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Pediatric trials for ARV experienced children Coleen K. Cunningham

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					          Pediatric trials for ARV experienced children
                      Coleen K. Cunningham

•   Epidemiology of treatment experience in pediatrics


•   How does the smaller number of HIV infected children as compared to
    adults impact on the type of trials that are feasible?


•   How does the management of HIV disease in children impact the type
    of trial design options as compared to adults?




1/11/01
                     Pediatric HIV

• Majority of HIV infected children are treatment
  experienced: in many cases multi-class experienced.
     – Evolution of treatment use in pediatrics: mono, dual
       and now heavy use of combinations
     – Decreased mortality: more of the infected children
       surviving years, decades
     – Few newly infected infants: limited new pool of
       treatment naïve young children



1/11/01
                     Pediatric HIV

• Majority of HIV infected children are treatment
  experienced: in many cases multi-class experienced.

     – Evolution of treatment use in pediatrics: mono,
       dual and now heavy use of combinations
     – Decreased mortality: more of the infected children
       surviving years, decades
     – Few newly infected infants: limited new pool of
       treatment naïve young children


1/11/01
              Pediatric HIV trends
• Since anti-retroviral became available, we have struggled
  to determine optimal use in pediatrics.
• AZT
• AZT/ddI
• AZT/3TC
• d4T/ritonavir
• 3 drug regimens- 1997




1/11/01
     Reported Rate (%) of Protease Inhibitor Use* among Subjects in
                          PACTG 219 prior to Jan 1, 1996


   80
   70
   60
   50
   40                                                Protease Inhibitor Use
   30
   20
   10
     0
           1995    1996     1997   1998   1999
          *Protease inhibitor use since last PACTG 219 visit

1/11/01
                     Pediatric HIV

• Majority of HIV infected children are treatment
  experienced: in many cases multi-class experienced.
     – Evolution of treatment use in pediatrics: mono, dual
       and now heavy use of combinations

     – Decreased mortality: more of the infected
       children surviving years, decades
     – Few newly infected infants: limited new pool of
       treatment naïve young children


1/11/01
      Mortality Rates (% per year) among HIV infected subjects
             enrolled in PACTG 219 prior to Jan 1, 1996


      6

      5

      4

      3

      2

      1

      0
            1996          1997           1998           1999

          Logrank test for trend significant P<0.0001
1/11/01
  Mortality Rates (% per year) by Race/ Ethnicity: HIV infected
      subjects enrolled in PACTG 219 prior to Jan 1, 1996


     8
     7
     6
     5
                                               White Non-Hisp
     4                                         Black Non-Hisp
     3                                         Hispanic
     2
     1
     0
          1996   1997     1998     1999



1/11/01
Mortality Rates (% per year) by age among HIV infected subjects
          enrolled in PACTG 219 prior to Jan 1, 1996


     7
     6
     5
     4                                           2- to <6 yrs
     3                                           6 to <13 yrs
                                                 >=13 yrs
     2
     1
     0
          1996   1997      1998      1999



1/11/01
                     Pediatric HIV

• Majority of HIV infected children are treatment
  experienced: in many cases multi-class experienced.
     – Evolution of treatment use in pediatrics: mono, dual
       and now heavy use of combinations
     – Decreased mortality: more of the infected children
       surviving years, decades

     – Few newly infected infants: limited new pool of
       treatment naïve young children


1/11/01
    Vertical transmission of HIV in PACTG studies:
                       1993-2000




                                        076
                                              185
                                                    316?



1/11/01   Modified from Spector 10/00
                    Pediatric HIV

• Children with HIV are primarily treatment experienced,
  often multi-class experience and many saw sequential
  mono and dual nucleoside therapy
• Exploring options for treatment experience children
  critically important for our patient population
• Important to evaluate treatment options, management
  strategies and effectiveness of new agents in this group




1/11/01
   How do pediatric numbers impact on trial design?

• How many HIV infected children are there?
• Are they potentially available to participate in clinical
  trials?
• What age groups are available?




1/11/01
          Children cared for at PACTG sites

  program # of sites   Total HIV   “new” HIV   HIV infected
                        infected    infected   adolescents
   NICHD        28       2671         413         1213


   NIAID        23       5824         736         1738


     total      51       8495        1149         2951




1/11/01
  Racial/ethnic make up PACTG:NICHD
  Racial and       Infants     Children        Adolescent Male       Adolescent
 ethnic groups                                                        Female
      (age)       (0-23 mo)   (2-4)   (5-12)   (13-19)   (20-24)   (13-19) (20-24)

  White (Non-       106        66      150       30        19        49      46
   Hispanic)
Hispanic/Latino     228       188      321       65        23        88      95

    African         976       618     1061      157       130       395      516
   American
      Asian          8         3          1      2         1         3        1

Other/Unknown        23        8       23        9         5         15      12
   /Biracial
     Totals         1341      883     1556      263       178       550     670



1/11/01
      How do pediatric numbers impact on trial design?

• Biggest concern with numbers is treatment of naïve
  children. Numbers for that cohort very limited. Only
  studies that could be done would be very small and
  focused
• Numbers of treatment experienced children much greater.
  Certainly, not the numbers that could be recruited for an
  adult study but definitely sufficient for efficacy trials using
  virologic endpoints.
• Pharmacokinetics, safety, antiviral activity could all be
  done for a range of age groups.

1/11/01
    Treatment factors unique to pediatrics
• Pharmacokinetics: vary with age, size, tanner staging
      – Must understand dosing for 2.5 kg, 4 weeks old through 100kg, 14
        years old

• Dosing: volume, palatability (have you tasted liquid
  ritonavir?), frequency (school schedules)
• Toxicities: may be easier or more difficult for children to
  tolerate drugs; many seem better tolerated but what will
  long term sequelae be? (lipid abnormalities, mitochondrial
  toxicities)



1/11/01
    Treatment factors unique to pediatrics
• Children generally dependant on an adult to deliver medicine
     – That adult may have limited ability to follow-through
     – Some parents feel guilty forcing their child to take foul tasting meds
     – Mother (or father) may be adjusting to treatment for their own disease

• Children have frequent minor infectious illnesses that are
  common in childhood that can lead to intermittent dose
  intolerance or periodic treatment with additional medications
  (antibiotics for OM, for example).
• Viral loads set-points are generally much higher in pediatrics.
• CD4 counts are normally much higher in children

1/11/01
             Pediatric treatment trials

• MUST run concurrent with adult trials
• MUST have pediatric formulations available
• PK, tolerability (including palatability), safety data are
  critical!
• Need to understand long-term safety
• Need to evaluate different management strategies




1/11/01
                Trial design options

• Majority of US pediatric treatment trials have been carried
  out within the PACTG
• PACTG has the scientific expertise and the patient base to
  carry out the trials
• Currently, a large number of treatment experienced
  children are receiving care at PACTG or affiliated sites.




1/11/01

				
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