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Sustained Response to Dolutegravir Through 96 Weeks in Antiretroviral Naive
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Regimens including the integrase inhibitor dolutegravir proved virologically noninferior to raltegravir regimens through 96 weeks in previously untreated adults [1]. Virologic nonresponse rates were 5% in the dolutegravir arm and 10% in the raltegravir arm, and 2% in each arm discontinued because of adverse events.
SPRING-2 trial investigators already reported noninferiority of dolutegravir to raltegravir at 48 weeks, with 88% assigned to dolutegravir and 85% assigned to raltegravir having a viral load below 50 copies at week 48 according to snapshot analysis [2]. At that point no detectable resistance mutations emerged among people with virologic failure of dolutegravir, whereas 1 person with failure in the raltegravir group had treatment-emergent integrase resistance mutations and 4 had treatment-emergent nucleoside resistance mutations.
SPRING-2 is a phase 3, double-blind, placebo-controlled trial that enrolled antiretroviral-naive adults with a viral load at or above 1000 copies. The investigators randomized 822 participants to once-daily dolutegravir or twice-daily raltegravir plus investigator-selected nucleosides (either abacavir/lamivudine or tenofovir/emtricitabine). Median age was 37 in the dolutegravir arm and 35 in the raltegravir arm, and about 85% in each arm were men and white. Slightly more than one quarter of participants in each arm (28%) had a pretreatment viral load above 100,000 copies.
Through 96 weeks of treatment, 62 people (15%) withdrew from the dolutegravir group and 79 (19%) from the raltegravir group. Lack of efficacy was the reason in 17 (4%) randomized to dolutegravir and 25 (6%) randomized to raltegravir. Adverse events accounted for withdrawal of 10 (2%) in both treatment groups. Average serum creatinine rose in both study arms through 48 weeks (+12.3 mmol/L with dolutegravir and +4.7 mmol/L with raltegravir) and increased moderately after that (week 0 to 96 dolutegravir +14.6 mmol/L, raltegravir +8.2 mmol/L).
A week-96 snapshot analysis determined that 81% randomized to dolutegravir and 76% randomized to raltegravir had a viral load below 50 copies. The adjusted difference of 4.5% (95% confidence interval -1.1% to 10.0%) confirmed that dolutegravir remained virologically noninferior to raltegravir through 96 weeks. In an analysis eliminating people with protocol-defined virologic failure through 96 weeks, 93% randomized to dolutegravir and 91% randomized to raltegravir had a sub-50-copy viral load at week 96.
Among people with a pretreatment viral load above 100,000 copies, 78% assigned to dolutegravir and 63% assigned to raltegravir had a week-96 viral load below 50 copies. The 96-week sub-50-copy response rate was also greater with dolutegravir than raltegravir among people who took tenofovir/emtricitabine with their integrase inhibitor (86% versus 77%) but not among those who took abacavir/lamivudine (74% versus 76%).
There were 22 virologic nonresponses in the dolutegravir arm and 43 in the raltegravir arm (5% versus 10%). Virologic nonresponse rates in people with a pretreatment viral load above 100,000 copies were 11% with dolutegravir and 22% with raltegravir. Respective virologic nonresponse rates in those with a pretreatment viral load below 100,000 copies were 3% and 6%.
Median CD4 gains were similar in the two study arms through 96 weeks: 276 with dolutegravir and 264 with raltegravir.
The SPRING-2 investigators concluded that dolutegravir and raltegravir both yield rapid and sustained antiviral activity and CD4 gains through 96 weeks of treatment and that both drugs are well tolerated.
References
1. Raffi F, Jaeger H, Motta D, et al. Dolutegravir is non-inferior to raltegravir and shows durable response through 96 weeks: results from the SPRING-2 trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract TULBPE17.
2. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381:735-743.
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