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Background: Scheduled treatment interruptions are being evaluated in an effort to decrease costs and side effects of highly active antiretroviral therapy (HAART). A schedule of 1 week on and 1 week off therapy offers the promise of 50% less drug exposure with continuously undetectable HIV RNA concentration.
Methods: In the Staccato study 600 patients on successful HAART were to be randomized to either continued therapy, CD4-guided therapy, or one week on, one week off therapy. A scheduled preliminary analysis evaluated effectiveness in the 1-week-on-1-week-off arm.
Results: Of 36 evaluable patients, 19 (53%) had two successive HIV RNA concentrations > 500 copies/ml at the end of the week off therapy, and were classified as virological failure. Most of those who failed took didanosine, stavudine, saquinavir, and ritonavir (11 patients). In these patients, there was no evidence of mutations suggestive of drug resistance, and plasma saquinavir levels were within the expected range. Two of three patients failing on triple nucleotides had drug resistance mutations, but nonetheless responded to reintroduction of triple nucleotide therapy. One of two patients taking nevirapine, and one of eight taking efavirenz, also failed. Both had resistance mutations at the time of failure, but not at baseline.
Conclusions: The 1-week-on-1-week-off schedule, as tested in the Staccato study, showed an unacceptably high failure rate and was therefore terminated.
Highly active antiretroviral therapies (HAART) decrease complications of HIV infections and prolong life expectancy. Nonetheless, concerns remain regarding complications and costs of HAART. Scheduled treatment interruptions (STI) have the potential to decrease side effects and expense, but still need to be properly evaluated in comparison to conventional (continuous) therapies.
Several types of STI are being explored. Long STI may have a fixed schedule (e.g., 2 months on, 2 months off therapy), or may be guided by the CD4 cell count: stop treatment once the CD4 cell count has risen, start it again after a fall. During long STI, HIV RNA concentrations rebound, with a probable increase in contagiousness and a decrease in CD4 cell counts.
In contrast, short STI only last a few days. Because viral rebound is not immediate, patients remain aviraemic, and CD4 cell counts are not expected to fall. Dybul et al. have published a small case series, using a 1-week-on-1-week-off schedule with the combination of stavudine, lamivudine, and ritonavir-boosted indinavir at a dosage of 800/100 mg twice daily. In eight patients more than 90% of measured HIV RNA concentrations were < 50 HIV RNA copies per ml, during a follow-up of 32-68 weeks.
Based on these preliminary data, the protocol of Staccato was devised, in order to compare long and short treatment interruptions of continuous therapy. From the start, an intermediary analysis was planned after randomization of the first 150 patients, in order to determine if viral load breakthroughs in the 1-week-on-1-week-off arm were more frequent than the expected acceptable limit of 10%.
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