The challenge of growing up HIV infected in resource-limited settings

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1 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

2 Outline Paediatric HIV epidemiology Challenges : HIV Diagnosis Morbidity and mortality Malnutrition Access and response to Antiretroviral therapy

3 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

4 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

5 Early Cessation of Breastfeeding Was Particularly Harmful for Children Who Became HIV-Infected Survival of HIV-infected Children with Positive Results before Age 4 Months by Group Assignment (Abrupt vs Standard Weaning) Continued Breastfeeding Stopped Breastfeeding p = 0.01 Kuhn L et al. NEJM 2008

6 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 1 st line ART

7 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,

8 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 ) kwashiorkor (K) 3.2 % (95% CI ) marasmus (M) Mortality at 24 wks - 32% marasmus; 20% kwashiorkor - compared to 1.7 % for non hospitalized children Prendergast A et al AIDS 2011

9 Increased Malaria morbidity 542 children diagnosed with P falciparum malaria and admitted to hospital, Western Kenya 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) Hb < 6g/dl (%) 64 % 41% * 35% # * # Mortality n(%) 8(33.2) 6(5.4) 13(3.2) <0.001 Davenport GC et al. Am J Hematol. 2010

10 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 ) 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

11 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

12 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

13 First line regimen in children from 36 low and middle income countries (UNAIDS report 2008)

14 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 months of age Median duration on ART was 10.5 months ( ) 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

15 Long term response to ART Thailand mortality: age < 1yr; CD4% < 5%; Wt-for-ht z score <-2 N=578 Collins I J et al CID 2010

16 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

17 Challenges of ART in children 1. Splitting adult FDC tablets may be effective but not recommended now (O Brien DP et al AIDS 2006) 4. PI syrups require refrigeration (Kaletra) 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

18 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

19 Prevalence of Immune Reconstitution Syndrome Cohort of 162 Ugandan children on ART 38% ( CI 31-36) developed IRIS Median Age 6 years (IQR 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 ( ) Pre-ART CD4% OR 4.39 ( ) CD8+ < 1000 cells/ul OR 4.56 ( ) Cough(current) OR 4.30 ( ) Orikiriiza J et al AIDS 2010

20 Thailand Lipodystrophy in Resource-Limited Settings 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

21 ADOLESCENTS - cause of acute hospitalization in Zimbabwe n= 139 Risk factors for death pubertal delay and other chronic illness Cause of admission Bacterial infections (pneumonia, bacteraemia, etc) HIV infected N=139 (%) 65 (47) Mycobacterial disease (MTB)* Fungal disease (Cryptococosis* and candida) 25 (18) 35 (25) Wasting syndrome* 15 (11) Non-infectious(severe anemia) 53 (48) * Top 3 causes of death Ferrand R et al PLoS 2010

22 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: Lightfoot M et al. Am J Health Behav 2005;29:

23 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

24 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.

25 A 12 year old girl before ART and one year later

26 GOD BLESS, THANK YOU

27 Acknowlegements Addy Kekitiinwa Linda Barlow Mosha Mary Glenn Fowler Elaine Abrams Children and caretakers in our care and treatment programs