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Dolutegravir Superior to Raltegravir at 48 Weeks in Integrase Inhibitor Naive
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Dolutegravir proved virologically superior to raltegravir at week 48 of a trial enrolling people with antiretroviral experience but still naive to integrase inhibitors (INI) [1]. Sub-50-copy response rates were 71% in the dolutegravir group and 64% in the raltegravir group, and the virologic failure rate was higher in the raltegravir arm.
The double-blind, double-dummy SAILING trial enrolled INI-naive people with virus resistant to two or more other antiretroviral classes and with a viral load above 400 copies. Researchers randomized them to dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily) plus an optimized background regimen including no more than two antiretrovirals; at least one drug in the background regimen had to be fully active.
Study participants had a median age of 42 years in the dolutegravir arm and 43 in the raltegravir arm; about one third were women and about 40% of African heritage. About 30% had a viral load above 50,000 copies. Median treatment duration at trial entry was 6.7 years in the dolutegravir arm and 6.0 years in the raltegravir arm. Half of study participants had virus resistant to at least three antiretroviral classes. One fifth of study participants used darunavir/ritonavir in the new regimen without primary protease inhibitor mutations.
Among 357 people treated in the dolutegravir arm, 55 (15%) withdrew by week 48, including 20 because of lack of efficacy and 4 with adverse events. Among 362 people treated in the raltegravir arm, 78 (22%) withdrew by week 48, including 42 because of lack of efficacy and 11 with adverse events.
A week-48 snapshot analysis determined that 71% randomized to dolutegravir and 64% randomized to raltegravir had a viral load below 50 copies. The adjusted treatment difference of 7.4% (95% confidence interval 0.7% to 14.2%, P = 0.03) indicated that dolutegravir is superior to raltegravir in this population. Virologic nonresponse rates at week 48 were 20% with dolutegravir and 28% with raltegravir; week-48 virologic data were unavailable for 9% in both treatment arms.
Among people with a baseline viral load above 50,000 copies, 62% randomized to dolutegravir versus 47% randomized to raltegravir had a week-48 viral load below 50 copies. Respective proportions with a sub-50 load at 48 weeks were 64% versus 58% for those starting treatment with fewer than 200 CD4s, 71% versus 62% for those not using darunavir or using darunavir with primary protease inhibitor mutations, and 72% versus 63% for those with a background regimen phenotypic sensitivity score of 2 or more.
Kaplan-Meier sensitivity analyses of proportions with a viral load below 50 copies at week 48 were 92.0% with dolutegravir versus 85.1% with raltegravir when treatment-related discontinuations counted as failure, and 93.7% versus 86.7% when efficacy-related discontinuations counted as failure.
At the 48-week point, 2 people randomized to dolutegravir versus 19 randomized to raltegravir had protocol-defined virologic nonresponse (<1% versus 5%) and 19 versus 26 had a protocol-defined rebound (5% versus 7%). Four people assigned to dolutegravir and 17 assigned to raltegravir had virologic failure with emergence of INI-resistant virus (1% versus 5%).
Rates of drug-related grade 2 to 4 adverse events were 8% with dolutegravir and 9% with raltegravir, any serious adverse events 9% with dolutegravir and 12% with raltegravir, and serious drug-related events less than 1% with dolutegravir and 1% with raltegravir. Average serum creatinine rose more with dolutegravir than raltegravir (11.1 versus 5.1 umol/L), reflecting previously described nonprogressive increases due to OCT2 inhibition with dolutegravir.
The researchers proposed that three factors drove the virologic superiority of dolutegravir at week 48: fewer withdrawals due to lack of efficacy, lower number of protocol-defined virologic failures, and lower rate of treatment-emergent resistance.
Reference
1. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir (DTG) is superior to raltegravir (RAL) in ART-experienced, integrase naive subjects: week 48 results from SAILING (ING111762). 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WELBB03.
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