icon-folder.gif   Conference Reports for NATAP  
  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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  (Sept 10-13, Denver, CO)
Report written for NATAP by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY
Investigational ARVs. Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, is generally safe, effective, well tolerated. When combined with emtricitabine (FTC), it is the only guidelines-preferred NRTI combination for initial ART. Still, in some patients it causes declines in GFR, proximal renal tubule dysfunction and may exacerbate the decline in bone mineral density (BMD) associated with ART initiation. Tenofovir alafenamide (TAF), an alternate prodrug of tenofovir, is investigational antiretroviral (ARV) in late stage clinical development. It achieves high concentrations in lymphocytes of tenofovir diphosphate, the active form, with lower plasma concentrations tenofovir, which could result in equal or greater efficacy with less toxicity. Sax et al presented 48 week results of a phase 2 randomized, double-blind trial in treatment-naive patients comparing TAF and TDF, each combined with FTC, elvitegravir and the pharmacokinetic enhancer cobicistat. Similar very high rates of viral suppression were seen (88% HIV RNA <50 copies/mL for both groups, FDA snapshot analysis). Very few virologic failures were seen. None of the 3 patients in the TAF arm eligible for resistance testing had resistance, while resistance was found in 2 of 3 in the TDF arm. The decline in estimated GFR was significantly less with TAF (-5.5 vs. -10.0 mL/min), as was the decline from baseline in BMD at both the hip (-0.62% vs. -2.39%) and the spine (-1.00% vs. -3.37%). No patient in either arm developed protocol-defined proximal renal tubulopathy, but sensitive urinary markers of proximal tubule dysfunction, retinol binding protein and beta-2 microglobulin, were significantly higher with TDF vs TAF. CD4 increases were 177 and 204 cells/ÁL in the TAF and TDF groups, respectively, a non-significant difference. Nausea was somewhat more frequent with TAF (21% vs. 12% with TAF) as was grade 3/4 neutropenia (5% vs. 2%) and LDL elevations (9% vs. 3%).
In a related abstract, in vitro cultures of primary osteoblasts exposed to a range of concentrations of TAF did not selectively concentrate tenofovir diphosphate, as did peripheral blood mononuclear cells. Toxicity to osteoblasts was not observed after exposures to concentrations of TAF reaching 1000-fold higher than those achieved with human dosing.
These studies suggest the novel tenofovir prodrug TAF may reduce the adverse renal and bone effects that occur in some patients using TDF. However, there may be a trade-off. The beneficial effect of TDF on plasma lipids may be lost and nausea may be increased. TAF produces much higher concentrations of tenofovir disphosphate in lymphoid cells. The study findings hint that hematologic toxicity, namely less robust CD4 reconstitution and neutropenia, could be a problem with TAF. These potential adverse effects will need to be carefully evaluated in phase 3 studies.
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 (STR) with Elvitegravir, Cobicistat, and Emtricitabine [E/C/F/TAF Versus E/C/F/TDF] for Initial HIV Treatment. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1464d.
2. Liu Y, Kitrinos K, Babusis D, et al. Lack of Tenofovir Alafenamide (TAF) Effect on Primary Osteoblasts in Vitro at Clinically Relevant Drug Concentrations. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-664.
ICAAC: TAF Comparable to TDF in Once-Daily Pill for ART-Naive: 48-Week Results - (09/14/13)
ICAAC: Lack of Effect of Tenofovir Alafenamide (TAF) on Primary Osteoblasts In Vitro at Clinically Relevant Drug Concentrations - (09/12/13)
ICAAC: TAF, a Tenofovir Prodrug, Not Preferentially Loaded or Toxic in Osteoblasts - Written by Mark Mascolini - (09/11/13)
53rd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy September 10-13 2013, Denver CO