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Very challenging case

  • 1.  Very challenging case

    Posted 16 days ago

    Okay, community, this is the most perplexing patient management situation I have dealt with in my 10 years seeing PLWH. I have already consulted several of my very experienced colleagues and they were just as stumped as I am. I know there are a lot of super smart and experienced HIV providers who weigh in on these threads, so please help me with this case-either tell me what I might be missing and provide me with some suggestions-or confirm what I think which is that I should just leave his ART regimen alone for now. Thanks so much, Steve


    Background Info-55 yr old African American male, HIV for at least 10 years, originally presented with full-blown AIDS about 10 years ago (I saw him in our local free clinic, he had systemic symptoms-fever, diarrhea, SOB-- and sent him promptly to the ER) with a CD4 count of zero, etc. Rocky course initially with behavioral health (bipolar) and substance abuse issues, also legal issues (incarceration), but got straightened out on a good psych med regimen (Abilify worked wonders for him) and has been a model patient for 5+ years-making all his appointments, following up on his labs, etc. (Seriously, I wish all my patients were that compliant). Has had housing precarity (couch surfing, etc.) which made me worry about med compliance (which was why I tried an injectable regimen pretty early on in this saga), but as far as I could tell he was med compliant. Has other medical conditions-hypertension, hyperlipidemia, pre diabetes, GERD, chronic pain-in addition to his bipolar disorder. And his other meds are Abilify, buspirone, omeprazole, HCTZ, rosuvastatin (low dose when he was on Prezcobix), metformin, ibuprofen, acetaminophen, and opioids when he has a pain management provider, which is intermittent.


    A couple more points-I tried a number of regimens but was mostly just winging it because the genotype results weren't helpful at all. I also tried once and then a second time an all injectable regimen to eliminate the possibility that he simply wasn't taking his oral meds or had some drug absorption issue that was causing the problem. He is now on a second all injectable regimen and frankly I'm shocked it's not working, which has made me wonder, since he's been absolutely fine clinically during this entire period, with CD4 counts staying between 700 and 1000, that maybe this was some kind of strange false positive lab test (picking up HIV RNA remnants-or maybe just leaking HIV out from dying dormant CD4 cells?)--but that would be very strange since I've never heard of something like this, although I've never had a patient like this either.


    In terms of his HIV management, he was cruising along with consistent suppression for many years (I've included several HIV results from 2021 and 2022 below to start things off), then he went over 200 in May of 2022 and has never been suppressed since. During this time I have done 10+ RTI and PI genotypes, 4 INSTI genotypes, and at least 3 Proviral DNA resistance studies. The results have been pretty consistent, as follows:


    The proviral DNA testing showed M184I both times, that was it.

    The INSTI genotypes have never come up with anything.

    The RTI and PI genotypes have never come up with any major mutations, just minor ones intermittently-A98S for RTIs and M36I, I62V, L63P, and H69Q for PIs.


    And here are his HIV results along with the regimen he was on at the time (I didn't include his CD4 counts because they have consistently been 700-1000 and never below 700):


    DATE HIV RNA Level ART Regimen


    8/10/21 105 Biktarvy

    11/9/21 69 Biktarvy

    2/14/22 30 Biktarvy

    5/11/22 226 Biktarvy

    9/19/22 267 Biktarvy

    3/6/23 447 Biktarvy

    4/24/23 911 Biktarvy

    9/18/23 271 Cabenuva

    11/20/23 444 Cabenuva

    1/29/24 427 Prezcobix/Tivicay

    4/1/24 704 Prezcobix/Biktarvy

    6/24/24 591 Prezcobix/Biktarvy

    8/15/24 629 Prezcobix/Biktarvy

    12/26/24 1690 Prezcobix/Biktarvy

    3/24/25 4000 Prezcobix/Biktarvy

    4/8/25 2380 Prezcobix/Biktarvy/Sunleca

    6/2/25 1160 Prezcobix/Biktarvy/Sunleca

    7/17/25 1080 Prezcobix/Biktarvy/Sunleca

    10/20/25 4900 Cabenuva/Sunleca

    11/19/25 3540 Cabenuva/Sunleca

    1/8/26 3060 Cabenuva/Sunleca




  • 2.  RE: Very challenging case

    Posted 15 days ago

    Some facilities do HIV drug blood levels(not in my area)

    Also the resistance assays don't add up, with increasing HIV viral load and resistance profile doesn't change, consider another lab

    just to confirm or refute present resistance assay



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    Patrick Aufiero
    Carolina Beach NC
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    Original Message


  • 3.  RE: Very challenging case

    Posted 14 days ago

    Have you sent a phenotype?  We had a patient with perinatally acquired HIV and very high viral loads initially who took years to suppress despite no resistance identified on genotypes and phenotypes. We enrolled them in a study at Pitt with Dr Deborah McMahon to evaluate for clonal expansion (which was not found to be the reason) but may be able to evaluate for this in your patient.  Therapeutic drug monitoring was sent to McGill in Canada and was reassuring. UNC Chapel Hill does ARV drug levels now (https://www.med.unc.edu/cfar/core-areas/clinical-pharmacology-analytical-chemistry/  ) as well as University of Florida (https://idpl.pharmacy.ufl.edu/wordpress/files/2026/01/IDPL-UFHealth-v-1.26.pdf).  I agree with keeping on Biktarvy unless they really prefer the injectable regimen.

     

    Jennie Dougherty, MSN, RN, CPNP-AC (she/her)

    Nurse Practitioner, Pediatric Infectious Diseases

    Duke Children's Hospital & Health Center

    office: 919-684-6335 / fax: 919-668-4859 / jp121@duke.edu

     




    Original Message


  • 4.  RE: Very challenging case

    Posted 14 days ago
    By the way, here is a link to a relevant publication for those who are interested:


    Original Message


  • 5.  RE: Very challenging case

    Posted 14 days ago

    Sorry, I forgot the link, here it is:

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6947923/#:~:text=Over%2050%25%20of%20latent%20reservoirs,priority%20for%20HIV%2D1%20eradication.

    Let me know if this doesn't work.



    ------------------------------
    Stephen Bickel
    TN
    ------------------------------

    Original Message


  • 6.  RE: Very challenging case

    Posted 15 days ago
    Thank you, David. That is so helpful and yes clinically this patient has been doing fine—totally stable— weight, energy, CD4 count all good throughout this several year period—cruising along just fine. That’s what’s been so perplexing about this whole situation.

    And I guess that brings up another issue that I would pose to the group— does it make sense to just put him back on Biktarvy (or Cabenuva) and be content with that viral load as long as he’s doing fine clinically and his CD4 count stays up ?—because none of the regimens I’ve switched him to has made a dent in his viral load—and clinically he did fine on just Biktarvy or Cabenuva and he felt no differently clinically (neither better nor worse) on any of the other combinations.

    Stephen


    Sent from my iPhone


    Original Message


  • 7.  RE: Very challenging case

    Posted 15 days ago
    David, I just read your note again and it sounds like you are recommending that I just go back to Biktarvy or Cabenuva and be content with the viral load elevation as long as he’s doing fine clinically—is that an accurate interpretation of what you wrote?

    Thanks again,

    Stephen

    Sent from my iPhone


    Original Message


  • 8.  RE: Very challenging case

    Posted 14 days ago

    I was asked about the response I got that I found helpful--it was sent to me directly and not to the forum--someone from the Hopkins team suggested the possibility of clonal HIV and, potentially in this case, polyclonal (a rare form of an uncommon situation) which would not be responsive to ARVs but the patient would have a rising or good CD4 and feel generally well. I think that fits quite well and explains a lot--Steve



    ------------------------------
    Stephen Bickel
    TN
    ------------------------------

    Original Message


  • 9.  RE: Very challenging case

    Posted 14 days ago
    Can someone explain this further, please? The clonal thing?
    Sent from my iPhone


    Original Message


  • 10.  RE: Very challenging case

    Posted 14 days ago
    The person who responded to me is quite an HIV expert but wants to stay off the group email thread, but I know from following these exchanges for a couple years that we have some other experts who often weigh in—I just happen to not be one of them—haha! So maybe someone else can elaborate here. I have gone back and forth with the Hopkins doc who suggested this possibility and we both agree his explanation fits this patient very well. Steve


    Original Message


  • 11.  RE: Very challenging case

    Posted 14 days ago

    AI is smarter than we are: 

    Open Evidence: 

    This is a fascinating case of nonsuppressible viremia (NSV) in a patient with excellent adherence, preserved CD4 counts, and minimal detectable resistance mutations. The pattern you're describing-persistent viremia (200-5000 copies/mL) despite multiple regimen changes including long-acting injectables, with stable high CD4 counts and no major resistance mutations-is consistent with clonal expansion of HIV-infected CD4+ T cells producing virus.

    What's Likely Happening

    Clonal expansion is a well-documented phenomenon where infected CD4+ T cells proliferate and produce virus despite effective ART.  This can cause persistent viremia that is not suppressible by regimen changes or intensification. Key features that match your patient:

    • Viremia persists despite confirmed adherence (you've tried injectables twice, eliminating absorption/adherence concerns)

    • No major resistance mutations despite extensive testing

    • Preserved CD4 counts (700-1000), indicating immune function is maintained

    • Progressive increase in viral load over time despite regimen changes

    The M184I mutation found only in proviral DNA (not plasma genotypes) is particularly telling. M184I is often associated with defective, hypermutated proviruses that may not be replication-competent.  This suggests the archived mutation may not be driving current viremia.

    Why Regimen Changes Haven't Worked

    Studies show that in patients with persistent low-level viremia due to clonal expansion, ART intensification does not reduce viremia.  The virus is being produced from long-lived infected cell clones that proliferate in response to:

    • Antigenic stimulation (CMV, other chronic infections) 

    • Homeostatic proliferation 

    • Integration site-dependent proliferation (when HIV integrates into cancer-related genes) 

    These clones can produce both replication-competent and defective virus. Importantly, recent research shows that even defective proviruses with 5'-leader defects can cause NSV up to ~1000 copies/mL, producing non-infectious virions that still register on viral load assays. 

    Drug Interaction Considerations

    Before accepting this as NSV, verify there are no polyvalent cation interactions affecting INSTI absorption.  Calcium, magnesium, iron, zinc supplements, or antacids can significantly reduce bictegravir and dolutegravir absorption. Given his multiple medications (calcium for bone health? iron? antacids with omeprazole?), this warrants careful review.

    For rilpivirine (in Cabenuva), acid-reducing agents like omeprazole can impair absorption.  This is a critical interaction that may have contributed to failure of both Cabenuva attempts.

    Clinical Implications

    Current guidelines state that patients with viremia ≥200 copies/mL despite confirmed adherence and high-barrier regimens (bictegravir, dolutegravir, boosted darunavir) are unlikely to benefit from further regimen changes.  The 2024 IAS-USA guidelines specifically recommend against ART intensification in this scenario (evidence rating AIa). 

    Your patient's clinical stability (excellent CD4 counts, no AIDS-defining illnesses) over years of detectable viremia supports that this represents clonal expansion rather than ongoing replication with resistance. Studies show NSV can originate from clones of 50-350 million cells producing virus. 

    What I'd Recommend

    Confirm this is truly NSV:

    1. Review all drug interactions - especially omeprazole with rilpivirine, and any supplements with INSTIs

    2. Consider therapeutic drug monitoring if available to confirm adequate drug levels

    3. If feasible, consider single-genome sequencing of plasma virus to look for identical sequences over time (hallmark of clonal expansion) 

    If confirmed NSV:

    • Continue current regimen (Cabenuva/Sunleca) without further changes 

    • Monitor viral load every 3 months and CD4 counts every 6 months 

    • Watch for virologic progression (sustained increase >1 log or development of resistance)

    • Maintain excellent adherence to prevent true resistance emergence

    The omeprazole-rilpivirine interaction is my biggest concern. If you haven't already, consider switching omeprazole to famotidine (taken 12 hours before or 4 hours after rilpivirine) or stopping acid suppression if clinically feasible.

    Would you like me to explore specific strategies for managing the omeprazole-rilpivirine interaction, or discuss the evidence for when NSV might warrant switching despite guidelines recommending against it?

    1.
    Antiretroviral Drugs for Treatment and Prevention of HIV in Adults: 2024 Recommendations of the International Antiviral Society–USA Panel.
    The Journal of the American Medical Association. 2025. Gandhi RT, Landovitz RJ, Sax PE, et al.New
    2.
    Clonally Expanded HIV-1 Proviruses With 5'-Leader Defects Can Give Rise to Nonsuppressible Residual Viremia.
    The Journal of Clinical Investigation. 2023. White JA, Wu F, Yasin S, et al.
    4.
    Antigen-Driven Clonal Selection Shapes the Persistence of HIV-1-infected CD4+ T Cells in Vivo.
    The Journal of Clinical Investigation. 2021. Simonetti FR, Zhang H, Soroosh GP, et al.
    6.
    The Forces Driving Clonal Expansion of the HIV-1 Latent Reservoir.
    Virology Journal. 2020. Liu R, Simonetti FR, Ho YC.
    8.
    Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV.
    Office of AIDS Research Advisory Council (2024). 2024. Roy M. Gulick, Alice K. Pau, Allison Agwu, et alGuideline
    9.
    HIV-Associated Complications: A Systems-Based Approach.
    American Family Physician. 2025. Jaqua EE, Tran MN, Bhat P.New
    10.
    HIV-1 Viremia Not Suppressible by Antiretroviral Therapy Can Originate From Large T Cell Clones Producing Infectious Virus.
    The Journal of Clinical Investigation. 2020. Halvas EK, Joseph KW, Brandt LD, et al.
    11.
    Persistent HIV-1 Viremia on Antiretroviral Therapy: Measurement and Mechanisms.
    Frontiers in Microbiology. 2019. Jacobs JL, Halvas EK, Tosiano MA, Mellors JW.



    ------------------------------
    Gerald Pierone
    Fort Pierce FL
    ------------------------------

    Original Message


  • 12.  RE: Very challenging case

    Posted 14 days ago
    Thanks, Gerald, and all I can say is “Wow”

    I’m still on the learning curve with AI but this certainly gets my attention as a tool for me to learn how to use more effectively.

    I’m still happy to have gotten pretty much the same answer from our Hopkins colleague expert.

    And amazing that they both arrived at the same conclusion.

    Also, for the group, three things I would note about this AI piece that I disagree with—or that need to be clarified:
    1) All the stuff about rilpivirine absorption is irrelevant because he’s on injectable rilpivirine
    2) I don’t see the point in continuing Sunleca at this point—instead just continuing with Cabenuva alone—since it didn’t benefit him clinically or lower his viremia
    3) It suggests not making regimen changes if the patient has persistent viremia despite being on a high barrier to resistance regimen and has confirmed adherence—but how do you confirm adherence besides DOT or blood levels?—hence the trials of injectables.

    Thanks again,

    Steve


    Original Message


  • 13.  RE: Very challenging case

    Posted 14 days ago

    I have never seen a case of NSV like this so kudos for sharing with the community. 

    Your points are well stated. 

    AI does sometimes make obvious errors like with the rilpivirine injectable absorption issue.  

    It may not matter much which specific regimen is chosen in this very unusual situation, but an injectable regimen makes sense. 

    The AI tools are advancing so quickly, we are entering uncharted territory in medicine, very exciting (and scary too), something big is definitely happening! 

    best, Gerry 



    ------------------------------
    Gerald Pierone
    Fort Pierce FL
    ------------------------------

    Original Message


  • 14.  RE: Very challenging case

    Posted 14 days ago
    Thanks, Gerald, and I totally agree with you!

    Steve


    Original Message


  • 15.  RE: Very challenging case

    Posted 14 days ago

    I've had one or two cases like this, though not with viral loads quite this high. Although we didn't have injectables then, intensification and modification of ART never made any difference, suggesting to me that this wasn't replicating virus. You asked about going back to Biktarvy, which would make sense if he was happy with it. It would be reasonable to use whatever regimen he prefers, provided it's a regimen with a high resistance barrier.  (The barrier for Biktarvy is somewhat higher than the barrier for Cabenuva.)



    ------------------------------
    Joel Gallant, MD, MPH
    Johns Hopkins University
    Baltimore, MD

    AXCES Research Group
    Santa Fe, NM
    ------------------------------

    Original Message


  • 16.  RE: Very challenging case

    Posted 14 days ago

    Thanks, Joel!

    Steve



    ------------------------------
    Stephen Bickel
    TN
    ------------------------------

    Original Message


  • 17.  RE: Very challenging case

    Posted 14 days ago
    Wow is right. I did not know about NSV. Thanks, community!

    Are there any non-hiv-related clinical implications of this clonal expansion of CD4 + cells? Is this condition pre-malignant? Is it analogous to a monoclonal gammopathy?


    Sent from my iPhone


    Original Message


  • 18.  RE: Very challenging case

    Posted 13 days ago

    Very interesting info on nonsuppressable viremia. Anecdotally we have a similar case that seems to have been triggered by an attempt at cure via a study. The person had always experienced viral suppression below 20 and then entered an HIV cure study. After treatment in the study, his virus rebounded during the analytic treatment interruption, and despite reinstitution of therapy, his HIV RNA has remained between 200-400 copies for several years now despite multiple changes in regimen including an injectable trial, and no evidence, ever, of resistance mutations. It is upsetting to the patient because he is questioning whether he can now transmit virus.



    ------------------------------
    Peter Shalit
    Tribalmed. PLLC
    Seattle WA
    ------------------------------

    Original Message


  • 19.  RE: Very challenging case

    Posted 13 days ago
    Thanks, Peter. Another interesting case. 

    Does anyone know if there are any neoplastic implications of this clonal expansion of CD4+ cells in non-supressible viremia?

    ( I asked in an earlier post but did not get any replies. I don't know if nobody knew the answer or no one saw the post!)

    Please LMK if there are ideas about this. 


    Thanks, 
    victoria behrman MD


    Sent from my iPhone



    Original Message


  • 20.  RE: Very challenging case

    Posted 12 days ago

    Victoria,

    I'm not aware of this being a problem, but then the number of such patients is small, so I'm not sure how robust the data are.



    ------------------------------
    Joel Gallant, MD, MPH
    Johns Hopkins University
    Baltimore, MD

    AXCES Research Group
    Santa Fe, NM
    ------------------------------

    Original Message


  • 21.  RE: Very challenging case

    Posted 12 days ago

    Is this your only case of unexplained viremia in your clinic/with that lab? 

    about 6 years ago we had a group of patients who had unexplained viremia and realized that the tubes were not being processed appropriately by a new phlebotomist. This is the abstract we published: https://pmc.ncbi.nlm.nih.gov/articles/PMC7777303/



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    Ruth Serrano
    San Antonio TX
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    Original Message


  • 22.  RE: Very challenging case

    Posted 12 days ago

    Yes, Ruth, this is the only case and I am virtually certain this is not lab or blood processing error. The results with this patient have been consistent over a couple of years and we've not had any other problems like this with any other patient over the same timeframe. Whenever we had viremia In other patients there was a reason we could find and then deal with successfully, except for this patient. Your experience with lab processing issues is definitely something we should always be thinking about, but I don't think it applies to this particular patient. Steve



    ------------------------------
    Stephen Bickel
    TN
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    Original Message


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