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:
Welcome to Viremic. I’m Chris Hoffman, and I’m here with my friend and colleague Eileen Scully. Eileen, welcome. Any updates on HIV or interesting tidbits from the news today?

Dr. Eileen Scully:
Well, hi, Chris. It’s great to be here.

One thing that’s been on my mind a bit is thinking about the future of an HIV vaccine. With the availability of long-acting agents like lenacapavir, sometimes we think we still need a vaccine? But I would say that our experience with hepatitis C, where we have really beautiful treatments but have not been able to stop new acquisition of hepatitis C points to how having good treatment is not the same as having good prevention. I’m still hopeful that someday we’ll have a vaccine that can prevent HIV acquisition.
It has been a scientific endeavor that’s had a massive amount of investment that hasn’t yet yielded a product. There’s some hesitation or concern in continuing those types of endeavors that puts that type of funding or that type of project at high risk, and that’s what we’ve seen over the last few weeks to months. A lot of projects where the outcomes are not exactly where we want them to be yet being on the chopping block. It looks like that’s happening around HIV vaccine research. Some of the larger consortium groups that have been working on this problem now for 2 decades or longer are at risk of being defunded.

It’s something for us as a community to think about. There’s that old saying that the best time to plant a tree is 20 years ago, but the second-best time is right now. Sometimes with vaccine research, we want the tree to be already grown, but the fact that it’s not there yet doesn’t mean that we shouldn’t be doing the work to plant it now. And infrastructure set up for research and testing around vaccines was transformative during the COVID-19 pandemic—allowed us to upscale, develop, and test vaccines much faster than we would have been able to without the existing expertise and infrastructure. So, it’s something I’m thinking about. I think There are lots of things that are important for people with HIV and for global health, but I definitely wouldn’t want to see us totally divest ourselves in work leading towards an HIV vaccine.

Chris, what are your thoughts about that?

Chris:
I totally agree. You highlight a number of the reasons for that. One is the infrastructure that has been set up and is needed to test a vaccine, whether it’s an HIV vaccine or COVID studies. Dismantling that infrastructure would be very unfortunate. The second is an effective HIV vaccine would be amazing. Some of these moonshot-type endeavors lead to so much additional basic science understanding that expand our knowledge and ability to intervene in other directions. I know your immunology understanding is way beyond mine, but I can imagine that the contributions to basic immunology from vaccine work in the HIV space has been profound over the last decades.

Eileen:
I totally agree. It will be another thing to add to our list of how we want the field to move forward and what we most need for people who are either at risk of acquiring HIV or living with HIV. I think there will be some forced prioritization.

Chris:
Definitely. In the meantime, getting people who could benefit from PrEP, whether it’s oral or injectable, cabotegravir or lenacapavir, need to remain high priorities.

Eileen:
I agree. Well, I’ll bring us back to the real world here instead of our moonshot research, and I have a case for you.

Chris:
Great, what do you have?

Eileen:
Okay, this is a 46-year-old woman; she presented initially with altered mental status and oral thrush. She has a history of HIV and limited engagement in care. Her last known treatment regimen was bictegravir/emtricitabine/tenofovir alafenamide, but has been off of therapy for some time— and not exactly clear when—looked through the refill history, looks like on the order of 6 months to a year. On this particular presentation, she was brought in by ambulance because her family found her to be what they described as sleepy and fairly difficult to engage, so they were worried that something was really wrong. When she got to the ED, she did have a head CT almost immediately that did not have a focal lesion. She had initial labs with a complete blood count that had a white count of around 2,000, absolute lymphocyte count was less than 1,200. Her HIV viral load on admission was 500,000, and her CD4 count was 35.

Given her altered mental status, she underwent a lumbar puncture. This was notable for markedly elevated opening pressure, low glucose, high protein, and a moderate pleocytosis. The white count was around 150. CSF studies were notable for nucleic acid testing for Epstein-Barr virus, cytomegalovirus, and JC virus, all of which were negative, and a positive cryptococcal antigen. Her CSF cultures were subsequently positive for cryptococcus as well.

We’ve been discussing mostly outpatient cases because I like to think that HIV is predominantly an outpatient disease here in the United States, where we have the availability of good treatments for almost all people. But we do still see people who present with these more severe types of presentations in the hospital.

Chris:
This is a really interesting case, and she certainly could have presented to the outpatient setting. It’s important to highlight the constellation of symptoms she had that led to, eventually, the diagnosis of cryptococcal meningoencephalitis.

Thinking back to the years when there were a lot more people with advanced HIV disease and less antiretroviral therapy. A persistent or worsening headache was often a reason to pursue further diagnostic workup and potential lumbar puncture, often leading to a cryptococcal meningoencephalitis diagnosis.

Now, for people living with HIV and not living with HIV, sometimes the cryptococcus diagnosis gets overlooked initially, probably less so in HIV, but certainly in the non-HIV space where we’re seeing a fair amount of cryptococcal meningitis among elderly individuals or immunosuppressed individuals.

In terms of your patient, a few things stand out to me. One is she is the perfect setup for cryptococcal meningitis—that she has such a profound immune deficiency with a CD4 count of 35. She also has the presentation of cryptococcal meningitis with altered mental status. Often headache would be part of that. She might be too altered to even notice her headache or may simply have more pressing issues than her headache to discuss.

The other surprising thing is her pleocytosis, which given her CD4 count of 35, I was surprised that she had 150 white cells in her CSF. That suggests she has ongoing inflammation, but perhaps you will shed some more light on that.

The final thing I would say is any patient coming in like this, I’m very worried about. Cryptococcal meningitis can progress very rapidly. The key thing at this point is to keep her brain from herniating by managing her opening pressure through repeated lumbar punctures. I’m sure you have more to fill us in on, so back to you Eileen.

Eileen:
Chris, your comments bring into focus a lot of the things one would need to consider when first encountering a patient like this.

In the modern era with excellent antiretroviral therapy, we don’t see cryptococcus as much. But as you mentioned, before the era of effective therapy, this was a major problem—at some point, probably accounted for about 15% of AIDS-related deaths and impacted maybe 5 to 8% per year of people with advanced HIV. One other thing to mention is that, while this is a somewhat classic presentation, it does have a high potential for both morbidity and mortality, and managing intracranial pressure is a critical step very early on.

The other thing to mention before we dive into her case is that there are other manifestations of cryptococcal disease outside of the central nervous system, in particular skin. Skin lesions from cryptococcus can be pleomorphic, but one of their presentations is with lesions that have an umbilicated center, which we classically think is always molluscum, but keep that on your differential if you see someone with advanced immune suppression who has skin lesions that aren’t behaving exactly in the way that you might expect them.

Pulmonary cryptococcosis is another presentation—can sometimes mimic even the acute respiratory distress that you might see with pneumocystis and needs to be on our differential when we’re looking at people with advanced immune suppression.

So, you highlighted a couple of the things about her case that are concerning. Even before we got the CD4 count—I gave it to you right away, but as we know in the hospital, usually that takes a day or two, and likewise for the viral load. With her absolute lymphocyte count of less than 1200, we knew she was definitely at risk for profound immune suppression, and with her history of limited engagement in care and also being off therapy for 6 months to a year, certainly had concerns for her to have an advanced HIV presentation.

I’ll highlight that she did have a head CT before they did the lumbar puncture. This is not because a head CT is going to be diagnostic of many things, but because if there is a space-occupying lesion that is preventing the free flow of CSF from the inside the skull down to the spine, then you’re at risk of creating a very high-pressure differential by removing some of the cerebrospinal fluid from the lumbar puncture and then putting the patient at risk of herniation, which obviously can be catastrophic. We still do those for patients with advanced immune suppression just to make sure that the risk of a lumbar puncture is not increased by the presence of that type of lesion.

You did point out that her white count was a bit high. I agree with that. And while we often say that when you have advanced immune suppression, you’ll have a low CSF white count and to not use that as a reason not to suspect meningeal inflammation, it can sometimes be high. I haven’t yet encountered a uniform explanation for why that is.

Her CD4 count of 35—we should keep in mind that patients who present to the hospital will often have a CD4 count that’s depressed even further than their baseline because acute infection on top of HIV can drive some further lymphopenia. So sometimes we see people with fairly low CD4 counts during a hospitalization that have a pretty dramatic rebound once their current reason for presentation has been addressed and even much faster than one would expect for CD4 reconstitution over time. That can also happen to individuals who are on antiretroviral therapy and fully suppressed. If you check a CD4 count at that time, you might get a little nervous, but often that’s related to the stress of the acute infection or whatever, “acute insults,” as we like to say, brought them into the hospital to begin with. That’s where we are for the beginning of the case.

Let me give you a little bit more about what happened with her, and then we can talk through some of the things that are important to consider for managing cryptococcus. She had a presumptive and confirmed diagnosis of cryptococcal meningitis and meningoencephalitis based on her depressed mental status. She was started on induction therapy. For most people, that’s recommended for approximately 2 weeks, followed by consolidation therapy. In the United States, where we have excellent monitoring for electrolytes and kidney function, we will usually do this with liposomal amphotericin plus flucytosine. The toxicity of these are often talked about—include both renal and electrolyte dysfunction, and the flucytosine can cause cytopenias. Classically, that’s what we start.

The other critical point in therapy is exactly the one you highlighted, which is lumbar punctures to manage the CSF pressure. In this particular case, they were doing almost daily lumbar punctures, and they were unable to get to a point where the CSF pressure was declining to a level where they did not need to continuously repeat lumbar punctures. At this point came a discussion of other potential therapeutic interventions and whether or not one should consider use of medications or use of a lumbar drain. We all know that corticosteroids are not routinely recommended unless they’re being used for the management of immune reconstitution inflammatory syndrome. That’s often what neurosurgical colleagues will use for management of increased intracranial pressure for other reasons.

It’s important as the HIV infectious diseases specialist to remember that this is a different case, and while a neurosurgery colleague might say, “Well, we should just give some corticosteroid,” that’s a different indication, and we should make sure to separate that clearly in our clinical decision-making. But whether or not you’ve seen lumbar drains used, and how frequently, or any good or bad results that you’ve seen with those.

Chris:
So, this comes up not as much these days as it used to. The starting point, as you highlighted, is that for cryptococcal meningoencephalitis, mortality comes from the increasing opening cerebral pressure and eventual herniation of the brainstem. Thus, management 1-2-3 is managing the opening pressure. The antifungal therapy is important for long-term success, but is not going to immediately have an impact on the opening pressure.

In terms of medical management of opening pressure, in other situations, there are approaches such as hypertonic saline or mannitol. Neither of these work in cryptococcal meningitis and there was in fact a RCT of mannitol for reducing opening pressure for cryptococcal meningitis that showed no benefit. So not only from a mechanistic perspective are these unlikely to work, but we actually have clinical trial evidence for that.

Steroids are a somewhat different question. In terms of the use sometimes in neurosurgery for vasogenic edema or other mass effect, that is not most of the picture in cryptococcal meningitis, where at least the believed pathophysiology has more to do with the arachnoid plexus and the disruption of reabsorption of CSF from the arachnoid plexus. So, steroids have a role in cryptococcal meningitis. And I have used them for later manifestations of IRIS or immune reconstitution inflammatory syndrome, but not in the immediate phase. There it’s a matter of draining the CSF, which is not being effectively drained by the arachnoid plexus, either through frequent lumbar punctures, which may need to be daily or even more than once a day.

At that point, it becomes hard to manage as there becomes more edema just in the lower back from lots of lumbar punctures. Then a spinal drain or even a shunt placement needs to be considered. Sounds like for this patient, a lumbar drain may be in the cards to help manage that. Two other points around managing the CSF: One is that things can progress very rapidly in terms of increasing opening pressure or increasing intercerebral pressure and brainstem herniation. The concern for that should always be high, even in somebody who seems to be doing well. If they start to have reduced level of consciousness or increasing headache, probably doing a lumbar puncture soon within the next minutes to less than an hour rather than waiting till later in the day is important. And if that needs to be done, frequently, then the lumber drain is really the way to go.

With every lumbar puncture, it’s helpful to remember that in a healthy adult, there are about 500 cc’s of spinal fluid produced per day. So, taking off 10 to 20 to 30 cc’s is not a huge volume compared to the total volume of spinal fluid around the brain, which is about 150 or more cc’s—the spinal cord and the brain is about 150 cc’s. So being aggressive with optimal pressure management is the critical step in initial treatment of somebody with cryptococcal meningoencephalitis.

Eileen:
Those points are all great, Chris, and I agree with the urgency of evaluating if you suspect that herniation may be impending or possible.

The other thing to always look for is cranial nerve palsies—so an excellent eye exam on admission and serial eye exams each day that you’re caring for a patient or if you ever have concern for an alteration in neurologic status—are critical.

Although we’re taking a very one-track approach to this case, I can tell you that in real life, all the individuals whom this case is drawn from had multiple other things going on, because as we always say, Occam’s razor applies in medicine except for in the setting of immunocompromise, in which case there are often multiple concurrent processes ongoing. For someone with this level of immune suppression, a good ophthalmologic evaluation is recommended because they may also have additional processes going on there.

But coming back to your points about CSF pressure, this becomes important because it feeds into the recommendations and considerations around the timing of antiretroviral therapy initiation, which is the next point I’d like to get into.

The critical questions are, what are the causes of morbidity and mortality associated with cryptococcus? As you’ve highlighted, increased intracranial pressure is one of the major sources of both of those things, if not the only. When you are able to achieve good management of the CSF pressure, that does influence options you have in how you can approach the other parts of the care, including the initiation of antiretrovirals. For this particular patient, she did get a lumbar drain placed. This allows continuous low-level drainage of CSF in order to get pressure closer to a level where there’s less likely to be any intracranial problems associated with it and to prevent the buildup over time.

As I’ve now obliquely referenced a few times, there are clear recommendations that in the context of cryptococcal meningitis, you don’t actually start antiretroviral therapy as soon as possible, and this is notable because most of the time we talk about start antiretroviral therapy as soon as you meet the patient, even on the day of first engagement. There are some good studies to say that rapid initiation of antiretroviral therapy in many settings, in particular for people who are asymptomatic and those without significant immune compromise, is very safe and has some potential significant benefits for engagement and for achieving viral suppression.

There are only a few cases where we have exceptions, and those are limited to cases where there’s a high risk for IRIS (and that syndrome is associated with morbidity and mortality itself); cryptococcal meningitis is one of them. The strongest recommendation for delay of antiretroviral therapy for cryptococcus comes from a CID paper from 2010 that was led by one of my co-fellows, Tariro Makadzange. This study was conducted in Zimbabwe, where they enrolled participants who were over 18 years, antiretroviral therapy-naive, and had a first diagnosis of cryptococcal meningitis. They randomized them to receive early antiretroviral therapy, within 72 hours after their diagnosis of meningitis, or delayed antiretroviral therapy, which was 10 weeks of treatment with fluconazole. That’s a major difference, and we should put a little bookmark there to think about when we’re talking about early versus late therapy in the United States or in the context of a hospitalization, what kinds of numbers we’re using. I will highlight that the antiretroviral therapy they used in this study was stavudine, lamivudine, and nevirapine because this was conducted in 2010—quite different than what we have available today.

Their primary endpoint was all-cause mortality. They looked at 54 participants, 28 in the early and 26 in the delayed, and they showed a significantly higher risk of mortality, almost 3 times higher in the early antiretroviral therapy group as compared to the delayed antiretroviral therapy group. The study was terminated early by the data safety monitoring board. One of the notable findings was that the median duration of survival was about 28 days in the early antiretroviral therapy group versus 637 days in the delayed antiretroviral therapy group. What that strongly suggested was that the initiation of antiretroviral therapy was associated with a complication right around the time of the cryptococcal meningitis. Many people felt this was likely to be IRIS-related and therefore that this would be one of the only cases in which we would defer antiretroviral therapy to drop the risk of that.

So, I’ll pause to talk a little bit about IRIS itself. The risk factors for it are somewhat pleiotropic, but in general, a CD4 count of less than 50 is associated with a higher risk of inflammatory consequences to many opportunistic infections. There’s a couple of different flavors of immune reconstitution that we talk about. There’s unmasking—which is that you are not symptomatic, you start antiretroviral therapy, and you develop symptoms. Then there’s what would be described as, a known diagnosis of cryptococcal meningitis, for example, and then you start antiretroviral therapy and develop an inflammatory syndrome to that known infection. The principles of trying to avoid this are, in layman’s terms, that the immune system has been totally beat up and distracted by trying fruitlessly to fight HIV, is alleviated from that fight by the antiretrovirals that drop the viral load. In that context, the immune system suddenly becomes aware and in tune to the presence of other pathogens, which are these opportunistic infections that have been existing. Once the immune system is a little bit more empowered, as one might teleologically describe it, then you have this very robust inflammatory response, and this can lead to fevers and other symptoms that can make what looks like a minor infection look much more significant. In the context of the CSF, where you might already have some blockage of drainage, as you’ve already described, now, if you have a very robust inflammatory response, that could further exacerbate the underlying conditions and lead to much, much elevated CSF pressure in this particular example. That’s the general thought behind it.

So, one of the principles of trying to avoid it is to drop antigen load. What that means is whenever there’s an infection, there’s parts of that infectious agent that are present. We refer to them as antigens, which is just things that the immune system recognizes. If you can decrease the quantity of that, get some of the, in this case, fungal load down, there’s less for the immune system to wake up and recognize. By giving a delay of antifungal therapy, we can hopefully get down the load of organism that is there, such that when the immune system is awakened by the initiation of antiretroviral therapy, you won’t have quite as much inflammation as you might have had otherwise.

The recommendations are in general that you wait until you have negative CSF cultures, with the first check being about 2 weeks after you start therapy. And of course, the culture takes some time after that. In general, people who are on induction therapy who have a known positive culture at baseline, which we don’t necessarily always have, will be treated with induction therapy for about 2 weeks. If their initial lumbar puncture still is culture-positive, then people will sometimes extend the course of induction therapy to achieve culture negativity before transitioning to a consolidation regimen, which will start after you’ve confirmed the negative culture, and that will be with high dose oral fluconazole. Typically, people perform a lumbar puncture after 1 week or 2 weeks of induction therapy to document this and then make this transition once they have the results. The duration of consolidation therapy should be for at least 8 weeks after documenting a negative CSF culture. Therefore, you get a nice buffer zone after negative culture to make sure you’ve eliminated any possibility of having live organisms that are still present.

I’ll pause there and see, Chris, if you had any comments or thoughts about those general considerations.

Chris:
Iris and cryptococcal meningoencephalitis is tricky. There are the issues of CSF reabsorption, which has a lot to do with antigen, can be worse with inflammation; then there is the encephalitis aspect of it, and individuals can have cryptococcomas within the CNS parenchyma, which can also lead to some inflammation. How much of that long-term is actually viable organisms or just cryptococcal antigen that is the mucinous capsid or other antigen that is present, is something I do not know, and I’m not sure if that’s well characterized. Given that, ideally, somebody has a sterile CSF culture, but that does not prevent any future IRIS from occurring. That is why I think you’re going down this path of the caution and care in when antiretroviral therapy is initiated and close follow-up of somebody on antiretroviral therapy.

And I’ll note the subsequent clinical trial to the one you mentioned in Zimbabwe that was conducted in South Africa and Uganda—the COAT study. They enrolled individuals with cryptococcal meningitis and randomized them to early initiation, which was within 48 hours of enrollment, typically 1 to 2 weeks after starting cryptococcal therapy, or delayed antiretroviral therapy, which wasn’t the 10 weeks in the Zimbabwe study, but was a median of 5 weeks after initiation of antifungal therapy. Similar to the Zimbabwe study, they observed a lower mortality in individuals with a delay in antiretroviral therapy initiation. About 45% of individuals died in the early antiretroviral therapy arm compared to 30% of the individuals in the delayed arm.

This is a disease with very high mortality. It’s possible that with different medical care in the United States, for example, than was provided in South Africa and Uganda, the mortality may be a little bit lower, but even in high-income settings, a very morbid disease with high mortality.

The other thing I wanted to bring up again is the management of the opening pressure. In the COAT study, about half the participants had an elevated opening pressure at diagnosis. Whether the opening pressure was elevated or not, receiving subsequent lumbar punctures was associated with a reduction in mortality. That highlights the importance of managing opening pressure and any sort of inflammatory process that’s going on.

The last thing I wanted to mention, again regarding the COAT study and subgroup analysis, is they looked at the risk of early antiretroviral therapy initiation and mortality based on the level of pleocytosis in the CSF at diagnosis. Individuals with very low pleocytosis, I believe less than 5 cells, so essentially no inflammatory process going on to the fungal infection around the brain, are the ones who had the highest mortality with early initiation of antiretroviral therapy, or I should say the largest difference between early and delayed antiretroviral therapy. Individuals who already had evidence of an inflammatory process going on with the pleocytosis had no difference in mortality between early and late initiation. I don’t think this matters clinically, but from a pathophysiological understanding, it’s important to understand what is driving some of the increased mortality, and IRIS, and who is at greatest risk for the worst IRIS outcomes.

Back to you, Eileen.

Eileen:
Chris, the one other factor that’s been associated with a high hazard ratio of having an IRIS-like syndrome for cryptococcal meningitis specifically is a positive culture. That, has driven some of the guidelines around using culture conversion as an indicator of when to start antiretroviral therapy, because that’s something at least we theoretically have interventions for. We could treat longer and hope to get there.

You’re highlighting a really important thing, which is that if there’s already inflammatory response there, if the immune system is capable and functional enough to generate that, then maybe there’s a little less added risk as opposed to a totally disabled immune system that is going to be discovering, quote/unquote, the presence of a pathogen for the first time in terms of the robustness of the inflammatory response.

You also highlighted in your comments that there’s less known about what would happen in a more resourced environment like the one we have here and the patient we’re describing here who has a lumbar drain, so in theory, has continuous ability to manage CSF pressure and hopefully prevent complications. That has always been a caveat for the recommendations in the DHHS guidelines and the IAS USA guidelines, that while there is a recommendation to defer therapy, it’s not clear that actually translates across all settings. There is one analysis of the European and North American databases, which included the COHERE, the NA Accord, and the CNIX databases. They used a marginal structure model to, quote, mimic a randomized controlled trial and did not see a real benefit to delayed versus early antiretroviral therapy in cryptococcal meningitis cases from these more resourced environments. Delayed was 14 to 56 days after initiation of antifungal therapy versus early, which is less than 14 days.

I’ll also highlight that, because from an inpatient perspective here in the United States, 14-day stays in the hospital are unusual. So, a lot of times when people are talking about early, we’re thinking they’ve only been in the hospital for a few days, and we’re already thinking about antiretroviral therapy. I usually provide some reassurance to teams that we can wait for the dust to settle for a few days and then make our decisions because we’re still considered to be early therapy if we’re starting in less than 14 days. Sometimes there’s competing priorities, where there’s one indication for early initiation of antiretroviral therapy and then another indication for waiting, and just having an idea of what early means—this is not a myocardial infarction where you have to have a door to balloon time—it’s a different kind of early window, which is usually broadly considered less than 2 weeks.

So now, what do we think about antiretroviral therapy initiation here? Based on some data from the Western countries, IAS USA now explicitly states that initiation of antiretroviral therapy should be about 2 to 4 weeks after antiretroviral therapy initiation. They specifically recommend initiation at around 2 weeks for those with clinical improvement in their symptoms, control of their intracranial pressure, and a negative CSF culture. And also, when they have the ability for continued monitoring. But it states that those who do not meet these criteria should generally initiate at 4 weeks after starting antifungal therapy. In theory, even someone who doesn’t meet some of these criteria would be recommended by the IAS USA guidelines to start at 4 weeks, although that is a lower level of evidence, graded as B3 in the recommendations.

The DHHS guidelines are not surprisingly a little bit more conservative, as they tend to be. They recommend to start antiretroviral therapy within 4 weeks of antifungal therapy, but then the very next sentence is about how CSF culture positivity is associated with IRIS. Since other parts of the recommendations clearly state that CSF culture negativity is very helpful, it’s kind of like, well, you can start within 4 weeks, but remember that CSF culture positivity is a risk.

In this particular case, the individual had a lumbar drain in place and still had positive cultures out to 4 weeks, so there was a lot of consternation about what should be done and how we could manage these questions of the risk versus benefit of starting antiretroviral therapy. At some point, people will show you that directed antimicrobial therapy alone is inadequate, that they actually need some immune system in order to clear whatever process is happening. This is the time when, while there are risks associated with immune reconstitution, it’s also the only pathway between advanced AIDS and health. So sooner or later, we’re gonna have to traverse this pathway and deal with those risks of inflammatory syndromes along the way. There’s just no other way to get from point A to point B in some cases. You just cannot clear out the infection adequately without having some reconstitution of your immune system.

This is a pretty ideal case—we have ongoing management of the CSF pressure, inpatient monitoring to make sure that if anything goes awry, we can try to address it with additional interventions. In this kind of situation, again, you would revisit the concept of corticosteroids, which you wouldn’t use for preventive therapy, but might have a role if there was acute exacerbation. But you can see that there’s only one option to move the care forward to advance the patient’s health, and that is to actually suppress the HIV and to manage the consequences.

I mentioned this specifically because this comes up with IRIS type of cases fairly frequently—an inpatient team will be worried that they might have IRIS to whatever it is that they have. In all of those cases, you can think about the antigen load, you can think about the potential implications of inflammation at the site of where you’re aware of the tissue-based infection, but in general, we only have one way to get people healthier, and that’s to reconstitute the immune system. So, we more need to do anticipatory management of the potential complications of inflammation rather than say, “Well, we can’t do antiretroviral therapy because that’s a risk.”

At least that’s my personal approach to those types of questions. But Chris, I’d love to hear yours.

Chris:
I couldn’t agree more. Eventually people living with HIV need to be on antiretroviral therapy for successful healthy outcomes, and in an individual with advanced HIV disease, the sooner we can do that safely, the better. And as you said, there’s some infectious processes that just will not respond to our antifungal or antibiotic therapy, and we need to reconstitute the patient’s immune system.

A couple of comments in terms of monitoring: The fungal culture can be extremely helpful to get. Sometimes the antigen can trip people up. The CSF cryptococcal antigen is likely to stay positive for months, if not years, given that the CSF is a relatively sanctuary site and clearing that antigen can take a long, long time. What can be helpful is titering the antigen to see that it’s declining. There’re some studies looking at that. And as you mentioned, the culture can be very helpful as well.

Eileen:
Those are great points, Chris. I’ll use that antigen comment to also add in that in endemic areas (which is essentially everywhere, because there’s very broad exposure to cryptococcus; it’s not something that you can avoid as we think of toxoplasma as potentially being able to avoid exposures, not so for cryptococcus), screening individuals with advanced HIV for cryptococcal antigenemia in the blood is also recommended. If there is asymptomatic antigenemia, then you can use the titer to determine whether or not you should have a lumbar puncture to determine whether or not there’s CSF involvement, which would change your recommended treatment. If you don’t have CSF involvement, there’s still recommended a short course of fluconazole to manage the presence of that organism and hopefully prevent progression to more serious complications.

Chris:
Very good point. Cryptococcal meningitis, cryptococcal meningoencephalitis is complicated. We see it less, and each presentation has variations on the theme, even more so these days in patients like this one who have been on and off of antiretroviral therapy, may have reconstituted their immune system at some point, are back down now to a CD4 count of 35, may have previously had cryptococcal meningitis. All of that changes some of the presentation as well as some of the immune recovery aspects and how the body responds to persistent antigen. Sometimes the guidelines are spot on, sometimes adaptation is needed, as you’ve already suggested. The guidelines hedge their bets also in terms of how to manage these things.

The last thing I would say is that steroids do have a role in IRIS. Depends on the type of IRIS, but they do have a role in cryptococcal meningoencephalitis. Typically, when I’ve used them, it’s after individuals have completed consolidation therapy and are on maintenance therapy, or at least have been initiated on consolidation therapy, and usually are on antiretroviral therapy, and have recurrent or severe headaches that are then managed with a long steroid taper.

Eileen:
We’ve covered one of the more common presentations in the olden days, but still one that comes up for our patients. As things become less frequent, we get a slightly higher risk of not doing all the things perfectly because we’re not doing them all the time. This is a very recoverable illness. So, while we’ve highlighted the potential severity, most of my patients who have cryptococcal meningitis are, within a few months, sitting in the clinic, and we’re talking about how much longer they need to stay on their consolidative fluconazole, and aiming towards full viral suppression and liberation from all of their opportunistic infection suppression or preventive therapies. This is something when done well, we can make a huge, meaningful impact on our patients and hopefully will lead to great outcomes where this becomes no longer a concern for that individual.

Chris:
Wonderful point. I have some patients who are high-functioning professionals, but years ago they had severe cryptococcal meningitis. I have a couple of patients who have CSF shunts in that were placed at that time and have done great, but with the wrong management, obviously they would not have made it now. And as you said, for your patient and for many others, good management of a highly morbid, mortal disease can lead to great outcomes.

Eileen:
Well, thanks so much for thinking through the case with me.

Chris:
Yeah, thanks. This was fun, Eileen. Look forward to our next case discussion. And thanks to all who’ve listened for joining. We really appreciate you taking this time.

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.