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First Single-Tablet PI Regimen With Darunavir and TAF at 48 Weeks
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ICAAC 2014. September 5-9, 2014. Washington, DC
Mark Mascolini
Cobicistat-boosted darunavir plus tenofovir alafenamide (TAF) and emtricitabine (FTC) yielded a 77% week-48 virologic response rate and less bone and renal toxicity than darunavir/cobicistat plus tenofovir/emtricitabine (TDF/FTC) in randomized a phase 2 trial [1].
Compared with TDF, TAF delivers more active tenofovir into cells and less into plasma. The resulting promise of fewer tenofovir-related side effects with TAF than with TDF was confirmed in a trial of TAF versus TDF with FTC and elvitegravir/cobicistat [2].
This double-blind, placebo-controlled trial involved 153 people naive to antiretrovirals and with at estimated glomerular filtration rate (eGFR) at or above 70 mL/min. Researchers randomized 103 of them to the TAF regimen and 50 to the TDF combination. Median age stood at 31 in the TAF arm and 36 in the TDF arm; 60% in both arms were white, one third were black, and more than 90% were men. Median pretreatment CD4 count measured 368 with TAF and 433 with TDF; respective viral loads were 4.67 and 4.58 log (about 47,000 and 38,000 copies).
At week 48 an FDA snapshot analysis determined that 76.7% randomized to TAF and 84.0% randomized to TDF had a viral load below 50 copies, a nonsignificant difference (weighted difference -6.2%, 95% confidence interval -19.9% to 7.4%, P = 0.35). No one stopped either combination because of lack of efficacy. Virologic failure rates at week 48 were 16% with TAF and 12% with TDF. The investigators noted that the trial was not powered to establish noninferiority of the TAF regimen, but they judged that viral suppression rates with the two regimens comparable.
Six people assigned to TAF (5.8%) and 2 assigned to TDF (4%) met criteria for resistance analysis because of viral rebounds. Mutations conferring resistance to darunavir, TDF, or FTC could not be found in samples from any of these people.
Two people randomized to TAF and 2 randomized to TDF stopped treatment because of adverse events (2% versus 4%), though most events in both arms were mild or moderate. Proximal renal tubulopathy accounted for one discontinuation in the TDF arm, while rash caused one discontinuation in the TAF group.
Through 48 weeks, average spine bone mineral density decreased significantly less with TAF than with TDF (-1.57% versus -3.62%, P = 0.003), as did hip bone mineral density (-0.84% versus -3.82, P < 0.001). The researchers noted that these TAF-related drops in bone mineral density are among the lowest in antiretroviral trials. No one in either arm had a fracture through 48 weeks of treatment.
Median eGFR fell significantly less in the TAF arm than the TDF arm (-2.9% versus -10.6%, P = 0.017). Median change in proximal tubular proteinuria rose significantly more with TAF than with TDF (+9% versus +54%, P = 0.003).
Changes in total cholesterol (40 versus 5 mg/dL), low-density lipoprotein cholesterol (26 versus 4 mg/dL), and triglycerides (29 versus -5 mg/dL) were significantly greater with the TAF regimen than with the TDF regimen through 48 weeks. But change in total-to-high-density lipoprotein cholesterol ratio did not differ significantly between the two arms (0.0 versus -0.2, P = 0.15).
Levels of tenofovir diphosphate, the active form of TAF and TDF, were 6.5 times higher in peripheral blood mononuclear cells with TAF than with TDF. Plasma tenofovir exposure measured as area under the concentration-time curve was 91% lower with TAF than with TDF.
The researchers proposed that this single-tablet regimen containing darunavir and TAF "offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved bone and renal safety with TAF."
References
1. Mills A, Ortiz R, Crofoot G Jr, et al. 48 Week study of the first PI-based single tablet-regimen (STR) darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus cobicistat-boosted darunavir and emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-647c.
2. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014;67:52-58. http://www.natap.org/2014/HIV/081814_02.htm
48 Week Study of the First PI-based Single Tablet-Regimen (STR) Darunavir/Cobicistat/Emtricitabine/ Tenofovir Alafenamide (D/C/F/TAF)
vs.
Darunavir (DRV) boosted by Cobicistat (COBI) and Emtricitabine/Tenofovir Disoproxil Fumarate (TVD) in HIV-Infected Treatment-Naïve Adults
Reported by Jules Levin
ICAAC 2014
September 5-9, 2014, Washington, DC
Anthony Mills1, Roberto Ortiz2,Gordon Crofoot, Jr.3, Cheryl McDonald4, Peter Shalit5, Jason Flamm6, David Shamblaw7, Michael Saag8, Huyen Cao9, Hal Martin9, Moupali Das9, Hui Liu9, Lijie Zhong9, Christian Callebaut9, Joseph Custodio9, Andrew Cheng9, Scott McCallister9.
1Southern California Men's Medical Group, Los Angeles, CA, 2 Orlando Immunology Center, Orlando, FL, 3 Gordon Crofoot MDPA, Houston, TX, 4Tarrant County Infectious Disease Associates, Forth Worth, TX, 5 University of Washington, Seattle, WA, 6 Kaiser Permanente, Sacramento, CA, 7 La Playa Medical Group and Clinical Research, San Diego, CA., 8University of Alabama, Birmingham, AL, and 9Gilead Sciences, Inc., Foster City, CA.
Program Abstract:
Background:TAF, a novel tenofovir (TFV) prodrug, provides higher intracellular levels of the active phosphorylated moiety TFV diphosphate and lower circulating TFV plasma levels relative to TDF. This Phase II trial compared the first PI-based STR D/C/F/TAF to DRV, COBI + F/TDF.
Methods: TN adults with eGFR ≥70 mL/min were randomized 2:1 to D/C/F/TAF (N=103) vs. DRV, COBI + F/TDF (N=50) qD, with matched placebos; stratifying by VL and race. W48 VL suppression rates (FDA Snapshot VL<50 c/mL, non-inferiority (NI), ITT), safety data including bone mineral density (BMD) and renal function tests are reported.
Results: Of 153 patients treated, 76.7% on D/C/F/TAF vs. 84.0% on DRV, COBI + F/TDF had VL<50 at W48 (weighted difference: -6.2% [95% CI -19.9% to 7.4%], p=0.35); there were no efficacy related discontinuations. Most AEs were of mild/moderate severity; 2 patients had AEs leading to discontinuation in each arm (TAF: rash, substance dependence; TDF: worsening of diarrhea, proximal renal tubulopathy.) The mean % change in spine BMD was -1.57 (TAF) vs. -3.62 (TDF), p=0.003, and in hip BMD was -0.84 (TAF) vs. -3.82 (TDF), p<0.001; there were no fractures in either group. The median decrease in eGFR (mL/min) was -2.9 (TAF) vs. -10.6 (TDF), p=0.017. The median % change in proximal tubular proteinuria was +9 (TAF) vs. +54 (TDF), p=0.003 for retinol binding protein/Cr ratio and -42.0 (TAF) vs. +2.3 (TDF), p=0.002 for urine ß-2 microglobulin/Cr ratio.
Conclusions: While underpowered for NI, the W48 VL suppression rates and safety data were comparable in both arms. The TAF arm had less change in spine and hip BMD and eGFR, consistent with results from a study of elvitegravir (E)/C/F/TAF in TN adults. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of DRV, and the potential for improved bone and renal safety with TAF.
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