Viremic – Cases in HIV

Announcer:
Welcome to Viremic–Cases in HIV, hosted by Dr. Eileen Scully and Dr. Christopher Hoffmann, both HIV specialists at Johns Hopkins, who explore quandaries in adult HIV care. Each case discussion includes medical history and diagnoses, challenges in care and treatment, and key evidence and guidelines that inform clinical decision making.

Cases are presented as a composite from the hosts’ clinical practice, with all identifying details removed to protect the privacy of patients. Case discussions are for informational purposes only and not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use only, not an endorsement.

Dr. Eileen Scully:
Hello and welcome to Viremic, a podcast where we talk about everything related to HIV. I’m Eileen Scully coming to you from Johns Hopkins. Today, I am so grateful to welcome my colleague here at Johns Hop-kins, who’s also a mentor and a friend, Dr. Joel Blankson.

Dr. Blankson earned an MD from Cornell and a PhD from Rockefeller in their joint program before com-ing to Johns Hopkins as an Osler medical resident. He completed training with infectious disease fellow-ship and then returned to the laboratory bench side for a postdoctoral fellowship with Dr. Bob Silicano. During that time, he continued to care for people living with HIV and began his career as an HIV immu-nologist. In the time since then, he’s made seminal contributions to our understanding of how CD8-positive T-cells respond to HIV, and in particular, to the immune responses of those very rare individuals who spontaneously control HIV even without medications.

Over many years as an investigator, he’s also maintained a strong focus on patient care. He continues to teach residents, which he’ll be doing right after we finish recording today, and running our inpatient HIV Polk service here at Hopkins. He is truly a model of the physician/scientist. It’s an honor to welcome you here to the podcast today, Joel. Thanks so much for joining us.

Dr. Joel Blankson:
Thank you, Eileen. It’s an honor to be here.

Eileen:
Before we dive into the case, I was hoping you would say a few words about why you followed your par-ticular career path of both clinical care and research. In the current climate, there’s so much uncertainty that might dissuade people. So, I would love people to hear about what you think makes this career unique and fulfilling.

Joel:
Sure, in college in New York City in the 80s, the AIDS epidemic was out of control, and we had no treat-ment for patients. It was clear that we needed to understand the disease a lot better to be able to come up with therapies. So that inspired me to become a clinician and a physician/scientist as well.

Eileen:
I love that reflection, Joel, because we’ve had a number of people who’ve talked about the urge to care for people in that moment. But you’re talking about that other urge, which is the urge to increase what we know. We know this also from the COVID pandemic, where you did amazing work. That’s a huge part of building a response.

Joel:
Yes, there’s so many things in medicine where we don’t have all the treatment that we need to take the best care of patients. So, we have to push and come up with better treatment modalities, and the only way we can do that is by doing the research.

Eileen:
That’s so true. I love centering that at this moment when I think many people have been questioning the value of research, especially when we’re not quite sure what it will lead to. But you’re exactly right—the only way we get things better is by learning more. So, thank you.

Now we will get started on our case for today. You’re seeing a new patient, a 28-year-old man, we’ll sug-gest, for this composite individual. He reports that he was recently tested for HIV and found to be posi-tive. He’s a man who has sex with men and was previously on PrEP with FTC/TAF but has not been pre-scribed it for more than a year.

His last HIV test was about 18 months ago. He recently received an anonymous notification from the health department that he’d been exposed to HIV. This prompted him to get tested with his primary care physician, and he was found to have a positive fourth-generation antigen/antibody screen.

He spoke with his primary care provider, who ordered a few more tests, including kidney and liver func-tion, complete blood count, an HIV viral load, and a CD4 count, and referred him to your clinic. As you’re reviewing the case before you meet him, you note that his HIV viral load was undetectable, and his initial CD4 count is 800. The remainder of his labs are unremarkable. His past medical history is only significant for acne during his teens and some mild dyspepsia for which he takes over-the-counter omeprazole.

When you’re seeing this type of result—a positive antigen/antibody test and a negative HIV viral load—what are the things that you’re sorting through in your mind?

Joel:
In this case, his last HIV test was 18 months ago, so this is a recent infection. I think about acute HIV dis-ease. He could theoretically be in the eclipse period. But typically, your viral load will come up before your antibody does, and if the fourth generation is positive, you would expect the viral load to be posi-tive. Now, he’s been on PrEP, and it’ll be good to know whether or not he’s been actually taking it more recently or not, because as we know, being on PrEP can lead to a delay in the diagnosis of HIV and could artificially suppress his viral load.

So, the last thing, or the most common thing in some cases, would be elite control, where patients have HIV as determined by a positive antibody test, but have undetectable viral loads. This is a diagnosis of ex-clusion, so you have to rule everything else out, including surreptitious antiviral drug use, but it does happen, so it’s something to be considered.

Eileen:
I can fill in some more history here. He has not been sexually active for about 2 months, which makes any kind of acute eclipse period weirdness very unlikely, although I agree with you that the eclipse period should be more antibody undetectability. He confirms that he’s been off PrEP, not just that he stopped being prescribed it.

You made a really important point there because sometimes people have PrEP around and they take it when they think they need it and then they don’t. So, just because he hasn’t been prescribed it doesn’t mean we shouldn’t ask him when he most recently took it, but he finished his last prescription about 10 months ago and reports that when he was on it, he took it very faithfully.

You repeated the viral load again just to make sure it wasn’t a random lab error, and that test is again un-detectable. Does that get us to elite control for this person?

Joel:
If you can rule out any antiretroviral drug use, it does get you to elite control. Go ahead.

Eileen:
As you say, ruling it out, I have experienced this where a patient was, as you say, surreptitiously taking ART. When I called him to discuss his undetectable viral load, he was open about it. But in this case, he confirms that he’s not taken any medications, hasn’t even taken the omeprazole recently, and he really did run out of that PrEP. I will give you that we’ve really excluded it, at least to the best of our ability.

Joel:
Then in that case, it does sound like elite control. I define that as being HIV antibody seropositive, having undetectable viral loads, less than the limit of detection, which in this case will be less than 20 copies per ml. Now, there’s a spectrum of patients who have lower viral loads.

We sometimes refer to “viremic controllers,” who have viral loads that are detectable, but less than 2,000 copies per ml. And then there are elite controllers who have completely undetectable viral loads. Sometimes we put them in the same blanket of HIV controllers. So, it is good to distinguish between the two cases. In this case, this is an elite controller because this viral load is less than 20 copies per ml.

Eileen:
Well, that’s very helpful. One other term I’ll throw in is “long-term non-progressor.” That nomenclature specifically refers to CD4 decline but typically is also associated with relatively lower viral loads, but I think it probably varies based on the paper. Do you agree with that?

Joel:
Yes, long-term immune control is based solely on the CD4 count. You can be a long-term non-progressor and have a very high viral load. It’s unlikely, but it does happen. And you can be an elite controller and have a very low CD4 count. That happens as well.

Eileen:
Before we move on any further, I’d love for you to talk a little bit about how you communicate this type of diagnosis with a patient. How do you explain elite control? What do you counsel them if they ask, “Does this mean I’ll always be an elite controller?”

Joel:
It’s typically something you have to go over more than once because it’s not an easy concept to under-stand. You tell patients, “You’re infected,” but there’s no virus in their blood. And they’re like, “What? Am I infected or not?” It’s something you have to repeat and try to get them to understand that most people have a viral load of at least 30,000 copies. There’s a spectrum of viral loads and they fall at the very, very low end. People have to understand that, yes, you’re elite now, but doesn’t mean you’re going to be elite forever.

There is a certain percentage of patients who will break through and become viremic. Other patients will stay with undetectable viral loads but have a gradual decline in the CD4 count. The patient has to under-stand that. They still need frequent testing to make sure that nothing changes.

Eileen:
That’s a great jumping off point for 2 other questions, one of which is, if an elite controller is off treat-ment, how frequently do you suggest monitoring their viral load? Every 6 months? Every 3 months? What’s your general practice? I don’t know that there’s a firm guideline here.

Joel:
I stay with the 6 months’ time frame. If you’re going to break through, it happens most frequently within the first year. But after the first year, there is a percentage of patients who do break through. Routine testing is needed. That’s what I would do—every 6 months.

Eileen:
Do patients ever ask if their immune system is sort of super-powered for other infections too? Is that a question that you’ve heard?

Joel:
Patients hear that they’re special, and they think that extends to other viruses and everything else. So, you have to keep explaining to them that this just pertains to HIV.

Eileen:
That leads us to the next thing I was hoping you could talk about. You’ve been studying people with these elite control phenotypes for more than 20 years. I was wondering if you could walk us through a high level of discussion of what we know and what we don’t know about how the immune system actual-ly does control HIV.

Joel:
The first thing I’ll say is that while we call everybody an elite controller, they are in fact a very heteroge-neous population of patients. Every elite might be a little bit different. Now what we do know is that most of these patients do in fact have replication-competent virus. So elite control is not due to them having some kind of defective virus. They have virus that can replicate.

We think it’s a host response that controls the virus. In terms of the mechanism, I like to joke that there have been more mechanisms proposed for elite control than there are elite controllers. Everybody has their own pet theory. But the most objective way of looking at this is with the genome-wide association studies, and every genome-wide association study ever done has pointed towards HLA alleles. HLA-B57 and HLA-B27 are overrepresented in most, or at least the majority of these, elite controllers. We know HLA presents antigen to CD8 T cells, and many studies have shown that these patients have superior qual-itatively impressive CD8 T-cells that can inhibit HIV replication. I think that’s the most likely mechanism by which viral replication is controlled in these patients.

Eileen:
Just to summarize what you’re saying—there’s a genetic predisposition, which is helpful, although not required, where the presenting component, the part that actually holds up the antigen or piece of a vi-rus, is a specific type and that leads to better T-cell responses to HIV.

Joel:
That is correct.

Eileen:
But it seems like now can you just test for that genetic predisposition and say this person will be an elite controller?

Joel:
You unfortunately can’t do that. I mentioned HLA-B57, and I’m sure that rings a bell to many people. They remember abacavir hypersensitivity is mediated by HLA-B57, and most of those patients are not elite. So yes, if you have HLA-B57, you’re more likely to become an elite controller, but the majority of patients who are HLA-B57 positive are not elite. Furthermore, you don’t need to have HLA-B57 or HLA-B27 to be an elite. So, there’s an association, but it’s not a one-to-one correlation.

Eileen:
A solid finding, but neither necessary nor sufficient, so I guess there’s still plenty of work for you to do in figuring out how all the elites become elite. We will get you back to the lab shortly, but before we do that, thank you for laying that foundation so our listeners can have a basic understanding of the state of the science of how elite control comes about.

Now let’s talk a little bit about what elite control means clinically, because you’ve got a 28-year-old man sitting in front of you wondering, “OK, so what does this mean for me?” In the current guidelines for treatment of HIV in general, we recommend antiretroviral therapy for all people, including elite control-lers. Can you give us a little insight into why that recommendation would exist?

Joel:
Well, one thing to know is that we have shown that the virus in elites does evolve over years. So, if you sequence the virus today and you sequence it in 2 years, the virus has evolved. That means there’s ongo-ing viral replication. The CD8 cells are really good at controlling viral replication, but they don’t com-pletely shut it off. This could be partially because you have viral replication in sanctuaries like B-cell folli-cles, where CD8 T-cells are not able to get in. If you have ongoing viral replication, there’s a good chance you’re going to have inflammation. There are lots of clinical studies showing that patients who are elite controllers have more inflammation than patients living with HIV who are on antiretroviral therapy. Again, remember, elite control is a very heterogeneous population of patients. The majority of elite con-trollers have more inflammation, but some have no inflammation at all.

Is this something that we just measure in the lab when we say “inflammation”? Mostly yes, but there have been studies that have looked at clinical outcomes and shown that patients who are elite control-lers are admitted more often than patients who are on antiretroviral therapy. There have also been stud-ies that have looked at carotid plaques and shown perhaps an increased frequency of carotid plaques in elites, although other studies have not confirmed that. So yes, that’s where we are.

Eileen:
So, the hierarchy you’re outlining there is that untreated HIV is the worst, no HIV is the best. Where do elites fall? Do they look like people on treatment? Do they look like healthy controls? It looks like, on at least some measures, they have more inflammation than people on treatment, so people who weren’t elite controllers but are now fully suppressed. With that impetus, we look to antiretroviral therapy to turn off that small amount of residual replication that you’re talking about that can be measured only in laboratory assays, but we know is probably happening somewhere in the body. Does that summarize it?

Joel:
That summarizes it pretty well, yes. And again, just to remind people that it’s a heterogeneous popula-tion. Some elites have a lot of inflammation, and some have none.

Eileen:
To drill down on that point a little bit, there’s no clinical marker we can send to figure out if an elite con-troller is one of the ones with inflammation or without, correct?

Joel:
That is correct. Nothing you can send in the lab directly, no.

Eileen:
I think that one of the drivers of the current recommendation is that many of the available regimens are so well tolerated with so few adverse effects that since we can’t identify those who will most benefit, we try to do what will benefit the median or the majority, which we believe in this case to be turning off that residual replication.

Joel:
That is absolutely correct, yes.

Eileen:
We should mention here that there have been 2 smallish clinical trials that have tested whether starting antiretroviral therapy causes a decrease in inflammation. They were not using clinical markers, but la-boratory-based markers, and both of them showed modest declines in inflammatory markers, nothing that was amazingly significant. The differences between the groups are also quite small, and there is a lot of heterogeneity.

Joel:
That’s correct.

Eileen:
So, I guess the first indication for treatment of an elite is that there’s likely some amount of replication of HIV that’s being controlled by the immune system, and ART will unload that burden. I guess that would be the first point that you would discuss with the patient. But now let’s talk about some of the other ways that we arrive for treatment.

You mentioned that the CD4 count can do some different things in elites. Over the years, I’ve had a few patients who, despite remaining undetectable, have had declining CD4 counts, and then we start them on treatment. Can you talk a little bit about this as an indication for ART for someone who opts not to start antiretroviral therapy initially?

Joel:
When I see declining CD4 T-cell counts, I think that’s a definite indication for treatment. There have been studies showing that when you put patients who have declining CD4 counts on antiretroviral therapy, the CD4 counts at least stabilize, and sometimes you see a small bump in the CD4 T-cells.

Eileen:
I feel like that was probably more relevant in the era prior to the recommendation for blanket treatment, but in the few patients who, with a shared decision-making discussion, don’t start treatment, this can be another data point that we will agree to follow as we continue to reassess whether or not the patient feels ART would be beneficial.

Finally, let’s talk about prevention of transmission. How do you think about undetectable = untrans-mittable for elite controllers?

Joel:
That’s a great question. We discussed the fact that there is residual viral replication. There haven’t been a lot of good studies looking to see whether you can find virus in the genital tracts of elite controllers and whether this is transmissible. We have published a case of a patient who’s elite who transmitted virus to their partner, but we don’t know when this transmission occurred.

So, elites can be viremic during primary infection. It’s possible that’s what happened before the immune system shut off via replication, and it’s possible that it happened later on. We don’t know. But given that there’s still some residual via replication, we don’t have a lot of information. I think putting patients on antiretroviral therapy will also minimize the possibility of transmission.

Eileen:
I think in the case of sexual transmission, that makes good sense as a discussion point and also will de-pend on the patient’s partner status and their sexual preferences and practices, but also something to be thought about in terms of prevention of vertical transmission and in breastfeeding for women who are elite controllers and go on to have pregnancies. In those cases, we certainly have much more data for suppression under ART than for natural suppression. So, I totally agree with you that those are situations in which I strongly favor treatment.

Joel:
Yes, absolutely. Every elite controller who becomes pregnant, we put on antiretroviral therapy, always. Yes.

Eileen:
Does being an elite controller factor into your choice of treatment agents? We all know where to find what the recommended first line agents are, but there’s not elite-specific guidelines. Do you think about it any differently?

Joel:
I’m much more likely to give a 2-drug regimen than a 3-drug regimen to these patients, just because there’s not a lot of viral replication, and if I can minimize the exposure to these drugs, it’s worthwhile to do that, yes.

Eileen:
I feel the same way, although evidence doesn’t rise to the level of a guideline, but from an opinion or just experience practice base, I have the same practice for things like dolutegravir/3TC for elite controllers.

Finally, Joel, I was wondering if you could take us a little bit into future considerations and can you comment on whether elite controllers are more likely to be cured of HIV?

Joel:
There are 2 ways to look at a cure. One is a functional cure, where virus remains in the immune system, holds it in check. So, by definition, elite controllers are functionally cured. Then there is eradication, where all replication-competent virus has been eliminated.

We think most elite controllers fall under the functional cure bucket rather than eradication. We started looking at the size of the viral reservoir in elite controllers many years ago. We found it was much, much lower than what you see in patients who are on antiretroviral therapy. So, reservoirs are present, but the frequency of infected cells is much lower.

Now there’s this new bucket of elites or subsection of elites that we call “exceptional elite controllers,” meaning they have even lower levels of infected CD4 T-cells. There’ve been 2 or 3 patients where no repli-cation-competent virus has been detected despite the fact that billions of CD4 T-cells have been assayed. Those patients may have eradicated the virus completely, but those are definitely the exception.

Eileen:
Got it. So, it sounds like they’re a model for having an immune system response that’s effective. That has potential implications for both vaccine development, because if you had this response even before you were exposed, maybe you’d do better, and also for this idea of a functional cure where your immune sys-tem can control the virus. But I think the other takeaway from what we’ve said so far is that, even with a “functional cure,” we’re still recommending treatment because of the heterogeneity of inflammation. So that’s a cautionary note about some of our goals in thinking about what we’re working towards with cure for more people living with HIV.

Joel:
Yes, I agree completely.

Eileen:
Okay, so let’s return to our gentleman. As you said at the beginning, took a few sessions to understand what this meant for him, that it does mean he’s HIV seropositive and he’s working on what that means for his identity, just as a human, but with some fewer risks than having a more typical course of HIV patho-genesis.

He did opt to start antiretroviral therapy and pretty soon settles into every 6 months to 1-year visits and continues to maintain undetectable viremia. Do you have any final thoughts or recommendations that you would give to people about how to think about elite controllers as patients?

Joel:
Just remember they are a very heterogeneous population of patients. Most of them probably would ben-efit from being on antiretroviral therapy. If they don’t want to be on antiretroviral therapy, I don’t have enough information to tell them that they have to be on antiretroviral therapy, and I will just continue to monitor them every 6 months, looking for both CD4 decline and whether or not they break through—whether the viral load becomes detectable.

Eileen:
So, if you’ve seen one, you haven’t seen them all, even though they’re rare. And we should do shared de-cision making with the scales are tipped towards therapy, but not in a way that makes it impossible to work with people who opt not to be treated currently.

Joel:
That’s exactly correct, yes.

Eileen:
All right, well, thank you so much for joining us today on Viremic. Joel, it has been such a pleasure and taken us through both clinical management and also the underlying mechanisms, and I’m sure that all of our Viremic listeners enjoyed it as much as I did.

Thanks to everyone for joining us and tune in for our next episode.

Announcer:
Viremic is sponsored by the Clinical Guidelines Program, a collaborative effort of the New York State De-partment of Health AIDS Institute and the Johns Hopkins University Division of Infectious Diseases.

Visit the program’s website at: HIVguidelines.org.

Viremic’s case discussions are for informational purposes only and not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use only, not an endorsement

The podcast is produced and edited by Mary Beth Hansen and Brian Hatcher with assistance from Jesse Ciekot and Laura LeBrun Hatcher.