Laughton B, Cornell M, Grove D, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS 2012; 26:1685-90.
To evaluate the effect of early versus deferred antiretroviral therapy (ART) on the neurodevelopment of infants participating in the Children with HIV Early Antiretroviral Therapy (CHER) trial.
Cape Town, South Africa.
Randomized controlled trial.
HIV-infected infants <3 months of age. Eligible children could have no underlying central nervous system abnormalities. Investigators also recruited HIV-exposed but uninfected and HIV-uninfected controls.
Neurodevelopmental maturation as measured by the Griffiths Mental Developmental Scale (GMDS). GMDS is measured as a continuous score and consists of five subscales: locomotor, personal-social, hearing and language, eye and hand coordination, and fine motor performance. Having a score more than two standard deviations below the mean is considered indicative of significant neurodevelopmental delay. GMDS was administered at 11 months of age.
HIV-infected children were randomized to either begin ART before 3 months of age or to defer initiation of ART until clinical or immunological progression. First-line ART included three drugs: zidovudine, lamivudine and lopinavir/ritonavir. Second-line ART was didanosine, abacavir and nevirapine.
The final analysis included 64 infants on early ART and 26 on deferred treatment. At enrollment, the treatment groups were comparable on mean absolute CD4 cell count (1746 vs. 2024 cells/ml, p=0.5), CD4% (34.8 vs. 34.9%, p=1.0) and plasma viral load (log10 RNA copies/ml: 5.66 vs. 5.64, p=0.8). Mean age of starting ART was 31.4 weeks in the deferred and 8.4 weeks in the early ART group (p<0.01). Twenty-four (92%) infants in deferred ART group were on ART at the time of the neurodevelopmental assessment. Mean time on ART before assessments was 18.7 weeks in the deferred and 40.9 weeks in the early ART group (p<0.01). On the GMDS, all scores were lower in the deferred vs. the early ART group. Overall and locomotor scores were significantly lower: mean (SD)=100.1 (13.8) vs. 106.3 (10.6), p=0.02 and 88.9 (16.3) vs. 97.7 (12.5), p<0.01, respectively. GMDS performance was similar between HIV-infected infants who received early ART and uninfected infants. Additionally, more infants on deferred ART compared with early ART experienced hospital admissions (46% vs. 30%). The deferred group stayed significantly longer in hospital than the early group (mean 9.4 vs. 2.4 days; p<0.01).
Children with HIV who start ART earlier have better short-term neurodevelopmental outcomes than infants for whom treatment is deferred and, in fact, are similar to uninfected infants. In addition, they have a lower incidence of illness requiring hospitalization, and, if hospitalized, are hospitalized for shorter periods of time.
The overall risk of bias in this trial is low, although sample sizes were small in the deferred ART and uninfected group. Randomization was computer-generated using balanced block randomization. Infants were randomly allocated to receive early or delayed therapy. There was no imbalance in the two treatment arms at baseline although uninfected children were less likely to be Xhosa-speaking. The trial was not blinded. The primary analysis was by intention-to-treat, and missing outcome data are addressed
This randomized controlled trial provides further evidence that starting ART early in infancy produces short-term improvements in neurological development and improved health. Neurodevelopmental delay has been a significant morbidity in HIV-infected infants who start ART later in low- and middle-income countries;(1, 2, 3, 4) in fact, HIV-infected infants who received early ART performed as well on GMDS as unexposed infants. These findings, and 5 other findings from the CHER trial, support the current World Health Organization treatment guidelines for infants that recommend all children under the age of 24 months begin ART at the time of HIV diagnosis.(5)
ART should not be withheld in infants but should be begun as soon as HIV infection is diagnosed. A key component in realizing the benefits of ART in infected infants is early diagnosis using HIV polymerase chain reaction testing at 6 weeks of age for children known to have been exposed.
- Bagenda D, Nassali A, Kalyesubula I, et al. Health, neurologic, and cognitive status of HIV-infected, long-surviving, and antiretroviral-naive Ugandan children. Pediatrics 2006; 117:729-740.
- Puthanakit T, Aurpibul L, Louthrenoo O, et al. Poor cognitive functioning of school-aged children in Thailand with perinatally acquired HIV infection taking antiretroviral therapy. AIDS Patient CareSTDS 2010; 24:141-146.
- Smith L, Adnams C, Eley B. Neurological and neurocognitive function of HIV-infected children commenced on antiretroviral therapy. S Afr J Child Health 2000; 2:108-113.
- Van Rie A, Harrington PR, Dow A, Robertson K. Neurologic and neurodevelopmental manifestations of pediatric HIV/AIDS: a global perspective. Eur J Paediatr Neurol 2007; 11:1-9.
- World Health Organization. Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access. Recommendations for a Public Health Approach (2010 revision) Geneva, Switzerland: World Health Organization, 2010.