Adults switching to bictegravir/alafenamide from a boosted protease inhibitor maintained high rates of virologic suppression without resistance, a phase-3 study found.
Gilead Sciences has announced detailed 48-week results from a Phase 3 study (Study 1878) evaluating the efficacy and safety of switching virologically suppressed HIV-1 infected adult patients from a multi-tablet regimen containing a boosted protease inhibitor (bPI) to a fixed-dose combination of bictegravir (50 mg) (BIC), a novel investigational integrase strand transfer inhibitor (INSTI), and emtricitabine/tenofovir alafenamide (200/25 mg) (FTC/TAF), a dual-NRTI backbone.
In the ongoing study, BIC/FTC/TAF was found to be statistically non-inferior to regimens containing bPIs and demonstrated no treatment-emergent resistance at 48 weeks.
“These data demonstrate the potential of BIC/FTC/TAF to match the efficacy of a boosted protease inhibitor regimen while also offering a high barrier to resistance and fewer interactions with other drugs,” said Dr Eric Daar, chief of the division of HIV medicine at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Centre and lead author of the study. “The findings, along with data from three other Phase 3 studies in both treatment-experienced and treatment-naïve patients, suggest that the investigational regimen of BIC/FTC/TAF may be appropriate for a broad range of people living with HIV.”
In the study, a total of 577 virologically suppressed adults with HIV taking regimens of boosted atazanavir (ATV) or darunavir (DRV) + abacavir/lamivudine (ABC/3TC) or FTC/tenofovir disoproxil fumarate (TDF) were randomised 1:1 to continue their bPI regimen or to switch to open-label co-formulated BIC/FTC/TAF once daily. At the primary endpoint of Week 48, switching to BIC/FTC/TAF was non-inferior to continuing on a bPI regimen with 1.7% of patients in each group having HIV-1 RNA ≥50 c/mL (difference: 0.0 percent, 95% CI: -2.5% to 2.5%, p=1.00); the proportion of patients with HIV-1 RNA <50 c/mL was 92.1% in the BIC/FTC/TAF arm and 88.9% in the bPI arm, according to FDA snapshot algorithm.
No patients in the BIC/FTC/TAF arm developed treatment-emergent resistance, and one participant on DRV/ritonavir + ABC/3TC developed a treatment-emergent NRTI mutation associated with abacavir. No renal adverse events leading to discontinuations or cases of proximal renal tubulopathy occurred with BIC/FTC/TAF. The incidence of grade 3 or 4 adverse events was 4% (n=13) for the BIC/FTC/TAF arm versus 6% (n=18) for the bPI arm; the incidence of grade 3 or 4 laboratory abnormalities was 16% (n=45) for the BIC/FTC/TAF arm versus 29% (n=83) for the bPI arm. The most commonly reported adverse events (all grades) in both arms included headache, diarrhoea, nasopharyngitis and upper respiratory tract infection.
“The combination of the unboosted integrase inhibitor bictegravir with the FTC/TAF backbone has the potential to further evolve HIV triple therapy with convenient dosing in a single-tablet regimen,” said Dr Norbert W Bischofberger, Gilead’s executive vice president, research and development and chief scientific officer. “We look forward to the opportunity to offer patients this next-generation therapy as part of our TAF-based portfolio of treatments for HIV.”
Gilead filed a New Drug Application for BIC/FTC/TAF with a Priority Review voucher on June 12, 2017, and the US Food and Drug Administration (FDA) set a target action date of 12 February, 2018, under the Prescription Drug User Fee Act. A marketing application for BIC/FTC/TAF is also under review in the EU and was validated by the European Medicines Agency (EMA) on 13 July.
Bictegravir in combination with FTC/TAF as a single-tablet regimen is an investigational treatment that has not been determined to be safe or efficacious and is not approved anywhere globally.
Background: Boosted protease inhibitor regimens (bPIs) are effective and often used in HIV-infected individuals with difficulties with adherence, but they can have drug-drug interactions and GI adverse effects. Bictegravir (B), a novel, potent integrase strand transfer inhibitor with a high barrier to resistance and low potential for drug-drug interactions, was coformulated with the recommended nucleoside reverse transcriptase inhibitor backbone emtricitabine (FTC)/tenofovir alafenamide (F/TAF) and demonstrated high efficacy and tolerability in randomized studies in treatment-naïve adults. This randomized Phase 3 study assesses efficacy and safety of switching to B/F/TAF from a multi-tablet regimen containing a bPI.
Methods: HIV-infected adults suppressed on regimens of boosted atazanavir (ATV) or darunavir (DRV) + abacavir/lamivudine (ABC/3TC) or FTC/tenofovir disoproxil fumarate (TDF), were randomized 1:1 to continue their current bPI regimen or switch to open-label coformulated B/F/TAF (50/200/25 mg) once daily. Primary endpoint was proportion with HIV-1 RNA ≥50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% confidence intervals (CI) using a margin of 4%. Secondary endpoints included proportion with HIV-1 RNA <50 c/mL and safety measures at W48.
Results: 577 participants were randomized and treated with B/F/TAF (n=290) or current bPI regimens (n=287): 17% women, 26% Black, median age 48 yrs. Most were receiving a bPI with FTC/TDF (85%) at screening. At W48, switching to B/F/TAF was noninferior to continuing bPI with 1.7% in each group having HIV-1 RNA ≥50 c/mL (difference -0.0%; 95.002%CI -2.5% to 2.5%, p=1.00); the proportion with HIV-1 RNA <50 c/mL was 92.1% in B/F/TAF vs 88.9% in bPI. No participant on B/F/TAF developed resistance to study drugs. One participant on DRV/ritonavir + ABC/3TC developed a treatment-emergent L74V mutation. Incidence of grade 3 or 4 AEs was similar (B/F/TAF 4%, bPI regimens 6%). No renal discontinuations or tubulopathy cases occurred with B/F/TAF.
Conclusion: Adults switching to B/F/TAF from a boosted PI maintained high rates of virologic suppression without resistance. B/F/TAF was safe and well tolerated.
Eric Daar, Edwin DeJesus, Peter Ruane, Gordon Crofoot, Godson Oguchi, Catherine Creticos, Jurgen K Rockstroh, Jean-Michel Molina, Ellen Koenig, Ya-Pei Liu, Kristen Andreatta, Hiba Graham, Andrew Cheng, Hal Martin, Erin Quirk