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Once- Versus Twice-Daily Raltegravir When Switching From a PI
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XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
A single-center trial found that replacing a protease inhibitor (PI) with raltegravir in a suppressive regimen is effective--as long as patients do not have a record of resistance to nucleosides (NRTIs) [1] (also observed in SWITCHMRK), although that depends because in the SPIRAL Study reported here and published last week patients with extensive nuke experience did do well after switching to raltegravir regimen because the authors think the patients were undetectable for 6 years prior to the switch. Twice-daily raltegravir looked more effective than once-daily raltegravir in this 24-week trial at Madrid's Carlos III Hospital, although the differences between once- and twice-daily dosing stopped short of statistical significance.
In the two randomized SWITCHMRK trials, people replacing suppressive lopinavir/ritonavir with raltegravir had a higher 24-week failure rate than people who continued the PIs [2], but probably because many patients had taken a failing nucleoside regimen. Covert nucleoside mutations could re-emerge after switching from a boosted PI if the replacement drug has a lower barrier to resistance, as raltegravir apparently does.
The Madrid ODIS trial involved 222 people who maintained a viral load below 50 copies for more than 24 weeks while taking a PI regimen. Carlos III investigators randomized 149 people to swap their PIs for once-daily raltegravir (800 mg) and 73 to switch to twice-daily raltegravir (400 mg). After 12 weeks 35 people taking twice-daily raltegravir were further randomized to continue twice-daily dosing and 38 were randomized to switch to once-daily raltegravir. There was no control group of people who continued their PI.
Seventy-seven study participants (33%) proportionately distributed across the three arms had a record of resistance to NRTIs. Overall time on antiretroviral therapy averaged 102 months. Almost half of study participants (48%) replaced atazanavir, while 28% replaced lopinavir and 13% fosamprenavir. Two thirds of these patients took raltegravir with tenofovir/emtricitabine, while one third took abacavir/lamivudine. CD4 count at the switch averaged 574 (+/- 308). A high proportion of patients, 46%, had hepatitis C virus coinfection.
Within 24 weeks of the switch, 13 people (6%) had virologic failure, including 12 taking once-daily raltegravir and 1 taking twice-daily raltegravir. That difference fell short of statistical significance (P = 0.18). Among 12 patients with virologic failure and a record of resistance to NRTIs, 11 were taking raltegravir once daily compared with 1 taking raltegravir twice daily, a difference that also stopped short of statistical significance (P = 0.14). The virologic failure rate among all people with prior NRTI resistance was 16.2%, compared with 0.7% in people without a record of NRTI resistance, a highly significant difference (P < 0.001).
Total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol fell significantly after raltegravir replaced a PI.
Multivariate analysis identified only two factors that predicted virologic failure after the switch: Prior resistance to NRTIs raised the risk more than 38 times, while prior virologic failure lowered the risk about 10%. Factors that did not predict virologic failure in this analysis were once-daily versus twice-daily raltegravir dosing, abacavir/lamivudine versus tenofovir/emtricitabine as the regimen backbone, or prior suboptimal antiretroviral therapy.
Some attendees expressed caution about interpreting the once-daily versus twice-daily impact on virologic response. Although once-daily raltegravir did not significantly favor virologic failure, trends ran in that direction and may have reached statistical significance in a larger trial. Presenting results for the ODIS investigators, Eugenia Vispo proposed that once-daily raltegravir may not be a good option for people with a record of NRTI failure.
Results of SPIRAL, a Spanish multicenter study of raltegravir replacing a ritonavir-boosted PI, were published shortly before the International AIDS Conference [3] and presented at the meeting. SPIRAL randomized 273 people with an undetectable viral load on a ritonavir-boosted PI for at least 6 months to continue the PI or to substitute raltegravir, a design similar to SWITCHMRK [2]. Forty-eight weeks after the switch, 97% taking raltegravir and 95% staying with their PI remained free of virologic failure. In the small proportion of people with virologic failure, half in each study group had once taken a regimen consisting of one or two NRTIs.
References
1. Vispo E, Barreiro P, Maida I, et al. Simplification from protease inhibitors to once or twice daily raltegravir: the ODIS trial. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract MOAB0102.
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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