Transient "Blips" in Viral Load

Transient Relapses or Blips in Viral Load in Patients on HAART

This past February at the Retrovirus Conference more basic science research suggested that low-level viral load blips could have negative implications for long-term suppression of viral load when a person is essentially <50 copies/ml. Since then several studies have been reported at conferences suggesting that may not be true. At the Resistance Workshop, AMJ Wensing (University Medical Centre, Utrecht, The Netherlands) reported on a study regarding the association between viral load "blips" above detection and resistance and viral load rebound. In patients who achieve plasma HIV RNA <50 copies/ml during HAART, transient relapses ("blips") of the plasma viral load to levels above 50 copies/ml are regularly observed in some individuals. The goal of this study was to determine the mechanisms underlying these transient relapses of the plasma (blood) viral load during HAART.

A key question may be what regimen a person is taking. In the Havlir study reported on below, patients were taking an indinavir regimen, and blips have not resulted in viral load rebound so far in the follow-up. However, in the Wensing study, patients were on indinavir (8), nelfinavir (1), nevirapine (1), saquinavir (1), NFV/SQV (2), and RTV/SQV (2) regimens.

Fifteen patients with a transient viral load relapse during HAART (3 or 4 drugs) were selected. The regimens of all patients included 3TC. All patients achieved viral load <50 copies/ml prior to relapse. Using an ultra-sensitive sequencing approach, the presence of resistance mutations was determined at the moment of relapse in both the protease and RT genes. Sequence analysis was performed using the ABI automated sequencer.

The median plasma viral load at the time of relapse was 72 copies/ml (range 50-1253). The genotype of the HIV plasma virus could be determined in 11 of the 15 patients. Primary mutations NRTI, NNRTI or protease inhibitors were seen conferring resistance to 1 or more of the administered drugs were observed in 8 of 11 patients, all of whom had the M184 3TC mutation in the RT gene. Some of the 8 patients were treatment na‘ve and some were experienced prior to the regimen they were taking at the time of this study. The median duration of follow-up after the relapse was 12 months. Failure of HAART, defined as plasma levels above 50 copies/ml, occurred in only one patient after the transient relapse. Some patients were treatment naive and some were not.

The authors concluded that 2 mechanisms account for the blips during HAART. In approximately half of the cases resistant viruses are selected, indicating that viral replication occurred due to incomplete suppression, probably caused by a temporary decrease in the active drug concentrations. In the remaining cases, blips were due to the production of wild-type viruses most likely caused by activation of pre-therapy infected memory cells. In both cases a transient relapse of the plasma viral load did not preclude successful inhibition of viral replication <50 copies/ml by HAART therapy for at least 1 year after the relapse. In speaking with several researchers, their instinct was that viral load might rebound given enough time.

Intermittent Viral Load Blips and Viral Load Rebound

Diane Havlir delivered an oral presentation at both Sitges & Durban on intermittent viral load blips (HIV RNA 50-200) and if they are predictive of virologic rebound (>200 copies/ml) in patients receiving initial combination therapy.

She defined intermittent viremia, for this study, as HIV RNA >50 copies/ml with a subsequent measure <50 copies/ml after confirming virologic suppression (<50 copies/ml) with 24 weeks of therapy with indinavir, AZT and 3TC. Virologic rebound is 2 consecutive HIV RNA >200 copies/ml. (ACTG 343 maintenance failures were excluded; in 343 some IDV-AZT/3TC recipients received a maintenance regimen with less drugs). The median duration of therapy of the patients in the study they used for this analysis (ACTG 343) was 84 weeks. In ACTG 343 they found:

Predictors Of Intermittent Viremia (>50 c/ml). Baseline HIV RNA and maintenance therapy were predictors of blips. Baseline resistance at 215 position and time to <200 c/ml HIV RNA were borderline significant in predicting blips.

They used a modified Roche PCR viral load test with a low detection limit of 2.5 copies/ml. They found that median viral load was higher in subjects with intermittent viremia (23 copies/ml) compared to those without intermittent viremia (P<0.001). Only 8% of RNA measures in patients with intermittent viremia were <2.5 copies/ml compared to 52% of patients without intermittent viremia (P=0.013).

Havlir concluded that in this study population in 343 intermittent blips did not lead to viral rebound within the time frame they looked at (84 weeks): 9/96 (9.3%) of patients with intermittent viremia had viral rebound; 20/145 (13.8%) with viral suppression had viral rebound. Baseline HIV RNA was the only predictor of virologic failure in the model they used.

They also looked at patients in the Merck 035 study, in which patients received indinavir+AZT/3TC. Again they found those with intermittent blips had higher median RNA (7.3 copies/ml) than those with suppressed viremia (2.5 copies/ml). But individuals with suppressed viremia also had blips, but their blips were <50 copies/ml. In this patient group with a median duration of 4.5 years of observation, 0/6 patients with intermittent viremia had viral rebound, and 0/7 patients with viral suppression had viral rebound.

Intermittent viremia (>2.5 copies/ml) was present in all patients treated for as long as 5 years. One resistant researcher I spoke with at this meeting found resistant virus when he observed blips. This resistant virus was not present before therapy. He thinks it's intuitive that given enough time, viral rebound will occur if there are blips. Havlir's study extends to 5 years in small numbers of individuals. Why do patients have persistent intermittent viremia? Havlir said it could be due to ongoing infection, latently infected cells, and sanctuaries.