Emília Sánchez

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

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. In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue–induced toxicity affected neurologic development.

Potential risk factors for vertical HIV-1 transmission in Catalonia, Spain : the protective role of Cesarean section

OBJECTIVEnTo evaluate the roles of certain potential risk factors on the vertical transmission of HIV-1.nnnDESIGNnProspective registry of infants born to HIV-1-infected women in Catalonia (north-east Spain) from 1987 to 1992.nnnMETHODSnA total of 599 infants, born in Catalan hospitals to 520 women who were identified as being HIV-1-infected during gestation or at delivery, were included. Data on mode of delivery, birth weight, gestational age and breast-feeding as well as the mothers age, her route of HIV-1 infection, clinical stage and p24 antigenaemia, were recorded. HIV-1 infection status of 489 (82%) of the infants was determined according to the criteria of the US Centers for Disease Control and Prevention. Risk estimates and odds ratio (OR) were calculated and logistic regression was performed.nnnRESULTSnThe overall rate of vertical transmission was 18.6% (95% confidence interval, 15.2-22.0%). Multivariate analyses revealed that Cesarean section was associated with a lower rate of vertical transmission (OR = 0.3; P = 0.001), as was maternal HIV-1 infection via injecting drug use (OR = 0.44; P = 0.02). Breast-feeding (OR = 6.9; P = 0.001), very low birth weight (< 1500 g; OR = 6.3; P = 0.001) and p24 antigenaemia (OR = 4.6; P = 0.04) were all related to increased risk. The crude rate of HIV-1 transmission was 6% among Cesarean births compared with 21% for infants born via vaginal deliveries. The population-attributable risk for vaginal deliveries was 61.7%.nnnCONCLUSIONSnThe results show a protective effect of Cesarean section in the absence of zidovudine prophylaxis. However, current research should be directed towards the individual and combined effects that antiretroviral agents and Cesarean section may have on mother-to-child HIV-1 infection.

Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment.

Background. Hyperlactatemia and lactic acidosis occur in HIV-infected adults receiving antiretroviral treatment. Our objective was to determine the incidence, course and risk factors for hyperlactatemia in our HIV-infected pediatric patients. Design. A prospective observational study of venous lactate concentrations during a 28-month period in 80 HIV-infected children, most of whom were receiving antiretrovirals. Methods. Venous blood lactate concentrations were measured every 6 months under optimal sample-obtaining conditions. Alanine values from the same blood sample were performed when lactate concentrations were elevated. Hyperalaninemia is observed only when mitochondrial oxidative phosphorylation is chronically disturbed. Results. Twenty-three patients (29%) were identified with hyperlactatemia, in 9 of the cases with normal alaninemia, probably caused by difficult venous punctures. The other 14 children (17%) had pathologic alanine concentrations with a mean lactate peak of 2.67 mmol/l (range, 2.05 to 4.9 mmol/l); none of them showed metabolic acidosis, and they were all symptom-free. Treatment was continued in all cases, and lactate has progressed spontaneously to normal values in 5 patients. Conclusions. Symptom-free hyperlactatemia was observed in HIV-infected children receiving nucleoside analog reverse transcriptase inhibitors. In our study, only a younger age at the beginning of antiretroviral treatment was a statistically significant risk factor for hyperlactatemia. Random measurements of blood lactate concentrations should be included in the clinical follow-up of those HIV-infected children <3 years of age who are treated with nucleoside analog reverse transcriptase inhibitors, symptomatic or not.

Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen.

Recent updates of the guidelines on the prevention of human immunodeficiency virus mother-to-child transmission have shortened the neonatal zidovudine prophylactic regimens from 6 to 4 weeks. We present a prospective observational study in a large cohort of mother-infant pairs and report that the 4-week regimen allows an earlier recovery of the anemia in these otherwise healthy infants.

Decreased Mitochondrial Function Among Healthy Infants Exposed to Antiretrovirals During Gestation, Delivery and the Neonatal Period.

Background: Antiretroviral (ARV)-associated mitochondrial toxicity in HIV/ARV-exposed healthy infants is a concern. Clinically relevant toxicity is rare. Hyperlactatemia is common but nonspecific, both increased and decreased mitochondrial DNA (mtDNA) level has been reported. Mitochondrial function has scarcely been investigated. Methods: In a prospective observational study of 133 HIV/ARV-exposed infants, mtDNA content was measured with quantitative real-time polymerase chain reaction, and mitochondrial respiratory chain enzymatic activity of complex IV (CIV) and mitochondrial mass (MM) were assessed spectrophotometrically from cryopreserved peripheral blood mononuclear cells obtained at 6 weeks and 3, 6 and 12 months of age and compared with a control group. Results: Most mothers (88%) received combined ARV therapy during pregnancy, and 92% of infants received zidovudine monotherapy. No infant had clinical evidence of mitochondrial disease during follow-up. Nonsignificant higher MM and lower mtDNA levels (normalized by MM) were observed over time in HIV/ARV-exposed infants. MM-normalized CIV activity was consistently lower in HIV/ARV-exposed children than in controls over time (0.09 vs. 0.35, 0.12 vs. 0.38, 0.13 vs. 0.24 and 0.14 vs. 0.24 nmol/min/mg at 6 weeks and 3, 6 and 12 months; P = 0.014, P < 0.0001, P = 0.065 and P = 0.011, respectively) and showed a linear trend toward normalization with age (P < 0.01). In HIV/ARV-exposed infants, an inverse correlation between CIV activity and mtDNA levels was observed until 6 months of age (r = −0.327, P = 0.016; r = −0.311, P = 0.040 and r = −0.275, P = 0.046). Conclusions: Mitochondrial-encoded CIV activity was consistently lower among HIV/ARV-exposed healthy infants and inversely correlated with mtDNA levels, suggesting upregulation of the latter.

Impact Of Cd4 T Cell Count On The Outcome Of Planned Treatment Interruptions In Early-treated Human Immunodeficiency Virus-infected Children

Early highly active antiretroviral therapy is recommended in all vertically human immunodeficiency virus (HIV)-infected infants. We describe the long-term immunologic outcome after planned treatment interruption (PTI) in 7 children diagnosed and treated during acute HIV infection (age <12 weeks). Children had remained a median of 57 months off treatment, 3 of them indefinitely. The 2 patients with the lowest nadir CD4% reinitiated highly active antiretroviral therapy because of a CD4 cell decline of <20%; 2 children resumed treatment because of clinical progression and parents wishes. All patients experienced a decrease in CD4% after PTI, which particularly affected the naive subpopulation. The interferon-&ggr; response against HIV-p24 antigen directly correlated with nadir CD4%. Our results suggest that early treatment in HIV-infected infants increases their potential to safely control viral replication after PTI for long periods.

Impact of human immunodeficiency virus coinfection on the progression of mother-to-child transmitted hepatitis C virus infection.

Data on mother-to-child transmitted human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection are scarce. A prospective observational study with a cohort of 70 HCV-infected children (13 of whom were HIV/HCV-coinfected; mean follow-up: 7.3 years) is presented. In our series, surrogate markers of disease progression (HCV viremia, maximum alanine aminotransferase values, and spontaneous HCV infection clearance) suggest that the evolution of liver disease in HIV/HCV-coinfected pediatric patients is more aggressive than it is in HCV-only infected children.

Detección de la disfunción tiroidea en la población gestante: está justificado el cribado universal

There is a controversy among different scientific societies in relation to the recommendations on whether universal screening for the detection of thyroid dysfunction during gestation should be performed or not. Although various studies have shown an association between subclinical hypothyroidism or hypothyroxinemia with obstetric problems and/or neurocognitive impairment in the offspring, no evidence on the possible positive effects of treatment of such conditions with thyroxin has been demonstrated so far. However, there is a general agreement about the need for treatment of clinical hypothyroidism during pregnancy and the risks of not doing so. Because it is a common, easily diagnosed and effectively treated disorder without special risk, the working Group of Iodine Deficiency Disorders and Thyroid Dysfunction of the Spanish Society of Endocrinology and Nutrition and Spanish Society of Gynaecology and Obstetrics recommends an early evaluation (before week 10) of thyroid function in all pregnant women. Given the complex physiology of thyroid function during pregnancy, hormone assessment should be performed according to reference values for each gestational trimester and generated locally in each reference laboratory. Thyrotropin determination would be sufficient for screening purposes and only if it is altered, free thyroxin or total thyroxin would be required. Adequate iodine nutrition is also highly recommended before and during pregnancy to contribute to a normal thyroid function in the pregnant women and fetus.

Mitochondrial assessment in asymptomatic HIV-infected paediatric patients on HAART.

BACKGROUNDnHAART can cause mitochondrial DNA (mtDNA) depletion, which may lead to mitochondrial dysfunction. We aimed to determine whether mtDNA and mitochondrial function abnormalities are present in peripheral blood mononuclear cells from asymptomatic HIV-infected children.nnnMETHODSnA cross-sectional study in peripheral blood mononuclear cells was performed in 47 asymptomatic (free from any HIV- or AIDS-related active condition or HAART-related toxicity), HIV-infected, HAART-treated children and adolescents and 27 uninfected healthy paediatric patients. We measured mtDNA and mitochondrial RNA (mtRNA) content by quantitative real-time PCR. Mitochondrial respiratory chain enzymatic activity of complex-IV (CIV) and mitochondrial mass (estimated by citrate synthase) were measured spectrophotometrically, and CIV protein subunit content was measured with western blot analysis.nnnRESULTSnA reduction in mtDNA levels was observed in HIV-infected children compared with controls (mean ± sem 4.47 ± 0.31 and 5.82 ± 0.48, respectively; 23% depletion; P=0.018), whereas similar levels of mtRNA, CIV protein subunit content and enzymatic activity were found in the two groups. These findings remained unaltered after considering mitochondrial abundance. Among HIV-infected children, mtDNA levels did not correlate with viral load, CD4(+) T-cell counts or lactataemia at the time of assessment. No differences were observed when current or past use of individual antiretroviral drugs or HAART regimens were taken into account.nnnCONCLUSIONSnDepletion in mtDNA from asymptomatic HIV-infected children did not lead to differences in mtRNA levels or mitochondrially-encoded CIV proteins, nor to CIV dysfunction. This may be explained by homeostatic-compensatory mechanisms at the transcription level or by the mild depletion we observed.

Evolution of mitochondrial DNA content after planned interruption of HAART in HIV-infected pediatric patients.

HAART-related long-term toxicities, many of them ascribed to mitochondrial (mt) toxicity of the nucleoside analogues, are being increasingly reported in HIV-infected children. HIV infection can also cause mt damage. Case series include 13 vertically HIV-infected pediatric patients (9 girls, median age 10.5 years) with optimal long-term response to a first-line HAART regimen who underwent planned treatment interruption (PTI). MtDNA content from peripheral blood mononuclear cells was assessed by means of a real-time PCR technique at PTI and 12 months later and expressed as an mtDNA/nuclear DNA ratio, together with lactate levels. At PTI, patients had remained a median time of 4.7 years on HAART and 4.3 years with complete suppression of viral replication. The main reason leading to PTI was treatment fatigue. One month after PTI, HIV plasmatic viral load had increased to 4.8 log copies/ml and stabilized thereafter. During the 12-month study period, all children remained free from any HIV-related clinical event. A progressive and significant decrease in median CD4 cell counts and percentages was observed 12 months after PTI. One year after PTI, the median mtDNA/nuclear DNA ratios had increased from 0.76 to 1.08 (p = 0.002) and lactate levels had decreased (from 1.12 to 0.73 mmol/liter; p = 0.019). Changes in mtDNA did not correlate with changes in lactate levels. No relationship was found between the evolution in mt toxicity markers and the rest of the clinical, immunological, and virological variables. In this series, PTI led to a partial restoration of mtDNA levels and a significant decrease in lactate values.