Genetic and reproductive toxicity of lamivudine, tenofovir disoproxil fumarate, efavirenz and their combination in the bone marrow and testicular cells of male mice

Abstract

<jats:title>Abstract</jats:title><jats:p>The combination of antiretroviral (ARV) drugs: lamivudine, tenofovir disoproxil fumarate (TDF) and efavirenz is among the preferred first-line regimens for adolescents and adults infected with HIV. However, knowledge on <jats:italic>in vivo</jats:italic> genetic and reproductive toxicity of each of these drugs and their combination is limited. We evaluated the genotoxicity of lamivudine, TDF, efavirenz and their combination utilizing the mouse micronucleus (MN) and sperm morphology tests. Histopathological analysis of the testes of exposed mice was also carried out. 0.016, 0.032, 0.064 and 0.129 mg/kg bwt of lamivudine, TDF and the combination; and 0.032, 0.064, 0.129 and 0.259 mg/kg bwt of efavirenz corresponding to 0.125, 0.250, 0.500 and 1.000 x the human therapeutic daily dose (HTD) of each of the ARVs and their combinations were administered to mice for 5 consecutive days. Data on MN showed a significant increase (p &lt; 0.05) across the tested doses of TDF, efavirenz and the combination, with the combination inducing lower frequency of MN than TDF and efavirenz. Lamivudine did not evoke significant induction of MN. Significant increase in frequency of abnormal sperm cells were observed in the tested samples, however, the combination induced the highest number of abnormal spermatozoa. The ARVs and their combination induced pathological lesions such as vacuolation and necrosis in mice testes. These findings suggest that the individual ARVs and their combination are potentially capable of activating genetic alterations in the bone marrow and germ cells of male mice thereby raising concern for long term use by HIV patients.</jats:p>

Reproductive and Oxidative Stress Toxicity of Dolutegravir-Based Combination Antiretroviral Therapy in Drosophila melanogaster

“…The Human immunodeficiency virus (HIV) infection is one of the leading causes of illness and deaths worldwide [1,2]. The antiretroviral drugs used against the HIV infection have yielded success, especially in the reduction of related incidences [2,3] and deaths [2], though at the peril of adverse drug reactions (ADRs) [4].…”

“…Also, an estimated 37.9 million [32.7-44.0 million] people were still infected globally as of 2018 [6,7]. Since HIV infection is incurable [1], infected patients take antiretroviral medications for life to delay immune compromise, opportunistic infections, and prevent transmission [8]. Thus HAART-related ADR studies are imperative.…”

“…Antiretroviral therapy evolved from the initial monotherapy [1,9] to the current combination antiretroviral therapy (cART), also called HAART [3]. HAART drugs consist of three antiretroviral medicines: two Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs), and any of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), Entry Inhibitors (EIs) or Integrase Strand Transfer Inhibitors (INSTIs) [10,11].…”

“…HAART drug-related ADRs include nausea, vomiting, and skin eruptions [4]. Other severe ADRs associated with HAART include induction of free radicals (reactive oxygen and nitrogen species, RONS) [18,19], reduced reproductive capacity [1,20], neurodegenerative diseases [21], and accelerated aging [22].…”

“…The reproductive and oxidative stress toxicities particularly are of serious clinical concern. Briefly, the majority of people on antiretroviral therapies are of childbearing age [9], and HAART drugs are known culprits in reproductive druginduced anomalies [20] and oxidative stress induction [1,3,9]. The literature is replete of the fact that over 75 % of genes implicated in aging, functional senescence, and human diseases are conserved in D. melanogaster [23].…”