Tenofovir Formulations: Out with the Old, In with the New

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor that is a new formulation of tenofovir.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NRTI) that is a new formulation of tenofovir.

Tenofovir alafenamide is intracellularly converted from its prodrug to tenofovir diphosphate, allowing for higher drug concentrations in peripheral blood cells and lower plasma levels compared with tenofovir disoproxil fumarate.1 These higher drug concentrations and lower plasma levels can be achieved with lower doses of tenofovir alafenamide, permitting less drug exposure to the kidneys and bones, which leads to decreased bone and kidney adverse effects.

Tenofovir Alafenamide in HIV/AIDS

One study that compared elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide demonstrated not only non-inferiority, but also significantly lower increases in serum creatinine, less proteinuria, and a smaller decrease in bone mineral density of the spine at 48 weeks.2

There are also a number of ongoing studies evaluating the use of tenofovir alafenamide as part of the NRTI backbone in single-tablet combinations with darunavir/cobicistat/emtricitabine and an investigational integrase inhibitor with emtricitabine/tenofovir alafenamide that does not require a boosting agent. In addition, phase 3 switch studies comparing tenofovir alafenamide/emtricitabine with tenofovir disoproxil fumarate/emtricitabine and rilpivirine/emtricitabine/tenofovir disoproxil fumarate with rilpivirine/emtricitabine/tenofovir alafenamide are underway.

Currently, tenofovir alafenamide is only available in a single-tablet regimen containing elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg (Genvoya). Unlike previous tenofovir disoproxil fumarate formulations, this combination tablet is safe to use without dosage adjustments in patients with a creatinine clearance >30 mL/min.

When available, tenofovir alafenamide dosing should be 10 mg by mouth once daily in the presence of protease inhibitors or boosting agents, whereas tenofovir alafenamide 25 mg should be given by mouth once daily with non-nucleoside reverse transcriptase inhibitors or integrase inhibitors.3

Tenofovir Alafenamide in Hepatitis B

In January 2016, Gilead Sciences submitted a new drug application for tenofovir alafenamide for the treatment of chronic hepatitis B virus (HBV) infection. Non-inferiority was demonstrated in 2 phase 3 trials in treatment-naïve and treatment-experienced individuals.4

Similar to the HIV studies, tenofovir alafenamide for demonstrated smaller decreases in bone mineral density in the hip and spine as well as median change in serum creatinine at 48 weeks.4 The proposed daily dosing for tenofovir alafenamide in HBV is 25 mg by mouth daily. If those co-infected with HIV, the same dosing principles would be followed based on the antiretroviral agents.

References

1. AIDSInfo. Tenofovir alafenamide. https://aidsinfo.nih.gov/drugs/print/514/tenofovir-alafenamide/0/1/professional. Updated December 17, 2015. Accessed February 2, 2016.

2. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015 Jun 27;385(9987):2606-2615.

3. Lawson EB, Martin H, McCallister S, Shao Y, Vimal M, Kearney BP. Drug interactions between tenofovir alafenamide and HIV antiretroviral agents. http://www.icaaconline.com/php/icaac2014abstracts/data/papers/2014/H-1012.htm. Published 2014. Accessed February 2, 2016.

4. Gilead Sciences. Gilead announces top-line results from two Phase 3 studies evaluating tenofovir alafenamide (TAF) for patients with chronic hepatitis B infection. https://www.gilead.com/news/press-releases/2016/1/gilead-announces-topline-results-from-two-phase-3-studies-evaluating-tenofovir-alafenamide-taf-for-patients-with-chronic-hepatitis-b-infection. Accessed February 2, 2016.