Viremic – Cases in HIV

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

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

Dr. Eileen Scully:
Hi, Chris. It’s great to be speaking with you today. I will start off with a challenging case that I think can take us through a couple of different considerations. This is a 28-year-old man [who] has a history of gonorrhea and chlamydia, about 4 times diagnosed over the last 3 years, who presented to a routine visit with his family doctor. His primary symptoms were fatigue, malaise, and muscle cramps.

He had routine labs which were notable for a basic metabolic panel with a creatinine of 9.2 mg/dL and a potassium of 6.1 mmol/L. His doctor called him and asked him to present to the emergency room for further evaluation. When his physical exam was done on presentation to the ED [emergency department], it was notable for oral thrush, tachycardia, normal blood pressure, clear lungs, and a soft abdomen. His admission labs were notable for a confirmation of the creatinine at >9 mg/dL [and] the elevated potassium still at 6.1 mmol/L. He had complete blood count and liver function testing that were unremarkable, and his urinalysis notable for proteinuria. An HIV antibody/antigen test was done and was reactive, with a viral load of about 3 million copies/mL and a CD4 count of 22 cells/mm3.

So we have a young, previously healthy man who’s presenting with new renal failure of unclear duration and with HIV and advanced immune suppression.

Before diving into the specifics of managing his clinical situation, Chris, I was going to ask you to comment on the initial history of relatively high frequency of sexually transmitted infections. When I first heard about this case, my initial thought was that we had already missed a major opportunity for HIV prevention. Can you talk about your approach to discussing HIV prevention and whether or not you think it could have helped us in this present situation?

Chris:
Sure, Eileen. Fascinating case and very unfortunate situation here that potentially was preventable.

The first thing I would say is well done for his PCP [primary care provider] to get these labs and then send him to the emergency department for further management. I think we could also say some shortcomings occurred and perhaps an opportunity to either go back to his primary care provider or others in that community providing medical care and discuss some of the risks for HIV, reasons for HIV prevention, and signals that HIV testing should occur and pre-exposure prophylaxis should be considered.

I think there was a missed opportunity for HIV testing. Certainly, anyone presenting with any STD [sexually transmitted disease]—gonorrhea, chlamydia, syphilis, or other STDs—is putting themselves at risk for HIV as well, and HIV testing should really have been considered at any of these GC [gonorrhea] or chlamydia episodes in the past. Then, moving on to the prevention side of things, certainly just counseling the patient on risk. Not everyone realizes the risk, or even if they do, they may not put themselves in that risk category. So discussing risk and ways to reduce risk—whether it is different partner selection, using condoms, or using pre-exposure prophylaxis (PrEP). And getting to the pre-exposure prophylaxis just very briefly, the New York State AIDS Institute PrEP guidelines would suggest that this individual was an excellent candidate for PrEP. Anyone with a bacterial STI [sexually transmitted infection] in the past year should be considered for PrEP because they are at increased risk for HIV.

Administering PrEP is simple—baseline tests to assess for HIV and rule out HIV before starting PrEP and baseline kidney function. Then follow up is fairly straightforward, especially in a young gentleman like this man [who] was 28 years old. The risk of kidney disease or any other complications of oral PrEP or injectable PrEP is extremely low. The key focus of monitoring is continued testing for STIs and acute HIV. So certainly a missed opportunity for HIV testing and PrEP, but at least he was gotten into care at this point.

Eileen:
Chris, you made a lot of excellent points. Hopefully everyone listening to this podcast has some interest in HIV. One of our areas where we can contribute in general is providing education to people who do not keep that as their primary interest, because medicine is massive. There are so many fields in which I do not know the most recent up-to-date recommendations. And so as a community of people providing care for people living with HIV, the more we can extend knowledge about PrEP, the better we can deploy this tool. So I agree with everything you said. I’ll also mention that his frequent STI diagnoses could be looked at as a risk, but I also see it as favorable in that he’s had testing. So he’s been engaged in care, and that gives us this opportunity to provide other preventive services, whether it’s HIV prevention or potentially also doxy-PEP [doxycycline post-exposure prophylaxis], which I think is something we’ll discuss on a future episode of this podcast.

Okay, now let’s turn back to the situation that we are in, which is a new HIV diagnosis in the setting of kidney injury. There are a few different types of kidney disease that are associated with HIV, and the landscape of what kinds of kidney diseases we see in people with HIV has definitely shifted over the last several years. To that point, I will mention that there’s a really nice review article in Nature Reviews Nephrology from May of 2024 that goes into detail about the complexion of HIV-related kidney disease in the past and what we’re seeing more of now [Diana and Naiker 2024]. To get to the bottom line there, currently, in most people with HIV in the United States, we see kidney disease that’s related to other comorbid conditions—hypertension, diabetes, or other etiologies. However, that’s not always true, and there are a few specific features and situations in which we need to think specifically about HIV-associated kidney diseases.

The first of those will be HIV-associated nephropathy, which is abbreviated as HIVAN. This is a process that presents with a couple of typical features, including often nephrotic-range proteinuria. On pathology, we’ll have a couple of different abnormalities that can be expected, including collapsing focal segmental glomerular sclerosis, but often also features of acute tubular injury.

This is a disease where we believe at least part of the pathology is related to direct HIV infection of cells within the kidney. And it is also associated with a strong genetic predilection. Previously, this was observed to have different incidences in different regions of the world and in different races in the United States.

We’ve been able to identify that that association is driven by the APOL1 risk alleles, which are associated with other kidney disease, not in the setting of HIV, but in particular when you carry one or more of these alleles, that can greatly increase your risk of having an HIV-associated nephropathy. That is not something we routinely test for, but it is something that you could consider, and in particular, if a patient presents [with] a family history of kidney disease, you might suspect that there is a presence of one or more risk alleles.

In this case, one of his parents had end-stage renal disease unrelated to HIV, but suggesting potentially the presence of a risk allele. Now, for HIV-associated nephropathy (we can talk about the treatment for that in a minute) are there any features of this case in particular that would make you concerned about that possibility and any reason why you would want to anticipate that diagnosis?

Chris:
You haven’t told me the ethnic origin of this gentleman, but as you mentioned, APOL1 is regionally distributed [and] believed to be related to survival benefit in the setting of African sleeping sickness. West Africa has the highest proportion of people living with the APOL1 allele that increases the risk for any cause of kidney disease, including HIVAN. If he is of African descent, then HIVAN is very high on the differential. If he’s not of African descent, [that] does not take HIVAN entirely off the differential, but moves it down.

In terms of factors that are associated with HIVAN, one is his very high viral load, not being on antiretroviral therapy (ART), having proteinuria ([and] certainly if this is nephrotic-range proteinuria). All of those go along with HIVAN, but without further diagnostic testing, there’s no additional way to distinguish HIVAN from other HIV-related kidney disease or non-HIV-related kidney disease, some of which we haven’t discussed yet.

You haven’t told me whether he also is living with hepatitis B or hepatitis C, but both of those are also associated with progressive kidney disease. I guess the last thing I would say is, and maybe you’ll talk about this, but ultrasound can be helpful, and an enlarged kidney on ultrasound is more associated with HIVAN than some other chronic kidney diseases, but also is not diagnostic.

Eileen:
Thank you for those thoughts, and I will give you a little more information. One of the main things to consider here is that in the absence of a biopsy, it’s very hard to differentiate between the causes of acute kidney injury. In many cases, that might have consequences for the planned management, so it is important to obtain a kidney biopsy when you are entertaining these diagnoses in order to specify the care for the underlying pathology. In this case, that was done, and the patient did indeed have focal segmental glomerular sclerosis, or FSGS, with focal collapsing features as well as acute tubular injury, with some dilatation and interstitial inflammation and tubulo-interstitial scarring. So overall, the pathology was highly consistent with HIVAN.

While we don’t have a trajectory to know how rapidly his creatinine rose, that was felt to be the working diagnosis in this case. Because there is an association of direct HIV activity with the pathology, it is one of the cases for relatively urgent initiation of antiretroviral (ARV) treatment.

Now, back when I was training, before we had a real focus on immediate linkage to care and initiation of treatment, even on the same day as diagnosis, there were relatively few times when we would immediately initiate ARVs. Suspected HIVAN is one of those cases, so we are next going to be presented with the problem of which ARV agent to choose in this context. But I’ll set that aside for a moment to talk a little bit about another type of HIV-associated kidney disease, which you were already alluding to.

Previously, we described HIV immune complex kidney disease, which is abbreviated as HVICK, as another form of pathology that can be observed in HIV. However, in this review from 2024 [Diana and Naiker 2024] and in speaking with colleagues, there has been a movement towards using more specific language because the pathology underlying here is immune complex deposition in the kidney. But that can be due to HIV or to other infectious etiologies, including, as you mentioned, hepatitis B and hepatitis C.

HIV immune complex disease is also more commonly observed in people who are viremic. I recently reviewed this to see if there were reliable reports of immune complex kidney disease in fully suppressed individuals. There are some suggestions that it can occur, but the etiologic connection between HIV and those immune complex depositions is a little bit weaker than in many other cases where we have definitive evidence for a connection.

In this case, the biopsy findings were not suggestive of this etiology and were consistent with HIVAN. He also did not have other underlying conditions that would be expected to predispose to an acute kidney injury. He did not have either hepatitis. He also had not had any new drug exposures, and the pathology was not consistent with an interstitial nephritis, [he] had not had any hypotension or other reasons for acute tubular necrosis. And those were also not features that were consistent with the urinalysis or the biopsy.
So now I will turn to the challenging step of you have someone with new kidney injury, and I’m gonna give you the task of thinking about how we would choose an initial ARV regimen when we have an acute change in creatinine, or even if it’s not acute, a change in creatinine that limits some of our other most easily chosen regimens.

So how do you approach this situation, Chris?

Chris:
First is to understand some of his social situation and also how he’s doing emotionally with this diagnosis of both HIV and severe kidney disease. Going from there, as you mentioned, the key thing for HIVAN is to get somebody on ART and get their viral load undetectable. With that, he can have improvement of his kidney function and reversal of his severe kidney disease and nephrotic syndrome. Without that, he will have progressive kidney disease and end-stage kidney disease and will require dialysis for renal replacement therapy. So working through that with him and seeing how he is emotionally coping with this and how he can be supported to be successful with ART in my mind is the first step.
Then your question of which regimen is definitely important and interesting. There are a number of factors to consider. One is which agents are renally cleared and need to be dose-adjusted or are contraindicated with advanced kidney disease. Right now, his estimated GFR is <10 or so, with his creatinine of 9. And then the other consideration, not really in my mind to decide on a regimen, but I think something to be aware of in the back of our minds is that many of our ARV therapies will physiologically increase creatinine without affecting kidney function, which is not a therapeutic problem, but can make interpreting labs a little more challenging in a patient where you’re hoping to see a recovery of kidney function.

So first in terms of renally cleared medications, the NRTIs [nucleoside reverse transcriptase inhibitors] such as lamivudine (3TC; Epivir), emtricitabine (FTC; Emtriva), tenofovir disoproxil fumarate (TDF; Viread), and tenofovir alafenamide (TAF; Vemlidy), all are renally cleared. Many of the other ARTs we use, such as the integrase strand transfer inhibitors (INSTIs), are not renally cleared, as well as protease inhibitors (PIs) are not renally cleared. So there’s certainly agents that can be used where his kidney function will not affect either dosing or concern for nephrotoxicity.

I’ll hand it back over to you, Eileen.

Eileen:
I think you raised a lot of the important points. And while we will often use some of these agents, in particular in the NRTI class, once we have a stable understanding of kidney function, even in the presence of GFRs that are altered, for someone who’s coming in with an acute disruption in their kidney function, we will often try to lean towards drugs for which there is not renal clearance, knowing that there is likely to be an evolution of their kidney function that may lead to rapid changes in the levels over time. So specifically for this type of case where you want to get the viral load down quickly and you would also like to not have to worry about whether or not you are having changes in drug exposure, choosing from classes like INSTIs and PIs, +/- the NNRTIs [non-nucleoside reverse transcriptase inhibitors], can get you to a quick full regimen, where you have likely full activity of 3 drugs or more against the HIV and will not have to worry about changes in renal function. Oftentimes when someone’s hospitalized, we will do this—give someone, for example, dolutegravir (DTG; Tivicay) and darunavir (DRV; Prezista) plus cobicistat (COBI; Tybost) or the same with the addition of an NNRTI. And then we’ll come up with a more stable regimen that’s a little bit more compact and more standard when individuals are ready for discharge [and] when we have an understanding of where their kidney function will settle out.

Is that your practice as well, Chris?

Chris:
Indeed. I liked the combination of DRV often with ritonavir (RTV; Norvir), but I guess you could use COBI and DTG. I’m so comfortable with it in many of my patients who have multiple drug resistance mutations and NRTIs as well as other alternative agents and NRTIs are not options for them. So my level of comfort in that setting transfers over to a patient like this who’s coming in with a very high viral load, with kidney disease, and a need to bring that viral load down quickly and effectively. In addition, the risk of drug resistance mutations is relatively low with that combination of DRV and DTG. And since we won’t have drug resistance test results before needing to start agents, I think another important consideration is to think about what we can use that has a very low risk of transmitted drug resistance.

Eileen:
Great points, Chris, and with integrase resistance still low in the community, at least in the United States, that gives us a lot of comfort there. Also, DRV is relatively hard to become resistant to and also an unusual transmitted resistance event. So our most at-risk agents for that type of resistance will be in the NNRTI class or the NRTI class, so making sure that if we’re employing either one of those, we can readjust our therapeutic strategy once we get the results from the genotype [test], which, as you mentioned, will probably take 1 to 2 weeks.

Now moving on to what we actually did: We did start therapy with DTG and DRV (boosted in this case), and the individual had a nice decline in viral load. Typically with initiation of an INSTI, we expect about a 2-log viral load decline in 2 weeks, which gives us a good indication that, even if we’re not anywhere near suppression, as with someone in this case who has a very high initial viral load, we are going towards where we want to be.

For him, one of our main hopes is that we’ll get some significant degree of renal recovery. That’s the reason for the urgency of initiating treatment for HIVAN, because we can, in some cases, arrest the progression of the pathology. Now, if there is an underlying risk allele—in some studies, having 2 APOL1 risk alleles was associated with an up to 50% risk of developing HIVAN in the setting of HIV infection—that is already someone who has a very high risk of kidney disease, period. So we may not get as much of a response, but in either case, we hopefully will get a substantial improvement and then one that we can maintain over time. For a patient like this, once the acute insult is over and his creatinine normalized down around 1.9 mg/dL and between 1.9 and 2.3 mg/dL on labs over time, so a substantial improvement in function, although I’ll note that even at those levels, there has been some loss of GFR.

Now we have to think about what our long-term ART choices are and how we think about kidney protection and the potential kidney toxicities of our ARV agents themselves. Chris, I thought maybe we could talk briefly about the history here of one of our major mainstay agents, tenofovir, in terms of its role in kidney disease and what your current thinking is about how you approach the use of tenofovir formulations in people either with kidney disease or people in whom you’re thinking about their risk of developing it.

Chris:
First, wonderful outcome for this gentleman that he’s not in end-stage renal disease, does not need dialysis, even if he will be living with long-term kidney injury. And just to mention again, while he’s on the 2 agents, the DTG and DRV, each one increases creatinine by about 0.1, just through that physiologic impact on creatinine clearance, but not on actual kidney function or EGFR. So keep that in mind in assessing his creatinine.

In terms of what next, in an individual without HIV drug resistance, being on this regimen is in my mind not ideal. if he can be taken off the boosted PI for his long-term care that probably will be beneficial. Going to a once-a-day, one-pill regimen like BIC/TAF/FTC (Biktarvy) may be an option for him.

You do raise the issue of the tenofovir. Tenofovir itself is nephrotoxic in the renal tubule. In the prodrug of TDF, the levels of tenofovir were much higher, increasing the risk of renal disease [Gallant, et al. 2005]. In both cohort studies of individuals on TDF, there was a slight decline over time in EGFR and an increased risk of acute kidney injury, especially in settings of another hit to the kidneys, whether from dehydration, sepsis, or other causes, such as this gentleman has already having kidney disease from his HIVAN and being at such high risk for any sort of kidney disease with the probably APOL1 allele variant.

TAF has much lower levels of tenofovir in the renal tubules and much lower risk of kidney injury. That said, there certainly are still concerns of the potential risk, especially in somebody with compromised renal function, like this gentleman. So he would probably be fine on it once he stabilizes his kidney function, but there’s some need for careful consideration and, I would say, discussing with him whether this is the approach he wants.

I’d finally like to mention abacavir (ABC; Ziagen), which for a long time was our “kidney friendly” NRTI because it’s not renally cleared; it’s hepatically metabolized. In the past, I used ABC in situations like we’re facing here with this individual. Given the data that’s fairly compelling for the cardiac risk for ABC, I avoid using it and would not advocate starting this gentleman on it at this point.

Eileen:
Those were all excellent points. As a trainee who came of age during the TDF era, we did a lot of urinalysis and urine phosphate testing because, as you mentioned, with the accumulation of TDF, the Fanconi syndrome, with a proximal tubulopathy with a renal tubular acidosis associated with a non-anion gap metabolic acidosis, low serum phosphate because of urine phosphate wasting, and that, in turn could be associated with osteomalacia, hypokalemia, and also glycosuria in the setting of a normal blood glucose. So we would be looking for individuals who are spilling glucose, spilling phosphate, and seeing the phosphate also low in the plasma, and seeing a normal glucose at the time when that was being wasted. For many of those individuals, if they were identified early enough before progressive renal failure, stopping the drug was adequate to lead to resolution. That was typically over the course of about 2 months.

Risks of developing this type of toxicity were with the concurrent use of PIs, and in particular in people who, as you mentioned, have a low GFR at baseline and therefore may have greater circulating tenofovir levels. These were all the things we used to worry about all the time. Now, with the transition to TAF, which has a lower intracellular accumulation, we’ve seen most of that pathology go away.

I will mention there are a few case reports of a Fanconi’s type of syndrome with TAF [Bahr and Yarlagadda, 2019]. I personally have one patient in whom this did occur on a TAF preparation. But there is probably an equal or greater number of case reports where someone had a prior documented episode of this type of tubulopathy with TDF and was successfully transitioned to a TAF preparation [Karris, 2017; Jiang, et al, 2023].

So I think it really goes both ways in that there is some small risk of tubular dysfunction with TAF, but also TAF can be employed in certain cases when you really need to do it, even if a person has evidence of prior TDF toxicity. Of course, in those cases, you would do it with very careful monitoring. I will mention that would be most commonly needed for someone with hepatitis B and not for someone with HIV. For HIV, we have so many other options that it’s rare that we are absolutely compelled to use tenofovir, whereas for hepatitis B we also have entecavir, but we don’t have the kind of array of menu options for treating hepatitis B active disease.

One last topic I thought we could briefly cover is the use of a dose adjustment for FTC or 3TC versus the use of fixed-dose combinations in individuals with impaired GFR. Classically, dose adjustment of 3TC was suggested because of the 86% renal clearance of this drug and FTC being comparable. However, there is very limited toxicity to high exposure to these medications. So while there is not a lot of data for the use of these drugs at standard dosing in individuals with renal compromise, many clinicians will continue fixed dose combinations because, overall, the benefits of allowing someone to have a complete HIV regimen in one 1 pill exceed the risks of the exposure to higher levels of 3TC or FTC.

This has been highlighted for me in a couple of cases in my own personal practice, where individuals who are split- dosing to allow the dose-adjustment of the 3TC or FTC component either had changes in their renal function with improvement where then they were underdosed on the medication or who had incomplete pharmacy fill where they were only getting one component of their regimen for a prolonged period of time despite being prescribed all of them. That’s happened to me a few times, actually, more than one would imagine.

How about you, Chris? What’s your experience and approach in in those settings where you could either use a fixed dose or use dose adjustment.

Chris:
I try to stick with the fixed doses as much as possible and with 3TC and FTC certainly go with that even with individuals with compromised kidney function and EGFRs <30 or even on hemodialysis.

Eileen:
I totally agree.

Well, thank you for talking through that case with me. It was, as you say, one of the very happy endings. This young individual doesn’t have to necessarily bear the lifelong burden of end-stage kidney disease. And hopefully with careful and thoughtful management of his HIV over time, we can minimize any drug-related exposures or other toxicities and give him the best chance he has for maintaining that function into a healthy, long life.

Chris:
Wonderful case, Eileen. Certainly wonderful outcome for this individual. And hopefully he’ll be able to remain on his ART, remain engaged in care. I think it highlights both the systems thinking for HIV care for the HIV clinician or infectious disease clinician, and also the critical role of all the subspecialists that we depend on for management of kidney disease, diagnosis of what’s going on with that, and certainly in many other arenas also in this care.

Announcer:
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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.