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More Than Doubled Risk of Progression in African Interruption Trial
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XVI International AIDS Conference, Toronto
Mark Mascolini
August 17, 2006
Confirming results of an earlier structured treatment interruption (STI) trial in Cote d'Ivoire [1], the DART study in Uganda and Zimbabwe found a higher risk of HIV disease progression in people who suspended treatment than in those who stayed on steady therapy [2]. The DART findings also line up with outcomes of most (but not all) STI studies outside Africa, including the international SMART trial [3,4].
DART's STI inquest, a substudy of the larger DART trial [5], differed from other recent STI studies in setting a 12-week on/off cycle rather than using CD4 counts as signals to suspend and restart therapy. The main DART study enrolled 3316 antiretroviral-naive people with a CD4 count below 200 cells/mm3 at two sites in Uganda and one in Zimbabwe, randomizing them to start AZT/3TC with either tenofovir, abacavir, or nevirapine.
After 48 to 72 weeks of treatment, 813 people with a CD4 count at or above 300 cells/mm3 were randomized to 12-week STIs or to continuous therapy. At that point the group's median CD4 count stood at 358 cells/mm3 (range 300 to 1054 cells/mm3), while the median lowest-ever CD4 count measured 132 cells/mm3 (range 1 to 199 cells/mm3). While 77% of people in the STI substudy took tenofovir or abacavir with AZT/3TC, 23% took nevirapine.
An independent safety panel shut down the STI substudy in March 2006 because of significantly higher disease progression rates in the STI group. Median follow-up measured 51 weeks (range 0 to 85 weeks) at that point, and people randomized to treatment breaks spent 49% of 388 person-years of follow-up on antiretroviral therapy.
Rates of a new or recurrent AIDS diagnosis or death stood at 8.2 per 100 person-years in the STI group (31 people) versus 3.2 per 100 person-years in the steady-therapy group (12 people).
Multivariate analysis showed a 2.73 times higher risk of a new World Health Organization (WHO) stage 4 diagnosis or death (P = 0.007) in the STI group, a 2.58 times higher risk of a new or recurrent WHO stage 4 diagnosis or death (P = 0.004), and a 2.95 times higher risk of a new or recurrent WHO stage 3 or 4 diagnosis or death (P < 0.001).
The most common clinical setbacks was esophageal candidiasis. When statisticians eliminated candidiasis from the analysis, the risk of new or recurrent WHO stage 3 or 4 disease or death was 1.78 times higher in the STI group, but that heightened risk lacked statistical significance (P = 0.19).
The DART team concluded that this STI strategy cannot be recommended.
References
1. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006;367:1981-1989.
2. Hakim J on behalf of the DART Trial Team. A structured treatment interruption strategy of 2 week cycles on and off ART is clinically inferior to continuous treatment in patients with low CD4 counts before ART: a randomisation within the DART trial. XVI International AIDS Conference. August 13-18. Toronto. Abstract THLB0207.
3. 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/mL) drug conservation (DC) vs the virological suppression (VS) arm? XVI International AIDS Conference. August 13-18. Toronto. Abstract WEAB0203.
4. 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.
5. DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS 2006;20:1391-1399.
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