Viremic – Cases in HIV

Announcer:
Welcome to Viremic – Cases in HIV, a podcast that explores the quandaries in adult HIV clinical care. In each episode, Drs. Eileen Scully and Christopher Hoffman, HIV specialists at Johns Hopkins, discuss a case, review challenges in the plan of care, and highlight evidence and guidelines that inform clinical decision-making. Now, here are your hosts, Eileen and Chris.

Dr. Chris Hoffmann:
Welcome to Viremic. I’m here with my friend and colleague Eileen.

Dr. Eileen Scully:
Thanks so much, Chris. It’s great to be here doing our favorite thing.

Chris:
So I’m going to start with something that caught my eye as HIV in the news, and that is more good news in HIV prevention. Recently, the PURPOSE 2 study was completed and published. That’s a study of using lenacapavir (LEN) subcutaneous injection every 6 months for prevention of HIV.

The PURPOSE 2 [study] follows PURPOSE 1, a study among cisgender women, which had remarkable results in no HIV infections among the women in that study who were randomized to LEN, and in the comparator arm, which was oral tenofovir/emtricitabine (TNF/FTC), there were infections. In the PURPOSE 2, that was among cisgender men, transgender women, and transgender men and non-binary individuals, there 3,000 participants in that study, randomized 2:1 to subcutaneous LEN or FTC/TDF. In that study, 2 participants in the LEN arm were diagnosed with HIV, compared to 9 in the FTC/TDF arm, again showing remarkable from HIV despite those incident infections. (I think in the future we’ll learn more about those incident infections.)

This was a fairly high-risk population during the study period. About one third of the participants were diagnosed some sort of STD. There was pretty heavy use of chem sex, about a quarter of the individuals. And overall, the adherence in both arms was fairly good, but as expected, much better in the LEN arm than in the FTC/TDF arm, where there was about 60% to 70% adherence.

What excites me about LEN over options is the infrequency of dosing, so improved adherence, but also the potential for easier dosing than, say, cabotegravir (CAB) in that LEN is subcutaneous. In these studies administered by a healthcare professional, but potentially will be self-administered in the future, which may make insurance coverage issues slightly easier to overcome than for CAB for some insurance plans.

Eileen:
Chris, I am so excited about LEN, and the PURPOSE 1 trial was an amazing result—to have that level of efficacy without requiring frequent visits is really amazing. There was an editorial in the New England Journal of Medicine [Jatt, et al. 2025] talking about whether or not LEN will obviate the need for a vaccine and basically saying that’s unlikely to happen. We still need durable protection that can last over years and doesn’t require regular injections. But let’s not let perfect be the enemy of good here. This is fantastic news, and it’s really nice to have LEN as a separate class than our first-line treatment options.

Typically when doing cabotegravir (CAB; Apretude)-based pre-exposure prophylaxis, which is also injectable and has a longer separation of dosing than daily pills, you then have the potential risk of acquiring HIV and then having integrase [strand transfer inhibitor; INSTI] resistance, which changes your first-line treatment options. LEN is a different class and allows us to eliminate that potential. So even if you were so unfortunate as to acquire HIV despite LEN, you could still use your first-line drugs, which is a great option to have. So I share your excitement, and I still think we need to work on an HIV vaccine, but I’m going to be excited about LEN nonetheless.

Moving on to what I was thinking about this week, I saw an individual who came in [to clinic] after some risky sexual encounters and had a rash, and it again raised the possibility of mpox. This is an individual with a prior episode of mpox, and this person was concerned that they had a new infection with that same agent.

It reminded me that while mpox is nowhere near the levels that we were observing here in Maryland or in other locations in the United States a few years ago, there are still sporadic cases being reported on a continuing basis, and there is the JYNNEOS vaccine available. This is a live, non-replicating orthopox vaccine produced from modified vaccinia virus, and it elicits both humoral or antibody-based and cellular T-cell responses to orthopoxviruses.

A recent study published in the Lancet [Hillus, et al. 2025] looking at the effectiveness of JYNNEOS against mpox reported about 57.8% effectiveness by 14 days after the first dose. That was subdivided to 84% effectiveness in people without HIV and about 35% in people with HIV. After 2 doses, they didn’t observe any mpox cases, so that’s reassuring, but even after 1 dose, there’s substantial protection. So keep that in mind for people who did not get vaccinated the first time around and remain potentially at risk.

Chris:
Did the patient receive the JYNNEOS vaccine?

Eileen:
My patient did not after his first episode and has been in and out of care since then, so unfortunately was presenting without the benefit of vaccination. But just bringing it back up as something that is still happening, although nowhere near the levels that we were observing recently.

Chris:
Did you recommend that he get vaccinated?

Eileen:
We were doing diagnostic workup for him initially, and we’ll have that conversation when the dust settles on what we think the acute syndrome was. But it is something to consider even in prior cases, in particular for people with varying immune status. My patient is sometimes on antiretroviral therapy (ART) and sometimes not. There are some data suggesting that irrespective of CD4 count, vaccines tend to perform a little bit better when you have viral suppression.

Chris:
I’m guessing he or she does not actually have mpox? Or still working that out?

Eileen:
Well, TBD.

Chris:
Got it. Why don’t we get into today’s case. A patient who came to me a few years back. His primary concern was that for several years, his viral load had been detectable, despite trying a few different and being extremely adherent to those regimens.

A little history about this gentleman—mid-50s, diagnosed in the early 1990s, started ART in the mid-1990s, initially with an older regimen of indinavir (IDV; Crixivan)/lamivudine (3TC; Epivir)/stavudine (D4T; Zerit).

Around this time, he reached his nadir, or believed to be nadir CD4 count of 197 cells/mm3. Unclear what his viral load was on that initial regimen, but then he was switched to boosted atazanavir (ATV; Reyataz), tenofovir (TNF; Viread), and emtricitabine (FTC) in the early 2000s, and with the assay used at that time, achieved an undetectable viral load.

Then a few years later, he required bowel surgery, leading to a potential malabsorption. At the time, he had a good CD4 count. With the assay used at that time, he had a viral load consistently less 75 copies/mL.

A year or so later, the assay changed to a more sensitive assay, and from then on, that’s early 2011 or 2012, his viral load was almost always just above detection—around 60 copies/mL in one of the early times, and his regimen was changed from the boosted ATV to raltegravir (RAL; Isentress) and abacavir (ABC; Ziagen). Viral load continued to be detectable, and he was changed again to boosted darunavir (DRV; Prezista) with ABC and 3TC. On that regimen, he did have an undetectable [viral load], but then remaining on the regimen, he had a viral load up to 300 copies/mL. I’m going to pause here. We still have a few years to bring you up to [when] he saw me, but what are your thoughts at this point?

Eileen:
When someone comes in with detectable viral loads, it’s always the question of who’s more anxious--is it the patient or the provider? These levels of detectable viremia are just one of those things that we all wish we could avoid, although, we tend to always want more data. Sometimes more data is more problems.

You mentioned that he was on maraviroc (MVC; Selzentry), raltegravir (RAL; Isentress), and abacavir (ABC; Ziagen). It’s a pretty atypical regimen. I’m wondering if he had kidney issues or some other indication to be on that combination.

Chris:
He does not have chronic kidney disease, and I’m unaware of any specific kidney issues that he was facing at that point, but it was prior to when I got to know him.

Eileen:
I think this is a great example of sometimes when you tried to read the tea leaves of prior regimens, there’s, clear data there. I always tell providers, if you see someone who comes in on DRV, ritonavir (RTV; Norvir), RAL, and etravirine (ETR; Intelence), and often with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; Truvada) or tenofovir alafenamide/emtricitabine (TAF/FTC; Descovy), know that that was the salvage regimen that allowed many people to get to viral suppression at a certain era when we had previously not been able to.

So make movements carefully, understanding that that individual probably has a lot of archived resistance, maybe not to our modern agents, but somewhere in their history. And at some point in their history, either was incredibly adherent to our poor treatment options in the 1990s or had struggles with adherence.

In this case, there may have been some trialing of new agents as they became available for real reasons like preferred side effect profiles or dosing intervals. But none of these regimens that you mentioned stood out for me as that was the one we used in all the patients who couldn’t achieve full viral suppression. the MRV, RAL, and ABC did make me think about potential for kidney issues and also potential for cardiovascular disease, for which sometimes we avoid protease inhibitors. And obviously, at that time, we’re avoiding the TDF formulation of tenofovir for kidney issues.

Chris:
The cardiovascular disease issues are interesting, especially with this gentleman, but taking him forward from that point, he was then on boosted DRV with ABC and 3TC for some time; continued bouncing around from elevations up to 300 copies/mL, down to undetectable; still maintaining relatively good CD4 count in the 600s. Because of the concern for potential, I guess, resistance at that time, his providers switched him, and perhaps because of a challenge of either absorption of the boosted DRV, given his prior bowel surgery, or the two-pill regimen, his provider switched him to a fixed-dose combination of dolutegravir (DTG; Tivicay), ABC/3TC (Triumeq). And his viral load continued to be in the 60 to 200 copies/mL range on that regimen.

I don’t remember the exact timing that the GenoSure Archive proviral DNA resistance testing became available. Prior to the availability of that, typically genotypic testing was not possible with the level of viremia that this gentleman had. But he did have the DNA genotypic testing done, which showed a variety of minor mutations, but no major resistance mutations to any agent—integrase strand transfer inhibitor (INSTI), nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI). But he was switched again at that time to boosted to DRV and the Triumeq (ABC/DTG/3TC).

What would you do next given the resistance information and the now 5 or more years of persistently detectable virus?

Eileen:
Let’s start out simply with definitions. The first is low-level viremia, generally defined as persistently detectable virus, but below the cutoff that we would typically classify as virologic failure. For the DHHS guidelines, failure is 200 copies/mL, so consistent detectability above that, on more than one assay in a row, or viral load greater than 1,000 copies/mL on a single assay. The range that we’re discussing here, it sounds like he wasn’t persistently above 200 copies/mL, then maybe below it at 180 copies/mL, maybe above 300 copies/mL one time, but then below again. So this would be more of a classic description of what we would call low-level viremia.

There’s another term that’s gaining some traction—called non-suppressible viremia—[which is] less focused on the actual level and more focused on the fact that we cannot get it to full suppression. We’ll come back to that a little bit later in the discussion.

One more note is that in the DHHS guidance we don’t necessarily recommend testing--you did mention that most of the time this is not possible when viral loads are in the low hundreds of copies/mL. The European guidelines do suggest that you attempt to get a genotype when you have a consistent viral load over 200 copies/mL. There’s, again, some expert disagreement there and always possible that’s something that should be considered on a case-by-case basis.

The first step with an evaluation of a low-level viremia case is to confirm adherence. It sounds like this individual presented a bit concerned about his low level of viremia, and the fact that there have been multiple changes in regimen suggests that either there was provider anxiety, or a combination of patient and provider anxiety, or patient anxiety. Is that correct? That he seemed invested in achieving suppression and was concerned about not having had that on his lab values?

Chris:
Yeah, Eileen for sure. Very was knowledgeable and also very knowledgeable about U=U (undetectable equals untransmittable) and focused on getting to an undetectable viral load.

Eileen:
We’ll come back to that U=U question in a few minutes. In terms of confirming adherence, I know there’s an intention and a desire for adherence, and usually what I do is just ask directly about how and when medications are taken. It’s not uncommon to have someone be taking their regimen incorrectly. But in this case, it seems unlikely.

One other thing that I would always check is for drug-drug interactions. Specifically for INSTI-based regimens, always check for concurrent use of a multivitamin or a supplement. As we know, those positively charged ions, like magnesium, calcium, things of that nature that are found in multivitamins and in standalone supplements can bind directly to the INSTIs and prevent their full absorption. The recommendation there is to separate any divalents from the administration of INSTI-containing regimens. If they are co-administered, do it in the context of a full meal, because with digestion for a full meal, those divalents aren’t isolated and having that negative interaction. In particular, to be aware of this in the case of patients on dialysis who are taking phosphate binders, and make sure those are taken with meals, as they should be if they’re taken concurrently with an INSTI.

That’s among the first things I would do, check, you know, did you just start Centrum Silver for men or some other supplement that might be causing that? Any luck on that for this individual?

Chris:
I did exactly that, reviewed his supplements, antacid use, which has lots of magnesium, lots of calcium, reviewed any other supplements, and there was no smoking gun there to interact with the DTG specifically.

Eileen:
Okay, so we struck out there. Occasionally in our clinic we’ve documented that the individual is very invested. We’ve ruled out any drug-drug interactions or anything else. Where there’s a possibility for absorption challenges, which can happen with gastric bypass surgery or any bowel surgery, where we’re not totally confident that we know the impact on drug absorption, you can check pharmacokinetic (PK) levels of some of the antiretrovirals (ARVs). Those are available in commercially-based assays that can be used for clinical management in select cases. So that’s one option. Did you consider that for him?

Chris:
Definitely. You’re exactly where we where we were going with this. Either he or perhaps his prior provider or perhaps both of them were concerned that the bowel surgery was affecting his ability to absorb these different ARV agents. So after reviewing his use of iron, magnesium, calcium, etc., [and] finding that that was not the issue, I went ahead to get the drug levels.

Eileen:
And how did those turn out for him?

Chris:
He was within the therapeutic range, towards the lower end of the therapeutic range, but not low enough to suggest that that was the reason for his persistent viremia.

Eileen:
Yeah, keep in mind that the lower end of the therapeutic range is still a multiple above the lowest inhibitory concentration. So, even if you’re at the low end of the range, it’s notable that that’s where you are, but it does not mean that you’re below the threshold for efficacy. I would say that in our collective experience of looking at this for a couple of challenging cases in our clinic, that seems to check out. Most of the time, it’s not actually a PK drug level issue.

Then I think we do what you’ve already described here, which is a detailed summary of the case to look for any patterns. One thing that’s important to be mindful of is that we often attribute changes in low-level viremia or other characteristics to changes in regimen. That can be true, that when you switch from one regimen to another, that may be the trigger for a change in your low-level viremia.

But the other possibility is that the HIV reservoir itself changes over time, and the T cell clones that are carrying around the HIV reservoir may also wax and wane over time. This may lead to periods where you’re more likely to have a little bit of low-level viremia because a clone specific for something you need to be doing, like, for example, controlling your CMV (cytomegalovirus), may be activated and expanded, leading to a little bit more production of HIV.

Keep in mind why we get concerned about things and why we don’t: If you’re having production of HIV, so it’s detectable in the blood, that’s not great, but it doesn’t necessarily mean that those HIV virions are causing new infections and perpetuating the cycle of expanding the reservoir. It could just be that those virions bud out off of the cell, are detected in the blood, and then have nowhere to go, because our currently onboard ART prevents a new cycle of infection.

This is a critical question and ties into the major concern we have about low-level viremia. Does low-level viremia predict rebound? Meaning, are you going to have virologic failure when you have a detectable viral load in this range?

There is somewhat mixed data on this, and some caution needs to be applied in whether we consider data from the international setting to be equivalent to data that we’re gathering from our clinics. There’s a paper looking at the African cohort study of adults in Uganda, Kenya, Tanzania, and Nigeria [Esber, et al. 2019]. It looked at about 1,500 individuals with more than 4,000 person years of follow-up. They did find that persistent low-level viremia was present at less than 200 copies/mL in about 20% of the cohort, between 200 and 499 copies/mL in about 2%, and another 2% was 500 to 999 copies/mL, so just below 1,000.

They found an increase in the hazard ratio (HR) for virologic failure associated with low-level viremia, but the cutoff for this was around 200 copies/mL; 200 to 499 copies/mL had an HR of 1.8, and 500 to 1,000 had a HR of about 2.4.

In a U.S.-based cohort looking at about 2,800 patients, they again saw low-level of viremia in about 5% in the range of 50 to 200 copies/mL and 4% in 200 to 500 copies copies/mL [Fleming, et al. 2019]. They did see both levels were associated with failure in an adjusted HR, but if you excluded ART-experienced patients, so people who likely had prior virologic failure, the 51 to 200 copies/mL level was no longer significant. There they saw an HR of about 4.3 for failure in those who had a low-level viremia between 200 and 500 copies/mL.

Overall, low-level viremia, less than 200 copies/mL in general, we can be reassuring about, although higher amounts require a bit more scrutiny for this question of whether having detectable virus is going to lead to virologic failure. Anything else you would add? As you know, there’s a lot of studies that have looked at this.

Chris:
That’s helpful, Eileen. I spoke to him to reassure him, number one, using the general guidelines cutoff of 200 copies/mL for concern. But there are studies that suggest that even a viral load less than 200 copies/mL in some individuals may predict future failure or other HIV-associated morbidity. He was very uncomfortable, but starting to be agreeable to the overall plan I was presenting. I also had a little bit of concern I couldn’t tell him 100% that his viral load okay.

So what can I do now to reassure myself as the clinician and him as the person with HIV?

Eileen:
One of the things that you raised was, even if I can tell this person that they’re unlikely to have virologic failure, does it contribute to anything else? So let’s talk about those 2 things. The first one is, does the level of viremia contribute to ongoing inflammation and related comorbidities? This is not clearly known.

There is a recent paper in Open Forum Infectious Disease (OFID) (we’ll link to it in the show notes) where they tried to address the consequences of low-level viremia for non-AIDS conditions, so serious non-AIDS events. This study looked at data from the U.S. Military HIV Natural History Study and included starting ART after 1996, stratified by level of low-level viremia. So they had 51 to 199 copies/mL, less than 200 copies/mL threshold, and then higher low-level viremia covering the whole range between 200 and under 1,000 copies/mL.

They found that low-level viremia in both strata was associated with serious non-AIDS events HRs, so higher HRs. Low-level viremia at about 1.3 HR hazard ratio increase for serious non-AIDS events and higher low-level viremia at about 1.6. So there’s a couple of caveats here. One is that low-level viremia could have been associated with incomplete adherence to multiple meds, not just ART. You could see more serious non-AIDS events because individuals who struggle with their ART also struggle with their anti-hypertensives. Or it could be related directly to inflammation from HIV components, even if you don’t have out-of-control HIV replication and immune depletion. So it’s still unclear what to do for this particular consideration.

Treatment intensification—adding ARVs to a regimen that hasn’t achieved full suppression but hasn’t had virologic failure—has never been shown to be successful. There was some hope that with novel agents like LEN, which we mentioned at the top of this podcast, we might see more benefit, but so far no studies have shown that there’s an agent you can add to eliminate low-level viremia when it occurs.

The potential increased risk with inflammation points to how important it is for risk factor modification for other serious non-AIDS complications. Specifically, doing all we can to treat the non-HIV-related risks that could be associated with this. And then the one other question you brought up early on is, does U=U, undetectable equals untransmittable, apply to low-level viremia?

In the original studies, there were threshold levels of either less than 200 copies/mL to be considered fully suppressed, and in one case, less than 400 copies copies/mL. There is a recent systematic review, which we’ll link to in the show notes, where they analyzed the risk of transmission at other ranges of low-level viremia [Broyles, et al. 2023]. And across 244 studies, they found 2 cases of transmission where the most recent viral load was less than 1,000 copies/mL, so within the range of what some would call low-level viremia.

However, in both cases where this transmission occurred, the viral load was done a while before the actual transmission date—50 days, so almost 7 weeks earlier for one case and 53 days for the other. There’s a high suspicion that the viral load at the time of transmission may actually have been higher. In terms of whether we can say U=U for this individual, I think this is a shared decision-making situation where you counsel that the available data suggests there’s extremely low risk of transmission.

As long as his viral load remains in the range that it’s been, and that in particular, for at least one of those studies, the cutoff was less than 400 copies/mL, which he’s never been over, which is additionally reassuring. How did that conversation go for you?

Chris:
Well it was a process, over time, he has accepted that U=U. He continued to be concerned why specifically he had this low level of viremia and how I could pinpoint the cause and provide him with greater reassurance that it wasn’t drug failure or that adding or changing his ART regimen would not help in this situation.

What you suggest to the two of us next?

Eileen:
We’re privileged to practice in a setting where we have dedicated clinicians and dedicated researchers. This patient would be a perfect candidate to be included in some of the studies of non-suppressible viremia or low-level viremia that look and see what’s actually happening to the virus. And this was one of the cases (slightly changed for this discussion) who was enrolled in a study led by Francesco Simonetti and Bob Siliciano and Janet Siliciano where they looked specifically at what was happening in the HIV reservoir [White, et al. 2023]. As we talked about before, the HIV reservoir is all these CD4 cells that have a copy of HIV in their genome but aren’t expressing it at most times. They’re the problem in this situation, meaning that once we stop ART, sooner or later, one of those HIV genomes that has been sleeping turns on, then you have rebound viremia, and high viral load, and all the consequences of HIV. In between, they’re generally very quiet, which makes it very hard to even identify which cells are carrying HIV.

Over time, as you age, as you have CMV or EBV or you get an influenza infection, different specific populations of T cells expand and make more copies of themselves and contract based on those needs. Occasionally, you’ll have a T cell that’s specific for something, like for example, the flu, that would expand when you actually got the flu, and that that would lead to a higher level of activity of the reservoir carried in that cell. That could mean you have a transient detectable viremia during that time.

For this patient, he was enrolled in one of these studies and they looked very carefully at the virus that was detected in the plasma and also at the reservoir. In this unique case, they found that the virus that was being produced was actually from a specific type of provirus or integrated HIV that lacked an important component of its genome. Without this part of the genome, it could make productive virions that were detectable in the plasma, but it was not capable of exponential replication and uncontrolled infection. So in this case, a slight error in the provirus led it to be able to be produced but not able for it to take over and dominate, [which] led to this unusual clinical situation where we weren’t able to fully suppress HIV production, although it does not look like he was having ongoing new seeding of the reservoir and new infection events.

Does that summarize it?

Chris:
Yeah, that’s helpful, Eileen. Through working with this patient, I learned a lot about residual viremia and non-suppressible viremia, maybe because I became more aware from him, but other patients I’ve taken care of also had this pattern.

And I’ve felt better equipped start the conversation about the potential causes. And when I’m fortunate enough to get them in one of Simonetti’s studies, learn about the underlying biology.

He has come to accept this is a clonal expansion of likely non-replication-competent virus and something that he may live with for many years. He seems comfortable now with not having an undetectable viral load.

I’m still concerned about the potential inflammatory or other non-AIDS-related morbidity that may be related to this and would like additional tools to help prevent diseases of inflammation in the future for him.

Eileen:
I agree. So to wrap up this illustrative case: Low-level and non-suppressible viremia are actually a common clinical conundrum, and it’s best interpreted with a clear summary of the clinical trajectory. So you identify whether it’s new, different, or has any associations with intercurrent changes in medications or health status. Start with the first things first--drug-drug interactions, absorption issues, adherence, adherence, adherence.

Stay tuned for more information about comorbidity risks associated with nonsuppressible viremia in the future. If we do develop targeted anti-inflammatory treatments, that would probably be what we would most want for individuals like this gentleman.

Then always keep in mind that each individual case has the potential to teach us a lot about the HIV reservoir, HIV pathogenesis, and the more we learn, the more we can offer to all of our patients. So thanks so much for sharing that case, Chris.

Chris:
Eileen, I learned a lot from you. it’s always a privilege to hear your insights from the virology and immunology side. I hope all of our listeners take something away from this.

Eileen:
Thank you, Chris, and looking forward to next time.

Chris:
And thanks to everyone for joining in. I look forward to another great discussion of an HIV case in our next episode of Viremic.

Announcer:
Thanks for listening to Viremic. If you enjoyed the show, please subscribe wherever you listen to podcasts. We’ll be back in a couple of weeks with a new case to discuss.

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

Visit the program’s website at HIVguidelines.org.

The podcast is produced and edited by Mary Beth Hansen and Brian Hatcher with appreciated assistance from Jesse Cicotte and Laura Lebrun Hatcher.

Viremic’s case discussions are presented for informational purposes only and are 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, not an endorsement.