1. Impact of Highly Active Antiretroviral Therapy on the Incidence of HIV- encephalopathy among perinatally- infected children and adolescents. Kunjal Patel, Sue X. Ming, Paige L. Williams, Kevin R. Robertson, James M. Oleske, and George R. Seage III, for the International Maternal Pediatric Adolescent AIDS Clinical Trials 219/219C Study Team.

2. HIV-encephalopathy among children Early cases reported in 1985 among children with AIDS. – –Active and persistent brain infection by HIV. – –Time from HIV infection to onset varied from 2 months to 5 years. – –Prevalence from 30-50%. – –Associated with shorter survival. Added as an AIDS-defining condition in 1987.

3. Clinical Features Loss of or failure to attain developmental milestones. Impaired brain growth. Symmetrical motor deficits. Varied rate and pattern of disease progression: –Rapidly progressive, or short periods of neurological deterioration followed by stable periods. –Discordant cognitive and motor impairment.

4. Incidence Studies 4% by 12 months of age (Lobato et al. 1995). 21% with median follow-up of 24 months (Cooper et al. 1998). 16% over 7 years post-infection (Tardieu et al. 2000). 1.2% in 2002 (Chirigoba et al. 2005).  Difficult to assess trend in incidence over time due to differences in time scales and study populations.

5. Antiretroviral studies Later age at diagnosis with antiretroviral therapy (Sánchez-Ramón et al. 2003). Improvements in neuropsychological functioning with zidovudine (Pizzo et al. 1988, Brouwers et al. 1990, Chirigoba et al. 2005, Saavedra- Lozano et al. 2006). Fewer neurologic abnormalities after treatment with combination NRTIs (McCoig et al. 2002).

6. Specific Aims Describe incidence of HIV-encephalopathy from 1994-2006. Determine the effect of highly active antiretroviral therapy (HAART) on the incidence of HIV-encephalopathy. Determine the effect of HAART on survival after diagnosis of HIV-encephalopathy.

7. Pediatric AIDS Clinical Trials Group (PACTG) Protocol 219/219C Prospective cohort study of HIV-exposed children (infected and uninfected) from more than 80 clinical sites in the US including Puerto Rico. –Assess the long-term effects of HIV infection and in utero and postnatal exposure to antiretroviral therapy. Extensive clinical, neuropsychological, and laboratory evaluations.

8. Study Population and Exposure 2,398 perinatally HIV-infected children enrolled in PACTG 219/219C from 1993-2006, with at least one neurological exam. –Baseline date was defined as the date of first neurological exam. HAART defined as the use of at least 3 drugs from at least 2 different classes of HIV therapy (NRTIs, NNRTIs, or PIs). –Once subjects initiated HAART they were assumed to remain on HAART for the duration of their follow-up.

9. Outcome HIV-encephalopathy determined by review of diagnoses recorded on neurological exam and standard diagnoses forms. –Pediatric neurologist reviewed all neurological diagnoses for each child and confirmed diagnosis and date of diagnosis of HIV- encephalopathy.

10. Follow-up and Analytic Approach Study participants were followed to the date of HIV-encephalopathy diagnosis, death, or the last study visit before May 31, 2007 (date of closure of PACTG 219/219C), whichever came first. Cox Regression Model with time-varying treatment (HAART vs. Non-HAART regimens) and the following baseline covariates: –Age, Gender, Race, Birthweight, CD4%.

11. Results (1) 126 prevalent cases of HIV-encephalopathy identified at baseline: –Prevalence = 5.3% (95% CI: 4.4, 6.2). –Median age at diagnosis = 1.7 years (Q1, Q3: 0.9, 3.9). Baseline characteristics of N=2,272 followed for incident analyses: –48% ≤ 5 years of age. –50% female. –55% Black. –24% had low birthweight (< 2500 grams). –19% severe immunosuppression (CD4<15%).

12. Results (2) By end of follow-up: –77 Incident cases of HIV-encephalopathy. –Overall incidence = 5.1 per 1000 person- years (95% CI: 4.0, 6.3). –Median age at diagnosis = 6.3 years (Q1, Q3: 3.3, 11.4). –Median length of follow-up = 6.4 years (Q1, Q3: 3.6, 9.9). –1,806 children had initiated HAART, 31 observed incident cases. –466 non-initiators, 46 observed incident cases.

13. Incidence and HAART use: 1994-2006 Incidence rate % on HAART

14. HR* (95% CI)p-value Antiretroviral Therapy HAART regimens Ref: Non HAART regimens 0.5 (0.3, 0.9) 0.01 Baseline CD4% <15% 8.4 (4.8, 14.8)<0.0001 15-24% Ref: ≥25% 1.7 (0.9, 3.5)0.1 Age at Baseline ≤ 1 year 3.4 (1.4, 8.4)0.009 2-5 years 1.7 (0.7, 3.9)0.2 6-10 years Ref: > 10 years 1.0 (0.4, 2.4)0.9 *Hazard ratio also adjusted for gender, race, and low birthweight. Estimated Effect of HAART on HIV-encephalopathy

15. HIV-encephalopathy, HAART, and survival HIV-encephalopathy associated with an increased risk of mortality: –HR*: 12.4 (95% CI: 8.5, 18.2). 43 deaths among the 77 incident cases. –Median survival after diagnosis of HIV- encephalopathy = 2.0 years. –HAART associated with improved survival after diagnosis of HIV-encephalopathy: HR*: 0.5 (95% CI: 0.2, 1.0). *Hazard ratio adjusted for age, gender, race, low birthweight, CD4%

16. Limitations Survivor cohort – children were not followed from birth: –Underestimate incidence. 795 perinatally infected children were excluded from analyses because they lacked a neurological exam in PACTG 219/219C. Viral load not available for most children in earlier years – unable to adjust. Outcome misclassification possible: –Chart abstraction of diagnoses – unclear if diagnoses made by pediatrician or pediatric neurologist.

17. Conclusions In the HAART era (post-1996) there was a 10- fold decrease in the incidence of HIV- encephalopathy. HAART regimens are effective in reducing the risk of HIV-encephalopathy among perinatally infected children and adolescents compared to non-HAART regimens. HAART regimens may also be effective in improving survival after diagnosis of HIV- encephalopathy compared to non-HAART regimens.

18. Acknowledgements Children and Families of IMPAACT (formerly PACTG) 219/219C. IMPAACT 219/219C Team and Participating Institutions. Funded by US National Institutes of Health (NIAID, NICHD: U01 AI068632, #5 U01 AI41110, #1 U01 AI068616).

19. Non-HAART regimens (N=466) No ARV = 38 (8%) 1 NRTI = 223 (48%) 2 NRTI = 171 (37%) 3 NRTI = 20 (4%) Other ARV = 14 (3%) –1 PI+1 NRTI, 1 NNRTI+1 NRTI, 1 PI+1 NNRTI, 2 PI

20. Incidence by calendar year YearIncidence per 1000 person-years 199413.8696 199521.3849 199615.4545 19974.9505 19983.2 19992.193 20001.2338 20011.7889 20022.5094 20031.4451 20040.7369 20051.5117 20061.5987