OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Bictegravir – Biktarvy®

(Bictegravir, Emtricitabine and Tenofovir Alafenamide Combination Product)

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Bictegravir	1611493-60-7	C21-H18-F3-N3-O5
Dolutegravir	1051375-16-6	C20-H19-F2-N3-O5
Elvitegravir	697761-98-1	C23-H23-Cl-F-N-O5
Raltegravir	518048-05-0	C20-H21-F-N6-O5

ANNOTATED BIBLIOGRAPHY

References updated: 10 April 2019

• Núñez M. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 505-18.

  (Review of hepatotoxicity of antiviral agents including drugs for HIV infection, although the integrase strand transfer inhibitors are not discussed).
• Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Hillal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1137-57.

  (Textbook of pharmacology and therapeutics).
• https://hivinfo​.nih.gov​/hiv-source/medical-practice-guidelines​/hiv-treatment-guidelines .

  (Regularly updated clinical guidelines on the use of antiretroviral agents in HIV-1 infected adults, adolescents and children).
• Cocohoba J, Dong BJ. Raltegravir: the first HIV integrase inhibitor. Clin Ther. 2008;30:1747–65. [PubMed: 19014832]

  (Review of the mechanism of action, pharmacokinetics and phase I-III studies of raltegravir; in combined phase III studies, ALT elevations above 5 times ULN occurred in 4.3% of 462 raltegravir treated vs 3.4% of 237 placebo treated patients who were receiving optimized background therapy; no hepatic serious adverse events were reported).
• Surgers L, Lacombe K. Hepatoxicity of new antiretrovirals: a systematic review. Clin Res Hepatol Gastroenterol. 2013;37:126–33. [PubMed: 23522569]

  (Review of evidence of liver injury in large clinical trials of newer antiretroviral agents including dolutegravir but not bictegravir concluded that "the overall hepatic tolerance is far better with the novel drugs in this review than with former ARV regimens"; ALT elevations occurred with equal frequency in dolutegravir and comparator arms, and one patient on raltegravir developed DRESS syndrome).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 12 [1.3%] cases were attributed to antiretroviral agents, but none to the integrase inhibitors–dolutegravir, elvitegravir, raltegravir or bictegravir).
• Sax PE, Pozniak A, Montes ML, Koenig E, DeJesus E, Stellbrink HJ, Antinori A, 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;390(10107):2073–82. [PubMed: 28867499]

  (Among 657 previously untreated adults with HIV infection who were started on combination antiretroviral therapy with bictegravir or dolutegravir with tenofovir and emtricitabine, HIV RNA suppression was similar in the two groups [89% vs 93%] as were the rates of adverse events, including ALT levels above 5 times ULN [2% vs 1%] which were usually attributable to concurrent hepatitis B or C).
• Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, Girard PM, 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(10107):2063–72. [PubMed: 28867497]

  (Among 631 adults with previously untreated HIV infection started on single tablet regimens, viral control [HIV RNA <500 copies/mL] at 48 weeks was similar with bictegravir/emtricitabine/tenofovir [92%] as with dolutegravir/abacavir/lamivudine [93%], while adverse event rates were slightly less, including discontinuations for adverse events [0% vs 1.3%], serious adverse events [6% vs 8%] and ALT elevations above 5 times ULN [0.6% vs 1.3%]).
• Daar ES, DeJesus E, Ruane P, Crofoot G, Oguchi G, Creticos C, Rockstroh JK, 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]

  (Among 577 adults with HIV infection switched to Biktarvy [bictegravir/ emtricitabine/ tenofovir] or maintained on previous combination regimen, HIV RNA suppression was similar in the two groups, as were overall as well as serious adverse event rates, ALT elevations above 5 times ULN occurring in 1% vs 2%).
• Molina JM, Ward D, Brar I, Mills A, Stellbrink HJ, López-Cortés L, Ruane P, 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]

  (Among 563 adults with HIV infection switched to bictegravir/emtricitabine/tenofovir or maintained on previous combination regimen, HIV RNA suppression was similar in the two groups [both 99%], as were overall [80% vs 80%] as well as serious adverse event rates [5% vs 8%], ALT elevations above 5 times ULN occurring in 2% vs 0%, all abnormalities occurring in patients with underlying pre-existing liver disease).
• Markham A. Bictegravir: first global approval. Drugs. 2018;78:601–6. [PubMed: 29564777]

  (Review of the mechanism of action, history of development, pharmacology, clinical efficacy and safety of bictegravir; mentions that elevations in serum ALT levels above 5 times ULN occurred in 1-2% of patients treated with bictegravir in clinical trials).
• Biktarvy--another INSTI-based combination for HIV. Med Lett Drugs Ther. 2018;60(1553):132–5. [PubMed: 30133424]

  (Concise review of the mechanism of action, efficacy, safety and costs of bictegravir combined with tenofovir and emtricitabine [Biktarvy]; mentions the flares of hepatitis B in co-infected subjects can occur when the combination is stopped).