Improving the Management of HIV Disease Vol. 6, no. 5 [World Conference on AIDS (12th: 1998: Geneva)]

International AIDS Society-USA

DR RICHMAN: Plasma HIV RNA is fulllength genomic RNA present in intact
virions produced by infected CD4+ lymphocytes in lymphoid tissue. In the lymphoid tissue of untreated patients or
patients treated with nRTI-only regimens, the RNA present is predominantly
of the same composition. With potent
therapy that results in plasma levels of
HIV RNA of <50 copies/mL, the RNA
changes its distribution and character
with much of it representing multiplyspliced transcripts. The mechanisms
involved in these changes have not been
well characterized.
34. You spoke of an increased
risk of virologic failure with
a large recovery of CD4+ cell
count. Can you comment
on the dampened increase
in CD4+ cell count seen with
hydroxyurea in light of this
risk factor? Is this potentially a contributing factor to
HIV benefit?
DR RICHMAN: ACTG 343 showed that
the patients with the greatest elevations
in CD4+ cell counts (which is probably
very encouraging immunologically) may

paradoxically provide more potential
host cells for outgrowth of suppressed
HIV. Regimens with borderline activity
may fail despite the greatest elevations in
CD4+ cell counts. Theoretically this situation may benefit from the suppressive
effects of hydroxyurea on CD4+ lymphocytes. Studies are in progress to examine
whether diminishing CD4+ cell activation with hydroxyurea will help suppress
viral replication in these patients.
35. Could genotypic or phenotypic testing results be
used as a reason for
changing therapy in the
absence of evidence of
virologic, immunologic,
or clinicalfailure?
DR D'AOuILA: I would not change therapy if genotypic changes or phenotypic
resistance was detected when plasma
HIV RNA levels remained adequately
suppressed. Resistance tests rely on an
initial PCR amplification step, which can
be prone to cross-contamination in the
laboratory and lead to a risk of a falsepositive result. I would not order resistance testing unless there was evidence of
virologic failure. In my view, virologic
failure should be the trigger for when to
change therapy and it will almost always
precede immunologic or clinical failure. I
define virologic failure as confirmed lack
of an adequate decrease in HIV RNA
within the first month or two after starting therapy, confirmed lack of suppression to below detectable levels (<50
copies/mL) after 6 months or more of
therapy, or a confirmed rise of greater
than 4-fold in plasma HIV RNA levels at
any time. If any of these criteria are met, I
would change therapy whether or not
immunologic or clinical failure was evi
dent and whether or not resistant virus
was present. Detection of virus resistant
to a drug may suggest which drug(s)
should not be used in the next regimen,
but it should not be used to indicate when
to change therapy.
DR CLOTET: The absence of evidence of
virologic failure means that a patient has
plasma HIV-1 RNA levels below detection (ie, <200 copies/mL). Generally,
plasma HIV RNA samples with more
than 1000 copies mL are needed to generate genotypic and phenotypic results.
Resistance testing is not likely to be useful when values are below this level. For
this reason, in the absence of virologic
failure, genotypic or phenotypic testing
cannot be used for guiding the change of
therapy.
Genotypic and phenotypic testing
should be used in a setting of virologic
failure (HIV RNA >1000 copies/mL) in
spite of the absence of immunologic or
clinical failure.
Currently, phenotypic assays are
becoming widely available. Phenotypic
assay manufacturers are building databases relating findings from their test to
later outcomes. The information generated will be very useful for selecting alternative regimens in case of virologic failure.
36. Do you recommend
genotyping or phenotyping prior to changing
medications or starting
medications if plasma
viral load is >iooo
copies/mL?
DR BRUN-VEZINET: In patients with
primary infection, therapy must be started without any delay. But in settings
where surveillance studies have demonstrated that 5% or 10% of virus isolates

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