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Similar 48-Week Response Rates With New
Integrase Inhibitor and Efavirenz in Naives
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Dolutegravir (S/GSK1349572) controlled viral replication faster than efavirenz in a phase 2b trial that enrolled previously untreated people, though at 48 weeks response rates were similar with dolutegravir and efavirenz [1]. Regimens based on this investigational integrase inhibitor appear to have a better safety profile than efavirenz-based combinations.
SPRING-1 is an ongoing multicenter, partially blinded phase 2b trial comparing three doses of dolutegravir with standard-dose efavirenz, both combined with either tenofovir/emtricitabine (selected by two thirds of investigators) or abacavir/lamivudine. SPRING-1 researchers randomized 205 antiretroviral-naive people with a viral load above 1000 copies and a CD4 count above 200 to 10, 25, or 50 mg of dolutegravir once daily or to efavirenz. Dolutegravir's developer has selected 50 mg as the dose for phase 3 trials enrolling integrase inhibitor-naive people.
The study group had a median age of 37 years (range 20 to 79), 86% were men, and 80% were white. Pretreatment viral load averaged 4.46 log (about 30,000 copies), and 21% had a viral load above 100,000 copies. The starting CD4 count averaged 324, and 63% had a CD4 count under 350.
A time-to-loss-of-virologic-response analysis determined that viral loads fell faster with all doses of dolutegravir than with efavirenz, though at week 48 response rates in the dolutegravir groups only modestly exceeded those in the efavirenz group:
10 mg dolutegravir once daily (53 people)
Week 16: 96% below 50 copies
Week 24: 96% below 50 copies
Week 48: 91% below 50 copies
25 mg dolutegravir once daily (51 people)
Week 16: 90% below 50 copies
Week 24: 90% below 50 copies
Week 48: 88% below 50 copies
50 mg dolutegravir once daily (51 people)
Week 16: 92% below 50 copies
Week 24: 92% below 50 copies
Week 48: 90% below 50 copies
Efavirenz (50 people)
Week 16: 58% below 50 copies
Week 24: 82% below 50 copies
Week 48: 82% below 50 copies
Fast virologic suppression is a trait dolutegravir shares with raltegravir, the only licensed integrase inhibitor. An assay that can detect a few as 2 HIV RNA copies/mL determined that 53% taking 50 mg of dolutegravir and 60% taking efavirenz had fewer than 2 copies at week 48.
Three people taking dolutegravir had protocol-defined virologic failure, but no integrase mutations arose in these people. No one taking the 50-mg dose had a confirmed viral load above 400 copies in the first 48 weeks.
Median CD4 counts rose more in the combined dolutegravir arms than in the efavirenz group (231 versus 174) through 48 weeks, but this difference stopped short of statistical significance (P = 0.076).
Four people quit in the efavirenz arm because of adverse events (8%), compared with 2 people (1%) randomized to dolutegravir. Ten people taking efavirenz (20%) had a grade 2 to 4 drug-related adverse event, compared with 13 (8%) in the three dolutegravir groups. Serious adverse events arose in 4 people taking efavirenz (8%) and 8 (5%) taking dolutegravir.
Gastrointestinal problems were the most frequently reported complaint (by 2% taking dolutegravir and 4% taking efavirenz), followed by metabolic events (3% dolutegravir, 0% efavirenz), psychiatric problems (0% dolutegravir, 6% efavirenz), and rash (0% dolutegravir, 4% efavirenz). Study clinicians did not consider any serious adverse events to be related to dolutegravir. There was no dose-response relationship with adverse events in the dolutegravir arm.
Grade 3 to 4 lab abnormalities arose in 14% taking efavirenz and 12% taking dolutegravir. "Bad" low-density lipoprotein cholesterol rose an average 0.55 mg/dL in the dolutegravir groups versus 15.88 mg/dL in the efavirenz group. No study participant had a grade 3 or 4 alanine aminotransferase elevation.
In vitro and clinical data indicate that dolutegravir inhibits the renal transporter responsible for tubular secretion of creatinine. But creatinine changes in this trial were small (+0.1 to +0.15 mg/dL), even though two thirds of study participants were also taking tenofovir. Dolutegravir had no impact on glomerular filtration rate as measured by iohexol clearance, but estimated glomerular filtration rate was not calculated.
Dolutegravir is also being studied for antiretroviral-experienced people [2].
References
1. Van Lunzen J, Maggiolo F, Phung B, et al. Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-na•ve adults: 48 week results from SPRING-1 (ING112276). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract TUAB0102.
2. Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 151LB. http://www.natap.org/2011/CROI/croi_33.htm.
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