1/11/01

Pediatric trials for ARV experienced childrenColeen 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

0

10

20

30

40

50

60

70

80

1995 1996 1997 1998 1999

Protease Inhibitor Use

*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

0

1

2

3

4

5

6

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

0

1

2

3

4

5

6

7

8

1996 1997 1998 1999

White Non-HispBlack Non-HispHispanic

1/11/01

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

0

1

2

3

4

5

6

7

1996 1997 1998 1999

2- to <6 yrs6 to <13 yrs>=13 yrs

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

0

5

10

15

20

25

30

<1993 1994 1997 2000year

Modified from Spector 10/00

076

185316?

1/11/01

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 HIVinfected

“new” HIVinfected

HIV infectedadolescents

NICHD 28 2671 413 1213

NIAID 23 5824 736 1738

total 51 8495 1149 2951

1/11/01

Racial/ethnic make up PACTG:NICHDRacial and

ethnic groupsInfants Children Adolescent Male Adolescent

Female

(age) (0-23 mo) (2-4) (5-12) (13-19) (20-24) (13-19) (20-24)

White (Non-Hispanic)

106 66 150 30 19 49 46

Hispanic/Latino 228 188 321 65 23 88 95

AfricanAmerican

976 618 1061 157 130 395 516

Asian 8 3 1 2 1 3 1

Other/Unknown/Biracial

23 8 23 9 5 15 12

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.