Hyperlactatemia and in utero exposure to antiretrovirals: is the control group the clue?

Perinatal antiretroviral (ARV) exposure has been related to hyperlactatemia and lactic acidosis in infants born to HIV-infected mothers. Our objective was to determine the incidence of these conditions during the first year of life in uninfected infants born to HIV-infected mothers and compare the data with infants born to mothers with hepatitis C virus (HCV) infection. We investigated the relationships between hyperlactatemia and neurological and neurodevelopmental disorders by conducting a prospective, comparative cohort study (October 2004 to October 2007) consecutively including children of HIV- and HCV-infected mothers. Liver enzymes, pH, lactic acid, and plasma amino acids were determined at 1.5, 3, 6, and 12 months of life. Pathological hyperlactatemia was defined as lactate >2.1 mmol/liter together with alanine >475 μmol/liter. Seventy-nine patients (39 HIV-exposed patients and 40 unexposed patients) were included. Baseline maternal characteristics in the two groups were similar. Almost 90% of HIV-infected mothers received HAART during gestation, while 10.3% were given AZT monotherapy. Eight newborns received combined therapy and 31 received AZT-based monotherapy. Twelve patients (five exposed and seven nonexposed) had some neurological disorder, and four other patients (one vs. three) showed signs of neurodevelopmental delay, with no significant differences between the groups (p=0.34). Pathological hyperlactatemia was detected in 56.4% (95% CI 39.6-72.2) and 57.5% (95% CI 40.9-73.0) of patients, respectively (p=0.92), and this condition was more frequent in preterm children (p<0.05). ARV use during pregnancy and the neonatal period was not associated with pathological hyperlactatemia. The presence of hyperlactatemia was not associated with neurological or neurodevelopmental disorders. No association was established between the use of ARV agents and the development of hyperlactatemia or neurological disorders in HIV-exposed children during their first year of life.

[1]  G. Aldrovandi,et al.  Antiretroviral Exposure and Lymphocyte mtDNA Content Among Uninfected Infants of HIV-1-Infected Women , 2009, Pediatrics.

[2]  M. L. Gómez,et al.  Exposición a antirretrovirales y crecimiento en una cohorte de niños no infectados, hijos de madre con VIH positivo , 2009 .

[3]  J. T. Ramos Amador,et al.  [Growth of uninfected infants exposed to antiretrovirals born to HIV-infected woman]. , 2009, Anales de pediatria.

[4]  J. Barbarà,et al.  Evolución de la transmisión vertical del VIH en Cataluña durante el período 1987-2003 , 2007 .

[5]  M. Hughes,et al.  In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children , 2007, AIDS.

[6]  K. Nagashima,et al.  Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long‐term to Zidovudine , 2007, Environmental and molecular mutagenesis.

[7]  K. Nagashima,et al.  Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor‐induced mitochondrial toxicity , 2007, Environmental and molecular mutagenesis.

[8]  P. Rustin,et al.  Clinical mitochondrial dysfunction in uninfected children born to HIV‐infected mothers following perinatal exposure to nucleoside analogues , 2007, Environmental and molecular mutagenesis.

[9]  R. Grunau,et al.  A Prospective Controlled Study of Neurodevelopment in HIV-Uninfected Children Exposed to Combination Antiretroviral Drugs in Pregnancy , 2006, Pediatrics.

[10]  M. Zeviani,et al.  Zidovudine Administration during Pregnancy and Mitochondrial Disease in the offspring , 2005, Antiviral therapy.

[11]  S. Wesselingh,et al.  Mitochondrial toxicity of nucleoside analogues: mechanism, monitoring and management. , 2005, Sexual Health.

[12]  R. Artuch,et al.  Hyperlactatemia in Human Immunodeficiency Virus–Uninfected Infants Who Are Exposed to Antiretrovirals , 2004, Pediatrics.

[13]  K. Nagashima,et al.  Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine. , 2004, AIDS research and human retroviruses.

[14]  V. Soriano,et al.  Could mitochondrial DNA quantitation be a surrogate marker for drug mitochondrial toxicity? , 2004, AIDS reviews.

[15]  G. Moyle.  Mitochondrial toxicity: myths and facts. , 2004, Journal of HIV therapy.

[16]  K. Nagashima,et al.  Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir , 2004, AIDS.

[17]  P. Harrigan,et al.  Nucleoside-related mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy: insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  B. Yip,et al.  Mitochondrial Toxicity in the Era of HAART: Evaluating Venous Lactate and Peripheral Blood Mitochondrial DNA in HIV-Infected Patients Taking Antiretroviral Therapy , 2003, Journal of acquired immune deficiency syndromes.

[19]  D. Money,et al.  Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy , 2003, The Pediatric infectious disease journal.

[20]  P. Rustin,et al.  Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort , 2003, AIDS.

[21]  Vernon E Walker,et al.  Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. , 2003, Journal of acquired immune deficiency syndromes.

[22]  M. Gerschenson,et al.  Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy. , 2003, Journal of acquired immune deficiency syndromes.

[23]  J. Smeitink,et al.  Mitochondrial Energy Metabolism , 2003 .

[24]  A. Mitchell,et al.  Secular changes in sleep position during infancy: 1995-1998. , 2003, Pediatrics.

[25]  M. Tardieu,et al.  Risk of early febrile seizure with perinatal exposure to nucleoside analogues , 2002, The Lancet.

[26]  I. Bruck,et al.  Developmental milestones of vertically HIV infected and seroreverters children: follow up of 83 children. , 2001, Arquivos de neuro-psiquiatria.

[27]  C. Giaquinto,et al.  Lactic acid levels in children perinatally treated with antiretroviral agents to prevent HIV transmission. , 2001, AIDS.

[28]  N. Shaffer,et al.  Safety of late in utero exposure to zidovudine in infants born to human immunodeficiency virus-infected mothers: Bangkok. Bangkok Collaborative Perinatal HIV Transmission Study Group. , 2001, Pediatrics.

[29]  L. Mofenson,et al.  Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: Absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts , 2000 .

[30]  M. Lampe,et al.  Lack of Evidence of Mitochondrial Dysfunction in the Offspring of HIV‐Infected Women: Retrospective Review of Perinatal Exposure to Antiretroviral Drugs in the Perinatal AIDS Collaborative Transmission Study , 2000, Annals of the New York Academy of Sciences.

[31]  P. Rhodes,et al.  Drug Safety during Pregnancy and in Infants: Lack of Mortality Related to Mitochondrial Dysfunction among Perinatally HIV‐Exposed Children in Pediatric HIV Surveillance , 2000, Annals of the New York Academy of Sciences.

[32]  C. Chougnet,et al.  Incorporation of Zidovudine into Cord Blood DNA of Infants and Peripheral Blood DNA of Their HIV‐1‐Positive Mothers , 2000, Annals of the New York Academy of Sciences.

[33]  M. Fowler,et al.  Lack of Definitive Severe Mitochondrial Signs and Symptoms among Deceased HIV‐Uninfected and HIV‐Indeterminate Children ≤ 5 Years of Age, Pediatric Spectrum of HIV Disease Project (PSD), USA , 2000, Annals of the New York Academy of Sciences.

[34]  M. Fowler,et al.  Early Cognitive and Motor Development Among Infants Born to Women Infected With Human Immunodeficiency Virus , 2000, Pediatrics.

[35]  D. Mtasiwa,et al.  Stroke mortality in urban and rural Tanzania , 2000, The Lancet.

[36]  U. Walker,et al.  Toxicity of nucleoside-analogue reverse-transcriptase inhibitors , 2000, The Lancet.

[37]  J. Poulton,et al.  HIV-1 therapy and fetal mitochondrial dysfunction , 1999, The Lancet.

[38]  P. Rustin,et al.  Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues , 1999, The Lancet.

[39]  A. Carr,et al.  HIV nucleoside analogues: new adverse effects on mitochondria? , 1999, The Lancet.

[40]  S. Gortmaker,et al.  Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. , 1999, JAMA.

[41]  R. Gelber,et al.  Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. , 1994, The New England journal of medicine.