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HIGHLIGHTS FROM HAMBURG Viral Load
The value of surrogate markers as predictors of clinical
outcome was discussed in several sessions today. Dr M. Elashoff from the FDA (USA)
reviewed clinical endpoint studies from the ACTG as well those from industry (Abbott,
Glaxo Wellcome, Pharmacia and Roche) which provide insight into the relationship between
HIV RNA and disease progression. The studies which included a total of over 5,500
patients, were analysed separately. Although there was considerable heterogeneity between
the studies, all demonstrated that reduction in plasma HIV RNA is associated with a
reduction in disease progression. Initial HIV RNA response can be quantified in various
ways including change from baseline, nadir value, and duration of HIV RNA reduction from
baseline. The studies presented showed that greater changes from baseline, lower nadir
values and a longer duration of HIV RNA suppression are all associated with a lower
clinical event rate. Dr Elashoff commented that nadir is an absolute value enabling some
degree of cross-study comparison and does not encounter the problems associated with mean
changes from baseline such as drop outs and the limit of quantifications. He added that
the FDA now suggest that clinical trials supporting registration monitor time to loss of
viral load supression (rebound above nadir) as a surrogate marker and have a duration of
at least 48 weeks. However, no claims of clinical benefit will be allowed without clinical
endpoint data.
Dr J. Montaner (Canada) presented data from the INCAS study
which suggest that suppression of viral replication to below 20 copies/mL is needed to
achieve a durable response. Patients in the INCAS trial were treated with ZDV+NVP, ZDV+ddI
or ZDV+ddI+NVP. Patients in the triple regimen achieved a 3 log10 reduction in
HIV RNA which was maintained out to 52 weeks. The ZDV+ddI arm retained a 2 log reduction,
whereas the ZDV+NVP arm had only a transient response. Just over 50% of patients in the
triple arm achieved HIV RNA <20 copies/mL compared to approximately 10% in the ZDV+ddI
arm and 0% in the NVP+ZDV arm. The median duration of plasma viral load suppression for
patients who achieved this cut off was 154 days compared to 7 days in those whose viral
load did not fall to this level (p=0.001). Interestingly, in a subset of patients whose
viral load fell to <20 copies/mL but then interrupted ddI therapy, HIV RNA did not
breakthrough. These data suggest that reducing HIV RNA to <400 copies/mL can no longer
be considered to be standard of care for HIV and that in patients attaining this level an
ultrasensitive HIV RNA analysis should be performed and if necessary treatment intensified
to reduce HIV to below detectability of this assay. The findings from the non adherent
patients suggest that a subtraction or maintenance therapy strategy may be viable in
patients whose HIV RNA nadir is <20 copies/mL.
Dr G. Tambassi (Italy) evaluated the efficacy of the
current hard gel formulation of SQV in combination with ZDV+3TC in 14 individuals with
symptomatic primary HIV infection (median HIV RNA 5.6 log10 copies/mL). HIV RNA
fell to below quantification in 7/8 patients at week 24 and 4/4 patients at week 36. This
was accompanied by a rapid normalisation in the CD4/CD8 ratio with a CD4/CD8 of >1 in
7/8 patients week 24 (median value 1.9). As expected, there was no immediate effect on CD4
count.
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