Late Breakers:
Viral Load
Abstract L-14: Interruptions in Abacavir dosing are not associated with increased risk of hypersensitivity in the HEART (NZT 4006) Study. This is a Glaxo funded retrospective look at a trial they originally performed to access adherence and the benefits of intense education + counseling vs counseling alone. There were 195 patients in this trial. MEMs caps were employed, therefore a good mechanism was in place for monitoring who interrupted therapy. 4 out of 195 experienced a hypersensitivity reaction during the course of the study. 0 out of 195 had hypersensitivity reactions after an interruption in their Abacavir. 74 % of patients had at least 2 therapy interruptions. 52% of patients had greater than 4 interruptions and those interruptions lasted greater than or equal to 2 days. 55% had a therapy interruption of greater than 5 days. Once again there were no hypersensitivity reactions in any of these groups who had interruptions of their Abacavir therapy.
Commentary:
This is important because this summer the FDA sent a letter to
health care providers stating that there had been two cases of Abacavir
hypersensitivity that seem to have been associated with therapy interruptions
among patients in whom no symptoms existed prior to the break in adherence.
These two reports came from community clinicians and to date there has
been no collaborating reports. This
issue remains worthy of attention as hypersensitivity to Abacavir can be quick
and fatal. If it remains rare, Abacavir will continue to be one of the
best-tolerated and potent nucleosides.
Abstract L-17: Comparison of continuous and intermittent therapy in a SIV animal model. This late breaker presented by Franco Lori looked at STIís in macaque monkeys. There were 3 arms to this study. One was no HAART, one continuous HAART, and one intermittent HAART. Intermittent HAART was defined as 3 weeks on, 3 weeks off. The antiretrovirals used were Tenofovir (PMPA), Videx (ddI), and Hydroxyurea. Viral load and CD4 responses were similar in continuous versus intermittent HAART. The important part of this study was yet another validation of the difference between STIís in the chronically infected versus the acutely infected. This group found that the rate of viral rebound decreased among the macaques who were acutely infected with subsequent interruptions of therapy. This phenomenon was not observed among the macaques that were chronically infected when they embarked on HAART and then STIís.
Commentary:
This report bolsters the Rosenberg/Walker and Hirschl observations on
STIís in humans that if a patient is started on HAART shortly after
seroconversion then the immune system, with interruptions of HAART, may
eventually be able to control viremia without the need for antiretrovirals.
However in those who start HAART after a longer period of infection, that
ability of the immune system to ever control HIV may be lost.
Remaining in defiance of these conclusions might be the work coming out
of Fauci/Dybal at the NIH. More
time will be needed to access their results.
Note
from Jules Levin: The reports from Rosenberg/Walker
are based on a small observational study which was not randomized nor
controlled. Last reported in September 28 2000 issue on Nature.
Although it appears promising and some thought leaders feel the findings
hold merit, others feel that a cause and effect relationship are lacking in this
research and feel additional research are needed to confirm these findings.
Merck has researched a naked DNA vaccine in animals which showed an immune
response consisting of a CD8 CTL response. This response blocked infection when
monkeys were challenged with SIV. Clinical development will test dosing, safety,
and its use as a therapeutic vaccine. It will take a year to pass through the
initial safety trials and reach human clinical efficacy studies. Of course,
until tested in HIV infected humans, requisite efficacy and safety remain in
question.
Abstract L-11:
IL-2 therapy produces no change in
HIV RNA after one year. This
was a CPCRA study attempting to answer the question; does adding IL-2 to HAART
increase the risk of increasing HIV viral replication?
This was open-label, randomized, placebo controlled trial.
511 patients were randomized to one of 3 arms:
placebo, 4.5 MIU subcutaneous injection of IL-2 for 5 days every 8 weeks
for at least 3 cycles, 7.5 MIU for 5 days every 8 weeks for at least 3 cycles.
After 3 cycles if patients T-cells were not 2 times baseline or <1,000
they were given more cycles of IL-2 following the original schedule they were
randomized to.
Note
from Jules Levin:
Since ICAAC, at Glasgow (see
Glasgow highlights on NATAP web site), a research group Brian Gazzard's lab at
Chelsea & Westminster reported seeing viral load blips in some individuals
receiving IL-2. A small group of patients had <50 copies/ml and received 5
day courses of IL-2. Viral loads were tested on day 1 and day 5 of courses. 7/10
patients were reported to have viral blips (between 50-400) on at least one
occasion on day five. In theory, if a person has archived resistance from prior
ART use, repeated viral blips could lead to viral rebound. The problem in trying
to understand if this could occur is that viral loads are checked in general
every 3-6 months in studies and so a viral load blip could be missed.
Diane
Havlir has reported at the Resistance Workshop that in following a group of
treatment naÔve patients (receiving indinavir+AZT.3TC in Merck 035 study) who
experienced viral load blips, after 5 years viral load did not rebound. This
could be because they were naÔve, because indinavir was used, or because given
more time resistance could emerge. Additional research suggests viral load blips
are more likely to occur when lymph node reservoirs have resistant virus. Most
people have resistant virus in reservoir archived somewhere if they've had prior
therapy and viral rebound accompanied by resistance.