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Bictegravir
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Potential Adverse Effects
Interactions with Other Drugs
Resistance
Implications of bictegravir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for bictegravir treatment
References
Related Resources
decorative spacerDHHS Guidelines
decorative spacerCharacteristics of Integrase Inhibitors
decorative spacerInteractions between INSTI & NNRTI or PI
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decorative spacerElvitegravir
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Class

Integrase inhibitor

Background
U.S. Manufacturer

Gilead Sciences

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Approval

Bictegravir was approved by the U.S. Food and Drug Administration (FDA) in 2018 as part of a coformulation that includes the nucleoside analogues tenofovir alafenamide (TAF) and emtricitabine. Bictegravir/TAF/emtricitabine is indicated for initial therapy for adults with HIV-1 infection and as a replacement regimen for adults who are on a stable antiretroviral regimen with virologic suppression and whose virus has no resistance to bictegravir, TAF, or emtricitabine. Bictegravir is not available as a single agent.

Approval of bictegravir/TAF/emtricitabine was based largely on two randomized, double-blind Phase 3 studies showing that initial treatment with this combination resulted in rates of HIV viral suppression that were comparable with those achieved by dolutegravir/abacavir/lamivudine and by dolutegravir + TAF/emtricitabine. (1,2)

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Formulation and Dosing

Bictegravir is currently available only in a coformulation with TAF and emtricitabine.

Dosing of Dolutegravir
AdultIn a fixed-dose combination tablet:
Bictegravir 50 mg + TAF 25 mg + emtricitabine 200 mg, 1 tablet QD
PediatricNot FDA approved

Abbreviations: QD = once daily; TAF = tenofovir alafenamide

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decorative spacerdecorative itemThere are no food restrictions.
decorative spacerdecorative itemNo dosage adjustment is required is required for patients with creatinine clearance ≥30 mL/min. Not recommended for patients with creatinine clearance <30 mL/min.
decorative spacerdecorative itemBictegravir has not been studied and is not recommended in patients with severe (Child-Pugh Class C) liver disease.
decorative spacerdecorative itemBictegravir has not been studied in pregnant women.
decorative spacerdecorative itemBictegravir interacts with other medications; dosage adjustments may be required and certain combinations are contraindicated. For more information about drug interactions, see "Interactions with Other Drugs" below and refer to the Database of Antiretroviral Drug Interactions.
decorative spacerdecorative itemConsult product labeling for detailed dosing information.
Clinical Use
Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services (DHHS) include the coformulation bictegravir/TAF/emtricitabine among the "recommended initial regimens for most people with HIV."

Bictegravir has been studied in two Phase 3 randomized double-blind studies in initial therapy, described above in "Approval." In the first, the combination of bictegravir/TAF/emtricitabine was compared with coformulated dolutegravir/abacavir/lamivudine. At 48 weeks, by snapshot analysis, 92% of recipients of the bictegravir regimen and 93% of recipients of the dolutegravir regimen had HIV RNA suppression to <50 copies/mL; the results met criteria for noninferiority of the bictegravir regimen (p = .78).(1) In the second study, bictegravir/TAF/emtricitabine was compared with dolutegravir plus coformulated TAF/emtricitabine. At 48 weeks, by snapshot analysis, HIV RNA suppression to <50 copies/mL was seen in 89% of the bictegravir group and 93% of the dolutegravir group; these results also met criteria for noninferiority.(2)

Two Phase 3 switch studies evaluated the efficacy and safety of switching patients with HIV RNA suppression on stable antiretroviral regimens (with no HIV resistance to integrase inhibitors or nucleoside analogues) to bictegravir/TAF/emtricitabine. An open-label study randomized patients on either atazanavir or darunavir (each with a pharmacokinetic booster) plus 2 nucleoside analogues to switch to the bictegravir coformulation or to continue their current regimen. After 48 weeks, virologic suppression to <50 copies/mL was maintained in 92% of the subjects who switched to bictegravir/TAF/emtricitabine and 89% of those who continued their previous regimen; the difference was not statistically significant.(3) A double-blind study randomized patients on either dolutegravir + abacavir/lamivudine (either as a single-pill combination or as 2 separate pills) to switch to bictegravir/TAF/emtricitabine or continue their current regimen. At 48 weeks, HIV RNA remained <50 copies/mL in 94% of the switch group and 95% of the group that did not switch.(4)

Bictegravir has not been studied in subsequent therapy, or in patients whose HIV virus has mutations that confer resistance to integrase inhibitors.

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Potential Adverse Effects

In the clinical studies described above, symptomatic adverse reactions to the bictegravir/TAF/emtricitabine coformulation were uncommon but included nausea, diarrhea, and headache; rash also has been reported. Laboratory abnormalities included increases in total bilirubin and in serum creatinine. Bictegravir inhibits tubular secretion of creatinine without affecting the actual glomerular filtration rate. In Phase 3 studies of initial therapy, serum creatinine increased by a median of 0.10 mg/dL by week 4 and remained stable to week 48.(1,2)

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with bictegravir is initiated.

Bictegravir has not been studied in pregnant women.

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Interactions with Other Drugs

Bictegravir is a substrate of hepatic isoenzyme CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A1. Other medications that induce these enzymes (particularly if they induce both) can reduce plasma concentrations of bictegravir, whereas drugs that inhibit them can increase plasma concentrations of bictegravir. The antimycobacterial drugs rifampin and rifapentine; the antiseizure drugs carbamazepine, phenytoin, and phenobarbital; and the herb and St. John's wort are among the drugs that may substantially decrease bictegravir plasma levels. Atazanavir may greatly increase bictegravir plasma levels.(5)

Bictegravir also inhibits the renal transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) and may increase levels of drugs that are substrates of these transporters, for example, metformin.(5)

Polyvalent cations (eg, aluminum, calcium, iron, and magnesium cations), including those contained in some antacids, laxatives, buffered medications, and mineral supplements, may interfere with gastrointestinal absorption of bictegravir. Polyvalent cations should be taken ≥2 hours before or ≥2 hours after bictegravir, though calcium or iron supplements may be taken with bictegravir if they are also taken with food. Proton pump inhibitors and H2 receptor antagonists do not affect bictegravir concentrations.(6)

Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

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Resistance

Integrase resistance mutations have been seen in in vitro studies of bictegravir, but clinical studies have produced no evidence to date of emergent, therapeutically significant resistance to bictegravir. Resistance associated with previous exposure to other integrase inhibitors may affect the efficacy of bictegravir, but this has yet to be evaluated in clinical studies.

Implications of bictegravir resistance for treatment with other antiretrovirals

In the Phase 3 studies described above (see Use in Initial vs Subsequent Therapy), no emergent resistance mutations have been reported in persons treated with bictegravir, and no other clinical data evaluating bictegravir resistance are available at this time. In in vitro studies, the R263K and M50I mutations were selected by bictegravir.(7) These mutations resulted in low-level phenotypic resistance to bictegravir, dolutegravir, and elvitegravir.

Bictegravir mutations are not expected to affect sensitivity to other classes of antiretroviral agents.

Implications of resistance to other antiretrovirals for bictegravir treatment

In vitro studies suggest that bictegravir may maintain activity in the setting of some resistance mutations selected by other integrase inhibitors (particularly elvitegravir and raltegravir), but to date there have been no clinical studies of bictegravir in persons with preexisting integrase inhibitor-associated mutations.(7)

Resistance mutations selected by other classes of antiretrovirals are not expected to contribute to bictegravir resistance.

References
1.   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 Nov 4;390:2063-72.
2.   Sax PE, Pozniak A, Montes ML, et al. 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 Nov 4;390:2073-82.
3.  Daar E, DeJesus E, Ruane P, et al. Phase 3 randomized, controlled trial of switching to fixed-dose bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) from boosted protease inhibitor-based regimens in virologically suppressed adults: week 48 results. In: Program and abstracts of ID Week 2017; October 4-8, 2017; San Diego, CA. Abstract LB-4.
4.  Molina JM, Ward D, Brar I, et al. Switch to bictegravir/F/TAF from DTG and ABC/3TC. In: Program and abstracts of the 2018 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston. Abstract 22.
5.  Zhang H, Custodio JM, Wei X, et al. Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 40.
6.  Biktarvy prescribing information. Gilead Sciences: Foster City, CA.
7.   Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016 Nov 21;60(12):7086-97.