New recs to prevent HIV transmission

The FDA just approved tenofovir alafenamide (TAF) 25mg along with emtricitabine (FTC) 200mg (Descovy) for HIV-1 preexposure prophylaxis (PrEP) to reduce HIV transmission from sex, though excluding those who have receptive vaginal intercourse (not evaluated), see https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic

--per the CDC: 38,739 people were diagnosed with HIV in the US in 2017; the US goal is to reduce new infections by 75% in the next 5 years and 90% in the next 10 years

--the current recommedation is based on the DISCOVER trial, comparing daily FTC/TAF (Descovy) with FTC/TDF (Truvada), in a randomized, double-blind study in North America and Europe, in 5387 adults treated at 94 sites in 11 countries. 60% were in the US (see http://www.croiconference.org/sessions/phase-3-discover-study-daily-ftaf-or-ftdf-hiv-preexposure-prophylaxis , and you can access the talk and slides presented)

    --patients were cis-men who have sex with men (MSM) and transgender women at high risk of getting HIV

    --all had at least 2 episodes of condomless anal sex (CAS) in past 12 weeks, or rectal GC/chlamydia or syphilis in past 24 weeks

    --mean age 36, 84% white/9% black/25% Latinx, 1% transgender women, 23% had prior PrEP use, 41% had >3 receptive partners with CAS in prior 90 days, 90% completed 48 weeks on study, with median follow-up of 84 weeks

    --primary endpoint was HIV acquisition rate per 100 person-years when 50% completed 96 weeks; safety was assessed every 12 weeks

    --of the 85% who remained in the study (6% discontinued by choice, 6% lost to followup): 

        --the rate of sexually-transmitted diseases was 99.5/100 person-yrs (essentially the same in both groups), suggesting that there was similar CAS exposure in both the TAF- and TDF-based groups

        --across both arms there were 21 HIV diagnoses, with infection rate of 0.21/100 person-yrs, also lower than expected if the TAF did not work

        --there were 1.5% adverse effects leading to discontinuations (mostly GI), so both drugs were well-tolerated and equally effective

Commentary
--the formal DISCOVER trial has not been published yet (to my knowledge), so unable to access the specific details other than the presentation and slides

--one prior concern was that the pharmacokinetics and levels achieved by TAF vs TDF are pretty different: eg, a small study found that the tenofovir plasma concentration was 90% lower in those on TAF (which is presumably why the renal/bone toxicities are better), though the intracellular levels were up to 4-fold higher (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854526/ , which documented peripheral blood mononuclear cell (PBMC)  tenofovir levels were 2.4 times higher, in the same patients switched from TDF to TAF in those initially on TDF/FTC/EVG/COBI (Genvoya). But the tenofovir levels in mononuclear cells are quite a bit lower in rectal tissues, one small study for example finding that TAF levels were 46 on TAF but 441 on TDF (almost 10 times lower!!!!), see http://www.natap.org/2019/CROI/croi_35.htm

--so, this does raise a few issues:

    -- TDF does work well in those people who take the Truvada erratically (see blogs/references listed below), with apparently complete clinical effectiveness if patients take as few as 15 pills per month. HIV prophylaxis does track with intracellular tenofovir concentrations, as found in prior PrEP studies with TDF. So, especially since the PBMC levels in rectal tissue are already lower with TAF, and since adherence to PrEP in the community setting is often suboptimal (see blogs below), will TAF work with less regular medication adherence?? it is certainly possible, for example, that TAF taken regularly does increase the intracellular tenofovir levels sufficiently in the rectal tissues. But would TAF maintain sufficient rectal tissue levels to be protective if taken less regularly???

    -- i am also a bit concerned that this FDA approval happened after just one trial, with such a specific target population (without including women or many African-American men), without the trial being published and able to be scrutinized well, and without any clear data on the efficacy of TAF/FTC in those who take the drug erratically (what actually is the minimally effective dose???)

    --and we do need studies in women who have vaginal sex, given their non-participation in the DISCOVER trial

    --one concern is that many patients’ insurance does not cover PrEP adequately, leaving many people without meds for financial reasons. It turns out that TDF is about to become generic, and the cost of TDF/FTC may be significantly less and more accessible to people. Perhaps this barrier to medication adherence would be much lower by continuing TDF/FTC when available generically???

--and, as with TDF-based PrEP, it is important to exclude hepatitis B infection, given the potential risk of HBV exacerbations if individual discontinues the tenofovir (as reported with TDF)

    --relevant prior blogs:

        --http://gmodestmedblogs.blogspot.com/2019/06/uspstf-guidelines-on-hiv-testing-and.html  for recommendations on PrEP

        --http://gmodestmedblogs.blogspot.com/2018/10/prep-mostly-given-to-white-men-and.html for issues of under-representation of women and minorities (as in the above study, as well)

        --http://gmodestmedblogs.blogspot.com/2015/09/hiv-pre-exposure-prophylaxis.html for the British PrEP trial

        --http://gmodestmedblogs.blogspot.com/2015/12/on-demand-hiv-pre-exposure-prophylaxis.html for the IPERGAY French trial, with intermittent PrEP effectiveness

        --and, hiv pre-exp prophylaxis med adher lancetID2014 in dropbox, or doi.org/10.1016/ S1473-3099(14)70847-3, which assesses actual infections as per number of PrEP pills taken, with no infections if take at least 15/month, and only 0.6/100 person-yrs if take 2-3/week

So, TAF/FTC may well be an advance in terms of decreased renal/bone toxicity. I am concerned, as noted above, that this drug may have been approved too early, prior to adequate studies (or even analysis of the current study), and that it may not be as good as TDF/FTC (the current PrEP med) if patients are less adherent to the meds. So, I am not quite ready to switch….

geoff​

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