A new integrase inhibitor known as bictegravir was found to be well tolerated and effective as HIV treatment in a 10-day monotherapy study, warranting further investigation of the drug, according to research presented at ASM Microbe 2016 in Boston, Massachusetts.
The study was designed to evaluate the short-term potency of bictegravir (BIC, GS-9883) compared with placebo at four different drug doses: 5 mg, 25 mg, 50 mg and 100 mg. Twenty participants were enrolled, with five participants in each arm – 4 of which received the study drug and one of which received a placebo.
Individuals living with HIV were enrolled who had never been treated with an integrase inhibitor, had a baseline viral load between 10,000 and 400,000 copies/mL and had a CD4 count above 200 copies/mm3. Nineteen of the 20 participants were men and 13 were white; six volunteers were black.
After 10 days of once-daily treatment using bictegravir with no booster, all four study arms saw rapid declines in viral load that were sustained through the treatment period. Average viral load reductions were as follows: yhe 5-mg group saw a -1.45 log10 copies/mL reduction in viral load; the 25-mg group saw a -2.08 log copies/mL reduction in viral load; the 50-mg group saw a -2.06 log copies/mL reduction in viral load; and the 100-mg group saw a -2.43 log copies/mL reduction in viral load.
There was a clear dose response relationship between dose and viral dynamics, noted lead study author Dr Joel Gallant, professor of medicine and epidemiology in the division of infectious diseases at the Johns Hopkins University School of Medicine and professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. When treatment was discontinued after day 10, viral rebound was delayed until day 14 for the 50-mg group and day 17 for the 100-mg group.
Three participants achieved viral loads below 50 copies/mL by the end of the treatment period (one in the 50-mg group and two in the 100-mg group).
In terms of safety, the drug was well tolerated. There were no serious adverse events or adverse events leading to discontinuation. The most common adverse events reported were headache in three participants and diarrhea in two participants.
Additionally, no resistance emerged after 10 days of treatment in any of the arms.
Going forward, Gallant stated that 75 mg would be the dose for bictegravir as a stand-alone drug. However, bictegravir is also currently being developed as part of a single-tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC, Emtriva). As a coformulation, the bictegravir dose will be 50 mg because TAF and emtricitabine increase exposure to bictegravir, Gallant said.
Background: Integrase strand transfer inhibitor (INSTI)-based regimens comprise 5 of the 6 DHHS recommended regimens for treatment of HIV-1. GS-9883 is a novel, unboosted INSTI with potent in-vitro activity against HIV-1.
Methods: HIV-1-positive INSTI-naïve subjects were randomized to receive GS-9883 5, 25, 50, or 100 mg, or placebo once daily for 10 days. Primary endpoint was time-weighted average HIV-1 RNA change from baseline on day 11 (DAVG). Mean change in HIV-1 RNA, PK, and safety and laboratory data were analyzed.
Results: 20 subjects received study treatment and completed the study. Most were male; median age was 29 years; median HIV-1 RNA was 4.32 log copies/mL. GS-9883 demonstrated a dose-dependent reduction in HIV-1 RNA, with increased exposures correlating with greater reductions in plasma HIV-1 RNA, up to 2.43 log copies/mL at Day 11 (Table). Response was durable through day 17 in the higher dose groups. PK/PD analysis suggested that near maximal efficacy was associated with GS-9883 exposures achieved at doses between 50 and 100 mg. No primary resistance mutations emerged. No serious adverse events (AEs) or clinically significant lab abnormalities were reported; there were no discontinuations due to AEs.
Conclusions: Daily dosing of GS-9883 for 10 days at 5, 25, 50 and 100 mg was well tolerated and resulted in rapid, dose-dependent decreases in HIV-1 RNA of > 2 log at the higher doses. Based on PK/PD analyses, exposures associated with 75 mg dose of single agent GS-9883 would provide near-maximal virologic response, with a predicted IQ for wild type HIV of ~20.
J Gallant, M Thompson, T Mills, E DeJesus, G Voskuhl, X Wei, J Zack, K White, H Martin, J Szwarcberg