Bictegravir, an investigational integrase inhibitor from
Gilead Sciences, was highly potent, well tolerated and worked as well as
dolutegravir (Tivicay) in a phase 2 clinical
trial, according to study results presented on Tuesday at the 2017 Conference on
Retroviruses and Opportunistic Infections (CROI) in Seattle and published in The Lancet HIV.
Due to their high potency and good tolerability,
integrase strand transfer inhibitors are an increasingly important part of
initial antiretroviral therapy and are included in most recommended regimens
for first-line treatment in European and US HIV treatment guidelines.
Bictegravir (formerly GS-9883) is an investigational
integrase inhibitor that can be taken once daily and does not require a booster – unlike Gilead's older integrase inhibitor elvitegravir, which must be boosted
As previously reported, bictegravir demonstrated high potency against
wild-type and resistant strains of HIV, favourable pharmacokinetics and an
improved resistance profile compared to older integrase inhibitors. In a 10-day
monotherapy study it reduced viral load by more than 2 log10 in people
At CROI Joseph Custodio of Gilead reported that bictegravir
was safe and well tolerated at doses ranging from 5mg to 600mg in healthy
volunteers. Bictegravir inhibits renal tubule transporters, which lowers
creatinine levels and leads to a decline in estimated glomerular filtration
rate, but it does not cause actual kidney function impairment, he explained.
Bictegravir is metabolised equally by the CYP3A4 and UGT1A1
pathways. Custodio said it has low potential to be either a 'victim' or
'perpetrator' of drug-drug interactions. Bictegravir levels rose by more than
300% when administered with both CYP3A4 and UGT1A1 inhibitors, and fell by up
to 75% when given with both CYP3A4 and UGT1A1 inducers. The drug had a
half-life of approximately 18 hours, indicating it is suitable for once-daily
dosing. Bictegravir had no effect on a common
oral contraceptive or ledipasvir/sofosbuvir (Harvoni) for hepatitis C, and administering it two hours before or
after minimises interactions with antacids.
Paul Sax of Brigham and Women's Hospital in Boston and
colleagues conducted a phase 2 placebo-controlled clinical trial comparing
bictegravir to dolutegravir for initial HIV therapy.
The study included 98 previously untreated adults.
Almost all were men, more than half were white and the median age was about 32
years. They generally had asymptomatic HIV infection with a median CD4
T-cell count of approximately 450 cells/mm3 and a median viral load of
about 4.4 log10 copies/ml at baseline. They had normal kidney
function and people with hepatitis B or C co-infection were excluded.
Participants in this double-blind study were randomly
assigned (2:1) to receive 75mg bictegravir or 50mg dolutegravir, each with
matching placebos. Both drugs were combined with 25mg tenofovir alafenamide (TAF)
and 200mg emtricitabine, taken once daily with or without food for 48 weeks. The
primary endpoint was the proportion of people with HIV RNA below 50 copies/ml at
Both treatments were highly effective, with 97% of
participants in the bictegravir arm achieving viral suppression at both 24 and
48 weeks, compared to 94% at 24 weeks and 91% at 48 weeks in the dolutegravir
arm. Dr Sax noted that given the small numbers, these differences were not
statistically significant and this study was not powered to determine full
One person in the bictegravir arm and two in the
dolutegravir arm had HIV RNA above 50 copies/ml at 48 weeks and had their virus sequenced for drug resistance. No significant resistance
was detected in either arm.
CD4 counts rose rapidly, as is typical with integrase
inhibitors. The mean CD4 cell gain was 258 cells/mm3 in the
bictegravir arm and 192 cells/mm3 in the dolutegravir arm, not a statistically
Both regimens were generally
safe and well tolerated, with no treatment-related serious adverse events and
no deaths. The most frequent adverse events were diarrhoea (12% in each arm) and
nausea (8% with bictegravir and 12% with dolutegravir). One bictegravir
recipient with a previous history of allergic dermatitis stopped treatment
early due to hives after 24 weeks.
filtration rate declines were -7.0 ml/min in the bictegravir arm and -11.3
ml/min in the dolutegravir arm at week 48, but there were no discontinuations
due to kidney-related adverse events and no cases of tubulopathy, according to
dolutegravir taken with TAF and emtricitabine "both demonstrated high
virologic response rates at week 24 that were maintained at week 48," the
researchers concluded. "Both treatments were well tolerated, and no
significant safety signal was detected in either arm."
These results were
promising enough to proceed with phase 3 trials using a single-tablet regimen
of bictegravir, TAF and emtricitabine. Dr Custodio noted that optimising the
formulation allowed for a lower 50mg bictegravir dose in the co-formulation.
Dr Sax said that four phase
3 studies are now fully enrolled. Two of these are similar to the current study
but will use the bictegravir single-tablet regimen rather than separate pills.
Another is comparing the bictegravir single-tablet regimen against the Triumeq
co-formulation of dolutegravir, abacavir and lamivudine.