By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a fixed-dose combination of elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) for the treatment of HIV-1 infections. TAF is a new prodrug for tenofovir, which is metabolized to tenofovir-diphosphate (TFV-DP). The fixed combination is marketed by Gilead as Genvoya.
INDICATIONS
EVG/COBI/FTC/TAF is indicated as a complete regimen for the treatment of HIV-1 infections in adults and pediatric patients ≥ 12 years of age.1 It can be used as initial treatment or as replacement therapy for patients who are virologically suppressed. Virological suppression is defined as HIV-1 RNA < 50 copies/mL on a stable regimen for at least 6 months.
DOSAGE
The dosage is one tablet orally once daily with food.1 Each tablet contains EVG (150 mg), COBI (150 mg), FTC (200 mg), and TAF (10 mg).
POTENTIAL ADVANTAGES
TAF provides lower plasma levels but higher intracellular tenofovir levels compared with another prodrug tenofovir disoproxil fumarate (TDF).2 TAF may be associated with reduced renal toxicity and less effect on bone mineral density (BMD).1,3
POTENTIAL DISADVANTAGES
TAF is associated with greater increase in total cholesterol, LDL-cholesterol, and triglycerides.3
COMMENTS
The safety and efficacy of EVG/COBI/FTC/TAF was assessed in five studies.1 Two were 48-week randomized, non-inferiority studies compared to EVGF/COBI/FTC/TDF. One study included virologically suppressed adults maintained on Atripla, Truvada + atazanavir + cobicistat or ritonavir, or EVG/COBI/FTC/TAF. A third study compared EVG/COBI/FTC/TAF to EVG/COBI/FTC/TDF in adults with renal impairment, and a fourth evaluated treatment-naïve adolescents. In the first two studies, treatment-naïve subjects (n = 1733) with a mean baseline HIV-1 RNA of 4.5 log10 copies per mL were randomized to EVG/COBI/FTC/TAF or EVG/COBI/FTC/TDF. Virological outcome (HIV-1 RNA < 50) was 92% for the TAF-regimen and 90% for the TDF-regimen. For virologically suppressed subjects, those randomized to the TAF-regimen (n = 799) had a virological outcome of 96% at week 48 compared to 93% for those who remained on their original regimen (n = 397). Similar results were observed at week 24 for subjects with renal impairment (n = 248), for both treatment-naïve or virologically suppressed subjects. Virological outcome in treatment-naïve adolescent subjects (n = 23) was 91% at week 24. The regimens had different effect on BMD. In the parallel study, there was a mean BMD change of -1.30% from baseline for the TAF-regimen compared to -2.86% for the TDF-regimen at the lumbar spine and -0.66% compared to -2.95%, respectively, at the total hip. In the switch study, BMD at lumbar spine and total hip increased by 1.86% and 1.95%, respectively, for those switched to the TAF-regimen and showed a slight decrease (-0.11% and -0.14%) when continued on their baseline regimen. The TAF-regimen showed a 30 mg/dL increase from baseline in total cholesterol compared to 13 mg/dL for the TDF-regimen (+18.5 vs 7.8%). LDL cholesterol increased by 14.4% vs 2.8%. Triglycerides increased by 25.7% vs 8.4%.
CLINICAL IMPLICATIONS
EVG/COBI/FTC/TAF provides an alternative to EVG/COBI/FTC/TDF. Currently, the latter is one of the recommended, complete, fixed-dose regimens for initial therapy with CrCl >70 mgL/min.5 EVG/COBI/FTC/TAF is an alternative with a potentially improved safety profile and is also approved for use in patients with CrCl > 30 mL/min. The cost of EVG/COBI/FTC/TAF is the same as EVG/COBI/FTC/TDF: $2577.66 for a 30-day supply.
REFERENCES
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Genvoya Prescribing Information. Gilead Sciences. November 2015.
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Markowitz M, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother 2014;69:1362-1369.
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U.S. Food and Drug Administration. FDA approved drug products. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo. Accessed Dec. 30, 2015.
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Sax PE, 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;385:2606-2615.
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AIDSinfo. Federally approved HIV/AIDS medical practice guidelines. Available at: http://aidsinfo.nih.gov/guidelines. Accessed Jan. 2, 2016.
