Clinical Trials in Adults with No Antiretroviral Treatment History
The primary safety assessment of BIKTARVY was based on Week 48 data from two randomized, double-blind, active-controlled trials, Trial 1489 and Trial 1490, that enrolled 1274 HIV-1 infected adult subjects with no antiretroviral treatment history. A total of 634 subjects received one tablet of BIKTARVY once daily [see Clinical Studies (14.2)].
The most common adverse reactions (all Grades) reported in at least 5% of subjects in the BIKTARVY group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of subjects who discontinued treatment with BIKTARVY, abacavir [ABC]/dolutegravir [DTG]/ lamivudine [3TC]), or DTG + FTC/TAF, due to adverse events, regardless of severity, was 1%, 1%, and <1%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 2% in the BIKTARVY group.
Table 1 Adverse ReactionsFrequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. No adverse reactions of Grade 2 or higher occurred in ≥ 1% of subjects treated with BIKTARVY.
(All Grades) Reported in ≥ 2% of HIV-1 Infected Adults with No Antiretroviral Treatment History Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis) | Trial 1489 | Trial 1490 |
|---|
| Adverse Reactions | BIKTARVY
N=314 | ABC/DTG/3TC
N=315 | BIKTARVY
N=320 | DTG + FTC/TAF
N=325 |
|---|
| Diarrhea | 6% | 4% | 3% | 3% |
| Nausea | 5% | 17% | 3% | 5% |
| Headache | 5% | 5% | 4% | 3% |
| Fatigue | 3% | 3% | 2% | 2% |
| Abnormal dreams | 3% | 3% | <1% | 1% |
| Dizziness | 2% | 3% | 2% | 1% |
| Insomnia | 2% | 3% | 2% | <1% |
Additional adverse reactions (all Grades) occurring in less than 2% of subjects administered BIKTARVY in Trials 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression.
Suicidal ideation, suicide attempt, and depression suicidal occurred in <1% of subjects administered BIKTARVY; all events were serious and primarily occurred in subjects with a preexisting history of depression, prior suicide attempt or psychiatric illness.
The majority (87%) of adverse events associated with BIKTARVY were Grade 1.
Clinical Trials in Virologically Suppressed Adults
The safety of BIKTARVY in virologically-suppressed adults was based on Week 48 data from 282 subjects in a randomized, double-blind, active-controlled trial (Trial 1844) in which virologically-suppressed subjects were switched from either DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY; and Week 48 data from 290 subjects in an open-label, active-controlled trial in which virologically-suppressed subjects were switched from a regimen containing atazanavir (ATV) (given with cobicistat or ritonavir) or darunavir (DRV) (given with cobicistat or ritonavir) plus either FTC/TDF or ABC/3TC, to BIKTARVY (Trial 1878). Overall, the safety profile in virologically suppressed adult subjects in Trials 1844 and 1878 was similar to that in subjects with no antiretroviral treatment history [see Clinical Studies (14.3)].
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving BIKTARVY in Trials 1489 and 1490 are presented in Table 2.
Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis) | Trial 1489 | Trial 1490 |
|---|
| Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. | BIKTARVY
N=314 | ABC/DTG/3TC
N=315 | BIKTARVY
N=320 | DTG + FTC/TAF
N=325 |
|---|
| ULN = Upper limit of normal |
| Amylase (>2.0 × ULN) | 2% | 2% | 2% | 2% |
| ALT (>5.0 × ULN) | 1% | 1% | 2% | 1% |
| AST (>5.0 × ULN) | 2% | 1% | 1% | 3% |
| Creatine Kinase (≥10.0 × ULN) | 4% | 3% | 4% | 2% |
| Neutrophils (<750 mm3) | 2% | 3% | 2% | 1% |
| LDL-cholesterol (fasted) (>190 mg/dL) | 2% | 3% | 3% | 3% |
Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 48. In Trials 1489 and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg per dL from baseline to Week 48 in the BIKTARVY group and was similar to the comparator groups who received ABC/DTG/3TC, or DTG + FTC/TAF. There were no discontinuations due to renal adverse events through Week 48 in BIKTARVY clinical trials.
Changes in Bilirubin: In Trials 1489 and 1490, total bilirubin increases were observed in 12% of subjects administered BIKTARVY through Week 48. Increases were primarily Grade 1 (1.0 to 1.5 × ULN) (9%) and Grade 2 (1.5 to 2.5 × ULN) (3%). Graded bilirubin increases in the ABC/DTG/3TC, and DTG + FTC/TAF groups, were 4% and 6%, respectively. Increases were primarily Grade 1 (3% ABC/DTG/3TC and 5% DTG + FTC/TAF) or Grade 2 (1% ABC/DTG/3TC and 1% DTG + FTC/TAF). There were no discontinuations due to hepatic adverse events through Week 48 in BIKTARVY clinical studies.
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BIKTARVY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
There are insufficient human data on the use of BIKTARVY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Bictegravir (BIC) and tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for FTC compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15–20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of BIKTARVY at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD) (see Data). During organogenesis, systemic exposures (AUC) to BIC were approximately 36 (rats) and 0.6 times (rabbits), to FTC were approximately 60 (mice) and 108 times (rabbits), and to TAF were approximately 2 (rats) and 78 times (rabbits) the exposure at the RHD of BIKTARVY. In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 30 times (BIC), 60 times (FTC), and 19 times (TDF) the exposures of each component in humans at the RHD.
Data
Human Data
Emtricitabine: Based on prospective reports to the APR of 3,406 exposures to FTC-containing regimens during pregnancy resulting in live births (including 2,326 exposed in the first trimester and 1,080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with the second/third trimester exposure to FTC-containing regimens.
Animal Data
Bictegravir: BIC was administered orally to pregnant rats (5, 30, or 300 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) on gestation days 7 through 17, and 7 through 19, respectively. No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (AUC) of up to approximately 36 (rats) and 0.6 (rabbits) times the exposure in humans at the RHD of BIKTARVY. Spontaneous abortion, increased clinical signs [fecal changes, thin body, and cold-to-touch], and decreased body weight were observed at a maternally toxic dose in rabbits (1000 mg/kg/day; approximately 1.4 times higher than human exposure at the RHD).
In a pre/postnatal development study, BIC was administered orally to pregnant rats (up to 300 mg/kg/day) from gestation days 6 to lactation/post-partum day 24. No significant adverse effects were observed in the offspring exposed daily from before birth (in utero) through lactation at maternal and pup exposures (AUC) of approximately 30 and 11 times higher, respectively, than human exposures at the RHD.
Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the RHD.
In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD.
Tenofovir alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures of approximately 2 (rats) and 78 (rabbits) times higher than the exposure in humans at the recommended daily dose of BIKTARVY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 55 (rats) and 86 (rabbits) times higher than human tenofovir exposures at the RHD. Since TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 12 [19] times higher than the exposures in humans at the RHD of BIKTARVY.
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
It is not known whether BIKTARVY or all of the components of BIKTARVY are present in human breast milk, affects human milk production, or has effects on the breastfed infant. Based on published data, FTC has been shown to be present in human breast milk. BIC was detected in the plasma of nursing rat pups likely due to the presence of BIC in milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data). It is unknown if TAF is present in animal milk.
Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving BIKTARVY.
Data
Animal Data
Bictegravir: BIC was detected in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10), likely due to the presence of BIC in milk.
Tenofovir alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.
Bictegravir: The chemical name of bictegravir sodium is 2,5-Methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-, sodium salt (1:1), (2R,5S,13aR)-.
Bictegravir sodium has a molecular formula of C21H17F3N3NaO5 and a molecular weight of 471.4 and has the following structural formula:
Chemical Structure (Biktarvy 01)
Bictegravir sodium is an off-white to yellow solid with a solubility of 0.1 mg per mL in water at 20 °C.
Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.
FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.2 and has the following structural formula:
Chemical Structure (Biktarvy 02)
FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).
Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.5 and has the following structural formula:
Chemical Structure (Biktarvy 03)
Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.
Cardiac Electrophysiology
In a thorough QT/QTc trial in 48 healthy subjects, BIC at doses 1.5 and 6 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval. In a thorough QT/QTc trial in 48 healthy subjects, TAF at the recommended dose or at a dose 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of FTC on the QT interval is not known.
Effects on Serum Creatinine
Mean change from baseline in serum creatinine in healthy subjects who received BIC 75 mg (1.5 times the approved recommended dosage) once daily with food for 14 days was 0.1 mg per dL on Days 7 and 14 compared to placebo. BIC did not have a significant effect on the estimated creatinine clearance or on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol).
Specific Populations
Patients with Renal Impairment
No clinically relevant differences in the pharmacokinetics of BIC, TAF, or its metabolite tenofovir were observed between subjects with severe renal impairment (CLcr 15 to 29 mL per minute estimated by Cockcroft-Gault method) and healthy subjects.
Patients with Hepatic Impairment
Bictegravir: Clinically relevant changes in the pharmacokinetics of BIC were not observed in subjects with moderate (Child-Pugh Class B) hepatic impairment.
Emtricitabine: The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
Tenofovir Alafenamide: Clinically relevant changes in the pharmacokinetics of TAF or its metabolite tenofovir were not observed in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7)].
Hepatitis B and/or Hepatitis C Virus Coinfection
The pharmacokinetics of BIC, FTC, and TAF have not been evaluated in subjects coinfected with hepatitis B and/or C virus.
Geriatric Patients
The pharmacokinetics of BIC, FTC, and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 3 trials of BIKTARVY showed that age did not have a clinically relevant effect on exposures of BIC and TAF up to 74 years of age [see Use in Specific Populations (8.5)].
Race and Gender
No clinically relevant changes in the pharmacokinetics of BIC, FTC, and TAF were observed based on gender or race.
Drug Interaction Studies
As BIKTARVY is a complete regimen for the treatment of HIV-1 infection, comprehensive information regarding potential drug-drug interactions with other antiretroviral agents is not provided.
BIC is a substrate of CYP3A and UGT1A1.
BIC is an inhibitor of OCT2 and MATE1. At clinically relevant concentrations, BIC is not an inhibitor of hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1 and OAT3, or CYP (including CYP3A) or UGT1A1 enzymes.
TAF is a substrate of P-gp and BCRP.
At clinically relevant concentrations, TAF is not an inhibitor of drug transporters P-gp, BCRP, hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1, OAT3, OCT2, MATE1, or CYP (including CYP3A) or UGT1A1 enzymes.
Drug interaction studies were conducted with BIKTARVY or its components. Tables 6 and 7 summarize the pharmacokinetic effects of other drugs on BIC and TAF, respectively. Table 8 summarizes the pharmacokinetic effects of BIKTARVY or its components on other drugs.
Effect of Other Drugs on BIKTARVY Components
Table 6 Effect of Other Drugs on BICAll interaction studies conducted in healthy volunteers.
| Coadministered Drug | Dose of Coadministered Drug (mg) | BIC (mg) | Mean Ratio of BIC Pharmacokinetic Parameters (90% CI); No effect = 1.00 |
|---|
| Cmax | AUC | Cmin |
|---|
| NA= Not Applicable |
| Ledipasvir/ Sofosbuvir (fed) | 90/400 once daily | 75 once daily | 0.98
(0.94, 1.03) | 1.00
(0.97, 1.03) | 1.04
(0.99, 1.09) |
| Rifabutin (fasted) | 300 once daily | 75 once daily | 0.80
(0.67, 0.97) | 0.62
(0.53, 0.72) | 0.44
(0.37, 0.52) |
| Rifampin (fed) | 600 once daily | 75 single dose | 0.72
(0.67, 0.78) | 0.25
(0.22, 0.27) | NA |
| Sofosbuvir/ velpatasvir/ voxilaprevir (fed) | 400/100/100+100 voxilaprevir Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily | 50 once daily | 0.98
(0.94, 1.01) | 1.07
(1.03, 1.10) | 1.10
(1.05, 1.17) |
| Voriconazole (fasted) | 300 twice daily | 75 single dose | 1.09
(0.96, 1.23) | 1.61
(1.41, 1.84) | NA |
| Maximum strength antacid (simultaneous administration, fasted) | 20 mL Maximum strength antacid contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL. single dose (oral) | 50 single dose | 0.20
(0.16, 0.24) | 0.21
(0.18, 0.26) | NA |
| Maximum strength antacid (2 h after BIKTARVY fasted) | 20 mL single dose (oral) | 50 single dose | 0.93
(0.88, 1.00) | 0.87
(0.81, 0.93) | NA |
| Maximum strength antacid (2 h before BIKTARVY fasted) | 20 mL single dose (oral) | 50 single dose | 0.42
(0.33, 0.52) | 0.48
(0.38, 0.59) | NA |
| Maximum strength antacid (simultaneous administration, fed Reference treatment administered under fasted conditions. ) | 20 mL single dose (oral) | 50 single dose | 0.51
(0.43, 0.62) | 0.53
(0.44, 0.64) | NA |
| Calcium carbonate (simultaneous administration, fasted) | 1200 single dose | 50 single dose | 0.58
(0.51, 0.67) | 0.67
(0.57, 0.78) | NA |
| Calcium carbonate (simultaneous administration, fed) | 1200 single dose | 50 single dose | 0.90
(0.78, 1.03) | 1.03
(0.89, 1.20) | NA |
| Ferrous fumarate (simultaneous administration, fasted) | 324 single dose | 50 single dose | 0.29
(0.26, 0.33) | 0.37
(0.33, 0.42) | NA |
| Ferrous fumarate (simultaneous administration, fed) | 324 single dose | 50 single dose | 0.75
(0.65, 0.87) | 0.84
(0.74, 0.95) | NA |
Table 7 Effect of Other Drugs on TAFAll interaction studies conducted in healthy volunteers.
| Coadministered Drug | Dose of Coadministered Drug (mg) | Tenofovir Alafenamide (mg) | Mean Ratio of Tenofovir Alafenamide Pharmacokinetic Parameters (90% CI); No effect = 1.00 |
|---|
| Cmax | AUC | Cmin |
|---|
| NA= Not Applicable |
| Carbamazepine | 300 twice daily | 25 single dose Study conducted with emtricitabine/tenofovir alafenamide. | 0.43
(0.36, 0.51) | 0.46
(0.40, 0.54) | NA |
| Ledipasvir/sofosbuvir | 90/400 once daily | 25 once daily | 1.17
(1.00, 1.38) | 1.27
(1.19, 1.34) | NA |
| Sofosbuvir/ velpatasvir/ voxilaprevir | 400/100/100 +100 voxilaprevir Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily | 25 once daily | 1.28
(1.09, 1.51) | 1.57
(1.44, 1.71) | NA |
Effect of BIKTARVY Components on Other Drugs
Table 8 Effect of Components of BIKTARVY on Other DrugsAll interaction studies conducted in healthy volunteers.
| Coadministered Drug | Dose of Coadministered Drug (mg) | BIC (mg) | TAF (mg) | Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No effect = 1.00 |
|---|
| Cmax | AUC | Cmin |
|---|
| NA= Not Applicable |
| Ledipasvir | 90/400 once daily | 75 once daily | 25 once daily | 0.85
(0.81, 0.90) | 0.87
(0.83, 0.92) | 0.90
(0.84, 0.96) |
| Sofosbuvir | 1.11
(1.00, 1.24) | 1.07
(1.01, 1.13) | NA |
| GS-331007 The predominant circulating nucleoside metabolite of sofosbuvir. | 1.10
(1.07, 1.13) | 1.11
(1.08, 1.14) | 1.02
(0.99, 1.06) |
| Metformin | 500 twice daily | 50 once daily | 25 once daily | 1.28
(1.21, 1.36) | 1.39
(1.31, 1.48) | 1.36
(1.21, 1.53) |
| Midazolam | 2 single dose | 50 once daily | 25 once daily | 1.03
(0.87, 1.23) | 1.15
(1.00, 1.31) | NA |
| Norelgestromin | norgestimate 0.180/0.215/0.250 once daily / ethinyl estradiol 0.025 once daily | 75 once daily | - | 1.23
(1.14, 1.32) | 1.08
(1.05, 1.10) | 1.10
(1.05, 1.15) |
| Norgestrel | 1.15
(1.10, 1.21) | 1.13
(1.07, 1.19) | 1.14
(1.06, 1.22) |
| Ethinyl estradiol | 1.15
(1.03, 1.27) | 1.04
(0.99, 1.10) | 1.05
(0.95, 1.14) |
| Norelgestromin | norgestimate 0.180/0.215/0.250 once daily / ethinyl estradiol 0.025 once daily | - | 25 once daily Study conducted with emtricitabine/tenofovir alafenamide. | 1.17
(1.07,1.26) | 1.12
(1.07,1.17) | 1.16
(1.08, 1.24) |
| Norgestrel | 1.10
(1.02, 1.18) | 1.09
(1.01, 1.18) | 1.11
(1.03, 1.20) |
| Ethinyl estradiol | 1.22
(1.15, 1.29) | 1.11
(1.07, 1.16) | 1.02
(0.92, 1.12) |
| Sertraline | 50 single dose | - | 10 once daily Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. | 1.14
(0.94, 1.38) | 0.93
(0.77, 1.13) | NA |
| Sofosbuvir | 400/100/100+ 100 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily | 50 once daily | 25 once daily | 1.14
(1.04,1.25) | 1.09
(1.02, 1.15) | NA |
| GS-331007 | 1.03
(0.99,1.06) | 1.03
(1.00,1.06) | 1.01
(0.98, 1.05) |
| Velpatasvir | 0.96
(0.91,1.01) | 0.96
(0.90, 1.02) | 0.94
(0.88, 1.01) |
| Voxilaprevir | 0.90
(0.76, 1.06) | 0.91
(0.80, 1.03) | 0.97
(0.88, 1.06) |
Mechanism of Action
Bictegravir: BIC inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of linear HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the virus.
Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.
Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
Antiviral Activity in Cell Culture
The triple combination of BIC, FTC, and TAF was not antagonistic with respect to antiviral activity in cell culture.
Bictegravir: The antiviral activity of BIC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes. In MT-4 cells (human lymphoblastoid T-cell line) acutely infected with HIV-1 IIIB, the mean 50% effective concentration (EC50) was 2.4±0.4 nM, and the protein-adjusted EC95 value was 361 nM (0.162 micrograms per mL). BIC displayed antiviral activity in activated PBMCs against clinical isolates of HIV-1 representing groups M, N, and O, including subtypes A, B, C, D, E, F, and G, with a median EC50 value of 0.55 nM (range <0.05 to 1.71 nM). The EC50 value against a single HIV-2 isolate was 1.1 nM.
Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and PBMCs. In PBMCs acutely infected with HIV-1 subtypes A, B, C, D, E, F, and G, the median EC50 value for FTC was 9.5 nM (range 1 to 30 nM) and against HIV-2 was 7 nM.
Tenofovir Alafenamide: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC50 values for TAF ranged from 2.0 to 14.7 nM. TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.1 to 12 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0.9 to 2.6 nM).
Resistance
In Cell Culture
Bictegravir: HIV-1 isolates with reduced susceptibility to BIC have been selected in cell culture. In one selection with BIC, a virus pool emerged expressing amino acid substitutions M50I and R263K in the HIV-1 integrase. M50I, R263K, and M50I+R263K substitutions, when introduced into a wild-type virus by site-directed mutagenesis, conferred 1.3-, 2.2-, and 2.9-fold reduced susceptibility to BIC, respectively. In a second selection, emergence of amino acid substitutions T66I and S153F was detected, and 0.4-, 1.9-, and 0.5-fold reductions in BIC susceptibility were observed with T66I, S153F, and T66I+S153F, respectively. In addition, S24G and E157K substitutions emerged during the selection process.
Emtricitabine: HIV-1 isolates with reduced susceptibility to FTC were selected in cell culture and in subjects treated with FTC. Reduced susceptibility to FTC was associated with M184V or I substitutions in HIV-1 RT.
Tenofovir Alafenamide: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.
In Clinical Trials
In Subjects with No Antiretroviral Treatment History: Pooled genotypic resistance analyses were performed on paired baseline and on-treatment HIV-1 isolates from subjects receiving BIKTARVY through Week 48 in Trials 1489 and 1490 [see Clinical Studies (14)] who had HIV-1 RNA greater than or equal to 200 copies/mL at the time of confirmed virologic failure, Week 48, or early study drug discontinuation. No specific amino acid substitutions emerged consistently in the 8 treatment failure subjects with evaluable genotypic resistance data and failed to establish an association with genotypic BIC resistance. There were no treatment-emergent NRTI resistance-associated substitutions detected in the 8 evaluated treatment failure isolates. Phenotypic resistance analyses of failure isolates found fold-changes in drug susceptibility below the biological or clinical cutoffs for BIC, FTC, and TFV, compared to wild-type reference HIV-1.
In Virologically Suppressed Subjects: In 2 switch trials, Trials 1844 and 1878 [see Clinical Studies (14)], of virologically suppressed HIV-1 infected subjects (n=572), only one subject with virologic rebound in the resistance analysis population had IN genotypic and phenotypic data, and 2 rebounders had RT genotypic and phenotypic data. No subjects had HIV-1 with treatment-emergent genotypic or phenotypic resistance to BIC, FTC, or TAF.
Cross-Resistance
Bictegravir: Cross-resistance has been observed among INSTIs. The susceptibility of BIC was tested against 64 clinical isolates expressing known INSTI resistance-associated substitutions listed by IAS-USA (20 with single substitutions and 44 with 2 or more substitutions). Isolates with a single INSTI-resistance substitution including E92Q, T97A, Y143C/R, Q148R, and N155H showed less than 2-fold reduced susceptibility to BIC. All isolates (n=14) with more than 2.5-fold reduced susceptibility to BIC (above the biological cutoff for BIC) contained G140A/C/S and Q148H/R/K substitutions; the majority (64.3%, 9/14) had a complex INSTI resistance pattern with an additional INSTI-resistance substitution L74M, T97A, or E138A/K. Of those evaluated isolates containing G140A/C/S and Q148H/R/K substitutions in the absence of additional INSTI-resistance substitutions, 38.5% (5/13) showed more than 2.5-fold reduction. In addition, site-directed mutant viruses with G118R (dolutegravir and raltegravir treatment-emergent substitution) and G118R+T97A had 3.4- and 2.8-fold reduced susceptibility to BIC, respectively.
BIC demonstrated equivalent antiviral activity with less than 2-fold reductions in susceptibility against HIV-1 variants expressing substitutions associated with resistance to NNRTIs, NRTIs, and PIs, compared with the wild-type virus.
Emtricitabine: Cross-resistance has been observed among NRTIs. FTC-resistant viruses with an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC.
Tenofovir Alafenamide: Cross-resistance has been observed among NRTIs. Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.
Bictegravir
BIC was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females. A carcinogenicity study in rats is ongoing.
BIC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
BIC did not affect fertility, reproductive performance or embryonic viability in male and female rats at 29 times higher exposures (AUC) than in humans at the recommended dose of 50 mg BIC in BIKTARVY.
Emtricitabine
In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (25 times the human systemic exposure at the recommended dose of 200 mg per day in BIKTARVY) or in rats at doses up to 600 mg per kg per day (30 times the human systemic exposure at the recommended dose in BIKTARVY).
FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose in BIKTARVY. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose in BIKTARVY.
Tenofovir Alafenamide
Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 151 times (mice) and 51 times (rat) those observed in humans after administration of the daily recommended dose of BIKTARVY. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 151 times (BIKTARVY) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.
TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 155 times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.
Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of BIKTARVY [see Warnings and Precautions (5.1)]. Advise the patient to not discontinue BIKTARVY without first informing their healthcare provider.
Drug Interactions
BIKTARVY may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort [see Contraindications (4) and Drug Interactions (7)].
Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.2)].
Renal Impairment
Advise patients to avoid taking BIKTARVY with concurrent or recent use of nephrotoxic agents. Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs [see Warnings and Precautions (5.4)].
Lactic Acidosis and Severe Hepatomegaly
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to BIKTARVY. Advise patients that they should stop BIKTARVY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.3)].
Missed Dosage
Inform patients that it is important to take BIKTARVY on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2.2)].
Pregnancy Registry
Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to BIKTARVY [see Use in Specific Populations (8.1)].
Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].
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