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: kznpidu@gmail.com

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: kznpidu@gmail.com

Paediatric Infectious Diseases Helpline