Nucleoside Reverse Transcriptase Inhibitors, Mitochondrial Dna and Aids Therapy

Lewis, William

doi:10.1177/135965350501002s03

Cited by 35 publications

(2 citation statements)

References 239 publications

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“…The health benefits of NRTI-based ART are undeniable; however, the prolonged use of NRTIs has been associated with adverse metabolic effects, such as dyslipidemia, lipodystrophy, hepatic steatosis, and lactic acidosis [ 3 ]. These side effects have been linked to NRTI-induced mitochondrial toxicity [ 4 , 5 , 6 , 7 , 8 ] and oxidative damage to mitochondrial DNA (mtDNA) [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…NRTIs, once intracellularly phosphorylated, compete with the native nucleotide pool to be incorporated into pro-viral DNA during its replication by HIV reverse transcriptase and promote early termination. NRTIs can also serve as substrates for POLG, which can hamper its mtDNA replication and repair activities, resulting in a multifactorial mitochondrial toxicity and altered mitochondrial function [ 7 , 14 , 15 , 16 , 17 ]. The physiological and biochemical consequences of mitochondrial toxicity include alterations in mitochondrial morphology, a reduction in mtDNA, disruption of OXPHOS, and increased reactive oxygen species (ROS) and oxidative stress [ 14 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of the Effects of Three Dual-Nucleos(t)ide Reverse Transcriptase Inhibitor Backbones on Placenta Mitochondria Toxicity and Oxidative Stress Using a Mouse Pregnancy Model

Balogun

Serghides

2022

Pharmaceutics

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Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the backbone of HIV antiretroviral therapy (ART). ART use in pregnancy has been associated with adverse birth outcomes, in part due to NRTI-induced mitochondrial toxicity. Direct comparison on the effects of commonly used dual-NRTI regimens on placental mitochondria toxicity in pregnancy is lacking. We compared zidovudine/lamivudine, abacavir/lamivudine, and tenofovir/emtricitabine using a mouse model and examined markers of placental mitochondrial function and oxidative stress. Zidovudine/lamivudine and abacavir/lamivudine were associated with lower fetal and placental weights compared to controls, whereas tenofovir/emtricitabine was associated with the least fetal and placental weight reduction, as well as lower resorption rates. Placental mitochondrial DNA content, as well as placental expression of cytochrome c-oxidase subunit-II, DNA polymerase gamma, and citrate synthase, was higher in tenofovir/emtricitabine-treated mice compared to other groups. Zidovudine/lamivudine-treated mice had elevated malondialdehyde levels (oxidative stress marker) compared to other groups and lower mRNA levels of manganese superoxide dismutase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the placenta compared to tenofovir/emtricitabine-treated mice. We observed differences in effects between NRTI regimens on placental mitochondrial function and birth outcomes. Tenofovir/emtricitabine was associated with larger fetuses, increased mtDNA content, and higher expression of mitochondrial-specific antioxidant enzymes and mitochondrial biogenesis enzymes, whereas zidovudine/lamivudine was associated with markers of placental oxidative stress.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of the Effects of Three Dual-Nucleos(t)ide Reverse Transcriptase Inhibitor Backbones on Placenta Mitochondria Toxicity and Oxidative Stress Using a Mouse Pregnancy Model

Balogun

Serghides

2022

Pharmaceutics

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Human Immunodeficiency Virus (HIV)

2006

Wiley Handbook of Current and Emerging Drug Therapies

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HIV impairs cells of the immune system and progressively destroys the body's ability to fight infections. Acquired immunodeficiency syndrome (AIDS) is the advanced state of HIV infection wherein the patient is severely immunocompromised and prone to developing opportunistic infections. The diagnosis of AIDS is triggered by the development of certain opportunistic infections or the detection of severe immunodeficiency. The highly mutable nature of HIV and the consequent development of drug resistance in patients taking antiretroviral therapy drive the need for new, more potent therapies and classes with novel mechanisms of action. Among emerging therapies in the conventional classes, a novel protease inhibitor (PI) TMC114 appears to be highly active against virus strains with several primary PI mutations. Among the non‐nucleoside reverse transcriptase inhibitors (NNRTIs), drug developers have sought to develop products that are active against the mutations that commonly lead to cross‐resistance against the entire class (e.g., K103N, Y181C); however, additional clinical data are required to assess their future role in treatment. Among the novel classes in later stages of development, which include the chemokine antagonists (CCR5 and CXCR4 antagonists), entry inhibitors, integrase inhibitors, and maturation inhibitors, the CCR5 antagonists and integrase inhibitors appear the most promising.

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Cardiovascular Toxicities of Life‐Saving Drugs: Antiviral Therapy

Kohler

Lewis

2010

Cardiotoxicity of Non‐Cardiovascular Drugs

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Nucleoside Reverse Transcriptase Inhibitors, Mitochondrial Dna and Aids Therapy

Cited by 35 publications

References 239 publications

Comparison of the Effects of Three Dual-Nucleos(t)ide Reverse Transcriptase Inhibitor Backbones on Placenta Mitochondria Toxicity and Oxidative Stress Using a Mouse Pregnancy Model

Comparison of the Effects of Three Dual-Nucleos(t)ide Reverse Transcriptase Inhibitor Backbones on Placenta Mitochondria Toxicity and Oxidative Stress Using a Mouse Pregnancy Model

Human Immunodeficiency Virus (HIV)

Cardiovascular Toxicities of Life‐Saving Drugs: Antiviral Therapy

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