Dataset Information

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

ABSTRACT: OBJECTIVE:To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI). DESIGN:Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study. METHODS:HIV-infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted average change from baseline to day 11 (DAVG11) for plasma HIV-1 RNA. HIV-1 RNA, adverse events (AEs), and laboratory assessments were evaluated through day 17. RESULTS:Twenty participants were enrolled (n = 4/group). Mean DAVG11 ranged from -0.92 to -1.61 across BIC doses versus -0.01 for placebo. Significant reductions in plasma HIV-1 RNA from baseline at day 11 were observed for all BIC doses compared with placebo (P < 0.001); mean decreases were 1.45-2.43 log10 copies/mL. Increased BIC exposures correlated with increased reduction in plasma HIV-1 RNA from baseline on day 11. Three participants on BIC (50 or 100 mg) achieved plasma HIV-1 RNA <50 copies/mL by end of study. Median Tmax ranged from 1.0 to 1.8 hours (day 1, postdose) and 1.3-2.7 hours (day 10), with median t1/2 ranging from 15.9 to 20.9 hours. No participant developed primary INSTI-R substitution through day 17. BIC was well tolerated, with no discontinuations because of adverse events. CONCLUSIONS:BIC is a novel, potent, unboosted INSTI that demonstrated rapid, dose-dependent declines in HIV-1 RNA after 10 days of monotherapy. BIC was well tolerated, and displayed rapid absorption and a half-life supportive of once-daily therapy in HIV-infected subjects.

SUBMITTER: Gallant JE

PROVIDER: S-EPMC5389589 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

Gallant Joel E JE Thompson Melanie M DeJesus Edwin E Voskuhl Gene W GW Wei Xuelian X Zhang Heather H White Kirsten K Cheng Andrew A Quirk Erin E Martin Hal H

Journal of acquired immune deficiency syndromes (1999) 20170501 1

<h4>Objective</h4>To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI).<h4>Design</h4>Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study.<h4>Methods</h4>HIV-infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted averag ...[more]

PMID: 28196003

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Project description:Bictegravir (BIC) is an integrase strand transfer inhibitor widely used in the treatment of HIV-1. Although its potency and safety have been demonstrated in older patients, pharmacokinetics (PK) data remain limited in this patient population. Ten male patients aged 50 years or older with suppressed HIV RNA on other antiretroviral regimens were switched to a single-tablet regimen of BIC, emtricitabine, and tenofovir alafenamide (BIC+FTC+TAF). Four weeks later, plasma samples were collected at 9 time points for PK. Safety and efficacy were also assessed up to 48 weeks. The median age (range) of patients was 57.5 (50 to 75) years. Although 8 (80%) had lifestyle diseases requiring treatment, no participants had renal or liver failure. Nine (90%) were receiving dolutegravir-containing antiretroviral regimens at entry. The trough concentration of BIC was 2,324 (1,438 to 3,756) (geometric mean [95% confidence interval]) ng/mL, which was markedly above the 95% inhibitory concentration of the drug (162 ng/mL). All PK parameters, including area under the blood concentration-time curve and clearance, were similar to those in young HIV-negative Japanese participants in a previous study. No correlations between age and any PK parameters were observed in our study population. No participant experienced virological failure. Body weight, transaminase, renal function, lipid profiles, and bone mineral density were unchanged. Interestingly, urinary albumin was decreased after switching. PK of BIC was not affected by age, indicating that BIC+FTC+TAF may be safely used in older patients. IMPORTANCE BIC is a potent integrase strand transfer inhibitor (INSTI), widely used for the treatment of HIV-1 as part of a once-daily single-tablet regimen that includes emtricitabine and tenofovir alafenamide (BIC+FTC+TAF). Although the safety and efficacy of BIC+FTC+TAF have been confirmed in older patients with HIV-1, PK data in this patient population remain limited. Dolutegravir (DTG), an antiretroviral medication with a similar structural formula to BIC, causes neuropsychiatric adverse events. PK data for DTG have shown a higher maximum concentration (Cmax) among older patients than younger patients and are related to a higher frequency of adverse events. In the present study, we prospectively collected BIC PK data from 10 older HIV-1-infected patients and showed that PK of BIC are not affected by age. Our results support the safe use of this treatment regimen among older patients with HIV-1.

Project description:Abstract Background Prospective studies examining long‐term therapeutic outcomes of the Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) regimen in human immunodeficiency virus (HIV) infection remain limited. This study assessed the actual efficacy and safety of BIC/FTC/TAF in HIV‐infected individuals in southwest China. Methods This was a single‐center, prospective study enrolling ART‐naïve (n = 32) and ART‐experienced (n = 177) HIV‐infected patients administered BIC/FTC/TAF treatment between March 2022 and August 2022. The data were collected until February 28, 2023. Virological reactions and adverse events to the treatment were recorded, and patient subjective feelings in the form of Electronic Patient Reporting Outcome (ePRO) were collected. The primary endpoint was the rate of patients with HIV viral load <50 copies/mL at Week 24. Results At Week 24, 87.5% and 95.5% of ART‐naïve and ART‐experienced HIV patients had a viral load <50 copies/mL, respectively. CD4 cell counts in ART‐naïve and ART‐experienced patients increased significantly by 163.5 cells/μL (p = .002) and 55.0 cells/μL (p = .022), respectively. By Week 24, no patients had discontinued the BIC/FTC/TAF treatment due to adverse events. Based on ePRO data, ART‐naïve and ART‐experienced patients at Week 24 had stable disease symptom burden, quality of life, and depression level after treatment with BIC/FTC/TAF. Conclusion BIC/FTC/TAF reduces the viral load in ART‐naïve patients with high viral load as well as ART‐experienced patients with residual viremia. The patient's subjective experience was maintained stable after treatment with BIC/FTC/TAF. This study also revealed a very low incidence for BIC/FTC/TAF drug‐related side effects. This study suggests BIC+FTC+TAF is a safe option for achieving and maintaining virological suppression, both in treatment‐naïve patients with high viral load and treatment‐experienced patients with baseline residual viremia. Since there were almost no drug‐related adverse events with this regimen, and patients' subjective experiences of their own disease symptom burdens, quality of life, and depression levels based on ePRO after treatment with this regimen remained stable, it can be deduced that patient compliance can be ensured. In this study, significant decreases in ALT, AST, and GLU levels were firstly detected in treatment‐naïve and treatment‐experienced patients at Week 24. In the future, the sample size and follow‐up time should be increased to confirm these findings."

Dataset Information

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

Publications

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

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