Bictegravir – A new Integrase Inhibitor in the pipeline

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Bictegravir matches dolutegravir for first-line treatment in Phase 2 studies

March Newsletter 2

Paul Sax at CROI 2017. Photo by Liz Highleyman,

Bictegravir, an investigational new integrase inhibitor, was highly potent, well tolerated and worked as well as dolutegravir (Tivicay – an existing integrase inhibitor) in a phase 2 clinical trial of people first starting treatment, according to study results presented at the CROI 2017 in Seattle and published in The Lancet HIV.

Due to their high potency and good tolerability, integrase strand transfer inhibitors (INSTIs) are an increasingly important part of initial antiretroviral therapy and are included in most recommended regimens for first-line treatment in European, US, and Australian 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 with cobicistat. Comparing bictegravir to dolutegravir is ideal as dolutegravir also does not require boosting with cobicistat and is currently a recommended first-line treatment (as a component of Triumeq or as Tivicay).

At CROI Joseph Custodio (of Gilead – the manufacturers of the drug) reported that bictegravir was safe and well tolerated at doses ranging from 5mg to 600mg in healthy volunteers. Bictegravir inhibits renal tubule transporters (a part of the kidneys), which lowers creatinine levels (a measurement of kidney function) and leads to a decline in estimated glomerular filtration rate (another measure of kidney function), but it does not cause actual kidney function impairment, he explained.

Custodio also said bictegravir has low potential to be either a ‘victim’ or ‘perpetrator’ of drug-drug interactions. The drug has a long half-life (a measurement of how long it remains in the blood before dropping below 50%) of approximately 18 hours, indicating it is suitable for once-daily dosing.

In the Phase 2 study comparing bictegravir to dolutegravir – conducted by Paul Sax and colleagues of Brigham and Women’s Hospital in Boston – there were 98 previously untreated adults. Almost all were men, more than half were white and the median age was about 32 years. They generally had no symptoms of HIV with a median CD4 T-cell count of approximately 450 and a median viral load of about 4.4 log10 copies (about 25,000 viral load) 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 viral load below 50 copies at 24 weeks.

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 non-inferiority.

CD4 counts rose rapidly, as is typical with integrase inhibitors. The mean CD4 cell gain was 258 cells in the bictegravir arm and 192 cells in the dolutegravir arm, not a statistically significant difference.

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).

Bictegravir and 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 (FTC). 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 (3TC). These studies are needed before bictegravir may become available for use (registered) and compete with dolutegravir (the first registered unboosted integrase inhibitor).


Zhang H et al. (Custodio J presenting) Clinical pharmacology of the HIV integrase strand transfer 
inhibitor bictegravir. Conference on Retroviruses and Opportunistic Infections (CROI 2017), 
Seattle, abstract 40, 2017.

View the abstract on the conference website.

View a webcast of this presentation on the conference website.

Sax P et al. Randomized trial of bictegravir or dolutegravir with FTC/TAF for initial HIV therapy. 
Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 41, 2017.

View the abstract on the conference website.

View a webcast of this presentation on the conference website.

Sax PE 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. February 14, 2017 (online ahead of print). Read the full text.

Source: Adapted from article by Liz Highleyman, produced in collaboration with 
Published: 14 February 2017.