Paediatric HIV

Paediatric HIV

衛生署疾病管制局中區傳染病防治醫療網

王任賢指揮官

Objectives

At the end of this presentation participants should be able to:

• Understand the pathogenesis of HIV in infants and children

• Recognise common presenting features of paediatric HIV

• Understand the strategies for management of HIV-affected infants and children

• Appreciate the application of paediatric HIV/AIDS management in the Jamaican context

Philosophy

• Life-cycle / developmental approach to issues of diagnosis and treatment

• Public-health approach to management– Prevention of HIV– Prevention of acute illnesses / opportunistic

infections– Preservation of immune function– Improving quality of life– Palliative care issues

Historical perspective• Paediatric HIV first recognised in 1986 in Jamaica• ‘Pioneers’ who initiated individual ‘pockets’ of paediatric HIV care• 2002: Development of Pediatric Infectious Diseases Clinics in

Greater Kingston region coordinated by Prof CDC Christie & the implementation of the Kingston Pediatric & Perinatal ProgramOverall Aim: Reduce MTCT

Improve survival & QOL of infected children and adolescents

• 2003: Program received a major boost in therapeutic and laboratory support through Clinton HIV/AIDS Initiative and Global Fund

• 2003-present: Established clinics in St. Ann’s Bay, Cornwall Regional, Mandeville, and MayPen Hospitals through outreach and preceptorship training

0

10

20

30

40

50

60

70

80

90

Nu

mb

er o

f C

ases

Cases

Deaths

Cases 1 1 4 10 7 9 12 12 30 27 49 44 55 70 83 66 81 67 61

Deaths 1 0 1 7 6 7 7 5 23 21 17 25 35 36 34 27 45 29 34

86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000 2001 2002 2003 2004

JAMAICAPediatric AIDS Cases & Deaths (1982 - 2004)

Source: Ministry of Health, Jamaica

Historical perspective

Dramatic fall in incidence of new cases of paediatric infections in US

Paediatric ARV History

•1988 – monotherapy with AZT

•1994 – dual therapy

•1998 – triple therapy with HAART

http://www.cdc.gov/hiv/graphics/images/l262/l262-3.htm

Key differences from infected adults

• Perinatal transmission• Effect of virus on immature immune

system• Virologic response• CD4+ response – reliance on CD4% to

determine severity of immunologic deterioration

• Clinical presentation• Diagnostic challenge in < 18 months

Possible routes of transmission

In-utero At Birth During breastfeeding

Other modes of transmission

• Sexual – abuse, exploitation, experimentation, consensual

• Transfusion (rare in Ja)

• Intravenous drug use (rare in Ja)

Natural history of paediatric HIV

Newborns: most studies – generally well at birth

Virologic response: increases rapidly in initial 2-3 months then slowly declines to virologic set-point after several months to years

Immunologic response: brisk and variable T cell proliferation; hence cannot rely on absolute CD4+ as marker of immune deficiency; CD4+ percent <15% indicative of severe immune deficiency

Virologic set-point: state of in-vivo equilibrium between viral production and elimination

Time (years)

Vir

olo

gic

res

po

nse

Child

Adult

Infection


Asymptomatic Mild to Moderate

Severe

Pattern of Clinical Progression


Patterns of Progression

Rapid

20 %

Intermediate

70 %

Slow

10 %

Rapid Progressors

• PCP• FTT• CNS invovlement• Chronic GE• Recurrent infections• CMV infection• Persistent candidiasis

Progression to AIDS

Early onset – perinatal infections in infants < 12 months

Commonest manifestations:

• recurrent pneumonia• recurrent diarrhoea• growth failure• neurological abnormalities

Slow Progressors

• Generally well until late childhood

• Some completely asymptomatic

• Few---progress to AIDS

• Main problems : pneumonia / Lymphocytic interstitial pneumonitis (LIP), stunting

Clinical manifestations

Generalised, persistent lymphadenopathy

Dermatitis

Mucocutaneous Candidiasis

Recurrent lower respiratory tract infections

• Bacterial pneumonia• Community acquired

infections• Need to always

consider tuberculosis • Increased occurrence

of LRTI associated with LIP

Pneumocystis jiroveci pneumonia (PCP)

Lymphocytic Interstitial Pneumonitis

Chronic lung disease

Wasting / FTT / Malnutrition

Hepatosplenomegaly

Neurodevelopmental abnormalities

• Developmental delay• Developmental regression• Spasticity, hyperreflexia• Impaired cognitive function • CT scan brain: generalized

cortical atrophy with ventricular enlargement and calcified basal ganglia (arrow)

• (Ref. D. Carli C et al, Ann Neurol 34(2): 198-205, 1993.)

Clinical manifestations

• Recurrent or persistent upper respiratory tract infection, sinusitus or otitis media

• Parotitis • Recurrent diarrhoea• Bacterial sepsis• Organ-specific

dysfunction

CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR, 1994. 43 (No. RR-12): p. 1-10

Reducing the impact of HIV on children

AIM

Increase survival

&

Improve quality of life

Give a child a chance

Early Intervention is the key

Framework for a comprehensive approach to

manage HIV in infants children

Prevent HIV

in women

Prevent unintended

pregnancy inHIV + women

PreventMTCT

Provide accessible treatment, care and support for HIV-infected women, their infants and families

Key aspects of management

• Prevention of HIV infection• Early diagnosis• Early detection – high index of suspicion• Prevention (& timely treatment) of common

childhood illnesses• Prevention and early treatment of opportunistic

infections• HAART – preserve / restore immune system• Palliative care• Multidisciplinary management approach

Management of HIV-exposed infant

• ARV prophylaxis (pre- and post-exposure)• Breastfeeding alternatives• Follow-up and monitoring• PCP prophylaxis – Cotrimoxazole• Diagnosis of HIV infection• Immunizations – National EPI recommendations• Nutrition• Growth & development• Clinical evaluation for stigmata of HIV infection• Challenges – follow-up, adherence to prophylaxis,

stigma of non-breastfeeding

Diagnosis of HIV infection in exposed infant

• Serial qualitative DNA PCR is currently the accepted standard for early diagnosis

• DNA-PCR [2 consecutive readings]– 1-2 months– 3-6 months

• Antibodies (Elisa)– 12 months in non-breastfed infant

• Others – RNA PCR, p24, viral culture • Passive transfer of maternal Ig G leads to

detectable antibody in uninfected children for up to 18 months

• Antibody tests e.g.ELISA not diagnostic until 18 months unless negative

Lancet 2004; 364: 1865-71

Diagnosis of HIV infection in child

HIV Elisa with confirmatory Western blot

[> 18 months of age]

Classification of paediatric HIV/AIDS

CDC Clinical Category

• N – asymptomatic

• A – mildly symptomatic

• B – moderately symptomatic

• C – severely symptomatic – AIDS defining conditions

CDC 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR, 1994. 43 (No. RR-12): p. 1-10


CDC Immune Category

CD4%, and age-specific CD4 count

• 1 – 25% [none/mild suppression]

• 2 – 15 – 24% [moderate suppression]

• 3 – < 15% [severe suppression]


WHO Staging System • Clinical Stage 1 (asymptomatic)• Clinical Stage 11 (mild to moderate)

– Chronic diarrhoea– Candidiasis – FTT– Persistent fever– Recurrent severe bacterial infections

• Clinical Stage 111(severely symptomatic)– AIDS defining conditions– Severe FTT– Progressive encephalopathy– Malignancy– Recurrent sepsis

Comprehensive management of HIV-infected child

• Multidisciplinary management approach

• Prevention (& timely treatment) of common childhood illnesses– Regular ambulatory care– Growth & development monitoring– Immunizations – National EPI guidelines;

influenza, pneumococcal

• Nutrition & food safety

Comprehensive management of HIV-infected child

• Prevention and early treatment of opportunistic infections– Cotrimoxazole– Fluconazole– Azithromycin– Aciclovir– Isoniazid– IVIG

• Palliative care

Antiretroviral Therapy

Preserve and restore immune system

Who, when, what, how???

• Several guidelines: Caribbean, Jamaican, WHO, DHHS…………..

• Bottom-line issues for consideration

–Feasible–Accessible–Affordable–Safe–Sustainable

–Practical

Practical guidelines

• Any HIV-infected infant or child with AIDS defining condition or severe immunosuppression (CD4 < 15%)

• All HIV-infected infants < 12 months of age, regardless of clinical, immunologic or virologic parameters

• All others – discuss and consider treatment according to guidelines

Practical considerations

• Limited range of paediatric formulations in Jamaica

• Initiation of therapy & adherence in children is caregiver – dependent

• Treatment options are limited

• Aim for practical, simplified regimes

Effectiveness of interventions in treating

Paediatric HIV/AIDS

The Jamaican Experience

Collaborators

• Kingston Pediatric & Perinatal HIV/AIDS Program (KPAIDS) Team

• University of the West Indies; University Hospital of the West Indies

• Jamaica Ministry of Health – Bustamante Hospital for Children, Comprehensive Health Centre, Spanish Town Hospital, National AIDS Program

• Elizabeth Glaser Pediatric AIDS Foundation (EGPAF), Pfizer Foundation

Aim

To characterize the effectiveness of interventions in a cohort of HIV-infected children and adolescents attending Paediatric Infectious Diseases Clinics in Greater Kingston, Jamaica

Objectives

• Describe the demographic and clinical & immunological profile of the cohort

• Determine enrollment pattern and uptake of Antiretroviral therapy (ART)

• Characterize outcomes related to hospitalisations, bacterial and opportunistic infections, growth, morbidity and mortality

Methods

• Longitudinal observational cohort study

• Paediatric Infectious Diseases Clinics at UHWI, BHC, CHC & STH

• HIV-infected infants and children consecutively enrolled in KPAIDS Program

• Period: 1 Sept. 2002 to 31 Aug. 2005

• HIV status confirmed by HIV DNA pcr, Elisa/WB where appropriate

Methods

• Training of healthcare personnel• Development of unified protocols for clinical

management • Primarily ambulatory surveillance; also in-patient

consultations, case management• Data tracking and audit – morbidity, mortality,

hospitalisations, laboratory markers (haematology, biochemistry, cultures, immunology, flow cytometry, viral load)

• Dbase management; analysis-Excel, Access, SPSS, EpiInfo where indicated

Comprehensive Interventions

• Integrated multidisciplinary approach to ambulatory treatment & care

• Increased access to care• Inpatient consultations• Immunisation*, nutrition,

growth/development surveillance

• MOH Jamaica guidelines*

• Prophylaxis: Opportunistic Infections [bactrim, fluconazole, azithromycin, isoniazid, clotrimazole]; beclomethasone/ salbutamol MDI

• ARV counselling, treatment, adherence and AE monitoring

• High index of suspicion for TB

Results

‘ Actively’ Enrolled

~ 162

Total Enrolled196

Deaths

13

Transfer

7

Lost to Follow-up

12

Migration Overseas

2

Enrollment Profile

Enrollment Pattern

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20

25

30

35

40

45

Bef or e P r ogr am Y ear 1 Y ear 2 Y ear 3

Yearl

y E

nro

llm

en

t (%

)

Before Program

Year 3Year 2Year 1

GenderFemale

107 (54.6%) Male

89 (45.4%)

Age

At Enrollme

nt

Median 5.0 yr; Range <1 to 19.0 yr; IQR 2.2-8.1yr

Current Age

Median 6.0 yr; Range <1 to 20 yr; IQR 4.0-10.0 yr

Mode of transmission

MTCT 88.8%

Sexual 7.1%

Transfu-sion 1.5%

Unknown

2.5%

Clinic Site Population

UHWI 51.5%

BHC 32.6%

CHC 9.2%

STH 6.6%

Guardian StatusFamily Care151 (77%)

Institution Care45 (23%)

Characteristics of Cohort

Clinical & Immunological Profile

CDC Category Profile

CDC

N – asymptomatic

A – mild

B – moderate

C - severe

NA

BC

E nr ol lment

Last Visi t0

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60

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80

90

NA B

C

Enrollment

Last Visit

1995 2001 2002 2003 2004 2005

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

0.0

Year

CD

4

perc

en

t

ANOVA

F 1.015; p=0.318

CD4+

Median CD4+ percentage by year

ARV Uptake

0

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80

90

100

Before Program Year 1 Year 2 Year 3

Cu

mu

lati

ve p

rop

ort

ion

on

A

RV

(%

)

Before Program

Year 2 Year 3Year 1

ARV Uptake

ARV Uptake

yes

no

Ever on ARV

62%

38%

Ever on ARVYesNo

AZT/3TC/NVPAZT/3TC/INDAZT/3TC/EFVAZT/3TC/D4TAZT/3TC/ABC

0

20

40

60

80

100

12085%

6%1%2%6%

ARV UptakeRegime 1

Zidovudine LamivudineNevirapine

ARV Uptake

• ARV-experienced group:– Regime 2 – 10.7%– Regime 3 – 5 %– Regime 4 – 0.8 %

• Reasons for regime change: toxicity/AE (13), clinical failure (8), ‘financial’ limitations (3), optimisation (2)

• ~ 80% (ARV-naïve) currently on initial regime

Adherence levels for children on ART

1325.9

8774.1

100

0

20

40

60

80

100

120

Overall Family Care Residentialcare

Per

cen

tag

e o

f re

spo

nd

ents

(%

)

Adherent Non-adherent

Factors affecting adherence

Factors significantly associated with non-adherence:

1. Older age of child (r=0.428,p=0.001)

2. Missing clinic appointments (r=0.340, p=0.018)

3. Nausea (p=0.003)

Adherence to ART• Adherence to pediatric ART 87%• Adherence correlated with immune-

reconstitution, measured by CD4 counts/percent• Adherence in institutions better because of

directly observed therapy (DOT) • Main reasons for non-adherence in children on

ART are caregiver-related• Knowledge about ART excellent except

development of resistance• Predictors of non-adherence: Older age of child,

missing appointments, nausea

Growth Outcome

• Weight, height, BMI values standardized to z scores (CDC 2000 growth chart)

• Baseline, 6, 12, 24 months since initiation of antiretroviral therapy

-2 -1.8 -1.6 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0

Baseline

6 mos

12 mos

24 mosWeight for Age Z- Score

[Median]

Weight for Age

-1.2 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4

Baseline

6 mos

12 mos

24 mosWeight for Height Z- Score

[Median]

Weight for Height

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4

Baseline

6 mos

12 mos

24 mosBMI for Age Z- Score

[Median]

BMI for Age

-1.8 -1.6 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0

Baseline

6 mos

12 mos

24 mosHeight for Age Z- Score

[Median]

Height for Age

Hospitalisation Profile

Median 1.0 (Range 0 to 20) hospital admissions

IQR 0 – 3 admissions

Event Incidence (per 100 patient months of follow-up)

No ARV On ARV

Hospitalizations 11.02 5.93

Pneumonia 4.71 2.49

Presumed PCP 0.58 0.05

Culture-positive sepsis

1.29 0.33

Tuberculosis 0.67 0.14

Toxoplasmosis CNS 0.13 0

CMV retinitis 0.04 0

Cryptosporidiosis 0.09 0

Cryptococcal meningitis

0.04 0

Urinary tract infection

1.29 0.96

Incidence Density

Deaths

0

1

2

3

4

5

6

Frequency of Deaths

Year 1 Year 2 Year 3

Deaths by Cohort Year

Series1A

Summary

Enrollment

Hospitalisation

Median CD4%

Deaths

2002 20052003 2004

ARV UptakeGrowth

Conclusions

• Improved survival of HIV-infected children and adolescents

• Improved their quality of life

Conclusions

• Developed an ambulatory surveillance model for Paediatric

HIV/AIDS treatment & care in a developing country

• Focused on a Public Health Approach

• Integrated with existing resources in Jamaica

• Fostered an excellent collaboration with Jamaica MOH & National

HIV/AIDS Program

Future Directions

Future Directions

• Reducing MTCT to < 2%• Strengthening paediatric HIV/AIDS treatment &

care capacity in rest of Jamaica• Palliative care issues• Challenges

– Issue of viral resistance– Limitations for treatment options– Maturing cohort of infected adolescents – transition to

adult life– Sustainability of treatment and laboratory monitoring

Acknowledgements

MOH, National AIDS Program

All participating and facilitating institutions

KPAIDS Team

Children and their caregivers

Documents

Paediatric HIV