Viremic – Cases in HIV

Announcer:
Welcome to Viremic–Cases in HIV, a podcast that explores 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:
Hi, welcome to another episode of Viremic. I’m Chris Hoffman and I’m joined by my friend and colleague Eileen Scully here to discuss HIV cases today.

Eileen, what do you have today for us on HIV in the news?

Dr. Eileen Scully:
Chris, it’s great to talk with you as always. Today, I thought I’d start with the third rail. Let’s talk about vaccines a little bit. A couple things going on in the news about vaccines, and I’d love to get some of your thoughts.

Just a few weeks ago in the New England Journal, the FDA published a piece where they outlined the strategy for thinking about seasonal COVID-19 vaccines. What they said was, that they, quote, anticipate that they will be able to make a favorable benefit to risk finding for adults over the age of 65 and for all persons above the age of 6 months with one or more risk factors that put them at high risk for severe COVID-19 outcomes. The next part of this is that they aren’t necessarily going to find a favorable benefit-to-risk for everyone else. So that raised a lot of questions initially.

If we drill down in this paper and then look specifically at the CDC’s 2025 list of medical conditions that increase a person’s risk of severe COVID-19, it’s actually quite reassuring. This list, includes a variety of conditions, including physical inactivity (which quite frankly, I wonder means if I qualify) but also a range of illnesses that estimates that about 30%, I think, of Americans would be covered under this regardless of their age and would be eligible for the vaccine.

The question then is for all the other people. That leads to the question of whether we need a recommendation per se or just a vaccine that’s approved and available. Here we get into some of the details around what insurance companies are required to cover, and whether or not all people, regardless of the type of insurance they have, will be able to get the vaccine if they choose to get it. That’s an important question—we’ll have to look at the impacts of changes in vaccine recommendation policy. But overall, this recommendation, while not exactly as it was before, actually covers many people in the United States, including all people living with HIV, which is one of the conditions on that list.

Chris, what were your initial responses to this change in policy announcement?

Chris:
One is just what will be covered by insurance. There are multiple factors that go into somebody’s decision regarding COVID-19 vaccination. I’m glad the list is pretty comprehensive of reasons for vaccination. I’m not sure if the FDA is usually in the business of recommending who should get vaccines and who should not, but be that as it may, I agree with the list. Overall, the list that has been announced outside of the FDA recommendations, including that pregnancy would not be a reason to get the COVID vaccine is concerning, given our experience with severe COVID among pregnant persons during earlier parts of the COVID epidemic. I think we’ve become a little complacent more recently with COVID, partly because so many people have antibodies either from prior infection or vaccination. And if there’s fewer infections and less vaccination, then we may be at risk for a worse COVID surge in the coming years.

Eileen:
Chris, you make some excellent points. About a week after the New England Journal paper, there was an announcement from Secretary Kennedy that they were not planning to keep the COVID vaccine on the pediatric schedule of immunizations and also not recommend it for pregnant women.

There was a really nice report by the CDC in April of 2025 that does drill down on who is getting COVID even as the pandemic has moved through many years. There does appear to be a unique risk in particular among the youngest children, ages 0 to 4 years. That population does appear to have a unique vulnerability that should require some specific attention and recommendations. For pregnant women, as you mentioned, there’s data from during the pandemic prior to the onset of available vaccination—the mortality associated with delivery was 14 times higher for women who had COVID-19 at the time of delivery. That’s hard to ignore in thinking about the potential risks to people who are pregnant.

You raise another point, which is we don’t really know how important vaccination is for an individual who’s had repeated exposures to COVID-19, whether they’re natural or vaccination.

In general, I do support the approach that’s proposed here, which is to gather more data, and in the New England Journal at least, to gather more data and try to understand who most benefits from vaccination and how to best target the outreach and recommendations so the people who most need it are aware of it and can access it. I do hope there’s more consideration around pediatrics and pregnancy. in particular because we do have such a wealth of safety data already available for those conditions.

Thanks so much for thinking about that with me. What’s been notable for you in the news?

Chris:
I thought there was an interesting commentary from the IAS USA HIV Drug Resistance Group published in CID recently regarding the use of proviral DNA sequencing for detecting HIV drug resistance.

Unlike standard resistance testing from circulating RNA, which is very short-lived, proviral DNA amplifies DNA from peripheral blood mononuclear cells, which leads to a greater diversity of sequences and also a lot more replication-incompetent sequences that may be integrated into the host genome but are not able to lead to any viral replication. That’s partly because of reverse transcription of HIV, which is error prone and also partly due to APOBEC G to A hypermutations.

Literature around genotyping using RNA is pretty robust to suggest improved outcomes when that is done prior to antiretroviral therapy initiation. There are really no randomized studies looking at proviral DNA amplification to guide treatment that have demonstrated an improved outcome, partly because it’s a technique that has somewhat limited applicability. In this commentary, they suggested a few situations where a clinician may want to consider using proviral DNA amplification. One is if there’s repeated failure of standard RNA amplification, perhaps because of relatively low level of viremia. Another is in somebody with an undetectable viral load and not a history of, or accessible data on, prior resistance and a switch to a regimen with a lower genetic barrier than the current suppressive regimen.

One example where that does occur sometimes is in a switch from an oral regimen to injectable cabotegravir plus rilpivirine. There’ve been a number of studies that have identified that individuals with rilpivirine resistance mutations identified through proviral DNA testing prior to switching to the cabotegravir/rilpivirine—that does confer an increased risk of failure. That may be the most useful situation for proviral DNA testing.

There were a few other examples suggested, including when a viral subtype was not previously recorded, especially if cabotegravir or rilpivirine is being considered because some of the subtypes are at higher risk for failure with that regimen. I thought it was time for a commentary from IAS USA and a nice summary of some of the strengths and weaknesses of that test, highlighting that with cabotegravir/rilpivirine in somebody with prior failure, but no history of a genotype, proviral DNA as a way to check for NNRTI resistance should be considered.

Any thoughts on that? How often do you do proviral DNA testing?

Eileen:
Chris, I agree that this was a topic ripe for a discussion, and I think this paper is provocative and outlines when it might be considered. I don’t use proviral that often. The most frequent setting is the one you described, where we’re considering a transition to cabotegravir/rilpivirine and we have some gaps in our knowledge about the prior treatment history. We do have a couple of cases that we’ve discussed in our clinical conference internally where we have discordance between the proviral genotype and the prevalent genotype over time. Those provide some interesting case studies as we think about how to apply this. Maybe we’ll circle back to one of those cases in the future. I think that would be a great discussion.

Chris:
Good point, Eileen—there’s likely both over and under identification of true drug resistance mutations with proviral DNA, but times when it’s useful.

Eileen:
All tests are a little bit wrong, but most can be useful. We just have to figure out where and how.

Chris:
So true. I think you have a case for us today, so back to you.

Eileen:
Today’s case is a woman in her later 40s with a history of kidney disease, cardiovascular disease, and HIV. She has achieved full viral suppression for more than a decade and has a nice, robust CD4 count greater than 500 and hasn’t ever actually been less than 200. She doesn’t exercise regularly, but she has a really active job—she works as a cleaner in a larger facility. She’s highly adherent to her medications, always refills on time. We’ve discussed lots of different things about her meds. She’s very familiar with them, can identify them all the time. I have absolutely no concerns about non-adherence for her. She’s not diabetic, and her BMI is 19. She’s a thin, fit appearing person. She does not drink alcohol and never has and has no history of illicit drug use, but she does smoke cigarettes—averaging only about 1 to 3 a day—but has not been able to quit, although she is motivated to do so. She has no family history of cardiovascular disease. She did have a brother who died from cancer a couple years ago. She does have a lot of stigma around her HIV diagnosis and has not disclosed it to anyone, but this has not interfered with her ability to either take her medications or maintain her care, comes to appointments regularly.

She does, I mentioned at the beginning, have this history of significant cardiovascular disease. This initially presented close to 10 years ago, at which point she’d been already virally suppressed for about 8 years. I mentioned more than a decade, but she’s close to two decades of suppression.

She was admitted with atypical chest symptoms in her early 40’s. She did make it to a catheterization, partially because she did have a troponin leak. I know one of the things that we often talk about in general medicine is that for women presenting with cardiovascular disease, their symptoms can sometimes be atypical, and also your risk calculation when you encounter a woman coming in is so much lower, both based on our clinical instincts and also based on the risk calculators that we use. But she did go for a catheterization and had near total occlusion of the right coronary, which was stented at that time. She was started on maximum medical management after that admission, to which she is also highly adherent. And she was readmitted a few years later with an atypical chest pain syndrome at rest, and at that point had moderate instant restenosis and was again recommended for intensive medical management, but no intervention was done or necessary at that time.

I’m bringing this case up for us today—a little bit different than some of the other ones we discussed—so we can dig into the concepts of non-infectious comorbidities associated with HIV. In this person, who in general, her only real risk factor for cardiovascular disease is her smoking, which is overall very minimal as compared to others.

And so, I thought maybe I’d start it off with how do you think about the risk associated with HIV of non-infectious comorbid conditions?

Chris:
Really interesting case. Unfortunate that even in her 40s, she already had a cardiovascular event.

I’m going to make a few comments and then ask about medications she was on for HIV earlier. Medications have long been considered as perhaps part of the reason that people living with HIV have an increased risk for heart disease. In addition to medications, HIV itself and lifestyle factors, and you’ve pointed out she has some fairly limited tobacco use, increases her risk slightly, but still rather surprising that a woman in her 40’s should have a heart attack.

It’s useful to start with the SMART study, which was indeed very smart. This study was started over 20 years ago, and one of the hypotheses that the study team had is that the antiretroviral therapies used at the time increased the risk for non-infectious comorbidities such as heart disease. To test that hypothesis, they randomized individuals to either start antiretroviral therapy with a CD4 count around 500 or to have intermittent antiretroviral therapy to keep the CD4 count above 250. What they found, perhaps negating that hypothesis, is that individuals who remained on antiretroviral therapy and thus had more time and exposure to that potential toxicity actually had a considerably lower risk of heart disease, kidney and hepatic disease. It led to a whole paradigm shift around the thinking about non-infectious comorbidities with HIV, from being related to medications to related to the virus, and helped lay the foundations for approaches to test and treat and initiating antiretroviral therapy as soon as somebody’s diagnosed with HIV.

Some of those medications that were considered do have lipid problems as well as probably some increased risk for cardiovascular disease include some of the early protease inhibitors. So, I’ll just ask for a little more information about her. Was she on some of those early protease inhibitors? And how long she was living with HIV before she was virally suppressed?

Eileen:
Great questions, Chris, and a beautiful summary of that study. She was started on therapy shortly after diagnosis, about 20 years ago, and was suppressed rapidly. Her initial therapy was atazanavir boosted with ritonavir and abacavir combined with 3TC.

She had some chronic kidney disease at that time and there was concern for the (I’m smiling as I talk about this), but one of the old things we used to talk about was the potential for atazanavir crystallization in the urine and atazanavir kidney stones, which is not something that people encounter much these days. At that point, she was changed to darunavir, continued on the 3TC, and rilpivirine was added to her regimen to give her 3 active drugs.

The darunavir was boosted with ritonavir. Subsequently, we modified her regimen a bit to get rid of any protease inhibitor in the context of her cardiovascular disease. She was put on dolutegravir together with the rilpivirine she was already on and 3TC. She actually opts to take all of those pills separately because she has a little bit of pill dysphagia and those 3 are nice small pills. She prefers to have more pills as long as they’re smaller.

The other thing threaded through these considerations is that she does have CKD. We were always aiming for renal neutral regimens to give us a little bit more flexibility and not having to watch her creatinine clearance very closely. She wasn’t on any old-style protease inhibitors, and she did achieve suppression very quickly, so her area under the curve of exposure to HIV viremia is actually quite short.

Chris:
Thinking back to those days of atazanavir, she was at the time on a regimen that was as cardio-neutral as possible. I think you wanted to mention a little bit more about cardiac risk in women.

Eileen:
The way you outlined the SMART study was so perfect in that the hypothesis going in was that this is something we’re doing to people and our medications may be increasing risk. At the beginning of the HIV epidemic, there were certainly significant side effects from the medications. But coming out of the SMART study, it looked like our drugs had gotten so good that the bigger actor was HIV itself. That was true for both the things we classically think of as being HIV-related, like opportunistic infections, but also for these comorbid conditions.

This laid the groundwork for thinking about inflammation as a central driver of comorbidities associated with HIV. And as you mentioned, there is some data on who this impacts the most. There’s some work done around the same time that looked at a couple of large cohorts and found that among people with HIV, there is an excess risk of cardiovascular disease. Drilling down, one of the things that stands out to me is that the risk associated with HIV is disproportionately higher for women, meaning while both men and women who acquire HIV have some increase in their risk of cardiovascular disease, the increase is relatively larger for women living with HIV.

This feeds into thinking about this particular patient. Looking back, I wasn’t involved in the care of this theoretical patient when they had their original cardiovascular events, but even through the “retrospectoscope” (which is always perfectly accurate), it’s not clear at all that you would have identified this person as someone at high cardiovascular risk. This patient is meant to be an example of those individuals who do seem to have a cardiovascular risk that comes from their HIV. Presumably some of that risk at least comes from ongoing inflammation related to the virus, even in the presence of viral suppression.

The landmark Reprieve Study, published in the New England Journal in 2023, aimed to see whether addition of statins in people who otherwise would not qualify for the use of statins would lower this HIV-associated cardiovascular risk. They enrolled people between the ages of 40 and 75 who had a low to moderate cardiovascular disease risk using the pooled cohort equation as the calculator to determine risk—about 7,700 individuals. I think it’s one of the largest studies ever done in people with HIV.

The median age was 50, and they did get to 31% women, which is great. Oftentimes in studies of HIV, we don’t see great representation of women. It was a global study.

The median screening LDL cholesterol level was 108, so not one that would have prompted initiation of a statin outside of the HIV indication. And 87.5% were fully suppressed. In general, this was a well-treated cohort. Among those who were not suppressed, the median viral load was 62 copies. So even there, we’re looking mostly at low level not uncontrolled viremia. The outcomes showed a reduction in risk of cardiovascular events with the addition of statin therapy, even in this low-risk group of individuals—that really is a practice changing finding.

It harkens back to things like the Jupiter trial, which was done many years ago, where they looked in people without HIV and found individuals who had a modest elevation in their CRP and otherwise normal profile and saw that statins had some benefit in reducing cardiovascular events, even in that group. It’s unclear whether the statin benefit is directly related to reducing lipids in the context of inflammation or whether there’s a statin immunomodulatory effect. But in either case, in people without HIV, there’s been a suggestion previously that statin addition does help. In this case, we don’t show specifically, or at least the primary clinical study did not show (did not look to see) whether statin addition led to reduction in inflammation or whether there was higher inflammation at baseline. But what it does show is that when you add a statin, you see a reduction in major adverse cardiovascular events, and they used hard MACE determination criteria. So, a very powerful study overall.

This led to an update in the DHHS panel guidelines about how we should approach statin therapy for people with HIV (we’ll have a link to those guidelines in the show notes). Basically, the recommendation for ages 40 to 75 is that when your 10-year ASCVD risk estimate is between 5 and 20%, then there’s a recommendation for a moderate intensity statin, and we give a couple of choices and doses of what could be used there. I should note here that REPRIEVE used pitavastatin because that was the statin that was available. It means that when we use other statins, we’re extrapolating that those will also have the same benefit. That’s something that we’ll only know with time because you can’t just repeat the study with all the other statins you might want to use. There’s also some helpful reminders about why we should use statins even outside of HIV to make sure that we’re not missing individuals in our practices who would already meet criteria for that.

I’ll mention briefly that pregnancy and breastfeeding are excluded from recommendations for statin therapy. Along these same lines, published In the Annals of Internal Medicine, there’s a clinical guideline paper that goes over how these recommendations were developed, and gives a nice summary of the overall evidence that led to this recommendation in the DHHS panels.

Chris, to your question about women specifically, one of the subgroup analyses from REPRIEVE has been looking at cardiovascular risk in women. There’s a paper published in the Lancet HIV in 2025 where they tested the performance of the pooled cohort equation to predict cardiovascular events across different participants. They only looked in the placebo arm here, so no statin modification. They found that the pooled cohort equation underestimates cardiovascular risk in particular among women and to the highest degree among Black or African-American women. It also underestimates the risk in Black or African-American men. This is another area to watch as we come up with our risk calculations and as we’re sitting with our patients in the office to decide who actually meets these criteria and would benefit from statin therapy—to make sure we’re thinking about whether or not we’re underestimating the risk in women, in particular women with HIV, and underestimating the number of them who would benefit from statin therapy.

So that was just quite the soliloquy, but I do love thinking about differences in how risk presents and how it comes into our clinical decision-making. Any thoughts, Chris?

Chris:
REPRIEVE was an amazing study—a lot of dedication from a lot of investigators and participants. When you raise the issue of women, I think there’s a cognitive bias when I see the estimated 10-year cardiovascular risk and some my female patients. Even when I’m planning to discuss a statin with them, it does give me less feeling of urgency compared to when I see a 10-year cardiovascular risk that would be higher just simply if they’re a man. And I wonder if I should simply be making those calculations—calculating what their risk would be if they were a man instead to avoid that bias. But I am trying to get pretty much all of my patients onto statins if they’re not already on a statin.

I don’t know if you’ve looked back for your 40-some year-old woman, what her cardiovascular risk was before she had the cardiovascular event diagnosed and if she would have fit the new guidelines for statin use.

Eileen:
Great question, Chris. First, I will point out that the pooled cohort equation performs this way because sex is actually included in it, because in general, female sex is protective against cardiovascular events. So, your bias is correct for the general population. It feeds into the cardiovascular risk calculator because it’s been shown that this actually does impact your likelihood of having an adverse cardiovascular event. The Data that are emerging from REPRIEVE at least (it’ll be interesting to see if this can be replicated in other cohorts or settings) is that that protective effect of female sex is not present when you’re looking at the risk associated in particular with HIV.

In this Lancet HIV paper, they recommend exactly as you suggest—that you apply a correction factor to the pooled cohort equation. What they recommend is for Black or African American women, it would be multiplying your original score by 2.8, and multiplying your original score by 2.6 for all other women, and multiply your original score by 1.25 for Black or African American men.

So exactly to your point, I went back (and I love online risk calculators because you can always just change one thing, like, okay, make them a nonsmoker or make their blood pressure a little bit higher or lower and try a couple of scenarios) and with the scenario that I presented today, which isn’t exactly the patient that I care for, her initial pooled cohort equation risk calculation value would be 2.5%. She wouldn’t have met any of the criteria. But if you multiply that by the correction factor, she then does fall into the 5 to 20% criteria that were set as the parameters that we would suggest for the use of a statin therapy.

Chris:
Interesting. Remembering to use the correction factor, whether it’s the precise one or at least doubling for women, African-American women, and maybe increasing by 50% for African-American men, sounds like a good practice for the 10-year risk from the pooled equation.

I’m going to bring up another one of her risk factors, and that’s something that’s been controversial for almost 20 years, which is ABC. Nearly 20 years ago, the European D:A:D study reported increased risk of cardiovascular disease and stroke among individuals who were receiving or had received abacavir.

A big challenge with studies like the D:A:D study and the subsequent NA ACCORD that also looked at it as channeling bias in that, like this woman, people with chronic kidney disease have long been more likely to receive abacavir, and chronic kidney disease is also a risk factor for cardiovascular disease.

There was a really interesting recent analysis from the report that you already described in which individuals, as you said, were at relatively low risk for cardiovascular disease based on the pooled equation. They also had to have relatively normal kidney function—I believe a grade 3 or 4 kidney function were exclusion, so EGFR greater than 60 among those individuals. So not really a lot of room for channeling bias, at least around kidney function, for which regimen they were on. In that secondary analysis from REPRIEVE, individuals who were receiving abacavir had a 40 to 50% increased risk of cardiovascular disease, either if they were currently receiving it or had received it in the past. And it’s actually pretty large change, although these people were overall at low risk, but by 96 months, about 8 % of individuals who had exposure to abacavir compared to less than 4% of individuals who did not have exposure to abacavir had a major adverse cardiovascular event, which has continued to influence my practice, but in my mind has fairly closed the deal that ABC increases cardiovascular risk and probably should be avoided when it’s at all possible to achieve a suppressive regimen.

Eileen:
I agree. The data around ABC have always lacked perfect clarity. But I think, where there’s a lot of smoke sooner or later, you feel like there must be something burning. The REPRIEVE analysis provides more support for that in particular, for all the reasons you mentioned about how there would not be as likely to be the channeling bias that’s been observed in other studies.

One of the things in the initial analysis, and you can correct me if I’m misremembering, was any abacavir use ever remained associated with a cardiovascular event, which, I would say, depressing. You like to think that any exposure once removed will eliminate that risk. That may be an overstatement. I’m not using that as a reason to continue people on abacavir. I, like you, look for any reason to change away from it, and in particular now that there are options like dolutegravir/3TC without the abacavir, which will work for many of the individuals for whom the 3-drug combination is the choice. But it does raise questions about the actual mechanism of that association.

As I think about those questions, I’m always smiling because there’s so much more to learn, so many more ways in which we could provide a better customized assessment to the individual in front of us about their risk and what the best interventions would be.

What this leaves us with is that we do know that HIV, even under fully suppressive antiretroviral therapy, does increase the risk of major adverse cardiovascular events, and there is good data to support that increase in risk is a little bit bigger for women as compared to men with HIV. We now have really nice data to say that statin initiation will reduce that risk, which is great news, because previously we only had traditional risk factor modification and antiretroviral therapy. Now we have another element in our armamentarium and that’s always good news.

As things go on, we’ll hopefully get some more information about the pathophysiology of this connection and maybe can even offer more targeted therapies to the people at highest risk because I still agree with you—I’m not sure this woman would have been identified. And I still think there’s more to be understood about why certain people develop these complications and other people don’t. In the meantime, we can minimize exposure to antiretroviral drugs that have any link to cardiovascular disease, in this case, abacavir, and do our best.

Chris:
Totally agree with you, Eileen, and remembering that all people with HIV have increased risk for heart disease, but especially a large increase among women and African Americans. In addition, we should consider ever having been exposed to ABC as an additional cardiovascular risk factor among people with HIV.

Any other comments, Eileen?

Eileen:
No, always such a pleasure to talk about HIV with you and thanks for doing this.

Chris:
Thanks so much, Eileen, and thanks to everyone who’s taken their time today to listen to our discussion. Very much appreciate it.

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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.