Long‐Term Administration of Abacavir and Etravirine Impairs Semen Quality and Alters Redox System and Bone Metabolism in Growing Male Wistar Rats

Abstract

Highly active antiretroviral therapy (HAART) is used in HIV-infected patients. Alongside the prolongation of patients’ life, adverse side effects associated with long-term therapy are becoming an increasing problem. Therefore, optimizing of HAART is extremely important. The study is aimed at evaluating the toxicity of abacavir and etravirine in monotherapy on the reproductive system, liver, kidneys, and bones in young, sexually mature, male rats. Thirty-six 8-week-old male Wistar rats randomized into three 12-animal groups received either normal saline (control), abacavir 60 mg/kg (AB group), or etravirine 40 mg/kg (ET group) once daily for 16 weeks. Semen morphology, oxide–redox state parameters (MDA, SOD, catalase, GPx, glutathione, GSH/GSSG ratio) in tissue homogenates (testes, liver, kidneys), and serum samples were studied. In bones, microcomputed tomography and a four-point bending test were performed. Total sperm count, sperm concentration, motility, and sperm morphology did not differ significantly in AB or ET groups compared to the control. In the flow cytometry of semen, an increased percentage of cells with denatured DNA was noticed for both tested drugs. However, no significant changes of oxide–redox state in testicular homogenates were found, except of increased SOD activity in the AB-receiving group. Additionally, ET significantly altered catalase and GPx in the liver and SOD activity in kidneys. Abacavir decreased catalase in the liver and GSH levels in kidneys. AB caused significant changes to bone microarchitecture (bone volume fraction, trabecular number, connectivity density, total porosity) and increased Young’s modulus. Etravirine had a greater impact on macrometric parameters of bones (tibial index, mid-tibial diameter, femur length). After 4 weeks in the ET group, a lower 1,25-dihydroxyvitamin D3 serum concentration was found. The results showed that abacavir and etravirine disturb oxidative stress. An increase in the percentage of sperms with chromatin damage suggests decreased fertility in rats receiving the studied drugs. Both drugs affected bone formation in growing rats. Additionally, etravirine disturbed vitamin D metabolism.

The anti-HIV drug abacavir stimulates β-catenin activity in osteoblast lineage cells

“…Although the combination of ABC/DTC/3TC was not bone stimulatory, ABC monotherapy increased Wnt/β-catenin signaling in osteoblasts in vitro and osteocyte-enriched bone tissue in vivo . While previous studies in Wister rats have noted increased trabecular bone mass with ABC treatment, ( 23 ) in the current study, we found no changes in BMD or microarchitecture in ABC-treated mice. The discrepancies could be explained by differences in treatment duration, 6-weeks vs 16 weeks in Matuszewska et al.…”

“…( 36 , 37 ) However, data from preclinical models have been more mixed. For example, both Conradie et al ( 38 ) and Matuszewsaka et al ( 23 ) noted bone loss with TDF treatment in rats, but neither detected elevated bone resorption marker levels. The reason for this discrepancy is unknown but has been noted in the clinic as well, with direct tissue assessments of bone biopsies from PLWH initiating TDF-based cART showing increased osteoclast surfaces with no corresponding change in CTX levels.…”

“…( 22 ) Others noted increased circulating Dickkopff-1 (Dkk1), another Wnt antagonist in rats treated with ABC. ( 23 ) Due to the importance of Wnt/β-catenin signaling in bone formation and the potential responsiveness to ARVs, we evaluated the impact of ARVs on Wnt/β-catenin signaling in osteoblasts.…”

Antiviral drugs

“…At the end of the study, the authors concluded that ETR interfered with vitamin D metabolism and oxidative stress which could potentiate infertility, however, no effects on bones in growing rats was reported. In conclusion, monitoring of vitamin D levels may be essential in patients on ETR ( Matuszewska et al, 2021 ) [E].…”

Hippocampus and Prefrontal Cortex Following the Use of Anti-Retroviral Therapy in Adult Wistar Rats: Therapeutic Role of Epigallocatechin Gallate

“…Current antiretroviral drugs are not curable and people with HIV will need to take them for the rest of their lives (Pasternak et al, 2021, Stern et al, 2021. However, the optimization of HAART, which requires long-term use, is not excluded from drug-related side effects (Matuszewska et al, 2021). HIV infection is associated with comorbidities that can be caused not only by HIV itself, but also by the toxicity of long-term use of antiretroviral therapy (ART) (Ogedengbe et al, 2018b).…”