Genotoxic and Cytotoxic Effects of Antiretroviral Combinations in Mice Bone Marrow.

Aroldo Vieira De Moraes Filho,Wanessa Fernandes Carvalho,Cláudia De Jesus Silva Carvalho,Débora Cristina Da Silva Lima,Cristiene Costa Carneiro,Kênya Silva Cunha,Thiago Bernardi Vieira,Daniela De Melo E Silva,Lee Chen-Chen,Camila Regina Do Vale,Cheryl A Stoddart

doi:10.1371/journal.pone.0165706

Aroldo Vieira De Moraes Filho, Wanessa Fernandes Carvalho + Show 9 more

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https://doi.org/10.1371/journal.pone.0165706

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Journal: PloS one	Publication Date: Nov 2, 2016
Citations: 18	License type: CC BY 4.0

Abstract

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.

Highlights

The fact that the human immunodeficiency virus (HIV) undergoes several mutations in DNA structure hinders the success of treatments with only one drug
All the animals survived the treatments and no clinical signs of toxicity were observed in any treated groups
DNA damage occurred at chromosomal level, suggesting that drug combinations can induce clastogenic and aneugenic effects

Summary

Introduction

The fact that the human immunodeficiency virus (HIV) undergoes several mutations in DNA structure hinders the success of treatments with only one drug. The highly active antiretroviral therapy (HAART), a combination of two or more antiretroviral drugs, has been used effectively and safely in the management of HIV/AIDS since 1996 [1,2,3,4]. Common guidelines for the management of HIV infection (HAART) include the following drug combinations: tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) and efavirenz (EFV) plus combivir [zidovudine (AZT) + 3TC] [5,6,7,8]. AZT had clastogenic effects such as sister chromatid exchange and reduction in telomere length.

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