Blip or Bloop: Is an Unexpected Low HIV RNA Level Real?: A Top HIV Clinical Development of 2016

Top 10 Clinical Developments of 2016
1. Donald Trump6. Return of the Antibodies
2. Switch Frenzy7. Is an Unexpected Low HIV RNA Level Real?
3. 2-Drug ART8. Dolutegravir and the Central Nervous System
4. Is HIV PrEP at a Tipping Point?9. TAF in Hepatitis B
5. Start ART Now10. New HIV infections in U.S. Are Down -- a Bit

Jay has been my patient since I was an infectious disease fellow, and I can't forget the conversation we had soon after he was diagnosed back in 1992, during which I convinced him to start HIV therapy -- with d4T and lamivudine (yikes!). A lot has happened since then, including some updates to his antiretroviral therapy, and together we have grown older. His health has been excellent, and his HIV RNA levels have always been undetectable -- that is, until last month. A routine semi-annual viral load returned at 70 copies/mL (the lower limit of detection for the assay used is 20 copies/mL). Jay was in a panic. He has never missed a dose of his HIV medication and denied any new medications or supplements or recent vaccinations. Was this just a blip? And, if so, what exactly caused it?

For years, we have dealt with occasional viral load blips as we have with Facebook friend requests from beautiful people in Estonia: as something that happens, which we don't understand and we don't respond to. But, do blips represent actual virus that have percolated above the rim of the limit of assay detection then simmer down? A small but provocative study conducted two experiments to answer this question.

In the first phase, a standard World Health Organization stock of HIV-1 was diluted to create 50 samples of blood with viral loads of 142, 71, 36, 18 and 9 copies/mL. Each batch of 50 samples was then shipped to three different commercial laboratories for analysis using the Cobas AmpliPrep/Cobas TaqMan v2.0 HIV-1 assay (Roche). As expected, there was some variability in quantification, but for the standards with 36 copies/mL and 18 copies/mL of HIV-1 RNA -- that is close to but below the assay's limit of detection -- 66% and 18% of the tests, respectively, yielded results with values ≥50 copies/mL. That is, even though the specimens truly contained less than 50 copies/mL of virus, a substantial proportion run through the test returned with a result above this level. None of the lowest concentrations of virus (9 and 4 copies/mL) were ever reported as detectable.

In the second part of the study, a single plasma specimen from four patients with prior suppression who now had a value indicating low-level virus (range 50-93 copies/mL) was run repeatedly on the Cobas TaqMan. Retesting of the same sample with the newly detectable HIV RNA result produced a repeat result below 50 copies/mL in 14 of 15 runs.

The Bottom Line

At present, when a treated HIV-positive patient's viral load unexpectedly becomes detectable, a call is made to a now nervous patient, a viral load and maybe a resistance test are ordered and blood is redrawn. Based on the data from this study, the investigators propose a new paradigm with less hassle and cost: simply having the same sample with the unexpected blip saved and retested. According to their data, in the vast majority of cases in which the patient has been adherent (i.e., pre-test probability of true rebound is low), the repeat result will be undetectable, and all can breathe a sigh of relief. If not, then the call can be made and repeat testing conducted. It is notable that new Food and Drug Administration guidance for clinical research trials allow for confirmation of virologic outcomes using a retest of the last collected specimen.

Understanding that such blips are likely a function of the inherent variability of an assay can save patients anxiety and the health care system money. For this to work, though, commercial laboratories need to be willing to save specimens for a couple weeks or so, at least from those with blips, and a mechanism for ordering reflex same-specimen testing needs to be created -- both of which seem very doable.

What are some other top clinical developments of 2016? Read more of Dr. Wohl's picks.

David Alain Wohl, M.D., is a professor in the Division of Infectious Diseases at the University of North Carolina at Chapel Hill, director of the North Carolina AIDS Training and Education Center and site leader of the University of North Carolina Chapel Hill AIDS Clinical Research Site.