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What Explains Disease Progression in SMART's Drug Break Group?
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XVI International AIDS Conference, Toronto
Mark Mascolini
August 16, 2006
Continuing analysis of the SMART treatment interruption trial confirmed what many suspected: The longer time spent at a lower CD4 count and higher viral load in the treatment break group largely accounted for their greater risk of HIV disease progression compared with the continuous therapy group [1]. A second analysis aimed to figure whether the higher progression risk in the drug-break groups was particularly high in any clinical or demographic subgroup.
SMART enrolled and monitored 5472 people before an independent safety panel halted the trial in January 2006. Almost all study participants, 95%, already had antiretroviral experience, and 71% had a viral load under 400 copies/mL when the study began. Participants' age averaged 46 years, 30% were black, 27% were women, and 15% had hepatitis C virus coinfection. Median CD4 count at enrollment measured 598 cells/mm3, and median lowest-ever (nadir) CD4 count was 251 cells/mm3.
People randomized to the treatment interruption group stopped antiretroviral therapy if their CD4 count stood above 350 cells/mm3 and started again if it dropped below 250 cells/mm3. They stopped once more if CD4s climbed back over 350 cells/mm3. People assigned to the continuous-therapy group were never supposed to suspend therapy.
Jens Lundgren (University of Copenhagen) analyzed the impact of CD4 counts and viral loads measured just before the 167 cases of disease progression (called the proximal CD4 count and proximal viral load). "Progression" meant a new opportunistic disease, death from opportunistic disease, or death from some other cause.
Median proximal CD4 count measured 343 cells/mm3 among 120 break takers who had disease progression versus 540 cells/mm3 among 47 steady-therapy enrollees who had a clinical setback or died. CD4% just before progression stood at 19% in the interrupters and 25% in the control group. Viral loads measured closest to progression were 4.4 log copies/mL for interrupters and 3.1 log copies/mL for noninterrupters.
For both the break group and the steady-therapy group, overall progression rates proved higher--to the surprise of no one--at lower CD4 tallies and higher viral loads. But in CD4 brackets under 350 cells/mm3, rates of opportunistic disease or death did not differ significantly between break takers and continuously treated people. Significant differences between the two groups came at proximal CD4 counts of 350 to 499 cells/mm3 and above 500 cells/mm3 (P < 0.05 for both comparisons). Progression rates were so much higher in the interruption group at these high CD4s precisely because so few people in the continuous-therapy group had a new opportunistic disease or died at high CD4s.
But what really mattered in SMART was something designed into this international trial: People in the treatment break group spent more time at a lower CD4 count and a higher viral load than did people in the steady-treatment group. Although the trial plan called for people to restart therapy when their CD4 count slipped to 250 cells/mm3, CD4 tallies don't drop in conveniently round numbers. So the median CD4 count at treatment resumption stood at 232 cells/mm3, and some people had fewer than 200 CD4 cells/mm3 when they restarted antiretrovirals (interquartile range 192 to 299 cells/mm3).
Lundgren proposed that lower CD4 counts and higher viral loads during follow-up in the interruption group "explain a large proportion of the observed differences in [progression] risk" between the two study arms. He added that total follow-up time with the most recent CD4 count under 350 cells/mm3 was much greater in the drug-break group (32%) than in the steady-therapy group (7%). That difference, according to Lundgren, "provides a partial explanation for the higher overall risk" of opportunistic disease or death in treatment interrupters.
Among people with more than 350 cells/mm3 just before disease progression, overall viral loads were 4.0 log copies/mL (10,000 copies/mL) in the drug-break group and less than 2.6 log (400 copies/mL) in the control arm. Thus, Lundgren figured, some of the higher progression risk in the drug holiday group may be explained by their higher viral load "resulting in impairment of immune function not reflected in peripheral blood CD4 count."
The second SMART analysis tried to sift out predictors of faster HIV disease progression by dividing enrollees into sundry subgroups when they started the study [2]. Two of these analyses proved telling:
Among people taking antiretrovirals when they signed up for SMART, having a viral load below 400 copies/mL conferred a 4 times higher risk of progression in interrupters versus noninterrupters. In contrast, among people starting SMART with more than 400 copies/mL, the risk of progression was only 1.2 times higher in interrupters than in noninterrupters. The difference between the risk rates for starting viral loads above and below 400 copies/mL was highly significant (P < 0.001).
SMART researchers noted a similar disparity in risk rates between blacks, Latinos, and whites. Progression risk proved greater in all three groups for interrupters than for noninterrupters. But the progression risk for interruptions versus noninterrupters was higher for blacks (3.7) than for Latinos (2.0) or whites (2.1) (P = 0.08). Wafaa El-Sadr (Harlem Hospital, New York) attributed the higher progression risk in blacks mainly to non-AIDS deaths in that group.
References
1. Lundgren JD on behalf of the SMART Study Group. Progression of HIV-related disease or death (POD) in the randomised SMART study: why was the risk of POD greater in the CD4-guided ((re)-initiate ART at CD4 < 250 cells/µL) drug conservation (DC) vs the virological suppression (VS) arm? XVI International AIDS Conference. August 13-18. Toronto. Abstract WEAB0203.
2. El-Sadr W for the SMART Study Group. Inferior clinical outcomes with episodic CD4-guided antiretroviral therapy aimed at drug conservation (DC) in SMART study: consistency of finding in all patient subgroups. XVI International AIDS Conference. August 13-18. Toronto. Abstract WEAB0204
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