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Better Renal and Bone (But Not Lipid) Changes
After Switch From E/C/F/TDF to E/C/F/TAF
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CROI: Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate - (02/27/15) oral talk by Paul Sax
CROI: Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy - (02/26/15) oral talk by David Wohl
CROI: Safety of Tenofovir Alafenamide in Renal Impairment - (02/27/15)
Efficacy and Safety of Switching to Simpler Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) in HIV-1/Hepatitis B Coinfected Adults in North America and Japan (NCT02071082): Week 48 Results - (08/16/15)
[parent study] Switching From a Tenofovir Disoproxil Fumarate (TDF)-Based Regimen to a Tenofovir Alafenamide (TAF)-Based Regimen: Data in Virologically Suppressed Adults Through 48 Weeks of Treatment - (07/22/15)
IDSA/IDWeek 2015, October 7-11, San Diego
Mark Mascolini
People who switched from suppressive Stribild (coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; E/C/F/TDF) to once-daily coformulated E/C/F plus tenofovir alafenamide (E/C/F/TAF) maintained viral control and had improving bone and kidney markers through 48 weeks in a randomized US trial [1]. Lipids rose more in the E/C/F/TAF arm than in the continued-TDF arm, and the total-to-high-density lipoprotein (HDL) cholesterol ratio worsened slightly in both arms.
TAF is an investigational tenofovir prodrug that proved virologically noninferior to tenofovir disoproxil fumarate (TDF) when each was coformulated with E/C/F and tested in two international phase 3 trials that enrolled antiretroviral-naive people [2]. Those trials found signals of better bone and kidney safety in the E/C/F/TAF arm.
The new analysis started with adults virologically suppressed while taking TDF plus either E/C/F, atazanavir/ritonavir/emtricitabine, or efavirenz/emtricitabine. Researchers randomized 959 participants to switch to E/C/F/TAF and 477 to continue their TDF regimen. All had a viral load below 50 copies for at least 48 weeks on their TDF combination and an estimated glomerular filtration rate (eGFR) at or above 50 mL/min. After 48 weeks 932 of 959 randomized to E/C/F/TAF and 444 of 477 who continued their original TDF-containing regimen maintained a viral load below 50 copies (97% versus 93%, P < 0.001).
In a prespecified analysis, researchers focused on 459 people originally taking E/C/F/TDF and randomized to continue that regimen (n = 153) or to switch to E/C/F/TAF (n = 306) for 48 weeks. Median age stood at 40 in the E/C/F/TAF group and at 42 in the E/C/F/TDF group. Respective proportions of women were 9% and 8%, of whites 70% and 69%, and of blacks 20% and 26%. Median CD4 count measured 693 in the E/C/F/TAF arm and 673 in the E/C/F/TDF arm and median eGFR 103 and 101 mL/min.
After 48 weeks, 301 of 306 people in the E/C/F/TAF group and 149 of 153 staying with E/C/F/TDF still had a viral load below 50 copies (98.4% versus 97.4%, difference 1.0, 95% confidence interval -1.9 to 3.9). There were 2 virologic failures in the E/C/F/TAF group and 1 in the E/C/F/TDF group (0.7% and 0.7%).
During the 48-week comparison, no treatment-related serious adverse events developed in either study arm. No one stopped E/C/F/TAF because of an adverse event, while 2 stopped E/C/F/TDF for rising serum creatinine. Median serum creatinine fell slightly in the E/C/F/TAF arm while rising in the E/C/F/TDF group, and the 48-week difference between the two groups was statistically significant (P < 0.001).
Four urine protein markers, including two markers of tubular proteinuria, fell after the switch to E/C/F/TAF while rising further in the continued-E/C/F/TDF arm (P < 0.001 for each between-arm difference). Spine bone mineral density (BMD) improved an average 1.33% in the 48 weeks after the switch to E/C/F/TAF while falling an average 0.50% with continued E/C/F/TDF, a significant between-arm difference (P < 0.001). Hip BMD also improved through 48 weeks in people trading E/C/F/TDF for E/C/F/TAF while dropping in the E/C/F/TDF arm (+1.15% versus -0.24%, P < 0.001). Proportions of participants with T-score-defined osteopenia or osteoporosis fell over 48 weeks in the E/C/F/TAF arm while remaining essentially unchanged in the E/C/F/TDF group.
Median total cholesterol, low-density lipoprotein (LDL) cholesterol, HDL cholesterol, and triglycerides all rose slightly in the E/C/F/TAF arm through 48 weeks. LDL cholesterol and triglycerides fell slightly in the continued E/C/F/TDF arm. The total-to-HDL ratio rose (worsened) from 3.5 to 3.8 in the E/C/F/TAF arm and from 3.5 to 3.6 in the E/C/F/TDF arm, a nonsignificant difference (P = 0.41).
The researchers suggested that "longer term data are needed to understand the clinical relevance of lipid changes in the TAF arm." They proposed that the improved kidney and bone signals after the switch from E/C/F/TDF to E/C/F/TAF reflects the approximately 90% drop in plasma tenofovir levels after TAF replaced TDF.
References
1. Thompson M, Morales-Ramirez J, McDonald C, et al. Switching from a tenofovir disoproxil fumarate (TDF) to a tenofovir alafenamide (TAF)-based single tablet regimen (STR): week 48 data in HIV-1 infected virologically suppressed adults. IDWeek 2015, October 7-11, San Diego. Abstract 725.
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;385:2606-2615.
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