There remains considerable argument over the role, if any, tenofovir (TDF, Viread) use plays in observed renal dysfunction during antiretroviral therapy. Long-term clinical studies such as GS903¹ have not reported declines in glomerular filtration rate (GFR) or occurrences of grade 2 or higher creatinine elevations through five years of therapy.

Clinical case series of renal dysfunction during tenofovir-based therapy have suggested several possible risk factors for renal dysfunction during tenofovir use, including more advanced HIV infection, injection drug use and didanosine (ddI, Videx)-coadministration. Indeed, several of these risk factors may represent risk factors for the observance of renal dysfunction in the HIV population as a whole.

In dogs, but not in other animals, high doses of tenofovir can lead to renal dysfunction. Using human renal proximal tubular epithelial cells (RPTECs), Francesce Vidal from Hospital Universitari Joan XXIII and Universitat Rovira I Virgili in Spain and colleagues tested various concentrations of a range of antiretrovirals, including tenofovir, zidovudine (AZT, Retrovir), didanosine, ritonavir (RTV, Norvir) and lopinavir (LPV) alone as well as in combination for up to 22 days.² The researchers then assessed cell viability, mitochondrial DNA content and cytochrome oxidase II (COII) mRNA expression. Didanosine showed a marked cytotoxicity and reduced mitochondrial DNA content in RPTECs significantly more than that of zidovudine and tenofovir. Tenofovir alone was not associated with a significant cytotoxicity and improved cell viability when it is in combination with zidovudine or didanosine.

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Slide by Francesce Vidal, M.D.; reprinted with permission of Gilead.

The combination of 10 µM ritonavir and 40 µM lopinavir significantly reduced RPTEC viability (P < .001). The authors conclude that tenofovir does not show any significant in vitro cytotoxicity or mitochondrial toxicity in human RPTECs whereas zidovudine exhibits minor and didanosine more profound effects both on the cell viability and the status of mitochondria.

Click to enlarge
Slide by Francesce Vidal, M.D.; reprinted with permission of Gilead.

Ritonavir and lopinavir are significantly cytotoxic in RPTECs only when combined together at concentrations substantially exceeding their therapeutic levels. Tenofovir does not enhance the cytotoxicity of lopinavir or ritonavir. Combining tenofovir with either nucleoside/nucleotide reverse transcriptase inhibitors or protease inhibitors does not further enhance cytotoxic effects. The results suggest that tenofovir is unlikely to be the unique offending drug in the reported cases of renal dysfunction in tenofovir-treated patients.

Footnotes

1. Gallant JE, Staszewski S, Pozniak AL, et al, for the 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients. JAMA. July 14, 2004;292(2):191-201.

2. Vidal F, Domingo J, Guallar J, et al. Effects of tenofovir on the in vitro toxicity of selected antiretrovirals in human renal proximal tubule cells. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1903.
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