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  • The analysis I’d like to present is titled the ‘Impact of highly active antiretroviral therapy on the incidence of HIV-encephalopathy among perinatally-infected children and adolescents.’
  • I’d first like to begin with some background on HIV-encephalopathy among children. Early cases of HIV-encephalopathy were reported in 1985 among children with AIDS. These children had an active and persistent brain infection by HIV and time from HIV infection to onset varied from 2 months to 5 years. The prevalence of HIV-encephalopathy among these children with AIDS was about 30-50% and diagnosis was associated with shorter survival. Consequently HIV-encephalopathy was added as an AIDS-defining condition in 1987.
  • The clinical features of HIV-encephalopathy include Loss of or failure to attain developmental milestones, Impaired brain growth, and Symmetrical motor deficits. There is also a varied rate of disease progression with some children having rapidly progressive disease and others having short periods of neurological deterioration followed by stable periods. There is also a variable pattern of disease with discordant cognitive and motor impairment. Some children may present with primarily cognitive deficits while others may present primarily with motor deficits and limited cognitive delay.
  • Over time there have been a number of studies looking at the incidence of HIV-encephalopathy. Although there may be a suggestion of decreasing incidence over time it is difficult to assess a trend in incidence over calendar time due to differences in times scales and study populations. For example, the first study published in 1995 found a cumulative incidence of 4% by 12 months of age while the last study found an incidence of 1.2% in the calendar year of 2002 irrespective of age. Pediatric Spectrum of Disease Study – cdc WITS French Perinatal HIV cohort Harlem hospital center Incidence of HIV encephalopathy in Malaysia – 8.2% in 2002 - almost 7 times greater than that found in harlem. all children on ARVs – 70% on triple drug therapy, 30% on dual therapy (ZDV and Stavudine).
  • There have also been a number of studies looking at antiretroviral therapy and HIV-encephalopathy. One study looked at the association between antiretroviral therapy and age at diagnosis and found therapy to be associated with a later age at diagnosis. The majority of studies looked at the effect of antiretroviral therapy after diagnosis of HIV-encephalopathy and found therapy to the associated with improvements in neuropsychological functioning and fewer neurologic abnormalities. None of these studies estimated the effect of therapy on incidence of HIV-encephalopathy.
  • The specific aims of our analyses were therefore to Describe incidence of HIV-encephalopathy from 1994-2006 to assess trends, to Determine the effect of highly active antiretroviral therapy (HAART) on the incidence of HIV-encephalopathy and finally to Determine the effect of HAART on survival after diagnosis of HIV-encephalopathy.
  • The Pediatric AIDS Clinical Trials Group Protocol 219/219C was used as the source population for our study. PACTG 219/219C is a prospective cohort study of HIV-exposed children from more than 80 study sites in the US. The purpose of this study was to assess the long-term effects of HIV-infection and in-utero and postnatal exposure to antiretroviral therapy. The children in this study underwent extensive clinical, neuropsychological, and laboratory evaluations. PACTG 219 began enrollment in April 1993 and followed children until 2000 when PACTG 219C began to follow children from 2000 to the present.
  • Our study population included 2,398 perinatally HIV-infected children enrolled in PACTG 219/219C from 1993-2006, with at least one neurological exam. Their Baseline date was defined as the date of first their 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.
  • HIV-encephalopathy determined by review of diagnoses recorded on neurological exam and standard diagnoses forms. A Pediatric neurologist reviewed all neurological diagnoses for each child and confirmed diagnosis and date of diagnosis of HIV-encephalopathy.
  • Study participants were followed to the date of HIV-encephalopathy diagnosis, death, or the last study visit before May 31, 2007, the date of closure of PACTG 219/219C, whichever came first. A Cox Regression Model was used to estimate the effect of time-varying treatment (HAART vs. Non-HAART regimens) on time to HIV-encephalopathy with the following baseline covariates: Age, Gender, Race, Birthweight, CD4%.
  • At baseline, 126 prevalent cases of HIV-encephalopathy were identified giving a prevalent of 5.3%. The median age at diagnosis of these prevalent cases was 1.7 years. The prevalent cases were subsequently removed from incident analyses. The baseline characteristics of the remaining 2272 children are provided on the slide. 48% of the study population was less than or equal to 5 years of age. Half were female and 55% were black. 24% had low birthweight and 19% had severe immunosuppression defined as CD4% less than 15%.
  • By the end of follow-up there were 77 incident cases of HIV-encephalopathy giving an overall incidence of 5.1 per 1000 person-years. The median age at diagnosis was 6.3 years, and the median length of follow-up was 6.4 years. 1806 children had initiated HAART and 31 incident cases were observed among them. 466 children never initiated HAART and 46 incident cases were observed among them.
  • This figure plots the incidence of HIV-encephalopathy between 1994-2006. As you can see there was a dramatic decline in incidence in 1995-1996, followed by a relatively stable incidence rate after approx 2002. If we plot the % of children on HAART by calendar year there is a suggestion that HAART is associated with the dramatic decline in incidence.
  • This table shows the estimated effect of HAART on incidence of HIV encephalopathy. We found HAART to be associated with a 50% decrease in the risk of HIV encephalopathy compared to non-HAART regimens. Severe immunosuppression was associated with an increased risk of HIV-encephalopathy relative to CD4%>25% and consistent with a previous incidence study, children less than 1 year of age had a higher risk of HIV-encephalopathy relative to older children. This association could also reflect a survivor effect.
  • In our full cohort, HIV encephalopathy was associated with an increased risk of mortality. Children with a diagnosis of HIV-encephalopathy had a 12 times increased risk of death compared to children without a diagnosis of HIV-encephalopathy. There were 43 deaths among the 77 incident cases observed during follow-up. The median survival after diagnosis of HIV-encephalopathy was 2 years. Among the 77 children with incident diagnoses of HIV-encephalopathy, we found HAART to be associated with improved survival compared to non-HAART regimens. The hazard ratio of this association was 0.50. 42% of deaths among children on HAART.
  • There are several limitations to acknowledge in our analyses. First our study population is a survivor cohort in that not all children were followed from birth. We may therefore have underestimated the incidence of HIV-encephalopathy. Second, 795 children were excluded from our analyses because they lacked a neurological exam in PACTG 219/219C. We still have to investigate further whether these children are different in some way from the children who had a neurological exam. Also, viral load was not available for more than half of the children in earlier years so we were unable to adjust for it on our analyses. A sub-analyses including only children with available baseline viral loads showed an even stronger protective effect of HAART than the one presented here. There was also potential for outcome misclassification. Diagnoses were abstracted from charts to it is unclear whether they were made by a pediatrician or a pediatric neurologist. N=3193 HIV-infected, perinatally infected children in 219/219C. 3193-2398=795 (25%). 989/2272 with VL data = 44% HR=0.3 (0.1, 0.9), p=0.02.
  • In conclusion, we found a 10-fold decrease in the incidence of HIV-encephalopathy in the HAART era. From our adjusted regression models we found HAART to be effective in reducing the risk of HIV-encephalopathy among perinatally infected children and adolescents compared to non-HAART regimens. Finally, HAART regimens may also be effective in improving survival after diagnosis of HIV-encephalopathy.
  • I would like to end by acknowledging the children and families of PACTG 219/219C as well as the 219/219C team and participating institutions. I would also like to acknowledge the funders of this study, NIAID, and NICHD.
  • Average of incidence from 2003-2006=1.3231

Transcript

  • 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. Estimated Effect of HAART on HIV-encephalopathy 0.009 3.4 (1.4, 8.4) ≤ 1 year 0.2 1.7 (0.7, 3.9) 2-5 years 0.9 1.0 (0.4, 2.4) 6-10 years Ref: > 10 years *Hazard ratio also adjusted for gender, race, and low birthweight. Baseline CD4% <0.0001 8.4 (4.8, 14.8) <15% 0.1 1.7 (0.9, 3.5) 15-24% Ref: ≥25% Age at Baseline 0.01 0.5 (0.3, 0.9) HAART regimens Ref: Non HAART regimens Antiretroviral Therapy p-value HR* (95% CI)
  • 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 1.5987 1.5117 0.7369 1.4451 2.5094 1.7889 1.2338 2.193 3.2 4.9505 15.4545 21.3849 13.8696 Incidence per 1000 person-years 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 Year