The challenge of growing up HIV

infected in resource-limited settings

Dr. Philippa Musoke

Department of Paediatrics

Makerere Unversity

Kampala Uganda

and

MUJHU Research Collaboration

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Outline

Paediatric HIV epidemiology

Challenges :

HIV Diagnosis

Morbidity and mortality

Malnutrition

Access and response to Antiretroviral therapy

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Paediatric HIV epidemiology

2.3 million HIV infected children worldwide

400,000 infants infected each year

90% are infected through Mother to Child Transmission

90% are found in sub-Saharan Africa

UNAIDS report 2010

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Data from African Perinatal Prevention Trials from

Breastfeeding HIV Transmission Study Meta-Analysis:

Mortality in Infected Children was 53% at 2 years

Median survival 1.6 years

By age 2.5 years, 60% mortality

Courtesy MG Fowler

Newell et al. Lancet 2004

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Stopped Breastfeeding

Continued Breastfeeding

Early Cessation of Breastfeeding Was Particularly

Harmful for Children Who Became HIV-Infected

p = 0.01

Survival of HIV-infected Children with Positive Results before Age 4 Months by Group Assignment (Abrupt vs Standard

Weaning)

Kuhn L et al. NEJM 2008

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Treatment of Pediatric HIV Infection in

Resource-Poor Countries is Often Significantly

Delayed, Resulting in Excess Mortality

Lack of identification of HIV infection in pregnancy

Lack of access to HIV DNA PCR testing using DBS

Lack of appropriate pediatric formulations

NVP exposure for PMTCT complicates 1st line ART

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Malnutrition and HIV infection

Most HIV infected children are malnourished

Median wt- and ht-for-age z-score <-2

In 30 different studies of children on ART (Sutclife)

30 – 50% of children hospitalized with severe acute malnutrition (SAM) are HIV+ (Bachou H)

Mortality of children with HIV and SAM is 4 times higher than those with SAM alone (30% vs 8%) (Fergusson P)

Severe pneumonia and SAM were risk factors for death in hospitalized children (Preidis GA J Pediatr 2011)

Fergusson P, et al Trans R Soc Trop Med Hyg 2008; Sutcliffe et al CG , Bachou H et al. Nutr J 2006,

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Severe malnutrition post ART

ARROW trial – Compared children who were hospitalized

with SAM ( both edematous and non-edematous types) and those not hospitalized

39/1207 (3.2%) were hospitalized (20 with edema)

Median days after ART initiation = 27 days 28 days (14-36) marasmus and 26 days (14 -56) for kwashiorkor

Children with advanced disease n =220 (CD4% & WAZ<-3 SD) 7.3% (95% CI 3.8–10.7) kwashiorkor (K)

3.2 % (95% CI 1.2–6.1) marasmus (M)

Mortality at 24 wks - 32% marasmus; 20% kwashiorkor

- compared to 1.7 % for non hospitalized children

Prendergast A et al AIDS 2011

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Increased Malaria morbidity

HIV infected (n=24)

HIV exposed (n=112)

HIV negative (n=406)

P value

Mean Haemoglobin

5.2 (2.9) 6.2 (2.7) 6.9 (3.5) 0.009

Hb < 6g/dl (%)

64 % 41%* 35%# 0.045*

0.008#

Mortality n(%) 8(33.2) 6(5.4) 13(3.2) <0.001

Davenport GC et al. Am J Hematol. 2010

542 children diagnosed with P falciparum malaria and admitted to hospital, Western Kenya

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Increase incidence of

Tuberculosis disease in HIV infected

children

Cohort of south African children randomized to INH or placebo(548 HIV+ and 804 HIV- infants) (Smith)

121 TB cases /1000 child-years (CI 95-153) HIV+

41 TB cases/1000 child-years (CI 31-52) HIV –

No benefit of INH prophylaxis

IRIS (20-30% of children on ART)

29% of IRIS events in children were TB –Uganda (Orikiriiza)

71% % of IRIS events in children were TB –S.Africa (Mahdi) Majority BCG adenitis

Mahdi SA et al NEJM 2011; Orikiriiza J et al AIDS 2009; Smith K et al AIDS 2009

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Challenge of TB/HIV co-infection

HIV infected children at higher risk of developing TB disease

More difficult to diagnose TB in HIV co-infected children

Interaction of anti-TB medications and ARVs

(Rifampicin lowers blood levels of NVP and Lopinavir/ritonavir)

Increasing the NVP to 200mg/m2/day or boosting the LPV/r with additional ritonavir is recommended

WHO ART guidelines for infants and children 2010

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Percentage of children accessing

Antiretroviral therapy

World wide - 38% of HIV infected children eligible for ART access therapy (Adults 43%)

Sub-Saharan Africa – 35 %

Latin America and Caribbean – 76%

South Africa and Botswana

ART coverage for children > adults

Botswana 80%

S Africa 65 %

UNAIDS report 2010

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

First line regimen in children from 36 low

and middle income countries (UNAIDS report 2008)

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Antiretroviral treatment response in

Resource-Limited Settings

3936 children aged < 5 yrs initiated HAART (MSF )

2971 were alive at time of analysis

90% from Africa and rest from Asia

50% were 12–35 months of age

Median duration on ART was 10.5 months (3.7 – 20.6)

Probability of remaining in care after 36 mths=0.75

Mortality-6.3% (249) Lost to FU-10.3% (407)

55% of all deaths occurred in the 1st 3-6 mths on ART

151 (3.8%) experienced severe drug toxicity

Sauvageot D et al Pediatr 2010

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Long term response to ART –Thailand

mortality: age < 1yr; CD4% < 5%; Wt-for-ht z score <-2

Collins I J et al CID 2010

N=578

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Monitoring response to ART in RLS

Weight measurement

Weight gain is an early sign of treatment response but does not predict treatment success

CD4 cell count

Most children have a good CD4 response on ART

May be available at regional centers

Viral load HIV-RNA

Not available in most RLS

Is VL needed for all children on ART(ARROW trial)

Sutcliffe CG et al Lancet Inf Dis 2008

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Challenges of ART

in children

4. PI syrups require refrigeration (Kaletra)

1. Splitting adult FDC tablets may be effective but not recommended now (O’Brien DP et

al AIDS 2006)

2. Adherence to syrups less than

tablets (Nahirya P - Abstract IAC 2010)

3. Need for dose adjustments as the child grows

Biadgilign S et al BMC Ped 2010 Vreeman RC et al PIDJ 2008 Nabukeera Barungi et al

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Burden of the limited paediatric antiretroviral

drug formulations

Months supply of ARV syrups

Fixed dose combination less bulky and easier to administer (single tabs vs FDC)

Photograph - Arrow Trial Uganda courtesy Bethany Naidoo

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Prevalence of Immune Reconstitution

Syndrome

Cohort of 162 Ugandan children on ART

38% ( CI 31-36) developed IRIS

Median Age 6 years (IQR 2.5-12 years)

Tuberculosis was the most common event=29%

Others - pruritic papular eruptions (PPE) , candida and pneumonia

Factors associated with IRIS

Male sex OR 2.96 (1.30-6.74)

Pre-ART CD4% OR 4.39 (1.62-11.08)

CD8+ < 1000 cells/ul OR 4.56 (2.01-10.34)

Cough(current) OR 4.30 (1.84-10.08)

Orikiriiza J et al AIDS 2010

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Lipodystrophy in Resource-Limited

Settings

Thailand

90 HIV+ children on ART (NNRTI)

Lipodystrophy – 9%, 47% and 65% at 48, 96 and 144 weeks

11% dyslipidemia

India

52 HIV + children ( 25 ART – non PI, 27 not on ART)

Only 4 had cholesterol

2 lipoatrophy, 3 triglycerides ( follow up 3 months)

Brazil

30 children (30% on PI) median duration on ART 28 mths

53% lipodystrophy, 60% dyslipidemia

Aurpibul L et al Antivir Ther 2007; Parakh A Indian J Pediatr; Sarni RO et al J Pediatr

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

ADOLESCENTS - cause of acute

hospitalization in Zimbabwe n= 139

Cause of admission HIV infected N=139 (%)

Bacterial infections (pneumonia, bacteraemia, etc)

65 (47)

Mycobacterial disease (MTB)*

25 (18)

Fungal disease (Cryptococosis* and candida)

35 (25)

Wasting syndrome* 15 (11)

Non-infectious(severe anemia) 53 (48)

Ferrand R et al PLoS 2010

Risk factors for death – pubertal delay and other chronic illness

* Top 3 causes of death

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Challenges in Adolescent HIV Care

Knowledge of HIV infection

Linking to (and retaining in) health care

Accepting (and adhering to) therapy

Mental health issues

Complexities of transition to adult care

High risk population for HIV transmission

40-60% of HIV-infected adolescents continue to engage in unprotected sex

Rice E et al. Prospect Sex Repro Health 2006;38:162-7

Murphy DA et al . J Adol Health 2001;29S:57-63

Sturdevant MS et al. J Adol Health 2001;29S:64-71

Kadivar H et al. AIDS Care 2006;18:544-9

Rotheram-Borus M et al. J Adoles 2001;24:791-802

Lightfoot M et al. Am J Health Behav 2005;29:162-71.

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Psychosocial challenges Multiple caretakers if orphans

Children become the caretakers to sick parents

Stigmatization in school

Depression and disclosure

Poverty

Lack of school fees

Transport

Skovdal M et al Global Health 2009

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Conclusion Despite multiple challenges, HIV infected

children can survive and their quality of life improved by:

Early infant diagnosis using DBS

Nutritional support including EBF

Early initiation of ART and adherence support

Appropriate ART formulations

Counseling and psychosocial support

There is a need for overall improvement in child health and survival if WE ….

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

A 12 year old girl before ART and one year later

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

GOD BLESS, THANK YOU Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Presented at the 3rd HIV pediatrics Workshop, 15 - 16 July 2011, Rome, Italy

Acknowlegements

Addy Kekitiinwa

Linda Barlow Mosha

Mary Glenn Fowler

Elaine Abrams

Children and caretakers in our care and treatment programs