What is the significance of blips in viral load?
Intermittent viraemia or ‘blips’ in plasma viral load have been observed in patients receiving antiretroviral therapy who achieve viral loads <50 copies/mL. These blips have been associated with slower rates of viral decay and enhanced rates of viral evolution, including the selection of drug resistant variants.
Diane Havlir of the University of California, San Diego, presented a retrospective analysis of data from the ACTG 343 and the Merck 035 studies in an attempt to determine the prevalence and predictive value of such blips . In both these trials subjects received combination therapy with ZDV/3TC/indinavir. Intermittent viraemia was defined as a plasma sample with HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL after achieving confirmed virologic suppression (<50 copies/mL) with 24 weeks of therapy. Eventual virologic rebound was defined as 2 consecutive HIV RNA measurements >200 copies/mL.
The frequency of intermittent viraemia of 241 subjects in ACTG 343 was found to be 40% for >50 copies/mL and 20% for >200 copies/mL. More than one episode >50 copies/mL was seen in 10% and 2 consecutive measures >50 copies/mL in 13%. When samples of patients without intermittent viraemia (>50 copies/mL) were reprocessed to an assay limit of 2.5 copies/mL all subjects were found to have evidence of blips above 2.5 copies/mL for up to 5 years of treatment.
Thirteen patients with intermittent viraemia were identified from the Merck 035. Six of these patients had intermittent blips >50 copies while 7 patients never had a sample >50 copies/mL. None of the 13 patients had viral rebound over a median 4.5 years of follow-up whether or not intermittent viraemia >50 copies had been measured. In ACTG 343 9/96 patients with intermittent viraemia had eventual viral rebound while 20/145 with no evidence of intermittent viraemia had viral rebound. There was no significant difference in the rates of eventual rebound if intermittent viraemia was or was not detected.
A separate presentation by Annemarie Wensing of the University Medical Centre, Utrecht, analysed genotype of HIV from plasma during intermittent viraemia . An ultrasensitive sequence approach was used to analyse the protease and reverse transcriptase genes from HIV isolated during transient viral relapse. The median viral load at the time of relapse was 72 copies/mL (range 50 – 1239). Mutations in the RT and protease gene conferring resistance to one or more drugs were observed in 8 of 11 patients, 6 of whom had the M184V substitution (amongst changes at other codons). However, despite the presence of these resistance mutations during the blip, only one of the eleven patients experienced subsequent virological failure during a median 12 months of follow-up. The investigators conclude that plasma HIV RNA blips during HAART were associated with selection of drug resistant HIV in the majority of cases. This may be due to transient replication, probably due to a temporary decrease in active drug concentrations. Blips of wild-type virus can also occur probably through activation of latent virus reservoirs. However, as in the previous study, blips were not associated with subsequent treatment failure, at least during the year of follow-up.
These frequencies of detection of blips are highly dependent on measuring intervals and actually catching the blip. Important issues are raised concerning the ‘loose’ vs ‘tight’ control of viraemia. Treatment switch or intensification would occur unnecessarily if only one or two measures above 50 copies/mL were the criteria for treatment alteration. 2 or 3 measures > 200 copies and rising over a month has been suggested as an appropriate point of intervention (almost all patients in this study failed to regain control of viraemia after 2 measures >200). It should be remembered, however, that this is regimen and patient specific. NNRTI based therapies have a low genetic barrier to resistance and blips may not be as tolerated as they appear to be with PI based combinations. Additionally, extensively treatment experienced patients may also have partially breached the genetic barrier of resistance and require less provocation with these blips before viral replication takes off.
There is an important issue of assay variability and reliability at the low levels of detection used in this study. However, even if these blips are artefacts, at least this tells us such artefacts do not impact longer term suppression and should not be acted upon.
- Havlir D, Levitan D, Bassett R et al. Prevalence and predictive value of intermittent viremia in patients with viral suppression. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 112.
- Cohen Stuart J, Wensing AMJ, Kovacs C et al. Mechanisms underlying transient relapses (‘blips’) of plasma HIV RNA in patients on HAART. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 137