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 Enrollment into MTCT-Plus 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 Enrollment into pMTCT programs HIV-infected partners and children pMTCT programs 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 Enrollment February 2003 – August 2004 n=5540 Children (35%) Adults (65%)

6. Children MTCT-Plus Enrollment August 31, 2004 n=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 s tavudine (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 z idovudine –Large volume/dose a child grows –Often associated with nausea –Anemia common side effect For example didanosine –Must be taken on empty stomach?

10. Challenges: Limitations of Pediatric Formulations For example l opinavir/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 example Nelfinavir (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 1 st & 2 nd 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

22. CountryChildren<2 First 3 months basic; use 10kg average wt Add for 10% AZT tox 15% NVP tox Total Month 1- 3, Children <2 1: Thailand: not patented 15 children Azt 12.5ml BID 15x12.5x2x 90=33,750ml 3TC 5ml BID 15x 5x2x90=13,500 NVP 10 ml BID 15x 10x2 x 90= 27,000 NLF: 250mg tab (sprinkled) 3BID 3x2x3ptx90=1620 tab ABC 5 ml BID 5x2x3ptsx 90=2700ml AZT 33750 ml 3TC 13,500 ml NVP 27000 ml NLF 1620 tab ABC 2700 ml

23. CountryChildren <2 Month 4- 6 Basic (see total month 1- 3) Add for 20% failure Total Month 4-6 1: Thailand: not patented 15 children AZT 33750 ml 3TC 13,500 ml NVP 27000 ml NLF 1620 tab ABC 2700 ml Azt/3tc/nvp AND Azt/3tc/abc: 3 to: DdI 25 mg tab: D4T:3x12.5x2x90= 6750ml NLF 3x 3 tab BIDx 90=1620 tab Azt3tc/nlf to: 1pt DdI D4t Kaletra Azt/3c/abc to: 1 pt DdI d4t nlf AZT 33700 3TC 13500 NVP 27000

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

27. Item DescriptionPO Supplier CurrencyPriceVATGeneric/Patented Abacavir 20mg/ml oral sol/BOT-240mlUSD31.32noPatentedGSK Abacavir 300mg tabs/PAC-60USD72.90noPatentedGSK Didanosine 100mg tabs/PAC-60ZAR114.87noPatentedBMS S.A./IHD Didanosine 25mg tabs/PAC-60ZAR114.87noPatentedBMS S.A./IHD Didanosine 50mg chewable tablets,pack of 60 ZAR114.87noPatentedBMS S.A./IHD Efavirenz 200mg caps/PAC-90ZAR320.16noPatentedMerck/IHD Lamivudine 150mg tabs/PAC-60USD11.70noGenericRanbaxy Lamivudine 150mg+Zidovudine 300mg/PAC-60USD19.40noGenericRanbaxy Lamivudine oral sol. 10mg/ml/BOT-100mlUSD2.00noGenericCipla LPV+RTV oral sol. 400+100mg/5ml/BOT-60mlUSD41.10noPatentedAbbott Nelfinavir 250mg tabs/PAC-270CHF90.90noPatentedHoffmann LaRoche Nevirapine 200mg tabs/BOX-60USD7.80noGenericRanbaxy Nevirapine oral susp. 50mg/5ml/BOT-240mlUSD17.50noPatentedBoehr. Ingel. Stavudine 15mg caps/PAC-56EUR5.32noPatented BMS Africa Exp. Stavudine 20mg caps/PAC-60ZAR40.54noPatentedBMS S.A./IHD Stavudine 30mg caps/PAC-60ZAR40.54noPatentedBMS S.A./IHD Stavudine 40mg caps/PAC-60ZAR40.54noPatentedBMS S.A./IHD Zidovudine oral sol. 50mg/5ml/BOT-100mlUSD1.60noGenericCipla

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. Antiretroviral (ARV) Status in Children n=276 Ever on ART 137 (50%) Currently on ART129 (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 switch 29 (21% of ever on ARVs)