptake. Again, I think this really gets back to the fact that this is being offered to encourage for generalists to do this because it doesn't take really any HIV expertise. It's really pretty straightforward, not too much different than offering birth control pills in many ways because of the fact that you just need to know the drug interactions that occur and to make sure that the person's taking it on a regular basis, certainly the oral ones.

And then, as I mentioned there, contraceptive care is given by lots of healthcare providers, and PrEP really isn't all that much different. So, I think that's something that we should really make sure that our colleagues understand.

[00:57:30]

Everyone Has a Role

Everyone has a role, and they're at the top of primary care providers, family medicine and internal medicine specialists, advanced practitioners, PAs and NPs, and clinical pharmacologists, and also other healthcare providers who manage STI, substance use disorders, and sexual health.

So the people who could actually start doing PrEP is a lot larger than it is right now, and this is probably where we're going to have to go in terms of expanding that 17% of PrEP-to-need ratio because there's just not enough HIV providers around who are doing this to make this happen. And that's kind of the reason that this whole fellowship exists, which is really great.

[00:58:02]

Framing PrEP as a Positive Health Choice

So framing PrEP as a positive health choice, I think this is something that there's a lot of stigma out there about PrEP because people think, number 1, one of the reasons that it is thought that women in Africa don't take their oral PrEP was for a couple of things.

Stigma. Number 1, that if they were found to have pills by a family, a boyfriend or husband, that they would be considered to be unfaithful, being unfaithful to their partner, and that may risk being thrown out of the house, being beat up, being cut off economically. So that's a real stigma that one has to really understand and talk about more in terms of empowerment and self-care or self-protection.

Again, acknowledge the stigma and try to work with it. That's probably why the injectables may be better in situations in communities where that actually is occurring more commonly. And also make sure that you're talking about not just using medications for prevention, but also behavioral risk as well.

[00:59:08]

Strategies to Address PrEP Stigma

I think I've gone over this a little bit more often already about addressing PrEP stigma, and I think this is really no different than other HIV stigma in general is added to that.

[00:59:18]

Mechanisms to Improve Conversations About PrEP

And conversations, normalizing PrEP as a prevention option for any person who's at risk. And again, I put this in the context when I actually talk about this and say, "If I had a vaccine for HIV, I would offer it to you as well, but I don't. So, let's talk about this instead." So, I think it's really a situation in which we're talking about not having more sex, not having unsafe sex, but protection of the person from a lifelong infection that is not curable at this point in time.

So, I'm going to stop there. I know you guys got to get to clinic and answer any questions you may have or any of those guys online. Thank you very much.

Q&A

Speaker: Thanks, Dr. Hardy. Yes, we are now taking questions for Dr. Hardy. Please, for our online learners, please use the Q&A function in Zoom to submit your questions. And do we have any questions in the room?

Dr. Hardy: Yes, Dr. Sattar?

Speaker: It seems so algorithmic and relatively easy to do, but it's hard to get a virus [inaudible].

Dr. Hardy: There has been. You know, you might remember that there were 2 things that were tried. You know, early in the Trump administration, well, I say late in the Trump administration in 2019-20, in his last year of office, he actually ruled out, you know, a big HIV program that was trying to emphasize getting more people tested, treated and prevented. What happened, of course, in 2020, is that the pandemic broke out as well. So, a lot of the plans and almost all the money that was put into this, and there was a big program called Ready, Start, PrEP that was ruled out during that period of time.

It was supposed to really, you know, sort of mobilize a lot of people to do PrEP, was tried for about a year and a half. It showed no results, and it was stopped. So Ready, Start, PrEP is gone.

And, you know, I can't say that it didn't work. It just because there was something else that was distracting the entire health care community away from this. So, you're right. You know, I think there needs to be a re-education, a revitalization of a program like that so that we don't make it difficult. Because, you know, what I tried to do when I talked about this in family medicine, PA, NP groups is let's not talk about HIV drugs. Let's talk about HIV prevention.

And rather than getting caught up into the fact that I don't know what to do with antiretrovirals, they're all complex, they all have side effects, blah, blah, blah. You start off with a conversation saying, "Would you like to offer your patients an effective, a 99% effective prevention for HIV?" And really go from that standpoint and then talk about how the options are really not too much different than birth control pills.

You know, I mean, there's daily options and there's injectable options, just like there is for birth control. So, I think we've kind of, you know, maybe approached this backwards. And instead of, you know, getting people excited about prevention with very similar medications we're already using commonly for birth control, we've jumped into this whole thing about the complexity of antiretrovirals.

And what we're finding, as this lecture I think just showed, is that the side effects are less than with therapy, and the effectiveness is greater. So, I mean, it's sort of like we need to kind of, I think, repackage this to get people who know nothing about HIV, but know about birth control pills and say, "If you didn't want your patient to become positive, what would you do? Did you know there's something you can do to offer that patient a really good chance of not becoming positive?"

I think that's the approach that many people would be more interested in doing rather than you even using the word "antiretroviral therapy," because that sends—it turns people off because they look upon that as a specialty drug. And as soon as they hear it's a specialty drug, they say, "I'm not a specialist. I'm a generalist. I'm a family medicine doctor. I don't do specialty stuff. That's the HIV people."

So, I think, you know, the approach we've taken has not been always so great. Plus, the time. I mean, I blame it on the pandemic more than anything else. I mean, that was a horrible time to roll anything new out like this.

What are your ideas about doing this better? What do you think?

Speaker: Yeah, we did some of that. [Inaudible].

Dr. Hardy: You know, I was glad that, you know, in California, there was legislation passed that made it legal and useful for pharmacists to be able to furnish all types of PrEP very early on, just like birth control, looks like more than that for pills. But again, I think we have to remember that California is very progressive in their medical care and that even that was opposed by the California Medical Association, that they felt like the pharmacists were encroaching upon a doctor's business. And I think we really have to be—you know, that was something that just got in the way completely.

It didn't stop California from doing it, but I bet it may stop it at other states in the country, is that they look upon this as competition, not as good health care. And I think that's something that needs to be carefully evaluated as well, because pharmacists, I think, would be great for this. Great for this.

I'm sorry, any questions online?

Speaker: I am not seeing any questions online. Dr. Hardy, would you advance one slide to put the QR codes up for us?

Oh, there's one more polling question.

Dr. Hardy: Sorry, I forgot to do that.

Speaker: That's okay.

Dr. Hardy: Okay, let's just advance to the—I'll let Jeremy take over because he knows what he's doing.

[01:06:00]

Thank You For Attending Our Program!

So, these are the QR codes in order to be able to get your CME.

Speaker: Yes, so please note the QR codes on the screen and the chat panel, which contains 2 important links: a downloadable slide deck from today's presentation, as well as the program evaluation link to complete and claim credit. You will need to log into or create a CCO account. Please claim your credit within 30 days, as it will expire afterwards.

And then any other last questions in the room?

Dr. Hardy: Any questions? Everyone looks pretty fully sated.

Speaker: Okay, I would like to thank all of our participants for joining us today and also Dr. Hardy for your teaching and expertise.

With that, we will conclude our program, and you now can disconnect. Thank you so much.

Dr. Hardy: Thank you. If anyone needs the slides for these, I'll be happy to send them to you. Yeah.

[END OF TRANSCRIPT]