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Biktarvy: The newest integrase strand inhibitor
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Integrase strand inhibitors are the newest class of antiretroviral agents on the market. They inhibit HIV replication by blocking the strand transfer step of HIV DNA integration into the host genome. Integrase inhibitors have emerged as the preferred treatment for HIV.
Elvitegravir and raltegravir were the first two integrase inhibitors to receive FDA approval. Both agents have good antiretroviral activity; however, raltegravir requires twice-daily dosing, and elvitegravir requires pharmacologic boosting by cobicistat, which is a strong inhibitor of CYP3A4, resulting in potential drug-drug interactions.
Dolutegravir, a second-generation, unboosted integrase inhibitor, was approved by the FDA in 2013. It has a higher barrier to resistance compared with the earlier generation integrase inhibitors. Dolutegravir is dosed once daily for most patients but requires twice-daily dosing when administered with certain medications or in the presence of integrase inhibitor resistance. It is available as a single agent or coformulated with abacavir/lamivudine (ABC/3TC). ABC has been associated with an increased risk for cardiovascular events and requires HLA-B*5701 testing before use to assess a patient’s risk for hypersensitivity reactions. Approved by the FDA in February, Biktarvy (Gilead Sciences) combines tenofovir alafenamide/emtricitabine (TAF/FTC) with the novel integrase inhibitor bictegravir in a single tablet. Bictegravir overcomes many of the pitfalls of these earlier integrase inhibitors.
Pharmacology
Compared with the other integrase inhibitors, bictegravir’s chemical structure is unique. It contains a bridged bicyclic ring and a distinct benzyl tail, which allows for greater solubility and oral absorption. This results in fewer drug-drug interactions and enhanced antiviral activity against integrase-resistant viruses. Drug-drug interactions are limited to potent dual inhibitors of CYP3A4 and UGT1A1 and strong inducers of CYP3A4. It is important to note that bictegravir is contraindicated with rifampin due to decreased bictegravir plasma concentrations, which may result in the loss of its therapeutic effect and the development of resistance to the drug. This may have serious implications for developing countries where HIV/tuberculosis coinfection is common.
Bictegravir has high in vitro activity against most integrase-resistant strains, including several that have reduced susceptibility to dolutegravir, and it has a high in vitro barrier to resistance. Pharmacokinetic studies found bictegravir to have about an 18-hour half-life. About one-third of the drug is excreted in the urine and two-thirds in feces. The dose of bictegravir is 50 mg daily in combination with TAF/FTC and can be taken with or without food. It is not recommended to be used in patients who have a creatinine clearance less than 30 mL/min or severe hepatic impairment; otherwise, no dose adjustments are required.
FDA approval studies
Two double-blind, multicenter phase 3 trials showed bictegravir combined with TAF/FTC to be noninferior to standard therapy for the treatment of HIV-1 in patients who were treatment naive. In the first, Gallant and colleagues (study 1489) assessed the efficacy and safety of bictegravir/TAF/FTC compared with dolutegravir/ABC/3TC. The researchers randomly assigned 631 participants to receive one of the two treatments. At 48 weeks, HIV RNA less than 50 copies/mL was achieved in 92.4% of patients in the bictegravir/TAF/FTC group and 93% of the dolutegravir/ABC/3TC group, which demonstrated noninferiority of the bictegravir regimen. In the second phase 3 trial, Sax and colleagues (study 1490) compared bictegravir/TAF/FTC with dolutegravir/TAF/FTC. There were 657 patients randomly assigned to receive one of the two treatments. At week 48, 89% in the bictegravir group and 93% in the dolutegravir group achieved an HIV RNA viral load of less than 50 copies/mL, demonstrating noninferiority of the bictegravir regimen to the dolutegravir regimen. No patients developed treatment-emergent resistance to any study agent in either trial.
Switch studies
Bictegravir has also been evaluated in two switch studies. To date, these studies have not been published, but results have been presented at national conferences. The first phase 3 study, by Daar and colleagues, included 577 patients who were virologically suppressed on a boosted protease inhibitor (bPI) and two nucleoside reverse transcriptase inhibitors. Patients either continued on this regimen or switched to bictegravir/TAF/FTC. After 48 weeks, 92% of patients who switched to the bictegravir regimen had viral RNA of less than 50 copies/mL compared with 89% who remained on the bPI regimen. The other phase 3 switch trial was conducted by Molina and colleagues. Patients who were receiving dolutegravir/ABC/3TC were either switched to bictegravir/TAF/FTC or continued on dolutegravir/ABC/3TC. At 48 weeks, HIV RNA remained less than 50 copies/mL in 94% of the switch group and in 95% of the group that remained on their dolutegravir regimen.
Safety and tolerability
Bictegravir was well-tolerated in these phase 3 trials. The most common adverse reactions included nausea, diarrhea and headache — and the rates of these reactions were comparable between the study groups. Bictegravir inhibits tubular secretion of creatinine without affecting the glomerular filtration rate. A slight increase in serum creatinine was noted in these studies, which was comparable to the dolutegravir groups.
Conclusion
Bictegravir is the latest integrase strand inhibitor to receive FDA approval. It is available as a combination product with TAF/FTC. Bictegravir has a high barrier to resistance and a lower potential for drug-drug interactions compared with other integrase inhibitors on the market. Bictegravir has been studied in four phase 3 trials to date and has performed well from both an efficacy and safety standpoint. Bictegravir combined with TAF/FTC is a convenient, new, single-pill, once-a-day option for patients with HIV.
- References:
- Biktarvy [package insert]. Foster City, CA: Gilead Sciences Inc.; 2018.
- Daar E, et al. Abstract LB-4. Presented at: IDWeek; Oct. 4-8, 2017; San Diego.
- Gallant J, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32299-7.
- Molina JM, et al. Abstract 22. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston.
- Sax PE, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32340-1.
- Tsiang M, et al. Antimicrob Agents Chemother. 2016;21;60:7086-7097.
- For more information:
- Kati Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
Disclosure: Shihadeh reports no relevant financial disclosures.