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  20th Conference on Retroviruses and
Opportunistic Infections
Atlanta, GA March 3 - 6, 2013
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New tenofovir prodrug virologically equivalent to TDF--and easier on kidneys and bone
  20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta

Mark Mascolini

Tenofovir alafenamide (TAF) coformulated with elvitegravir, cobicistat, and emtricitabine controlled HIV as well as tenofovir disoproxil fumarate (TDF) coformulated with the same drugs through 24 weeks and had a superior kidney and bone safety profile [1]. This ongoing double-blind, active-controlled, phase 2 trial offers the largest comparison of these once-daily single-tablet regimens so far.

Compared with TDF, TAF yields 90% lower plasma tenofovir levels, which TAF developers hope will translate into fewer kidney and bone side effects. But the new prodrug achieves 5-fold higher intracellular tenofovir diphosphate concentrations than TDF.

All participants in this phase 2 trial had a viral load above 5000 copies/mL, an estimated glomerular filtration rate at or above 70 mL/min, and sensitivity to emtricitabine and tenofovir. The primary endpoint was the percentage of participants with a viral load below 50 copies/mL at week 24 with the FDA snapshot analysis.

The 112 people randomized to TAF and the 58 randomized to TDF were similar in median age (34 and 38), proportion of men (96% and 98%), and proportions of whites and blacks (67% and 30% versus 69% and 28%). Only about 10% of study participants had symptomatic HIV infection, with no difference between arms. Median viral load stood at 4.55 log in the TAF group and 4.58 log in the TDF group, and a slightly lower proportion randomized to TAF had a viral load above 100,000 copies (17% versus 28%). Median pretreatment CD4 count was 385 with TAF and 397 with TDF. No one tested positive for HBV or HCV.

After 24 weeks, 87.5% randomized to TAF and 89.7% randomized to TDF had a viral load below 50 copies/mL to yield a nonsignificant weighted difference of -4.9% (95% confidence interval -15.7% to 5.9%, P = 0.36).

Fifteen people (13.4%) randomized to TAF and 6 (10.3%) randomized to TDF did not have a viral load below 50 copies at week 24, but only 2 in the TAF group (1.8%) and 5 in the TDF group (5.2%) never reached a sub-50 load. The others had blips, rebounds, or discontinuations. Four people taking TAF and none taking TDF stopped treatment because of an adverse event, only one of which (photosensitivity) was attributed to study drugs. CD4 counts rose by an average 163 cells in the TAF group and 177 cells in the TDF group, a nonsignificant difference (P = 0.76).

As anticipated, tenofovir diphosphate levels in peripheral blood mononuclear cells at week 4 or 8 were substantially (5.3-fold) higher with TAF than with TDF. In contrast, tenofovir exposure in plasma was much lower with TAF than TDF (area under the concentration-time curve 326.2 versus 3795.2 ng x h/mL).

Through 24 weeks no serious adverse events arose in either study arm, and more than 90% of all adverse events were grade 1 or 2. Total and LDL cholesterol gains through 24 weeks were greater with TAF than with TDF, but so were gains in HDL cholesterol. So the week-24 total-to-HDL cholesterol ratio did not differ between study arms (0.1 in both).

Serum creatinine rose in both treatment arms through 4 weeks, then leveled off. At week 24 median change in serum creatinine was significantly lower with TAF (0.07 versus 0.12 mg/dL, P = 0.02). There were no renal adverse events or discontinuations in either group and no cases of proximal renal tubulopathy.

Bone mineral density scans at baseline and week 24 showed almost no decline in the spine or hip with TAF (-0.8% and -0.3%), compared drops of -2.5% (P = 0.002) and -2.0% (P < 0.001) with TDF.


1. Zolopa A, Ortiz R, Sax P, et al. Comparative study of tenofovir alafenamide vs tenofovir disoproxil fumarate, each with elvitegravir, cobicistat, and emtricitabine, for HIV treatment. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 99LB.