September 14, 2003
Dr. Maggiolo from Italy provided details of this current study in a slide presentation. He started by sharing with the audience that BASTA -- the title of this study -- means "enough or stop" in Italian. An apt name for a study that examines the question of how much treatment for HIV infection is enough.
There are a number of STI study designs. This one looked at STI based on CD4 count response to therapy. The general approach is to treat HIV infection when CD4 counts go below a critical threshold and then interrupt therapy when the CD4 counts rise above a certain level. Depending on the CD4 count parameters that are selected for starting and stopping therapy, this strategy usually translates into relatively long periods of time off and on therapy -- months to years. The SMART study follows a similar scheme, although the study details are quite different.
This study was a prospective, randomized, controlled trial that enrolled patients with CD4 counts >800 cells/mcL and HIV-RNA levels <50 copies/mL on antiretroviral therapy (ART). These patients were randomly assigned (2:1) to either interrupt ART or continue with their present therapy. In the STI arm the goal was to maintain a CD4 count >400 cells. The primary endpoint of the study was the proportion of patients remaining above 400 CD4 cells/mcL in the STI arm compared with the control. Secondary endpoints included predictors of time off therapy, metabolic changes, tolerability, costs and virologic resistance.
One hundred fourteen patients were enrolled in the study (76 in the STI arm, 38 in the control arm). The two groups were similar in baseline characteristics. The 18-month follow-up data was presented.
Eight of the 38 patients in the control group discontinued therapy -- one patient experienced virologic failure, one had medication toxicity, another patient was lost to follow-up and five withdrew consent. This high rate of discontinuation in the control group was an interesting aspect of this study and suggests that patients with high counts (in this study at least) were making the decision to stop treatment despite physician or study recommendations.
In the STI arm two patients withdrew because of HIV-related low blood counts (cytopenia). Two patients also had an acute retroviral syndrome following treatment withdrawal that did not recur when these patients had a second STI. Twenty-one percent of patients in the STI group restarted treatment because their CD4 count dropped below 400 cells/mcL. At any one time point the percentage of patients with a CD4 count below 400 was never greater than 3 percent.
The mean per-patient time on treatment was 12.1 percent of the follow-up period in the STI group. With multiple logistic regression, the only independent predictor of CD4 cell depletion was the lowest (nadir) prior value of CD4 cells (p<0.001).
|Nadir CD4||Mean Duration of First Off Therapy|
|<200 cells||6.9 months (not over 10 months)|
|200-350 cells||14.1 months|
|351-500 cells||17.8 months|
|>500 cells||all continue off therapy|
When the patients in the STI group resumed therapy, there was a prompt rise in CD4 cells and no evolution of viral resistance was noted.
The net result of this study was that it showed ART may be safely discontinued in patients who have CD4 counts over 800 cells/mcL. This was especially true for those patients who had higher CD4 counts to begin with. A patient's lowest previous CD4 count was a good predictor of the success of STI. Those individuals who started therapy with more than 500 CD4 cells did extremely well, none had to restart therapy due to a drop in CD4 cells below 400 after 18 months. Even those with a CD4 cell nadir in the 200-500 range were able to stay off treatment between 14 and 18 months.
This randomized study is ongoing and it will be interesting to see longer term follow-up of this interesting approach. At the least this study adds to the growing literature that shows it is reasonable to discontinue therapy in patients who were started on treatment a few years ago when treatment guidelines were more aggressive than contemporary standards.
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