Patient Selection and Propensity Score Matching
As shown in the flowchart (Fig.1), a total of 1065 patients were screened and 823 patients were eligible for participation, 299 of whom (36.3%) started a TDF-containing cART. Table 1 showed the baseline characteristics of TDF users and non-TDF users before and after PSM. After matching, there were 130 (33.3%) patients in TDF group, and all baseline variables were well balanced (P > 0.05 for all).
The median age was 30 years among TDF users, and 27 years among non-TDF users. Most enrolled patients were male and were infected via male-male sex. Of 823 patients, 178 (21.6%) experienced RRF, and 451 (54.8%) experienced RKFD over a median follow-up of 10 (interquartile range [IQR], 2-20; maximum 90) months. In TDF users, 97 experienced (32.4%) RRF, and 183 (61.2%) experienced RKFD. There were 4424 eGFR measurements for TDF users. For each group, there was a median of 7 eGFR measurements per person (IQR, 3-11) and the median interval between eGFR measurements was 90 (IQR, 30-90) days.
Comparison of one linear and piecewise linear mixed effects models.
We compared eGFR trajectories by one linear and piecewise linear models (Table 2), with the piecewise model allowing a change of the eGFR slope at a given time point. Log likelihood ratio test between the two models indicated that nonlinear trajectory of eGFR was a better fit than the traditional one assuming a single linear process across the entire period of observation (P < 0.001 for all).
Time points on nonlinear trajectories of eGFR.
For non-TDF users, the time points were 2.55 years (Table 2, model 1), 2.15 years (Table 2, model 2), and 2.15 years (Table 2, model 3). The difference of eGFR slopes were -4.79 (-5.84, -3.74), -5.43 (-6.47, -4.40) and -4.28 (-6.24, -2.33), respectively.
For TDF users, the time points on nonlinear trajectory of eGFR were significantly different from that of non-TDF users. For example, the time points were 1.40 years and 2.30 years in model 2. The difference of eGFR slopes were -10.14 (-14.44, -5.85) at 1.40 years and -8.54 (-12.67, -4.41) at 2.30 years. Similar results were obtained in model 1 and 3 (Table 2).
The relationship between eGFR and duration of cART.
The eGFR changed over time in both groups (Fig.2, Additional file 1: Fig.S1, S2). There was a reverse S-shaped relationship between eGFR and duration of cART for TDF users, but a different temporal trajectory for non-TDF users, in all three models. The S-shaped trajectory was observed markedly in model 1 (Additional file 1: Fig.S1B) and model 2 (Fig.2B).
Average changes in eGFR over time on different cART duration among TDF or non-TDF users.
Table 3 showed average eGFR changes per year for the two groups according to cART duration. For TDF users, we obtained different results when the duration of cART was categorized using different time points in all three models. The exp (β) was -5.31 (95% CI: -6.57, -4.06) for cART less than 1.40 years and -3.71 (95% CI: -5.97, -1.45) for 2.30 years or more. However, the exp (β) was reverse, 4.83 (95% CI: 1.38, 8.28) for 1.40 to 2.30 years. For models 1 and 3, these time points were nearly the same, and similar trends were indicated in eGFR with increasing duration of cART (Table 3).
For non-TDF users, before the time points, a longer duration of cART was associated with a slight increased eGFR in all three models; after the time points, there was an inverse association between eGFR and duration of cART (Table 3).
Nonlinear progression of renal function over time.
Two outcome definitions, RRF and RKFD, were used to assess whether renal dysfunction progression consists with the nonlinear trajectory of eGFR (Table 4). For patients without TDF exposure, use of cART for 2.15 years or more, the risk of RRF increased steadily to 2.05 per year (95% CI: 1.54, 2.71). For patients using TDF, there was an increased risk of RRF for those using cART less than 1.40 years (adjusted odds ratio [aOR]: 3.33 per year; 95% CI: 2.34, 4.75) and for those using cART for 2.30 years or more (aOR: 1.58 per year; 95% CI: 1.03, 2.43). However, those using TDF for 1.40 to 2.30 years had a decreased risk of RRF (41% decrease per year; 95% CI: -75%, 39%).
There was no increased risk of RKFD among non-TDF users who received cART for 2.15 years or more, nor among TDF users who received cART for less than 1.40 years. But, each additional one year of TDF exposure was associated with a 78% (95% CI: -91%, -49%) decreased risk of RKFD from 1.40 to 2.30 years, and a nearly 3-fold (95% CI: 1.08, 7.27) increased risk of RKFD for those on TDF for more than 2.30 years. Similar trends were observed in PSM data (Table 4).
Two sensitivity analyses, one conducted with imputed datasets and the other with patients not using PIs, indicated these results were robust (Additional file 1: S2 to S5).