In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity.
Several studies have reported an increased incidence of auditory dysfunction among HIV/AIDS patients. We used auditory HEI-OC1 cells in cell viability, flow cytometry and caspases 3/7-activation studies to investigate the potential ototoxicity of fourteen HIV antiretroviral agents: Abacavir, AZT, Delavirdine, Didenosine, Efavirenz, Emtricitabine, Indinavir, Lamivudine, Nefinavir, Nevirapine, Tenofovir, Ritonavir, Stavudine and Zalcitabine, as well as combinations of these agents as used in the common anti-HIV cocktails Atripla™, Combivir™, Epzicom™, Trizivir™, and Truvada™. Our results suggested that most of the single assayed anti-HIV drugs are toxic for HEI-OC1 auditory cells. The cocktails, on the other hand, decreased auditory cells' viability with high significance, with the following severity gradient: Epzicom ∼ Trizivir >> Atripla ∼ Combivir > Truvada. Interestingly, our results suggest that Trizivir- and Epzicom-induced cell death would be mediated by a caspase-independent mechanism. l-Carnitine, a natural micronutrient known to protect HEI-OC1 cells against some ototoxic drugs as well as to decrease neuropathies associated with anti-HIV treatments, increased viability of cells treated with Lamivudine and Tenofovir as well as with the cocktail Atripla, but had only minor effects on cells treated with other drugs and drug combinations. Altogether, these results suggest that some frequently used anti-HIV agents could have deleterious effects on patients' hearing, and provide arguments in favor of additional studies aimed at elucidating the potential ototoxicity of current as well as future anti-HIV drugs.
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 2100 West 3rd Street, Los Angeles, CA 90057, USA.
Pru
P
Thein
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 2100 West 3rd Street, Los Angeles, CA 90057, USA.
Gilda M
GM
Kalinec
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 2100 West 3rd Street, Los Angeles, CA 90057, USA.
Channy
C
Park
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 2100 West 3rd Street, Los Angeles, CA 90057, USA. Electronic address: fkalinec@mednet.ucla.edu.
Federico
F
Kalinec
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D002331:Carnitine / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D009925:Organ of Corti / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D019380:Anti-HIV Agents; D004338:Drug Combinations; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D002331:Carnitine