Evaluation of Oral Antiretroviral Drugs in Mice With Metabolic and Neurologic Complications

Abstract

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

<p>Antiretroviral Therapy-Associated Metabolic Complications: Review of the Recent Studies</p>

“…The safety and efficacy of antiretroviral drugs have been monitored, as has the metabolic alteration during the treatment period tested in preclinical trial studies. 13 – 16 Conradie et al 13 examined the effects of ART on bone metabolism and lipodystrophy in rats. Stavudine (6.2 mg/kg), tenofovir DF (26.6 mg/kg), lopinavir/ritonavir (70.8 mg/kg), and water (1.5 mL) were subjected orally to 40 male rats for 9 weeks.…”

“…Metabolic consequences of PIs administration in mice has been reported. 15 , 16 C57BL/6 mice were assigned combined lopinavir/ritonavir (50/12.5 to 200/50 mg/kg) for 3 weeks. There were significant changes in metabolic parameters showing hyperlipidemia, hyperinsulinemia, and lipodystrophy symptoms as the dose-dependent manner.…”

“…The findings indicated that PIs, particularly lopinavir/ritonavir treatment, result in lipodystrophy symptoms which are similar to those found in human. 15 Tsai et al 16 examined the 4-week treatment effects of lopinavir/ritonavir in C57BL/6 mice. Increased total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels were observed in addition to intracellular lipid accumulation.…”

“…In a mice model, daily administration of abacavir/lamivudine and lopinavir/ritonavir may probably increase metabolic disorders regardless of HIV infection. 16…”

Timing, Dosage, and Adherence of Antiretroviral Therapy and Risk of Osteoporosis in Patients With Human Immunodeficiency Virus Infection in Taiwan: A Nested Case-Control Study

“…However, discontinuation of ART results in drug resistance, viral reactivation, and disease progression (Meintjes et al, 2017;Dubrocq and Rakhmanina, 2018). Long-term ART is associated with adverse effects such as hyperlipidemia, cardiovascular disease, osteoporosis, diabetes, and renal disease (Kwong et al, 2006;De Wit et al, 2008;Capeau et al, 2012;Achhra et al, 2016;Grant et al, 2016;Dorjee et al, 2017;Hoy et al, 2017;Tsai et al, 2017;Nan et al, 2018;Tsai et al, 2018).…”