The new formulation of tenofovir, tenofovir alafenamide (TAF), was associated with less harm to bones and kidneys than the older formulation, tenofovir disoproxil fumarate (TDF, Viread), according to a study presented at CROI 2015 in Seattle, Washington.
The study, which was presented by Paul Sax, M.D., analyzed combined safety results of two randomized controlled studies. While the bone and kidney safety profile of TAF was favorable, it had less of a positive effect than TDF on lipids (cholesterol and triglycerides).
TAF was formulated in order to address certain shortcomings of TDF. TDF is absorbed and converted rapidly into tenofovir, and it circulates in high concentrations in plasma. TAF, by contrast, is much more stable in plasma, and is not converted into tenofovir until it is inside the cell. Once inside the cell, tenofovir is converted through the active tenofovir diphosphate, which is the active antiviral component. However, TAF achieves higher intracellular concentrations and lower plasma concentrations.
This is important because the high levels of “off target” tenofovir in the plasma is sometimes associated with clinically significant renal and bone disease. In contrast, the administration of just 25 mg of TAF a day delivers tenofovir plasma concentrations that are 90% lower than those seen with the 300 mg of TDF, but it has comparable antiviral activity.
Furthermore, a phase-2 study provided preliminary evidence suggesting that TAF was associated with reduced renal and bone effects.
That was a small study, however, so the results needed to be confirmed by well-designed, adequately-sized clinical trials with very extensive renal and bone endpoints.
The antiviral efficacy findings from these studies were also presented at CROI 2015, and demonstrated the noninferiority of the single tablet of elvitegravir/cobicistat/emtricitabine/TAF compared to elvitegravir/cobicistat/emtricitabine/TDF (Stribild).
These studies also looked at changes in both arms of measures of renal function and bone mineral density (BMD) in the spine and hip, serum creatinine, and treatment-emergent proteinuria at week 48.
The studies followed nearly 1,800 participants. Baseline characteristics were well matched. The population was fairly healthy, with a median age in the low 30s. The median CD4+ cell count was over 400 and only a small proportion of participants had viral loads over 100,000 copies/mL. Participants had normal baseline renal function, with normal glomerular filtration rates (eGFR), calculated to be 114 and 117 in the respective arms.
As expected, the PK findings matched what had been seen in earlier studies. Plasma tenofovir levels were 91% lower with TAF than with TDF. In addition, an analysis showed that TAF achieved intracellular tenofovir-diphosphate levels that were four times higher than achieved by TDF.
Change in eGFR
There was a prompt decline in eGFR by week 2, which is consistent with the effects of cobicistat on renal tubular secretion of creatinine. However, the magnitude of this change was actually significantly smaller in the TAF than the TDF arm: -6.6 and -11.2, respectively. This was a median increase in creatinine of about 0.8 mg/dL.
Renal Adverse Events and Tubulopathy
The most important finding was that no renal adverse events lead to discontinuation in the TAF arm, but there were four in the TDF arm (a rate of about 0.5%, which is what has been seen in other studies of TDF when given with cobicistat or with boosted protease inhibitors).
There were no cases of overt Fanconi-syndrome/proximal renal tubulopathy. Subclinical tubulopathy was defined as confirmed abnormality in any of these two categories at two consecutive post-baseline visits, and there was one such case in the TDF arm and no cases in the TAF arm. There were a few laboratory abnormalities, but the rates were low.
Changes in Quantitative Proteinuria at Week 48
There was a small decline in the TAF arm versus an increase in the TDF arm, and these both were statistically significant. The researchers also looked at two other novel ways of measuring urine tubular function: retinal binding protein and beta-2 microgoagulin, which are both small molecular weight proteins that get freely filtered in the glomerulis and then are taken up in the proximal tubules. Whenever anything affects the proximal tubules, these proteins become detectable in the urine. And again, there was significantly less effect on these renal tubular markers in the TAF arm versus the TDF arm.
Changes in Spine and Hip BMD Through Week 48
About 1% of the participants in this study had fractures but there were no fragility fractures. However, dual-energy X-ray absorptiometry (DXA) scans were used to assess bone density at baseline, week 24, and at week 48. Again, TAF had a significantly smaller effect on bone density at the spine and in the hip. The hip reduction in particular was very small in the TAF arm.
Fasting Lipids at Week 48
Tenofovir is known to have a direct lipid lowering effect (on total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) -- even in people who are HIV negative. Consequently, lipid levels were higher in the TAF arm (which delivers lower plasma tenofovir concentrations) than the TDF arm. However, despite total cholesterol, the HDL ratio was the same at the end of the study in both study arms.
"In these two large comparative, two large randomized clinical trials detailed protocol-specified renal and bone endpoints confirmed that TAF had a more favorable effect than TDF," Sax concluded. He also pointed out that another study in a poster presentation at CROI this year showed that switching to TAF had an improvement in bone mineral density and markers of kidney function.
Theo Smart is an HIV activist and medical writer with more than 20 years of experience.
Follow Theo on Twitter: @theosmart.