1. Early diagnosis and treatment options for children living with HIV
Dr Siobhan Crowley
Paediatric & Family HIV Care
World Heath Organization,

2. Overview Progress Rationale for early diagnosis and treatment
Ways forward
Revised WHO recommendations

3. More children are receiving ART
Increased from 75,000 in 2005 to almost 200,000 in 2007
19 of 20 countries with highest PMTCT burden are in sub-Saharan Africa
90% of burden is in 20 countries
The number of children receiving ART increased form about 75,000 in 2005 to almost 200,000 in 2007, However, many children living with HIV are still not receiving treatment, and mortality among them remains high.
The estimation of need for ART will need to be revised based on these recent revised criteria for eligibility for ART in infants , hence coverage is not provided
Most children receiving ART are older and the mortality in the first few months of starting ART remains high, retention in care continues to decline beyond the first year , and most children are starting ART very late
Average age of children starting ART in the KIDS-ART-LINC Cohort Collaboration (17 participating clinics) was 4.9 years ( with only 12% <12-month)
70% - had severe immunodeficiency,
60% - started on a NNRTI based regimen
The 2-year risk of death on ART was 6.9% (95% confidence interval [CI]: ),
And was independently associated with:
baseline severe anaemia (adjusted hazard ratio [aHR]: 4.10 [CI: ]),
immunodeficiency (aHR: 2.95 [CI: ])
advanced clinical disease (aHR: 3.65 [CI: ]);
Risk of LTFU was 9.5% (CI: ), higher in children with severe clinical status. And persists out through the second year.
Only 8% of infants born to pregnant women with HIV in 2007 were tested for
HIV within the first two months of birth. In addition, only 4% of infants born
to women living with HIV initiated co-trimoxazole prophylaxis as indicated in
WHO guidelines.
Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

4. ART outcomes - more good news
National programmes reporting good outcomes
1 year survival estimated as 93-95%
2 year survival 91%

5. Country Treatment Outcomes Malawi #
5% mortality 6 mo, 13% at 12 mo
> Death & default in younger kids
Zambia
Overall 6.6 mortality, good CD4 responses, higher mortality in <18mo most early
Haiti #
81% in 12 mo, 9% mortality
Kenya
Decreased hospitalisation; 6-9 % mortality
Cote d'Ivoire
% mortality at 36 mo, RNA < 300 in 46-66%
Thailand #
Decreased hospitalisation; 5.7% mortality decreased to 0.6 after 24 wks
Tanzania
0% mortality (instutionalised orphans)
South Africa
8.6 % mortality most early; 80% RNA undetectable at 12 mo
15% mortality at 12 mo, 70% RNA < 400
MSF (Asia, Africa ) #
3% mortality/ 8% LFU at 12 mo;
7% still severe immunosuppression at 12mo
China
2% mortality, 55% RNA < 400 at 12 mo;
Cambodia #
92 % survival at 24 mo; 81% RNA undetectable
# programme reporting
Sutcliffe. Lancet Infect Dis 2008;8: 477–89

6. Children are Starting Treatment Late
Baseline Median Age
Baseline Median CD4
Janssens/Cambodia N=212
6.0 yrs 6%
George/Haiti
N=100
6.3 yrs
12%
Wamawala/Kenya
N=67
4.4 yrs
Reddi/S Africa
2007 N=151
5.7 yrs 8%
Puthanakit/Thailand N=107
7.7 yrs 5%
Kamya/Uganda
N=250
9.2 yrs
8.6%
Rouet/Cote d’Ivoire N=78
6.5 yr
Meta-analysis 1,195 children from 8 African clinical trials
53% >5 years of age, 70% severe immune deficiency, 12% aged < 12 months
(KIDS-ART-LINC)
Arrive 2008

7. Starting ART when severely immunodeficient increases mortality
Months from ART start
Probability of Death After Starting ART
Immune Deficient at Start ART
Not Immune Deficient at Start ART
6 months
7.8%
1.8%
12 months
8.2%
2.2%
6% excess mortality
Arrive E et al. 14th CROI, Los Angeles, CA, 2007 Abs. 727
73% median age > 5 years of age, > 50% start with severe immune deficiency, most deaths within 6 months of starting ART.
Risk factors for death:
low CD4
< 18 months age
WHO stage 3/4
Viral load greater than 6·0 log
severe malnutrition
Sutcliffe et al. Lancet Infect Dis 2008;8: 477–89

8. CHER STUDY : 76% Reduction in the Risk of Death with Immediate Compared to Deferred ART
0.00
0.20
0.40
0.60
0.80
1.00 3 6 9 12
P =
Deferred
Immediate
Most deaths occurred within
first 6 months (i.e., before age 10 months)
Failure Probability
16%
deferred
CHER: Trial recruited and enrolled 377 infants with confirmed HIV infection without advanced immune suppression between 6 and 12 weeks of age who had CD4 cell percentages equal to or greater than 25 percent. 
Eligible infants were randomly enrolled in one of three groups
immediate antiretroviral therapy (Zidovudine (AZT) + Lamivudine (3TC) + Lopinavir/Ritonavir (LPV/r) for 40 weeks,
immediate antiretroviral therapy for 96 weeks,
control group: ART was only initiated after doctors observed signs of clinical or immunological progression (e.g. CD4 cell percentage decline)
Deferring the start of ART until an infant has clinical or immunologic decline was the standard of care in South Africa; however, the specific immunologic and clinical criteria for starting therapy in this study were slightly different from South African or World Health Organization (WHO) guidelines, and were changed over time to reflect revised WHO recommendations.  In this study, ART is started or restarted when %CD4 dropped below 20 % for infants greater than one-year old or %25 for infants less than one-year old or if symptomatic and severe disease occurs as defined by (CDC) criteria. All participants followed a schedule of regular clinical visits for a minimum of 3.5 years, with the clinical team available 24 hours a day for consultation, referrals and advice. All children received Co-trimoxazole and Pneumococcal vaccine
Inclusion:
HIV DNA PCR confirmed HIV infection
CD4 >25%
ART naïve except for pMTCT
Age <12 weeks
ART Regimen: ART: ZDV + 3TC + LPV/r
On June 20, 2007, the DSMB reviewed the interim data and found a significant increase in survival among infants who received immediate ARV therapy (96 percent) compared to infants who received therapy later (84 percent) based on declining immune function linked to a defined CD4+ T-cell count and/or clinical progression. 
Based on this finding, the DSMB recommended that no additional infants be placed in the deferred-treatment arm of the study and infants in this arm be evaluated for potential initiation of ARV therapy. The DSMB also recommended that all infants enrolled in the study be followed for the planned duration of approximately 3.5 years.
20% breast fed
Endpoints:
Primary: Death OR failure of 1st line ART regimen
Secondary, including:
Cumulative rate of disease progression and hospitalisation
Grade 3 & 4 adverse events
Development of ART Resistance
Death rate per 100 person-years (Arm 2&3 vs 1)
3 months vs 41
3 to 6 months vs 23
6 to 12 months vs 9
Conclusions:
Starting ART before 12 weeks of age in HIV infected infants without sign of severe or advance immunodeficiency reduces early mortality by 75% 4%
immediate
Time to Death (months)
Patients at risk 52 99
145
213
252
Immediate 22 44 72
104
125
Deferred
Month 12
Month 9
Month 6
Month 3
Month 0

9. Entry points for children - Malawi
Kenya -
IPD 69%
Cote D' Ivoire
64% IPD
12% PMTCT
24% PLHA Index
18%

10. Southern Africa – HIV prevalence in population based surveys
Botswana
Swaziland
South Africa
Source: CSO, Measure DHS. Swaziland Demographic and Health Survey Preliminary report, NACA, CSO. Botswana AIDS Impact Survey II Central Statistics Office: Gaborone, Botswana, Shisana, O., et al., South African National HIV Prevalence, HIV Incidence, Behaviour and Communication Survey, HSRC Press: Cape Town, 2005.
SLIDE courtesy of E Gouws UNAIDS

11. only 8% of HIV exposed infants tested in 1st 2 months of life
only 4 % started on co-trimoxazole
We can only diagnose HIV in the first months of life using virological tests (HIV DNA PCR, HIV RNA PCR or bDNa or NASBA or ultrasenstive p24 antigen) As it takes some time to develop HIV infection and for HIV to start replicating, testing immediately at birth will not detect all those infants who HAVE HIV. To date the HIV DNA PCR is the only testing method that can be performed using DBS specimens ( i.e. and is therefore most useful in context of PMTCT follow up. HIV RNA methods are reliable can be done on plasma and whole blood specimens and are well suited to inpatient or sick infants where specimens using DBS are not essential) For ALL methods robust QA is required.
Estimation of proportion of truly infected infants detected by testing at certain ages if all infants are breastfed would produce numbers as below for South Africa , base don performance of HIV DNA testing
E.G.
South Africa Tot infected (BF) % missed diagnosis at time of testing of total if BF
Birth
1st week
2nd week
3rd week
4th week
6th week
2nd month
3rd month
4th month
5th month
6th month
The ongoing missed diagnosis reflects those who have recently acquired HIV through breastfeeding and are in the window period. Estimated numbers do not adjust for those who would have died. WHO therefore recommends to perform testing at or around 4-6 weeks for PMTCT follow up and whenever sick or HIV is suspected in infants known to be exposed.
Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

12. Ways forward Each infection can and should be prevented
Early diagnosis prior to disease progression
Earlier initiation of ART
Expand PITC and screening for HIV in health care facilities

13. WHO recommendations for provider initiated testing approaches infants & children
Population
Recommendation
Strength of recommendation
HIV exposure unknown
Ask all about HIV exposure as early as possible
Strong
Unknown HIV exposure High HIV burden
Ensure /maternal/ infant testing within first 6 weeks or at first contact with health system
Conditional – (HIV prevalence)
HIV exposed
Virological testing at 4-6 weeks of age
Any signs or symptoms suggestive of HIV
Age appropriate testing urgently
Sibling, parent or carer has HIV (family)
Age appropriate testing

14. WHO -new recommendations for starting ART in infants
All infants under 12 months of age with confirmed HIV infection should be started on antiretroviral therapy, irrespective of clinical or immunological stage.
GRADE Evidence profile = Moderate
Strength of Recommendation = STRONG

15. What ART to Start in infants – 2008 revision
NVP triple ART
No infant or maternal
ARV exposure
18%
34%
PI triple ART#
Sd NVP or NNRTI containing ART
MTCT ARV
Exposure
NVP triple ART
Non NNRTI exposure
Unknown infant
maternal MTCT
Exposure
NVP triple ART
# If no PI is available use NVP triple ART
Simplified weight based dosing availabe at;

16. Immunological thresholds to start ART
Age
%CD4
CD4/mm3 #
Infants < 1 yr
All- irrespective of CD4
12-35 months
<20
<750
36-59 months
<350
5 years or over
<15
As in adults
# Absolute CD4 count is naturally less constant and more age-dependent than %CD4;
it is not therefore appropriate to define a single threshold.

17. Thank you Please feel free to contact me if you need more information
Dr Siobhan Crowley
Acknowledgments:
HIV Care and treatment: Technical Reference group
Paediatric ARV dosing working group
WHO colleagues
Lynne Mofenson
Eleanor Gouws
F Dabis/V Leroy
Robert Gass/Patricia Doughty