Mitochondrial DNA depletion, near-fatal metabolic acidosis, and liver failure in an HIV-infected child treated with combination antiretroviral therapy

Church, Joseph A.; Mitchell, Wendy G.; González-Gómez, Ignacio; Christensen, Jim; Vu, Tuan; DiMauro, Salvatore; Boles, Richard G.

doi:10.1067/mpd.2001.112653

Cited by 62 publications

(25 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the lactic acidosis/hepatic steatosis syndrome may be more common than previously appreciated in adults (Boubaker et al, 2000;Lonergan et al, 2000;Ter Hofstede et al, 2000) and children (Church et al, 2000) treated with NRTIs. d4T treatment causes lipodystrophy (Saint-Marc et al, 1999).…”

Section: Toxicity From Other Nrtis: Varying Tissue Targetsmentioning

confidence: 78%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

159

111

View full text Add to dashboard Cite

Section: Toxicity From Other Nrtis: Varying Tissue Targetsmentioning

confidence: 78%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

159

111

View full text Add to dashboard Cite

“…10 Data regarding NRTI-induced HLA in the pediatric age are still scarce. To our knowledge, only 1 case of LA acidosis in an HIV-infected infant has been described, by Church et al 26 We recently documented a prevalence rate of 17% (14 of 80) for asymptomatic HLA in our cohort of HIV-infected pediatric patients, 27 after using the same inclusion criteria for LA measurements. These data are similar to those reported by Desai et al 28 (prevalence rate: 32%, 41 of 127 patients) in the other pediatric series in which LA levels have been investigated.…”

Section: Discussionmentioning

confidence: 98%

“…16 Finally, neurologic symptoms (spastic gait and a generalized developmental regression) appeared 5 months before LA acidosis was identified and steadily improved after discontinuation of NRTIs in the only case of LA acidosis in a pediatric HIV-infected patient reported to date. 26 According to the classification of probability level for the diagnosis of a mitochondrial respiratory chain deficit by Barret et al, 15 analogous to that used for inherited mitochondrial diseases, the 3 patients that we report would be classified as "possible" mitochondrial dysfunction cases (symptoms compatible with those described in inherited mitochondrial diseases plus persistent significant HLA). Our prevalence rate of "possible" mitochondriopathy was 2.4% (95% confidence interval: 0%-5.1%), whereas the prevalence rate in the French cohort for "established" plus "possible" mitochondriopathy was 1.05% (28 of 2644 patients).…”

Section: Discussionmentioning

confidence: 99%

Hyperlactatemia in Human Immunodeficiency Virus–Uninfected Infants Who Are Exposed to Antiretrovirals

et al. 2004

View full text Add to dashboard Cite

ABSTRACT.Objective. Exposure to nucleoside analogues in fetal or early life has been associated with rare clinically significant mitochondrial toxic effects, mainly neurologic symptoms. Lactate (LA) measurements have been used to monitor nucleoside-related mitochondrial toxicity. Our aim was to determine the prevalence, clinical evolution, and risk factors for hyperlactatemia in our cohort of human immunodeficiency virus (HIV)-uninfected children who were exposed to antiretrovirals.Methods. We conducted a prospective observational study of 127 HIV-uninfected infants who were born to HIV-infected women. Clinical symptoms suggesting mitochondrial dysfunction were analyzed in routine follow-up, and LA and alanine plasma levels were obtained at 6 weeks, 3 months, 6 months, and 12 months in all patients. Elevated alanine levels, together with hyperlactatemia, suggest chronic mitochondrial injury.Results. Most (85%) women received highly active antiretroviral therapy (HAART) during pregnancy (mean duration: 31 weeks) and zidovudine during labor (93%). Most (96%) children received zidovudine alone. Hyperlactatemia with hyperalaninemia was detected in 63 children in at least 1 of the measurements. Mean LA levels were significantly higher in children who were exposed to nucleoside analogue reverse transcriptase inhibitors than in control subjects (2.88 vs 1.61 at 6 weeks, 2.78 vs 1.49 at 3 months, 1.89 vs 1.39 at 6 months, and 1.71 vs 1.24 at 12 months; peak levels: 8.06, 10.1, 7.28, and 4.48 mmol/L, respectively). In 44 patients, LA levels progressed spontaneously to normality within the first year of life. Three girls presented a slight and self-limited delay in psychomotor development, with LA peak levels of 7.3, 4.0, and 4.6 mmol/L. Only the gestational use of didanosine was associated with a higher risk of hyperlactatemia.Conclusions. H uman immunodeficiency virus (HIV) vertical transmission rates have been dramatically reduced in developed countries thanks to antiretroviral (ARV) treatments, elective cesarean section, and refraining from breastfeeding. 1 The morbidity that ARV may cause in fetal and early life of HIV-uninfected children is still unclear, and thorough research of this condition is warranted.Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are included in most ARV regimens. These drugs inhibit both HIV reverse transcriptase and DNA polymerase ␥, an essential protein for mitochondrial DNA replication in human cells. [2][3][4] Mitochondria are basic for the generation of adenosine triphosphate through oxidative phosphorylation. When this system is disturbed, an altered oxidoreduction status occurs, shifting the pyruvate/lactate (LA) equilibrium in the direction of LA; similarly, an increase in ketone bodies and alanine is observed. 5,6 Because mitochondria are ubiquitous, impaired oxidative phosphorylation may affect virtually all organ systems, giving rise to a variety of clinical syndromes. 5,7 Inherited mitochondrial diseases may affect infants to different degrees: from a severe multisy...

show abstract

“…Recently, lactic acidemia in AIDS gained attention as an important clinical problem found both in adults (Boubaker et al, 2000;Lonergan et al, 2000;Ter Hofstede et al, 2000) and in children (Church et al, 2000). Treatment with certain NRTI (stavudine, lamivudine) resulted in anion gap acidosis (Miller et al, 2000;Moore et al, 2000).…”

mentioning

confidence: 99%

Combined Antiretroviral Therapy Causes Cardiomyopathy and Elevates Plasma Lactate in Transgenic AIDS Mice

Lewis

Haase

Raidel

et al. 2001

Laboratory Investigation

View full text Add to dashboard Cite

SUMMARY:Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4 -3⌬ gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG ϩ HAART cohort, left ventricular mass increased 160% by echocardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 Ϯ 2.0 mM). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG ϩ HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice. (Lab Invest 2001, 81:1527-1536.

show abstract

Mitochondrial DNA depletion, near-fatal metabolic acidosis, and liver failure in an HIV-infected child treated with combination antiretroviral therapy

Cited by 62 publications

References 9 publications

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Hyperlactatemia in Human Immunodeficiency Virus–Uninfected Infants Who Are Exposed to Antiretrovirals

Combined Antiretroviral Therapy Causes Cardiomyopathy and Elevates Plasma Lactate in Transgenic AIDS Mice

Contact Info

Product

Resources

About