On Nov. 5, the U.S. Food and Drug Administration (FDA) approved elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF), which will be marketed as Genvoya, for the treatment of HIV. The difference between E/C/F/TAF and elvitegravir/cobicistat/ emtricitabine/tenofovir (Stribild) is that the former contains TAF (tenofovir alafenamide), a prodrug of tenofovir, which has shown better bone and kidney safety than tenofovir disoproxil fumarate (TDF, Viread). A few weeks before the FDA approval, at ID Week 2015 in San Diego, Calif., I caught up with Eric Daar, M.D., chief of HIV medicine at Harbor-UCLA Medical Center, to talk about his study of how the new coformulation measures up to its predecessor, specifically among older adults.
Welcome, Dr. Daar. Can you start off by telling me more about TAF and what your study is about?
Hopefully people are familiar with TAF; it's been around for a little while. The goal with TAF is to be able to use a very small pill -- which will be great for coformulation -- that will result in low levels of tenofovir in the plasma but high levels in the tissue, where it works. The goal is that the low levels in the plasma will be associated with less tenofovir-associated toxicity -- particularly bone and renal toxicity.
The two large randomized controlled trials looking at TAF as an alternative to TDF in their quad pill demonstrated non-inferiority: equivalent efficacy and a very, very similar side-effect profile.
However, there was less of a decline in glomerular filtration rate in the TAF arm -- which isn't completely understood -- compared to the TDF arm. More compelling is that there was less of a decline in bone mineral density among those taking TAF than those taking TDF.
Lots of other studies have been done with TAF -- switch studies, first-line studies -- and all of them seem to show the exact same thing. There are studies looking at TAF to essentially replace tenofovir/emtricitabine (Truvada) as a fixed-dose combination, and to replace rilpivirine/tenofovir/emtricitabine (Complera) as a single-tablet regimen. Those studies are underway and haven't been presented yet.
This will hopefully provide an option that's a little better tolerated for people who use the familiar regimen.
[Our study] as well as other post hoc analyses, looked at subsets of patients that we think are relevant, and that are often understudied. With this particular poster, we looked at older people -- which is defined as greater than or equal to 50. They tried to break it down, actually, with a higher age group -- greater than 65 -- but the numbers get really tiny.
They found about 10% of the people that were enrolled in these two trials -- there were about 1,600 people in these two studies -- about 10% of them received TAF. They were able to see, within this older age group, whether the data essentially looks similar to what was seen in the overall population.
When they looked at the greater-than-50 age group, comparing TAF to TDF, they found very similar efficacy, consistent with the parent study.
More important is looking at adverse events. Older people are going to be at greater risk for things like renal toxicity and bone loss, since they already have lower bone mineral density. Again, the numbers were pretty small. But what they found was that the results look almost exactly the same for the comparison between TAF and TDF in people over 50 as they do in the overall population -- meaning, there was less of a decline in glomerular filtration rate in the people who received TAF versus TDF that were over 50 and less of a decline in bone mineral density in that group.
[Researchers] always look at some of the other potential early markers of nephrotoxicity: proteinuria, and changes in renal tubular protein handling, which is thought to perhaps be an early effect of tenofovir toxicity.
What they saw here is exactly what they've seen in the parent study: You see an adverse effect with TDF on both proteinuria and renal tubular proteins, and less of an effect -- and in fact in some cases even an improvement, at least a measurable improvement, if not statistically significant -- when you use TAF versus TDF.
I think the conclusion from this study is that even in people over 50 -- it can't speak to an older age group -- all of the findings from the overall study seem to apply to that group as well.
It seems pretty straightforward that TAF may be a bit of a game-changer. There don't seem to be any downsides.
That's exactly right. There are clearly no obvious downsides from any of the studies. There seems to be a very real benefit for bone mineral density. And the renal [toxicity] is certainly no worse, and the data suggest that it's better -- although it still hasn't been completely explained why that's the case.
It's hard to explain the observation that all of the effects happen in the first couple of weeks, and then nothing happens after that. That's not how we usually think about drugs that cause nephrotoxicity causing the problem; we usually think of it as slow, progressive process over time.
But it's certainly no worse, and it may very well be better.
This transcript has been lightly edited for clarity.