African multi-site 2-year neuropsychological study of school-age children perinatally infected, exposed, and unexposed to human immunodeficiency virus

CITATION: Boivin, M. J. et al. 2020. African Multi-Site 2-Year Neuropsychological Study of School-Age Children Perinatally Infected, Exposed, and Unexposed to Human Immunodeficiency Virus. Clinical infectious diseases, 71(7): e105–e114. doi:10.1093/cid/ciz1088The original publication is available at https://academic.oup.com/cid/Background Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). Methods We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child’s age and sex, and selected personal/family control variables. Results The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. Conclusions Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.https://academic.oup.com/cid/article/71/7/e105/5649306?login=truePublishers versio

Pharmacokinetics of antiretroviral drugs in infancy

Infancy (from birth until 1 year of age) is a time of rapid changes within the body of a child. These changes affect pharmacokinetics in many ways. The CHER study1 showed that early antiretroviral treatment reduces mortality and disease progression amongst infants acquiring HIV infection before 12 weeks of age. As a result the World Health Organization has recently revised treatment initiation recommendations in children less than one year of age: all infants under 12 months of age with confirmed HIV infection should be started on antiretroviral therapy, irrespective of clinical or immunological stage2. Dosing in infants is challenging because drug concentrations are highly variable, there is frequently scant pharmacokinetic information in young children, and few suitable drug formulations are available. Furthermore, adherence to treatment is reliant on the caregiver, rather than the patient. Peri- and postnatal HIV transmission are reduced by maternal highly active antiretroviral treatment (HAART). However, the benefits and risks to breast fed infants of exposure to maternal antiretroviral drugs during lactation are poorly understood. In this article we review the pharmacokinetics of antiretroviral drugs relevant to South African infants, and highlight some of the challenges to delivering antiretroviral treatment in safe and effective doses

Efavirenz plasma concentrations at 1, 3, and 6 months post-antiretroviral therapy initiation in HIV type 1-infected South African children

The aim of this study was to quantify the plasma efavirenz concentrations over 6 months in black HIV-1-infected South African children (3–14 years), from resource-limited households, attending an outpatient clinic. The children were antiretroviral treatment (ART) naive and received efavirenz in combination with two nucleoside reverse transcriptase inhibitors according to South African national guidelines. Two blood samples were taken between 12 and 20 h after the last efavirenz dose at 1 ( n ¼ 58), 3 ( n ¼ 54), and 6 ( n ¼ 54) months post-ART initiation. A total of 328 efavirenz mid-dose plasma samples from 58 patients was determined with a validated liquid chromatography tandem mass spectrometry method. Viral suppression ( < 25 copies = ml) was achieved in 95% of the children after 6 months on ART. The median (range) plasma concentration at time points 1 and 2 were 2.06 (0.10–11.14) and 1.80 (0.14–10.70) m g = ml with respective mean ( SD) blood sampling times of 15.24 (2.03) and 16.91 (2.03) h post-evening dose. Efavirenz plasma samples within the therapeutic range of 1–4 m g = ml accounted for 58%; 17% were < 1 m g = ml and 25% were > 4 m g = ml over the 6 months. Efavirenz levels persistently > 4 m g = ml were recorded for 13 (23%) children and 3 (5%) children had persistent efavirenz levels < 1 m g = ml. Possible reasons for efavirenz plasma levels outside the accepted therapeutic range include genetic variation in drug metabolism, incorrect dosing, drug–drug interactions, and nonadherence. However, these need to be further explored and the importance of sequential plasma levels has been highlighted in this stud