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New research at CROI suggested that protection against HIV could be close to 100% from daily TDF/FTC (Truvada) and this should change previous reservations about PrEP as an intervention. 
In some studies, daily Truvada dramatically reduced the incidence of HIV infection, especially in high-risk individuals, (by 42% in MSM in the iPrEX study) but produced conflicting results in other studies (notably the FEM-PrEP study in heterosexual African women).
All studies have proved complicated to interpret due to the high rates of self-reported adherence but the likely very low rates of actual adherence demonstrated in PK sub-studies finding low levels of tenofovir and FTC in both active and placebo arms. The projected efficacy of PrEP increased dramatically when PK results were taken into account (to 92% in iPrEX). 
This proven protection could potentially increase real-life adherence compared to that seen in historical studies. If someone knows they will be protected rather than being a participant in a placebo controlled trial, and that this protection is so effective it could eliminate the risk of HIV, this could change the pattern of low use, even in less adherent patients.
PrEP studies are further complicated by the differences in pharmacokinetic properties of individual drugs, by differences in absorption of each drug in the male and female genital tract as well as in rectal tissue, and by the intracellular concentration of the active metabolites at each sites. Differences between human and animal drug absorption may limit how closely efficacy against vaginal and rectal exposure can be interpreted from macaque studies.
At CROI new modeling data showed that the protection from PrEP may be even greater than previously thought. The report that protection approaches 100% argues for new considerations for how PrEP might be incorporated as a health intervention.
Other studies at the meeting addressed some of the concerns for why PrEP has not been universally protective in other some studies.
iPrEX: Modeled Prediction of 99% Protection With Daily Adherence
Peter Anderson and colleagues presented a late breaker oral PK analysis of intracellular drug concentrations in the iPrEX study and correlated this with levels of adherence in the Strand Study. 
This group used regression model to estimate efficacy of PrEP based on intracellular levels of tenofovir diphosphate (TDF-DP) in viable PBMCs from 48 cases matched to 144 uninfected controls. The researchers then established TDF-DP levels achieved on observed therapy of 2, 4 and 7 day dosing in a separate PK study of 24 HIV negative volunteers (the Strand study). Finally, they used the iPrEX regression models from i-PrEX on the Strand study data to estimate PrEP efficacy based on 2, 4 and 7 day dosing.
In iPrEX, detectable tenofovir levels in either plasma or cells was seen to have steadily fallen from baseline to time of infection, to only 8% of cases (at infection) compared to approximately 40% of uninfected controls. In the month prior to infections these rates were 11% vs 50% respectively suggesting that infections occurred during periods of low drug exposure.
In the Strand study, dosing 2, 4 and 7 days a week produced median (IQR) levels (fmol/million cells) of TDF-DP of 11 (6-13), 32 (25-39) and 42 (31-47) respectively. This compared to levels of 11 fmol/M (4-11) in 8% of iPrEX cases with detectable TDF and 16 fmol/M (9-47) in the 44% of controls with detectable levels. Daily dosing could be imputed from drug levels for 18% of iPrEX controls (and that 82% controls were likely to be taking less than daily dosing).
Regression modelling produced and estimated EC90 of 16 fmol/M viable cells (95%CI 3-28) with sensitivity estimates of less than 23 fmol/M producing estimates for risk reduction of 76% (56-96%), 96% (90->99%) and 99% (96->99%) for 2, 4 and 7 day dosing (see Table 1).
Table 1: Estimates for Risk Reduction in iPrEX
||TDF-DP fmol/M viable cells (95%CI)
||Risk reduction (95%CI)
|2 / week
||9 (7 -13)
|4 / week
||30 (23 - 37)
|7 / week
||45 (32 - 59)
This study involved 615 v-PBMC and 1146 plasma samples were tested from 1212 time points (302 cases, 910 controls) but limitations include that drug levels were only proximal to time of exposure and that the impact of FTC levels were not studied.
The confidence intervals for the target IC90 of >15.6 fmol/M viable cells (95%CI 3.0 to 28.2) appears wide and this should be confirmed in future studies.