Viremic – Cases in HIV

Case 24 Transcript

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

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

Dr. Eileen Scully:
Welcome to Viremic, a podcast where we discuss all things HIV. I’m Dr. Eileen Scully coming to you from Johns Hopkins in Baltimore, and today I am joined by my friend, colleague and co-host, Dr. Chris Hoffmann.

Before we begin, just a reminder that if you like this episode, please share it with a colleague and follow us wherever you listen to podcasts. We’d love to hear what you think. Please leave a comment or send us an email at viremicpodcast@jh.edu. and feel free to leave suggestions for future topics.

How are you today, Chris?

Dr. Christopher Hoffmann:
I’m doing well, Eileen. Always a pleasure to be talking HIV with you.

Eileen:
Today I have a case for us that is a combination of a few cases I’ve seen over the last decade or so and highlights a significant but not super common opportunistic infection, and I’m going to dive right in with the history.

Our hypothetical patient today, will be a 42-year-old man who presents with untreated HIV, with a viral load of greater than 1 million copies per milliliter, and a CD4 count of 10. He was tested and found to be HIV seropositive a few years ago but did not engage with care until recently.

He had been feeling unwell over the several months prior to presentation. He reports a poor appetite; weight loss, which was significant enough that he needed to buy new clothes; and some sweats at home, most commonly at night. He has not checked his temperature at home, so he doesn’t know if he has a fever, but he has noted white spots in his mouth, and says that he feels ready to start treatment for HIV.

What tests do you send as your baseline evaluation for someone who presents with this level of advanced immunosuppression?

Chris:
Fortunately, we do not see this type of patient that much these days, and that can lead to maybe feeling a bit intimidated or overwhelmed initially and reinforces the importance of a structured approach. There are good lists of initial tests to send, including ones in the New York State guidelines at hivguidelines.org (the primary care guidelines) as well as other references.

Before though getting into the specific tests, I think understanding a bit more about this patient and why he’s coming now, why he was not able to engage in HIV care previously, are going to be pretty important things to understand. In terms of specific tests, they’re the general tests that everyone should get with HIV: viral load, CD4 count, kidney function, liver labs, hemoglobin, platelet count, white blood cell count, lymphocyte count. And then some more specialized tests, including serologies for viral hepatitis, hepatitis B surface antigen, surface antibody, hepatitis C antibody. Typically, I do hepatitis A also.

Then moving on to the specifics for somebody with a low CD4 count, there are 2 considerations—one is prophylaxis for prevention of developing an opportunistic infection, and one is knowing if he actually has an opportunistic infection that could worsen or develop an IRIS at the start of antiretroviral therapy.

Somebody with a CD4 count of 50 would be appropriate to use prophylaxis for pneumocystis as well as toxoplasma if his toxoplasma IgG is positive. So doing a toxo IgG is appropriate here. Then other testing is directed by symptoms. There are a few things that you’ve mentioned, [e.g.] the night sweats, which could point to a disseminated mycobacterium avium intracellular infection.

I don’t normally obtain that in an outpatient, but certainly if this person was admitted, I would get that, and possibly even in this situation, depending on what more I hear.

There’s the possibility of doing cryptococcal antigen testing from the blood, which, in some settings is routinely done in anyone with a CD4 count less than 100, potentially reasonable for this individual, although the prevalence in the United States is a bit lower.

Another test to consider would be for TB infection with a IGRA test, such as a QuantiFERON Gold or T-Spot or a tuberculin skin test, especially if there’s any consideration of exposure from immigrant status or any other epidemiologic risk factors.

Please point out what I may have missed there, Eileen. I just want to make sure he has a safe course on antiretroviral therapy, minimizing risks for IRIS and development of any opportunistic illnesses, as he initiates antiretroviral therapy.

Eileen:
Chris, that’s a great list. I also love how you divided it—the screening tests that we do to risk stratify for the development or emergence of an opportunistic infection, and then those types of tests that we would use to pursue a diagnosis, which is usually driven more by a symptom complex as opposed to just an immune status.

We think of having a very low CD4 count as being a very immunosuppressive condition, which it is, but at any given moment, you don’t necessarily have manifestations of an opportunistic infection. So, I’d agree with many of the things you said. I do come down a bit stronger on the serum cryptococcal antigen testing, and I routinely do that for anyone who’s less than 200, but definitely in those who have CD4 counts less than 50. I’ll just remind our listeners that if you do have a positive antigen test, you should proceed with a CSF evaluation just to rule out a CNS infection in individuals who do have positive antigenemia. But yes, I think that’s a great start.

In general, the same principles of starting therapy early and often continues to be your overriding guiding approach to HIV at new presentation.

We can’t rule out everything all the time, but that’s okay. Things that require attention will declare themselves, and we do have more opportunities to check many of these tests over time and in particular if symptoms emerge.

But let’s go back to our hypothetical patient. On your exam, he does in fact have oral thrush, and he’s got temporal wasting consistent with his report of his symptoms at home. His cranial nerve exam and detailed neurologic exam are thankfully totally intact. He has mild tachycardia, no abnormalities on lung exam, normal oxygen saturation, and no peripheral edema. He has scattered violaceous macules that he reports are new on the upper extremities in addition to the oral thrush, and no other rashes that were noted. Since you can’t see these imaginary lesions, I will tell you that they have an appearance that is highly consistent with Kaposi sarcoma [KS].

Chris, can you comment on what you think of when you hear about KS lesions in a person with AIDS?

Chris:
Eileen, this is an interesting development and maybe why he came to see you and is now very interested in antiretroviral therapy. There are a number of things that come to my mind when I’m suspecting Kaposi sarcoma, or somebody comes to me concerned about Kaposi sarcoma. The first is that Kaposi sarcoma has a longstanding stigma as a visual manifestation of advanced HIV disease, and in the bad old times, [it was] often a harbinger of rapid progression of disease and mortality. Individuals who were alive and first diagnosed with HIV or knew people living with HIV at that time still carry a strong fear of KS, and fear of the stigma that it can carry if somebody sees those skin lesions on them. So that’s number one—talking with this patient about Kaposi sarcoma and what it means at this point. I’ll take a step back and talk a little about the skin lesions.

First, Kaposi sarcoma can be clinically diagnosed. Even if I have a high suspicion, I often send somebody to dermatology for a biopsy for confirmation. Typically, KS skin lesions have a little bit of a halo or hemosiderin deposition around them because of the vascular nature of Kaposi sarcoma lesions. The angioproliferation is not a functional blood vessel, but one that is lacking its basement membrane and is highly permeable, thus there’s an extravasation of hemosiderin and also red blood cells. There can be some scattered petechiae as well that yellowish to reddish halo around typically a violaceous lesion. If I see that, I’m pretty convinced it’s Kaposi sarcoma.

The other thing that I do is a very careful oropharyngeal exam. KS on the skin often also will be seen in the oropharynx, especially the hard palate, in a large proportion of people with advanced HIV and significant Kaposi sarcoma. Finally, given his CD4 count, I would have some concern for visceral Kaposi sarcoma as well, either pulmonary involvement or gastrointestinal involvement, or just bulky lymphadenopathy. You haven’t told me about the lymphadenopathy on the exam, nor any GI or pulmonary symptoms, but I would probably at this time circle back and re-ask some of those symptom questions.

I’m sure you already have obtained a social history, but in the U.S., it’s primarily seen among men who have sex with. In many other parts of the world, certainly in Sub-Saharan Africa, it affects both men and women simply due to different transmission patterns of Kaposi sarcoma-associated virus or HHV8. Maybe you wanted to share more about some of the epidemiology of KS and HHV8.

Eileen:
Kaposi sarcoma is a malignancy, but it is a virus-driven malignancy. The virus responsible for causing this cancer is HHV8. HHV8 can occur in the absence of causing cancer, and it does in the U.S. general population. It’s probably in less than 10% by seroprevalence surveys. The seroprevalence is as high as 20% and [ranging] upwards of 50 to 60% among MSM who are living with HIV in the United States. Globally, there are major differences, with rates as high as 10 to 20% in the general population of some Mediterranean countries and as high as 90% in some sub-Saharan African countries. So exactly as you’re highlighting, Chris.

HHV8 as a virus, as the etiologic agent of Kaposi, also causes several other diseases. This was one of those things that when you’re a fellow, a lot of these words were thrown around, and they never really crystallized for me as to how they differ and what all these processes are. So, we’ll just take a minute to list some of them, although we don’t have time to talk about all of them today. One of the possibilities is multicentric Castleman’s disease, a lymphoproliferative disorder driven by HHV8. There’s primary effusion lymphoma, a transformation event where it’s a malignancy of a B cell that develops a lymphomatous-type presentation that often causes effusions, either pericardial effusions or pleural effusions. And there’s an HHV8 positive variant of diffuse large B cell lymphoma. There’s also an inflammatory syndrome, which is an inflammatory cytokine storm type of syndrome known as KSHV or Kaposi sarcoma herpes virus-associated inflammatory cytokine syndrome or “KICS.”

To summarize, this is a virus that is asymptomatically present in a portion of the population globally. The portion that it’s present in varies a good bit by region, and there is an enrichment of being seropositive in those who are living with HIV and who are men who have sex with men, specifically in the United States.

That virus can cause cancer of a couple of different types. Kaposi sarcoma is a transformation event of an endothelial cell, as you mentioned, that is associated with increase of angioproliferation, so these abnormal blood vessels that proliferate and create violaceous nodules. In other cases, it’s a transformation event of a lymphoma, of a lymphocyte into a lymphomatous cell. So, the same virus can cause problems in different cell types, and these can present differently. You can have both problems at the same time or only one.

In this case, what we’ve got is probably some lesions that look like or are consistent from a clinical perspective with a KS- type lesion. You’ve already mentioned a couple of features of the lesions themselves. There’s a couple of stages that they can go through. Initially, a flat and erythematous to violaceous macule—that’s earliest. Then a slightly more raised or indurated plaque, and then finally, a nodular stage, where they’re more dome-shaped and may become ulcerated or have other features. It can be a clinical diagnosis based on the appearance, but if there is a biopsy, the finding for Kaposi sarcoma is this proliferation of spindle cells, and that’s specifically the sort of the thing you look for on the pathology. These are these endothelial cells that have been transformed into malignancy through HHV8 expression.

Chris, at this point, you’ve done an oropharyngeal exam; he only has thrush. You’ve done a skin exam, and he’s got a few scattered violaceous lesions. He’s got HIV, which is somewhat symptomatic based on weight loss and other things, but really is giving you no other symptom complex to specifically direct you for further workup.

Chris:
Eileen, I’d like to get him on antiretroviral therapy with a suppressed viral load as soon as possible, given that there’s no evidence of a CNS process that would put him at risk for a severe IRIS complication.

After reviewing lots of other things, I typically tell somebody like this who has a low CD4 count that the recovery may be bumpy and they may actually feel worse initially, but they should not despair and should not stop the antiretroviral therapy. Some of that bumpiness could be from KS—10 to 20% develop a KS IRIS, which can be increased angioproliferation of these lesions. The lesions themselves can get larger. Sometimes there may be a hidden lesion that then can present. There can also be a bit of inflammation around that lesion. He is certainly at risk for all kinds of other opportunistic infections. As we always say in HIV, people can have more than one diagnosis (Occam is often wrong when it comes to HIV). So that’s where I would start with him and go through that carefully and let him know how to get in contact with me the moment he’s unsure about whether he’s feeling worse or is concerned about any complications or side effects from his medications.

Eileen:
I do the same thing. The "[It] may get worse before it gets better," is always part of my initial discussion. I think that is helpful for framing the experience for patients. I also tend to tell them that they have to see me a lot at the beginning, but pretty soon they’ll be seeing me much less frequently and kind of use that as “This is a great time for us to get to know each other,” and then you’ll just come back in for visits when you’re doing much better and fully suppressed.

For this case, if you have what looks like T0-stage skin-only KS lesions, ART alone is the initial recommendation for treatment. In a substantial proportion of patients, that will be adequate to lead to resolution of the lesions.

Exactly as you mentioned, an IRIS-like phenomenon with peri-lesional inflammation does occur with some frequency. There’s been trials to see if pairing ART with chemotherapy can help to alleviate this, and while it may, it didn’t actually improve outcomes. So that’s generally not recommended for limited early-stage disease.

One other thing I’d note is that there is a relative contraindication to use of corticosteroids in HHV8-related processes. This is because there are a few case reports of explosive progression of KS-related disease in patients with HIV who are treated with corticosteroids specifically. In general, we do try to avoid immune suppression or corticosteroids, as they may enhance or accelerate the progression of KS-related disease.

As far as other direct therapies, there are some antiviral agents that have in vitro activity against HHV8, but none of them have been shown to have any efficacy. So, in general, we don’t use direct acting antiviral agents.

Our patient did exactly as you would have recommended and initiated ART. I love the insight about how the visible lesions and the history of stigma around KS specifically may have been a major motivator for him. I have had patients for whom that is definitely the case. He reported 100% adherence to his Biktarvy and overall had good tolerance of his medications and had significant improvement of his oral thrush, which was a big relief.

He’s coming back to see you about 1 to 2 weeks. He did report a few new symptoms, and although he had your contact information, he waited until his appointment. He started to develop frequent nosebleeds and had worsening fatigue and some loose stool that was dark in color about 1 to 2 weeks after starting the antiretroviral therapy. On exam when he came back into clinic, he had multiple large, violaceous lesions in the nasal mucosa and one on the palate as well. He also had multiple new skin lesions, and on his clinical labs, his hemoglobin had dropped considerably, although his platelet count remained stable. So where am I leading you now, Dr. Hoffman?

Chris:
It sounds like he has IRIS to the Kaposi. There are a number of potential possibilities, but what points in that direction is an unmasking IRIS to lesions that were not seen on his initial presentation, but now have developed after starting antiretroviral therapy, especially those in his nasal mucosa as well as in the GI system, starting with the oropharynx.

As I already mentioned, the palate is a very common place to see KS lesions, but the rest of the GI system can be involved also, especially in somebody with such a low CD4 count and profound immunodeficiency. You also mentioned the potentially melenic stool and the decrease in his hematocrit, which is concerning for GI bleed and would tie well with GI-KS and the rest of his GI system or small bowel especially. That is a concern and maybe an indication to treat with anti-neoplastic agents.

I’ll pause there, but before turning it back over to you, Eileen, I wanted to reiterate what you said about steroids—that they can promote KS development. Steroids interfere with some suppressive cytokines such as TGF beta, which can suppress development of KS progression. When that’s suppressed, the hypothesis is that the lesions can worsen. It also can affect other cytokines and that’s also been pointed to as a potential mechanism of steroids specifically to promote the development of KS. It’s concerning enough that steroids have limited to no role in somebody with KS and concerns for visceral KS because enlarging lesions can cause bowel obstruction, or if there’s pulmonary involvement, can cause airway obstruction that can be fatal.

Eileen:
Chris, thanks for those points. There’s a lot of mechanistic debate about exactly how the corticosteroid relationship works. There’s old literature that suggests a HHV8 promoter is actually responsive to glucocorticoids, so you can drive transcription and increase viral load directly, which looks to be true in some experiments and not others. I think it is one of those complex things—it might be a secondary cytokine effect, might be a direct effect on virus production. But regardless, there’s clinical data to suggest that for at least some individuals, corticosteroids can really accelerate progression.

It is unusual. Usually in ID where people are worried about steroids and we’re like, “Eh, it’s okay,” but this is one of those cases where I am very reticent and actually recommend against their use.

The other thing about this particular case is not only IRIS, but actually accelerated KS, because you did examine his mouth initially and there wasn’t any lesion there, so this is a new lesion as opposed to an inflammatory response to a lesion that was present. The IRIS component, I think, is certainly present and may actually be the driver of blood loss and the inflammation of these lesions, leading to more oozing blood loss wherever they’re located.

In his case, I would also characterize it as an accelerated progression of the process itself, even independent of immune reconstitution phenomena. That also is suggested by the fact that he has multiple new skin lesions, again, not just that they’re getting inflammation [and] were there before, but are actually brand new. This is definitely a clinical presentation that occurs, and I’ve seen it in a few cases over the last few years.

Use of chemotherapy is important in this context and is somewhat urgent, because as these lesions grow, they become more friable and risk of blood loss accelerates. Patients can have life-threatening GI bleeds.

A few points about visceral [KS] and how you make decisions about use of chemotherapeutic agents: You try to stage whether the disease is skin only. For someone who has massive progression of their skin-only disease, that’s also an indication to use chemotherapy. It’s not like, “If it’s only the skin, we don’t care,” but as you mentioned, presence of a lesion on the oral mucosa, including the palate, is highly suggestive. In some case series, [it] is associated with visceral disease either lower down in the GI tract or in the pulmonary system in as high as 60% of cases.

Then your next question is how much diagnosis do you do? We frequently do bronchoscopy to evaluate and then also upper endoscopy to look for lesions. In the bronchoscopy, the findings on visual examination are pathognomonic. If you see the appropriate nodules, it is not a good idea to biopsy as these are highly vascular lesions that will bleed and can cause acute lung injury with that noxious stimulus of bleeding into the lungs. In our well-resourced settings, we often do invasive evaluations to see exactly what is there—you’ve already brought up Occam on this podcast once, he’s not always right. You can have other causes of GI-related blood loss: ulcer disease, HSV-related ulcerations in the esophagus, or other things, so it is reasonable to do a direct inspection to confirm your suspicion. I share with you the overall clinical diagnosis of this individual absent the ability to do any additional studies would be likely skin and visceral KS, with a component of immune reconstitution, but also rapid KS progression that would funnel us into the approach for semi-urgent chemotherapy.

Chris:
I totally agree, I would want to get my oncologist colleagues on the phone and see how they wanted to address this. I do defer a little bit to the oncologists because they’re the ones who actually have to initiate chemotherapy, at least at Hopkins. Antiretroviral therapy remains part of the treatment here, and despite the worsening of his lesions and perhaps his fear that the antiretroviral therapy is harming him, there needs to be a lot of reassurance that antiretroviral therapy is essential.

Eileen:
That’s a great point, Chris, and needs to be communicated with the multidisciplinary team because as we all know, initiation of chemotherapy, [with] significant complications like GI bleeding, can sometimes lead to periods where patients are not being fed regularly in the hospital or have additional challenges with taking medication. We need to be thoughtful about making sure they have good exposure to antiretroviral agents because even if you do have a negative inflammatory consequence from suppressing the HIV, it is the only way to regain the immune system. That’s what you need to ultimately control this process.

Chris:
Couldn’t agree more.

Eileen, I’m going to guess that you have managed to facilitate an admission for this gentleman and that he is starting chemotherapy and continuing his antiretroviral therapy at this time. In my experience, outcomes are pretty good, but there can still be a rocky course and potentially other opportunistic infections. Kaposi sarcoma virus or HHV-8 can cause a whole bunch of different conditions, and within each of those conditions, there can be a huge amount of heterogeneity. So careful evaluation and appropriate diagnostic testing, which may be biopsy, may be clinical, may be endoscopic or bronchoscopic direct visualization, remain so important for KS. Keep it on a differential with a low CD4 count, but also sometimes skin lesions, not so much visceral disease, but skin lesions can occur at higher CD4 counts.

With effective antiretroviral therapy, and the majority of individuals living with HIV in the United States now having an undetectable viral load, up to a third of people presenting with Kaposi sarcoma have an undetectable viral load and a CD4 count >350. Most of those individuals have skin-limited disease and management can be as simple as excisional biopsy of a skin lesion. I raise this point because KS can still terrify patients and being able to reassure of the wide range of presentations and the fact that it can present without profound immunodeficiency has helped at least some of my patients.

Eileen:
That’s a great perspective, Chris. We see it in general infectious disease practice in the transplant community. Oftentimes you can slow the progression of lesions with just lightening of immunosuppression and allowing the body to better respond. Totally agree that it can be not the stigmatizing thing that it used to be and also not always requiring substantial intervention.

In the case example I’ve given today, we obviously have the opposite end of the spectrum with someone with substantial systemic symptoms related to KS. I agree with you that, in general, many of these patients will do quite well with chemotherapy as a primary intervention to slow the progression of the KS-related pathology and then allow the immune reconstitution to position that individual to have better control.

Cases do sometimes develop in ways that are unexpected. We can’t always simplify to only one process, and when you have high amounts of HHV-8, which is associated with KS activity, you can also see some of the other KS-related processes—the lymphomatous presentations, the inflammatory cytokine presentation. So just keep that present. If patients develop symptoms that would be associated with one of these other manifestations of HHV-8, having one does not protect you from getting the others. I mentioned that because the appropriate chemotherapeutic approaches are different for each of these different processes. You’ll want to be discussing that possibility with your collaborating oncology team to make sure that you’re adjusting to changes in the patient’s course over time. I have had a couple of overlaps. I had a KS and then primary effusion lymphoma; I had a KS and then a KICS. [You] have to be aware that where you start is not always where you end up. This is something that has historical stigma associations that are important to consider, has potential significant systemic complications that we have to also be aware of and for which we want to be exceptionally careful about the use of corticosteroids, but also can be treated and patients can do extremely well, sometimes with relatively minimal intervention.

Chris:
I enjoyed hearing about this case or composite cases and thinking about KS, something that I don’t think about that much because fortunately the frequency of severe KS is much lower these days than it used to be, at least at Hopkins.

Eileen:
To summarize, KS is an HHV8-driven malignancy with varying epidemiologic profiles in the global context. Disease severity can range from relatively mild and skin-limited to a systemic illness requiring chemotherapy. We hope this has given you some framework for approaching it.

To our listeners, thanks for joining in to another episode of Viremic. Please send any comments or questions to viremicpodcast@jh.edu. And we’ll be back in 2 weeks to talk about vaccines in people living with HIV—how we approach the discussion, what the barriers are, and maybe even what our favorite vaccines are.

Announcer:
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.

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

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