In vivo genotoxicity evaluation of efavirenz (EFV) and tenofovir disoproxil fumarate (TDF) alone and in their clinical combinations in Drosophila melanogaster

- All medicines tested induced genotoxicity using the comet assay.
- Both combinations tested had antagonistic effects using the comet assay.
- Only EFV alone was not mutagenic/recombinogenic using SMART.
- Mitotic recombination was the major event induced by all treatments.
- Both combinations tested had antagonistic effects using SMART.

This study focuses on the antiretrovirals efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir analog of adenosine 5′-monophosphate, which belongs to the class of nucleotide reverse transcriptase inhibitors. Both compounds act on the mechanisms of HIV replication, inhibiting the action of reverse transcriptase and thus preventing viral DNA synthesis. The toxic and genotoxic potential of EFV and TDF alone and in combinations {EFV + combivir [zidovudine (AZT) + lamivudine (3TC)] and TDF + 3TC} were assessed using the comet assay and the somatic mutation and recombination test (SMART) in Drosophila melanogaster. The results indicate that EFV was toxic at high concentrations and induced genotoxicity using the comet assay, but showed neither mutagenic nor recombinogenic effects using SMART. In combination with combivir, EFV exhibited antagonic genotoxic effects in both tests. Inversely, TDF did not show toxicity but induced genotoxicity at all concentrations tested in both the comet assay and SMART. The prevalence of recombinogenic events in all treatments with TDF alone and in combination with 3TC was detected using SMART. Homologous recombination is an important parameter to be taken into consideration in the evaluation of carcinogenicity of medicines used in antiretroviral therapy regimens, due to the need for lifelong adherence and the unknown effects of long-term treatments.