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.
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.
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.
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.
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.
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
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:
blips (>50 c/ml) in 96/241 (40%)
viremia (>200 copies/ml) in 47/241 (20%)
than 1 episode (>50 c/ml) in 24/241 (10%)
consecutive HIV RNA (>50 c/ml) in 32/241 (13%)
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.
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
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.
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.