Viral load blips are likely due to lab error and not cause for concern

Viral load blips are the result of statistical fluctuations in the test used to measure viral load levels, and not clinically significant, according to the results of a study from Johns Hopkins University School of Medicine, published in the February 16^th issue of the Journal of the American Medical Association (JAMA).

Viral load test results may sometimes rise above the limit of detection, even after combination antiretroviral therapy has reduced HIV levels to less than the limit of detection (50 copies per ml of blood). This isolated result showing viral load above 50 copies/ml is called a 'viral blip'. Although several studies have shown that even when several such blips occur, people who experience them are not at increased risk of treatment failure compared to people who maintain viral load below 50 copies/ml, others have found that viral load blips can be a signal that virological failure may well occur soon.

In order to investigate the clinical significance of viral load blips, researchers at Johns Hopkins enrolled seven men and three women (of whom seven were black and three were white) in a four month intensive study which took blood samples, on average, every three days. These blood samples were tested for drug resistance at baseline, and then sent to two different, independent labs for viral load measurements; the blood also underwent extensive drug level testing and genotypic resistance.

The ten participants in the study were all on highly active antiretroviral therapy (HAART) that had suppressed HIV levels to less than 50 copies/ml for a median of 34 months (range 11-79 months). All ten had begun anti-HIV therapy with a very low nadir CD4 count (a median of 18 cells/mm³; range, 1-129 cells/mm³) and a very high median pre-treatment viral load (a median of 516,000 copies/ml; range, 152,000->750,000 copies/ml). Four of the participants had previously experienced viral load blips, measured at a median of 97 copies/ml (range, 61-108 copies/ml) an average of 15.7 months before the study began (range, 2-30 months) and in all cases their viral loads returned to below 50 copies/ml without any change in treatment.

During the study, nine of the ten participants were found to have a total of 18 blips (a median of two blips each (range, 0-5). Nine blips were detected by one lab, eight by the other, and only one by both labs.The typical blip was brief (median duration, 2.5 days; range 2-11.5 days) and low in magnitude (median, 79 copies/ml; range, 51-201 copies/ml). One only participant experienced a blip higher than 200 copies/ml.

When the data were analysed for statistical significance, blips were only marginally associated with patient reported non-adherence (p=0.08). This supports the work of Miller and others, previously reported on aidsmap here. The authors say: “Extensive analysis of drug concentrations over time revealed wide…variation [within participants] but no correlation between drug concentrations and blips, raising concerns about the usefulness of therapeutic drug monitoring in the management of patients experiencing blips.” In fact, most blips (78%) occurred when drug levels were above the suggested trough concentrations.

The researchers also found that there was no association between blips and:

• the demographic parameters of gender, age or ethnicity
• the clinical parameters of CD4 cell nadir, CD4 cell count at study entry, pre-treament viral load, duration of HIV infection, duration of virological suppression, and the number of prior blips
• intercurrent illnesses (including pharyngitis/sinusitis, cold, and oral herpes outbreak)
• flu vaccination (given during the study to nine of the ten participants).

The plasma of nine of the ten participants underwent extensive genotypic resistance testing throughout the study. New resistance mutations were not found immediately after blips. A mutation (M461) appeared in the virus of one of the participants eight weeks after a blip, and then disappeared. “Given the patient’s history of poor adherence and prior exposure to multiple protease inhibitors,” write the investigators, “this is likely to be an archival mutation not detected in baseline sampling. Taken together, these results refute the notion that resistance arises during or immediately after blips.”

The authors suggest that blips are caused due to the "normal biological and statistical varation" that exists when viral load hovers around 15-20 copies/ml. "Importantly, the blips were not reproducible between the two labs, not occurring in the same samples," says lead investigator, Robert Siciliano. "This is consistent with the idea that the blips are simply statistical fluctuations in the [viral load] assay."

The study authors conclude by suggesting that blips “may not be cause for clinical concern,” and they call for further studies “to define when detectable viremia should trigger a change in therapy.” Until then, they postulate that “blips with a magnitude of greater than 200 copies/ml or blips that are detected in at least two independent or consecutive measurements may be more of a cause for concern.”