AHFS Class:

• HIV Integrase Inhibitors 8:18.08.12

Generic Name(s):

• Bictegravir Sodium, Emtricitabine, and Tenofovir Alafenamide Fumarate

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF) is a fixed-combination antiretroviral agent containing bictegravir (human immunodeficiency virus type 1 [HIV-1] integrase strand transfer inhibitor), emtricitabine (HIV-1 nucleoside reverse transcriptase inhibitor), and tenofovir alafenamide (HIV-1 nucleotide reverse transcriptase inhibitor).1

Treatment of HIV Infection

The fixed combination of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF) is used as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥14 kg who are antiretroviral-naïve (have not previously received antiretroviral therapy) or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no known or suspected substitutions associated with resistance to bictegravir or tenofovir.1

Clinical Experience

Antiretroviral-naïve Adults

Efficacy of BIC/FTC/TAF in antiretroviral-naïve, HIV-infected adults was evaluated in 2 randomized, double blind, active-control, noninferiority phase 3 studies (study 1489; NCT02607930 and study 1490; NCT02607956).1,2,3,11,12,14 These studies indicated that BIC/FTC/TAF was noninferior to the fixed combination of abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC) at 48, 96, and 144 weeks (study 1489) and was noninferior to a regimen of dolutegravir in conjunction with the fixed combination of emtricitabine and tenofovir alafenamide fumarate (FTC/TAF) at 48, 96, and 144 weeks (study 1490).1,2,3,11,12,14

In study 1489, 629 antiretroviral-naïve adults (mean age 34 years, 90% male, 57% white, 36% Black, 3% Asian, 22% Hispanic/Latino, mean baseline plasma HIV-1 RNA level 4.4 log₁₀ copies/mL, mean baseline CD4⁺ T-cell count 464 cells/mm³) were randomized in a 1:1 ratio to receive BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or ABC/DTG/3TC (abacavir 600 mg, dolutegravir 50 mg, lamivudine 300 mg) once daily.1,2 The primary end point was virologic response (defined as a plasma HIV-1 RNA level <50 copies/mL) at 48 weeks.2 Results at 48 weeks indicated that BIC/FTC/TAF is noninferior to ABC/DTG/3TC in the proportion of patients achieving virologic response (92.4 and 93%, respectively).2 The mean increase in CD4⁺ T-cell count from baseline was 233 cells/mm³ in those receiving BIC/FTC/TAF compared with 229 cells/mm³ in those receiving ABC/DTG/3TC.2 Treatment outcomes were similar across subgroups (i.e., age, sex, race, baseline viral load, and baseline CD4⁺ T-cell count).1 At 96 weeks, 88% of patients receiving BIC/FTC/TAF and 90% of patients receiving ABC/DTG/3TC were still virologically suppressed (i.e., plasma HIV-1 RNA level <50 copies/mL); treatment-emergent resistance was not reported in any patient in either treatment group.11 At 144 weeks, 82% of patients receiving BIC/FTC/TAF and 84% of patients receiving ABC/DTG/3TC remained virologically suppressed with a plasma HIV-1 RNA level <50 copies/mL.1,14 The mean increase in CD4+ T-cell count from baseline to week 144 was 299 cells/mm³ in those receiving BIC/FTC/TAF compared with 317 cells/mm³ in those receiving ABC/DTG/3TC.1,14 No treatment-emergent resistance was reported in either treatment group.14

In study 1490, 645 antiretroviral-naïve adults (mean age 37 years, 88% male, 59% white, 31% Black, 3% Asian, 25% Hispanic/Latino, mean baseline plasma HIV-1 RNA level 4.4 log₁₀ copies/mL, mean baseline CD4⁺ T-cell count 456 cells/mm³) were randomized to receive BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or a regimen of dolutegravir 50 mg in conjunction with FTC/TAF (emtricitabine 200 mg and tenofovir alafenamide 25 mg) once daily.1,3 The primary end point was virologic response (defined as a plasma HIV-1 RNA level <50 copies/mL) at 48 weeks.3 Results at 48 weeks indicated that BIC/FTC/TAF is noninferior to a regimen of dolutegravir and FTC/TAF in the proportion of patients achieving virologic response (89.4% and 92.9%, respectively).1,3 The mean increase in CD4⁺ T-cell count from baseline was 180 cells/mm³ in those receiving BIC/FTC/TAF compared with 201 cells/mm³ in those receiving the regimen of dolutegravir and FTC/TAF.3 Treatment outcomes were similar across subgroups (i.e., age, sex, race, baseline viral load, and baseline CD4⁺ T-cell count).1 At 96 weeks, 84% of patients receiving BIC/FTC/TAF and 86% of patients receiving dolutegravir and FTC/TAF were still virologically suppressed (i.e., plasma HIV-1 RNA level <50 copies/mL); treatment-emergent resistance was not reported in any patient in either treatment group.12 At 144 weeks, 82% of patients receiving BIC/FTC/TAF and 84% of patients receiving dolutegravir and FTC/TAF remained virologically suppressed with a plasma HIV-1 RNA level <50 copies/mL.1,14 The mean increase in CD4+ T-cell count from baseline to week 144 was 278 cells/mm³ in those receiving BIC/FTC/TAF compared with 289 cells/mm³ in those receiving dolutegravir and FTC/TAF.1 No treatment-emergent resistance was reported in either treatment group.14

Antiretroviral-experienced Adults

Efficacy of BIC/FTC/TAF in antiretroviral-experienced adults was primarily evaluated in a randomized, double-blind, active-control, noninferiority, phase 3 study (trial 1844; NCT02603120) and a randomized, open-label, active-control, noninferiority, phase 3 study (trial 1878; NCT02603107).1,8,9

In trial 1844, 563 previously treated adults with baseline plasma HIV-1 RNA levels <50 copies/mL for at least 3 months and no history of treatment failure (mean age 45 years, 89% male, 73% white, 22% Black, 17% Hispanic/Latino, mean baseline CD4⁺ T-cell count 723 cells/mm³) were randomized to either switch to BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or continue their baseline antiretroviral regimen of ABC/DTG/3TC.1,8 At 48 weeks, 94% of those receiving BIC/FTC/TAF had a plasma HIV-1 RNA level <50 copies/mL compared with 95% of those who continued to receive ABC/DTG/3TC.1,8 The mean change in CD4⁺ T-cell count from baseline was -31 cells/mm³ in those receiving BIC/FTC/TAF compared with 4 cells/mm³ in those who continued to receive ABC/DTG/3TC.1,8

In trial 1878, 577 previously treated adults with baseline plasma HIV-1 RNA levels <50 copies/mL for at least 6 months, no previous treatment with an INSTI, and no history of treatment failure (mean age 46 years, 83% male, 66% white, 26% Black, 19% Hispanic/Latino, mean baseline CD4⁺ T-cell count 663 cells/mm³) were randomized to either switch to BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or continue their baseline antiretroviral regimen (at baseline, 15% were receiving cobicistat- or ritonavir-boosted atazanavir or darunavir concomitantly with the fixed combination of abacavir and lamivudine [abacavir/lamivudine], 85% were receiving cobicistat- or ritonavir-boosted atazanavir or darunavir concomitantly with the fixed combination of emtricitabine and tenofovir disoproxil fumarate [emtricitabine/TDF]).1,9 At 48 weeks, 92% of those receiving BIC/FTC/TAF had plasma HIV-1 RNA levels <50 copies/mL compared with 89% of those who continued to receive their baseline regimen.1,9 The mean change in CD4⁺ T-cell count from baseline was 25 cells/mm³ in those receiving BIC/FTC/TAF compared with 0 cells/mm³ in those who continued to receive their baseline regimen.1,9 Treatment outcomes in trial 1844 and trial 1878 were similar across subgroups (i.e., age, sex, race, and region).1

An additional randomized, double-blind, active-control, noninferiority, phase 3 study examined the safety and efficacy of switching to BIC/FTC/TAF in 565 adults with baseline plasma HIV-1 RNA levels <50 copies/mL on a stable regimen of dolutegravir plus either emtricitabine/tenofovir alafenamide (FTC/TAF) or emtricitabine/tenofovir disoproxil fumarate (FTC/TDF).16 Patients were randomized 1:1 to receive BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or dolutegravir 50 mg plus FTC/TAF (emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily.16 The primary endpoint was the proportion of patients with virologic failure (plasma HIV-1 RNA ≥50 copies/mL) at week 48.16 The median age was 51 years in the BIC/FTC/TAF group and 50 years in the dolutegravir plus FTC/TAF group; the majority of participants were white and male.16 Virologic failure at 48 weeks occurred in 0.4% of patients treated with BIC/FTC/TAF and 1.1% of patients treated with dolutegravir plus FTC/TAF, demonstrating noninferiority of BIC/FTC/TAF.16 At week 48, plasma HIV-1 RNA levels <50 copies/mL were documented in 93.3% of patients treated with BIC/FTC/TAF and 91.1% of patients treated with dolutegravir plus FTC/TAF.16

Additional studies have examined the efficacy and safety of BIC/FTC/TAF in various subgroups of patients, including elderly, women, and Black patients, and are described below.1,15,17,18

An open-label single-arm trial (trial 4449) evaluated the efficacy and safety of switching from a stable antiretroviral regimen to BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) in 86 virologically-suppressed HIV-1 infected adults ≥65 years of age.1,15 The mean age of patients treated with BIC/FTC/TAF was 70 years.1 The primary endpoint was the proportion of patients with HIV-1 RNA >50 copies/mL at week 48; no patient had HIV-1 RNA >50 copies/mL at week 48, and 91% of patients remained virologically suppressed at week 48 (defined as HIV-1 RNA <50 copies/mL).1 At week 96, no patients had HIV-1 RNA ≥50 copies/mL; the rate of virologic suppression at week 96 was 74.4%; however, virologic data were missing for 22 patients largely due to the impact of the COVID-19 pandemic.15

An open-label, randomized, active-controlled noninferiority trial evaluated the efficacy and safety of BIC/FTC/TAF in 470 women with HIV-1 who were virologically suppressed (plasma HIV-1 RNA levels <50 copies/mL) on their current antiretroviral regimen containing either TAF or TDF.17 Patients were randomly assigned (1:1) to switch to BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or stay on their baseline antiretroviral regimen.17 The primary outcome was the proportion of patients with virologic failure (plasma HIV-1 RNA ≥50 copies/mL) at week 48.17 The median age of patients was 39 years in the BIC/FTC/TAF group and 40 years in the group continuing baseline ART.17 Switching to BIC/FTC/TAF was noninferior to continuing the baseline antiretroviral regimen in terms of virologic failure rates at week 48; virologic failure was observed in 1.7% of patients in both treatment groups.17 The proportion of patients with documented plasma HIV-1 RNA <50 copies/mL at week 48 was 95.7% in the BIC/FTC/TAF group and 95.3% in the group continuing baseline ART.17

An additional randomized, open-label, active-controlled noninferiority trial (BRAAVE) evaluated the efficacy and safety of BIC/FTC/TAF in 495 Black or African American adults with HIV-1 who were virologically suppressed (plasma HIV-1 RNA levels <50 copies/mL) on their current antiretroviral regimen of 2 NRTIs plus a third agent.18 Patients were randomized 2:1 to switch to BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily or stay on their baseline antiretroviral regimen.18 The primary outcome was the proportion of patients with virologic failure (plasma HIV-1 RNA ≥50 copies/mL) at week 24.18 The median age of patients was 49 years; 32% of participants were ciswomen, 2% were transwomen, and 10% had documented baseline M184V/I mutation.18 Switching to BIC/FTC/TAF was noninferior to continuing the baseline antiretroviral regimen in terms of virologic failure rates at week 24; virologic failure was observed in 0.6% of patients who switched to BIC/FTC/TAF and 1.8% of patients who continued baseline ART.18 Virologic suppression (plasma HIV-1 RNA <50 copies/mL) at week 24 was confirmed in 96.3% of patients who switched to BIC/FTC/TAF and 94.5% of patients who continued baseline ART.18

Pediatric Patients

Efficacy of BIC/FTC/TAF in pediatric patients was evaluated in an open-label, single-arm trial (trial 1474; NCT02881320) that included 50 virologically suppressed adolescents 12 to <18 years of age weighing ≥35 kg (cohort 1), 50 virologically suppressed children 6 to <12 years of age weighing ≥25 kg (cohort 2), and 22 virologically suppressed children ≥2 years of age weighing 14 to <25 kg (cohort 3).1,19

Patients in cohort 1 of trial 1474 (mean age 14 years, mean baseline weight 51.7 kg, 64% female, 27% Asian, 65% Black, baseline median CD4⁺ T-cell count 750 cells/mm³, median CD4⁺ T-cell percentage 33%) were switched from their existing regimen to 1 tablet of BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily.1,19 At week 48 after switching to BIC/FTC/TAF, 98% of these pediatric patients remained virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).1,19

Patients in cohort 2 of trial 1474 (mean age 10 years, mean baseline weight 31.9 kg, 54% female, 22% Asian, 72% Black, baseline median CD4⁺ T-cell count 898 cells/mm³, median CD4⁺ T-cell percentage 37%) were switched from their existing regimen to 1 tablet of BIC/FTC/TAF (bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg) once daily.1,19 At week 24 after switching to BIC/FTC/TAF, 100% of these pediatric patients remained virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).1

Patients in cohort 3 of trial 1474 (mean age 5 years, mean baseline weight 18.8 kg, 50% female, 23% Asian, 73% Black, baseline mean CD4+ T-cell count 1104 cells/mm³, mean CD4+ T-cell percentage 33.4%) were switched from their existing regimen to BIC/FTC/TAF (bictegravir 30 mg, emtricitabine 120 mg, tenofovir alafenamide 15 mg) once daily.1 At week 24 after switching to BIC/FTC/TAF, 91% of these pediatric patients remained virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,201,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an INSTI, a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) is a co-formulation of 2 NRTIs (tenofovir alafenamide and emtricitabine) and an INSTI (bictegravir).200 In the HHS adult and adolescent HIV treatment guideline, BIC/FTC/TAF is listed as a recommended regimen for most people with HIV.200

In the HHS pediatric HIV treatment guideline, BIC/FTC/TAF is recommended as a preferred regimen for children ≥2 years of age weighing ≥14 kg.201

In the HHS perinatal HIV treatment guideline, BIC/FTC/TAF is listed as an alternative regimen for use in pregnancy as safety, pharmacokinetic, and efficacy data in pregnancy are more limited than data for preferred regimens.202

General

Pretreatment Screening

• Determine serum creatinine, estimated creatinine clearance, urine glucose, and urine protein prior to initiation of the fixed combination of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF).1 In patients with chronic kidney disease, also assess serum phosphorus.1
• Test for hepatitis B virus (HBV) infection prior to initiation of BIC/FTC/TAF.1

Patient Monitoring

• Monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein during treatment in all patients as clinically appropriate.1 In patients with chronic kidney disease, serum phosphorus also should be assessed.1
• For several months after discontinuation of BIC/FTC/TAF, closely follow hepatic laboratory and clinical monitoring for signs of acute exacerbation of hepatitis B in patients coinfected with HBV infection.1

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for antiretroviral medications (e.g., DOR, TAF, TDF) during the medication use process should be avoided as their use has been associated with serious medication errors.219

Administration

The fixed combination BIC/FTC/TAF is administered orally once daily without regard to food.1

In children unable to swallow the whole fixed combination tablet of BIC/FTC/TAF, the tablet can be split, and each part swallowed separately; the full dose must be consumed within approximately 10 minutes.1

Store bottles below 30ºC.1 Store blister packs at 25ºC (excursions permitted between 15-30ºC).1

Dosage

Fixed combination tablets of BIC/FTC/TAF contain bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate; dosage of bictegravir sodium is expressed in terms of bictegravir and dosage of tenofovir alafenamide fumarate is expressed in terms of tenofovir alafenamide.1

Fixed-combination tablets of BIC/FTC/TAF are available in 2 different strengths: bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, and bictegravir 30 mg, emtricitabine 120 mg, and tenofovir alafenamide 15 mg.1

Pediatric Dosage

HIV-1 Infection

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric patients weighing ≥25 kg, the usual dosage of BIC/FTC/TAF is 1 tablet containing 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide once daily.1

For the treatment of HIV-1 infection in pediatric patients weighing ≥14 kg to <25 kg, the usual dosage of BIC/FTC/TAF is 1 tablet containing 30 mg of bictegravir, 120 mg of emtricitabine, and 15 mg of tenofovir alafenamide once daily.1

Adults

HIV-1 Infection

For the treatment of HIV-1 infection, the usual adult dosage of BIC/FTC/TAF is 1 tablet containing 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide once daily.1

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary if BIC/FTC/TAF is used in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

BIC/FTC/TAF is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dosage adjustments are not necessary if BIC/FTC/TAF is used in patients with an estimated creatinine clearance of ≥30 mL/minute, or in virologically-suppressed adult patients with end-stage renal disease (ESRD; estimated creatinine clearance <15 mL/min) who are receiving hemodialysis.1 On hemodialysis days, the dose of BIC/FTC/TAF should be administered after dialysis treatment.1 BIC/FTC/TAF has not been studied in pediatric patients with a creatinine clearance of <30 mL/minute.1

BIC/FTC/TAF is not recommended in patients with an estimated creatinine clearance 15 to <30 mL/minute, in patients with ESRD (estimated creatinine clearance <15 mL/minute) who are not receiving chronic hemodialysis, and in antiretroviral naïve patients with ESRD (estimated creatinine clearance <15 mL/minute) who are receiving chronic hemodialysis. 1

Geriatric Use

The manufacturer does not provide recommendations on dosage adjustments in geriatric patients; however, increased sensitivity to BIC/FTC/TAF in some older individuals cannot be ruled out.1

Pregnancy

In pregnant individuals who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no known substitutions associated with resistance to the individual components of the drug, the recommended dosage of BIC/FTC/TAF is 1 tablet containing 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide once daily.1 Reduced drug exposures have been observed with use of BIC/FTC/TAF in pregnancy.1 Viral load should be monitored closely.1

Contraindications

• Concomitant use of dofetilide since serious and/or life-threatening adverse effects due to possible increased dofetilide plasma concentrations may occur.1
• Concomitant use of rifampin since substantially decreased plasma bictegravir concentrations may occur and result in loss of virologic response and development of resistance.1

Warnings/Precautions

Warnings

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV and HBV

A boxed warning regarding the risk of hepatitis B virus (HBV) infection exacerbation in HIV-infected patients is included in the prescribing information of BIC/FTC/TAF.1 HIV-infected patients should be tested for HBV infection before antiretroviral therapy is initiated.1

In HIV-infected patients with HBV coinfection, severe acute exacerbations of HBV infection, including liver decompensation and liver failure, have occurred following discontinuance of preparations containing emtricitabine and/or tenofovir disoproxil fumarate (TDF; tenofovir DF).1 Such reactions could occur following discontinuance of BIC/FTC/TAF.1

Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after BIC/FTC/TAF is discontinued in patients coinfected with HIV-1 and HBV.1 If appropriate, initiation of HBV treatment may be warranted, especially in patients with advanced liver disease or cirrhosis.1

Other Warnings and Precautions

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

Concomitant use of BIC/FTC/TAF with certain drugs may result in substantial drug interactions, which may lead to loss of therapeutic effect of BIC/FTC/TAF and possible development of resistance or possible adverse effects from increased exposures of concomitant drugs.1

The potential for drug interactions should be considered prior to and during treatment with BIC/FTC/TAF and the patient should be monitored for adverse effects associated with concomitant drugs.1

New Onset or Worsening Renal Impairment

Renal impairment, including acute renal failure, proximal renal tubulopathy, and Fanconi syndrome, has been reported during postmarketing experience in patients receiving products that contained tenofovir alafenamide.1 While other confounding variables were present in most cases that may have contributed to the development of renal toxicity, it is also possible that these factors helped precipitate the adverse event.1

Serum creatinine, estimated creatinine clearance, urine glucose, and urine protein should be determined prior to initiating BIC/FTC/TAF and monitored during treatment in all patients as clinically appropriate.1 In patients with chronic kidney disease, serum phosphorus also should be assessed.1

BIC/FTC/TAF is not recommended in adult or pediatric patients with severe renal impairment (estimated creatinine clearance 15 to <30 mL/minute), in adult patients with ESRD (estimated creatinine clearance <15 mL/minute) not receiving chronic hemodialysis, and in treatment-naïve patients with ESRD who are receiving chronic hemodialysis.1

Patients receiving a tenofovir prodrug who have impaired renal function or are receiving a nephrotoxic agent (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]) are at increased risk of developing adverse renal effects.1

BIC/FTC/TAF should be discontinued in patients who develop clinically important decreases in renal function or evidence of Fanconi syndrome.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs), including emtricitabine and the tenofovir prodrug TDF, alone or in conjunction with other antiretrovirals.1

BIC/FTC/TAF treatment should be interrupted in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (signs of hepatotoxicity may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy.1 During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium , M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); such response may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) also have been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Use of Fixed Combinations

The usual cautions, precautions, contraindications, and interactions associated with each component of BIC/FTC/TAF should be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.1

BIC/FTC/TAF is used alone as a complete regimen for the treatment of HIV-1 infection and use in conjunction with other antiretrovirals is not recommended.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to BIC/FTC/TAF during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1

The manufacturer states that data regarding use of BIC, FTC, and TAF in pregnant women have not established a drug-associated risk of birth defects, miscarriage, or other adverse maternal or fetal outcomes.1 Prospective reports to the APR reveal that of over 500 BIC exposures during pregnancy resulting in live births, the prevalence of birth defects was 4.3% following first trimester exposure and 1.8% following second-/third-trimester exposure.1 Of over 6500 FTC exposures during pregnancy resulting in live births, the prevalence of birth defects was 2.9% following first trimester exposure and 2.8% following second-/third-trimester exposure.1 Of over 1200 TAF exposures during pregnancy resulting in live births, the prevalence of birth defects was 3.9% following first trimester exposure and 4.8% following second-/third-trimester exposure.1

In an open-label, multicenter, single-arm, phase 1b study, the pharmacokinetics, safety, and efficacy of BIC/FTC/TAF during pregnancy were evaluated.1,20 The trial included 33 virologically suppressed (HIV-1 RNA <50 copies/mL) pregnant adult women with no known substitutions associated with resistance to BIC, FTC, or TAF.1,20 The patients were administered BIC/FTC/TAF (containing 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide) once daily from the second or third trimester through postpartum.1,20 Of the 32 patients who completed the study, 100% maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum.1,20 The baseline median CD4⁺ cell count for evaluable patients was 558 cells/µL; median change in CD4⁺ cell count from baseline to Week 12 postpartum was 159 cells/µL.1,20 Of the 29 neonates assessed, all had a negative/nondetectable HIV-1 polymerase chain reaction result at birth and/or at 4 to 8 weeks post-birth.1,20 Safety findings were consistent with those observed in other adult trials involving BIC/FTC/TAF.1

Lactation

Published literature demonstrate that BIC, FTC, and TAF are present in human milk.1

There are no reported adverse effects of FTC or TAF on the breastfed child; no data exist on the effects of BIC on breastfed children.1 It is not known whether BIC/FTC/TAF affects human milk production.1

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Pediatric Use

Safety and efficacy of BIC/FTC/TAF have not been established in pediatric patients weighing <14 kg.1

Safety and efficacy of BIC/FTC/TAF have been established for the treatment of HIV-1 infection in pediatric patients weighing 14 kg or more.1 Use of BIC/FTC/TAF in pediatric patients 2 to <18 years of age weighing at least 14 kg is supported by results of clinical trials in adults, and by results of an open-label study in 3 age-based cohorts of pediatric patients.1 Patients in these cohorts were virologically suppressed, and received BIC/FTC/TAF for a treatment duration of 24 or 48 weeks.1 No patients 2 years of age were enrolled in these clinical studies of BIC/FTC/TAF; the youngest patient was 3 years of age at enrollment and weighed at least 14 kg.1 Safety and efficacy of BIC/FTC/TAF in these pediatric patients were similar to that in adults, and there was no clinically important difference in exposures of the components of BIC/FTC/TAF in these pediatric patients compared with adults.1

Adverse effects reported in pediatric patients receiving BIC/FTC/TAF are similar to those reported in adults receiving the drug.1

Geriatric Use

In studies of virologically-suppressed patients 65 years of age and older receiving BIC/FTC/TAF, 90% of 111 subjects were 65-74 years of age, and 10% were 75-84 years of age.1 These studies identified no overall differences in response based on safety or efficacy between older adults and younger adult subjects, although greater sensitivity of some older individuals cannot be ruled out.1

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A) does not have a clinically important effect on the pharmacokinetics of tenofovir alafenamide.1 Moderate hepatic impairment (Child-Pugh class B) does not have a clinically important effect on the pharmacokinetics of bictegravir or tenofovir alafenamide.1 Hepatic impairment is not expected to affect the pharmacokinetics of emtricitabine.1

BIC/FTC/TAF is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 Data are not available to date regarding the pharmacokinetics or safety of BIC/FTC/TAF in such patients.1

Renal Impairment

Serum creatinine, estimated creatinine clearance, urine glucose, and urine protein should be determined prior to initiating BIC/FTC/TAF and routinely monitored during treatment in all patients as clinically appropriate.1 In patients with chronic kidney disease, serum phosphorus also should be determined.1

There are no clinically important differences in the pharmacokinetics of bictegravir, tenofovir alafenamide, or tenofovir in individuals with severe renal impairment compared with healthy individuals.1

Common Adverse Effects

The most common adverse effects (≥5% incidence) in patients receiving BIC/FTC/TAF include diarrhea, nausea, and headache.1

The following drug interactions are based on studies that used bictegravir sodium, emtricitabine, or tenofovir alafenamide fumarate alone or the fixed combination of bictegravir, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF) or are predicted to occur.1

Potential drug interactions associated with each drug in the fixed combination should be considered.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Bictegravir is a substrate of cytochrome P-450 (CYP) isoenzyme 3A.1 The drug does not inhibit CYP isoenzymes (including CYP3A) at clinically relevant concentrations.1

Emtricitabine is not a substrate of CYP isoenzymes; emtricitabine does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.218

Tenofovir alafenamide does not inhibit CYP isoenzymes (including CYP3A) at clinically relevant concentrations.1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that are potent inducers of CYP3A and also are inducers of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 enzyme (decreased plasma concentrations of bictegravir; possible decreased antiretroviral efficacy and development of resistance).1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that are potent inhibitors of CYP3A and also are inhibitors of UGT1A1 (increased plasma concentrations of bictegravir).1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase

Bictegravir is a substrate of UGT1A1.1 Bictegravir and tenofovir alafenamide do not inhibit UGT1A1.1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that are potent inducers of CYP3A and also are inducers of UGT1A1 (decreased plasma concentrations of bictegravir; possible decreased antiretroviral efficacy and development of resistance).1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that are potent inhibitors of CYP3A and also are inhibitors of UGT1A1 (increased plasma concentrations of bictegravir).1

Drugs Affecting or Affected by P-glycoprotein Transport

Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) transport.1 The drug does not inhibit P-gp.1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that induce P-gp (decreased absorption and decreased plasma concentrations of tenofovir alafenamide; possible decreased antiretroviral efficacy and development of resistance).1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that inhibit P-gp and breast cancer resistance protein (BCRP) (increased absorption and increased plasma concentrations of tenofovir alafenamide).1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Tenofovir alafenamide is a substrate of BCRP.1 The drug does not inhibit BCRP.1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that inhibit P-gp and BCRP (increased absorption and increased plasma concentrations of tenofovir alafenamide).1

Drugs Affecting or Affected by Multidrug and Toxin Extrusion Transporter

Bictegravir inhibits multidrug and toxin extrusion transporter (MATE) 1.1 Therefore, bictegravir may increase plasma concentrations of drugs eliminated by MATE1 (e.g., dofetilide).1

Tenofovir alafenamide does not inhibit MATE1.1

Drugs Affecting or Affected by Renal Organic Anion Transporters

Bictegravir and tenofovir alafenamide do not inhibit renal organic anion transporter (OAT) 1 or OAT3.1

Bictegravir and tenofovir alafenamide do not inhibit hepatic organic anion transporter polypeptide (OATP) 1B1 or OATP1B3.1

Drugs Affecting or Affected by Renal Organic Cation Transporters

Bictegravir inhibits renal organic cation transporter (OCT) 2.1 Therefore, bictegravir may increase plasma concentrations of drugs eliminated by OCT2 (e.g., dofetilide).1

Bictegravir and tenofovir alafenamide do not inhibit OCT1.1 Tenofovir alafenamide does not inhibit OCT2.1

Drugs Affecting or Affected by Bile Salt Export Pump

Bictegravir and tenofovir alafenamide do not inhibit bile salt export pump (BSEP).1

Drugs Affecting Renal Function

The emtricitabine and tenofovir components of BIC/FTC/TAF are principally excreted by the kidneys by a combination of glomerular filtration and active tubular secretion.1

Potential pharmacokinetic interactions if BIC/FTC/TAF is used concomitantly with drugs that reduce renal function or compete for active tubular secretion (e.g., acyclovir, aminoglycosides [gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]); may result in increased concentrations of emtricitabine, tenofovir, and/or the concomitant drug and may increase the risk of adverse effects.1 Concomitant use of BIC/FTC/TAF and nephrotoxic drugs should be avoided.1

Anticonvulsants

Concomitant use of carbamazepine or oxcarbazepine with BIC/FTC/TAF may result in decreased bictegravir and tenofovir concentrations.1 Concomitant use of carbamazepine (300 mg twice daily) and tenofovir alafenamide (single 25-mg dose) in fixed combination with emtricitabine results in decreased peak plasma concentrations and AUC of tenofovir.1

Concomitant use of BIC/FTC/TAF and phenobarbital or phenytoin is expected to decrease plasma concentrations of bictegravir and tenofovir alafenamide.1

Concomitant use of BIC/FTC/TAF with carbamazepine, oxcarbazepine, phenobarbital, or phenytoin is not recommended; an alternative anticonvulsant should be considered.1

Antimycobacterial Agents

Rifabutin

Concomitant use of rifabutin (300 mg once daily) and bictegravir (75 mg once daily) under fasting conditions decreases bictegravir peak plasma concentrations by 20%, AUC by 38%, and trough plasma concentrations by 56%.1 Concomitant use of rifabutin with BIC/FTC/TAF may decrease plasma concentrations of tenofovir alafenamide.1

Concomitant use of rifabutin and BIC/FTC/TAF is not recommended.1

Rifampin

Concomitant use of rifampin (600 mg once daily) and bictegravir (single 75-mg dose) under fed conditions decreases bictegravir peak plasma concentrations by 28% and AUC by 75%.1 Concomitant use of rifampin and BIC/FTC/TAF may decrease plasma concentrations of tenofovir alafenamide.1

Concomitant use of rifampin and BIC/FTC/TAF is contraindicated.1

Rifapentine

Pharmacokinetic interactions with rifapentine are expected (decreased bictegravir and tenofovir alafenamide plasma concentrations).1

Concomitant use of rifapentine and BIC/FTC/TAF is not recommended.1

Antiretroviral Agents

Fixed-combination BIC/FTC/TAF should not be used in conjunction with any other antiretrovirals.1

Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations

Pharmacokinetic interactions reported when a single 1.2-g dose of calcium carbonate was administered simultaneously with a single 50-mg dose of bictegravir in the fasting state (decreased peak plasma concentrations and AUC of bictegravir).1 No clinically important pharmacokinetic interactions were observed when a single 1.2-g dose of calcium carbonate was administered simultaneously with a single 50-mg dose of bictegravir under fed conditions.1

Pharmacokinetic interactions reported when a single 324-mg dose of ferrous fumarate was administered simultaneously with a single 50-mg dose of bictegravir in the fasting state (decreased peak plasma concentrations and AUC of bictegravir).1 No clinically important pharmacokinetic interactions were observed when a single 324-mg dose of ferrous fumarate was administered simultaneously with a single 50-mg dose of bictegravir under fed conditions.1

Concomitant use of BIC/FTC/TAF with laxatives, buffered preparations, or other preparations containing polyvalent cations may decrease plasma concentrations of bictegravir.1

BIC/FTC/TAF and supplements containing calcium or iron can be administered simultaneously with food.1

Administration of BIC/FTC/TAF in the fasting state simultaneously with or 2 hours after supplements containing calcium or iron is not recommended.1

Dofetilide

Concomitant use of dofetilide and BIC/FTC/TAF may increase dofetilide plasma concentrations and increase the risk of serious and/or life-threatening adverse effects.1

Concomitant use of dofetilide and BIC/FTC/TAF is contraindicated.1

Ethinyl Estradiol and Norgestimate

Concomitant use of the fixed combination of norgestimate and ethinyl estradiol with bictegravir or tenofovir alafenamide does not have a clinically important effect on ethinyl estradiol, norelgestromin, or norgestrel concentrations.1

Clinically important pharmacokinetic interactions are not expected if BIC/FTC/TAF is used concomitantly with oral contraceptives containing ethinyl estradiol or norgestimate.1

GI Drugs

Antacids

Pharmacokinetic interactions were reported when a single dose of antacid containing aluminum, magnesium, and simethicone was administered simultaneously with a single 50-mg dose of bictegravir in the fasting or fed state (decreased peak plasma concentrations and AUC of bictegravir).1 Similarly, decreased peak plasma concentrations and AUC of bictegravir were observed when a single 50-mg dose of the drug was administered in the fasting state 2 hours after the antacid.1 No clinically important pharmacokinetic interactions were observed when a single 50-mg dose of bictegravir was administered in the fasting state 2 hours before the antacid.1

BIC/FTC/TAF should be administered in the fasting state at least 2 hours before or 6 hours after antacids containing aluminum or magnesium.1 Administration of BIC/FTC/TAF simultaneously with or 2 hours after an antacid containing aluminum or magnesium is not recommended.1

BIC/FTC/TAF and antacids containing calcium carbonate may be administered simultaneously with food.1 Administration of BIC/FTC/TAF in the fasting state simultaneously with or 2 hours after antacids containing calcium carbonate is not recommended.1

Sucralfate

Concomitant use of sucralfate and BIC/FTC/TAF may decrease plasma concentrations of bictegravir.1

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir

Clinically important pharmacokinetic interactions are not expected if sofosbuvir is used concomitantly with BIC/FTC/TAF.1

Sofosbuvir and Velpatasvir

Clinically important pharmacokinetic interactions are not expected if the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) is used concomitantly with BIC/FTC/TAF.1

Sofosbuvir, Velpatasvir, and Voxilaprevir

Concomitant use of the fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) with bictegravir or tenofovir alafenamide does not have a clinically important effect on sofosbuvir, velpatasvir, voxilaprevir, bictegravir, or tenofovir alafenamide concentrations.1

Clinically important pharmacokinetic interactions are not expected if sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with BIC/FTC/TAF.1

HCV Replication Complex Inhibitors

Ledipasvir and Sofosbuvir

Concomitant use of the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) with bictegravir or with tenofovir alafenamide does not have a clinically important effect on ledipasvir, sofosbuvir, bictegravir, or tenofovir alafenamide concentrations.1

Clinically important pharmacokinetic interactions are not expected if BIC/FTC/TAF is used concomitantly with ledipasvir/sofosbuvir.1

Metformin

Concomitant use of metformin hydrochloride (500 mg twice daily), bictegravir (50 mg once daily), and tenofovir alafenamide (25 mg once daily) increases metformin peak plasma concentrations by 1.3-fold, trough plasma concentrations by 1.4-fold, and AUC by 1.4-fold.1

If BIC/FTC/TAF and metformin are used concomitantly, refer to the prescribing information for metformin.1 The benefits and risks of concomitant use should be considered.1

Midazolam

Concomitant use of midazolam with bictegravir and tenofovir alafenamide does not have a clinically important effect on midazolam concentrations.1

Sertraline

Concomitant use of sertraline with tenofovir alafenamide does not have a clinically important effect on sertraline concentrations.1

St. John's Wort

Pharmacokinetic interactions are possible if St. John's wort ( Hypericum perforatum ) is used concomitantly with BIC/FTC/TAF (decreased concentrations of bictegravir and tenofovir alafenamide).1

Concomitant use of St. John's wort and BIC/FTC/TAF is not recommended.1

Voriconazole

Concomitant use of voriconazole (300 mg twice daily) and bictegravir (single 75-mg dose) under fasting conditions increases AUC of bictegravir, but does not substantially affect peak plasma concentrations of bictegravir.1

Description

The fixed combination of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF) contains a human immunodeficiency virus (HIV) integrase strand transfer inhibitor (INSTI) antiretroviral (bictegravir; BIC), an HIV nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral (emtricitabine; FTC), and a nucleotide reverse transcriptase inhibitor antiretroviral classified as an HIV NRTI (tenofovir alafenamide; TAF).1

Bictegravir inhibits the activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome.1 Integration is required for viral replication; therefore, inhibition of integration prevents propagation of viral infection.1 Bictegravir is active against HIV-16,7 and also has some in vitro activity against HIV type 2 (HIV-2).1,6

Emtricitabine is inactive until converted intracellularly to an active 5'-triphosphate metabolite.1 After conversion to the pharmacologically active metabolite, the drug acts as a reverse transcriptase inhibitor antiretroviral.1 Emtricitabine is active against HIV-1 and also has some in vitro activity against HIV-2.1

Tenofovir alafenamide is a tenofovir prodrug and is inactive until hydrolyzed intracellularly by cathepsin A to form tenofovir and subsequently metabolized by cellular kinases to the active metabolite (tenofovir diphosphate).1 After conversion to the pharmacologically active metabolite, the drug acts as a reverse transcriptase inhibitor antiretroviral.1 Tenofovir is active against HIV-1 and has some in vitro activity against HIV-2.1

HIV-1 resistant to bictegravir, emtricitabine, or tenofovir has been produced in vitro.1 In clinical trials evaluating BIC/FTC/TAF, no specific bictegravir or NRTI resistance-associated substitutions emerged in patients receiving BIC/FTC/TAF who were considered to be virologic treatment failures.1 Cross-resistance between bictegravir and other HIV INSTIs (e.g., dolutegravir, elvitegravir, raltegravir) has been reported.1 Cross-resistance also occurs among HIV NRTIs.1

Following oral administration of the components of BIC/FTC/TAF, peak plasma concentrations of bictegravir, emtricitabine, and tenofovir occur at 2-4, 1.5-2, and 0.5-2 hours, respectively.1 Administration of BIC/FTC/TAF components with a high-fat meal (approximately 800 kcal, 50% fat) increases mean systemic exposures of bictegravir and tenofovir by 24 and 63%, respectively, compared with administration in the fasting state; mean systemic exposures of emtricitabine are comparable to those observed with administration in the fasting state.1 Bictegravir is over 99%, emtricitabine is <4%, and tenofovir alafenamide is approximately 80% bound to plasma proteins.1 Bictegravir is metabolized by cytochrome P-450 (CYP) isoenzyme 3A and uridine diphosphate-glucuronsyltransferase (UGT) 1A1.1 Emtricitabine is converted intracellularly to the active 5'-triphosphate metabolite, but is not substantially metabolized further.1 Tenofovir alafenamide is hydrolyzed intracellularly in peripheral blood mononuclear cells (PBMCs) and macrophages by cathepsin A to form tenofovir (the major metabolite), which is then phosphorylated to the active metabolite tenofovir diphosphate; in vitro studies indicate tenofovir alafenamide also is converted to tenofovir by carboxylesterase 1 (CES1) in hepatocytes.1 Following a single dose of bictegravir, 60% is excreted in feces and 35% in urine.1 Emtricitabine is principally excreted in urine (70% of a dose) and to a lesser extent in feces (14% of a dose).1 Following a single dose of tenofovir alafenamide, 32% is excreted in feces and <1% is eliminated in urine.1 The median terminal plasma half-lives of bictegravir, emtricitabine, and tenofovir alafenamide are 17.3, 10.4, and 0.5 hours, respectively.1 The half-life of tenofovir diphosphate, the active metabolite of tenofovir alafenamide, is 150-180 hours within PBMCs.1 There are no clinically important differences in the pharmacokinetics of the components of BIC/FTC/TAF in pediatric patients 6 years of age or older weighing 25 kg or more compared with pharmacokinetics of the drugs reported in adults.1

Advice to Patients

• Advise patients of the critical need for compliance with HIV therapy and importance of remaining under the care of a clinician.1 Advise patients of the importance of taking the fixed combination of bictegravir sodium, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1
• Advise patients that BIC/FTC/TAF is a complete regimen for treatment of HIV-1 infection and should not be used in conjunction with other antiretrovirals.1
• Inform patients that testing for hepatitis B virus (HBV) infection is recommended before antiretroviral therapy is initiated.1 Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of emtricitabine and/or tenofovir disoproxil fumarate (TDF; tenofovir DF) in HIV-infected patients coinfected with HBV and may occur with BIC/FTC/TAF.1
• Advise patients that renal impairment, including cases of acute renal failure or Fanconi syndrome, has occurred in patients receiving tenofovir prodrugs.1 Advise patients to not use BIC/FTC/TAF concomitantly with or shortly after nephrotoxic agents (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1
• Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs), including emtricitabine and/or TDF, in conjunction with other antiretrovirals.1 Advise patients to contact a clinician if symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., unusual muscle pain, shortness of breath or fast breathing, cold or blue hands and feet, dizziness or lightheadedness, fast or abnormal heartbeat, nausea, vomiting, unusual/unexpected stomach discomfort, weakness or unusual tiredness) occur.1
• Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals with advanced HIV infection.1 These symptoms may be due to an improvement in immune response, enabling the body to fight infections that may have been present with no obvious symptoms.1 Advise patients to immediately inform a healthcare provider if any symptoms of infection occur.1
• Inform caregivers that the BIC/FTC/TAF tablet may be split for children with difficulty swallowing the whole tablet.1 If the tablet is split, the portions must all be taken within approximately 10 minutes.1
• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1 Inform patients that there is a registry that monitors fetal outcomes of women exposed to BIC/FTC/TAF during pregnancy.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Gilead Sciences. Biktarvy^® (bictegravir, emtricitabine, tenofovir alafenamide) tablets prescribing information. Foster City, CA; 2024 Apr.

2. 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; 390:2063-72. [PubMed 28867497]

3. Sax P, Pozniak A, Montes M. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet . 2017; 390:2073-82. [PubMed 28867499]

5. Gallant J, Thompson M, DeJesus E. Antiviral activity, safety, and pharmacokinetics of bictegravir as 10-day monotherapy in HIV-1-infected adults. J Acquir Immune Defic Syndr . 2017; 75:61-66.

6. Tsiang M, Jones G, Goldsmith J. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother . 2016; 60:7086-97.

7. Neogi U, Singh K, Aralaguppe S. Ex-vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV type 1 non-B subtypes. AIDS . 2018; 32:469-76.

8. Molina JM, Ward D, Brar I et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet HIV . 2018; 5:e357-e365. [PubMed 29925489]

9. Daar ES, DeJesus E, Ruane P et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial. Lancet HIV . 2018; 5:e347-e356. [PubMed 29925490]

10. Oliveira M, Ibanescu RI, Anstett K et al. Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir. Retrovirology . 2018; 15:56. [PubMed 30119633]

11. Wohl DA, Yazdanpanah Y, Baumgarten A et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV . 2019; 6:e355-e363. [PubMed 31068270]

12. Stellbrink HJ, Arribas JR, Stephens JL et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV . 2019; 6:e364-e372. [PubMed 31068272]

14. Orkin C, DeJesus E, Sax PE, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials. Lancet HIV. 2020;7(6):e389-e400.

15. Maggiolo F, Rizzardini G, Molina JM, et al. Bictegravir/emtricitabine/tenofovir alafenamide in older individuals with HIV: Results of a 96-week, phase 3b, open-label, switch trial in virologically suppressed people ≥65 years of age. HIV Med . 2023;24(1):27-36.

16. Sax PE, Rockstroh JK, Luetkemeyer AF, et al. Switching to Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Virologically Suppressed Adults With Human Immunodeficiency Virus. Clin Infect Dis . 2021;73(2):e485-e493.

17. Kityo C, Hagins D, Koenig E, et al. Switching to Fixed-Dose Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) in Virologically Suppressed HIV-1 Infected Women: A Randomized, Open-Label, Multicenter, Active-Controlled, Phase 3, Noninferiority Trial. J Acquir Immune Defic Syndr . 2019;82(3):321-328.

18. Hagins D, Kumar P, Saag M, et al. Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Black Americans With HIV-1: A Randomized Phase 3b, Multicenter, Open-Label Study. J Acquir Immune Defic Syndr . 2021;88(1):86-95.

19. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial. Lancet Child Adolesc Health . 2021;5(9):642-651.

20. Zhang H, Hindman JT, Lin L, et al. A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV. AIDS . 2024;38(1):F1-F9.

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218. Gilead Sciences. Emtriva^® (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2018 Dec.

219. Institute for Safe Medication Practices. ISMP list of error-prone abbreviations, symbols, and dose designations. 2024.