Genotoxic and Cytotoxic Effects of Antiretroviral Combinations in Mice Bone Marrow

• Published in: PloS one Vol. 11; no. 11; p. e0165706
• Main Authors: Moraes Filho, Aroldo Vieira de, Carvalho, Cláudia de Jesus Silva, Carneiro, Cristiene Costa, Vale, Camila Regina do, Lima, Débora Cristina da Silva, Carvalho, Wanessa Fernandes, Vieira, Thiago Bernardi, Silva, Daniela de Melo E, Cunha, Kênya Silva, Chen-Chen, Lee
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.11.2016; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; Antiretroviral agents; Antiretroviral drugs; Antiretroviral Therapy, Highly Active; Apoptosis; Bioassays; Biology and Life Sciences; Body weight; Bone marrow; Bone Marrow - drug effects; Carcinogenesis; Carcinogens; Combivir; Comet Assay; Cytotoxicity; Damage detection; Deoxyribonucleic acid; DNA; DNA damage; Dose-Response Relationship, Drug; Drug Combinations; Drug therapy; Drug Therapy, Combination - adverse effects; Drugs; Efavirenz; Erythrocytes; Gel electrophoresis; Genotoxicity; Health aspects; Highly active antiretroviral therapy; HIV; Human immunodeficiency virus; In vivo methods and tests; Lamivudine; Lamivudine - administration & dosage; Lamivudine - adverse effects; Lentivirus; Medicine and Health Sciences; Mice; Micronuclei, Chromosome-Defective - chemically induced; Mitochondrial DNA; Retroviridae; Tenofovir; Tenofovir - administration & dosage; Tenofovir - adverse effects; Therapy; Toxicity; Tumors; Viruses; Zidovudine; Zidovudine - administration & dosage; Zidovudine - adverse effects; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165706

Commonly used guidelines for the management of human immunodeficiency virus (HIV) infection (highly active antiretroviral therapy, HAART) include drug combinations such as tenofovir disoproxil fumarate (TDF) + lamivudine (3TC) and combivir [zidovudine (AZT) + 3TC] + efavirenz (EFV). These combinations may enhance the genotoxic effects induced by such drugs individually, since the therapy requires lifelong adherence and the drugs have unknown effects during treatment. Thus, the evaluation of the benefits and risks of HAART is of great importance. In order to assess the cytotoxic and genotoxic potential of three concentrations of each of the antiretroviral combinations TDF + 3TC (800 + 400, 1600 + 800, and 3200 + 1600 mg/kg body weight, BW) and combivir + EFV (200 + 100 + 400, 400 + 200 + 800, and 800 + 400 + 1600 mg/kg BW) after two exposure periods (24 h and 48 h), in the present study the in vivo comet assay (single-cell gel electrophoresis) and the mouse bone marrow micronucleus test were used. Neither TDF + 3TC nor combivir + EFV induced DNA damage at any concentrations tested after 24 h or 48 h using the comet assay. After 24 h, both combinations increased the micronucleus frequency at all concentrations tested. After 48 h, combivir + EFV increased the micronucleated polychromatic erythrocyte (MNPCE) frequency at the two highest concentrations tested. Polychromatic erythrocytes (PCE)/normochromatic erythrocytes (NCE) ratio was high for both combinations, suggesting that they can be mitogenic. Since genotoxicity may be related to carcinogenesis, it is necessary to conduct further studies to verify the long-term mutagenic effects of these drugs.