ART during infancy

Brian Eley

Paediatric Infectious Diseases Unit

Red Cross War Memorial Children’s Hospital

Department of Paediatrics & Child Health

University of Cape Town

Black RE, et al.

Lancet 2010;375:1969-1987

Under-5 mortality, 1970-2010

Rajaratnam JK, et al. Lancet 2010;375:1988-2008

Under-5 mortality in SA, 2008 (Countdown to 2015 Decade Report (2000-2010)

Neonatal

29%

Diarrhoea

9%

Injuries, 2%

Pneumonia, 6%

Other, 9%

Preterm, 41%

Asphyxia, 23%

Infection, 18%

Other, 9%

Congenital, 8%

Tetanus, 1% Diarrhoea, 1%

Cumulative mortality of HIV-infected

children in sub-Saharan Africa

Newell ML et al. Lancet 2004; 364: 1236–43

0.6

0.5

0.4

0.3

0.2

0.1

0

0 100 200 300 400 500 600 700 800 900

Cumulative

probability

of death

Age at last visit or death (days)

Not infected (n=2183)

Infected (n=707)

Overall (n=3468)

Unknown HIV status (n=578)

Survival from time since infection for infection

perinatally and through breastfeeding

Marston M et al. Int. J. Epidemiol. 2011;40:385-396

Early infant mortality due to AIDS

Bourne DE, et al. AIDS 2009;23:101-106

Benefits of ART during infancy

CHER trial: mortality rates

Variable Immediate

treatment

(n = 252)

Deferred

treatment

n = 125

Total

(n = 377)

Death, n (%) 10 (4%) 20 (16%) 30 (8%)

Follow-up

(person years)

205 94 299

Mortality rate

per 100 person

years (95% CI)

4.9

(2.3; 9.0)

21.2

(13.0; 32.7)

10.0

(6.8; 14.3)

Comparison of early-therapy groups and deferred-treatment group:

Hazard ratio (95% CI): 0.24 (0.11; 0.51), p<0.001

Violari A, et al. N Engl J Med 2008;359:2233-2244

Benefits of early ART

Reduced Disease Progression1

Progression to CDC stage C or severe stage B: 26% (deferred-therapy group) vs 6%

(early-therapy group); HZ=0.25, 95% CI: 0.15-0.41, p<0.001

Lower BCG-IRIS incidence2

10.9 vs 54.3 per 100 person years in infants with CD4 ≥ 25% at enrolment on early-

therapy vs deferred-therapy group; HR=0.24, 95% CI 0.11-0.53,p<0.001; Infants with

CD4 < 25% at enrolment on early-therapy had intermediate incidence: 41.7/100py

Improved neurodevelopmental outcome3

Early ART (n=38) associated with better locomotor quotient s [p=0.010] and general

quotients on Griffiths Mental Development Scales [p=0.02] than deferred ART (n=77)

Reduced incidence of otorrhoea4

29% on deferred ART and 9% on early ART developed otorrhoea; risk ratio: 3.1, 95% CI

1.31-7.36, p=0.01

1Violari A, et al. N Engl J Med 2008;359:2233-2244 2Rabie H, et al. Int J Tuberc Lung Dis 2011;15:1194-200

3Laugton B, et al. 5th IAS Conference, 2009, Abstract no: MOPEB080 4Hainline C, et al. BMC res Notes 2011;4:448

Early ART initiation preserves memory B cells

Pensieroso S et al. PNAS 2009;106:7939-7944

Early ART maintains anti-measles and -tetanus

antibody titres above protective threshold

Pensieroso S et al. PNAS 2009;106:7939-7944

When should we start ART?

When to initiate ART?

Age categories < 24 mo ≥ 24 mo to 59 mo

≥ 5 yrs

When should ART be started?

All regardless of clinical / CD4

WHO 3 or 4, or CD4 ≤ 25%, or

CD4 < 750 cells/mm3

WHO 3 or 4, or CD4 <

350 cells/mm3

Strength of recommendation

Strong Strong Strong

WHO, 2010. http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf

Definition of early ART

• CHER: ART started between 6 & 12 weeks of

age1

– HIV DNA PCR positive

– Viral load > 1000 copies/ml

– CD4 ≥ 25%

• Ideal age for HIV DNA PCR testing2

– 4-6 weeks of life or at the earliest opportunity

thereafter

• ART during infancy should be regarded as an

urgent intervention without compromising pre-

ART preparations

1Violari A, et al. N Engl J Med 2008;359:2233-2244 2 http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf

Expedited ART initiation (fast tracking)

• Policy of NDoH since 25 February 2009

• Focuses on vulnerable groups of adults

and children

• Explicit recommendations:

– Vulnerable patients should not experience a

delay in referral to an ART site of > 1 wk

– ART should be started within 2-4 wks of entry

to ART site

NDoH memorandum, signed bt Dr ND Kalombo, 25 February 2009

Fast tracking HIV-infected infants

• Fast tracking should ideally imply that HIV-

infected infants are started on ART within 2 – 4

weeks of drawing blood for DNA PCR testing.

This implies: – Diagnosing HIV infection, giving post-test counselling and

referral of HIV-infected infants must be completed within 1 – 2

weeks of drawing blood for the DNA PCR test

– Pre-initiation preparations at the ART clinic should be completed

and ART commenced within a further 1 – 2 weeks

• Hospitalised HIV-infected infants: initiate ART

before discharge

Eley B. Sensitive Midwifery Nov 2010:16-18

How well are we doing?

Early diagnosis: 2009 - 2011 trends

Province Total PCR

tests: all ages

Total PCR tests:

<2 months

% of total PCR:

<2 months

% positivity: <2

months

Mar

2009

Dec

2011

Mar

2009

Dec

2011

Mar

2009

Dec

2011

Mar

2009

Dec

2011

EC 2,838 2,571 1,053 1,474 37.1% 57.3% 6.4% 2.6%

FS 1,175 1,207 435 751 37.0% 62.2% 9.2% 3.5%

GP 5,748 5,066 2,779 3,408 48.3% 67.3% 6.2% 2.6%

KZN 5,991 3,399 56.7% 2.2%

LP 1,699 1,855 676 1,136 39.8% 61.2% 9.5% 2.2%

MP 1,820 2,043 790 1,256 43.4% 61.5% 8.1% 2.5%

NC 298 330 123 165 41.3% 50.0% 7.3% 3.0%

NW 1,600 1,448 654 874 40.9% 60.4% 7.3% 2.4%

WC 1,673 1,428 912 1,071 54.5% 75.0% 3.1% 2.2%

Total 16,851 21,939 7,422 13,534 44.0% 61.2% 8.4% 2.5%

Courtesy of Gayle Sherman, NHLS routine statistics, January 2012

Paediatric ART cohorts in SA (Initiation on ART between 1 June 1999 and 29 February 2008)

Cohort Level of

care

1st year

of ART

Number

on ART

Median (IQR) age No (%) <1 yr

at initiation

Harriet Shezi All levels 2001 2183 55.9 (21.9-90.3) 328 (15.0)

Rahima Moosa All levels 1999 1023 44.0 (15.9-84.4) 202 (19.8)

Red Cross

Children’s

Tertiary 2001 839 16.1 (6.3-59.0) 351 (41.8)

Tygerberg Tertiary 2000 690 21.6 (8.5-59.0) 240 (34.8)

Khayelitsha Primary 2001 650 41.7 (20.3-74.2) 94 (14.5)

Gugulethu Primary 2001 262 47.1 (18.3-82.4) 42 (16.0)

McCord Secondary 2003 431 72.4 (33.0-109.2) 33 (7.7)

All cohorts All levels 1999 6078 42.7 (14.7-82.5) 1290 (21.2)

Davies M-A, et al. S Afr Med J 2009;99:730-737

Fatti, G, et al. J Acquir Immune Def Syndr 2011;58(3):e60-e67

Characteristics of Children Starting ART 2004-2009

Paediatric ART at RCWMCH & in WC

2007 2008 2009 2010 2011

New ART enrolments 196 213 229 204 170

New ART enrolment in WC 1019 1231 1180 860 475

% of total WC at RCWMCH 19.2% 17.5% 19.4% 23.7% 35.8%

ART enrolments < 6 mo 89

(45.5%)

126

(59.2%)

117

(51.5%)

93

(45.6%)

77

(45.3%)

Inpatient ART enrolments 127

(64.8%)

168

(78.9%)

196

(85.6%)

175

(85.8%)

138

(81.2%)

ICU ART enrolments 30

(14.1%)

40

(17.5%)

28

(13.7%)

19

(11.2%)

Down referrals 163 234 187 183 189

No. HIV outpatients at the

end of the year

337 310 310 313 283

Severe pneumonia in early infancy

Eley BS & Nuttall JJC , In Lala MM & Merchant RH; 2011:451-463

HIV-related deaths at RCWMCH

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Number 95 117 139 148 140 142 132 106 94 69 54 46

0

20

40

60

80

100

120

140

160

Nu

mb

er

A Westwood, personal communication

2002-2010: 68.9% decline in HIV-related deaths

2010: 46/354 (13.0%) deaths were HIV-related

Conclusion

Early diagnosis & treatment are essential

components of effective care for HIV-infected

infants

Increased ART coverage during early infancy

is required to reduce HIV-associated hospital

morbidity & mortality