Massive Hepatic Steatosis and Lactic Acidosis in a Patient with AIDS Who Was Receiving Zidovudine

Olano, Juan P.; Borucki, Michael J.; Wen, Julie; Haque, Abida K.

doi:10.1093/clinids/21.4.973

Cited by 108 publications

(65 citation statements)

References 16 publications

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“…In contrast to previous reports, 22 there was no lactate elevation in individuals receiving stavudine compared with zidovudine, although lactate was somewhat higher with D drug treatment in our study. We are unable to determine the exact reasons for this discrepancy, but possible explanations include the HCV status of our principal study population, 17 effects on mitochondria or hepatic tissue unrelated to mtDNA depletion (as demonstrated for zidovudine 4,5,23 ), and additional mitochondrial toxicity in extra-hepatic tissues. 9,24 Our study was also not powered to examine associations between hyperlactatemia and NRTI therapy.…”

Section: Discussionmentioning

confidence: 94%

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

et al. 2004

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A ntiretroviral therapy (ART) has significantly decreased the HIV-associated morbidity and mortality in industrialized countries. 1 ART usually consists of a combination of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (NNRTI), or of three NRTIs. 2 With prolonged exposure to antiretroviral drugs, clinicians became aware of long-term side effects of individual ART components. Many adverse effects of the NRTI class of anti-HIV drugs are now related to the fact that NRTIs undergo intracellular triphosphorylation, then inhibit the replication of mitochondrial DNA (mtDNA) by interacting with gamma-polymerase. 3 In vitro studies point toward differences between the potencies of the individual NRTIs in depleting mtDNA, with the socalled "D drugs" zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) being relatively strong inhibitors of polymerase-gamma compared with the other currently licensed nucleoside analogues (so-called "non-D drugs"). 4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; mtDNA, mitochondrial DNA; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; HCV, hepatitis C virus; nDNA, nuclear DNA; ULN, upper limit of normal; ALT, alanine aminotranferase. From

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Section: Discussionmentioning

confidence: 94%

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

et al. 2004

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“…During the pre-highly active antiretroviral therapy (HAART) era, AZT monotherapy in AIDS patients was closely associated with myopathy, cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10]. Subsequent work in HIV negative rat models treated with AZT confirmed the presence of the same type of toxicities in the rat [11,15].…”

Section: Discussionmentioning

confidence: 99%

“…AZT capitalizes on human immunodeficiency virus's (HIV) unique method of replication by inhibiting the viral reverse transcriptase, which blocks the life-cycle of HIV and effectively slows the progression of AIDS. When given in monotherapy at high doses over long periods of time, AZT is known to cause damage to many tissues, including a mitochondrial skeletal muscle myopathy, a dilated cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10][11]. These conditions are related to AZT use and not to the progression of AIDS since when patients experiencing one or more of these adverse effects discontinued AZT therapy, the adverse effects would resolve [8,9].…”

Section: Introductionmentioning

confidence: 99%

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Lynx

Bentley

McKee

2006

Biochemical Pharmacology

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Abstract3′-Azido-3′-deoxythymidine (AZT) is a staple of highly active antiretroviral therapy (HAART). Prior to HAART, long-term use of high-dosage AZT caused myopathy, cardiomyopathy, and hepatotoxicity, associated with mitochondrial DNA depletion. As a component of HARRT, AZT causes cytopenias and lipodystrophy. AZT-5′-triphosphate (AZTTP) is a known inhibitor of the mitochondrial polymerase γ and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart mitochondria, AZT phosphorylation beyond AZT-5′-monophosphate (AZTMP) was not detected. Rather, AZT was shown to be a more potent inhibitor of thymidine phosphorylation (50% inhibitory concentration (IC 50 ) of 7.0 ± 1.0 μM) than AZTTP is of polymerase γ (IC 50 of >100 μM), suggesting that depletion of mitochondrial stores of TTP may limit replication. This work has investigated whether an identical mechanism might account for the hepatotoxicity seen with long-term use of AZT. Isolated rat liver mitochondria were incubated with labeled thymidine or AZT, and the rate and extent of phosphorylation were determined by HPLC analysis of acid-soluble extracts of the incubated mitochondria. The results showed that in the phosphorylation of thymidine to TMP, liver mitochondria exhibit a higher V max and K m than heart mitochondria, but otherwise heart and liver mitochondria display similar kinetics. AZT is phosphorylated to AZTMP, but no further phosphorylated forms were detected. In addition, AZT inhibited the production of TTP, with an IC 50 of 14.4 ± 2.6 μM AZT. This is higher, but comparable to, the results seen in isolated rat heart mitochondria. KeywordsAZT; Liver mitochondria; Thymidine; Mitochondrial toxicity; Thymidine kinase 2; Reverse transcriptase inhibitors Abbreviations AIDS, acquired immunodeficiency syndrome; AZT, 3′-azido-3′-deoxythymidine; AZTDP, 3′-azido-3′-deoxythymidine-5′-diphosphate; AZTMP, 3′-azido-3′-deoxythymidine-5′-monophosphate; AZTTP, 3′-azido-3′-deoxythymidine-5′-triphosphate; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; IC 50 , 50% inhibitory concentration; S.E.M., standard error of mean

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“…It is thought that these severe side-effects, which were not predicted by short-term treatment studies, are related to the toxic effect of FIAU on host mitochondrial DNA. A similar syndrome has been reported as a rare adverse event with other nucleoside analogues such as zidovudine (Olano et al, 1995). The morphology and function of mitochrondria have been carefully studied in patients receiving lamivudine with no evidence, as yet, of similar phenomena (Honkoop et al, 1997a).…”

Section: Other Antiviral Agentsmentioning

confidence: 81%

Treatment of Chronic Viral Hepatitis

Main

McCarron

1998

Antivir Chem Chemother

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Interferon-α therapy has proved effective for up to 40% of patients with adult-acquired chronic hepatitis B virus (HBV) infection and for 20-25% of those with chronic hepatitis C virus (HCV) infection. Nucleoside analogues, such as lamivudine and famciclovir, are showing promise as antiviral agents for chronic HBV and the combination of interferon-α and ribavirin is proving to be successful therapy for 40-50% of patients with chronic HCV. In this article we review current therapy and discuss future strategies of the therapy of chronic viral hepatitis.

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Massive Hepatic Steatosis and Lactic Acidosis in a Patient with AIDS Who Was Receiving Zidovudine

Cited by 108 publications

References 16 publications

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Treatment of Chronic Viral Hepatitis

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