Initiation of antiretroviral therapy after the critical neuronal developmental period of the second postnatal year affects white matter microstructure in adolescents living with HIV
Rapid maturation of major white matter pathways occurs in the first 2 years of life, indicating a critical neuronal developmental period. The impact of initiating antiretroviral therapy (ART) in children perinatally infected with HIV-1, after the age of 2 years on neurocognitive functioning and white matter development in adolescence has not been studied. Forty-six adolescents who initiated ART during the first 2 years of life (< 2 years) and 79 adolescents who initiated ART after 2 years of age (> 2 years), with perinatally acquired HIV were enrolled in the Cape Town Adolescent Antiretroviral Cohort. Adolescents completed a comprehensive neurocognitive battery testing a number of cognitive domains. Diffusion tensor imaging (DTI) was done to determine fractional anisotropy (FA), mean diffusivity (MD), axial diffusion (AD), and radial diffusion (RD) in a region of interest analysis. Neurocognitive performance was similar between adolescents who initiated ART < 2 years or > 2 years. There was a trend towards attention (p = .07) and working memory (p = .05) being poorer in the group who initiated ART > 2 years. FA was lower in the > 2-year group in the superior corona radiata (p = .03), and the external capsule (p = .04). MD was higher in the > 2-year group in the cerebral peduncle (p = .02), the superior corona radiata (p = .01), and the superior fronto-occipital fasciculus (p = .03). RD was higher in the > 2-year group in the superior corona radiata (p = .02), the cerebral peduncle (p = .01), and the superior fronto-occipital fasciculus (p = .01). However, the higher AD in the > 2-year group in the superior corona radiata was not in the expected direction (p = .01). Initiation of ART after the neuronal development period of the second postnatal year is associated with white matter alterations on neuroimaging.
KeywordsAdolescent HIV Neuroimaging Antiretroviral therapy Neurodevelopment
Source of funding
JH has received support from Medical Research Council (MRC) of South Africa. HZ and DS are supported by the National Research Foundation (NRF) and the Medical Research Council (MRC) of South Africa. This research was supported by NICHD under grant R01HD074051.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- Ackermann C, Andronikou S, Laughton B, Kidd M, Dobbels E, Innes S, van Toorn R, Cotton M (2014) White matter signal abnormalities in children with suspected HIV-related neurologic disease on early combination antiretroviral therapy. Pediatr Infect Dis J 33:e207–e212. https://doi.org/10.1097/INF.0000000000000288 CrossRefPubMedPubMedCentralGoogle Scholar
- Ackermann C, Andronikou S, Saleh MG, Laughton B, Alhamud AA, van der Kouwe A, Kidd M, Cotton MF, Meintjes EM (2016) Early antiretroviral therapy in HIV-infected children is associated with diffuse white matter structural abnormality and corpus callosum sparing. Am J Neuroradiol 37:2363–2369. https://doi.org/10.3174/ajnr.A4921 CrossRefPubMedGoogle Scholar
- Benedict RHB, Schretlen D, Groninger L, Brandt J (1998) Hopkins verbal learning test? Revised: normative data and analysis of inter-form and test-retest reliability. TCN The clinical neuropsychologist 12:43–55. https://doi.org/10.1076/clin.18.104.22.1686
- Crowell CS, Huo Y, Tassiopoulos K, Malee KM, Yogev R, Hazra R, Rutstein RM, Nichols SL, Smith RA, Williams PL, Oleske J, Muller WJ (2015) Early viral suppression improves neurocognitive outcomes in HIV-infected children. AIDS 29:295–304. https://doi.org/10.1097/QAD.0000000000000528 CrossRefPubMedPubMedCentralGoogle Scholar
- Hoare J, Fouche J-P, Spottiswoode B, Donald K, Philipps N, Bezuidenhout H, Mulligan C, Webster V, Oduro C, Schrieff L, Paul R, Zar H, Thomas K, Stein D (2012) A diffusion tensor imaging and neurocognitive study of HIV-positive children who are HAART-naïve “slow progressors”. J Neuro-Oncol 18:205–212. https://doi.org/10.1007/s13365-012-0099-9 CrossRefGoogle Scholar
- Hoare J, Fouche J-P, Phillips N, Joska JA, Paul R, Donald KA, Thomas KGF, Stein DJ (2015b) White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa. AIDS 29:1793–1801. https://doi.org/10.1097/QAD.0000000000000766 CrossRefPubMedGoogle Scholar
- Laughton B, Cornell M, Grove D, Kidd M, Springer PE, Dobbels E, van Rensburg AJ, Violari A, Babiker AG, Madhi SA, Jean-Philippe P, Gibb DM, Cotton MF (2012) Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS 26:1685–1690. https://doi.org/10.1097/QAD.0b013e328355d0ce CrossRefPubMedPubMedCentralGoogle Scholar
- Li J, Wu G, Wen Z, Zhang J, Lei H, Gui X, Lin F (2015) White matter development is potentially influenced in adolescents with vertically transmitted HIV infections: a tract-based spatial statistics study. AJNR Am J Neuroradiol 36:2163–2169. https://doi.org/10.3174/ajnr.A4417 CrossRefPubMedGoogle Scholar
- Mori S, Wakana S, Nagae-Poetscher LM, Van Zijl PCM (2005) Two-dimensional atlas of brain white matter tracts. In: MRI atlas of human white matter. Elsevier, pp 33–237Google Scholar
- Puthanakit T, Ananworanich J, Vonthanak S, Kosalaraksa P, Hansudewechakul R, van der Lugt J, Kerr SJ, Kanjanavanit S, Ngampiyaskul C, Wongsawat J, Luesomboon W, Vibol U, Pruksakaew K, Suwarnlerk T, Apornpong T, Ratanadilok K, Paul R, Mofenson LM, Fox L, Valcour V, Brouwers P, Ruxrungtham, K. (2013) Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: The PREDICT neurodevelopmental study. Pediatr Infect Dis J 32:501–508Google Scholar
- Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TEJ (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505. https://doi.org/10.1016/j.neuroimage.2006.02.024 CrossRefPubMedGoogle Scholar
- Uban KA, Herting MM, Williams PL, Ajmera T, Gautam P, Huo Y, Malee KM, Yogev R, Csernansky JG, Wang L, Nichols SL, Sowell ER, Pediatric HIVAIDS Cohort and the Pediatric Imaging, Neurocognition, and Genetics Studies (2015) White matter microstructure among youth with perinatally acquired HIV is associated with disease severity. AIDS 29:1035–1044. https://doi.org/10.1097/QAD.0000000000000648 CrossRefPubMedPubMedCentralGoogle Scholar
- Wechsler D (2003) Wechsler intelligence scale for children. In: 4th editionGoogle Scholar