Mitochondrial Toxicity of Tenofovir (Viread), Emtricitabine (Emtriva), and Abacavir (Ziagen) Alone and in Combination with Other NRTIs

Some nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) combinations can cause additive or synergistic interactions in vitro and in vivo. One possible adverse event of NRTI is mitochondrial toxicity, or damage to energy-producing structures within cells.

The NRTIs d4T (stavudine; Zerit), ddI (didanosine; Videx), and the now discontinued ddC (zalcitabine; Hivid) have been most strongly associated with mitochondrial toxicity in HIV patients.

As reported recently in Antiviral Therapy, German researchers evaluated the mitochondrial toxicity of tenofovir (Viread), emtricitabine (Emtriva), and carbovir -- the active form of abacavir (Ziagen) after it is processed in the body -- alone, with each other, and in combination with additional NRTIs.

HepG2 human hepatoma cells were incubated with tenofovir, emtricitabine, carbovir, ddI, d4T, 3TC, and AZT (zidovudine; Retrovir) at concentrations equivalent to 1x and 10x clinical steady-state peak plasma levels (Cmax).

NRTIs were also used in double and triple combinations. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA), and the mtDNA-encoded respiratory chain subunit II of cytochrome c oxidase (COXII) were monitored for 25 days. Elevated lactate or lactic acidosis is a potential sign of mitochondrial toxicity.

Results

·         Tenofovir and 3TC had no or minimal toxicity.

·         Emtricitabine moderately reduced hepatocyte proliferation independent of its effects on mtDNA.

·         ddl and d4T induced a time- and dose-dependent loss of mtDNA and COXII, decreased cell growth, and increased levels of lactate and intracellular lipids.

·         Carbovir and AZT strongly impaired hepatocyte proliferation and increased lactate and lipid production, but did not induce mtDNA depletion.

·         The dual combination of tenofovir plus 3TC had only minimal toxicity.

·         Tenofovir plus FTC slightly reduced cell proliferation without affecting mitochondrial parameters.

·         All other combinations exhibited more pronounced adverse effects on mitochondrial endpoints.

·         Toxic effects on mitochondrial parameters were observed in all combinations that included ddI, d4T, AZT or carbovir.

·         Tenofovir and 3TC both attenuated ddI-related cytotoxicity, but worsened the effects of carbovir and AZT.

Conclusion

In conclusion, the authors wrote, “The data demonstrate unpredicted interactions between NRTIs with respect to toxicological endpoints and provide an argument against the liberal use of NRTI cocktails without first obtaining data from clinical trials.”

Medizinische Universitätsklinik, Department of Rheumatology Et Clinical Immunology, Freiburg, Germany.

12/04/07

Reference
N Venhoff, B Seltzer, K Melkaoui, and UA Walker. Mitochondrial toxicity of tenofovir, emtricitabine and abacavir alone and in combination with additional nucleoside reverse transcriptase inhibitors. Antiviral Therapy 12(7): 1075-1085. 2007.