Early Safety of Tenofovir Alafenamide in Patients With a History of Tubulopathy on Tenofovir Disoproxil Fumarate

A Randomized Controlled Clinical Trial

L Hamzah; D Williams; AC Bailey; R Jones; F Ibrahim; CG Musso; K Burling; B Barbini; L Campbell; FA Post

Disclosures

HIV Medicine. 2020;21(3):198-203. 

In This Article

Discussion

We comprehensively evaluated kidney function and bone turnover and observed no change in renal and bone biomarkers during 12 weeks of exposure to F/TAF in 16 individuals with a history of TDF-associated treatment-limiting PRT. While these data suggest that there were no immediate demonstrable adverse effects of TAF on kidney function, longer term safety data are required to confirm the safety of TAF in this vulnerable group of patients, and hence this study will continue to follow all participants until at least 96 weeks.

Clinical trial data suggest that TAF may be a suitable option for people with HIV infection who have mild-to-moderate CKD,[11] and, while some case reports suggest that TAF may also be an option for those who experienced treatment-limiting PRT on TDF,[12–15] others have reported acute kidney injury (AKI) with and without tubular function abnormalities in selected individuals receiving TAF.[19–22] While these cases raise the possibility of TAF nephrotoxicity, in one case the patient took an overdose (300 mg of TAF among other compounds); the second patient had liver cirrhosis and diabetes, actively used heroin and cocaine, had multiple co-medications and presented with AKI and nephrotic syndrome; the third patient had decompensated liver cirrhosis, actively used alcohol, underwent treatment for hepatitis and also presented with AKI and nephrotic syndrome; and the fourth patient presented with AKI shortly after switching from TDF, which he had tolerated for the past 10 years, each suggesting that other factors could have contributed to and/or were responsible for the kidney injury. It is also unclear whether the second, third and fourth patients had undetectable HIV viral loads (an indication of adherence to TAF-containing ART) at AKI presentation.

The data presented in this report should be interpreted with a number of limitations in mind. Although this is the largest case series of TAF after TDF-associated PRT to date, we present data on only 16 patients, and we did not reach our target sample size (20 in each arm), which affected our ability to detect differences in RBPCR and other renal biomarkers between the two groups or the occurrence of potential tubular toxicity. As regular monitoring of kidney function is standard clinical practice, PRT is often recognized before the development of severe kidney disease, including Fanconi syndrome, and resultant bone pathology (osteomalacia and fractures). This may have resulted in the inclusion of several patients with 'softer' phenotypes in the trial. Although most would probably have developed severe PRT with continued TDF exposure,[5] others might not have progressed beyond subclinical renal tubular dysfunction.[17] It should be noted, however, that the observed fasting urine osmolality, eGFR and TmPO4/GFR values were considerably lower than their expected values,[23] suggesting that we enrolled a population with (residual) renal dysfunction who may be at risk of adverse renal effects from even low-level tubular tenofovir diphosphate exposure as typically achieved with TAF. Finally, current analyses are restricted to the first 12 weeks of exposure to TAF (after which subjects in the control arm switched to TAF), which may have been too short a period for changes in renal biomarkers to emerge; however, studies in which participants with impaired renal function switched from TDF to TAF showed rapid (within 1–2 weeks) reductions of urinary RBP,[11] suggesting that 12 weeks might have been sufficient to detect an adverse biomarker signal of TAF renal toxicity.

In conclusion, 12 weeks of TAF exposure did not adversely affect urinary biomarkers in people with HIV infection who had a history of PRT while taking TDF-containing ART, suggesting that TAF may be a suitable treatment option for this population, allowing the administration of ART regimens with enhanced potency, reduced pill burden, and activity against hepatitis B virus. Longer term effects of TAF on renal tubular function in this population will be reported in due course.

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