Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome

Sundar, Krishnamurthy; Suárez, Miguel Ángel; Banogon, Petra E.; Shapiro, Janet

doi:10.1097/00003246-199708000-00034

Cited by 130 publications

(70 citation statements)

References 23 publications

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“…Muscle carnitine deficiency and lipid storage as well as mitochondrial DNA depletion were described in well-nourished adult HIV-infected patients treated with zidovudine, many of whom complained of myopathic signs and symptoms (fatigue, myalgia, weakness and increased serum creatine phosphokinase) (Dalakas et al, 1990,1994). Ragged-red fibres as well as hepatic steatosis, lactic acidosis and cytochrome c deficiency have also been described in nucleoside analogue-treated patients Lenzo et al, 1997;Sundar, 1997;Megarbane et al, 1999;Brinkman et al, 1999;Carr et al, 2000). The suggested causes of these induced myopathies may be related to the reduction of muscle carnitine, probably because of decreased carnitine uptake.…”

Section: Discussionmentioning

confidence: 98%

Low serum carnitine in HIV-infected children on antiretroviral treatment

et al. 2003

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Objective: HIV-infection and antiretroviral therapies are associated with energy dysfunction and lipid metabolism in adults. Our aim was to detect a possible carnitine deficiency in HIV-infected children on antiretroviral treatments. We analysed the relation among serum carnitine, its amino-acid precursors (methionine and lysine), clinical evaluation and antiretroviral therapy. Design and setting: Cross-sectional study performed in a tertiary care hospital. Subjects: A total of 79 HIV-infected children on antiretroviral therapy, monitored prospectively in our hospital. Interventions: Antiretroviral therapy included nucleoside analogues plus protease inhibitors and/or non-nucleoside analogues. Carnitine was analysed by an enzymatic-spectrometric procedure, and amino acids by ion exchange chromatography. Reference values of carnitine and amino acids were established in apparently healthy children who underwent presurgical analysis for minor surgery. Results: Serum free and total carnitine, acylcarnitines, methionine and lysine were significantly lower in HIV-infected children compared with our reference values for similar ages (Po0.0001; Student's t-test). Low carnitine values were observed in 37% of our HIV-infected children. A significantly positive correlation was observed between serum total carnitine and methionine or lysine (Po0.0001 and P ¼ 0.005, respectively; Pearson test). No relation was observed between serum carnitine and clinical stage of HIV infection, immunological or nutritional status or lipodystrophy. Free and total carnitine were significantly lower (P ¼ 0.002 and 0.033, respectively) in HIV-infected patients on protease inhibitors (N ¼ 56) compared with those on other treatments (N ¼ 23). Conclusions: Low serum carnitine concentration was observed in 37% of our HIV-infected children on antiretroviral therapy. Malabsorption or defective synthesis may also account for the low serum carnitine values detected in these patients. Sponsorship: Grant FIS 99/1270.

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Section: Discussionmentioning

confidence: 98%

Low serum carnitine in HIV-infected children on antiretroviral treatment

et al. 2003

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“…Clinical adverse effects due to NRTI-induced mitochondrial toxicity frequently occur in liver tissue (23,27). Therefore, the in vitro experiments performed to assess the mitochondrial toxicity of PNA were carried out with HepG2 cells.…”

Section: Cytotoxicity and Evaluation By Electron Microscopy Of Mitochmentioning

confidence: 99%

“…Most previous studies demonstrated that these adverse effects of nucleoside analogs are directly associated with mitochondrial injury, on the basis of the abnormal morphology of mitochondria, depletion of mitochondrion-encoded enzyme subunits, and decreased mitochondrial gene number (2,3,5,6,10,11,14,15,29). Clinical toxicities due to the mitochondrial dysfunction induced by nucleoside analogs may limit the use of certain treatment regimens and may even produce fatal complications, as documented for some cases of severe lactic acidosis (2,12,13,26,27). Therefore, it is important to evaluate new drugs from the nucleoside analogs for their potential to cause mitochondrial toxicity by measuring specific markers of toxicity, such as the level of mitochondrial DNA (mtDNA) synthesis or production of lactic acid in drug-treated cell cultures (1,2,5,6,12,20,29).…”

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confidence: 99%

In VitroMitochondrial Toxicity of Metacavir, a New Nucleoside Reverse Transcriptase Inhibitor for Treatment of Hepatitis B Virus

Zhang

Jiang

et al. 2010

Antimicrob Agents Chemother

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Therapy with nucleoside reverse transcriptase inhibitors (NRTIs) can be associated with mitochondrial toxicity. In vitro studies have been used to predict the predisposition for and characterize the mechanisms causing mitochondrial toxicity. Metacavir (PNA) is a novel synthetic nucleoside analog for oral administration with potent and specific antiviral activity against hepatitis B virus (HBV). We assessed the potential for mitochondrial toxicity of PNA in long-term cultures of HepG2 hepatoma cells by measuring mitochondrial function (through lactate secretion), levels of mitochondrial DNA (mtDNA), and the activities of respiratorychain complexes I to IV. Exposure of HepG2 cells to PNA at concentrations up to 50 M for 15 days resulted in no deleterious effect on cell proliferation, levels of lactate or mtDNA, or enzyme activities of respiratorychain complexes I to IV. In contrast, dideoxycytosine at 10 M and zidovudine at 50 M have significant effects on cell proliferation, levels of lactate and mtDNA, and enzyme activities of respiratory-chain complexes I to IV. However, PNA at a supratherapeutic concentration of 250 M could result in significant alterations in the levels of mtDNA and the activities of respiratory-chain complex enzymes, revealing evidence of the potential mitochondrial toxicity of PNA. In summary, these in vitro results indicate that the potential for PNA to interfere with mitochondrial functions is low.

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“…HIV management also includes dealing with the toxicities of these drugs [27,28,[30][31][32][33], drug-drug interactions, difficulties with the need for 100% adherence [34], lack of long-term efficacy of regimens in real life settings [35][36][37][38][39], cost, co-morbid illnesses such as hepatitis and tuberculosis, opportunistic infections and their prophylaxis, substance abuse, mental illness, and the social situations of patients (housing, nutrition, stigma, family/reproductive counseling, secondary prevention, etc.). Adding to the complexity is the fact that there is no one answer for any of these issues.…”

Section: Key Principles and Complexities Of Antiretroviral Therapymentioning

confidence: 99%

Approaches to antiretroviral therapy in China

Gilliam

Redfield

2005

Cell Res

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China has recognized the threat of HIV to its population and responded with a national antiretroviral treatment (ART) program. However, high ART failure rates and the spread of resistance within populations are important realities to consider when developing and managing ART programs in China and worldwide. Concepts which will define treatment success and local and national programmatic goals are 1) access to ART, 2) durability of ART at the patient level, 3) scalability of treatment modalities, and the 4) sustainability of the program at the community or national level. In the face of limited resources, China must also consider when to start ARV therapy, which agents to use, when to switch them, and how to treat highly experienced patients with drug resistance. The optimal ARV regimen to start with is changing frequently with the introduction of new agents and the presentation of new data. Currently, a regimen including tenofovir, emtricitabine or lamivudine and a nonnucleoside reverse transcriptase inhibitor appears to have optimal characteristics to treat HIV/AIDS in China. However, critical to all of these choices is the evaluation of programs implemented to insure wide scale success. China has wisely begun this process of evaluating the performance of local programs through systematic monitoring and evaluation of treatment outcomes. This will allow regimens and programs that work to be expanded, and programs with high failure rates to be eliminated. In the end, evidence based data supporting treatment strategies will allow China to successfully confront its AIDS epidemic early and prevent its tragic consequences

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Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome

Cited by 130 publications

References 23 publications

Low serum carnitine in HIV-infected children on antiretroviral treatment

Low serum carnitine in HIV-infected children on antiretroviral treatment

In VitroMitochondrial Toxicity of Metacavir, a New Nucleoside Reverse Transcriptase Inhibitor for Treatment of Hepatitis B Virus

Approaches to antiretroviral therapy in China

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