Bictegravir in Initial Therapy

Bictegravir (BIC) is an investigational integrase inhibitor that is being studied as part of a coformulation with tenofovir alafenamide (TAF) and emtricitabine (FTC). Two Phase 3 trials comparing a single-tablet regimen of BIC/TAF/FTC (50/25/200 mg) with regimens containing dolutegravir (DTG) plus 2 NRTIs in treatment-naive individuals were presented at the 9th IAS Conference on HIV Science in July. These both were double-blind, placebo-controlled, randomized noninferiority trials.

The GS-1489 trial compared BIC/TAF/FTC with the single-pill tablet DTG/ABC/3TC; subjects were given their assigned single-pill combination plus matching placebo once daily. Patients had to be negative for HLA-B*5701, have an estimated glomerular filtration rate (eGFR) of ≥50 mL/min, no hepatitis B infection, and no resistance to the NRTIs on baseline resistance testing; 17% percent of participants had a baseline HIV RNA level of >100,000 copies/mL.

At week 48, by FDA snapshot analysis, HIV RNA was <50 copies/mL in 92.4% of patients on BIC/TAF/FTC and 93.0% of patients on DTG/ABC/3TC (difference -0.6%, 95% confidence interval [CI]: -4.8% to 3.6%; p = .78); this met the study criteria for noninferiority. No treatment-emergent resistance to any study drug was found in the 5 patients (1 in the BIC arm, 4 in the DTG arm) who met criteria for resistance testing. Nausea, sleep disturbance, and mood symptoms occurred more frequently in patients who received DTG/ABC/3TC. There were no notable differences between the groups in changes in renal or lipid parameters or in bone mineral density.

The GS-1490 study compared BIC/TAF/FTC (in 320 subjects) with the combination of DTG + TAF/FTC (in 325 subjects); subjects also took matching placebo, for a total of 3 pills per day. Subjects were required to have an eGFR of ≥30 mL/min. At baseline, 21% in the BIC group and 17% in the DTG group had HIV RNA levels of >100,000 copies/mL.

At week 48, by FDA snapshot analysis, HIV RNA was <50 copies/mL in 89% of the BIC/TAF/FTC group and 93% of the DTG + TAF/FTC group (difference -3.5%, 95% CI: -7.9% to 1.0%; p = .12); this outcome met the study criteria for noninferiority. The on-treatment analysis showed that 98.9% and 99.7% of subjects in the BIC and DTG arms, respectively, had HIV RNA levels of <50 copies/mL. As in GS-1489, no new resistance mutations were seen in the few patients with virologic failure. Reported adverse effects (including nausea) did not appear to be significantly different in the 2 groups. eGFR decreased slightly less in the BIC group (-7.3 mL/min) than in the DTG group (-10.8 mL/min), (both BIC and DTG inhibit tubular excretion of creatinine); no information was given on changes in bone mineral density. Small and similar increases in fasting lipid parameters were seen in both study groups.

Clinical Bottom Line

These studies demonstrate that coformulated BIC/TAF/FTC is noninferior to two gold-standard regimens comprised of DTG with 2-NRTI backbones, and in fact suggest that BIC/TAF/FTC is better tolerated than the coformulation DTG/ABC/3TC. Importantly, rates of virologic suppression were very high with all regimens, and no resistance mutations were seen in the rare cases of virologic failure.

BIC/TAF/FTC is likely to be approved by the FDA in the coming months; the availability of a powerful and unboosted integrase inhibitor coformulated with the TAF/FTC NRTI backbone will be welcome. It is likely to be used widely in initial therapy, but a number of questions remain to be studied. Areas in which more data are needed include BIC's efficacy and tolerability in women (the 1489 and 1490 studies involved <16% women), drug-drug interactions involving BIC (few data have been released to date), real-world information on virologic failure with BIC/TAF/FTC and resulting resistance mutations, and the use of BIC against viruses with preexisting integrase resistance mutations.

References

  • Gallant J. Lazzarin A, Mills A, et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, vs ABC/DTG/3TC in treatment-naive adults at week 48. In: Program and abstracts of the 9th IAS Conference on HIV Science; July 24-26, 2017; Paris, France. Abstract MOAD015LB.
  • Sax PE, Pozniak A, Arribas J, et al. Phase 3 randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-dose combination (B/F/TAF) vs dolutegravir (DTG) + F/TAF in treatment-naive HIV-1 positive adults: week 48 results. In: Program and abstracts of the 9th IAS Conference on HIV Science; July 24-26, 2017; Paris, France. Abstract TUPDB0201LB.
  • Gallant J. Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017 Aug 31. doi: 10.1016/S0140-6736(17)32299-7. [Epub ahead of print]