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TAF: New Data on Tenofovir Alafenamide Fumarate
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Tenofovir alafenamide fumarate (TAF) is an investigational prodrug of tenofovir that in studies to date appears to have less renal and bone toxicity than the current tenofovir product, tenofovir disoproxil fumarate (TDF). This is because TAF is metabolized to tenofovir in lymphocytes and macrophages (as well as hepatocytes and some other cells), whereas TDF is converted to tenofovir in the blood. With TAF, levels of active tenofovir in plasma are about 90% lower, while levels in lymphocytes are higher.

Three studies of TAF (10 mg) coformulated with elvitegravir, cobicistat, and emtricitabine, (EVG/COBI/FTC) were presented recently at the International AIDS Society Conference; these help delineate the efficacy and safety of TAF. All were switch studies done in patients already on other ART regimens.

1) In a large study (GS-US-292-0109), more than 1,400 patients with HIV suppression on a regimen containing TDF/FTC with a third agent (EVG/COBI, efavirenz, or boosted atazanavir) were randomized 2:1 to change to EVG/COBI/FTC/TAF or to remain on their baseline regimen; the study was open label.[1] The key findings are as follows:

At 48 weeks, 97% of those who switched to the EVG/COBI/FTC/TAF regimen and 93% of those who remained on their original regimen had HIV RNA levels of <50 copies/mL. This difference was statistically significant, but was attributable to lower rates of virologic suppression in the efavirenz- and boosted atazanavir-containing regimens; there was no difference in virologic outcomes between the EVG/COBI/FTC/TAF and the EVG/COBI/FTC/TDF groups.
Markers of renal tubular function (urine protein/creatinine ratio, urine albumin/creatinine ratio, retinol-binding protein/creatinine, and beta-2-microglobulin/creatinine) showed statistically significant improvements in TAF patients when compared with those on TDF. The presenter noted (but did not show the data) that serum creatinine decreased by about 0.1 mg/dL in patients who switched from TDF plus either ritonavir-boosted atazanavir or EVG/COBI. Creatinine increased slightly in those who switched from TDF/FTC/efavirenz. The clinical significance of these changes is not clear.
Bone density at the spine and hip (as measured by DEXA scan) increased (about 1.8% and 1.4%, respectively) in patients switched to the TAF regimen and decreased slightly in those who remained on TDF-containing regimens; the difference between groups was statistically significant.
Fasting lipid levels increased in the TAF switch group: Total cholesterol increased by a median of 22 mg/dL, and LDL and triglyceride levels increased by a median of about 10 mg/dL.

2) A second study (a substudy of GS-112) evaluated the effect of switching from stable suppressive ART to EVG/COBI/FTC/TAF in a group of 242 patients with preexisting "mild-moderate" renal impairment (estimated GFR [eGFR] 30-69 mL/min).[2] This is a single-arm open-label study. Researchers presented 48-week results that analyzed renal function and bone density changes according to whether the pre-switch ARV regimen included TDF. The median baseline eGFR was 56 mL/min in the overall study group (58 mL/min in those on TDF before the switch, 53 mL/min in the non-TDF group; 40% and 24%, respectively, had eGFR >60 mL/min at baseline). It showed:

No significant changes in actual GFR as measured by iohexol clearance in either group 24 weeks after the switch to EVG/COBI/FTC/TAF. At 48 weeks, estimated GFR differed according to the estimating equation that was used, but by all methods it appeared that switching from a non-TDF regimen to the EVG/COBI/FTC/TAF regimen caused slightly worse decrements in eGFR than for the group previously on TDF. Urine protein/creatinine ratio, urine albumin/creatinine ratio, retinol-binding protein/creatinine, and beta-2-microglobulin/creatinine decreased significantly in the group previously on TDF but changed little in the other group.
Patients switching from TDF had statistically significant increases in mean bone mineral density at spine and hip, and smaller (not statistically significant) increases occurred in the group previously on non-TDF regimens.
Total cholesterol, LDL cholesterol, and triglyceride levels increased (19 mg/dL, 7 mg/dL, and 12 mg/dL, respectively) from baseline in subjects who switched from TDF to TAF, while total cholesterol, LDL, and HDL decreased (11 mg/dL, 5 mg/dL, and 4 mg/dL, respectively) in the group that switched to EVG/COBI/FTC/TAF from non-TDF-containing regimens.

3) The third study evaluated the effect of TAF on both HIV and hepatitis B virus (HBV) in HIV/HBV-coinfected patients.[3] Here, 72 HIV/HBV patients whose HIV was suppressed on ART were switched from their previous regimens to EVG/COBI/FTC/TAF. At baseline, 96% were taking TDF (with FTC or 3TC), and 86% had HBV DNA levels of <29 IU/mL.

At 48 weeks, HIV remained <50 copies/mL in 92% of the group, while HBV suppression to <29 IU/mL increased to 92%; no patients with HBV suppression at baseline had detectable HBV DNA at week 48 (several subjects withdrew or were lost to follow up before week 48).
2/70 patients also lost HBsAg and/or gained HBsAb and 2/30 patients lost HBeAb and 1/30 gained HbeAb. Liver fibrosis, as assessed by the FibroTest serum biomarker score, remained stable in 75%, worsened in 10%, and improved in 15% of study subjects.
As in the studies described above, switch to EVG/COBI/FTC/TAF was associated with improvements in biomarkers of renal tubular function. It also was associated with decreases in markers of bone turnover.

Clinical Bottom Line
From these and previous data, it appears that the potency of TAF (at least in the combination regimen EVG/COBI/FTC/TAF) is equivalent to that of TDF. The studies suggest that markers of renal and bone safety are better than with TDF (and that lipid profiles are somewhat worse), but several caveats are important and other observations are important:

TAF and TDF were not compared in isolation in any of the trials described above, nor was TAF studied as a single variable. Rather, the regimen of EVG/COBI/FTC/TAF was compared with other past or present regimens. This is important because issues of convenience (ie, the single-tablet regimen of EVG/COBI/FTC/TAF vs multiple pills in some other regimens), creatinine-perturbing effects of COBI, and drug-drug interactions that affect TDF and TAF levels were not isolated. Thus, it is hard to come to definite conclusions about the effects of TAF itself.

The virologic superiority of EVG/COBI/FTC/TAF in the first study discussed above was driven primarily by discontinuations of patients assigned to remain on efavirenz- or boosted atazanavir-containing regimens and not by factors having to so with TAF specifically; virologic outcomes between the group that switched to EVG/COBI/FTC/TAF and the group that remained on EVG/COBI/FTC/TDF were the same.

Regarding renal safety, these studies showed minimal or no changes in creatinine and actual eGFR after a switch to TAF from TDF-containing or other regimens, and the clinical significance of the reported improvements in proteinuria and other biomarkers of tubular function is not clear.

The safety of TAF in patients with chronic kidney disease also is not clear; the study presented above (#2) comprised patients who mostly had eGFR >55 mg/mL, and did not stratify the data to show the portion of the group with lower baseline eGFRs. Effects in those with poorer renal function are not known, and will require more study.

Bone safety appears better with the TAF-containing regimen than with TDF-containing regimens, but no substantial clinical outcome data are available to date.

In patients with HBV coinfection, TAF appears to maintain (and perhaps to slightly improve) HBV suppression while maintaining HIV control. The study (#3) described above did not include a reference group, so no comparisons with other HBV-active regimens can be made.

Cost issues regarding TAF may be barriers to its use, especially since TDF is expected to become available in generic formulations in the near future.

Applications for several coformulations containing TAF have been submitted to FDA for approval; decisions will be made in the coming months.

1. Mills T, Andrad J, DiPerri G, et al. 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. In: Program and abstracts of the 2015 International AIDS Society Conference; Vancouver; July 19-22, 2015. Abstract TUAB0102.
2. Gupta S, Pozniak A, Arribas J, et al. Subjects with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 48 weeks. In: Program and abstracts of the 2015 International AIDS Society Conference; Vancouver; July 19-22, 2015. Abstract TUAB0103.
3. Gallant J, Brunetta J, Crofoot G, et al. 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 co-infected adults in North America and Japan (NCT02071082): week 24 results. In: Program and abstracts of the 2015 International AIDS Society Conference; Vancouver; July 19-22, 2015. Abstract WELBPE13.