October 9th, 2017

What Should We Do About Persistent Low-level Viremia?

Thanks to our mail person for taking this portrait of our pets Louie and Otto. You can tell by their expressions that they miss us.

Here’s a most entertaining email about a tricky case (some details changed for the usual reasons), with my annotations in brackets:

Subject: Regimen intensification?

Hi Paul:

Long-time reader, first time caller. [Love that intentional mixed metaphor — should we start a radio talk show?]

We have a pt who was on TDF/FTC/EFV for a decade. He was undetectable the whole time. [He must have been difficult for his friends and family to find! Ha ha ha.]

He agreed to modernize, and another doc switched him to TDF/FTC/RPV, then TAF/FTC/RPV. He suddenly had a viral load that hovered just above the threshold of detectable — e.g. 59, 86, 101 — and it refused to go away. [Bad viral load!] So, we switched him to ABC/3TC/DTG. But he still has a persistent low viral load… like 95, 81, 72. [There is clearly no trend. Isn’t my statistical acumen impressive?] He says his adherence is virtually 100% and his partner confirms it. We were suspicious, but pharmacy also said he’s picking up his meds on time.

Interestingly, he admits he took TDF/FTC/EFV on weekdays only and stayed undetectable (grrrrr), so of course he wants to switch back! [Hey, that strategy probably works fine for that regimen.] He has no major mutations on a genotype run during the TDF/FTC/RPV phase, and no major mutations on an archive genotype either.

*{#%*$, Paul?! Do we switch him to a PI regimen, or just intensify by adding another agent. If so, which one? Do we check blood levels? Who does that? Or is he just not taking his meds every day, like before?

I know you’re a very busy man, Paul. [Nah. Just sitting here writing this blog post.] If you could take a moment to link me to any discussions, posts, or articles on this topic, I would be forever grateful.

With high hopes you can help! […which I am about to disappoint.]

Dorabella [I wanted to put her real name here, as she had aspirations to be detected on Google searches. But it’s a no-no for patient queries.]

Oh my, so much to unwrap here! Because when it comes to persistent low-level viremia in treated HIV patients, there’s much agony, gnashing of teeth, and confusion.

This is not the isolated low-level result preceded and followed by an undetectable one, the entertainingly termed “blip.” The blipologists of the world all agree blips mean essentially nothing (hence putting themselves out of business).

This patient’s situation is much tougher. So here, in a lazy bulleted list, are a bunch of things we know — and mostly don’t know — about this tricky situation of persistent low-level viremia.

  • These patients have a higher HIV “reservoir.” If you look back, they often a history of advanced HIV disease, and/or very high pre-treatment HIV RNA.
  • There are at least two types of low-level viremia patients. The first are those who are fully adherent to their meds, and their HIV RNA has been persistently detectable since we started using the more sensitive RT-PCR assays, especially compared to the bDNA, may it R.I.P. The second type are practicing “white coat adherence” — that is, not taking their medications very much, then remembering to do so again a few weeks before coming in for an appointment. A quick call to the pharmacy for a refill frequency check can sort this out.
  • Some studies show low-level viremia is more likely to happen on boosted PI-containing regimens. The smart virologist Carlo Federico Perno from Italy has a nice theory why this is the case. It’s some combination of the mechanism of action of the PIs, where they act in viral replication, the defective virions, and the resistance barrier. So I wouldn’t switch to a boosted PI; this might make things worse.
  • Several (but not all) studies suggest they are at greater relative risk of eventually developing true virologic failure, compared to those with undetectable HIV RNA.  For example, in this study, a viral load between 50–200 was OK, but not 201–499. In this one, even 50-200 wasn’t benign — more failures. Regardless, the absolute risk is still quite low, especially if adherence is good. And they do not appear to be slowly developing resistance to their regimens.
  • Intensification won’t work. Throwing more drugs at this low-level viremia on treatment doesn’t lower the viral load further. We know this from studies and from anecdotal clinical experience.
  • They are not sick. Their CD4 cell counts remains stable, and they don’t get opportunistic infections. Data are mixed whether this low-level viremia is associated with higher levels of inflammation and immune activation markers, but you can’t do much about that even if it’s true.
  • Hey, what about “undetectable = uninfectious”? Does this still count? Hmmm, tough one. We simply don’t know if they are more likely to transmit HIV to others compared to those with undetectable HIV RNA. Reassuringly, the viral load thresholds in the major HIV transmission studies were all higher than most patients with low-level viremia, including the one in this case. This query forced me to look it up, so here they are:  Rakai (1500 cop/mL, untreated); 052 (400 cop/mL); PARTNERS (200 cop/mL); and Opposites Attract (200 cop/mL). (You’re welcome.) Isn’t that at least somewhat reassuring?

For the record, there’s a reason “Dorabella” didn’t just go to the HIV treatment guidelines for guidance, as there is ready acknowledgement that we just don’t know exactly what to do. Here are the blunt assessments from DHHS and IAS-USA, respectively:

“There is controversy regarding the clinical implications of persistent HIV RNA levels between the lower limit of detection and <200 copies/mL in patients on ART.”
“Data are inconsistent about long-term effects of persistent HIV RNA between 50 and 200 copies/mL, and current data are insufficient to guide clinical management.”

Given this uncertainty, here’s what I wrote back:

Hi Dorabella,

Tough one! First, is it possible that you switched from the bDNA assay to the RT-PCR right around the time his regimen changed? That’s important, because if so, it would explain why he went from “undetectable” (<75 copies/mL) to low-level detectable — it’s not the regimen, it’s that the RT-PCR is more sensitive.

Second, we don’t really know what to do with these patients who have persistent low-level viremia. They have a higher viral reservoir, and some might eventually fail therapy (probably those with poor adherence), but intensification doesn’t seem to work. So keep him on a high resistance barrier regimen, like the one he’s on — or theoretically even better, switch to TAF/FTC, DTG.

Third, can I steal this case for the blog?



She obviously said yes to that last query!

15 Responses to “What Should We Do About Persistent Low-level Viremia?”

  1. omar sued says:

    Dear Paul
    Thank for this topic that summarize many discussions and doubts.
    Could you please elaborate your “theoretically even better? Are you talking about efficacy? adverse events?. He will require 2 pills. How about Genvoya?

    • Paul Sax says:

      The synergistic resistance profile of tenofovir plus lamivudine is theoretically better than abacavir plus lamivudine (both of which lose susceptibility with M184V). Would not use Genvoya, as resistance barrier is lower with EVG than DTG.


  2. Alexandra Danforth says:

    I have a case of a patient who was originally started on TDF/FTC with DRV/c. He has persistent low level viremia as well and we did try adding DTG to the regimen with zero change in his VL levels. Eventually we stopped the DRV/c and switched to TAF/FTC. He is concerned about his perpetually detectable viral load but I’ve assured him we are doing all we can.

    Thanks for addressing this!

  3. Sol A says:

    Thank you so much for this post, very timely.
    I have a similar patient who was diagnosed with advanced AIDS and even since he was started on ART (ABC/3TC/DTG) he has never been completely undetectable, his viral load has been between 80s-150s for the last year. Pharmacy refills are almost on time (3-5 days delay).

    It made me pretty uncomfortable so I ended up adding DRV/c…
    Maybe I will end up switching him to TAF/FTC/Bictegravir when it is around the corner and in one pill?


  4. Benny says:

    We have a number of cases in our clinic like this. Typically we would intensify by adding 2 agents and not just a single agent. By adding two agents we are usually able to get patients back down to undetectable. After some time on “mega HAART” we deintensify and stop one agent and maintain undetectable VL.

    • Paul Sax says:

      Interesting! Might be worth reporting this in a case series, as many studies of intensification show no effect on low-level viremia.


  5. Michelle Nemer says:

    To answer your question, which may have been rhetorical, yes you should do a radio talk show!! I would listen, and likely frequently call in!

  6. Kathy Brown says:

    I typically have one of our HIV pharmacists talk with the patient about any vitamins, minerals or other supplements they may be taking that can interfere with absorption of the newer meds. Atripla had less of these and was usually taken on an empty stomach. Newer meds need some food (or a lot, for rilpivirine). This brings some of our low level viremia people back to undetectable.

    • Paul Sax says:

      You have better luck than I with this approach! I find there are some patients (usually in the category I described — high baseline VL and/or low CD4) who just can’t get the test to “undetectable.”


  7. Tim says:

    If the TDF/FTC/EFV was working well for 10 years and the patient is requesting that regimen, why not just switch back? I don’t see the need to “modernize” if he was tolerating the EFV.

    I think this case illustrates an important teaching point in ID (and life in general): if it’s not broken then don’t fix it.

  8. Dorabella says:

    DING DONG! Flowers… Plumber… Caaandygram… I’m just a friendly dolphin.

    PAUL, you’ve done it again. I laughed, I cried, I ding donged, and I LEARNED. I have never read that 5-day on/2-day off study with EFV/whatever before! It really made me think about NNRTI’s with a little more respect. If RPV didn’t have that dang 400 cal requirement, I’d be all over it. Is this new NNRTI going to be different in that respect? (there is a new NNRTI, right)

    IDEA! Let’s call the new one Enirafarine because it’s a palindrome.

    OK, let’s get back to the grit here. What I’m hearing is, intensification is not going to work. It reminds me of the attempt to get peoples’ CD4 up by adding like maraviroc to a suppressive regimen.

    Question #1: In the above example, do you think he would go back to suppressed on Atripla? If yes, why then would intensification with (hypothetically) EFV not work?

    Question #2: I kinda know a guy named Steve Deeks (but he doesn’t know me, though I did give him a flu shot about 14 years ago and it was the scariest moment of my life). He is all over this low-level viremia in elite supressors and how it is related to inflammatory markers. What’s your take on this?

    Question #3: Do you think Alabama could beat the Patriots?*

    Your ding-a-ling,

    * credit to PFTCommenter and his hot take after week one: https://www.barstoolsports.com/chicago/mmbm-could-alabama-beat-the-patriots

    • Dorabella says:

      Thank you Paul, for allowing this message to be posted. I was just about to repost it without the goofiness, as not to disrupt your very serious business. (Using my non-work address btw)

      I’m rather happy to see the return-to-Atripla advocates. A bit of info for anyone who actually reads this far, the patient does have sleep disruption with efv but he’s willing to tolerate it if it means better outcomes.

  9. Petrick says:

    Dear Paul,

    Some of us may have taken things a bit too far . We emphasize adherence to the point of 30 minutes to 1 hour . Is there any truth that patient should take his drugs daily on time and not be late by 1-2 hours ? Or is it just enough that he takes his drugs daily and we should not be worried about the time he takes it ? Our usual drugs are AZT/3TC or TDF/3TC with Nevirapine/Efavirenz combination .


  10. Michael Hodges says:

    Paul – great summary. am I missing something …. why not switch back to what worked? You did not mention if the original triple combo was tolerated or not but assuming “all was well” sometimes modernization is not for the best.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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