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This advertisement was supported by the Grant Number U2G GH001142, funded by the U.S. Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the U.S. Centers for Disease Control and Prevention or the Department
of Health and Human Services
Referral or advice for children with:• HIV infection:
• Neonatal ART initiation• Treatment failure• Complications/Side-effects/Opportunistic infections.
• Tuberculosis:• Complicated Tuberculosis• Tuberculosis not responding to treatment• Complications or side-effects from treatment.
• Other Serious Infections or Suspected Primary Immunodeficiency
TOLL FREE NUMBER
0800 00 66 03 (Free from any TELKOM Line)
*Standard cellular rates apply to calls from cellphonesOr email: [email protected]
Paediatric Infectious Diseases Helpline
HIV related Paediatric Mortality
Dr M LawlerPaediatric Infectious Diseases
UKZN
Overview• Why do children die
• Global state of Paediatric HIV/ART
• Causes of death in Paediatric HIV population
• Best practices in Paediatric care:– Diagnosis– When to start– What to start
• Have HIV services reversed the trend enough to meet MDG 4?
• Preventing HIV-related deaths
What is the most common cause of death in children < 5?
1 Diarrhoeal disease
2 HIV related illness
3 Perinatal related issues
4 Road traffic accidents
HIV burden in children worldwide
• Globally, 3.2 million children under 15 were living with HIV in 2013
• 9.1% of all people living with HIV.
• Of these 91% live in sub-Saharan Africa• 6% in Asia and the Pacific • 3% rest of the world
• 240 000 children worldwide acquired HIV in 2013: one new infection every two minutes
Children (aged 0–14 years) living with HIV, globally
Source: UNAIDS 2013 estimates.
Children with HIV in sub-Saharan Africa???
• 1. Have a normal lifespan
• 2. Survive their 10th birthday
• 3. Often die in infancy
• Sub-Saharan Africa - > 50% die by age 2 years without ART
• Vs 8% of HIV-exposed uninfected infants
• With ART - mortality rates in HIV-infected children are estimated to be at least 30 times higher • OI• Common childhood illnesses
• Diarrhea• Pneumonia• Malaria• Malnutrition
Opportunistic infection-related mortality
among children living with HIV in the
United States and Europe
• PACTG and PACTS since 1997 – Decreased overall mortality and in OI-
related mortality after intro ART– Overall mortality declined to 0.8 deaths
per 100 person-years in the post-ART era from pre-ART rates of 7.2 to 18 deaths per 100 person-years
• UK and Ireland – Decrease in overall mortality from 8.2
deaths per 100 person-years before 1997 to 0.6 per 100 person-years by 2006
• OI deaths decreased dramatically with the advent of ART
• PACTS cohort – 31.8% of deaths prior to 1991– 16.9% in years of monotherapy and dual
therapy (1991–1996)– 9.1% when combination therapy was
available
OI causing death in USA
• Mycobacterium avium complex (MAC) • Cryptosporidium
– Pre ART major cause of death
• Pneumocystis jirovecii pneumonia (PCP)
• CMV – Remained stable
Opportunistic infections among
childrenliving with HIV in resource-limited
settings
• Thailand – 27% of all causes of mortality in the pre-
ART era (1989–2002) – Decreased to 5.7% in the post-ARTera
(2003–2009)
• Specific OIs– PCP and recurrent salmonella
septicaemia decreased– Mycobacterial and systemic fungal
infections increased
• Adults and Children
• WHO stage 3 or 4 conditions in Asia and Africa
• OI 14 times more than patients in a European cohort in the first 3 months after ART initiation
Incidence of WHO Stage 3 and 4 Conditions following Initiation of Anti-Retroviral Therapy in Resource Limited SettingsAndrea J. Curtis1, et al PlosOne December 2012 | Volume 7 | Issue 12 | e52019
• Even if ART is available– HIV-infected children in resource-limited
settings continue to experience high levels of morbidity and mortality from OI
– Alarcon JO, Freimanis-Hance L, Krauss M, Reyes MF, Cardoso CA, Mussi-Pinhata MM, et al. Opportunistic and other infections in HIV-infected children in Latin America compared to a similar cohort in the United States. AIDS Res Hum Retroviruses 2012; 28:282–288.
• 8 deaths per 100-child years vs approximately 0.8–0.9 deaths per 100 child-years in developed countries
• Highest burden of OIs – Africa– WHO stage 3 condition was three times
as high as in Asia
Common childhood illnesses among
children living with HIV
• Soweto, South Africa –Pneumonia, diarrhea, and malnutrition
–Prior to the availability of ART
• DRC–Causes of death in children on ART included septic shock and diarrhea
Diarrhea in HIV children
WHY• Underlying
immunocompromised state• Comorbid infections• Malnutrition
Persistent diarrhea• High risk of mortality
Restoration of immune function with ART is a critical component of prevention and treatment of diarrhea in children with HIV infection
Respiratory disease • Botswana
– 83% of deaths among HIV-infected children
– vs 27–42% in the United States
• Cape Town– Pneumonia was the most common
serious bacterial illness – Causes including Streptococcus
pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae
• Other causes PJP and CMV
HIV Care Cascade
EMTCT
Opinion
• Which part of the care cascade is the most important ie will impact the most on child outcomes
• 1. EMTCT• 2. EID• 3. Linkage to care• 4. Treatment• 5. Retention in care
EMTCT
2010 - ART initiation from 14 gestational weeks
• Lifelong treatment for women with CD4 counts <350 cells/μL
• CD4 >350 cells/μL – AZT monotherapy (Option A)
(2010)– Combination ART (Option B)
(2013)
• Eliminate new HIV infections among children by 2015
• Reduce HIV-related maternal mortality by 50%
• 2013 (2015)– Lifelong ART in pregnant and
breastfeeding women regardless of clinical stage or CD4 count (Option B+)
• AIM– Simplifying PMTCT implementation– Harmonising drug regimens used for
pregnant and non-pregnant populations– Avoiding treatment interruption– Covering future pregnancies
Prendergast AJ, et al. Arch Dis Child 2015;100(Suppl 1):s48–s52. doi:10.1136/archdischild-2013-305548
Global State of Paediatric ART
UNAIDS report on the global AIDS epidemic 2013. Available at: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf
Projected impact on new child HIV infections by programmes to prevent mother-to-child transmission,
21 Global Plan priority countries in sub-Saharan Africa, 2009–2015
2009 2012 20150
50,000
100,000
150,000
200,000
250,000
300,000
350,000
New
HIV
infe
ction
s
2012 coverage maintainedARV coverage scaled up to 90%Eliminate unmet need for family planningReduce incidence by 50%Target
Diagnosis
• Optimal timing of HIV testing in children is a balancing act
Need for early testing
Sensitivity of test
Question
• What are the current testing periods for HIV in children?
• 1. Birth,10 weeks, 18 weeks, 6 weeks after breastfeeding and 18 months, anytime if symptomatic
• 2. 6 weeks, 18 months• 3. Birth in high risk, 6 weeks, 4 weeks
after breastfeeding, 18 months• 4. 6 weeks, after breastfeeding, 18
months
Virologic Testing and Mortality Rates in Neonates
1. Dunn DT, et al. AIDS 1995;9:F7–11;
Birth 2–4 weeks 3–6 months
Sensitivity 55% 90% 100%
Specificity 99.8% 100% 100%
Sensitivity and specificity of neonatal PCR
Early Infant DiagnosisWHO 20131 SA
Guidelines2DHHS
Guidelines3 BHIVA4
Birth X X (high risk) X
2–4 weeks X
4–6 weeks X XX (2 weeks
post prophylaxis)
10 weeksX (1 month
post prophylaxis)
12 weeksX (2 months
post prophylaxis)
18 weeks X ( on 12 weeks NVP)
4–6 months X
6 weeks after stopping breastfeeding
X(POST BF
ONLY)X
Symptomatic infant X X X X
Positive DNA PCR KZN – July 2014
Unpublished data,personal communication
1 month
2 month
3 month
4 month
5 month
6 month
7 month
8 month
9 month
10 month
11 month
12 month
13 month
0
5
10
15
20
25
30
Percentage positive pcrsColumn1Column2
76% diagnosed in Hospital24% diagnosed in Clinic
Virologic Testing and Mortality Rates in Neonates
. Bourne DE, et al. AIDS 2009;23:101–6
Peak of mortality in South Africa & timing of virological testing & early treatment in different cohorts
10 32 54 76 98 11100
1000
2000
3000
4000
HIV
-rel
ated
dea
ths
Age at death (months)6-weekPCR
Results
ART
initi
ation
und
er c
urre
ntre
com
men
datio
n of
6-w
eek
PCR
test
Treatment
Prendergast AJ, et al. Arch Dis Child 2015;100(Suppl 1):s48–s52. doi:10.1136/archdischild-2013-305548
First WHO Paed Guideline
Percentage of adults (aged 15+) and children (aged 0–14) living with HIV who were receiving antiretroviral therapy in 2013, in 21 priority countries
Source: 2013 estimates from UNAIDS, WHO and UNICEF.
Chad
Cameroon
Democratic Republic of the Congo
Côte d’Ivoire
Ethiopia
Ghana
Nigeria
Burundi
Angola
Lesotho
United Republic of Tanzania (the)
Uganda
Malawi
Zimbabwe
Kenya
Zambia
South Africa
Namibia
Swaziland
Botswana
Children living with HIV are one third less likely to
receive antiretroviral therapy compared to
adults.
Key Barriers to Paediatric ART Initiation
• Individual level factors:1
– Fear and stigma
– Caregivers unawareness of HIV symptoms
– Living without parents
– Unemployment of the caregiver
– Lack of perinatal prophylaxis
– High transportation costs to the clinic
• Health system issues:
– Failure to link perinatal, well baby care to paediatric ART care
– Problems with diagnosis of paediatric HIV (especially <18 months)
– Healthcare worker
• Lack of identification of common HIV symptoms
• Reluctance to start ART in children – perceived to be complicated
– Poor decentralisation of services1. Boender TS, et al. AIDS Res Treat 2012;817506
When do we start ART in children
• 1. Less than 1 year
• 2. Less than 5 years
• 3. WHO Stage 3/4 or CD4 <350 cells/μl
• 4. All of the above
When To Start ARTAge WHO 20131 SA guidelines2 DHHS (USA)3 BHIVA4
<1 year Start all Start all Start all Start all1–3 years Start all Start all CDC B/C or
VL >100 000 c/mL or CD4 <1000 cells/μl/25%
CDC B/C or CD4 <1000
cells/μl/25%*
3–5 years Start all Start all CDC B/C or VL >100 000 c/mL
or CD4 <750 cells/μl/25%
CDC B/C or VL >100 000 c/mL
or CD4 <500 cells/μl/20%*
>5 years WHO Stage 3/4 or CD4 <500 cells/μl
(prioritize <350 cells/μl)
WHO Stage 3/4 or CD4 <350 cells/μl
CDC B/C or VL >100 000 c/mL
or CD4 <350 or 500 cells/μl
CDC B/C or CD4 <350 or
500 cells/μl
*consider VL >100 000 c/mL
1. WHO. The use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2013 revision. Available at: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf; 2. The South African Antiretroviral Treatment Guidelines 2013. Available at: http://www.sahivsoc.org/upload/documents/2013%20ART%20GuidelinesShort%20Combined%20FINAL%20draft%20guidelines%2014%20March%202013.pdf; 3. DHHS. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. July 31, 2012. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf; 4. BHIVA guidelines for the management of HIV infection in pregnant women 2012. Available at: http://www.bhiva.org/documents/Guidelines/Pregnancy/2012/hiv1030_6.pdf
Violari A, et al. IAS 2007 abstract WESS103
ART initiated before 12 weeks reduces early mortality in
young HIV-infected infants: evidence from the Children with HIV Early
Antiretroviral Therapy (CHER) Study
Avy Violari, Mark Cotton, Di Gibb, Abdel Babiker, Jan Steyn, Patrick Jean-Philippe, James McIntyre
PHRU, University of Witwatersrand; KID-CRU, Stellenbosch University; MRC-CTU UK; DAIDS NIAID, NIH
Mortality Rates
Violari A, et al. IAS 2007 abstract WESS103
VariableEarly Treatment
(arm 2/3)n=252
Deferred Treatment
(arm 1)n=125
Totaln=377
Died (%) 10 (4%) 20 (16%) 30 (8%)Person Years of follow-up 167 79 246
Rate per 100 PY (95% CI) 6.0 (2.9; 10) 25.3 (15.5; 39.0) 12.2 (8.2; 17.4)
Hazard Ratio 0.24 (0.11; 0.51)P-value 0.0002
When To Start ART in Children Aged 2–5 Years: A Collaborative Causal Modelling Analysis of Cohort Studies from Southern Africa
Schomaker M, et al. Plos Medicine 2013;10:e1001555
0.00
0.01
0.02
0.03
0.04
Mor
talit
y
Follow-up time (months)0 3 9 12 18 27 301 6 15 21 24 33 36
Intervention*750,25% Always ART
Estimated cumulative mortality forimmediate vs. deferred ART
*Estimated cumulative mortality (including 95% bootstrap CI, dashed lines) over 3 y if ART was given irrespective of CD4 count and CD4% (‘always ART’) and if ART was given if the CD4 count was below 750 cells/mm3 or the CD4% was below 25% (‘750,25%’)
Estimated probability of falling below a CD4 count of 750 cells/mm3 or a CD4 of 25%
0
25
50
75
Follow-up time (years)0 1 2 3
100
Thre
shol
d re
ache
d (%
)
What effect have these efforts had on reducing childhood AIDS - related
mortality
Decline in early life mortality in a high HIV prevalence rural area of South Africa: evidence of HIV prevention or treatment impact?James Ndirangua,et al AIDS 2010 24:593–602
South African child deaths 1990–2011: have HIV services reversed the trend enough to meet Millennium Development Goal 4?Kate J. Kerbera et al AIDS 2013, 27:2637–2648
U5M > 1990
Recommendations for prevention of
opportunistic infections and common
childhood illnesses among children living
with HIV
Cotrimoxazole
• Dramatically reduce the risk of OIs –PCP and toxoplasmosis –Provide protection against common diseases such as malaria
TB and Crypto
• IPT for all HIV-infected infants and children with a history of contact with a known TB case
• WHO does not recommend the use of fluconazole for primary prophylaxis of cryptococcal infection in children and adolescents
Interventions to decrease the burden of commonchildhood illnesses
• Routine immunizations – Pneumovacc and the Hib vaccine
• Prevent a large proportion of HIV-associated and non-HIV associated pneumonia in children
– South Africa• Reduction in invasive pneumococcal disease
attributed to pneumococcal conjugate vaccination was 60 times higher in HIV-infected
• Improving the health of families
This advertisement was supported by the Grant Number U2G GH001142, funded by the U.S. Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the U.S. Centers for Disease Control and Prevention or the Department
of Health and Human Services
Referral or advice for children with:• HIV infection:
• Neonatal ART initiation• Treatment failure• Complications/Side-effects/Opportunistic infections.
• Tuberculosis:• Complicated Tuberculosis• Tuberculosis not responding to treatment• Complications or side-effects from treatment.
• Other Serious Infections or Suspected Primary Immunodeficiency
TOLL FREE NUMBER
0800 00 66 03 (Free from any TELKOM Line)
*Standard cellular rates apply to calls from cellphonesOr email: [email protected]
Paediatric Infectious Diseases Helpline