1/11/01 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 *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 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

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

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: Modified from Spector 10/ ?

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

1/11/01 Racial/ethnic make up PACTG:NICHD

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.