Mitochondrial toxicity and HIV therapy

White, Alex J.

doi:10.1136/sti.77.3.158

Cited by 185 publications

(134 citation statements)

References 119 publications

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“…The patients had been HIV-positive for a median of 2 (range 1-18) years in group 2, for 9 (1-16) years in group 3 and for 7 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) years in group 4, and both groups 3 and 4 had been treated with HAART for a median of 5 years.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…In contrast, lactic acidosis represents a relatively uncommon (approximately 2 per 1000 person-years) but life-threatening clinical syndrome in which lactate homeostasis is completely decompensated [3], characterized by a pH o7.25 and a plasma lactate level 45 mmol/L [4]. The syndrome of hyperlactataemia is well known in HIV-infected patients receiving antiretroviral therapy, particularly in those on stavudine [5]. Host risk factors have been identified for NRTI-associated lactic acidosis, including concurrent liver disease, female gender and obesity [6].…”

Section: Introductionmentioning

confidence: 99%

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Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

et al. 2004

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It is unknown whether high levels of lactate result from enhanced production or decreased degradation. We therefore investigated differences in the kinetics of plasma lactic acid in HIV-infected patients receiving or not receiving highly active antiretroviral therapy (HAART) and in uninfected controls after submaximal ergometric exercise. MethodsTen healthy controls, 11 HIV-infected therapy-naïve patients, 15 HIV-infected patients on HAART with normal baseline lactate levels, and nine HIV-infected patients on HAART with elevated baseline lactate levels >2 mmol/L performed 10 min of ergometric exercise, with a heart rate of 200 beats/min minus age. Lactate levels were measured at baseline, at the end of exercise and 15, 30, 45, 60 and 120 min thereafter. ResultsMean baseline lactate levels were 1.4, 1.5, 1.5 and 2.8 mmol/L in the controls, the therapy-naïve patients, the patients on HAART with normal lactate levels and the patients on HAART with elevated lactate levels, respectively. Maximum lactate levels after exercise were similar in all groups (9.7, 9.4, 9.0 and 10.1 mmol/L, respectively). Significant differences were found in the slope of lactate decline between controls and untreated individuals (P 5 0.038) and between patients on HAART with normal baseline lactate and patients on HAART with elevated baseline lactate (P 5 0.028). ConclusionsDifferences in lactate metabolism do exist between healthy controls and HIV-infected therapy-naïve individuals. Thus, HIV infection in itself may influence lactate levels. Elevated baseline lactate levels are associated with a delayed decline of lactate after exercise. These results could be explained by impaired lactate clearance. Lactate production upon exercise does not seem to be affected by baseline lactate levels. Fig. 1).Mitochondria have a pivotal role in cellular energy homeostasis, producing adenosphine biphosphate (APT) by oxidative phosphorylation. Under normal aerobic conditions, glucose is metabolized to pyruvate, which is further degraded in the mitochondrion to CO 2 , H 2 O and ATP. Lactate production can be induced by anaerobic glycolysis, by a defect in the oxidative phosphorylation of peripheral tissue or as a result of defective mitochondrial DNA (mtDNA)-encoded proteins. The primary site of lactate clearance is the liver and, to a lesser extent, the kidney and the skeletal muscle itself. The sole pathway for lactate utilization leading to stable lactate concentrations of less than 2 mmol/L is conversion back to pyruvate and then to glucose in the Cori Cycle, which depends on ATP and sufficient oxidative phosphorylation. Thus, impaired lactate clearance may be the result of a mitochondrial dysfunction in the liver [8] or in other tissues, for example skeletal muscle.Skeletal muscle cells, which have high amounts of mitochondria and high oxidative requirements, are the most important producers of lactate, especially during exercise. Elevated lactate levels could also be caused by increased production (see Fig. 1). Whether hyperlactataemia associated w...

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Section: Patient Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

et al. 2004

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“…Data have shown that some adverse effects, including myopathies (zidovudine), neuropathies (stavudine, didanosine, and zalcitabine), fatty degeneration of the liver and lactic acidosis (didanosine, stavudine, and zidovudine), and, possibly, partial lipodystrophy (mainly stavudine), can occur after the administration of nucleoside analogs [3,[5][6][7][8] . Implicated in the production of the adverse effects are interference with mitochondrial function based on abnormal morphology of muscle mitochondria, depletion of mitochondrial-encoded enzyme subunits and decreased mitochondrial gene number [2,5,9] . Nucleoside analogs associated with mitochondrial injury include the HIV nucleotide reverse transcriptase inhibitor (NRTI) zidovudine (AZT), which has been associated with mitochondrial myopathy with histological features of ragged-red fibers, and with mtDNA depletion in HIV patients [10][11][12] and in rat skeletal muscle [13] , and the NRTI…”

Section: Introductionmentioning

confidence: 99%

“…By mimicking the structure of natural nucleoside, the nucleoside analogs can competitively act in the active center of enzymes and be embedded in the synthesizing virus DNA strand, and thus terminate the extension of DNA strands and inhibit the virus replication. However, because HBV DNA polymerase is somehow similar with human DNA polymerase, these nucleoside analogs may also have an affinity for the DNA polymerase in host cells, resulting in potential adverse effects on the normal host tissue cells [2][3][4] . Data have shown that some adverse effects, including myopathies (zidovudine), neuropathies (stavudine, didanosine, and zalcitabine), fatty degeneration of the liver and lactic acidosis (didanosine, stavudine, and zidovudine), and, possibly, partial lipodystrophy (mainly stavudine), can occur after the administration of nucleoside analogs [3,[5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration

et al. 2009

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Aim: To explore the potential mitochondrial toxicities and their severities of intravenously administered metacavir, a nucleoside analog, in rhesus monkeys. Methods: Totally 21 rhesus monkeys were randomly divided into 4 groups: metacavir 120 mg/kg group, metacavir 40 mg/kg group, zidovudine(AZT) 50 mg/kg group, and blank control group. Animals were killed after the completion of dosing or further observed in a 4-week recovery phase. Changes of structure of mitochondria in liver, kidney, skeletal muscles, and cardiac muscles were observed under transmission electron microscope(TEM). Changes of the activities of mitochondrial respiratory chain complexes and mitochondrial DNA were also determined. Results: In metacavir 120 mg/kg group, some mitochondrial injuries were found in skeletal muscle, cardiac muscle, and liver, including that some cristae was broken and became sparse in density in the skeletal muscle, the morphology and size of mitochondria remained unchanged. Metacavir decreased the activities of respiratory chain complexes I and II and the mtDNA contents in three tissues in a dose-dependent manner; however, the extent of such decrease was lower than that in AZT 50 mg/kg group. The mitochondrial injuries in metacavir 40 mg/kg group were mild in each tissue and no obvious change in mitochondrial function was noted. On week 4 in the recovery phase, results showed that all these injuries were reversible after drug withdrawal. Conclusion: These results suggest that metacavir has not a high risk for potential mitochondrial-related effects in rhesus monkeys.

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“…Many of these studies confirmed the increased relative risk of lactataemia with d4T-and ddI-vs. AZT-based regimens. 56 However, lactate measurement as a predictive marker of decompensated mitochondrial toxicity was limited by the fact that many patients on full-time NRTI therapy and neonatal recipients of short courses of NRTIs have asymptomatic hyperlactataemia that does not progress to decompensated lactataemia. 57,58 Also, lactate lacks specificity and is influenced by technical and physiological variability.…”

Section: Research History Of Nucleoside Reverse Transcriptase Inhibitmentioning

confidence: 99%

Mitochondrial dysfunction and human immunodeficiency virus infection

Watt

2011

Journal of Endocrinology, Metabolism and Diabetes of South Afri

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Human immunodeficiency virus (HIV) infection and the pharmacological treatment thereof have both been shown to affect mitochondrial function in a number of tissues, and each may cause specific organ pathology through specific mitochondrial pathways. HIV has been shown to kill various tissue cells by activation of mitochondrial apoptosis. Nucleoside analogues, used extensively to treat HIV infection, are known to influence a number of steps affecting mitochondrial DNA integrity. This review describes the basic physiology, pharmacology and pathophysiology of HIV infection and the nucleoside analogues regarding mitochondrial function and discusses the progress made in this field with respect to the measurement of these effects and the prediction of potential drug toxicity.Peer reviewed.

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Mitochondrial toxicity and HIV therapy

Cited by 185 publications

References 119 publications

Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration

Mitochondrial dysfunction and human immunodeficiency virus infection

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