Overview

Tenofovir alafenamide (TAF) is a prodrug of the active metabolite tenofovir, which belongs to the drug group of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). In Malaysia, TAF is approved for the treatment of chronic hepatitis B or used in combination with other antiretroviral agents for the treatment of adults and adolescents infected with human immunodeficiency virus type 1 (HIV-1).^1-2

Tenofovir disoproxil fumarate (TDF), the older tenofovir prodrug that is widely used for the treatment of HIV infection and hepatitis B infections, was first internationally approved for use in 2001^3-4. The newer TAF was internationally approved in 2015, and later approved for use in Malaysia by the Drug Control Authority (DCA) in 2018.^5-6 There are currently 7 products containing TAF and 16 products containing TDF registered with the DCA.⁶

Background of Safety Issue

It has come to our knowledge that the Australian Therapeutic Goods Administration (TGA) is updating the product information for TAF to include the risk of renal adverse effects in October 2021.⁷

Tenofovir-associated nephrotoxicity, such as acute tubular necrosis, Fanconi syndrome (multiple defects in proximal tubular reabsorption leading to urinary wasting of glucose, phosphate, potassium, bicarbonate, uric acid, amino acids and other solutes), and acute renal failure, is already well-known with TDF.^4,5,8,9 Proximal renal tubulopathy and other renal adverse events have been reported in less than 1% of individuals using TDF.⁹

TDF is converted to tenofovir in the plasma and excreted via glomerular filtration and active tubular secretion at the proximal tubules of the kidney.⁴ Conversely, TAF is more stable in the plasma and is converted to tenofovir intracellularly, resulting in a mean 91% lower plasma tenofovir exposure when compared TDF.^4,5,8,9 Tenofovir is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase; thus, accumulation of tenofovir in proximal tubular cells may lead to mitochondrial injury or dysfunction.^3-5  It is hypothesised that reduced circulating tenofovir levels may result in fewer renal adverse events.^8-9

Given its unique pharmacokinetic characteristics, TAF has a more favourable renal safety profile than treatment with its predecessor TDF.^4,5,8,9 Hence, patients have been commonly switched from TDF to TAF-based antiretroviral regimens.⁸ Nevertheless, as described in local package inserts, a potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with TAF cannot be excluded.^1-2

As TAF has become more widely available, post-marketing cases of acute kidney injury in patients using TAF started to emerge.⁵ Reported post-marketing renal adverse effects associated with TAF include acute renal failure, proximal renal tubulopathy, and Fanconi syndrome.⁸ Pathological evidence of acute tubular injury and mitochondrial injury from the kidney biopsy has been reported in a literature case report of TAF nephrotoxicity.⁵ A review of published literature on TAF-associated nephrotoxicity showed the general prognosis was good and renal function could spontaneously recover after the withdrawal of the TAF-containing regimen.⁵ Of note, possible drug synergism in the pathophysiology of proximal tubular dysfunction has also been reported in a case report of proximal renal tubulopathy in an HIV-infected patient treated with TAF and gentamicin.⁸

Adverse Drug Reaction Reports¹⁰

NPRA has received one (1) report with three (3) adverse events suspected to be related to TAF, compared to 210 reports of 364 adverse events received for TDF. The three (3) adverse events reported for TAF are dizziness, feeling hot and rash maculo-papular. No report of renal adverse effects related to TAF has been received thus far. However, there are 53 renal adverse effects reported for TDF, which include blood creatinine increased (12), acute kidney injury (6), acute renal failure (3), Fanconi syndrome (3), and Fanconi syndrome acquired (2).

Advice for Healthcare Professionals

• Be aware of the possibility of renal adverse events following the use of TAF, especially when it is prescribed in patients
• with underlying renal disease or at risks for renal impairment,
• taking nephrotoxic drugs concomitantly,
• with smaller body stature or low body weight.
• Assess the patient’s renal function before initiating treatment and routinely monitor renal function during treatment with TAF.
• Consider stopping TAF in patients who develop clinically significant decreases in renal function or evidence of nephrotoxicity.
• Report all suspected adverse events associated with TAF-containing products to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). VEMLIDY (tenofovir alafenamide) 25mg film-coated tablets [Package Insert]. 2020 Dec [cited 2022 Jan 20] The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted)
2. National Pharmaceutical Regulatory Agency (NPRA). DESCOVY (emtricitabine/tenofovir alafenamide) 200mg/25mg film-coated tablets [Package Insert]. 2019 Jul [cited 2022 Jan 20] The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted)
3. National Pharmaceutical Regulatory Agency (NPRA). VIRADAY (tenofovir disoproxil fumarate/ emtricitabine/efavirenz) 300mg/200mg/600mg tablets [Package Insert]. 2021 Mar [cited 2022 Jan 20] The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted)
4. Nishijima T, Gatanaga H, Oka S. Tenofovir nephrotoxicity among Asians living with HIV: reivew of the literature. Glob Health Med. 2019; 1(2):88–94. Available from: https://dx.doi.org/10.35772%2Fghm.2019.01021
5. Ueaphongsukkit T, Gatechompol S, Avihingsanon A, Surintrspanont J, Iampenkhae K, Avihingsanon Y, et al. Tenofovir alafenamide nephrotoxicity: a case report and literature review. AIDS Res Ther. 2021;18(1):53. Available from: https://doi.org/10.1186/s12981-021-00380-w
6. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Jan 20] Available from: https://www.npra.gov.my
7. TGA Australia. Medicines safety update: Tenofovir alafenamide and renal adverse effects [Internet]. 2022 Jan 6 [cited 2022 Jan 20]. Available from: https://www.tga.gov.au/publication-issue/tenofovir-alafenamide-and-renal-adverse-effects
8. Heron JE, Bloch M, Vanguru V, Saunders J, Gracey DM. Renal proximal tubulopathy in an HIV-infected patient treated with tenofovir alafenaide and gentamicin: a case report. BMC Nephrol. 2020; 21(1):339. Available from: https://doi.org/10.1186/s12882-020-01981-9
9. Gupta SK, Post FA, Arribas JR, Eron JJJ, Wohl DA, Clarke AE, et al. Renal safety of tenofovir alafenamide vs tenofovir disoproxila fumarate: a pooled analysis of 26 clinical trials. AIDS. 2019;33(9):1. Available from: http://dx.doi.org/10.1097/QAD.0000000000002223
10. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2022 Jan 17]. Available from: https://www.npra.gov.my (access restricted)

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli