1. 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 cellphones Or email: kznpidu@gmail.com Paediatric Infectious Diseases Helpline

3. 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

5. 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

7. 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

8. Children (aged 0–14 years) living with HIV, globally Source: UNAIDS 2013 estimates.

9. Children with HIV in sub- Saharan Africa??? 1. Have a normal lifespan 2. Survive their 10 th birthday 3. Often die in infancy

10. 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

11. Opportunistic infection- related mortality among children living with HIV in the United States and Europe

12. 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

13. 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

14. OI causing death in USA Mycobacterium avium complex (MAC) Cryptosporidium –Pre ART major cause of death Pneumocystis jirovecii pneumonia (PCP) CMV –Remained stable

15. Opportunistic infections among children living with HIV in resource- limited settings

16. 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

17. 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 Settings Andrea J. Curtis1, et al PlosOne December 2012 | Volume 7 | Issue 12 | e52019

18. 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

19. Common childhood illnesses among children living with HIV

20. 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

21. 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

22. 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

23. HIV Care Cascade EMTCT

24. 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

25. 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%

26. 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

28. Prendergast AJ, et al. Arch Dis Child 2015;100(Suppl 1):s48–s52. doi:10.1136/archdischild-2013-305548

29. 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 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 200920122015 0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 New HIV infections 2012 coverage maintained ARV coverage scaled up to 90% Eliminate unmet need for family planning Reduce incidence by 50% Target

30. Diagnosis Optimal timing of HIV testing in children is a balancing act Need for early testing Sensitivity of test

31. 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

32. Virologic Testing and Mortality Rates in Neonates 1. Dunn DT, et al. AIDS 1995;9:F7–11; Birth2–4 weeks3–6 months Sensitivity55%90%100% Specificity99.8%100% Sensitivity and specificity of neonatal PCR

33. Early Infant Diagnosis WHO 2013 1 SA Guidelines 2 DHHS Guidelines 3 BHIVA 4 BirthXX (high risk)X 2–4 weeksX 4–6 weeksXX X (2 weeks post prophylaxis) 10 weeks X (1 month post prophylaxis) 12 weeks X (2 months post prophylaxis) 18 weeks X ( on 12 weeks NVP) 4–6 monthsX 6 weeks after stopping breastfeeding X (POST BF ONLY) X Symptomatic infantXXXX

34. Positive DNA PCR KZN – July 2014 Unpublished data,personal communication

35. 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 10325476981110 0 1000 2000 3000 4000 HIV-related deaths Age at death (months) 6-week PCR Results ART initiation under current recommendation of 6-week PCR test

36. Treatment Prendergast AJ, et al. Arch Dis Child 2015;100(Suppl 1):s48–s52. doi:10.1136/archdischild-2013-305548 First WHO Paed Guideline

37. 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.

38. 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 services 1. Boender TS, et al. AIDS Res Treat 2012;817506

39. 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

40. When To Start ART AgeWHO 2013 1 SA guidelines 2 DHHS (USA) 3 BHIVA 4 <1 yearStart all 1–3 yearsStart 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 yearsStart 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 yearsWHO 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 http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf http://www.sahivsoc.org/upload/documents/2013%20ART%20GuidelinesShort%20Combined%20FINAL%20draft%20guidelines%2014%20March%202013.pdfhttp://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdfhttp://www.bhiva.org/documents/Guidelines/Pregnancy/2012/hiv1030_6.pdf

41. 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

42. Mortality Rates Violari A, et al. IAS 2007 abstract WESS103 Variable Early Treatment (arm 2/3) n=252 Deferred Treatment (arm 1) n=125 Total n=377 Died (%)10 (4%)20 (16%)30 (8%) Person Years of follow-up 16779246 Rate per 100 PY (95% CI) 6.0 (2.9; 10)25.3 (15.5; 39.0)12.2 (8.2; 17.4) Hazard Ratio0.24 (0.11; 0.51) P-value0.0002

43. 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 Mortality Follow-up time (months) 03912182730161521243336 Intervention* 750,25% Always ART Estimated cumulative mortality for immediate 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/mm 3 or a CD4 of 25% 0 25 50 75 Follow-up time (years) 0123 100 Threshold reached (%)

44. What effect have these efforts had on reducing childhood AIDS - related mortality

45. 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

46. 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

47. Recommendations for prevention of opportunistic infections and common childhood illnesses among children living with HIV

48. Cotrimoxazole Dramatically reduce the risk of OIs –PCP and toxoplasmosis –Provide protection against common diseases such as malaria

50. 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

51. Interventions to decrease the burden of common childhood 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

53. 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 cellphones Or email: kznpidu@gmail.com Paediatric Infectious Diseases Helpline