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new viremia in new dx of DM?

  • 1.  new viremia in new dx of DM?

    Posted 12-25-2022 20:00
    Hi everyone,
    I'm a HIV primary care physician in the northeast/mid atlantic and I have a pt who is an early 60s cisgender man who has been positive since 1999, and has had VL <200 since ~2018, until very recently. I'm having trouble figuring out why VL is suddenly rising.

    There are two relevant changes which coincide with this timeline of suddenly unsuppressed VL. First, an acute progression of previously diet controlled diabetes from a1c 7.5 in May 2022 to 13.2 in September 2022. The other is transition from Genvoya to Biktarvy in August 2022. adherence is excellent, and historically has been. pt is very concerned about this, and I'm feeling stumped. I initially thought it could be unexpected resistance but repeat genotype last month had only M184V as RAM.

    Medication changes: started metformin and rybelsus at time of DM dx (did not tolerate sglt2 and reluctant to try insulin). Supplements: started taking milk thistle toward the end of the summer, was taking probiotics transiently, and takes centrum daily multivitamin spaced apart from ART.

    This is my second year out of training, so of course much to learn. I was not able to find DDI between his supplements and biktarvy. I'm trying to think creatively about why this could be happening - could the dramatic endocrinologic shift of florid hyperglycemia shift the metabolism of ART and cause viremia?

    HIV hx
    dx 1999, cd4 nadir 54 at time of dx
    ART hx: Kaletra => Complera => Genvoya => Biktarvy (8/2022)
    prior GT late 2000s with M184

    recent labs
    9/2022: VL 28, CD4 716 (40%)
    10/2022: VL 161, CD4 669 (40%)
    11/2022: VL 4,940, CD4 600 (44%)
    11/2022 GT with M184V as only RAM. no RT or INI resistance.
    - non-RAM: PR L10I, G16E, E35D, M36I, L63T, I93L

    thanks in advance!

    Vanessa Ferrel
    Philadelphia PA

  • 2.  RE: new viremia in new dx of DM?

    Posted 12-26-2022 22:31

    Hi Vanessa. 

    That's a really tricky case. It sounds like you've already explored a lot of possible causes of his viremia - he's spacing out his multivitamin and doesn't have any new resistance. Is it possible that with all the changes in his medications that he's getting mixed up about which pill is his Biktarvy? Have you had him bring in his medications to talk through how he's taking them? Does the pharmacy say that he's been picking up his Biktarvy on time? There's nothing about hyperglycemia that should impact the efficacy of his ARVs or his viral load and it doesn't sound like he has any other drug interactions to worry about. One other thought is that you could have him stop the multivitamin for a while… I think it's unlikely to have enough of an interaction to cause this degree of viremia, but it would take out one potentially confounding factor. 

    Keep us posted on how things go!


    Lealah Pollock, MD MS
    UCSF, National Clinician Consultation Center, Perinatal HIV Hotline
    San Francisco CA

  • 3.  RE: new viremia in new dx of DM?

    Posted 12-29-2022 09:39
    I think there are a lot of details about this case that are missing from the presentation and hence it's difficult to precisely give advice. From the description, the diabetes issue is the much more important issue to address than the viremia in the setting of preserved CD4 count. People die or have severe outcomes from this degree of hyperglycemia in the short term but will not suffer from AIDS in the short term. That is also a very symptomatic state and the patient should have been describing polyurea polydipsia and weight loss along with fatigue and likely other problems.
    I presume there are corroborating glucometer readings to correspond to the extreme rise in the hemoglobin A1C. I would assume as well that he is being cared for in this respect by a diabetologist. I find it incredible that he would be able to control his blood sugars without the use of insulin. The only scenario that I can explain the discrepant hemoglobin A1C results is pancreatic failure which would mean insulin is not made and hence his current treatment is not gonna do it.
    There is the possibility that the high hemoglobin A1C is an error.
    Lack of adherence to medications certainly seems to be the most likely reason for the viremia and I recall my biggest regrets as an HIV provider not ensuring by a simple call to their pharmacy that my at-risk - but believable - patients with this problem we're not at least picking up their medications. I did not like the automatic refill of delivered medications in poorly adherent patients because it was not possible to check this.
    While we would like to control outcomes in our patients I'm not sure that entrusting non adherent patients to come in for medication administration is much of a fail safe. This group of patients is also the group that tends to miss visits. I don't wish to overgeneralize but responsible people are responsible and irresponsible people are irresponsible.
    I suspect there was some event in the interim between the two hemoglobin A1C results that you have not listed or the result is false. Pancreatitis can lead to pancreatic failure as an example.
    Everyone who is prescribing injectables should consider having a contingency plan should the patient not show up for their injection.
    David Bebinger, MD
    Worcester, Massachusetts
    David M. Bebinger, MD
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  • 4.  RE: new viremia in new dx of DM?

    Posted 12-27-2022 08:50
    Hi Vanessa:

    Interesting case.......

    My first thought is big picture: CD4 > 500 w/40% consistently so immunologically, your patient is fine for the near future.


    In general: three things may cause a trend in VL rise; 
    #1. Poor Adherence
    #2. Resulting development of resistance due to poor adherence
    #3 Illness

    I can tell you that in my > 25 years of HIV care, there have been several times when patients whom I thought were adherent, they in fact it ended up that they were not. Therefore, this possibility is ALWAYS on the differential.

    You certainly are approaching it correctly by addressing what is addressable and measurable.

    First, getting their DM under control is first and foremost as we know it is also an immune disorder that can affect their HIV labs.
    Second, you have already checked for and found that you basically have no clinically significant resistance present.

    Third unfortunately, you will never actually be able to objectively measure which is adherence. You could call the pharmacy and check their refill dates. This may or may not give you some information. But if you see it is not being done on a faithful 30-day schedule, it could rule poor adherence in. If not, it will not rule adherence out unfortunately. I have had patients who faithfully refill their meds but incredibly did not take them faithfully at home. That was the reason for the increase that finally came out later in their care through our continuous adherence conversations. Remember, patients hate to "disappoint" their providers. 

    I remember the old adage from when I was in med school; "Common things happen commonly". The most common reason for viral increase is always poor adherence. Especially after I have objectively ruled out everything else by objective measurables. 

    This is one reason why I like Long Acting (LA) injectables. At least I can objectively measure their adherence by the timing of their visits (or lack thereof) to receive their injections. I do not have to wonder about that issue as I have had to for years with pill taking. Unfortunately, with the current options, LAs are for select, appropriate patients.

     Happy New Year!

    Angel I. Ribó PA-C, MPAS, AAHIVS, DFAAPA
    Ribó Consulting LLC
    90 N. Lakewalk Drive 
    Palm Coast, FL 32137
    C: 903-445-9396 
    F: 833-490-1306

  • 5.  RE: new viremia in new dx of DM?

    Posted 12-27-2022 12:27
    Was patient virally suppressed on Genvoya?  what was the reason to switch him off Genvoya?  To get off COBI? 

    Ask about use pill organizer, affordability of meds, memory issues and filling patterns.  (yes we have patients that fill  on time every month but are also stockpiling, intentional or not). 

    Do you have an HIV pharmacist who can do a phone consult with patient to tease out fill list of OTC and herbals to look for interference?  Seems to me most DDI's lead to viral blips, not nearly 5,000.  I'd ask patient to stop all nonessentials and repeat viral load after 21 days of consecutive Biktarvy (and abstain from sex or other risk reductions)

    Good luck. 

    Joshua Rohr
    Seattle WA

  • 6.  RE: new viremia in new dx of DM?

    Posted 12-27-2022 19:13
    Hi Vanessa,

    I would agree with the others.  It seems like the only explanation is non adherence.  Why did his Hgba1c go from 7.5 to over 13 in four months?  That's a huge jump!   Sounds like he stopped his diabetes meds at that time, or at least cut back on taking them.    The large increase in hgba1c in a short time period, as well as loss of viral suppression at the same time, seems to suggest non compliance.

    Adam Zweig
    AIDS Healthcare Foundation
    San Diego CA

  • 7.  RE: new viremia in new dx of DM?

    Posted 12-28-2022 15:07
    I would suggest using this website for DDI.
    It recommends not co-administering Biktarvy and St. John's Wort. 

    Quality of evidence: Very Low


    Coadministration has not been studied and is contraindicated in the product labels for Biktarvy as St John's wort may substantially decrease bictegravir and tenofovir alafenamide plasma concentrations which may result in loss of therapeutic effect and development of resistance.

    Larry Lyle
    San Diego CA

  • 8.  RE: new viremia in new dx of DM?

    Posted 12-29-2022 15:19
    I agree with the majority of responses that the latest viremia is likely from non-adherence to medication.

    I did want to address the sudden a1c increase. It happened to one of my patients with longstanding HIV, who was switched from his old regimen (TDF/FTC + NVP) to biktarvy and had a dramatic a1c increase in the subsequent 3 months, including a hospital admission for DKA. I found this brief report of accelerated hyperglycemia in 3 patients newly started on biktarvy. This is from almost 2 years ago so there may be more cases, I don't know if this has been studied in more detail although I know we are getting more and more information about the metabolic implications of INSTI-based regimens and bictegravir in particular.

    Bictegravir-Based Antiretroviral Therapy-Associated Accelerated Hyperglycemia and Diabetes Mellitus

    Louise Austin PA-C
    New York NY

  • 9.  RE: new viremia in new dx of DM?

    Posted 12-30-2022 16:06
    Thanks, Louise. I had not heard about this risk but it's more evidence that integrase inhibitors are not a panacea. I have a cadre of about 50 very long term NVP patients (now mostly on FTC/TAF with it, a few still on FTC/TDF) - most have been on it for over two decades without issues. Shiny new drugs are not always better than old ones. I'm trying to keep my legacy NVP patients on NVP, which costs less than $20 a month, and does not appear to have any long term toxicity - the liver toxicity is a hypersensitivity that occurs early in therapy. A few of these pts are paying cash for NVP plus TDF/FTC which means their cost of HIV treatment is less than $40 a month, using GoodRx for NVP and for TDF/FTC.

    Peter Shalit, MD, PhD, FACP, AAHIVS 
    Cabrini Tower, 901 Boren Ave Suite 850, Seattle, WA 98104 
    P 206-624-0688 F 206-624-2432  

  • 10.  RE: new viremia in new dx of DM?

    Posted 02-01-2023 13:14
    Hi Vanessa,
    Great summary. I don't have much to add except to say that, now that we are using the GLP1s so much more, I do wonder whether we will find that their effect on GI motility / gastric emptying does have some interaction with ARVs in some patients. Whether this could have to do with delayed absorption of interfering cations, or absorption of the ARVs themselves, it seems plausible to me. Liverpool reports that this interaction is thought to be inconsequential but is not thoroughly studied - I hope someone is planning a study!
    That said, I agree with other folks that missed doses are more likely the issue.

    Julia Cooper MD, AAHIVS
    New York, NY

  • 11.  RE: new viremia in new dx of DM?

    Posted 02-12-2023 19:18

    Hi Vanessa, 

    This is an interesting case! One thing that might be good to look at is vaccinations around the time of both the A1c and VL increases. I've seen a few patients with very well-controlled diabetes that the Moderna COVID vaccine transiently increased their glucose levels resulting in spikes requiring short-term use of insulin. I have not seen anything yet in terms of shifts in VL but their may be some changes there as well. I'd be curious to hear if there have been any recent changes. 

    Sean Yaphe, MD, MPH
    Family Medicine Physician, Clinique L'Actuel
    Montreal, Quebec, Canada

    Sean Yaphe
    Clinique L'Actuel
    Montréal QC

  • 12.  RE: new viremia in new dx of DM?

    Posted 09-05-2023 14:23

    Thank you all for your thoughts! I definitely agree in the context that adherence challenges would make the most sense in terms of new viremia, but I did not end up cracking the case in that regard. Fortunately, after a ~3 month period of dm+hiv instability, many we were able to get both conditions well controlled, with an undetectable viral load and an a1c below 7%. Thanks to Louise for sharing the case series on accelerated hyperglycemia, it's given me a lot to think about with both this patient and another who presented similarly from a hyperglycemia standpoint - I'll share in a separate post. and Julia, you bring up a great point about the possibility of GLP1s affecting ART absorption/metabolism - I'm sure as we see these medications more commonly co-administered, we might start to see some trends!



    Vanessa Ferrel, MD MPH
    Philadelphia PA