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)