Challenges to Pediatric Antiretroviral Treatment Elaine Abrams, David Hoos MTCT-Plus.
Post on 27-Mar-2015
214 Views
Preview:
Transcript
Challenges to Pediatric Antiretroviral Treatment
Elaine Abrams, David Hoos
MTCT-Plus
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
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
pM
TC
T p
rog
rams
MT
CT
-Plu
s
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
3626
1908
MTCT-Plus EnrollmentFebruary 2003 – August 2004
n=5540
Children (35%)
Adults (65%)
Children MTCT-Plus Enrollment August 31, 2004
n=1908
8%
92%
Other children
Children of Most Recent Pregnancy
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
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
Challenges: Limitations of Pediatric Formulations
• For example zidovudine
– Large volume/dose a child grows– Often associated with nausea– Anemia common side effect
• For example didanosine – Must be taken on empty stomach?
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
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
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
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?
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
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
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)
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
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
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
Country Children<2First 3 months basic; use 10kg average wt
Add for 10% AZT tox15% NVP tox
Total Month 1-3, Children <2
1: Thailand: not patented15 children
Azt 12.5ml BID 15x12.5x2x 90=33,750ml3TC 5ml BID15x 5x2x90=13,500NVP 10 ml BID15x 10x2 x 90= 27,000
NLF: 250mg tab (sprinkled)3BID3x2x3ptx90=1620 tabABC 5 ml BID5x2x3ptsx 90=2700ml
AZT 33750 ml3TC 13,500 mlNVP 27000 mlNLF 1620 tabABC 2700 ml
Country Children<2Month 4-6Basic (see total month 1-3)
Add for 20% failure
Total Month 4-6
1: Thailand: not patented15 children
AZT 33750 ml3TC 13,500 mlNVP 27000 mlNLF 1620 tabABC 2700 ml
Azt/3tc/nvp AND Azt/3tc/abc: 3 to:DdI 25 mg tab: D4T:3x12.5x2x90=6750mlNLF 3x 3 tab BIDx 90=1620 tab Azt3tc/nlf to: 1ptDdID4tKaletraAzt/3c/abc to: 1 ptDdId4tnlf
AZT 337003TC 13500NVP 27000
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
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
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
Item Description PO PO PO PO Supplier
Currency Price VAT Generic/Patented
Abacavir 20mg/ml oral sol/BOT-240ml USD 31.32 no Patented GSK
Abacavir 300mg tabs/PAC-60 USD 72.90 no Patented GSK
Didanosine 100mg tabs/PAC-60 ZAR 114.87 no Patented BMS S.A./IHD
Didanosine 25mg tabs/PAC-60 ZAR 114.87 no Patented BMS S.A./IHD
Didanosine 50mg chewable tablets,pack of 60 ZAR 114.87 no Patented BMS S.A./IHD
Efavirenz 200mg caps/PAC-90 ZAR 320.16 no Patented Merck/IHD
Lamivudine 150mg tabs/PAC-60 USD 11.70 no Generic Ranbaxy
Lamivudine 150mg+Zidovudine 300mg/PAC-60 USD 19.40 no Generic Ranbaxy
Lamivudine oral sol. 10mg/ml/BOT-100ml USD 2.00 no Generic Cipla
LPV+RTV oral sol. 400+100mg/5ml/BOT-60ml USD 41.10 no Patented Abbott
Nelfinavir 250mg tabs/PAC-270 CHF 90.90 no Patented Hoffmann LaRoche
Nevirapine 200mg tabs/BOX-60 USD 7.80 no Generic Ranbaxy
Nevirapine oral susp. 50mg/5ml/BOT-240ml USD 17.50 no Patented Boehr. Ingel.
Stavudine 15mg caps/PAC-56 EUR 5.32 no Patented BMS Africa Exp.
Stavudine 20mg caps/PAC-60 ZAR 40.54 no Patented BMS S.A./IHD
Stavudine 30mg caps/PAC-60 ZAR 40.54 no Patented BMS S.A./IHD
Stavudine 40mg caps/PAC-60 ZAR 40.54 no Patented BMS S.A./IHD
Zidovudine oral sol. 50mg/5ml/BOT-100ml USD 1.60 no Generic Cipla
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%
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%
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%
Antiretroviral (ARV) Status in Children n=276
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 switch 29 (21% of ever on ARVs)
top related