PrEP, another blog

PrEP, another blog

here is another blog on the FDA approval of tenofovir alafenamide (TAF) combined with emtricitabine (FTC) for preexposure prophylaxis to prevent HIV transmission, written by Jon Pincus and sent with his permission. the advantage of TAF over tenofovir disoproxil (TDF) is its decreased renal/bone toxicities. Jon goes into more depth than i did and has a somewhat different angle, so i thought it might be useful to pass around. his email/blog is in response to questions circulating around about the benefit of this new FDA recommendation.

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In summary - I would not use TAF yet for PrEP though in theory it might be better for PWID (people who inject drugs), I think we need to focus on getting and keeping folks on PrEP and not on which drug to use and that the push towards TAF is also problematic given the huge cost differential between TDF and TAF and the likely availability of generic TDF/FTC in 2021. 

I’m not sure we have enough data at this point to change practice and I think the limited data there is supports the FDA decision except that the FDA based it’s approval on a single study instead of their usual practice of at least two studies.  The FDA decision of course does not preclude using TAF for PrEP in cis gender women or PWID.  The data presented to the FDA from the Discover trial was actually much better for TAF/FTC than I had expected however it is one study and I still would not use TAF for PrEP except for patients where I am concerned about renal toxicity e.g. older patients with baseline elevated creatinine or risk factors for CKD.  I have one patient with baseline CKD who has been on PrEP with TAF for over a year now. 

There is a nice review of the data presented to the FDA and some of the rationale for their decisions - https://www.fda.gov/media/129607/download

There is also an excellent review of some of the pK issues related to this discussion at - http://regist2.virology-education.com/2016/11transmission/07_Garrett.pdf

The data for PreP efficacy is highly variable from one trial to another and is likely related to variable adherence rates in different trials (graph from Garret reference above). 

The data in women and PWID has not been as consistent or robust as the data in MSM and there were concerns from the manufacturer about their ability to do a trial in women. Obviously that is not an excuse though from their perspective it is logical to do the trials initially in the groups they feel are most likely to show efficacy.  They did petition the FDA for approval in cis gender women based on extrapolation from other trials but this was not accepted and I agree with that decision.

The problem in part is that we do not know how PrEP works and how important tissue concentrations are vs plasma levels vs PBMC concentrations. Limited data suggests that TAF results in ~ 2 fold lower female genital tract concentrations vs TDF.  Rectal concentrations are also ~10 fold lower with TAF vs TDF which is why even with the Discover trial data I would be reluctant to use TAF for PrEP until we have more information. That said, TAF produces significantly higher PBMC (peripheral blood mononuclear cell) concentrations and assuming this is the relevant surrogate marker for parenteral transmission TAF may be a better choice for PWID.  So extrapolating from the available data I would be more comfortable using TAF for PWID but would wait for further data for use in MSM, TGW or cis gender women. 

The data from the Discover trial also seem to support that the main issue is medication adherence (or perhaps drug levels).  9/22 seroconverters had discontinued drug before seroconversion or had a drug interruption prior to seroconversion. The issue of infections in the first few weeks and with treatment interruptions are controversial.  The early infections may be subjects that became infected before starting PrEP or may reflect the faster time to therapeutic PBMC levels with TAF vs TDDF and the longer tail for TAF vs TAF.

TAF/FTC	TDF/FTC

person years

4370

4386

HIV infections

7

15

infections/110 pt yrs

0.160

0.342

infections during first few weeks

1

4

low TDF levels at infection

5

10

I think the most important issues with PrEP are not TAF/FTC vs TDF/FTC (or even TAF or TDF) but rather the very low use of PrEP in at risk patients (especially AA MSM and PWID and patients in the Southern US) and the very high drop out rates.  The most striking data for me is the Kaiser data - 

initially Kaiser reported that at 1 year out of 972 patients “on prep” there were no HIV infections while 42% of patients had an STI

However - 2 patients who had lapses in insurance did seroconvert for HIV

Then they reported their full data for 2012-2017

7,124 patients referred for PrEP

     26 tested HIV + during their PrEP assessment

4,991  started PrEP

1,303 of the 4,991 stopped PrEP and 11 of those patients tested HIV+

2,107  patients did not start PrEP and 22 of those patients tested HIV+

So while there were 0 HIV infections among patients “on” PrEP there were 61 HIV infections among patients eligible for PrEP leading me to conclude that we should exert our efforts on education, engagement, adherence and navigation to reduce barriers to PrEP. 

The other concern I have about the use of TAF/FTC for PrEP is that in the absence of proven clinical superiority I’m not clear how we decide as a society that it is worth the additional expense.  In fact in the Partners PrEP trial they were not able to show superiority of TDF/FTC over TDF.

This is a significant issue because TDF/FTC and TAF/FTC both cost ~$1800 a month.  However generic TDF is $35 a month on Goodrx while brand name Viread (TDF) is $1,192.  If I had no insurance and had to pay for PrEP myself, I’d find it hard to justify the extra $1765 a month and I think from a global perspective we would achieve more from devoting those funds to prep navigation programs.  In September 2021 FTC is scheduled to go generic so we could be looking at generic prep in 2021/2 and for young patients without significant risks for CKD or bone loss I’m not sure I see the justification for what will then likely be the much higher costs of TAF/FTC. 

Personally, I think that this was a huge mistake by the FDA. It widens the treatment equity gap and it leaves cis gender women with less options. There should be a public outcry against this and the FDA should know what a travesty it is that they did this.
I know this didn’t address your comment Jen but I think it’s important to dissent on this topic to the FDA.