September 14, 2003
PLATO (which stands for pursuing late treatment options) is an international collaboration of 13 HIV cohort studies which to date have contributed 2,488 patients manifesting triple-class virologic failure (defined as HIV RNA > 1,000 copies/mL > four months while receiving NRTIs, NNRTIs and protease inhibitors [PIs] either sequentially or in combination).
At the Paris IAS meeting (Abstract # 576), data from PLATO were presented which looked at the chances for virologic success at two years for the same population of patients who failed triple-class regimens (median CD4+ T-cell count was 199 cells/mm3, median viral load was 4.59 log copies/mL, median duration of ART/HAART was 4.71/2.5 years).
The rate of successful virologic suppression at two years for the cohort was only 17 percent -- which confirms the difficulty in managing these patients. Positive factors leading to virologic success at two years (defined as RNA < 500 copies/mL) included more recent development of failure, the HIV experience of the patient's physician and the addition of one to two new drugs. Negative factors included being off all treatment or time off PIs with a viral load > 1000 copies/mL.
This presentation was the mirror image of the Paris data, except that it focused on death as the major endpoint (as opposed to virologic success). Predictors of death from time of triple-class failure were analyzed using Cox proportional hazards models.
After a total of 5,015 patient years of follow-up, there were 276 deaths with 66 percent HIV-related among patients with known causes of death (5.5/100 patient years with a two, three and four-year predicted mortality of 10, 15 and 21 percent).
The median CD4+ T-cell count closest to death was 16 cells/mm3. The risk of death was most closely linked to the latest CD4 count taken; plasma HIV RNA levels were not an independent predictor. Other independent risk factors for death included not taking antiretroviral therapy (ART), prior clinical AIDS, age (higher if older) and infection via injecting drug use.
Since stopping ART near death is a common practice that could be a confounding variable, another analysis was performed looking at stopping ART for at least three months prior to the time point of analysis. Less of an effect was seen for the link between no ART and increased risk for death but there was still a relationship. This has been noticed previously in other studies, such as one from Veronica Miller in the Frankfort cohort.
For the PLATO study, stopping ART for > three months prior to the analysis point had a hazard ratio of 1.95 for increased risk of death. That observation was noted to be consistent with the results of CPCRA 064 (the structured treatment interruption study looking at the effect of four months off therapy; for a summary, click here) , recently published in the New England Journal of Medicine.
The goal for patients failing all three standard classes of antiretrovirals was proposed to be maintaining the CD4+ T-cell count at > 200 cells/mm3. Additional risk factors to consider in an approach to this patient population are the role of structured treatment interruptions and increasing viral loads (if > 10,000 copies/mL or returning to pre-HAART set-point then increased risk for death observed). Coupled with their earlier report (Paris IAS, mentioned above) the PLATO data offers compelling proof that new drugs and novel strategies are sorely needed.
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