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CROI 2017: Integrase Inhibitor Bictegravir Matches Dolutegravir for First-Line HIV Treatment


Bictegravir, an investigational integrase inhibitor from Gilead Sciences, was highly potent, well tolerated and worked as well as dolutegravir (Tivcay) in a Phase 2 clinical trial, according to study results presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle and published online 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 U.S. and European 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.

As previously reported, bictegravir demonstrated high potency against wild-type and resistant strains of HIV, favorable pharmacokinetics, and an improved resistance profile compared to older integrase inhibitors. In a 10-day monotherapy study, it rapidly reduced viral load by more than 2 login people with HIV.

At CROI Joseph Custodio from Gilead reported that bictegravir was safe and well-tolerated at doses ranging from 5 mg 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 metabolized equally bythe 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 2 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 infectionwith a median CD4 T-cell count of approximately 450 cells/mm3 and a median viral load of about 4.4 log copies/mL at baseline. They had normal kidney function and people with hepatitis B or C coinfection were excluded.

Participants in this double-blind study were randomly assigned (2:1) to receive 75 mg bictegravir or 50 mg dolutegravir, each with matching placebos. Both drugs were combined with 25 mg tenofovir alafenamide (TAF) and 200 mg 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 24 weeks.


  • Both treatments were highly effective.
  • 97% of participants in the bictegravir arm and 94% in the dolutegravir arm achieved viral suppression at 24 weeks.
  • 97% and 91%, respectively, had undetectable HIV RNA at 48 weeks.
  • Given the small number of patients, these differences were not statistically significant and this study was not powered to determine full non-inferiority.
  • 1 person in the bictegravir arm and 2 in the dolutegravir armhad HIV RNA >50 copies/mL, but no significant resistance was detected in either arm.
  • CD4 cell gains were 258 cells/mm3 in the bictegravir arm compared 192 cells/mm3 in the dolutegravir arm, not a 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 diarrhea (12% in each arm) and nausea (8% with bictegravir and 12% with dolutegravir).
  • 1 bictegravir recipient with a previous history of allergic dermatitis stopped treatment early due to hives after 24 weeks.
  • Estimated glomerular filtration rate declined by -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.

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. Custodio noted that optimising the formulation allowed for a lower 50 mg bictegravir dose in the coformulation.

Sax said that 4 Phase 3 studies are now fully enrolled; 2 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 a coformulation of dolutegravir, abacavir, and lamivudine (Triumeq).

"The high virologic response rates seen in this study show that the pairing of bictegravir with [TAF/emtricitabine] could potentially offer patients and physicians a new HIV treatment option with pre-clinical data supporting few drug interactions and a high barrier to resistance," Sax said in a Gilead press release.



H Zhang, JM Custodio, X Wei, et al. Clinical Pharmacology of the HIV Integrase Strand Transfer Inhibitor Bictegravir. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 40.

P Sax, E DeJesus, G Crofoot, et al. Randomized Trial of Bictegravir or Dolutegravir with FTC/TAF for initial HIV therapy. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 41.

PE Sax, E DeJesus, G Crofoot, 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).

Gilead Sciences. Gilead Presents New Phase 2 Data on Bictegravir, an Investigational Integrase Strand Transfer Inhibitor for the Treatment of HIV. Press release. February 13, 2017.