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New Studies of Dolutegravir at ICAAC 2013.

The newest addition to the antiretroviral (ARV) armamentarium is dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI). It shares with the other members of this therapeutic class a favorable safety and tolerability profile, potency, and rapid suppression of HIV replication. It also has the advantages of once-daily dosing without a pharmacokinetic enhancer and a higher genetic barrier to resistance. At ICAAC 2103, Feinberg et al reported the 48 week results of the FLAMINGO trial [1], a randomized, open-label comparison of DTG 50 mg daily and ritonavir-boosted darunavir (DRV/r) 800/100 mg daily. To complete the regimen, investigators chose tenofovir/emtricitabine in 67% of patients. The rest received abacavir/lamivudine. The study included 242 treatment-naive patients in each arm. Using the FDA snapshot analysis, 90% in the DTG arm and 83% in the DRV/r arm had an HIV RNA <50 copies/mL, which established statistical non-inferiority between regimens and also the statistical superiority of DTG (p=0.025). Virologic failure and discontinuations for adverse events accounted for only slightly more than half of the difference in treatment success between arms. There was a disproportionate number discontinuations for other reasons in the DRV/r arm. DTG appeared to outperform DRV/r in those with baseline viral load >100,000, although the difference was not due to virologic failure. Choice of NRTI backbone did not affect the response rate. CD4 lymphocyte counts increased 210/mm3 in both arms. Diarrhea was somewhat more common with DRV/r. Grade 3/4 laboratory abnormalities did not differ between groups. Small increases in creatinine were seen in the DTG groups due to inhibition of creatinine secretion. The mean increase from baseline in LDL was significantly less with DTG (3.1 vs. 14.1 mg/dL, p<0.001). Only 2 patients with viral failure in each arm qualified for resistance testing. No relevant resistance mutations were found. This study provides support for DTG-based ART as a good choice for first line therapy. The finding of superiority, however, is not compelling because this was an open-label study, there was an excess of discontinuations for reasons other than efficacy or safety in the DRV/r and the magnitude of the difference was small (7% with the lower bound of the 95% CI below 1%).

Another presentation examined DTG’s efficacy in demographic subsets of participants in two previously published trials [2]. The SAILING study was a randomized, double-blind comparison of DTG and raltegravir (RAL) in treatment-experienced, INSTI-naive subjects, while VIKING-3 was a single arm open-label study of high dose DTG (50 mg twice daily) in INSTI-experienced patients. Both studies employed optimized background ARVs. In SAILING, the overall superiority of the DTG arm was found to be preserved when analyzed by race and gender, but DTG did not appear to be superior to RAL in patients 50 years of age or older. In the VIKING study, responses to DTG-based ART appeared to be equivalent when analyzed by race, gender and age above and below 50. This analysis should help clinician feel confident that the benefits of DTG-based treatment accrue similarly to a variety of patient groups.

1. Feinberg J, Clotet B, Khuong M-A, et al. Once-Daily Dolutegravir (DTG) is Superior to Darunavir/Ritonavir (DRV/r) in Antiretroviral‑Naive Adults: 48 Week Results from FLAMINGO (ING114915). 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1464a.
2. Hagins D, Lazzarin DA, Kumar P, et al. Dolutegravir in Key Demographic Subgroups of Treatment-Experienced HIV-infected Populations. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1460

Source: Reporting from Denver for the PRN News: David H Shepp, MD