Cognitive, neurological and adaptive behaviour functioning among children with perinatally-acquired HIV infection Anita Shet, Smitha Holla, Vijaya Raman, Chitra Dinakar, Sapna V, Mysore Ashok St. John’s Medical College Hospital Bangalore, India 23-27 July 2012, Washington DC

Background Increased access to ART for children will result in improved survival. HIV is now a chronic disease. Neurocognitive and behavioral functioning of HIV-infected children: an important area to address. We all know that Drawn our attention to the subtle and not-so-subtle complications of HIV, and one of these includes neurocognitive and behavioral functioning of HIV-infected children.

Background In infancy: delay in motor and mental development. Drotar D et al. Peds 1997; Chase C et al. Pediatrics 2000. Later childhood: poorer neurocognitive functioning in comparison to HIV-uninfected children. Jeremy RJ, et al. Pediatrics 2005; 380-7 Impact of ART: improvement in some test scores. Martin SC, et al. Dev Neuropsychol 2006 Other risk factors: malnutrition, poverty, parental illness and death. If we look at some of the accumulated literature on this topic,

Specific Aims To examine the effects of HIV infection on cognitive, neurological, and behavioral functioning on children by comparing these areas in HIV-infected and HIV-uninfected children. To determine whether clinical, immunological, and treatment status can predict adaptive behavior and neurocognitive functioning in HIV-infected children. So we decided to conduct a pilot cross-sectional study to:

Methods Recruitment sites Inclusion criteria Exclusion criteria Parameters HIV Positive HIV Negative Recruitment sites St. John’s Hospital pediatric ID clinic; Sneha Care Home St. John’s Hospital general pediatric clinic; Prithvi Home Inclusion criteria 4-16 yrs Regular HIV care 4-16 years Well child Exclusion criteria Severe opportunistic infections Known HIV encephalopathy or other neurological disease Known seizure disorder or other neurological disease

Specific Testing Tools Neurological Testing Motor, sensory, cranial, cerebellar examinations. Soft neurological signs using Physical and Neurological Examination for Soft Signs (PANESS) tool. Cognitive Testing 3.5 to 6 yrs: Wechsler Preschool & Primary Scales of Intelligence (WPPSI) 7-16 yrs: Wechsler Intelligence Scale for Children, 3rd Ed (WISC-III) (Verbal and Performance IQ) Adaptive Behaviour Ability to adjust to different situations for day-to-day functioning. The Vineland Adaptive Behaviour Scales (VABS) assesses personal and social functioning.

Results: Patient characteristics Parameters HIV Positive (82) HIV Negative (85) p Age (yrs) 8.5 ± 2.7 8.7 ± 2.8 0.7 Males (%) 59 (47, 71) 55 (45, 65) Orphans (%) 29 (19, 39) 38 (29, 49) 0.2 Annual income ($) 840 912 0.4 Parental education (yrs) 9 10 0.1 Coming to results you can see that the 2 groups were well matched for age (mean age….) gender and orphan status.

Results: Patient characteristics Parameters HIV Positive (82) HIV Negative (85) p Age (yrs) 8.5 ± 2.7 8.7 ± 2.8 0.7 Males (%) 59 (47, 71) 55 (45, 65) Orphans (%) 29 (19, 39) 38 (29, 49) 0.2 Annual income ($) 840 912 0.4 Parental education (yrs) 9 10 0.1 Underweight (%) 71 (62, 82) 36 (26, 46) < 0.001* Stunted (%) 83 (75, 91) 28 (17, 37) < 0.001 * Anemia (%) 39 (28, 52) 23 (13, 33) 0.02 *

Results: Patient characteristics Parameters HIV Positive (82) HIV Negative (85) Age at diagnosis 6.8 ± 3.1 - HIV Clinical Stage 78% were WHO stage 1 or 2 Current CD4 (%) 25 (16, 39) Children on ART (%) 48% ART Regimen (65%) d4T + 3TC+ NVP

Soft Neurological signs PANESS Score HIV Positive (82) HIV Negative (85) p Total Score 7.5 (3, 13) 4 (2, 10) 0.02 Age 4-6 yrs 16 (12, 20) 16 (8, 21) 0.8 Age 7-10 yrs 5.5 (3, 9) 3 (1, 5) 0.008 Age ≥ 11 yrs 3 (1, 6) 2 (1, 5) 0.3 Boys 8.5 (5, 16) 5 (2, 10) 0.03 Girls 5 (2, 13) 4 (1, 10) 0.4 HIV-infected children had higher scores Difference most marked at ages 7-10 yrs. Boys with HIV had more abnormal soft neurological signs.

Cognition: IQ Scores IQ Score HIV Positive (82) HIV Negative (85) p Total IQ Score 75 ± 13 88 ± 15 < 0.001 IQ Verbal 78 ± 14 90 ± 17 IQ Performance 76 ± 13 87 ± 15 HIV-infected children had lower IQ scores compared to HIV-uninfected children, irrespective of age, sex, orphan status, anemia status

Adaptive behaviour (VAB) VAB Score HIV Positive (82) HIV Negative (85) p Total score 94 ± 10 95 ± 13 0.6 Age ns Males vs Females Orphans 96 ± 9 89 ± 10 0.008 Non-orphans 99 ± 13 0.01 The results were a little more complicated when we looked at the scores with respect to orphan status: among the non-orphans - Adaptive behaviour scores were similar for both HIV-infected and uninfected children – at all ages, and both in males and females. Among the orphans HIV-infected children had higher/better scores than orphans without HIV.

IQ Scores: ART status Score Total IQ p=0.006 p=0.06 p=0.02 Not on ART (39) On ART (43) Score Then we focused on only the children who were HIV positive. As expected, use of ART (represented by the green bars) was associated with significantly higher total IQ scores, and performance IQ scores, with a trend seen in verbal IQ scores, when compared to those children not on ART (as seen in the orange bars). Suggesting that ART has a role in improving overall cognitive functioning. Total IQ Performance IQ Verbal IQ ART may have a role in improving overall cognitive functioning

IQ Scores in children not on ART Age IQ Score (SD) p 4 – 6 years 78.0 (11.7) 7 – 10 years 77.1 (11.3) >10 years 75.7 (17.3) 0.01 When we looked more closely at the children who were not on ART, we found that mean total IQ scores demonstrated a tendency to decrease with increasing age. These decreases are relatively small – but does this indicate subtle worsening of the cognitive impairment among those children who seem to be clinically doing well, but not on ART – with possible uncontrolled viral replication occuring? Among children who were not on ART, mean total IQ scores demonstrated a tendency to decrease with increasing age

IQ Scores and VABS: Immunological status CD4 ≥ 15% 78 Low CD4 (<15%) 96 IQ Score 69 VABS score 89 We also found that immunological status appeared to influence cognitive and behavioral functioning. Clearly those children with higher Cd4 levels (>15%) – seen in the blue - had higher IQ scores compared to those with low CD4 levels – seen in yellow bars. And a similar finding among the VABS scores. Total IQ Score VABS

Multivariate regression analysis Cognition Independent factors that affected IQ scores: HIV status (OR 9.1) Weight-for-age Z score (OR 2.5) Hemoglobin (OR 2.1) Adaptive behaviour and soft neurological signs HIV status had no independent effect

Conclusions HIV-infected children had higher risk of having abnormal soft neurological signs. and lower IQ scores compared to HIV-uninfected children, irrespective of age, gender, orphan status, anemia status. indicating subtle neurocognitive impairment that may be related to perinatal HIV infection. Malnutrition and anemia had a definite role in poor cognitive outcomes. Use of ART has a positive effect, and subtle worsening may be seen among those children not on ART.

Recommendations Routine neurocognitive assessments in children Early initiation of ART Early intervention and stimulation, with focus on educational and emotional development

Acknowledgements St. John’s Research Society for funding support National AIDS Control Organization Sneha Care Home and Prithvi House staff Staff at the ID and general pediatric clinics Children and caregivers who participated