Renal Safety of Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate

A Pooled Analysis of 26 Clinical Trials

Samir K. Gupta; Frank A. Post; José R. Arribas; Joseph J. Eron Jr; David A. Wohl; Amanda E. Clarke; Paul E. Sax; Hans-Jürgen Stellbrink; Stefan Esser; Anton L. Pozniak; Daniel Podzamczer; Laura Waters; Chloe Orkin; Jürgen K. Rockstroh; Tatiana Mudrikova; Eugenia Negredo; Richard A. Elion; Susan Guo; Lijie Zhong; Christoph Carter; Hal Martin; Diana Brainard; Devi SenGupta; Moupali Das

Disclosures

AIDS. 2019;33(9):1455-1465. 

In This Article

Results

We included a collective 9322 individuals across 26 studies (Appendix Table 1, http://links.lww.com/QAD/B470). Participants either initiated or switched to regimens containing TAF (n = 6360) or initiated or continued on regimens containing TDF (n = 2962) (Table 1). Baseline median age was 42 years, 21% were women, and 27% were of black race. Pooled data included exposure of 12 519 person-years to TAF and 5947 person-years to TDF.

Primary Analyses

Incidence of proximal renal tubulopathy events. In the dataset including all 26 studies, 14 of which were double blinded, there were no cases of PRT or Fanconi syndrome reported in the TAF group (Figure 2). Ten cases of PRT, including Fanconi syndrome, were reported by site investigators for the TDF group (0.34% of participants, P < 0.001 vs. TAF). Of the PRT cases, nine of 10 were investigator reported as study drug related, nine of 10 occurred during blinded therapy, and eight of 10 resulted in study drug discontinuation. Appendix Figure 1, http://links.lww.com/QAD/B470 shows the specific ART regimens, duration of study drug exposure relative to onset of PRT and relatedness to study drug as determined by the site investigator. The timing of PRT development was variable but often occurred well into therapy, including three of 10 cases developing in participants who were virologically suppressed on TDF for at least 6 months at the time of enrolment (Appendix Figure 1, http://links.lww.com/QAD/B470).

Figure 2.

Cases of proximal renal tubulopathy and renal adverse events leading to study drug discontinuation across 26 clinical studies. The incidence of proximal renal tubulopathy and renal discontinuation events were determined using pooled data from 26 studies as described in the Methods section. Differences between treatment groups compared using Fisher exact test.

Discontinuations due to renal adverse events. In the dataset including all 26 studies, three of 6360 individuals (0.05%) who received TAF discontinued study drug due to renal adverse events compared with 14 of 2962 (0.47%) participants in the TDF group (P < 0.001) (Figure 2). Of the 14 participants in the TDF group, four were in open-label studies and the remainder were in double-blinded studies; 12 of 14 discontinuations were reported as study drug-related. All three participants in the TAF group were enrolled in open-label studies, and no discontinuations were reported as study-drug related. Appendix Figure 2, http://links.lww.com/QAD/B470 shows the specific ART regimens, duration of study drug exposure relative to onset of the renal adverse event, as well as relatedness to the study drug as determined by the investigator. Appendix Table 4, http://links.lww.com/QAD/B470 provides clinical narratives describing the renal discontinuation events.

Secondary Analyses

We next sought to compare secondary renal outcomes between TAF-based and TDF-based regimens both in the settings of treatment-naive ART initiation and regimen switch in virologically suppressed PLH. To this end, we identified two ART-naive studies and five switch studies that were randomized, included both TAF and TDF arms, and included at least 48 weeks of follow-up (Figure 1).

Total of all renal adverse events in antiretroviral therapy-naive people living with HIV. Based on pooled data from two randomized, double-blinded studies of treatment-naive PLH, clinical renal adverse events through week 96 were reported significantly less frequently in the TAF group than in the TDF group [47/866 (5.4%) vs. 74/867 (8.5%), P = 0.042].

Changes in renal laboratory parameters and biomarkers in antiretroviral therapy-naive people living with HIV. In treatment-naive PLH, median change from baseline at weeks 48 and 96 in SCr was significantly lower in the TAF group compared with TDF group [difference in least squares mean (LSM) −0.03 mg/dl, P ≤ 0.001 at week 96] (Figure 3a). Similarly, we noted that median CrCl had declined less in the TAF group compared with the TDF group (difference in LSM 6.0 ml/min, P ≤ 0.001 for week 96) (Figure 3b).

Figure 3.

Longitudinal changes in renal laboratory parameters. Serum creatinine (a) and creatinine clearance (b) were determined longitudinally as described in the Methods section, and are depicted as median change from baseline (purple = tenofovir alafenamide, orange = tenofovir disoproxil fumarate). In each panel, the first plot depicts pooled data from two treatment-naive studies, and the second plot depicts data from five virologically suppressed studies. Differences between treatment groups in changes from baseline were compared using linear regression (baseline demographics and disease characteristics selected from step-wise procedure adjusted).

In treatment-naive PLH, we observed that treatment-emergent proteinuria at week 96 (defined as 1+ or greater proteinuria by dipstick on any occasion) was reported for fewer people in the TAF group compared with those in the TDF group [307/862; (36%) vs. 354/865 (41%); P = 0.034].

Treatment-naive PLH initiating TAF-based regimens had greater decreases or smaller increases from baseline through week 96 in median urinary biomarkers (UACR, RBP : Cr, β2M : Cr) compared with TDF (Figure 4). At week 96, median UACR decreased by 5.2% with TAF vs. an increase of 4.9% with TDF (P ≤ 0.001) (Figure 4a). Median RBP : Cr increased by 13.8% with TAF compared with an increase of 74.2% on TDF (P ≤ 0.001) (Figure 4b). Median β2M : Cr declined by 32.1% with TAF compared with an increase of 33.5% on TDF (P ≤ 0.001) (Figure 4c).

Figure 4.

Longitudinal changes in renal biomarkers. Urine albumin to creatinine ratio (a), retinol binding protein-to-creatinine ratio (b), and β2-microglobulin-to-creatinine ratio (c) were determined longitudinally as described in the Methods section and are depicted as median percentage change from baseline (purple = tenofovir alafenamide, orange = tenofovir disoproxil fumarate). In each panel, the first plot depicts pooled data from two treatment-naive studies, and the second plot depicts data from five virologically suppressed studies. Differences between treatment groups in changes from baseline were compared using linear regression (baseline demographics and disease characteristics selected from step-wise procedure adjusted).

Total of all renal adverse events in virologically suppressed people living with HIV. We evaluated pooled data from five randomized studies (two open-label, three blinded) of virologically suppressed PLH who switched from TDF-containing to TAF-containing regimens or continued their baseline TDF-based regimen. We observed no difference in the rate of reported clinical renal adverse events in these switch studies [114/2291 (5%) vs. 89/1801 (5%), P = 1.00].

Changes in renal biomarkers in virologically suppressed people living with HIV. For virologically suppressed PLH, there was a greater reduction in median SCr from baseline in the TAF group compared with the TDF group (difference in LSM −0.03 mg/dl, P ≤ 0.001 for week 96) (Figure 3a). Median CrCl increased in the TAF group while no change was seen in the TDF group (difference in LSM 5.2 ml/min, P ≤ 0.001 for week 96) (Figure 3b).

In virologically suppressed PLH, we observed that treatment-emergent proteinuria at week 96 (defined as 1+ or greater proteinuria by dipstick on any occasion) was reported for fewer people in the TAF group compared with those in the TDF group [636/2287 (28%) vs. 561/1794 (31%); P = 0.04].

In virologically suppressed participants switching from TDF to TAF, TAF-based regimens had greater decreases or smaller increases from baseline through week 96 in median renal biomarkers (UACR, RBP : Cr, β2M : Cr) compared with TDF (Figure 4). Median UACR decreased by 5.4% on TAF and increased by 27.0% on TDF (P ≤ 0.001) (Figure 4a). Median RBP : Cr decreased by 2.3% on TAF and increased 61.2% on TDF (P ≤ 0.001) (Figure 4b). Median β2M : Cr decreased by 25.8% with TAF and increased by 53.0% on TDF (P ≤ 0.001) (Figure 4c).

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