Concurrent zidovudine-induced myopathy and hepatoxicity in patients treated for human immunodeficiency virus (HIV) infection

Chen, Sharon C.‐A.; Barker, Stephen M.; Mitchell, David; Stevens, Susan M.B.; O’Neill, Peter; Cunningham, Anthony L.

doi:10.3109/00313029209063634

Cited by 35 publications

(13 citation statements)

References 10 publications

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“…Because most of the patients were also receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors, neither class of which has been associated with lactic acidosis, we cannot exclude a metabolic interaction among these drug classes. Similar to other reports describing the lactic acidosis/hepatic steatosis syndrome, our patients had received nucleoside analogue therapy for several months before presentation, and most of them were overweight, had gastrointestinal complaints, hepatomegaly, slightly elevated aminotransaminases, and evidence of hepatic steatosis, either by imaging or biopsy [1,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In contrast, our patients had much milder elevations in lactate levels.…”

Section: Discussionsupporting

confidence: 73%

“…Previous series have reported a mortality rate 150% [1,5,10,16]. Of 36 cases reported in the literature, the majority required hospitalization, and two-thirds died [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. These higher morbidity and mortality rates may be from spectrum bias resulting in identification of only the most severe cases.…”

Section: Discussionmentioning

confidence: 94%

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Hyperlactatemia and Hepatic Abnormalities in 10 Human Immunodeficiency Virus-Infected Patients Receiving Nucleoside Analogue Combination Regimens

Lonergan

Behling

Pfander

et al. 2000

Clinical Infectious Diseases

188

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During a 6-and-a-half month period, we identified 10 human immunodeficiency virus (HIV)-infected men who were receiving antiretroviral regimens, including nucleoside analogues, and who developed unexplained reproducible hyperlactatemia in association with either abdominal symptoms or an unaccounted-for elevated alanine aminotransferase level, or both. After careful consideration of the possible etiologies, antiretrovirals were discontinued; lactate levels normalized in all patients. The estimated incidence of this phenomenon in our clinic was 20.9 cases per 1000 person-years of nucleoside analogue treatment. These observations extend the spectrum of the nucleoside analogue-induced lactic acidosis/hepatic steatosis syndrome by the identification of a subtle and perhaps earlier form, which has characteristic symptoms and laboratory abnormalities, and a favorable prognosis on discontinuation of antiretroviral therapy.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 94%

Hyperlactatemia and Hepatic Abnormalities in 10 Human Immunodeficiency Virus-Infected Patients Receiving Nucleoside Analogue Combination Regimens

Lonergan

Behling

Pfander

et al. 2000

Clinical Infectious Diseases

188

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“…9 It is well known that AZT causes hepatotoxicity. 10,11 It was reported recently that AZT causes ultrastructural damage to liver mitochondria. 12 A single study in 1991 proposed that AZT causes oxidation of deoxyguanosine in mtDNA from mouse liver.…”

Section: Resultsmentioning

confidence: 99%

“…9 Hepatotoxic effects of AZT have been known for some time. 10,11 Ultrastructural damage to liver mitochondria of rats treated with AZT has been recently reported. 12 We show in this article that AZT causes oxidative damage to liver mtDNA, that this damage is the result of an increase in peroxide production by mitochondria, and that it can be prevented by administration of supranutritional doses of antioxidant vitamins.…”

mentioning

confidence: 99%

Zidovudine (Azt) Causes An Oxidation of Mitochondrial Dna in Mouse Liver

et al. 1999

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Zidovudine (3'-azido-2',3'-dideoxythymidine [AZT]) inhibits human immunodeficiency virus replication and delays progression of acquired immune deficiency syndrome. We have recently found that, in muscle, AZT causes oxidative damage to mitochondrial DNA (mtDNA) and other signs of mitochondrial oxidative damage. The aim of this work was to test if AZT causes oxidative damage to liver mtDNA. In our study, an experimental mouse model was used in which mice were administered AZT (10 mg/kg body weight/d) in drinking water. Liver mtDNA of mice treated with AZT had 40% more of the oxidized, mutagenic nucleoside, 8-oxo-7,8-dihydroxy-2'deoxyguanosine (8-oxo-dG) than untreated controls. This oxidative damage to mtDNA is caused by a significant increase (of over 240%) in peroxide production by liver mitochondria from AZT-treated mice, which was prevented by dietary administration with vitamins C and E.

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“…(29) In HIV-positive patients, electron microscopy on liver and muscle showed characteristic enlarged mitochondria with paracrystalline inclusions, allowing the distinction of myopathies caused by either HIV or AZT. (30) Studies in macaques infected with the simian immunodeficiency virus demonstrated that assessment of mitochondrial metabolic activity of blood mononuclear cells could provide a new prognostic tool. (31) Using in situ hybridisation detected by electron microscopy and cellular fractionation, high levels of HIV RNA in mitochondria were found in acutely (but not chronically) infected cells, suggesting that HIV RNA import into mitochondria can compromise mitochondrial function; (32) unfortunately, to our knowledge, such observation has never been repeated.…”

Section: Dual Role Of Mitochondria In Cell Life and Deathmentioning

confidence: 99%

Mitochondria in the pathogenesis of lipodystrophy induced by anti‐HIV antiretroviral drugs: actors or bystanders?

2001

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Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.

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Concurrent zidovudine-induced myopathy and hepatoxicity in patients treated for human immunodeficiency virus (HIV) infection

Cited by 35 publications

References 10 publications

Hyperlactatemia and Hepatic Abnormalities in 10 Human Immunodeficiency Virus-Infected Patients Receiving Nucleoside Analogue Combination Regimens

Hyperlactatemia and Hepatic Abnormalities in 10 Human Immunodeficiency Virus-Infected Patients Receiving Nucleoside Analogue Combination Regimens

Zidovudine (Azt) Causes An Oxidation of Mitochondrial Dna in Mouse Liver

Mitochondria in the pathogenesis of lipodystrophy induced by anti‐HIV antiretroviral drugs: actors or bystanders?

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