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

Abstract

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...

Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean

“…The findings of this investigation are consistent with those of previous studies that found no association between in utero ARV exposure and neurologic outcomes, such as MD, [10][11][12][13]20,21 neurologic events, 14,21 and congenital abnormalities 15 among HEU infants. However, there are other studies that did find associations between in utero ARV exposure and MD, 4,8 hyperlactatemia, 22 febrile seizures, 6 and neurologic dysfunction. 7 Our analysis examined differences by specific ARV drug among all cART-exposed infants, while other studies compared cART-exposed infants to those unexposed.…”

Increased mtDNA Levels Without Change in Mitochondrial Enzymes in Peripheral Blood Mononuclear Cells of Infants Born to HIV-Infected Mothers on Antiretroviral Therapy

“…2 A similar potential for mitochondrial toxicity from in utero exposure to ARV therapy has been suggested by primate studies, in which dose-related fetal abnormalities in mitochondrial structure and function have been reported in skeletal muscle, cardiac muscle, and brain. 3,4 Although transient hyperlactatemia is common in infants perinatally exposed to ARV therapy, 5,6 only rare cases of symptomatic hyperlactatemia have been reported. In these cases of lactic acidosis, the central nervous system was involved frequently and seems to be particularly vulnerable to mitochondrial insults.…”

Developmental delay and behavioral disorders in 59 HIV-exposed uninfected infants

“…The inhibitory effect of ZDV on both HIV reverse transcriptase and DNA polymerase γ, an essential protein for mitochondrial DNA replication, is well known (2,3); the impact of the other NRTIs and other classes of ARV is less clear. Mitochondrial dysfunction due to ARV exposure before, during, or after birth is a broader toxicity that could have a continuing influence on childhood development; so, it is not surprising to find in our study a significant association between antenatal exposure to multiple NRTIs and developmental delay and/or behavioral disorders; however PACTG 219/219C found no overall association between ARV exposure in utero and neurologic development at 2 years of age in 1,037 HEU (9).…”

“…However, this benefit is counterbalanced with possible adverse drug effects related to in utero and neonatal exposure to antiretroviral (ARV) drugs: premature delivery, birth defects, short-term reversible biological abnormalities (anemia, neutropenia, hyperlactatemia) or persistent clinical and biological abnormalities (mitochondrial toxicity) (2)(3)(4). In high-income countries, guidelines recommend treating pregnant women with triple-combination ART and to increase the number of HIV infected women receiving therapy before conception; so fetuses are more and more exposed to ARV during gestation.…”