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Biktarvy

Generic Name: Bictegravir Sodium, Emtricitabine, and Tenofovir Alafenamide Fumarate
Class: HIV Integrase Inhibitors
Chemical Name: 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one
Molecular Formula: C21H18F3N3O5C8H10FN3O3SC21H29N6O5P
CAS Number: 1611493-60-7

Medically reviewed on March 5, 2018

Warning

Warning: Post Treatment Acute Exacerbation of Hepatitis B1

See full prescribing information for complete boxed warning.1

  • Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Closely monitor hepatic function in these patients. If appropriate, anti-hepatitis B therapy may be warranted.1

Introduction

See also: Atripla

The fixed combination of bictegravir sodium, an HIV-1 integrase strand transfer inhibitor (INSTI), and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs), is an antiretroviral agent.1

Uses for Biktarvy

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate has the following uses:

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is a three-drug combination of bictegravir (BIC), an HIV-1 INSTI, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 NRTIs, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Biktarvy Dosage and Administration

General

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is available in the following dosage form(s) and strength(s):

Tablets: 50 mg of bictegravir (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of tenofovir alafenamide fumarate). 1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

  • Testing: Prior to or when initiating bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, test for HBV infection. Prior to or when initiating bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus.1

  • Recommended dosage: One tablet taken once daily with or without food.1

  • Renal impairment: Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute.1

  • Hepatic impairment: Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with severe hepatic impairment.1

Cautions for Biktarvy

Contraindications

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is contraindicated to be co-administered with: 1

  • Dofetilide.1

  • Rifampin.1

Warnings/Precautions

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Patients with HIV-1 should be tested for the presence of chronic HBV infection before or when initiating antiretroviral therapy.1

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Patients coinfected with HIV-1 and HBV who discontinue bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.1

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

The concomitant use of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to: 1

  • Loss of therapeutic effect of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate and possible development of resistance.1

  • Possible clinically significant adverse reactions from greater exposures of concomitant drugs.1

See Drug Interactions section in Full Prescribing Information for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate therapy; review concomitant medications during bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate therapy; and monitor for the adverse reactions associated with the concomitant drugs.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.1

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also 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 treatment.1

New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate in subjects with no antiretroviral treatment history with eGFRs greater than 30 mL per minute, and in virologically suppressed subjects switched to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate with eGFRs greater than 50 mL per minute, renal serious adverse events were encountered in less than 1% of subjects treated with bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate through Week 48. Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute.1

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.1

Prior to or when initiating bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, and during treatment with bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.1

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of the fixed combination of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.1

Risk Summary: There are insufficient human data on the use of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate 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 US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the US 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD). 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. 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.1

Emtricitabine Human Data: 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 US 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.1

Bictegravir Animal Data: 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. 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.1

Emtricitabine Animal Data: 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.1

Tenofovir Alafenamide Animal Data: 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Lactation

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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate or all of the components of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate 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. 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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Bictegravir Animal Data: 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.1

Tenofovir Alafenamide Animal Data: 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.1

Pediatric Use

Safety and effectiveness of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate in pediatric patients less than 18 years of age have not been established.1

Geriatric Use

Clinical trials of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.1

Renal Impairment

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended in patients with severe renal impairment (estimated creatinine clearance [CLcr] below 30 mL per minute, estimated by Cockcroft-Gault. No dosage adjustment of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is recommended in patients with CLcr greater than or equal to 30 mL per minute. 1

Hepatic Impairment

No dosage adjustment of bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Therefore, bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is not recommended for use in patients with severe hepatic impairment.1

Common Adverse Effects

Most common adverse reactions (incidence greater than or equal to 5%, all grades) are diarrhea, nausea, and headache. 1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Because bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.1

  • Consult the Full Prescribing Information prior to and during treatment for important drug interactions. 1

Actions and Spectrum

Mechanism of Action

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate is a fixed dose combination of antiretroviral drugs bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF).1

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. 1

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, ε, and mitochondrial DNA polymerase γ.1

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.1

Spectrum

Bictegravir: The antiviral activity of BIC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (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.1

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.1

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).1

Resistance

Bictegravir in Cell Culture: 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.1

Emtricitabine in Cell Culture: 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.1

Tenofovir Alafenamide in Cell Culture: 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.1

Individuals with No Antiretroviral Treatment History in Clinical Trials: Pooled genotypic resistance analyses were performed on paired baseline and on-treatment HIV-1 isolates from subjects receiving bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate through week 48 in Trials 1489 and 1490 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-1.1

Virologically Suppressed Individuals in Clinical Trials: In 2 switch trials, Trials 1844 and 1878 , 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.1

Bictegravir Cross-Resistance: 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.1

Emtricitabine Cross-Resistance: 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.1

Tenofovir Alafenamide Cross-Resistance: 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.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

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 bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Advise the patient to not discontinue bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate without first informing their healthcare provider.1

Drug Interactions

Bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate 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.1

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.1

Renal Impairment

Advise patients to avoid taking bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate 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.1

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate. Advise patients that they should stop bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.1

Missed Dosage

Inform patients that it is important to take bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance.1

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate.1

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Bictegravir Sodium, Emtricitabine, and Tenofovir Alafenamide Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

50 mg bictegravir, 200 mg emtricitabine, 25 mg tenofovir alafenamide

Biktarvy

Gilead Sciences Inc.

AHFS Drug Information. © Copyright 2018, Selected Revisions March 5, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Gilead Sciences, Inc. Biktarvy (bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate) ORAL prescribing information. 2018 Feb. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=664cb8f0-1f65-441b-b0d9-ba3d798be309

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