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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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TAF Comparable to TDF in Once-Daily Pill for ART-Naive: 48-Week Results
  53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
Tenofovir alafenamide (TAF), replacing TDF in the one-pill once-daily Stribild combination, controlled HIV as well as TDF-containing Stribild through 48 weeks in a trial involving 170 antiretroviral-naive adults [1]. Estimated glomerular filtration rate (eGFR) changed less with TAF than with TDF (tenofovir disoproxil fumarate), and bone mineral density dropped less with TAF.
TAF is a tenofovir prodrug that yields higher intracellular and lower plasma concentrations of tenofovir diphosphate, tenofovir's active metabolite. In a double-blind placebo-controlled phase 2 trial, researchers compared standard TDF-containing Stribild (elvitegravir/cobicistat plus TDF/emtricitabine) and a coformulation that substitutes TAF for TDF. Antiretroviral-naive study participants were randomized in a 2-to-1 ratio to the TAF pill or the TDF pill. Everyone had a CD4 count above 50 and an eGFR at or above 70 mL/min. No one tested positive for HBV or HCV.
In the TAF and TDF groups, median age stood at 34 and 38, pretreatment CD4 count at 385 and 397, and pretreatment viral load at 4.55 and 4.58 log10 copies/mL (about 35,500 and 38,000 copies). Almost all study participants were men, two thirds were white, and about 30% were black. Median pretreatment eGFR was 115 mL/min in the TAF group and 113 mL/min in the TDF group. In a pharmacokinetic substudy involving 26 participants, tenofovir diphosphate exposure was 5.3-fold higher in peripheral blood mononuclear cells with TAF than with TDF and tenofovir plasma exposure was 91% lower with TAF than TDF.
Snapshot analysis at 48 weeks determined that 99 of 112 people randomized to TAF (88.4%) and 51 to 58 randomized to TDF (87.9%) had a viral load below 50 copies. In a missing-data-equals-failure analysis, 48-week response rates were 90.2% with TAF and 89.7% with TDF. Seven people in the TAF group and 6 in the TDF group (6.3% and 10.3%) were rated virologic nonresponders. Four people (3.6%) assigned to TAF and none assigned to TDF discontinued treatment because of an adverse event. Median CD4 counts rose by 177 cells with TAF and by 204 with TDF.
Six people met criteria for resistance analysis, 3 in each arm. No one in the TAF group had detectable resistance mutations. In the TDF group, two reverse transcriptase mutations (M184V and K70E, associated with emtricitabine and TDF respectively) arose in 1 person with persistent viremia, and M184V and E92Q (an integrase mutation) evolved in another person with a virologic rebound at week 32.
eGFR declined with both regimens in the first weeks of therapy, then stabilized. At week 48 median eGFR fell 5.5 mL/min with TAF and 10.0 mL/min with TDF, a significant difference (P = 0.041). No renal tubulopathy occurred in either treatment arm, and renal tubular proteins changed less in the TAF arm. Bone mineral density declined significantly more in the spine and hip with TDF than with TAF (P < 0.001 for both comparisons).
A slightly higher proportion of people taking TAF than TDF had any grade 3 or 4 lab abnormality (25% versus 17%), principally low-density lipoprotein cholesterol (9% versus 3%), creatine phosphokinase (6% versus 3%), and neutropenia (5% versus 2%). Nausea was more frequent with TAF than TDF (21% versus 12%).
1. Sax P, Brar I, Elion R, et al. 48 Week study of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF), each in a single tablet regimen with elvitegravir, cobicistat, and emtricitabine for initial HIV treatment. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H1464d.
48 Week Study of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF), Each in a Single Tablet Regimen (STR) with Elvitegravir, Cobicistat, and Emtricitabine [E/C/F/TAF vs. E/C/F/TDF] for Initial HIV Treatment
Reported by Jules Levin
53rd ICAAC, Denver, CO
September 10-13, 2013
P. Sax1, I. Brar2, R. Elion3, A. Zolopa4, R. Ortiz5, H Wang6, C Callebaut6, H Martin6, M Fordyce6,
S. McCallister6
1Brigham and Women's Hosp, Boston MA, US; 2Henry Ford Hosp, Detroit MI, US; 3George Washington
Univ. Hosp, Washington DC, US; 4Stanford Univ, Palo Alto CA, US; 5Orlando Immunology Ctr, Orlando, FL, US; 6Gilead Sciences, Foster City CA, US
GS-US-292-0102 - Week 48 Analysis
- Treatment-na´ve patients on E/C/F/TAF had high levels of virologic
suppression, comparable to STB, through Week 48
- Plasma TFV levels lower and PBMC TFV-DP levels higher with E/C/F/TAF
- No resistance seen in the E/C/F/TAF arm
- Patients on E/C/F/TAF had a smaller decrease in eGFR
- No renal discontinuations and no tubulopathy seen in either arm
- Less change in renal tubular proteins
- Patients on E/C/F/TAF had a significantly smaller decrease in bone mineral density of hip and spine, supported by bone biomarkers