ASM Microbe 2016: New Integrase Inhibitor Bictegravir Looks Promising in Early Studies


Gilead Sciences' novel integrase inhibitor bictegravir (formerly GS-9883) demonstrated favorable pharmacokinetics, good tolerability, an improved resistance profile compared to older drugs in its class, and potent antiviral activity in laboratory and human studies, according to a set of posters presented at ASM Microbe 2016 last month in Boston.

Integrase strand transfer inhibitors (INSTIs) are an effective and well-tolerated class of antiretroviral drugs, and currently are included in most recommended regimens in U.S. and European HIV treatment guidelines. However, the first drug in this class, Merck's raltegravir (Isentress), is taken twice-daily, as is ViiV's newer dolutegravir (Tivicay, also in the Triumeq coformulation) if a patient has pre-existing integrase resistance or is taking potentially interacting drugs. Gilead's earlier elvitegravir (Vitekta, also in the Stribild and Genvoya coformulations) must be boosted with cobicistat or ritonavir.

Scott Lazerwith and colleagues from Gilead synthesized and tested several new integrase inhibitor candidates to look for agents with higher potency. They identified bictegravir, a compound with a larger molecular structure known as the "A-ring" and a novel configuration of the "D-ring," providing better binding to the HIV integrase enzyme and good metabolic stability.

Bictegravir was found to have potent activity against wild-type (non-mutated) HIV in laboratory studies and improved potency against virus resistant to older integrase inhibitors. It showed improved pharmacokinetics in rats and dogs, and had a half-life of about 19 hours in humans, allowing for once-daily dosing.

Gregg Jones and colleagues further examined the in vitro resistance profile of bictegravir, again showing potent activity against wild-type virus and mutants resistant to nucleoside/nucleotide reverse transcriptase inhibitors, NNRTIs, and protease inhibitors.

Bictegravir had a "markedly improved" resistance profile compared to raltegravir and elvitegravir, and was more potent than dolutegravir against HIV isolates from patients with high-level INSTI resistance. Both bictegravir and dolutegravir had a higher barrier to emergence of resistance than elvitegravir. Mutations selected by bictegravir showed low-level cross-resistance to raltegravir or dolutegravir, and intermediate cross-resistance to elvitegravir.

"Bictegravir exhibits an unsurpassed resistance profile that supports its further clinical development for the first-line treatment of HIV infection," the researchers concluded. "In addition, bictegravir may be suitable for the once-daily treatment of HIV-infected patients with pre-existing INSTI resistance."

Manuel Tsiang and colleagues, also from Gilead, further analyzed the in vitro antiviral activity of bictegravir alone and in combination with tenofovir alafenamide (a component of coformulations including Genvoya), emtricitabine (Emtriva), and darunavir (Prezista).

They found that bictegravir alone was highly potent against a diverse range of wild-type HIV-1 clinical isolates as well as HIV-2, and it demonstrated synergistic activity when combined with the other antiretrovirals, with minimal toxicity in human laboratory cell lines, CD4 T-cells, and macrophages. Bictegravir specifically inhibited HIV, with no measurable activity against hepatitis B or C or other viruses.

Finally, Joel Gallant from the Southwest Care Center in Santa Fe and colleagues conducted an early clinical trial testing bictegravir monotherapy for 10 days in people with HIV (NCT02275065).

This Phase 1 study included 20 adults with chronic HIV infection. Participants were either antiretroviral treatment-naive, or treatment-experienced but had not previously used integrase inhibitors and were off all antiretrovirals for at least 12 weeks. All but 1 were men, most were white, and the mean age was 35 years. At baseline they had a mean CD4 count of approximately 440 cells/mm3 and a mean HIV RNA level of 4.4 log copies/mL.

Participants were randomly assigned to receive bictegravir at doses of 5, 25, 50, or 100 mg, or placebo, once-daily on an empty stomach for 10 days. Drug resistance testing was done at baseline and the day after the final dose.


"Bictegravir 10 day monotherapy led to rapid declines in HIV-1 RNA from baseline that were sustained through the treatment period with no viral breakthrough," the investigators concluded.

Based on these findings, the 50 mg dose of bictegravir was selected for further clinical development in a coformulation with TAF and emtricitabine as a single-tablet regimen for HIV treatment.



S Lazerwith, R Cai, X Chen, et al. Discovery of GS-9883, an HIV-1 Integrase Strand Transfer Inhibitor (INSTI) with Improved Pharmacokinetics and In Vitro Resistance Profile. ASM Microbe. June 16-20, 2016. Abstract Sunday-414. View abstract.

G Jones, J Goldsmith. A Mulato, et al. GS-9883, a Novel HIV-1 Integrase Strand Transfer Inhibitor (INSTI) with Optimized In Vitro Resistance Profile.ASM Microbe. June 16-20, 2016. Abstract Sunday-413. View abstract.

M Tsiang, E Kan, L Tsai, et al. Antiviral Activity of GS-9883, a Potent Next Generation HIV-1 Integrase Strand Transfer Inhibitor. ASM Microbe. June 16-20, 2016. Abstract PW-031/Sunday 416. View abstract.

J Gallant, M Thompson, T Mills, et al. Novel INSTI GS-9883 10 Day Monotherapy in HIV-1 Infected Subjects. ASM Microbe. June 16-20, 2016. Abstract PW-030/Sunday-415. View abstract.

Other Source

Gilead Sciences. Gilead Presents Preliminary Data on Bictegravir, an Investigational Integrase Strand Transfer Inhibitor for the Treatment of HIV. Press release. June 20, 2016.