Challenges to Pediatric Antiretroviral Treatment

1. Challenges to Pediatric Antiretroviral Treatment Elaine Abrams, David Hoos MTCT-Plus

2. What is the MTCT-Plus Initiative? Comprehensive HIV Care and Treatment program for women and their families: • women identified as HIV infected through pMTCT programs • their HIV-infected infants and children • their HIV-exposed infants • HIV-infected family/household members

3. Women attending ANC clinics pMTCT programs Enrollment into pMTCT programs Enrollment into MTCT-Plus HIV-infected partners and children • Long-term HIV care services, including: • • Family-centered services • • Clinical & immunologic monitoring • • TB prophylaxis & treatment • • Prophylaxis for opportunistic infections • • Antiretroviral therapy when indicated • • Psychological & social support services • Prevention services • • Nutritional counseling & support • Access to family planning services • Community outreach MTCT-Plus

4. Fundamentals of MTCT-Plus • Comprehensive HIV care & antiretroviral treatment • Family-centered care • Attention to psychological, social and environmental issues • Involvement of persons with HIV and outreach to community resources

5. MTCT-Plus EnrollmentFebruary 2003 – August 2004n=5540 Children (35%) Adults (65%)

6. Children MTCT-Plus Enrollment August 31, 2004n=1908 Other children Children of Most Recent Pregnancy

7. Challenges to Pediatric ART • Limited pediatric formulations • Not all ART available in liquid formulation • Many caps/pills only available in adult doses • No FDC for small children • Poor palatability/tolerability of several critical medications • Difficulties of managing dosing and administration in the household

8. Challenges: Limitations of Pediatric Formulations • For example stavudine (D4T) • Liquid formulation requires refrigeration • No published data on bioavailability or stability of opened capsules • Smallest capsules (15mg) not widely available • Complexity of opening capsules, dissolving in water and measuring specific volume

9. Challenges: Limitations of Pediatric Formulations • For example zidovudine • Large volume/dose a child grows • Often associated with nausea • Anemia common side effect • For exampledidanosine • Must be taken on empty stomach?

10. Challenges: Limitations of Pediatric Formulations • For example lopinavir/ritonavir • Stability at high temperatures has not been established. • Dosing has not been determined for children < 6 months of age. • Significant interaction with rifampin • Bitter taste of liquid/relatively large size of capsules

11. Challenges: Limitations of Pediatric Formulations • For example Efavirenz (EFV) • Dosing not established for children < 3 years of age For exampleNelfinavir (NLF) • Not liquid formulation. Must administer crushed tablets. Powder not feasible. • Proper dose for infants still under discussion

12. Challenges: Using Adult Formulations • Not all tabs are scored • May need smaller dose then 1/2 pill ?1/4 pill • Individual drugs within FDC may not be evenly distributed within tablet; accurate dosing not assured when tab is halved • Capsules can be large and difficult to swallow • Opening capsules and dividing contents can be complex for caregiver and inaccurate re: dose

13. Challenges: Choosing the 1st-Line Regimen • Choice of first-line therapy • Efficacy of nevirapine-based combination therapy during infancy/primary infection not well studied • Impact of single-dose nevirapine used for pMTCT on the potency of NNRTI-based regimen • If PI-based therapy is used for first-line treatment, what is the best second-line therapy?

14. Challenges: Dosing Pediatric ART • Dosing is based on weight or body surface area (BSA) • Use of BSA not practical • Doses must be recalculated frequently in a growing child • Weight-based conversions for BSA have been developed, but have not been tested. These estimations risk: • Toxicity if dose is too high • Development of resistance is dose is too low

16. Challenges: Feasibility of Implementing Widespread ART • Developing simple, feasible algorithms for • When to start treatment • Monitoring and managing and toxicity • Monitoring efficacy & determining failure • Developing feasible guidelines for 1st & 2nd line ART as well as toxicity changes

18. Challenges: Treatment of HIV & TB • No studies in children examining pharmacokinetics of ART for children receiving TB treatment • Significant pharmacologic interactions between protease inhibitors and rifampin • Interactions between nevirapine and rifampin • Efavirenz dosing not known for young children (< 3 years, <10kg)

19. Additional Challenges • Adherence to ART • Limitations of formulations • Inconvenience of measuring multiple liquids/administering multiple pills • Need for committed adult caretaker • Development of pediatric expertise & “comfort” within health care systems

20. Complications in Procurement and Supply Chain Management for Pediatric ARV • Quantification • Multiple formulations and sizes of pills • Minimum order sizes for some medications • Maintenance of cold chain/multiple definitions of ‘room temperature’ • Limited product information re stability especially at higher temperatures

21. Quantification in “Immature” Programs • Pediatric enrollment based upon pre-existing cohorts, success of pMTCT intervention, family factors: Difficult to predict • Needs for toxicity regimens and second line therapy hard to quantify with limited historical data from programs that rely on CD4 and not viral load

24. Supply Limitations • Minimum order size: e.g. nelfinavir • Not all dose sizes registered: e.g. efavirenz • Lead times for ordering additional dose sizes may not complement program needs

25. Multiple Formulations and Dose Size • E.g. D4t liquid; 15mg, 20mg, 30mg, 40mg tablets • Difficulty of managing and ordering small amounts of stock, especially with unpredictability of uptake/age of children

26. Pricing for Pediatric Formulations • Access prices limited for pediatric formulations • Limited generic competition • Registration status information limited • Registration status variable; international procurement agents have less flexibility to seek exception to lack of registration status

28. Baseline Characteristics HIV-Infected Children (N=276) No. (%) Child most recent pregnancy (<= 18 mos) 100 36% Child most recent pregnancy (> 18 mos) 33 12% Other children born to index woman 105 38% Other children living in household 38 14%

29. Baseline Characteristics HIV-Infected Children (N=276) CDC Immunologic Categories No. % No evidence of suppression 66 24% Moderate suppression 93 34% Severe suppression 96 35% Missing values 21 7%

30. Baseline Characteristics HIV-Infected Children (N=276) CDC/WHO Category % Category N 42% Category A/WHO l 22% Category B/WHO ll 26% Category C/WHO III 7% Missing 2%

31. Ever on ART 137 (50%) Currently on ART 129 (47%) For Children on ART: Median (min-max) time in program, n=137 239 days (15 days-574 days) Median (min-max) time since ARV initiation,n=137 167 days (1 day-574 days) Median (min-max) time to 1st ARV change, n=29 46 days (0 days*-415 days) # with at least one ARV switch29 (21% of ever on ARVs) Antiretroviral (ARV) Status in Children n=276