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"Staggering" Did Not Ward Off NNRTI Resistance in SMART Drug Breaks
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Strategies to prevent emergence of nonnucleoside (NNRTI)-resistant virus when suspending an NNRTI regimen proved only partly successful among patients in the SMART treatment interruption trial [1]. The much-discussed "staggering" option--stopping an NNRTI first then stopping the nucleosides a few days later--did not work faultlessly, though it proved safer than stopping the NNRTI and nukes simultaneously. Replacing the NNRTI with a protease inhibitor (PI) and later stopping the PI and nucleosides simultaneously looked like it might be the best tactic.
SMART itself famously made plain that suspending antiretroviral therapy on the basis of CD4 counts significantly widens the risk of AIDS and some non-AIDS diseases [2]. The resistance analysis involved 984 SMART enrollees who took a holiday from an NNRTI regimen with a viral load below 400 copies. Among 688 people who later resumed an NNRTI medley, 601 (87.4%) pushed their viral load back under 400 copies 4 to 8 months after restarting.
First the SMART team focused on 515 people who stopped then restarted an NNRTI, dividing them into three groupsÑ98 people who stopped all drugs in their regimen simultaneously (against the advice of SMART planners), 307 who staggered the stop of the NNRTI and nucleosides, and 110 who switched from an NNRTI to a PI before stopping all drugs.
While 82% of those who shelved their antiretrovirals simultaneously reached an undetectable viral load after restarting, 90% who staggered their stop and 95% who first switched to a PI recontrolled their viral load. Statistical analysis factoring in AIDS at baseline determined that people who staggered their NNRTI stop almost doubled their chance of resuppressing HIV after resuming an NNRTI regimen compared with people who quit all drugs simultaneously (odds ratio 1.94, 95% confidence interval 1.02 to 3.69, P = 0.04). Compared with the simultaneous stoppers, people who switched to a PI before stopping antiretrovirals more than tripled their chance of recontrolling HIV (odds ratio 3.64, 95% confidence interval 1.37 to 9.64, P = 0.009).
The SMART team then scrutinized 141 people with a viral load above 1000 copies within 2 months of a drug break and resistance test results after interrupting therapy. Ten of 61 (16.4%) who interrupted all drugs simultaneously had one or more NNRTI-related mutations, compared with 7 of 56 (12.5%) who staggered their interruption and only 1 of 24 (4.2%) who switched to a PI before the drug holiday. Despite the trend to better results with the PI-switch tactic, the resistance-rate difference from the simultaneous group was not statistically significant (P = 0.35). PI mutation rates did not differ greatly between the three groups.
Compared with people who stopped their NNRTI and nucleosides simultaneously, those who staggered the interruption had a 27% better chance of reharnessing HIV (hazard ratio 1.27), a difference just bordering on statistical significance (95% confidence interval 1.00 to 1.60). But people who switched to a PI before taking a drug holiday had a 41% better chance of resuppression compared with simultaneous stoppers, a clearly significant advantage (95% confidence interval 1.07 to 1.87, P = 0.04).
The results confirm earlier reports that stopping all drugs in an NNRTI regimen simultanesouly poses a risk of resistance and later virologic failure. Although the SMART findings suggest that replacing an NNRTI with a PI before stopping all antiretrovirals may be safer than staggering the interruption of an NNRTI and nucleosides, SMART's Zoe Fox (Royal Free Hospital, London) does not believe this analysis is big enough to support that conclusion.
References
1. Fox ZV, Phillips AN, Cohen C, et al. Viral re-suppression and emergence of drug resistance following interruption of a suppressive NNRTI-containing regimen in the SMART study. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 3.
2. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
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