Bictegravir at CROI 2018: Switching Studies and Drug Resistance Analyses
Bictegravir at CROI 2018: Switching Studies and Drug Resistance Analyses
March 7, 2018
As the most recently approved integrase inhibitor (February 2018 in the US, still pending in the EU) reports about bictegravir were included both in an oral presentation and in several posters. Bictegravir is only available in a fixed dose combination (FDC) with F/TAF.
Switching to Bictegravir/F/TAF From Dolutegravir Plus 3TC/ABC
Jean Michel Molina from St. Louis Hospital, Paris presented results from a double-blind, placebo-controlled phase 3 study that randomised 563 participants on stable dolutegravir (DTG)-based ART to either switch to B/F/TAF or the DTG/3TC/abacavir FDC.
The primary endpoint was viral load suppression <50 copies/mL at 48 weeks, with non-inferiority defined using 4% margin for 95%CI 4%.
Baseline demographics included 88% men and 73% white, with median CD4 count of approximately 700 cells/mm3 and eGFR 101 mL/min (IQR: 84 to 122).
Results are relatively easy to report, with high efficacy and safety in both arms and few significant differences.
At week 48, viral load was <50 copies/mL in 93.6% vs 95.0% (p=0.59) in the bictegravir vs dolutegravir arms, with 1.1% vs 0.4% (p=0.62) having detectable viral load. This showed a marginal, non-significant numerical difference in favour of the dolutegravir arm of 0.7% (95%CI: -1.0 to +2.8), but still meeting the criteria for non-inferiority for bictegravir.
There were few serious side effects, with 2% (n=6) vs 1% (n=2) stopping treatment in the bictegravir vs dolutegravir groups, respectively. Two deaths were both in the bictegravir group, but not related to study drugs. The only CSF-related events were in the bictegravir arm: one report of suicidal ideation (also not judged related) and one report of abnormal dreams.
Side effects of any grade were reported by about 80% of each group, mainly mild, with the most common reports being equally balanced: upper respiratory tract (10% vs 10%), nasopharyngitis (7 vs 8%), headache (7% vs &%), diarrhoea (9% vs 5%), all bictegravir vs dolutegravir respectively. Of these, side effects assigned as relating to study medication did favour the bictegravir arm (8% vs 16%, p=0.01).
Laboratory abnormalities were mild and overall were reported more often with bictegravir (17% vs 11%). These were mainly higher LDL (5% each arm), increased ALT or amylase (both 2% vs 0) and CK (2% each). There were no drug-related grade 3/4 lab changes.
The bictegravir arm also had a small early increase in eGFR by week 4 that was sustained to week 48 (+1.0 vs -1.8 mL/min) that was statistically significant (p<0.001). This was reported as being linked to greater inhibition of tubular secretion of creatinine with dolutegravir. There were no significant differences in measure of quantitative proteinuria at week 48, showing high level of renal safety in both groups, and no significant changes in bone density (measured at the hip and spine) or for lipids.
Switching to Bictegravir/F/TAF in Women and Adolescents on Stable ART
A greater amount of data on women switching to B/F/TAF was presented as a poster from a randomised phase 3 switching study conducted in Uganda, Russia, Thailand, USA and Dominican Republic.. This study randomised 470 women 1:1 to either remain on current ART, largely elvitegravir-based (E/C/F/TAF n=125; E/C/F/TDF n=98; atazanavir/r+FTC/TDF n=13); or change to B/F/TAF.
Demographics included greater ethnic diversity (37% black, 28% white, 21% Asian). As with the study above, CD4 count and eGFR were high (approximate median >700 cells/mm3 and 100 mL/min respectively).
At week 48, viral load remained undetectable (<50 copies/mL) in 96% vs 95% in the B/F/TAF group vs. control arm group, with no significant difference in rate of viral failure (0.1, 95% CI -2.9 to +2.99), meeting criteria for non-inferiority.
Results on switching to B/F/TAF in adolescents on stable ART (viral load <50 copies/mL for > 6 months) were presented from a small prospective single arm study.3
Baseline demographics for the 24 participants included median age 15 years (range 12-17), median weight 48.9 kg (range 36.1 to 88.6 kg), 79% women, 52% black and median CD4 count 708 cells/mm3.
Drug levels for all three components were similar to those achieved in adult studies, with pharmacokinetic parameters generally falling within the expected acceptable geometric mean.
The most common treatment emergent side effect was upper respiratory tract infection (21%, 5 of 24) but side effects reported in more than two participants were mild-moderate and not related to study drug, and no related discontinuations. The only grade 3/4 laboratory abnormality was haematuria in four young women, coinciding with menses in 3/4 cases.
However, median changes in eGFR ranged from -8.0 to -14.0 mL/min/1.73 m2 between week 2 and 24, but this was not considered clinically significant.
High rates of acceptance of the pill size was reported with high adherence (88% taking >95% of medication over 24 weeks. The poster also showed the smaller physical size of the bictegravir FTC, being smaller than both E/C/F/TAF and DTG/3TC/ABC.
Drug Resistance With Bictegravir
Two posters at CROI 2018 presented results of resistance analyses, in the few people with viral failure at week 48 in bictegravir development studies.
The first poster reported on combined efficacy and resistance result from two phase 3 treatment-naive studies (n=634 on B/F/TAF, n= 325 on DTG + F/TAF and n=315 DTG/ABC/3TC). Entry criteria included baseline screening for drug resistance, although not for integrase resistance. This poster also provided a breakdown for the 10% of participants who had non-B HIV sub-type.4
In the small numbers of people with viral failure at week 48 (n=17, all sub-type B), there were no cases of development of new drug resistance associated with any of the study drugs. One participant who was later found to have INSTI resistance at baseline (G140S+Q148H) that was phenotypically sensitive to bictegravir and partially sensitive to dolutegravir. This person had undetectable viral load < 50 copies/mL at week 4 and that was maintained through week 72 on B/F/TAF.
The second analysis was from two randomised, placebo-controlled switch studies in participants on stable ART (n=572 on B/F/TAF, n=281 on DTG/ABC/3TC and n=287 on elvitegravir-based STR or PI = 2NRTIs).
There was no detectable new resistance the 1.4% (8/572) of B/F/TAF treated patients experienced viral failure at week 48. This included 40 participants who started with archived NRTI mutations at baseline associated with resistance to FTC or TAF. Of these, 97% (35/36) on B/F/TAF maintained undetectable viral load at week 48: 100% (5/5) with K65R/N, 100% (8/8) with only M184V/I/T (18/18), 92% with M184V and other NRTI-R (12/13), and 100% with ≥2 TAMs (4/4).
There were no cases of new resistance developing in either the bictegravir or dolutegravir groups.5
Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections (CROI 2018), 4-7 March 2018, Boston.
[Note from TheBodyPRO: This article was originally published by HIV i-Base on March 7, 2018. We have cross-posted it with their permission.]
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