Pharmacokinetics and full phase 2 results for bictegravir, a new integrase inhibitor
Simon Collins, HIV i-Base
Two oral presentations on a new integrase inhibitor bictegravir were included in the first session at CROI 2017 looking at new treatment and treatment strategies.
Bictegravir (formerly GS-9883) is a once-daily integrase inhibitor (INI) that has in vitro activity against many INI-resistant viruses and a plasma half-life of 18 hours.
Bictegravir has high protein binding (99%) limiting likely penetration to sanctuary sites but does not require boosting or need to be taken with food.
Clinical results were presented by Paul Sax from Brigham and Women’s Hospital in Boston from a phase 2 in treatment naive participants, with dolutegravir as the comparator. 
This was a randomised double-blind, placebo controlled, 48-week study. The study randomised 98 treatment naive participants 2:1 to either bictegravir 75 mg (n=75) or dolutegravir 50 mg (n=33), both taken once daily with FTC/TAF as background NRTIs. This was a non-inferiority study with the primary endpoint of viral suppression at week 24 and secondary efficacy and safety endpoints at week 48.
Baseline characteristics were similar in each arm and included >90% male, 55% white, median age 30 to 36 years (range 19 to 68). In the bictegravir vs dolutegravir arms, median viral load was 4.41 vs 4.48 log, with 15 vs 21 people >100,000 copies/mL and median CD4 count was 441 vs 455 cells/mm3, with 5 vs 9 participants with CD4 <200 cells/mm3.
At week 24, viral suppression to <50 copies/mL by snapshot analysis was achieved by 97% vs 94% in the bictegravir vs dolutegravir groups respectively (difference +2.9; 95%CI: –8.5% to +14.2%, p=0.50). For the secondary endpoint at week 48, these rates were 97% vs 91% (difference: +6.4; 95%CI: –6.0% to 18.8%, p=0.17), with no statistical difference between groups. Two patients discontinued from each arm, one in each was lost to follow up, with one due to side effects in the bictegravir arm and one due to adherence in dolutegravir arm. No patients discontinued to lack of viral efficacy and only one person in each arm discontinuing for other reasons while viral load was above 50 copies/mL.
CD4 increases were similar in each arm: +258 vs +192 cells/mm3, p=0.16.
Tolerability in both groups was also good with no discontinuations due to treatment-related side effects or deaths – and no significant other differences between groups – though the study number were small.
The most common side events were diarrhoea (12% in each group) and nausea (8% vs 12%). One participant in the bictegravir group discontinued due to urticaria (hives) after week 24. Grade 2 to 4 lab abnormalities including creatinine kinase, AST, hyperglycemia, ALT, LDL, amylase, haematuria, and gylcosuria occurred in 2% to 13% of participants by were generally similar in each group. Small reductions in eGFR (reported with integrase inhibitors) were also similar.
A second oral presentation on bictegravir, by Joseph Custodio from Gilead Sciences, provided pharmcokinetics on this new compound from single (5 mg to 600 mg) and multiple dose (5 mg to 300 mg over 14 days) evaluations for potential drug interactions in HIV negative volunteers. 
Potency of the compound is impressive, with mean plasma concentration more than 20 x above the IC95 at 24 hours and low intrapatient differences.
Bictegravir exposure was dose proportional for doses from 25 mg to 100 mg. Elimination was approximately 60% ± 5.5% from faeces and 35% ± 5.0% from urine with glucuronidation and oxidation contributing to the major clearance pathways.
The drug interaction study showed increased bictegravir AUC (61-74%) by CYP3A4 inhibitors (voriconazole and darunavir/c), with a greater increase (~4-fold) by potent dual inhibitors of UGT1A1 and CYP3A4 (atazanavir and atazanavir/c).
Bictegravir AUC was reduced by 75% by rifampin, a potent CYP3A4/UGT1A1/P-gp inducer and by 38% with rifabutin.
These early results show the potential for bictegravir to be an important new drug and phase 3 studies are already underway using a fixed dose combination coformulated with FTC/TAF.
This FDC uses an improved formulation of bictegravir that only requires a 50 mg dose. Although food increased bictegravir levels of the single formulation by >80%, in the FDC combination this is reduced to a 20% increase. Although both formulations could be taken with or without food, bictegravir will only be marketed as a component of an FDC.
The full results of the phase 2 study are also published online in the Lancet HIV. 
- Sax PE et al. Randomized trial of bictegravir or dolutegravir with FTC/TAF for initial HIV therapy. CROI 2017, 13-16 February 2017, Seattle. Oral abstract 41.
- Zhang H et al. Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. CROI 2017, 13-16 February 2017, Seattle. Oral abstract 40.
- Sax P et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial. The Lancet HIV (14 February 2017). DOI: http://dx.doi.org/10.1016/S2352-3018(17)30016-4