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Trading a Ritonavir-Boosted PI for Twice-Daily Raltegravir in SPIRAL
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XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
Link to recently published SPIRAL Study:
Raltegravir Switch from PI Effective - Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study - pdf attached - (07/05/10)
A Spanish trial found no virologic response difference between continuing a suppressive ritonavir-boosted protease inhibitor (PI) regimen and switching the PIs to twice-daily raltegravir [1]. Unlike participants in the two SWITCHMRK trials [2], people in the Spanish SPIRAL study who had a record of earlier resistance or virologic failure did not do worse when they switched to raltegravir than when their kept their PI.
In the international SWITCHMRK trials, patients who swapped suppressive lopinavir/ritonavir for raltegravir had a higher 24-week failure rate than those who stayed with the PIs [2]. Previous failure of a nucleoside-containing regimen and resulting archived nucleoside mutations appeared to explain the higher failure rate with raltegravir, which has a lower barrier to resistance than boosted PIs. But results of the smaller SPIRAL trial suggested that earlier nucleoside failure may not unduly imperil a raltegravir replacement regimen. Differences between SPIRAL and SWITCHMRK could account for the apparently divergent outcomes.
SPIRAL enrolled 286 people taking a boosted PI with two or more other antiretrovirals for at least 6 months and with a viral load below 50 copies for at least 180 days. The investigators randomized 143 to continue their PI and 143 to switch to twice-daily raltegravir. Everyone kept the same other antiretrovirals.
At randomization median CD4 counts were in the 500s and median age in the mid-40s. Study participants had taken a median of 5 antiretroviral regimens for a median of 10 years. About 40% had a history of virologic failure, and about one quarter had a record of reverse transcriptase mutations. About 45% were taking lopinavir and about 35% atazanavir.
After exclusion of 9 patients, the study groups included 139 people randomized to raltegravir and 134 randomized to a continued PI. Thirteen people in the raltegravir arm (9%) discontinued treatment, 3 because of adverse events and 2 because of virologic failure. Fourteen people (10%) discontinued their PI, 3 because of adverse events and 2 because of virologic failure.
In the primary 48-week intention-to-treat switch-equals-failure analysis, 124 of 139 people taking raltegravir (89%) and 116 of 134 maintaining their PI (87%) remained free of virologic failure. In an on-treatment analysis, 124 of 128 switching to raltegravir (97%) and 116 of 122 sticking with their PI (95%) remained free of virologic failure.
In a 48-week on-treatment analysis, sub-50-copy response rates were consistently (if marginally) higher with raltegravir than a continued PI in people with (1) prior virologic failure, (2) prior virologic failure or prior suboptimal therapy, or (3) prior resistance mutations. Response rates exceeded 90% in all of these subgroups regardless of regimen, except for PI-maintainers with prior resistance mutations, and their response rate exceeded 85%. Participants without these characteristics had almost identical response rates whether moving to raltegravir or staying with their PI.
SPIRAL senior investigator Jose Gatell listed some differences between SPIRAL and SWITCHMRK that may contribute to the varying results: open-label versus double-blind, double-dummy; 48 weeks versus 24 weeks; no need to confirm a viral load above 500 in SWITCHMRK; different nucleoside backbones; substantially shorter median duration of suppression before entry to SWITCHMRK; shorter minimum duration of virologic suppression before entry to SWITCHMRK; only lopinavir/ritonavir in SWITCHMRK. The combined SWITCHMRK trials included 707 people, compared with 286 in SPIRAL.
In SPIRAL the percentage of people with total cholesterol above 200 mg/dL fell from 41% to 15% through 48 weeks in the raltegravir arm, but also dwindled (from 38% to 29%) in the continued PI arm. Percentages of patients with low-density lipoprotein cholesterol above 160 mg/dL declined from 12% to 3% in the raltegravir group and from 12% to 8% in the PI group.
The SPIRAL investigators published their findings shortly before the International AIDS Conference [3].
References
1. Martinez E, Larrousse M, Llibre JM, et al. Simplification of antiretroviral therapy by switching from ritonavir-boosted protease inhibitors to raltegravir in virologically suppressed HIV-1-infected patients (SPIRAL): a randomised open-label trial. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract MOAB0103.
2. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375:396-407.
3. Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24:1697-1707.
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