HIV, the brain and children
Polly Clayden, HIV i-Base
The developing brain is known to be a target for HIV, and there is concern about the long-term effect on the cognitive and behavioural development of HIV-positive children.
Additionally before the introduction of HAART, the prevalence of HIV encephalopathy in HIV-positive children was up to 50%.
Two studies published in the 10 September 2009 edition of AIDS, examine long-term neurocognitive and psychiatric outcomes of vertically infected adolescents and the impact of HAART on HHIV encephalopathy among children and adolescents in two American cohorts.
Impact of AIDS diagnoses on neurocognitive and psychiatric outcomes of vertically infected adolescents
Sarah Woods and colleagues conducted a retrospective cohort study at the Childrens Hospital of Philadelphia, USA, to examine the association between previous AIDS and neurocognitive and psychiatric outcomes in vertically infected adolescent long-term survivors. 
Adolescents attending the HIV clinic, born before 1 September 1995 and above 11 years of age were enrolled this study in which those with previous CDC Class C diagnosis (AIDS defining) were compared to those with non-Class C diagnosis.
Of the 172 meeting these criteria 39 (23%) patients had died, 45 (26%) transferred and 7 (4%) were lost to follow up. The remaining 81 adolescents were eligible for evaluation of whom 38 (46.9%) were girls and 58 (71.6%) were African-American. Their median age was 15.2 years (range 11.1-23.8, IQR 13.2-17.2 years). Almost half (47%) the participants were Class C and there were no significant differences in sex, race or current age between the class C and non-Class C groups. HIV diagnosis was at a median of 9 months and Class C diagnosis was at a median of 3.1 years of age. Of the Class C group, 51% had at least one additional Class C diagnosis.
Most recent viral load, CD4 percentage and CDC immunological category were similar in both groups. By the end of the study period 93% of the cohort were receiving HAART. There was no difference between the groups in those achieving and not achieving an undetectable viral load when on HAART. The cohort was heavily treatment experienced and patients with Class C diagnosis had received a greater number of regimens p=0.002. Of this group 68.4% had initiated HAART before their AIDS diagnosis.
The median full scale intelligence quotient (FSIQ) of the cohort, measured on the Weschler Intelligence Scale for Children-IV (WISC-IV) or the Weschler Abbreviated Scale of Intelligence, was 87 (IQR 78-99), which falls within the average category.
However, Class C patients had significantly lower median FSIQ than non-class C, 82 (IQR 73-90) vs 93.5 (IQR 84-100) respectively, p=0.0003. Learning disabilities had been diagnosed in 42% of the cohort and 17% had a lifetime history of HIV-related progressive encephalopathy (HPE).
Almost half the cohort (47%) had a diagnosed psychiatric illness and18.5% had multiple psychiatric illnesses. Treatment with psychotropic medications had been prescribed to 32% of the cohort, and 16% had a history of mental health hospitalisation.
The investigators performed a multivariate logistic regression analysis, adjusted for age at ART initiation, to look at the association between Class C diagnosis and neurocognitive and psychiatric status.
They found a significant association between previous Class C diagnosis and neurocognitive impairment: learning disabilities, adjusted OR 4.1 (95% CI 1.5-11.1), p=0.014 and lower FSIQ (median), -12.1 (-18.7 to 5.5), p=0.002. There was also significant association with psychiatric diagnosis AOR 3 (95% CI, 1.1-8.1), p=0.027, in particular multiple psychiatric diagnosis AOR 19.3 (95% CI, 2.3-162.6), p=0.001; mood disorder AOR 3.3 (95% CI, 1.1-10), p=0.023 and receiving mental health treatment AOR 4 (95% CI, 1.3-13), p=0.042.
The investigators found no difference in FSIQ or rates of learning or psychiatric disorders between Class C patients starting HAART before and after their AIDS diagnosis. But they noted that the number of patients with Class C disease was small and they were underpowered to detect even modest associations in this sub-analysis.
Impact of HAART on encephalopathy
Kunjal Patel and colleagues from The PACTG 219 study team looked at the effects of HAART and CNS penetrating regimens on the incidence of HIV encephalopathy in perinatally infected children and adolescents.  This study was conducted between 1994 and 2006 in a large American multicentre paediatric cohort.
The study followed 2398 perinatally infected children with at least one neurological examination.
The investigators used Cox regression models to estimate the effects of time varying HAART vs non HAART and time varying medium and high CNS penetrating regimens vs low CNS penetrating regimens on the incidence of HIV encephalopathy. They also looked at overall survival and survival following encephalopathy diagnosis. Covariates included baseline age and CD4 percentage, sex, ethnicity and birth weight. Secondary analyses used Cox models to estimate the effects of HAART and CNS penetrating regimens on HIV encephalopathy also adjusted for viral load and to evaluate the effect of HIV encephalopathy on mortality.
There were 2398 children, with a median of 6.4 years of follow up, included in this analysis. At baseline the 2272 children followed for incident HIV encephalopathy and survival analyses were equally divided between the sexes, the majority (85%) were less than or equal to 10 years of age, 24% had low birth weight, 56% had a CD4 percentage above 25% and there were no viral load data for 54%.
At the time of their first neurological examination 35% of children were on a HAART regimen and 27% were on a high CNS penetrating regimen. During the study period there were 77 incident cases of HIV encephalopathy, giving an incident rate of 5.1 per 1000 person years (95% CI 4-6.3).
The investigators reported a 10-fold decline in incidence of HIV encephalopathy. This began in 1996 and stablised after 2002. This decrease paralleled a significant increase in the use of HAART in the cohort.
They found the risk of developing HIV encephalopathy in children initiated on HAART was halved compared to those who were not on HAART (hazard ratio 0.5, 95% CI 0.29-0.86), p=0.01. Baseline CD4 less than 15% was associated with over 8-fold increase in risk of developing HIV encephalopathy (hazard ratio 8.41, 95% CI 4.79-14.76). Infants were also at greater risk, age less than or equal to 1 year at first neurological examination was associated with a over 3-fold increase in HIV encephalopathy (hazard ratio 3.38, 95% CI 1.36-8.44).
In the subanalysis looking at ranked CNS penetrating regimens, the investigators found a 41% reduction in incidence of HIV encephalopathy in high CNS penetrating regimens compared to low (hazard ratio 0.59, 95% CI 0.31-1.10). Due to the small sample size in this analysis, this association was not significant, p=0.64.
Across the cohort (n=2272) both HAART and high CNS penetrating regimens were associated with increased survival, hazard ratio 0.41(95% CI 0.29-0.58), and hazard ratio 0.31(0.22-0.45), both p<0.0001, compared to no HAART and low CNS penetrating regimens respectively.
Children with an HIV encephalopathy diagnosis had a 12-fold increase in risk of death compared to those without (hazard ratio 12.42, 95% CI 8.46-18.24).
There was a 50% increased survival benefit associated with HAART use among the 77 children with an incident diagnosis of HIV encephalopathy (hazard ratio, 0.51, 95% CI 0.25-1.05) but this was not statistically significant, p=0.07. High CNS penetrating regimens were associated with greater survival benefit, giving a 74% reduction in risk of death (hazard ratio 0.26, 95%CI 0.11-0.61, p=0.002) compared to low penetrating regimens.
Wood and colleagues write that their findings suggest that early HAART, initiated before the onset of symptomatic HIV, may be warranted to protect the developing CNS in children with HIV. For infants, they suggest that alongside CHER findings, and in keeping with some recent guideline changes, that HAART should be given to all infants immediately after birth. However, in an accompanying commentary, Marc Tadieu suggests that it is not possible to conclude directly from this study that very early treatment would have prevented class C events and possibly ensure normal cognitive and behavioural development, although, it is tempting to do so.
Patel and colleagues found HAART use to be highly effective in reducing the risk of HIV encephalopathy. They suggest that among children with HIV encephalopathy diagnosis, treatment decisions should take into account the effectiveness of ARVs in penetrating the CNS, as high CNS penetrating regimens offered increased survival benefit (74% reduction in risk of death compared to low penetrating). Editorial commentary from Bruce Brew describes HIV, the brain, children and neuro-HAART as a complex mix and suggests it is time for randomised clinical trials to establish whether neuro-HAART treats brain disease better than standard HAART.
- Wood SM et al. The impact of AIDS diagnoses on long-term neurocognitive and psychiatric outcomes of surviving adolescents with perinatally acquired HIV. AIDS 2009, 23:1859-1865.
- Patel K et al. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS 2009, 23:1893-1901.