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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

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Challenges to pediatric antiretroviral treatment

Challenges to Pediatric Antiretroviral Treatment

Elaine Abrams, David Hoos


What is the mtct plus initiative
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

pMTCT programs

Enrollment into pMTCT programs

Enrollment into


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


Fundamentals of mtct plus
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

MTCT-Plus EnrollmentFebruary 2003 – August 2004n=5540

Children (35%)

Adults (65%)

Children MTCT-Plus Enrollment August 31, 2004n=1908

Other children

Children of Most Recent Pregnancy

Challenges to pediatric art
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
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 formulations1
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?

Challenges limitations of pediatric formulations2
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 formulations3
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

Challenges using adult formulations
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
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
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
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
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
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
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
Quantification in “Immature” Programs Pediatric ARV

  • 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

Supply limitations
Supply Limitations Pediatric ARV

  • 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
Multiple Formulations and Dose Size Pediatric ARV

  • 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
Pricing for Pediatric Formulations Pediatric ARV

  • 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

Baseline characteristics hiv infected children n 276
Baseline Characteristics Pediatric ARVHIV-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 2761
Baseline Characteristics Pediatric ARV 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 2762
Baseline Characteristics Pediatric ARV 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 Pediatric ARV 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