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

Abstract

Background: In response to recent reports of mitochondrial dysfunction in HIV‐uninfected infants exposed to antiretroviral (ARV) prophylaxis, the Perinatal Safety Review Working Group reviewed deaths in five large HIV‐exposed perinatal cohorts in the United States to determine if similar cases of severe mitochondrial toxicity could be detected. We describe the results of this review for the PSD cohort. Methods: Hospitalization, clinic and death records for deceased HIV‐uninfected and HIV‐indeterminate children who were less than 5 years of age were reviewed. Standard definitions were used to classify HIV infection status and the likelihood that signs and symptoms were related to mitochondrial dysfunction. Children were classified as having signs and symptoms that were considered (1) unrelated, (2) unlikely, (3) consistent with, or (4) likely related to mitochondrial disease. SIDS deaths were put into a separate category. Results: 8,465 of 13,125 HIV‐exposed children were either HIV‐uninfected or HIV‐indeterminate. Among the 84 deaths in the subgroup of 8,465 children, 9 were considered in Class 2 (unlikely), 4 were considered in Class 3 (consistent with), and none were considered in Class 4 (likely). 97% of those children who received ARV prophylaxis received zidovudine alone. None of the HIV‐uninfected deaths were classified in 2, 3, or 4; and only one of these was exposed to ARV prophylaxis. Among the 3 HIV‐indeterminate children who were classified in 3 (consistent with), 2 had no or unknown ARV exposure before 1994 when use of ZDV prophylaxis became the standard of care. Both HIV‐uninfected and HIV‐indeterminate children with ARV exposure or unknown exposure had lower mortality rates than children without ARV exposure. Conclusion: Monoprophylaxis with ZDV was not associated with higher death rates in the cohort of 8,465 children or with any findings likely consistent with mitochondrial dysfunction among the 85 deaths. Ongoing monitoring of drug safety in large multi‐site prospective cohort studies of HIV‐exposed children is essential in the era of highly active antiretroviral therapy.

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

“…Our analysis included only infants with exposure to three or more ARV drugs in utero since this is the treatment regimen most relevant to the current international treatment guidelines for HIV-positive pregnant women and because women not on ARVs during pregnancy likely differ in important ways from those who have access to care and are treated with ARVs. 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.…”

“…9 Beyond the IMPAACT P1025 results, findings from the initial FPCS were not supported by results from many other groups, including investigators from several US cohorts who reviewed >20,000 HEU subjects and found no deaths due to MD. [10][11][12][13] However, these US-based studies were limited to evaluating causes of mortality and were not able to assess neurologic morbidity.…”

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

“…10 To date, reports concerning NRTI toxicity in children who are exposed perinatally to ARV are contradictory. Although large population-based studies have failed to demonstrate signs or symptoms suggesting mitochondrial injury in NRTI-exposed HIVuninfected children, 9,[11][12][13] other authors have reported rare severe neurologic damage consistent with mitochondrial dysfunction 14,15 and a higher risk of febrile seizures below the age of 18 months 16 in these otherwise healthy patients. The aim of our study was to determine the prevalence, clinical consequences, evolution, and risk factors for hyperlactatemia (HLA) in our cohort of HIV-uninfected infants who were exposed to ARV during gestation, labor, and/or the neonatal period.…”

Evaluation and Management of the Infant Exposed to HIV-1 in the United States

“…Mitochondrial dysfunction should be considered in children with perinatal ARV exposure who present with severe clinical findings of unknown etiology, particularly neurologic findings. [67][68][69][70][71][72][73][74] Information regarding in utero and/or neonatal ARV exposure should be part of the ongoing permanent medical chart of the child, particularly for uninfected children. Children with in utero ARV exposure who develop significant organ-system abnormalities of unknown etiology, particularly of the nervous system or heart, should be evaluated for potential mitochondrial dysfunction.…”

“…[64][65][66][67] However, should an infant develop severe clinical symptoms of unknown etiology, particularly neurologic symptoms, serum lactate concentration should be determined. If the serum lactate con-centration is significantly abnormal in an infant with compatible clinical symptoms, an expert in pediatric HIV-1 infection should be consulted regarding potential early discontinuation of prophylaxis.…”