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. 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 new prodrug of tenofovir. Tenofovir alafenamide (TAF) has replaced the tenofovir disoproxil fumarate (TDF) component of two commonly used drug combinations for HIV-1 infection. The elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/TAF combination is marketed as Genvoya, and FTC/rilpivirine (RPV)/ TAF as Odefsey. The corresponding TDF combinations are Stribild and Complera.
Indications
These four-drug and three-drug combinations are approved as complete treatment of HIV-1 infections for patients ≥ 12 years of age as initial treatment in those with
no antiretroviral treatment history or to replace a stable antiretroviral regimen in those who are virologically suppressed (< 50 copies/mL) for at least six months with no history of
treatment failure and no known substitutions associated with resistance to the individual components.1,2
FTC/RPV/TAF is indicated for infections with HIV-1 RNA ≤ 100,000 copies/mL.
Dosing
Patients take Genvoya and Odefsey once daily with food. Each Genvoya tablets contain EVG (150 mg), COBI (150 mg), FTC (200 mg), and TAF (10 mg). Each Odefsey tablet contains FTC (200 mg), RPV (25 mg), and TAF (25 mg).
Potential advantages
TAF is a more efficient prodrug and is less likely to affect bone mineral density (BMD) and cause renal toxicity.3
Potential disadvantages
Subjects who received EVG/COBI/FTC/TAF experienced greater increases in serum lipid compared to the TDF counterpart.1
At week 48, total cholesterol showed a 30% increase compared to 13%. Corresponding increases for LDL-cholesterol and triglycerides were +15% vs. +3%, and +29% vs. +10%, respectively.
Comments
Tenofovir as a chemical entity has poor membrane permeability and is unable to be converted intracellularly to active tenofovir diphosphate (TFV-DP). TDF was the first approved prodrug for TFV-DP. It is metabolized to tenofovir and subsequently intracellularly to TFV-DP. However, it has been associated with renal toxicity and a decrease in BMD due to high system exposure. TAF, a new prodrug, provides pharmacologically active TFV-DP at one-tenth the oral dose and 90% lower systemic exposure.3 Results from two pooled studies in which subjects were randomized to EVG/COBI/FTC/TAF (n = 866) or the corresponding TDF formulation (n = 867), showed a mean change in lumbar spine BMD from baseline to week 48 (-1.30% for TAF vs. -2.86% for TDF). Changes in total hip were -0.66% and -2.95%.1,4 In addition, those randomized to TAF had significantly smaller mean serum creatinine increases and less proteinuria. In subjects who were randomized to switch from a TDF to a TAF regimen (n = 959) or remained on their previous TDF regimen (n = 477), changes in hip BMD from baseline at week 48 was 1.47% for TAF and -0.34% for TDF.6 Changes were 1.56% and -0.44% for spine BMD along with improvement in glomerular filtration. In virologically suppressed patients with creatinine clearance of 30-69 mL/min, switching to a TAF regimen was associated with minimal change in glomerular filtration rate but with improvement in proteinuria and albuminuria as well as BMD.5 Clinical trials showed comparable efficacy between the TAF and TDF combinations, both as initial treatment and those subjects with virologically suppressed HIV-1 who switched from the TDF to TAF formulation.1,2,4,6,7
Clinical implications
FTC/COBI/EVG/TAF and FTC/RPV/TAF provide effective and safer antiretroviral treatments than the TDF counterparts, although there is potential for an increase in plasma lipids. The cost for FTC/RPV/TAF is the same for the TDF formulation ($2346 for a 30-day supply). EVG/COBI/FTC/TAF is slightly less than the TDF formulation ($2571 vs $2704).
REFERENCES
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Genvoya Prescribing Information. Gilead. March 2016.
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Odefsey Prescribing Information. Gilead. March 2016.
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Ray AS, et al. Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res 2016;125:64-70.
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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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Pozniak A, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine,
in HIV-infected patients with renal impairment: 48-Week results from a single-arm, multicenter, open-label phase 3 study.
J Acquir Immune Defic Syndr 2016 71:530-537.
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Mills A, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in
antiretroviral regimens for virologically suppressed adults with HIV-1 infection: A randomised, active-controlled,
multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis 2016;16:43-52.
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Wohl D, et al. A randomized, double-blind comparison of
tenofovir alafenamide (TAF) vs. tenofovir disoproxil fumarate (TDF),
each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F)
for initial HIV-1 treatment: Week 96 results. J Acquir Immune Defic Syndr 2016 Jan. 29 [Epub ahead of print].
