1. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Paediatric HIV Research: Status, priorities and ethical considerations Dr Nigel Rollins Child and Adolescent Health and Development, World Health Organization, Geneva

2. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Acknowledgements Siobhan Crowley, Department of HIV Ying Lo Ru, Department of HIV Alasdair Reid, UNAIDS

3. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Children living with HIV2.0 million [1.9 – 2.3 million] New HIV infections in 2007370 000 [330 000 – 410 000] Deaths due to AIDS in 2007270 000 [250 000 – 290 000] 2007 global HIV and AIDS estimates Children (<15 years)

4. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 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 Progress has been made in treating children Estimated need as of 2006 Great variance within countries

5. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 ART outcomes - good news across the globe National programmes reporting good outcomes 1 year survival estimated as 93-95% 2 year survival 91%

6. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 1 ADULT FDC AM & PM 1 BABY FDC AM & 1 PM 1 ADULT FDC AM & 0.5 PM 2 BABY FDC AM & PM 2 BABY FDC AM & 1 PM 0.5 ADULT FDC AM + PM Same dosing irrespective of FDC, or same dosing for all three single ARV agents Most dose adjustments done in 1 st year Adapted from T. NUNN Revised simplified dosing

7. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Children everywhere are Starting Treatment Late Baseline Median Age Baseline Median CD4 Janssens/Cambodia 2007 N=212 6.0 yrs6% George/Haiti 2007 N=100 6.3 yrs12% Wamawala/Kenya 2007 N=67 4.4 yrs6% Reddi/S Africa 2007 N=151 5.7 yrs8% Puthanakit/Thailand 2007 N=107 7.7 yrs5% Kamya/Uganda 2007 N=250 9.2 yrs8.6% Rouet/Cote d’Ivoire 2006 N=78 6.5 yr8% 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

8. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Starting late increases mortality Months from ART startProbability 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 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 Arrive E et al. 14th CROI, Los Angeles, CA, 2007 Abs. 727 Sutcliffe et al. Lancet Infect Dis 2008;8: 477–89

9. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Early identification of infected children –Diagnostic / screening algorithms e.g. in IMCI –HIV testing algorithms –Universal screening at immunisation clinics Monitoring of disease progression / ART response in settings with minimal / intermittent lab support –Target weight gain –Clinic-based technology Feasibility of nurse-led ART initiation / management –Type and methods of support Research priorities

10. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Tuberculosis 1/3 of the world’s population is infected with TB Only 5-10% actually develop TB disease during their lifetime –Risk of progression highest in young children and soon after infection –Increased risk with HIV, malnutrition, immunocompromise One fifth of all TB cases occur in children and young people Approximately 11% of all TB cases occur in children <15

11. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Children living with HIV are up to 20 times more likely to develop TB than HIV negative children –Increased risk of exposure –Increased risk of progression from infection to disease TB is commonest cause of illness & death in people living with HIV in Africa Data on the situation in children are scant The burden of HIV in confirmed and clinical cases of TB in children ranges from 11-70% Main challenge is making a definitive diagnosis of TB in children TB/HIV

12. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Research priorities Acute need for more research on TB in children, esp those living with HIV –True burden of disease –Better diagnostics that don’t rely on sputum –Clarity on optimal regimens for treatment of TB and MDR TB in combination with ARVs –TB vaccine safety of BCG in children on ARVs New more effective TB vaccine

13. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Western & Central Europe<200[<100] Middle East & North Africa5700 [3800 – 8000] Sub-Saharan Africa 330 000 [300 000 – 360 000] Eastern Europe & Central Asia3200 [2400 – 4300] South & South-East Asia 21 000 [14 000 – 29 000] Oceania<1000 North America < <500 [<200] Latin America4600 [4200 – 8300] East Asia2000 [1200 – 3100] Caribbean 1800 [1500 – 2100] Preventing HIV infection in infants and children Total: 370 000 (330 000 – 410 000)

14. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 % Pregnant women with HIV who received ARV drugs to reduce mother-to-child transmission increased - 49% still received only single dose nevirapine Distribution of ARV regimens, 2007Percentage of pregnant women with HIV receiving ARVs for PMTCT in low- and middle-income countries, 2004-2007 Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

15. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Provider-initiated HIV testing and counselling increases access for PMTCT Percentage of pregnant women receiving an HIV test by region, 2004-2007 (low- and middle-income countries) Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

16. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Preventing HIV infection in infants and children Primary prevention of HIV Prevention of unwanted pregnancies Prevention of transmission from HIV-infected women to their infants Appropriate treatment, care and support Source: Strategic approaches to the prevention of HIV infection in infants. WHO 2002. HIV prevalence in pregnant women at first ANC visit, Thailand, 1991-2007 Paediatric HIV infections in Thailand, 1994-2007

17. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Recommended first-line ART regimens for eligible pregnant women Mother AntepartumAZT + 3TC + NVP twice daily IntrapartumAZT + 3TC + NVP twice daily PostpartumAZT + 3TC + NVP twice daily InfantAZT x 7 days* * If the mother receives < 4 wks of ART during pregnancy, give 4 wks of infant AZT Source: Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. WHO 2006

18. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Source: Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. WHO 2006 Mother Antepartum AZT IntrapartumSd-NVP + AZT/3TC PostpartumAZT/3TC for 7 days InfantSd-NVP + AZT for 7 days* * If the mother receives < 4 wks of ART during pregnancy, give 4 wks of infant AZT Recommended ARV-prophylaxis for pregnant women not eligible for ART

19. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Initiating ART is based on clinical and/or immunological assessment - only 12% of pregnant women were assessed for ART Recommendations for initiating antiretroviral treatment in pregnant women based on clinic stage and availability of immunological markers 1 WHO Clinical Staging CD4 testing not available CD4 testing available 1Do not treat Treat if CD4 cell count < 200/mm 3 2Do not treat 3TreatTreat if CD4 cell count < 350/mm 3 4Treat Treat irrespective of CD4 cell count 1 Women have lower CD4 cell counts during pregnancy compared to postpartum, partly due to pregnancy-related haemodilution. The impact of this on using CD4 350 threshold in pregnant women is not known. Source: Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. WHO 2006 Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, 2008

20. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 HIV and infant feeding technical consultation Geneva, October 25-27, 2006 CONSENSUS STATEMENT The most appropriate infant feeding option for an HIV-infected mother should continue to depend on her individual circumstances ………… Exclusive breastfeeding is recommended for HIV-infected women for the first 6 months of life unless replacement feeding is acceptable, feasible, affordable, sustainable and safe (AFASS) for them and their infants before that time. When replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breastfeeding by HIV- infected women is recommended.

21. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Maternal ARV prophylaxis studies antepartum and postpartum (Triple ARVs/ART) Between age 4-6 weeks and 6-7 months HIV transmission rates % TR at 6 months 4 observational studies showed reduced HIV breastfeeding transmission rates 6 mos EBF Courtesy: Lynne Mofenson

22. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Two randomized controlled infant ARV prophylaxis studies Negative at birth and 6 mos (SWEN) and 9 mos. (PEPI) HIV TR RR 0.80, p=0.16AHR 0.56, p<0.001 14 wks NVP 6 wks NVP Control sd NVP Control sd NVP AZT x 7 Swen Study Team, Lancet 2008; 372:300-13, Kumwenda NI et al NEJM 2008;10.1056,

23. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Maternal triple ARV regimens for prophylaxis Impact of stopping triple ARVs on women's health Optimal regimens differentiated by maternal CD4 Safety for the mother and the infant Transmitted HIV drug resistance to the infant Optimum duration of ARV prophylaxis (?until EBF discontinued or lifelong) Feasibility and cost Research priorities

24. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Extended infant ARV prophylaxis –Optimal duration and safety of prolonged nevirapine, or other ARVs e.g. 3TC, administration to HIV negative infants –Resistance and impact on prophylaxis and future treatment options in infants who become infected despite prophylaxis –Feasibility – under what circumstances would infant prophylaxis be preferred to maternal prophylaxis Infant feeding –Under what circumstances to recommend a woman to stop breastfeeding at about 6 months? –Can an infant be adequately fed from 6-12 months without any milk and still achieve normal growth and development? Research priorities

25. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 ‘PMTCT’ As a term it has –Constrained our understanding of what is needed –Focussed the outcome of value to be what happens to ‘the child’ –Partitioned service delivery Greater understanding of the relationship between treatment and prevention –Requires a different way of thinking, and organisation of services –To achieve HIV-free survival of the child, it is essential to protect maternal health and survival ‘Integrated Care of Women and Children in the context of HIV’

26. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 ‘Integration’ PMTCT and ART services ‘6 characters in search of an author.’ Luigi Pirandello. 1921 PMTCT and Prevention services ANC + PMTCT and postnatal services ANC + PMTCT and family planning PMTCT and A/N services Integrated mother and child health cards

27. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 How can effective interventions be scaled up to reduce infections to children and protect women? ?

28. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 From proof of principle to implementation Cannot simply extrapolate practices implemented at one pilot site (even 2-3 sites) and expect the same outcomes –Promotion of exclusive breastfeeding

29. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Implementation Research How do we get transmission below 5% at scale?

30. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Why do academics and funders not, more commonly, engage these questions? Implementation research not seen as a serious science Requires a different way of looking at problems - unfamiliar territory Out there – not in here Not in control (of the system) Needs to work with non-researchers and DoH –multidisciplinary team Different skills and perspectives

31. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Other ethical challenges in paediatric HIV research How to balance the child’s interests (survival) vs. the mother’s interests (confidentiality)? Developing models of care that might place child at risk because of dependency e.g. hospital or home for MDR / XDR TB Rx. How to assess understanding in the assent process? If effective vaccines are identified, how can these be given to infants or children in order to prevent infections in adolescence? How to respect the sexual and reproductive rights of HIV- infected adolescents in order to achieve risk-reduction interventions for other?

32. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009 Other ethical challenges in paediatric HIV research What responsibility do research centres have to help local services improve their quality of care vs. setting up parallel structures? Is it reasonable to research models of care that cannot be scaled-up to address the greater need?