What Should We Do About Persistent Low-Level Viremia?

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!

[Note from TheBodyPRO.com: This article was originally published by Journal Watch on Oct. 9, 2017. We have cross-posted it with their permission.]