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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

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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

Challenges to pediatric antiretroviral treatment

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

Challenges to pediatric antiretroviral treatment

MTCT-Plus EnrollmentFebruary 2003 – August 2004n=5540

Children (35%)

Adults (65%)

Challenges to pediatric antiretroviral treatment

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 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

  • 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

  • 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

  • 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 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 2761

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 2762

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 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 switch29 (21% of ever on ARVs)

Antiretroviral (ARV) Status in Children n=276

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