Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children

Background Having 90% of patients on antiretroviral therapy (ART) and achieving an undetectable viral load (VL) is one of the 90:90:90 by 2020 targets. In this global analysis, we investigated the proportions of adult and paediatric patients with VL suppression in the first three years after ART initiation. Methods Patients from the IeDEA cohorts who initiated ART between 2010 and 2014 were included. Proportions with VL suppression (<1000 copies/mL) were estimated using: (i) strict intention-to-treat (ITT) – loss to follow-up (LTFU) and dead patients counted as having detectable VL; and (ii) modified ITT – LTFU and dead patients were excluded. Logistic regression was used to identify predictors of viral suppression at one year after ART initiation using modified ITT. Results A total of 35561 adults from 38 sites/16 countries and 2601 children from 18 sites/6 countries were included. When comparing strict with modified ITT methods, the proportion achieving VL suppression at three years from ART initiation changed from 45.1% to 90.2% in adults, and 60.6% to 80.4% in children. In adults, older age, higher CD4 count pre-ART, and homosexual/bisexual HIV exposure were associated VL suppression. In children, older age and higher CD4 percentage pre-ART showed significant associations with VL suppression. Conclusions Large increases in the proportion of VL suppression in adults were observed when we excluded those who were LTFU or had died. The increases were less pronounced in children. Greater emphasis should be made to minimise LTFU and maximise patient retention in HIV-infected patients of all age groups.

To evaluate the effect of pH-altering agents on S/GSK1349572 exposure in healthy subjects. S/GSK1349572 is an unboosted, once-daily, next-generation HIV integrase inhibitor. In the first study, 16 subjects received four single-dose treatments: (i) S/GSK1349572 50 mg; (ii) S/GSK1349572 50 mg with a multivitamin (MVI; One A Day Maximum); (iii) S/GSK1349572 50 mg with a liquid antacid (Maalox Advanced Maximum Strength); and (iv) S/GSK1349572 50 mg 2 h before an antacid. In the second study, 12 subjects received a single dose of S/GSK1349572 alone and on day 5 of omeprazole. All treatments were well tolerated. MVI co-administration modestly decreased S/GSK1349572 AUC by 33%. Concurrent antacid co-administration reduced S/GSK1349572 AUC by 74% and staggered antacid dosing significantly diminished this interaction, with a reduction in S/GSK1349572 AUC of 26%. Omeprazole did not significantly affect S/GSK1349572 exposure. S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir’s antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir’s prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic.