Care for HIVinfected Children

1
Care for HIV-infected Children

• Philippa Musoke
• Department of Paediatrics and Child Health,
  Makerere University
• And MUJHU Research Collaboration
• Uganda

2
Outline

• Epidemiology, Natural history
• OI Prophylaxis and Immunization
• Nutritional support
• Antiretroviral therapy guidelines for RLS
• Success and Challenges of HAART in children

3
Epidemiology

• 2.3 million HIV-infected children worldwide
• 90 found in sub-Saharan Africa
• 90 infected through MTCT
• High rates of seropositive pregnant women

4
Morbidity and Mortality Priorto HAART

• Developed world
• 18 die within 3 years
• 80-90 die after 8-9 years
• Sub-Saharan Africa
• 50 die by 2 years of age
• 70 die by 3 years of age
• 5-10 long term survivors

Newell ML, AIDS 2004, Barnhart HX Paediatr 1996,
Spira R 1999
5
Survival in the HAART Era

• USA
• 81 reduction in mortality from 1994 -1999 (Selik
  RM et al)
• Europe
• 80 reduction in mortality in Norway in the HAART
  era (Ormacisen V)
• Sub-Saharan Africa
• Botswana annual mortality reduced from 5 2003
  to 0.3 in 2006
• S. Africa HAART-90 1 yr survival in children
  (median age 5 yrs) 2007 (Reddi A)
• Asia
• Thailand 5 mortality in 1st 24 wks on HAART,
  0.6 in the next24 wks (median age 7yrs) 2007(
  Puthanakit T)

6
Ten Point Management PlanPaediatric HIV

• Early Diagnosis of HIV infection
• Growth and development monitoring
• Immunizations
• Nutritional supplements and education
• Psychosocial support
• Aggressive treatment of acute infections
• OI Prophylaxis and treatment
• Adolescent care, treatment and support
• Mother and family care and treatment (MTCT plus)
• Antiretroviral therapy as indicated

7
Early Diagnosis

• HIV RNA (plasma) and DNA PCR (cell pellet)
• Sensitivity and specificity increases with age of
  infant
• Sensitivity
• 29 in 1st week of life
• 79 in 1st month of life
• gt 90 after 1 month of life
• Specificity
• 93 before 3 months and 100 after 3 months
• Dried Blood spots for DNA PCR
• Have been used successfully in the field
• HIV DNA PCR at 6 -10 wks of age

8
Confirming HIV Positivity in Infancy

• Recommend at least 2 positive viral tests on
  separate specimens (HIV RNA or DNA PCR)
• However, clinical symptoms with a positive rapid
  test or ELISA can be used to identify infants for
  treatment (WHO)
• Final confirmation is at 18 months using the HIV
  ELISA or HIV rapid tests
• Early Infant diagnosis is critical for care
  treatment

9
OI Prophylaxis

• Prophylaxis for Opportunistic Infections
• Bacterial - co-trimoxazole
• Malaria/toxoplasmosis co-trimoxazole
• Mycobacterial - Isoniazid
• Cryptococcal fluconazole
• Herpes - acyclovir

10
MortalityChildren with HIV Antibiotic (CHAP)
Trial (Chintu C et al Lancet)
1.00
HR0.57 0.43-0.77 p0.0002
0.80
Proportion alive
0.60
Cotrimoxazole
Placebo
0.40
0
.5
1
1.5
2
Years from randomisation
265
232
177
106
47
Cotox
269
211
143
72
29
Placebo
11
Co-trimoxazole for prevention of malaria in
HIV-infected children
12
Co-trimoxazole Prophylaxis Recommendation

• HIV exposed infants until 12 months of age
• Start at 4-6 weeks of age or at earliest contact
  with clinic
• Stop if confirmed HIV negative at 12 -18 months,
  at least 6 wksafter BF
• All HIV-infected children lt 1 year of age
• HIV Children 1- 5 years clinical WHO stage 2, 3,
  4,
• Children gt 5 yrs can use adult recommendations
• Other indications2o prophylaxis after an acute
  episode of PCPSame dose used for bacterial
  prophylaxis (5mg TMP/kg/day)
• Alternative dapsone-2mg/kg/dose
• In practice most RLS countries recommend
  prophylaxis- regardless of CD4 cell count
  

WHO Guidelines for OI
13
INH Prophylaxis

• Recommended in HIV-infected adults with pos. PPD
  skin test
• Most RLS countries not implementing
• Most national TB programs recommend INH
  prophylaxis for children lt 5 yrs exposed to an
  adult with sputum for TB
• HIV-infected children at highest risk of
  developing TB
• No standard recommendation of INH prophylaxis in
  HIV-infected children
• One study completed another ongoing

14
Benefit of INH prophylaxis

• 263 children
• 50 INH arm
• Median FU 5.7 (2 - 9.7)mths
• Results
• Mortality 8 in INH and 16 PL (HR 0.46)
• TB incidence 5 cases INH and 13 cases PL
• (HR 0.28 p0.005)
• Cx confirmed TB all in PL arm

Zar HJ et al BMJ 2007
15
Immunisations

• All EPI Vaccines
• BCG, DPT, OPV, HIB, Hep B Measles
• New BCG recommendation
• Avoid BCG vaccine in HIV-infected
  children(associated with disseminated BCG
  disease)
• Newer vaccines
• Pneumococcal conjugate vaccine
• Rotavirus vaccine

16
BCG in HIV-infected children

• Increased incidence of BCG adenitis
• Increased incidence of disseminated BCG
• Regardless of whether they are symptomatic or
  asymptomatic

17
BCG adverse event in HIV-positive child
Courtesy G Hussey
18
Current WHO Recommendations

• Whether or not HIV-infected infants are
  symptomatic, they should NOT be immunized with
  BCG

19
Newer Vaccines

• Pneumococcal conjugate vaccine
• HIV-infected children have reduced antibody
  responses
• Recommended in HIV-infected children
• Still expensive so not available in most RLS
  countries
• Rotavirus vaccine
• Expensive but should be recommended for all
  children in RLS countries
• No studies in HIV-infected children

20
Nutritional Supplementation

• Some HIV-infected children are severely wasted
  and stunted ( gt -2 SD WAZ and HAZ)
• 40-50 of children admitted with severe
  malnutrition are HIV infected
• Plumpynut and F75 and F100 are recommended for
  severe malnutrition
• Nutritional supplementation is an integral part
  of care and treatment of HIV-infected children
• Macronutrient and micronutrient

21

• AntiretroviralTherapy in Children

22
Children are NOT small Adults - clinically,
immunologically, virologically

• Most children are vertically infected
• Immature immune system but active thymus
• Faster rate of disease progression
• High HIV-1 RNA viral load, especially in infants
• Good immunologic response to ART
• CD4 cell count high and variable in young
  uninfected children CD4 less so
• Implications for ART decisions and monitoring

Courtesy Di Gibb, MRC UK
23
Children are NOT small Adults - Drug handling

• Drug dosing varies with size and age
• Dose adjustment by size (weight / surface area)
• Age important even after adjusting for size
• Adherence and tolerability of drugs
• Tolerability of formulations varies with age
• Adherence depends on caregivers

Courtesy Di Gibb, MRC UK
24
How do differences in children impact on ART
management strategies

• ART pharmacokinetics, tolerability and toxicity,
  formulations and regimens
• Strategies for using ART in children
• When to start?
• What to start with?
• How and when to switch?
• Can ART be stopped?
• Maintain efficacy while minimising toxicity
• Efficacy of ART following perinatal exposure
  

25
Paediatric antiretroviral therapyin RLS

• Inadequate early infant HIV diagnosis testing
  centers
• Limited appropriate paediatric formulations
• Dose based on weight and weight changes as child
  grows
• Inadequate number of trained healthcare workers
  comfortable with treating children
• Adherence dependent on the caregiver who may
  change from time to time
• Resources mainly focused on adult ART with
  management of children lagging behind

26
WHO 2006
27
Age-specific recommendationto initiate ART
WHO pediatric guidelines ART 2006
28
Probability of Death within 1 year by TLC in
Ugandan cohort
29
1st line Regimens (WHO 2006)

• 2NRTI NNRTI
• ZDV 3TC NVP/ EFV ( EFV gt10kg)
• d4T 3TC NVP/ EFV ( EFV gt10kg)
• ABC3TC NVP/ EFV ( EFV gt10kg)
• Fixed Dose Combinations (adult tablets)
• d4T3TCNVP AZT/3TC/NVP AZT/3TC/ABC
• OptionTriple NNRTI AZT3TC ABC may be used for
  simplification(beware lower virological
  efficacy if used initially)
• Recently Paediatric FDC available - WHO
  pre-qualified, available through the Clinton
  Foundation

30
Failure in Children on HAART

• Clinical
• Poor weight gain, new OI, new stage 2, 3 or 4
  disease
• Immunological
• Reduction in CD4 or cell count to baseline or
  below
• lt 50 of peak CD4 or absolute count
• CD4 indicative for severe immunosuppression for
  age
• Virological
• Must have at least 6 months of an effective
  regimen
• Adherence checked
• Depends on baseline viral load and age

WHO 2006
31
2nd line regimens (WHO 2006)

• If first lineAZT /d4T 3TC NNRTI? ABCddI
  LPV/rABC3TC NNRTI? AZTddI LPV/r
  (can also continue 3TC)
• Limited access to ABC, TDF, (and enfuvirtide)
• Do not use d4TddI because of toxicity

32
Monitoring HAART in RLS

• Growth - Wt, Ht nutritional status (z-scores)
• Neurological improvement
• Developmental milestones
• Lab CD4, CD4 cell count and viral load

33
Adherence Measures
Nabukera et al
34
Early Initiation of HAART in Infants Improves
Survival

• CHER TRIAL !!

35
CHER Primary Objective

• To compare time to failure of 1st line ART (due
  to clinical progression, immune deterioration or
  ART-limiting toxicities) or death among 3
  randomized arms
• Infants who defer treatment until they develop
  clinical or immunologic criteria
• Infants who start ART at 6-12 weeks of age,
  continue for one year and stop
• Infant who start ART at 6-12 weeks of age,
  continue for two years and stop

36
CHER Time to Death in Deferred ART (Arm 1) vs
Immediate ART (Arms 2 3)
1.00
P 0.0002
0.80
Failure Probability
0.60
0.40
0.20
0.00
0
3
6
9
12
Time to Death (months)
Patients at risk
37
Risk of Death with Deferred ART (Arm 1) vs
Immediate ART (Arms 2 3)

• Death rate per 100 person-years
• Arms 23 Arm 1
• 3 months 10 vs 41
• 3 to 6 months 4 vs 23
• 6 to 12 months 3 vs 9

38
Relying on cutting tablets in half isnot always
feasible
39
Blister Packs make administrationof drugs easier
40
Response to HAART after sdNVP exposure at
birth
41
Single-Dose NVP Prophylaxis is Associated with
Acquisition of NVP Resistance in Infants Failing
ProphylaxisAZT and no Maternal NVP Dose May
Reduce Resistance
SD NVP
AZT SD NVP
100
SD NVP, no maternal SD NVP
87
80
60
with Resistance
40

20
0
Thai
S Africa (NO
Cote
Thai
Malawi
Thai
S Africa
S Africa
HIVNET 012
SAINT
Malawi
mom NVP)
d'Ivorie
(NVAZ NO
(with mom
(NVAZ with
mom NVP)
NVP)
mom NVP)
Clade E,B C A E,B
C E,B C C A,D C
C CRF01,
06
42
Lockman S et al NEJM 2007
43
Response to NVP-containing HAART in sdNVP
exposedvs non-exposed children
N 30 NU 22 NE
44
Summary

• Need to
• Provide PMTCT to all HIV-positive women
• Diagnose HIV early
• Provide CTX prophylaxis regardless of CD4 count
• Initiate HAART early to reduce mortality
• Monitor adherence closely
• Provide psychosocial support