Causes and Consequences of Incomplete HIV RNA Suppression in Clinical Trials

The current goal of antiretroviral treatment is suppression of HIV RNA below 50 copies/mL. However, there is evidence for residual low-level plasma viraemia below 50 copies/mL for people with HIV RNA suppression on antiretroviral treatment. It is not clear whether more profound suppression of HIV RNA would lead to a lower risk of virological failure on antiretroviral treatment or emergent drug resistance. There is high variability in the currently used HIV RNA PCR assays for samples with HIV RNA levels close to the detection lower limit of 40-50 copies/mL. For patients who have HIV RNA levels just above 50 copies/mL (often called single blips), a repeat sample should be taken to investigate the possibility of technical error. In a systematic review of 48-week efficacy from randomized clinical trials (N = 8,083), patients were significantly more likely to show HIV RNA levels between 50-400 copies/mL while taking first-line boosted PI-based HAART (7.3%) compared with first-line NNRTI-based HAART (4.5%) (p < 0.01). However in a systematic review of emergent drug resistance at failure in the same trials, there was also a significantly lower risk of emerging drug resistance after virological failure of boosted PI-based HAART (p < 0.01). Therefore, HIV RNA blips between 50-400 copies/mL may have different consequences for different classes of antiretrovirals. The most widely used method to analyse HIV RNA in clinical trials - time to loss of virological response (TLOVR) - uses two consecutive HIV RNA measurements to define both virological success and failure. However, other methods may improve precision and increase statistical power.