PK advantages of TAF/FTC over TDF/FTC for HIV PrEP might compensate for low adherence: sub-analysis of DISCOVER study
Simon Collins, HIV i-Base
A new analysis from the large phase 3 international DISCOVER study showed that the better pharmacokinetic (PK) properties of F/TAF over F/TDF could lead to advantages in some populations, especially is adherence is difficult. 
The results from DISCOVER study was presented earlier this year at CROI, finding non-inferiority for TAF/FTC compared to TDF/FTC. In this study 5,387 gay men and transgender women at high risk of HIV were randomised (1:1) to either daily F/TAF or daily F/TDF with matching placebo.
At the primary endpoint (when 50% of participants had reached week 96) there were 22 infections: 7 vs 15 in the F/TAF vs F/TDF arms respectively. This gave an incidence of 0.16 vs 0.34 per 100 patient years of follow up (PYFU) and an incidence rate ratio (IRR) of 0.47 (95%CI: 0.19 to 1.5) numerically showing a 53% advantage for F/TAF meeting criteria for non-inferiority (though importantly this was not statistically significant).
After allowing for people who were found to be HIV positive at baseline (n=1 vs 4), only one participant in each arm became HIV positive with medium or high drug levels suggesting good adherence. However, with suboptimal drug levels, there were fewer new infections with F/TAF (n=5 vs 10). See Table 1.
Table 1: HIV infections in DISCOVER study
|Total HIV infections||7||15|
|Positive at baseline||1||4|
|Low drug levels||5||10|
|Infections with adherence||1||1|
As there were no reported differences between arms at any time point in HIV risk based on number of partners, newly diagnosed rectal STIs or adherence this led researchers to use a nested case-control study (matched 1:5) to look for pharmacokinetic differences.
Throughout the study, adherence was high in both arms, with less than 80% adherence (in observed analysis) only reported by <4% of participants by self-report and <8% by pill count at all timepoints. This was also supported by TFV-DP levels in dried blood spot (DBS) in the pharmacokinetic sub-study (n=536), again at all timepoints out to week 96. In both cases and controls, low drug levels by DBS at diagnosis was associated with increased risk of HIV acquisition (p<0.001). This was reported as equivalent to taking less than two doses per week with F/FTAF and less than four doses a week with F/TDF.
These differences were supported in the large PK sub study (n=324) that reported 98% vs 68% of participants in the F/TAF vs F/TDF groups had intracellular drug levels above the EC90. Median TFV-DP in PBMCs were also 6.3-fold higher with F/TAF at 404 vs 61 fmol/million cells.
Two other PK advantages were also reported for F/TAF compared to F/TDF.
Firstly, protective drug levels are achieved more quickly with F/TAF, with median intracellular levels of TFV-DP reaching EC90 in PBMCs within two hours (and within four hours for all participants), compared to needing three daily doses with F/TDF.
Secondly, after reaching steady state levels with daily dosing, F/TAF provided a longer period of cover after stopping PrEP – keeping TFV-DP levels above the EC90 for a median of 16 days compared to a median of 10 days with F/TDF.
Both these properties would be likely to benefit on-demand dosing but it is important to remembers that these analyses were based on comparing earlier PK studies for each formulation and were not linked to efficacy results in DISCOVER.
The plausibility of better pharmacokinetic properties providing more comprehensive PrEP coverage in the context of low adherence is important.
However, the DISCOVER study also showed that in the context of good adherence both formulations were highly effective, with only 22 infections during 8756 PYFU, with no differences in efficacy. Even with on-demand dosing F/TDF is so effective that it is recommended in IAS-USA and EACS guidelines for protection for anal sex. [3, 4]
Now branded PrEP 2:1:1 in the US, on-demand dosing is also now recommended in certain situations by major US health providers in San Francisco and New York, which is significant given FDA only approved daily dosing.
For the majority of people to be able to benefit from F/TAF it will need to be priced much closer to F/TDF. This will need much lower pricing In the UK and other countries that now have access to generic F/TDF.
- Spinner C et al. DISCOVER study for HIV pre-exposure prophylaxis (PrEP): F/TAF has a more rapid onset and longer sustained duration of HIV protection compared with F/TDF. 10th IAS Conference on HIV Science. Mexico City. 21–24 July 2019. Oral late breaker abstract TUAC0403LB.
- Hare CB et al. The phase 3 DISCOVER study: daily F/TAF or F/TDF for HIV preexposure prophylaxis. 4–7 March 2019, Seattle. Oral abstract 104.
- Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society–USA Panel. JAMA. 2018 Jul 24;320(4):379-396. doi: 10.1001/jama.2018.8431.
- European AIDS Clinical Society. European AIDS Clinical Society Guidelines. V 9.1. EAC Society website. www.eacsociety.org/files/2018_guidelines-9.1-english.pdf. Published October 2018. Accessed March 13, 2019
- Bajko MS. SF health officials embrace non-daily PrEP dosing regimen. Bay Area Reporter. (27 Feb 2019).
- NYC department of health and hygiene.An “on-demand” dosing schedule for PrEP to prevent HIV. 2019 Alert number 15, (28 June 2019).
- Street M. New York City adopts PrEP “on demand” as acceptable prevention strategy. Out magazine (11 July 2019).