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Michael S. Saag, MD: Hello. I'm Dr Michael Saag, professor of medicine and infectious diseases at the University of Alabama at Birmingham. Welcome to season 2 of the Medscape InDiscussion Podcast series on HIV.
Today we're going to discuss antiretroviral therapy (ART) guidelines. What's new in the field? Let me first introduce our guest, Dr Raj Gandhi. Dr Gandhi is a professor of medicine at Harvard Medical School, co-director of the Harvard Center for AIDS Research, and the director of HIV Clinical Services and Education at Massachusetts General Hospital. He's been actively involved in HIV care and research since 1996. Welcome to InDiscussion, Raj.
Rajesh Gandhi, MD: Good to be here. Thank you for having me.
Saag: Let's talk about some of the practicalities of when to start treatment. We're going to dig right in. How do you put this into context of when to start?
Gandhi: It's a good question. Over the past few years, there's really been a sea change in how we think about when to start treatment. You and I remember back before 2015, when there was really an intense debate as to when to start ART. That debate was essentially between the group that thought we should hit early, hit hard vs those who thought we should wait until the CD4 count fell usually below 350. A lot of that debate was fueled at the time by the recognition that the latent reservoir meant that ART could not cure HIV. Essentially, people need to be on therapy for a lifetime. It was also fueled by the fact that a lot of those early drugs, especially in the 1990s and early 2000s, were quite toxic — drugs like zidovudine (AZT), stavudine (d4T), didanosine (ddI), and the early protease inhibitors. It was in 2015 that the START study came out and showed that we should start HIV therapy regardless of CD4 count. The group that started early did better than the group that deferred ART. That's led to a "treat all" approach that is regardless of CD4 count. That's where we are today.
Saag: A lot of us were pushing for this approach back in the late 1990s because the biology was coming out saying that it was viral replication, this ongoing onslaught to the immune system of 1 to 10 billion viruses produced a day. When you give ART, you reduce that by orders of magnitude. We later found out that it's actually the virus itself that causes immune deficiency by gumming up the works of binding to CD4 cells and not letting the immune system talk to itself. I think that we've discovered along the way, too. You're right — the START trial was the icing on the cake, in my estimation. A lot of us were starting therapy on just about everyone, even going back to 2008 or 2009.
Gandhi: In that regard, one thing that has really come to the fore is not only do we start treatment regardless of CD4 count, but we also often start as soon as a patient is ready to start, as soon as they want to start — sometimes even on the same day or in the same few days after diagnosis, as long as you can line up the insurance. There's no reason to delay if the patient wants to start.
Saag: Exactly. I think the one place where we jump into treatment as fast as we can is in somebody with acute seroconversion syndrome. Can you take a minute and describe what that is and why we do that?
Gandhi: Acute HIV is the weeks that follow acquisition of HIV. Sometimes people have really distinctive symptoms. They can have fevers, they can have mouth sores, they can have pharyngitis. It can be a mononucleosis-like illness. So in anyone who you see with that constellation of symptoms, definitely think of HIV and think of ordering both an HIV RNA test and an antibody test. You want to order the RNA test because RNA turns positive even earlier than the antibody.
One of the reasons we treat acute HIV is for symptoms. Those people who have those symptoms will feel better if you start ART, and occasionally you'll avoid a complication. I've seen a patient with acute HIV who had meningoencephalitis, and certainly that's the kind of patient for whom ART will treat their symptoms and their condition. Even if the patient doesn't have symptoms, there's a lot of good theoretical reasons to treat acute HIV. You preserve their immunity, you preserve the ability for their CD4 cells to support their CD8 cells. There's a lot of theoretical immunologic benefit to treatment.
Last, but I will say not least, you can interrupt transmission. We know that someone who's had acute HIV is by definition someone who's been exposed to HIV, and therefore if you treat them, you will get them to undetectable sooner and therefore help reduce transmission to other people.
Saag: That is underscored by the fact that usually during acute infection, the viral load or the amount of RNA in the bloodstream is in the millions of copies. It settles down afterward. Viral load is an indicator of relative infectiousness, if you will. If somebody has a viral load of 6 million, they're much more likely to transmit the virus than, say, if the viral load were 60,000 or 6000, for sure.
Saag: Let's transition a little bit now that we know when to start treatment. Let's talk about what treatment to choose. This has changed dramatically in the past two decades. How do you put this all together in terms of what agents to choose? We have a lot of great regimens to choose from right now. How do you tell them apart?
Gandhi: We now have more than 30 possible medications to use. I used to put up a slide that looked like a NCAA bracket, where the drugs were going down to the Final Four and the final two. But now I think we're really at a pretty short list of what we consider first-line therapies.
You and I are both members of the International Antiviral Society (IAS)-USA. We recently put out guidelines in which we recommend for initial therapy that we give for most people one pill once a day, and that's usually in the form of an integrase inhibitor, either dolutegravir or bictegravir/emtricitabine/tenofovir alafenamide, I would say that's the most commonly used combination these days.
There are some instances where you can use two drugs rather than three. When we both started out, three drugs were always the mainstay. There is a combination of dolutegravir/lamivudine (3TC) that can be used for initial therapy, but I usually don't use it in someone with a very high viral load, where it hasn't been studied, or a very low CD4 count, where I want to use the extra additive benefit of having three drugs on board. I would say the first-line therapy is integrase inhibitor, usually with emtricitabine/tenofovir alafenamide.
Saag: It seems like a lot of us are using these medications almost 85%-90% of the time. What might be the exceptions where you would lean away from either an integrase inhibitor, or maybe more specifically, a tenofovir-based regimen?
Gandhi: One instance where you absolutely need the tenofovir on board is if the person has hepatitis B, because you need the tenofovir for the HIV but also for the hepatitis B. But at times you might steer away from tenofovir. The older formulation of tenofovir is called tenofovir disoproxil fumarate (TDF). TDF can affect the bone and the kidney. I would steer away from TDF in someone who has preexisting kidney disease or in someone who has preexisting bone disease — let's say osteoporosis or even osteopenia. The newer formulation of tenofovir goes by the acronym of TAF, tenofovir alafenamide, that you can use down to an estimated glomerular filtration rate (eGFR) of about 30. You can use it in moderate kidney disease. Once you get to severe kidney disease, below an eGFR of 30, then I would avoid even TAF.
Saag: I want to underscore that comment you made about hepatitis B because we mentioned the two-drug regimen of dolutegravir/3TC (lamivudine), and you don't want to use that with somebody who has hepatitis B co-infection because you'll get resistance to the 3TC within about 6 months or less. We want to make sure there's a tenofovir component in there.
What about resistance? Do you check for resistance before you prescribe? That would delay treatment by 4-6 weeks. How do you manage that?
Gandhi: That's a good question. I send the blood test, but I don't wait for the results. Fortunately, we're getting our resistance test back within about a week. We have an opportunity, if we need to, to adjust. But resistance is not seen in the majority of cases — that is, transmitted drug resistance where someone acquires resistant HIV. That happens probably well under 15% of the time and maybe even under 10% of the time. It depends on the drug you're looking at. I do send the test. I find it useful to know the information in the future should I need to change something. But most of the time, I'm going ahead with one of those first-line combinations and just adjusting if 4 or 5 or 6 days later, the resistance test tells me I need to do something else.
Saag: As recently as 5-7 years ago, we commonly used abacavir. That's fallen out of favor in the past couple of years because of the potential cardiovascular toxicity. To get that drug started, we typically ordered a special HLA B 5701 haplotype test. Do you still order that just to have it on the record, or do you just not bother with that anymore?
Gandhi: I certainly did order that for sure when I was using more abacavir, but since the concern you raised about abacavir and cardiovascular disease, these days, I'm not starting abacavir-containing regimens. I will admit that in the past few years, I've stopped ordering the HLA B 5701 test for that reason.
Saag: What about the use of another two-drug regimen? That would be either the injectable dolutegravir with rilpivirine, or there's also two-drug regimens that include rilpivirine and an integrase strand transfer inhibitor as a pill. Do you use those and under what circumstances?
Gandhi: The two-drug combination I use the most is dolutegravir/3TC because there are good data for it. There also are good data on a pill version of dolutegravir/rilpivirine, and so I used that for a while. I don't use it as much because our patients have to take rilpivirine with a fairly hefty meal — several hundred calories at least. Usually that's not a problem, but nevertheless I and our patients find it to be one other consideration.
Dolutegravir/rilpivirine is a good choice, but I use it somewhat less than dolutegravir/3TC. The thing to know about dolutegravir/rilpivirine is in the studies that supported it — they're called the SWORD studies — it was supported in people who did not have prior treatment failure. Do be a little cautious about dolutegravir/rilpivirine, especially if someone has failed an non-nucleoside reverse transcriptase inhibitor (NNRTI). The injectable, I think I'm using more and more, and that has the advantage.
If you have someone who is suppressed on oral therapy (ie, their viral load is undetectable), they have an option of switching over to an every-other-month injection of cabotegravir/rilpivirine. The advantage is that some people just hate taking a pill every day. It reminds them of their HIV. Maybe they have not yet disclosed their HIV status to their friends and family, and there's stigma around having to take a pill every day; sometimes they're even hiding their medicines. The advantage of cabotegravir/rilpivirine is you can take it just six times a year and it works almost as well as taking daily oral therapy, and in the vast majority of people, it keeps them suppressed. The disadvantage — and this depends on the person — is that the patients have to come to your clinic every 2 months. They can't self-administer this injection. It's administered in an awkward place in the gluteus medius, and it's just not some place that patients can find themselves. They have to get themselves down to the clinic. I would say it's becoming more and more popular.
Saag: I agree. It adds a little bit of extra burden on the clinic to track this and to get patients back in. I think most of us are figuring out ways to do that.
Let's pivot here a little bit and look at the incredible success that we've had over the past 25-30 years. Back in the 1980s and a lot of the 1990s, we saw people dying right and left of HIV. Now, with effective therapy, people are living not necessarily a full normal lifespan, but it is darn close to normal. I was just with Mary Fisher, the AIDS activist, this past weekend. She celebrated her 75th birthday, which was an incredible outcome. I've been taking care of her since the early 1990s, and it's just such a joy to see a lot of our patients getting older. With that comes some challenges of how to manage their ART and how to make adjustments as they get older. Could you help us understand a little bit of that and how you think about modifying ART or not as people get older?
Gandhi: That's a terrific question. You're absolutely right: Over half of the patients in my clinic are now over the age of 60, and it really is a sea change compared with 10 years ago, and especially compared with 20 years ago, where it was unfortunately rarer to see people live into their 70s and beyond.
A couple of things I'll say as people get older is that they often get other illnesses, and with those illnesses come other medications. One reason the IAS-USA and all the guidelines have moved away from some of our older combinations is to avoid drug-drug interactions. We used to use protease inhibitors frequently. We used to use what are called boosted regimens, which are regimens where there's a pharmacologic booster. We tend to avoid those now, especially in older people, because of drug-drug interactions. If someone is on a high dose of certain statin, for example, then that can interact with the meds that we used to use for HIV. That is a consideration. Sometimes we are still forced to use those older medicines. Maybe someone has HIV drug resistance. It is important as people are taking newer medicines to be aware.
I'm going to give you one very common example: An over-the-counter medicine, fluticasone, interacts with some of our older medicines. If you have an older person who, let's say, has chronic obstructive pulmonary disease (COPD) and they're taking the inhaled steroid, you do have to be very focused in on what we call polypharmacy — avoiding drug interaction. That's one thing, as an example that I pay more attention to.
Saag: We had a podcast earlier in this current series with Charlie Flexner, who went over a lot of these drug-drug interactions, and I'll refer the listeners to that if they want to hear more about it.
As you watch these changes happening, you have led the IAS-USA guidelines in the last iteration, which was released on December 1, 2022. It's very up to date. How do you go about incorporating things that are part of our changing world, like COVID and the introduction of mpox over the past summer? How do you go about in bringing this together to create a coherent document, yet provide folks with the up-to-date changes that have happened over the summer and into the current time?
Gandhi: It's safe to say that our field is never anything short of dynamic. Things are always coming at us. COVID and mpox are good examples, and these are now being layered on top of HIV because obviously people with HIV, like everyone else, can get COVID. People with HIV certainly have had some severe cases of mpox.
Let me start with COVID. For a person who has well-controlled HIV and has a very good CD4 count, let's say 500 or more, they're likely to do just as well or badly with COVID as someone else. Their HIV probably doesn't enter into the mix in terms of their COVID outcomes. The really important thing to say here is if I've got a person with HIV who's got a low CD4 count, they're at quite high risk for severe COVID. If I have a patient with a CD4 count of 200, especially if they're not on therapy, I'm worried about their COVID. In that regard, what can we do about it? We can do two things about it. One, we can get our patients all on ART, which is a goal for everyone. Second, we can make sure our patients with HIV are vaccinated and boosted.
In the last hours before we recorded this podcast, the US Food and Drug Administration (FDA) was in the midst of giving some new guidance and authorizations around boosters. I know even as we're recording, the CDC is meeting and we'll probably hear soon where they end up. I wouldn't be surprised if we're giving the so-called spring boosters for 2023 in people who are over the age of 65 or people who are immunosuppressed. Keep your eye on that, but do urge your patients with HIV to get boosted.
The other thing is if they get COVID, which of course people do, the therapies are largely the same as they are in people without HIV. Nirmatrelvir-ritonavir (Paxlovid), remdesivir, and molnupiravir are the same treatments that we use in our patients without HIV. Don't worry about the nirmatrelvir-ritonavir even if their patient is on ritonavir; because it's such a short course, it's not going to create any disruption. That's how I think about COVID.
Saag: I think that's a great point about the ritonavir because everyone kind of wonders, am I overdosing? Actually, no, because we used to use 600 mg twice a day of ritonavir in a liquid capsule formulation that had to be refrigerated. Those days are long gone. Even though the drug worked pretty well as an antiviral, it was ridiculously hard to tolerate.
Gandhi: Mpox thankfully has gone down in numbers compared with last summer. What we've learned in a little under a year is that the people who have the worst clinical outcomes with mpox are that same group that we worry about with the low CD4 count and not on therapy. There was a really eye-opening study that Dr Orkin from the UK led, where she made a cogent argument that mpox in some ways is an opportunistic infection. If you've got a person with a low CD4 count, you should be worried about them with mpox because it can be very severe and in a good proportion of people it can even lead to mortality. All the more reason to test anyone with mpox for HIV. If they have HIV, get them on therapy, take extra care, and maybe consider treatments like tecovirimat in immunosuppressed people with HIV.
Saag: I'm wondering what we might expect this summer. Are you concerned about another wave of mpox? I heard a lot discussed about that.
Gandhi: I think we will have a wave, but hopefully it'll be a small one. I think a number of people have been vaccinated and not everybody at risk has been vaccinated, but a good proportion are. I do think there have been some changes in terms of the behaviors and sexual partners. I'm hoping it will be more of a wavelet or maybe not a wave at all. Time will tell.
Saag: It's a good time for us to double down on getting that second vaccination, because I think that will go a long way.
We only have a few minutes left. Let me give you a chance to look into the future. With all the progress being made, what are our current gaps and how do you see those being filled?
Gandhi: I think we need to continue to work on getting people diagnosed earlier. Even in a wealthy country like ours, a good proportion of people present with low CD4 counts. We know that when you start ART with a low CD4 count, your outcomes aren't as good. That's what we've learned over the past years. Earlier diagnosis is key.
I think there is still a role for new drugs, in particular long-acting options. We alluded to the fact that for some people, taking a pill every day is a challenge and if we could get it down to twice a year, I think that could really help those people if we had an every-6-month option.
One thing we wrote about in the guidelines that you mentioned earlier, but I want to stress here, is management of substance use disorder and people with HIV. It really is an integrative approach. You can't treat the substance abuse without HIV. You can't treat HIV without treating the substance abuse. They go hand in hand.
Those are some of our ongoing challenges. That's why I continue to be excited about the work we do.
Saag: I agree completely. We actually had an earlier podcast on substance use that we can refer folks to as well.
As we anticipated, this time has gone by very quickly. Today, we've been talking with Dr Raj Gandhi about ART current updates. What we heard was that we're starting ART in most people at the time of initial presentation. We want to especially focus on getting treatment started very early for people with acute infection and get that done right away. We want to get started as soon as we can and make sure the patient is ready, but most patients really are.
As far as initiating therapy, most of us are now grounding our treatments in integrase strand transfer inhibitors as the anchor, often with either co-formulated or added tenofovir-based regimens and usually with FTC or 3TC. We talked about the nuanced but important issue about whether someone has hepatitis B co-infection, because if they do, then they really need to maintain the tenofovir. If they don't have hepatitis B co-infection, we could think about some of the two-drug regimens, like dolutegravir with 3TC or dolutegravir with rilpivirine, especially as a potential injectable that allows every-other-month injections, which help some of our folks.
We talked about the challenges of keeping guidelines up to date, most recently the new information about COVID and mpox. We anticipate in the future that we'll see more medications that allow us to use either injections or perhaps even longer-acting therapies, where we theoretically could dose once every 6 months or perhaps once a year; there's a lot of activity about that.
Finally, we spoke about the very important issue of making sure that we're taking care of the whole patient in terms of substance use and other challenges that a lot of our patients have. We didn't mention psychiatric illness, and it's sometimes hard to get patients to a psychiatrist, but we really need to continue to push for that.
Dr Gandhi, thank you very much for joining us today and thank all of you for tuning in. If you haven't done so already, please take a moment to download the Medscape app that allows you to listen to and subscribe to this podcast series on HIV as well as several others. For now, this is Michael Saag for InDiscussion.
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Cite this: What's New in the Field of Antiretroviral Therapy Guidelines for HIV? - Medscape - Aug 15, 2023.