September 28, 2012
In July 2012, the U.S. Food and Drug Administration (FDA) approved, for the first time, an antiretroviral drug for the prevention of HIV. To be specific, the FDA approved the fixed-dose combination pill tenofovir/emtricitabine (Truvada). The drug has existed for years as an HIV treatment option, but the FDA's action this past summer made it the first drug approved for HIV pre-exposure prophylaxis, or PrEP for short.
As we prepare for the introduction of PrEP into clinical settings throughout the U.S., there are understandably a huge number of questions. To address many of these questions and obtain guidance for health care professionals across the clinical spectrum on how to prepare for and adjust to the rollout of PrEP, I spoke by phone with Antonio E. Urbina, M.D., the associate medical director at St. Luke's and Roosevelt Hospital's Center for Comprehensive Care's West 17th Street Clinic in New York City. Prior to that, Urbina was, for many years, the medical director of education and training at St. Vincent's Comprehensive HIV Center.
Months of conjecture and debate have taken place regarding the use of HIV pre-exposure prophylaxis, or PrEP. Now we're finally at the point where PrEP is ready to be used in clinical situations. What do we know so far about the basics of when and how to use it?
One thing is very clear from the data. Not just animal data -- which was the first data that showed that, if you give uninfected animals the same drugs that we give to people who are HIV positive, and then you expose them to strains of SIV, which are very similar to HIV, you can prevent infection in these animals. That data has been available for a long time.
Now we've got multiple studies -- not just the iPrEx study, but a lot of other studies -- that have unequivocally shown that pre-exposure prophylaxis is effective when it's given to high-risk individuals. So the science is there. I think a lot of us are overjoyed that, finally, the scientific community and the political will are there to prevent new infections from occurring.
You mention high risk. Let's get into the details a little bit, as far as the proper use of PrEP as we move forward. What constitutes high risk?
Ultimately, it's a subjective question; it's a continuum. Not everybody is always at high risk at every point in their life. They go in and out of risky behavior.
But if we're starting to evaluate persons for PrEP, we do want to give it appropriately to people who are at high risk. Generally how that's defined is: persons who knowingly engage with others who are known to be HIV positive. That's one definition.
Another one is: persons who engage in sexual activity in an area that has a high prevalence of HIV, and who also have inconsistent or no condom use.
There are also people who are coming to your office or clinic with multiple sexually transmitted infections. I think that would categorize another person that may be a potential candidate for PrEP.
Then there are other kinds of high-risk behavior: anyone who exchanges sex for other commodities, such as money, shelter, food or drugs; persons who are substance users; persons who were recently incarcerated.
Again, it's a really subjective call: anyone who's HIV negative that you feel is putting themselves at risk. I think any of those could be candidates for PrEP.
A lot of the risk factors that you just outlined get into some pretty sensitive issues that I think many people within the health care field might be a little bit wary of bringing up with a patient. Topics such as sex and drugs, even within the clinical field, tend to be not easily broachable with patients. If part of the process of determining whether to offer PrEP to a patient consists of making that kind of analysis or examination of their sexual -- and, perhaps, drug use -- risks, how does a health care provider navigate that?
Medical training doesn't really provide a good background for health care providers speaking with patients about these kinds of sensitive issues. For some, it's always going to be very difficult for them to interview patients and have a dialogue about risky behavior.
Before, it was just risk-reduction counseling and safer sex; distributing condoms. But now, with PrEP, we have an additional tool, a chemoprophylaxis agent that could be given to patients. In order to determine if a patient is eligible, you really are going to have to have these difficult and often-sensitive questions, or questions that may be embarrassing to the patient.
What it really boils down to is trust. It's trust between you the individual provider and the patient who's sitting opposite you. All of us are really going to have to break down those barriers and say, "In order for me to prescribe something that I think may benefit you, may actually prevent you from acquiring HIV, we're going to have to sit down and talk about what may be some difficult issues. And I want you to be as honest with me as you can."
Now, I think you can phrase things in a way that may normalize behavior. So, for example, instead of saying, "Do you use drugs?" or something like that, which kind of already has a negative connotation, what I'd typically tend to do would be to say, "Do you find it difficult, on the weekends when you go out, not to use?"
It is important how you frame the question, how you start to get a history, so that you can put patients at ease, make them comfortable and, I think most importantly, let them know that you're not judging their behavior. But, again, that's a difficult task, and there are going to be some people who are better at it than others.
I don't always think that it has to be the provider; I think it can be anyone on the health care team who can approach the patient. I'm very much in favor of using people who are more skilled, who have that level of emotional intelligence that can connect to patients and elicit that information -- sexual history, drug-using history, things like that. Sometimes that could be a nurse, a social worker, a patient navigator, etc.
To what extent does the burden fall on the patient, or the client, to request PrEP? How much information can any health care provider just make generally available -- like in a waiting room or within the office -- to let patients know that PrEP exists, versus waiting for patients to find out about it themselves and then come in saying, "I've heard about this; can I try it?"
Already now, we are having patients coming in and saying, "A friend of mine told me about something that I can take." Or often it's somebody who's already infected [and doesn't yet know it] who will come and say, "I heard that there's possibly something that I can take."
I think information is power. I think having things in the waiting room that explain what PrEP is -- even something that simply says "Did you know?" and then lists out what it is, how it's prescribed, etc. -- I think that's a useful tool. And information about PrEP would really benefit anyone.
We want to get that dialogue started, because even if a patient isn't an ideal candidate for PrEP, or let's just say that after you offer them PrEP that they decide to say no, it's still an opportunity to engage them in a conversation about HIV, about actually reducing their risk, about getting HIV tested, about being screened for sexually transmitted infections. It's just a great opportunity. And PrEP can be the catalyst for it.
Do any of those waiting room materials that you just referred to exist yet?
No. In the offices and the clinics that I've been to, I haven't seen anything yet out there giving information about PrEP.
Are there people for whom you definitely would not want to offer PrEP?
I would say yes. The data with PrEP shows that adherence is key. PrEP needs to be taken daily in order for it to be most effective. That information needs to be parlayed to patients very clearly, because you don't want people thinking that they can intermittently take PrEP and it's going to be effective. You have to make sure that the patient understands the science and understands the data that shows you have to have a high level of adherence in order for PrEP to be effective.
I would say that, if a patient could not commit to taking the tablet daily, then that patient would not be a good candidate for PrEP.
Are there any red flags that would indicate that?
Before starting someone on PrEP, I would form an agreement with that patient that they would follow my recommendations.
The recommendations include that they get frequent HIV testing. PrEP is indicated for persons who are HIV negative, obviously. Studies show that in people who had very early infection, but whose infection was not picked up, and who were started on PrEP, in some of those patients, not only did it not work, but they actually developed resistance to those medications.
So, if a patient can't commit to coming in, getting a baseline HIV test, and also getting frequent HIV testing -- in the studies, a lot of them did monthly HIV tests, but the guidance says at least every two to three months -- if a patient can't commit to coming in and being monitored, I think that that would be a red flag.
I would clearly state all of the agreements that I think would be essential before I actually prescribed someone with PrEP. Because PrEP, if it's not monitored, could be potentially hazardous: These are medications that we give to patients with HIV; they have potential toxicities that, if they're not picked up early, can have really bad outcomes.
So, again, I would clearly state: "I will need to see you at least every three months to check in, monitor adherence, do an HIV test, monitor some of your labs." PrEP is not something where you can write a prescription and have 11 refills. That's where I think really we can get ourselves into some pretty serious problems.
What about clinical reasons to potentially not prescribe PrEP?
The great thing about the HIV scientific community is the miraculous work that they've done with drug discovery and development. The lifespan of those with HIV now approximates those that are HIV negative. I have a patient who's 86 years old. And the most recent data from a large cohort trial, the D:A:D study, found that there's no real signal for any major toxicity from antiretroviral agents. If you look at the big causes of death, it's non-AIDS-associated malignancies, non-AIDS infections, and cardiovascular and liver complications. But there's not a big signal from really any of the antiretrovirals.
It doesn't mean that they cannot potentially cause adverse events; and we know those. Truvada itself, if you're looking at patients' adverse reactions: They were mild. Only a couple of symptoms occurred with more frequency in those who were prescribed Truvada. Those were headache, a little bit of abdominal pain and some weight loss.
But some of the more potentially serious side effects could include some issues with the kidneys. So far, the data haven't shown any alarming trends, just a little signal of some abnormalities with kidney function. All of those normalized with discontinuation of Truvada.
Another potential clinical side effect is some bone mineral density [BMD] loss, or what's called osteopenia. But again, that has been mild and typically reversible with discontinuation of the medications.
Are the potential concerns large enough that there should be some kind of threshold where a clinician says, "This person's BMD is a little bit too low; I shouldn't even be prescribing Truvada or tenofovir/FTC for PrEP"?
With the bone mineral density loss, I think that's going to be a call by the provider. If the risk of that person acquiring HIV is greater than your concerns about any further bone mineral density loss -- there are also drugs that persons can take to reverse this loss -- then I think that would still be an appropriate patient for PrEP.
For the kidney function test, that's again why it's important to monitor baseline kidney function and to have the patient come in frequently to check the kidney function to make sure that there are not any increases or worsening of kidney function.
PrEP really hasn't been looked at closely in the real world. We don't know about the patients that are, let's say, abusing methamphetamine, and going on these binges, and getting severely dehydrated, and not drinking [water]. What does that mean with someone who is also taking a PrEP medication? Is that going to increase their risk for something bad happening to their kidneys? I don't think that we know that yet.
How about comorbid conditions? Are there any particular conditions that, if a person has it, they should either delay PrEP until that condition has been managed, or avoid PrEP entirely?
I don't think we have that data quite just yet. We know that we use these medications in patients that already have established HIV infection and we know that we can give them at the same time, and that as long as patients are monitored that they do OK.
But there is the potential that PrEP medications can interact with other disease states. For example, someone with hepatitis C is more at risk for liver toxicity. Someone who has diabetes or elevated blood pressure: They're more at risk for kidney toxicity. So when you're combining patients with these comorbid conditions and an antiretroviral medication, there is the potential.
That's the kind of data that we need now, when PrEP starts to get rolled out: this real world, community-level data about real people coming in who are not just young, healthy adults -- but elderly patients, patients with a lot of comorbid conditions, substance-using patients, etc.
I think that all of those have the potential to interact with each other. But I don't think that any of those is ultimately a reason for not prescribing PrEP.
How about pregnant or nursing women?
Right now, the guidance is that you really should screen women for PrEP, not just to make sure that they're not already HIV infected, but that they're not pregnant.
It isn't to say that you cannot prescribe PrEP for a pregnant woman, especially if you feel that she's at high-risk for HIV acquisition. But we don't really have good data in HIV-negative women about the effects of these medications on the fetus.
Also, it isn't just women who are pregnant, but also women who are breastfeeding. Because we know that these drugs do cross into the breast milk, and then the baby can be exposed to the PrEP medications.
Now, with that said, currently HIV-positive women who are pregnant are prescribed these same types of medications. There's this antiretroviral pregnancy registry that collects all data from HIV-positive women that have been exposed to these antiretroviral medications. And to date there really hasn't been a big signal for severe birth defects, with the exception of very specific antiretroviral agents [other than Truvada]. The data in HIV-positive pregnant women support that these drugs can be used safely.
But again, you really would want to identify women who are pregnant to let them know what the data is in HIV-positive women who have been exposed to these medications -- that there isn't that same type of data in women that are HIV negative and that there are potentially unknown risks, but that there has been extensive data [in pregnant women with HIV].
So, an HIV-negative woman who is pregnant but, let's say, at super-high risk for HIV acquisition: That's a decision that can be made between her and her provider about whether or not to start PrEP.
You referred previously to the importance of discussing adherence. We just walked through a few of the issues related to what needs to be discussed and considered with different populations. Let's take a step back and look broadly at: What is the informal checklist that health care providers should be going through in their heads when they are first broaching the subject of PrEP with a patient?
The CDC [U.S. Centers for Disease Control and Prevention] has issued guidances. Last January, they issued them for PrEP for MSM [men who have sex with men], and then just this summer they issued guidance for heterosexuals, serodiscordant couples.
You definitely want to determine eligibility. The first and most important thing is to document that the patient is HIV negative. This is really, really key -- I'll try to walk you through this: HIV tests can only pick up infection that's at least about a month old. These HIV tests, even the rapid test, those are what are called antibody tests. They take about a month [from the moment a person is infected with HIV] to come out positive.
So, if somebody was in very early infection and they went to get an HIV antibody test, or a rapid test, even though they were infected that test would read negative, because the HIV was still in that window period.
Typically, people with very early infection -- it's called acute or primary HIV infection -- have signs and symptoms. They're sick. They have fever, body aches, headache. Sometimes they'll have a rash, sore throat.
It's very similar to flu symptoms, right?
Very, very similar to flu symptoms. If someone comes in and you feel that they're eligible for PrEP, and their HIV antibody test is negative, yet they have these signs and symptoms, you need to defer starting PrEP until you can definitively say that this is not early HIV infection before you start. Because, again, what we talked about before: If you start someone on these medications [when they're already HIV positive], because it's not an optimal HIV regimen, then you will potentially cause them to select for resistance. And not only will they acquire HIV, but potentially a strain of HIV where they're actually resistant to the medication. So that's one thing that you definitely want to screen before starting a patient.
Before we move on from that, for those people, would the recommendation be, "Come back in a month; we'll do another rapid test, or maybe an ELISA"? Or would you recommend that they get, let's say, a PCR test to see whether they have an HIV viral load?
The guidance says you can do either one: You can either defer and test them in a month, once they're beyond that window; or you can do a test like a viral load test that can actually detect the presence of the virus. Either one.
I would probably want to do the viral load test, or a test that would specifically be able to detect virus. But the big issue here is that you pause and wait to either repeat the antibody test or to do another diagnostic test that will actually detect the virus.
Other things that you would want to screen for are just to make sure that their kidney function is normal. Also, importantly, the current medications for PrEP also have activity against hepatitis B, which could be a good thing, especially if a person has active hepatitis B. But if a person does have active hepatitis B, and you start them on this medication that will have activity against it, if all of a sudden you should interrupt or stop the Truvada, the patient is at risk for having a flare of their hepatitis B. Because once you take away the medication that's suppressing the hepatitis B virus, it can come back, and their liver enzymes can go up. They may become jaundiced, meaning a yellowing of the skin or under the eyes.
This is also a great opportunity, in terms of primary prevention, to actually immunize them or vaccinate them against hepatitis B, if they don't show any evidence of being infected.
Those are some of the things that you would want to do before initiating PrEP. Then, when you begin PrEP, you really want to have the patient understand that the medication has to be taken daily. Generally, you do not want to prescribe more than a 90-day, or three-month, supply. That's to ensure that they come back in for repeat HIV testing, but also so that you can monitor their adherence to the medications, and also monitor their labs. All of those are very important right at the start.
Then you basically would want to follow patients every two to three months, have them come in.
It's also recommended that you screen patients for any sexually transmitted infections. The reason for that is we know that if a patient acquires a sexually transmitted infection (STD) -- let's say, syphilis, gonorrhea or chlamydia -- that increases their chances of acquiring HIV. If a patient has an STD that enhances the efficiency of HIV gaining access into the body and causing infections, we know that we would want to treat those patients for their sexually transmitted infection.
Again, I think it's just a great opportunity to engage patients. In the iPrEx study, at baseline, 60% of the participants reported unprotected receptive anal intercourse. So that's already a pretty high rate.
iPrEx was a study specifically involving MSM, right?
Correct: MSM and transgendered women. What they found throughout the study was that those rates [of unprotected, receptive, anal intercourse] were nearly halved: By the end of the study, it was more like 30% of patients. So they were actually able to get more patients to use condoms consistently.
And that's an important message for PrEP, as well: PrEP has only been studied as part of a comprehensive prevention package, and that's how it was shown to be effective. It's about combining consistent condom use, lowering your number of sexual partners, treating any sexually transmitted infections and knowing your partner's status. All of these things really have to come together in order for PrEP to be most effective. It's not just giving somebody a medication and saying, "See you later." Because we know PrEP is not 100% effective. We know that there were [viral] breakthroughs even in patients that were on PrEP. And we know that certain behaviors can enhance the efficiency of HIV being acquired.
So, really, PrEP should not be used in isolation, but with a combination of all these other prevention practices and messaging.
Is there anything that patients and providers should know about cost-related issues? What kind of coverage is there for PrEP?
I think that's a moving target, as well. Once the FDA approves a drug for an indication, then typically what happens is that Medicaid will start to reimburse. Then it will be the commercial insurances, and then the pharmaceutical companies -- they have [traditionally] provided patient assistance programs for patients that can't afford the medications.
But I think that is the big elephant in the room: If PrEP is not covered, that's really going to limit its use, particularly for patients who just can't afford it. Then we're going to have this further split of only the wealthy being able to afford an effective prevention tool.
But again, typically, after the FDA approves a drug for indication, then the commercial insurances, Medicaid, etc., will start to reimburse the product.
All right, it still sounds like a bit of a question mark on that front. It sounds like there are a number of question marks on many fronts, as we move forward toward the actual implementation of PrEP in clinical settings. What other questions are there, at least in your mind, as far as the rollout goes?
I think people are waiting. They're in this kind of limbo with PrEP. There's an indication; it's been approved; the science is there; the data is there; the studies are there. But there is still a lot of confusion about: "How am I, as a doctor, going to be able to do this?" And more importantly: "Who can I turn to if I can't do this? What are my support tools?"
I think a couple of the key obstacles are just going to be buy-in: buy-in from the medical profession and the medical societies. Once we start to get that, then I think that buy-in will trickle down, and I think there will be more acceptance about this being as effective as, like, malaria prophylaxis or screening your patients who are diabetics with eye exams.
Again, I think the whole reimbursement issue is a big obstacle -- not just for the medications, but for the actual medical visits. How am I going to get reimbursed for these multiple visits that I'm going to have to do for patients who are on PrEP?
Also, there's a bit of uncomfortableness about having to discuss these issues that often go with high-risk HIV acquisition -- substance use, intravenous drug use, etc. -- all of these behaviors. "How can I, as a sole provider, manage these issues?"
I think all of these issues right now are causing a little bit of unrest, a little bit of uncomfortableness. That's why I don't really think we're seeing people grabbing the reins on this and moving forward.
I also think you have to really be thoughtful about the infrastructure of how you're going to set up dispensing PrEP, and what's going to be the context of that visit. Some ideas that have come out are that you may want to incorporate this as a sexual health clinic, or a men's health clinic, or a transgender sex health clinic [would]: where patients can come in; they can get treated for their sexually transmitted infections; get HIV testing. Then one could determine their risk for HIV acquisition and, with a team-based approach, start to move forward with PrEP.
I think that's how I would feel most comfortable: if I, as a provider, also had a team that I could work with. What I'm thinking about is a social worker who could work with me, or with a provider, in terms of reinforcing the messaging of risk reduction, distributing condoms, making sure they're coming in, getting tested and adhering to their medications.
Because of those unknowns about how best PrEP would be dispensed, I think you're right: I don't think that there's been a big scale-up quite just yet.
It's probably also worth noting, to one of your last points there, that even in the context of a clinical setting -- where there might be only a single provider in an office and one assistant -- throughout the country there are still HIV service organizations that are staffed by people who might be pretty knowledgeable about this, and might be willing to lend a hand.
Yeah, absolutely. I think that those are going to be the best models for PrEP, because just like you said, I think they are best equipped right now.
Organizations that offer HIV services: I think this is a great way to expand their service portfolio to reach out to those that are HIV negative, but at high risk. So I think that's a great suggestion, and I think that's what we'll start seeing: HIV service organizations, designated AIDS centers, really maybe taking the lead on PrEP.
Do you agree with the argument that some have made during the lead-up to PrEP's approval that, if people start taking PrEP widely, they will stop taking other risk-reduction measures, and might ultimately end up increasing their risk? Not just necessarily for HIV, but for other sexually transmitted diseases, also?
That's a very legitimate concern. The data to date has not supported that. The iPrEx trial did show an increase in condom use and a decrease in sexually transmitted infections.
To be fair, as you noted earlier, a lot of those pre-approval studies for PrEP involved more comprehensive prevention that was also done alongside the provision of PrEP. They were giving out condoms. They were counseling people on safer sex.
Right, and I think that that is a legitimate concern. That's why I really do think that you have to be very mindful about, when you decide to initiate PrEP, that you think about these types of contingencies. I think that an agreement between patient and provider, or between the patient and the health care team, about how PrEP is best used, how it can be most effective, really needs to be discussed. I think that there should be "stopping rules" for when PrEP could be irresponsible or may lead to more harm.
But that's the real-world data that I don't think we have quite just yet. Once PrEP does become available, are there going to be certain groups that now feel it gives them license to forgo the condom, to forgo having safer sex?
In Switzerland, they just published data that, when they looked at the rates of new hepatitis C infections in a cohort of patients -- and this is very recently -- there were more new hepatitis C infections in MSM, or males who have sex with males, than in the intravenous drug using population. I think [those data] support a lot of [these] issues. The support of needle exchange [for instance] -- but also that there are other pathogens, other diseases, that are transmitted through unsafe sex. I think one of the more concerning ones is hepatitis C, but also other sexually transmitted infections as well. So I think that is a potential risk. But that argument, in and of itself, I don't think should put the kibosh on PrEP.
Again, there has to be thought in how a provider, an institution, an organization, is going to dispense PrEP. I think there have to be very clear discussions that are ongoing about how PrEP is not something to be used by itself; that it has to be part of a prevention package.
Is there anything that we haven't touched on that you'd like to note about PrEP before we close up?
I think we did cover a lot of ground. I think PrEP, just like PEP [post-exposure prophylaxis] and antiretroviral medications in those that are HIV positive, is going to mature and advance. I think that the therapies are going to change over time, and that -- as it starts to get implemented, as it starts to get scaled up -- we're going to learn some very important lessons.
Chemoprophylaxis is something that could potentially really change the HIV epidemic, not just in the U.S., but around the world. Because we really do have to do something. There are still 50,000-plus new infections every year [in the U.S.]. We've done really lousy with HIV prevention, I think because it's difficult to change behavior. So here's something that we can combine with behavioral interventions. It's something that we can use as a catalyst to engage patients in healthy lifestyles.
Dr. Urbina, thank you so much for taking the time to talk about this.
This transcript has been edited for clarity.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.