July 15, 2003
Structured treatment interruption (STI) is an area of keen research interest and a number of studies on STI were presented at this meeting. There are many different reasons that STI is considered. This abstract presented updated information from a prior trial (CPCRA 064) that used an STI strategy in a salvage or rescue setting.
The rationale for STI in HIV salvage therapy is to produce a reversion to wild-type virus prior to restarting treatment in those patients who have multi-drug resistant virus and limited or no treatment options. It has been observed that a period of treatment interruption often leads to partial or complete reversion to wild-type virus. The hope is that wild-type reversion may enhance the efficacy of salvage therapy despite the presence of archived viral resistance.
The study presented in this abstract was an expanded look at data obtained from the CPCRA 064 study which has been reported previously (Jody Lawrence, CROI 2003). This study randomized 270 patients to either immediate or delayed salvage therapy based on resistance testing. Those randomized to the STI arm were observed off therapy for four months prior to restarting ART. The patients eligible for enrollment were triple-class experienced, with virologic failure defined as HIV-RNA more than 5,000 copies/mL. These patients were highly experienced, with an average exposure to 10.6 antiretroviral medications, and had 14 baseline gene mutations. The mean CD4 count was 240 cells and mean viral load was about 100,000 copies/mL (5 log).
As reported previously, STI in this salvage setting was not beneficial and, in fact, this study was stopped prematurely because more patients in the STI arm had clinical AIDS-related events. Additionally, those randomized to the STI arm had a significant CD4 cell decline and no advantage in viral load response to therapy.
This updated analysis of the original study was performed to see if any subgroups benefitted from STI. The subgroups are based on stratification according to CD4 count, viral load and resistance testing. In the subgroup with more than 100 CD4 cells there was a sustained increase of about 40 CD4 cells in the no-STI group compared to an initial drop and then return to baseline in the STI group. There were no differences in viral load reduction (approximately 1 log) in both groups.
In the subgroup with less than 100 CD4 cells there was a less vigorous viral load reduction of about 0.5 logs in both the immediate and delayed STI groups. The CD4 response was also blunted in the delayed STI group compared to the immediate salvage group.
The response to STI was also analyzed based on phenotypic sensitivity score (PSS) and was found to be no different between the groups. However, it was noted that reversion to wild-type virus occurred more commonly among STI patients with higher CD4 counts and that these patients seemed to have better viral load and CD4 results on treatment. The overall conclusion of this study was that no benefit from STI could be identified among the subgroups studied.
This updated report failed to identify any STI benefit in subgroups from the CPCRA 064 study. Despite these disappointing results for STI in the salvage setting, there remains much interest in the potential significance of the wild-type reversion that may occur with treatment discontinuation. We can probably count on future studies with different designs to further characterize and explore the therapeutic implications (if any) of wild-type reversion and the dynamics of salvage therapy initiation.
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