Peep The New HIV Guidelines w/Dr. James Riddell

– What’s up Z-pack? It’s your boy, ZDoggMD and I am here with somebody you will recognize if you’re a fan of the show. This is my brother-in-law Dr. James Riddell. He is Professor of Internal Medicine Division of Infectious Diseases at the University of Michigan. And happens to be family. And we are on Oahu right now having a grand old time working hard like we always do. And Dr. Riddell, or Jamie to his homies if you’re nasty. Just did a editorial in JAMA that will have just come out about some new guidelines for the management of HIV. And I thought it would be really good to pick an expert’s brain about the management of a disease that for many people it’s fallen off our radar collectively. But it is still absolutely relevant on the front lines treating so many people which is, in a way, which is now a chronic disease instead of a death sentence. How we got there is a long story but what we do now is what you seem to be interested. Thanks for joining us.

– Yeah, absolutely. Yeah, it’s a pleasure.

– Are you having fun here ’cause I mean, I’m just sayin. Out the window here. When we’re done I’ll show you the view. It’s pretty dope. I mean, what got you interested in doing this editorial about the new guidelines. Why do they matter?

– Yeah so the guidelines are really important. They summarize all of the most recent data that’s available on treatment of HIV. So they release that every couple of years. Like every two years. Last one was in 2016.

– What’s the society called?

– So it’s The International AIDS Society USA that puts out these guidelines periodically.

– Sounds like a party bunch, man.

– Very, very smart people.

– Yeah, yeah.

– And they’re picked up by other, and they’re similar to other guidelines that are available. So there’s also the Department of Health and Human Services guidelines. If you go to a website called aidsinfo.gov it’s sort of the main place to go. All these guidelines are consistent. These guidelines in particular are published in JAMA every couple of years. The first ones are published in 1996.

– Wow.

– So if you remember way back then that was like in the days of you know, AZT. The protease inhibitors had just, you know sort of come out. Saquinavir. Indinavir. I mean, there’s drugs that we just don’t even use anymore. If they’ve changed dramatically, that’s like 22 years ago. So over that time. But all these new drugs developed. All kinds of new things we learned about HIV.

– Isn’t it interesting? It’s like HIV management is one of the greatest success stories of pharma. Like we were actually able to turn something that was invariably a death sentence except for those handful of non-progressors into something that’s managed as a chronic disease. And as an infectious disease doc, what’s interesting about Jamie is he’s really a primary care doc for people with HIV/AIDS. And so you have to handle the whole patient. Do these patients also have another primary doc, or no?

– Usually not, I mean often we’re their only doctors because we see these patients once every sort of three to six months, kind of time frame, very frequently, and so a lot of times because their insurance coverage these days.

– Yeah, yeah.

– It’s very hard to find primary care doctors. And so often we’re the only ones taking care of these patients, and so we provide all the primary care, all the vaccinations, you know, screening for cancer, mental health’s a big issue. So all of those things we manage in our clients.

– You said vaccinations. It’s bad enough that these folks have HIV, potentially AIDS, and now you wanna give them autism?

– Is that really what you’re about, professor? Now, and all joking aside, so, the new guidelines, what are the big take homes from what’s changed in what they ask?

– Yeah, so it’s happened over the last sort of five to six, seven, eight years as a change from protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

– NNRT’s, yeah.

– NNRTI’s, right. A change as using those as sort of your base drug to integrase inhibitors.

– Oh.

– Or INSTI’s as the other abbreviation for it, INSTI.

– I’m not very familiar with those drugs, teach me.

– Yeah, so integrase inhibitors, they’re really interesting drugs. They prevent HIV when it’s transcribed from RNA to DNA, it prevents that DNA transcript from being integrated into the host genome.

– Oh.

– So it inhibits the enzyme that causes that transfer to occur.

– Got it.

– And it turns out these drugs are very potent, so if you just give it, with monotherapy in like an experimental setting, viral loads go down, almost two logs, which is a large amount compared to other drugs, so they’re very potent.

– Yeah.

– And it turns out they have very few side effects, which obviously is very great for patients. And they can be combined into these single tablet regimens, so you kinda have this perfect combination, right, of a very potent drug that has what we call a very high genetic barrier to resistance, so meaning that it takes a lot, the virus has to mutate quite a bit to cause resistance to occur.

– Right, as opposed to AZT, or something, which, yeah, very quickly, monotherapy.

– It can happen if you have them on it more quickly. And so these drugs, it’s hard to develop resistance to them, they’re very potent, they have few side effects, and they can co-formulate into a single tablet. So, as you might imagine, that’s sort of the perfect sort of stem.

– How new are these?

– So, it’s been, I think the first integrase inhibitors were Raltegravir and, I’m guessing it’s probably been, like maybe I wanna say eight years, seven or eight years at this point. That was the first one that came out.

– Right.

– But what’s interesting is Raltegravir has to be given twice a day and it’s not co-formulated with into a single tablet regimen. So with these new guidelines, Raltegravir has actually fallen into alternative therapy, interestingly enough. Whereas the drugs that can be even once a day are still a primary therapy.

– Got it, which makes sense, because there’s less likelihood you’re going to develop resistance if you have a multidrug in one pill. Adherence is easier.

– That’s right, because adherence is so much easier.

– How about cost, though?

– Yeah, cost, I’m not super familiar with cost. I think they’re all fairly on par. And these are single tablet regimens, so it’s all your drugs in one regimen.

– Yeah.

– So as you can imagine that’s more expensive than the individual components.

– Yeah, yeah.

– But I think from what I understand of the cost, it’s on par with other regimens. Obviously newer drugs are more expensive, and so that does come into a play when we’re talking about these drugs going generic.

– Right.

– ‘Cause some of these drugs have now been around long enough that they’re going generic. So Tenofovir for example has gone generic. And what’s interesting about that is, TAF, which is just tenofovir alafenamide, has just been developed by the same company, interestingly enough. And it does not have the same side effects as tenofovir.

– Oh.

– So tenofovir can cause kidney damage and bone thinning. This new formulation does not.

– Oh, wow, what’s the difference, do you know?

– Yeah, it’s really interesting. So the difference is, this new drug gets concentrated into cells very rapidly.

– Uh huh.

– And the plasma levels–

– Are low.

– Are lower!

– Ahh.

– And so it does not get filtered through the kidney exactly, it doesn’t circulate. And so–

– Science!

– I love it.

– It’s amazing, isn’t it? So it’s designed that way, so that there’s gonna be an issue where you have cheap generic, probably tenofovir, which can have some side effects versus TAF which is virtually the same drug which doesn’t have side effects.

– Ooh.

– It’s more expensive. So it’s gonna be a challenge to see how this all gets sorted out.

– Those wily pharma people. As soon as something goes generic, “We’ll just make a slightly better brand name version!”

– It’s interesting, isn’t it. And so, we’ll see what happens with that. And that’s actually addressed in the guidelines, interestingly enough.

– Is it, yeah.

– Because, so how do you make that decision about switching, then, from tenofovir to TAF?

– Right.

– Right like, for all of my patients, I’ve been doing that, why wouldn’t you, right? Because it’s the safer drug.

– Right.

– But when cost comes into it, how do you deal with that? So I don’t have a great answer.

– Uninsured patients, indigent patients, et cetera, yeah.

– Right, or these drug assistance plans, the state drug assistance plans, they have a defined budget, how are they gonna spend that money?

– And so, are they gonna be pushing people to stay on tenofovir ’cause it’s cheaper?

– Right.

– And so that’s a real struggle.

– So what are the goals of the guidelines? Do they set some sort of end points, “We like to see this happen,” and–

– Yeah, so the guidelines are really, I sort of have a love-hate relationship with the guidelines. I love them.

– And I wanna interrupt you for a sec, because I have a love-hate relationship with guidelines period. Because they are, it’s a bunch of old guys sitting around a table looking at evidence, you’re one of them!

– Right.

– But you’re not very old. And so, it’s always a little bit a mix of evidence and intuition, and yeah.

– Yes, so that’s the issue, you can see sort of opinion creeping in there.

– Yeah.

– And so, that’s where the peer review process is important.

– Mm.

– So hopefully the people who are reviewing these guidelines will pick up on where the opinion is there, and where really you should be focusing more on specific data. I’ll give an example. There’s a statement in the guidelines about the use of Genvoya, which is a combination integrase inhibitor and dialysis.

– Mm.

– There’s some, a little bit of data, suggesting that that’s okay. But there’s not a lot of data, there’s not peer reviewed data.

– Mhmm.

– So when you see statements, you’ll see a statement in the guidelines saying, “Well, it’s okay, there is some data for use of, “this drug in dialysis.” But you have to think to yourself, okay, what is that data?

– Yeah, yeah.

– Is the critical interpretation, and should I really be doing that?

– Yeah.

– With just, say, a study that was 100 patients, it was an abstract form and not published, you know what I mean?

– Yeah, yeah.

– And so when you read the guidelines, you have to be critical.

– Yeah.

– And if you see something there that doesn’t make sense, check the reference.

– Is that your job as an editorial writer? So you’ve written this piece in JAMA, looking at the guidelines. Is your role to kind of be another look at this and go, “Eh, this makes sense, this is a little squirrelly.”

– Absolutely, yes. So my role, what I tried to do in my editorial was to say, okay, here’s the things that are new and interesting, exciting. So, for example, the things we’re talking about, integrase inhibitors. Now, bictegravir, which is a new integrase inhibitor and dolutegravir are the two preferred integrase inhibitors. That’s important. And then the other integrase inhibitors have been bumped down to alternative, raltegravir we talked about.

– Right.

– We didn’t talk about elvitegravir. Elvitegravir is in a drug called Genvoya, it’s kind of combined.

– Yeah.

– But the problem with that drug is.

– It’s metabolized through cytochrome P450, and so you get these drug interaction issues.

– Yeah, with everything, yeah.

– Yeah with everything. So that’s been bumped down to alternative. So I thought that was really interesting. So that’s sort of one thing I tried to convey. But the other is sort of what you just said, sort of interpreting critically what’s in there.

– Yeah.

– So, I mentioned one thing I was a bit critical about. The other thing I was critical about, they talk, there’s a section there on cash transfers. Are you familiar with this?

– No.

– Incentivization. So, you have–

– This sounds interesting.

– And so, our goal as HIV practictioners is to get people to take medication every day.

– Yeah.

– So that it suppresses viral load to undetectable levels and also makes sure folks are coming back in to get lab monitoring, coming into clinic visits, making sure they don’t have any side effects to the drug, and making sure everything’s going okay. So, but in some cases, that doesn’t happen.

– Mm.

– For whatever reason, patients are unable to come back to clinic visits, whether that’s related to mental illness, substance use, any of the number of socioeconomic factors. Difficulty with transportation.

– Upstream medicine, all the social determinants and stuff.

– Yeah. And so, how do you maybe add an incentive to try to overcome some of those barriers? Right, so, if it’s travel, what about providing money–

– Right.

– To alleviate that. Or, if it’s missing work, again, providing some cash assistance to compensate for that missed work. Interesting idea, right?

– Kinda paying for adherence.

– Exactly, so does that work?

– Huh.

– So that’s been a question, and so that’s something I’m also interested in studying overseas. So we’re developing a study for that right now.

– Where overseas?

– That was in Mozambique.

– Oh, that’s just down the street, Mozambique. Go somewhere real, dude. That’s not even a foreign country.

– It’s a passage in eight minutes. So, they studied this in the US, and in one study, in drug users, who were seeking treatment.

– Mm.

– You know, seeking in rehab, they used, after they left rehab, they used cash transfers to try to get them to come in.

– Okay, so I was actually gonna say, it sounds like something that would work, and I’ve never heard of this, it sounds like something that would work in the opioid world to test. Now, would it actually work?

– Does it work, that’s the question.

– Does it work.

– In this situation, it did not.

– Oh.

– Interestingly enough.

– Yeah, it doesn’t surprise me.

– And so that population, maybe it’s not gonna work, but in another study that was done where they just took different health clinics, so this was done in New York City and DC, Washington DC, and they took a bunch of different, I think it was 18 different clinics where they randomized them to either provide cash transfers to patients or not. And the cash transfer group, they actually did suppress the viral load more often than the non-cash transfer group. So I think it was about a 3.8% difference, which was .01, P=.01, it was, this was an amount.

– Yeah.

– So there may be some benefits there.

– Well, here’s the question, do they look specifically at their adherence or could it have been that they were buying food with that money?

– It could be anything.

– And better nutritional support.

– It could be any of those things, and actually that’s a good point. A better nutritional support will improve adherence.

– Right.

– Because, often, and this occurs actually in the developing world, hunger–

– Yeah.

– So the reason why patients often do not take their HIV medicine, because it can induce hunger.

– Right, right.

– And so again, that was our idea in Mozambique, was to see if we could overcome some of that with cash transfers.

– It’s interesting, because you have a medication that says take with food. If food is a limiting factor, that’s another piece. And again, because we talk a lot on the show about social determinants of health and how they really are almost everything. 80, 90% of effect. And then you have us at 10%.

– Right.

– But you know what’s interesting about what a lot of what you’re saying is, a lot of people don’t realize infectious diseases, HIV in particular, is a intellectual paradise in terms of having to think a lot. So you’re thinking about the best drug regimens, you’re thinking also about social determinants and how to coordinate care. You’re a primary care physician and specialist at the same time, and you have to look at the economics of the drugs.

– Right.

– And the subtleties of, how are you gonna suppress viral load? You said something earlier off camera about 90, 90, 90, some sort of goal.

– Yeah.

– What is that?

– Yeah, so 90, 90, 90 goal, this is sort of a global sort of ambition to diagnose 90% of patients who have HIV. So, interestingly you’d say, well these numbers we have, you know there’s 1.1 million people infected with HIV in the United States.

– That’s a lot of people.

– That’s a lot of people. It’s also an estimate, because there’s about, I think it’s around 10% or 20%, I believe, that are considered to be undiagnosed. So that’s a problem, right?

– Yeah.

– Because, that’s 20% of people who don’t know they have HIV, who are more likely, the most likely, actually, to transmit to others.

– Yeah.

– So one goal is to try to decrease that number of people who are undiagnosed.

– Mhmm.

– So that’s the first 90. The second 90 is, okay, once you’re diagnosed, these people need to get into medical care.

– Yeah.

– So 90% of the people who are diagnosed get into medical care.

– Got it.

– So that’s the second one. You’d think, well, piece of cake, right?

– Right.

– But it doesn’t happen.

– Yeah, of course not.

– And so many people are not, even after they’re diagnosed, they’re not getting in to see doctors.

– Try that goal with diabetes, you’re never gonna reach 90. What’s the third 90?

– So the third 90 is 90% of those who are in care with undetectable HIV viral bug. Because we know that number one, if your viral is undetectable, that’s good for your health. It’s going to maintain your CD4 cell count, and it has all kinds of health benefits. Decrease inflammation. And the second big part of it is, you’re basically, you cannot transmit HIV to others if your viral is undetectable.

– Mm.

– This has now been shown in several studies.

– Yes.

– And this is this u equals u, sort of campaign, I don’t know if you’ve heard of this.

– No.

– Undetectable equals transmittable.

– Oh wow.

– And so, its’ really been empowering, actually, for patients to understand that now, because a lot of patients are very fearful. Even with condom use, in terms of having sexual relations with others, is they’re worried about transmission.

– Yeah.

– HIV.

– You know, that u plus u campaign definitely beats the campaign that I was proposing which is, u plus me equals us. Which is probably not a great, you know, avoid sexually transmitted illness campaign. And, speaking of, you mentioned preventing transmission. Is the pre-exposure prophylaxis that exists in HIV, is that commented on in the guidelines, and if so, how?

– It is, yeah. And so I think this is also really important. Actually the last two guidelines have mentioned prep as being an important component of controlling the AIDs epidemic, and so that’s what I like about how they’ve structured the guidelines. So now it’s not just about treating people who have HIV, it’s about addressing the epidemic as a whole.

– Ah.

– And so a big part of that is, one, diagnosis, like we just talked about, diagnosing people enhanced testing, broadened testing, but two is prevention with prep, so that’s Truvada that we use for prep, and making sure that’s available to people who are at risk. In addition to condom education about condom use. And then they also do address this issue of trying to figure out how to make sure patients are following up with care. Maintaining care, maintaining adherence, that’s all addressed in these guidelines, which I think is also just very important to think about. And also, you having to realize these guidelines are a starting point.

– Right.

– And so, the guidelines are there. We have this incredibly complex medical system that should be able to take care of these patients, yet we’re not able to. Why is that?

– Are any of us surprised, working in the healthcare system?

– Right. I mean, and when you look at right now, where are we? So right now, only about 50% of patients who are diagnosed with HIV have undetectable viral loads.

– Ah.

– I think that’s horrible.

– Yeah, it’s terrible, yeah.

– Because we have the capability to do it, we have the physicians to do it, we have the medications to do it. We’re in a rich country, why can’t we do better?

– Yeah.

– You look at some of these other developing countries, they’re able to achieve these 90, 90, 90 goals. And I think a big part of it is the fact that they have free medication and free healthcare. So it’s very easy for patients to access healthcare and get to medications. Even with the system we have of ADAP, AIDs Drugs Assistance Program, it requires paperwork to be filled out, like every six months, you have to document this that and the other thing. Do people do that?

– Don’t do it.

– Don’t do it, whatever, life gets in the way. So they stop taking their medications because they’ll go to the pharmacy, and the pharmacist says, oh, your ADAP ran out.

– Oh.

– You can’t get your meds. And so a patient at that point has one of two options. They can call our clinic, have our social workers help ’em figure it out, or they can just say, eh, I’m too busy right now.

– Yeah, and then the viral load goes back up.

– And the viral load goes back up.

– And then, suppressing it might be harder next time if there’s resistance developed.

– Exactly, that’s exactly it.

– Wow. And again, none of this surprises me or any of the Z-pack, because we know how American healthcare works. And I’m not saying, wave a magic wand and have single pair, although that may be one answer, it may be more we need to think very cleverly about the barriers to treatment, overcoming them in certain populations, and then being a little egalitarian about it. If we’re doing this for HIV/AIDs, can we do this for cancer and for drug abuse, and for all the other things–

– Hepatitis C.

– Hepatitis C, diabetes, undiagnosed untreated diabetes, rampant. All of those things. So, to sort of summarize it all, what’s your big hope people will take away from these guidelines and what do you think are the biggest sort of challenges and opportunities coming up now for HIV.

– So I think the biggest takeaway from me, and so how have I changed my practice, for example.

– Yeah.

– You know, sort of in regard to these guidelines, I think the biggest way I’ve changed my practice recently is the use of bictegravir, which is one of those preferred integrase inhibitors I mentioned. Bictegravir is a new one, it’s just like dolutegravir, which is one of the more potent effective ones that we have. It’s combined with TAF and emtricitabine in a single tablet. So why is this drug of interest and why do I think it’s good? Number one, again, it’s very potent, low genetic barrier to resist, er, high genetic barrier to resistance. And so I think it’s very useful for rapid start situations. This is the other thing we haven’t talked about is when to start antiretroviral therapy.

– Yeah, right, yeah.

– And that’s another new thing in the guidelines, they’re recommending basically immediate start.

– Oh, right away, soon as you’re diagnosed.

– As soon as you’re diagnosed, as soon as you’re seen by a physician, you start treatment right away. You don’t wait. And so that, previously–

– Yeah.

– We get labs, and we would see what the CD4 count of viral load was, went through resistance testing.

– Oh, yeah, yeah, yeah. Jump through the hoops, yeah.

– Yeah, jump through the, that’d take a month, and maybe the patients would come back, maybe they wouldn’t–

– Maybe they wouldn’t, so you miss that opportunity.

– So you miss an opportunity, so what we found now with several studies, is if you start treatment right away, patients like it. They expect it, you reduce the viral load much faster, so when you compare it with usual care, people in these rapid start protocols reduce their viral to undetectable in about a month and a half or so. Compared to like four months in the old system. So that’s a good thing, right, because the faster you reduce your viral load, the less likely you’re gonna transmit HIV to others, your health is better.

– Yeah.

– And so rapid start is the way to go. Now, circling back around to the medication, so what medication would be best to use in a rapid start situation? Well, you want one that we’re not gonna have a resistance issue. You want it to be very potent in a single tablet regimen, preferably taken with or without food, for the other reason we were just mentioning. And this new drug, bictegravir, with TAF and emtricitabine fits that bill.

– Mm.

– And so I think it’s a drug that we’re going to be seeing used much more often and that’s figured prominently in the guidelines–

– Awesome.

– As a first line option. So that’s sort of one thing–

– Mhmm.

– I took away from it. The second is of course the rapid start. I think it’s been reinforced that that’s the way to go–

– Important, yeah.

– It’s important. So I think that those are the two big–

– Big takeaways for people treating HIV. And for patients.

– For people treating HIV, yeah.

– Well, let me ask you this question. So, for my fans who are often afraid of needle sticks exposure, has anything changed in the guidelines as far as post-exposure management?

– You know, they don’t talk a lot about post-exposure prophylaxis in these guidelines.

– Mhmm.

– One thing, though, that I will say that will affect that. So, dolutegravir is one of the drugs that we have been using for post-exposure prophylaxis.

– Right, the nurse gets a stick, it’s an HIV positive patient.

– So the other new thing in the guidelines that just came up, I’m actually surprised they were able to fit ’em in, because it’s just hot off the presses from about a month ago.

– Yeah.

– Dolutegravir has been found to have a slight increase in neural tube defects in pregnancy.

– Oh, okay, that’s key, yeah.

– Which is important to know about. So this is a study, it was being done in Botswana, they were comparing dolutegravir-based regimens with other regimens. And they found that the people who were taking the dolutegravir-based regimens had a .9% incidence of neural tube defects in pregnancy, whereas the baseline was around 0.1%.

– Ah.

– So it does seem like there might be something there, but what’s interesting is other studies have not shown that.

– Right.

– And so this is preliminary data, so again getting back to sort of the interpretation–

– Of guidelines, yeah.

– How important that is.

– Yeah.

– But this is something that’s been released by the FDA and WHO, so it’s out there.

– Mhmm.

– And I think for right now, until we know more, dolutegravir should be avoided in pregnancy. So, circling back around to PEP, post-exposure prophylaxis, if your nurse, who is potentially pregnant or wants to conceive, dolutegravir as part of PEP should be avoided.

– Got it, got it, got it.

– For that reason.

– That’s good to know, so these kind of things actually have practical implications for frontline providers who maybe don’t think they’ll ever intersect with the HIV world.

– That’s right.

– Because sometimes life gets in the way, and our work gets in the way. And the last question is, what do you think are the are there big financial conflicts, these are multi-billion dollar blockbuster drugs, are there big financial conflicts in terms of incentives, in terms of designing these guidelines? Like, is pharma paying for the guidelines? ‘Cause that’s a common question people will be hearing.

– Yeah, that’s a good question. No, this is an independent group. As far as I know, is not funded by pharma, you know, in JAMA, you can dig through and find out what all the conflicts of interest are.

– Yeah.

– They’re all in there.

– Yeah.

– And a lot of the folks who write these guidelines, they do do big studies, they do have some pharma funding because they’re helping develop these drugs, I mean all of us in the academic community–

– Are contributing.

– Are part, we’re all contributing to the development of these drugs ’cause we have academic clinics, and we have the capability and know-how to do these clinical studies, and so, yes, I’m sure some of the people who are writing these guidelines have been involved in the development of these drugs.

– Yeah.

– Just because of what they do. But, I think you’re right, again you just have to look at what’s there and interpret it with caution, when you do see conflicts.

– Yeah.

– But I think they’re sort of inevitable.

– Yeah. But knowing what they are, having them be disclosed.

– Exactly.

– And then making decisions in an educated way.

– Based on that.

– With the help of people who, like Dr. Riddell, write editorials to help us parse through complicated guidelines that may not be perfect, ’cause no guidelines are.

– That’s right.

– And so, this again, hot off the presses in JAMA, new guidelines for HIV/AIDs management, Dr. Riddell has an editorial in JAMA that just came out, and we’re lucky enough to talk with him here on the beautiful island of Oahu. Happens also to be my brother-in-law, ’cause like Trump, I’m all about the nepotism, you know what I’m saying? Arr, matey! Should we show ’em what the view is?

– Oh, definitely.

– Look at this, Z-pack. This is where we’re talking. I mean, come on. Come on! Come on, CME to the extreme, people. Jamie, thank you again for everything.

– Absolutely, it’s my pleasure.

– And we out, peace.