DTG remains active against those with single mutations, but accumulation of resistance mutations in the Q148 pathway can compromise

DTG activity. Those with serial genotypic tests (n = 224) and wild-type virus at baseline (n = 22) accumulated INSTI mutations on average by 224 days, with equal distribution of the three major pathways. Overall, high-level DTG resistance was predicted in 12% of patients with RAL- or EVG-resistant virus (Q148 + ≥2 additional integrase mutations; the majority with Q148 + G140 + E138). Thus, those failing treatment Tanespimycin cost regimens containing first-generation INSTI should be changed early to preserve selleck chemicals the second-generation INSTI with high barrier to resistance. Clinical Trials of Dolutegravir CH5183284 in vitro (Table 2) Clinical trials

of DTG have been conducted in both treatment-naïve and treatment-experienced patients. Most clinical trials are statistically powered for non-inferiority to demonstrate that the new treatment is no less effective than standard therapy. In certain circumstances, superiority may be demonstrated. Clinical equivalence (Δ) is the largest difference that is clinically acceptable such that a larger difference would alter clinical practice [26]. In a non-inferiority trial, clinical equivalence should be clearly defined such that non-inferiority is demonstrated when the 95% confidence interval (CI) falls entirely to the right of the lower limit (−Δ). If the 95% CI of the tested treatment effect lies both above the lower limit of the pre-specified difference (−Δ) and above zero, the trial was properly designed and carried out in accordance with requirements of a non-inferiority trial, and the two-sided P value for superiority is presented according to the intention

to treat (ITT) principle remains significant (P < 0.05), then superiority may also be claimed [26]. Trials Morin Hydrate Among ART-Naïve Participants SPRING-1 (NCT00951015) is a dose-finding study comparing the increasing daily doses of DTG 10, 25, or 50 mg to efavirenz 600 mg with a dual-NRTI background regimen (FTC/TDF or abacavir (ABC)/lamivudine (3TC) in a randomized, open-label (dose-masked) trial [27]. Participants and investigators were not blinded to the study drug, but were blind to the DTG dose. Across the dosing spectrum of DTG, the rate of viral decay was robust and 50 mg daily dosing of DTG remained efficacious and well tolerated to 48 and 96 weeks [27, 28]. No treatment-emergent mutations were detected [28]. Creatinine clearance rose in week 1, gradually returning to baseline by week 48. Lipid profile was more favorable than with EFV with little to no increase from baseline [27, 28]. SPRING-2 (NCT01227824) followed as the first trial to compare the efficacy of two INSTI’s head to head: 400-mg twice-daily RAL versus 50-mg once-daily DTG in ART-naïve patients [29].