Table 2 Comparisons of covariate-adjusted mean values of pharmacokinetic features between PrEP and non-PrEP users via the targeted minimum loss-based estimation (TMLE) method

PK feature	PrEP User Status	Mean (95% CI)^a	Two-sided raw p-value^b	Two-sided adjusted p-value^c
Clearance [CL (L/day)]	PrEP	0.60 (0.54, 0.66)
	Non-PrEP	0.52 (0.46, 0.58)
	*Difference*	0.08 (0.03, 0.13)	0.002	0.005
Volume of the peripheral compartment [Vp (L)]	PrEP	5.24 (2.59, 7.90)
	Non-PrEP	4.88 (2.18, 7.58)
	Difference	0.36 (−0.55, 1.28)	0.44	0.73
Distribution half-life (day)	PrEP	2.35 (0.00, 8.10)
	Non-PrEP	2.37 (0.00, 8.30)
	Difference	−0.02 (−0.42, 0.38)	0.94	0.94
Elimination half-life (day)	PrEP	16.83 (4.40, 29.26)
	Non-PrEP	17.39 (10.45, 24.34)
	Difference	−0.56 (−8.04, 6.91)	0.88	0.94
Steady-state area under the curve [AUC^d (day/mL)]	PrEP	1.74 (1.55, 1.92)
	Non-PrEP	2.03 (1.83, 2.23)
	*Difference*	−0.29 (−0.45, −0.14)	<0.001	<0.001

All comparisons were adjusted for age, body weight, race, behavioral risk score, creatinine clearance (CrCl), IFN-γ, and IL-10 levels based on data from PrEP users (n = 24) and non-PrEP users (n = 24). One PrEP user and one non-PrEP user had missing baseline specimen hence missing IFN-γ and IL-10 levels. All TMLE estimation results of means were averaged over 20 runs with a fixed random seed on top of the 10-fold cross-validation estimation procedure to ensure stability of the estimates. A bootstrap procedure based on 500 datasets was used to calculate the empirical variances of the estimates for each group and to derive the 95% confidence interval, as well as to test for a non-zero mean difference between the two groups via the Wald test. The Holm method was used to adjust for multiple comparisons of the five PK features.
^aCovariate-adjusted mean by targeted minimum loss-based estimation (TMLE) (See Methods for more details).
^bConfidence intervals (CIs) and p-values based on empirical variances estimated via the bootstrap procedure. Bold = significant
^cP-values adjusted by the Holm method to control for family-wise error rate.
^dArea under the time-concentration curves divided by dose amount.

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