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Paediatric HIV Research: Status, priorities and ethical considerations Dr Nigel Rollins Child and Adolescent Paediatric HIV Research: Status, priorities and ethical considerations Dr Nigel Rollins Child and Adolescent Health and Development, World Health Organization, Geneva 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, Acknowledgements Siobhan Crowley, Department of HIV Ying Lo Ru, Department of HIV Alasdair Reid, UNAIDS International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

2007 global HIV and AIDS estimates Children (<15 years) • Children living with HIV 2007 global HIV and AIDS estimates Children (<15 years) • Children living with HIV 2. 0 million [1. 9 – 2. 3 million] • New HIV infections in 2007 370 000 [330 000 – 410 000] • Deaths due to AIDS in 2007 270 000 [250 000 – 290 000] International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Progress has been made in treating children Estimated need as of 2006 ü More Progress has been made in treating children Estimated need as of 2006 ü More children are receiving ART ü Increased from 75, 000 in 2005 to almost 200, 000 in 2007 ü 19 of 20 countries with highest PMTCT burden are in sub. Saharan Africa Great variance within countries International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

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

Revised simplified dosing 1 ADULT FDC AM & PM 1 ADULT FDC AM & Revised simplified dosing 1 ADULT FDC AM & PM 1 ADULT FDC AM & 0. 5 PM 0. 5 ADULT FDC AM + PM 2 BABY FDC AM & 1 PM Same dosing irrespective of FDC, or same dosing for all three single ARV agents Most dose adjustments done in 1 st year 1 BABY FDC AM & 1 PM Adapted from T. NUNN International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Children everywhere are Starting Treatment Late Baseline Median Age Meta-analysis 1, 195 children from Children everywhere are Starting Treatment Late Baseline Median Age 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 Janssens/Cambodia 2007 N=212 George/Haiti Baseline Median CD 4 6. 0 yrs 6% 6. 3 yrs 12% 4. 4 yrs 6% 5. 7 yrs 8% 7. 7 yrs 5% 9. 2 yrs 8. 6% 6. 5 yr 8% 2007 N=100 Wamawala/Kenya 2007 N=67 Reddi/S Africa 2007 N=151 Puthanakit/Thailand 2007 N=107 Kamya/Uganda 2007 N=250 Rouet/Cote d’Ivoire 2006 N=78 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Starting late increases mortality Months from ART start Probability of Death After Starting ART Starting late increases mortality Months from ART start Probability of Death After Starting ART Immune Deficient at Start ART Not Immune Deficient at Start ART 6 months 7. 8% 6% excess mortality 1. 8% 12 months 8. 2% 2. 2% Arrive E et al. 14 th CROI, Los Angeles, CA, 2007 Abs. 727 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 CD 4 • < 18 months age • WHO stage 3/4 • viral load greater than 6· 0 log • severe malnutrition Sutcliffe et al. Lancet Infect Dis 2008; 8: 477– 89 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Research priorities • Early identification of infected children – Diagnostic / screening algorithms e. Research priorities • 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 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 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

TB/HIV • Children living with HIV are up to 20 times more likely to TB/HIV • 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Research priorities • Acute need for more research on TB in children, esp those 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Preventing HIV infection in infants and children Western & Eastern Europe Central Europe & Preventing HIV infection in infants and children Western & Eastern Europe Central Europe & Central Asia <200 North America <500 [<200] [<100] 3200 [2400 – 4300] East Asia Middle East & North Africa Caribbean 1800 [1500 – 2100] Latin America 4600 [4200 – 8300] 5700 [3800 – 8000] Sub-Saharan Africa 330 000 [300 000 – 360 000] 2000 [1200 – 3100] South & South-East Asia 21 000 [14 000 – 29 000] Oceania <1000 Total: 370 000 (330 000 – 410 000) 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 % Pregnant women with HIV who received ARV drugs to reduce mother-to-child transmission increased - 49% still received only single dose nevirapine Percentage of pregnant women with HIV receiving ARVs for PMTCT in low- and middle-income countries, 2004 -2007 Distribution of ARV regimens, 2007 Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008 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 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Preventing HIV infection in infants and children • • Primary prevention of HIV Prevention 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 HIV prevalence in pregnant women at first ANC visit, Thailand, 1991 -2007 Paediatric HIV infections in Thailand, 1994 -2007 Source: Strategic approaches to the prevention of HIV infection in infants. WHO 2002. International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Recommended first-line ART regimens for eligible pregnant women Mother Antepartum AZT + 3 TC Recommended first-line ART regimens for eligible pregnant women Mother Antepartum AZT + 3 TC + NVP twice daily Intrapartum AZT + 3 TC + NVP twice daily Postpartum AZT + 3 TC + NVP twice daily Infant * AZT 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Recommended ARV-prophylaxis for pregnant women not eligible for ART Mother Antepartum AZT Intrapartum Sd-NVP Recommended ARV-prophylaxis for pregnant women not eligible for ART Mother Antepartum AZT Intrapartum Sd-NVP + AZT/3 TC Postpartum AZT/3 TC for 7 days Infant * Sd-NVP + AZT for 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 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 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 CD 4 testing not available CD 4 testing available 1 Do not treat 2 Do not treat 3 Treat if CD 4 cell count < 350/mm 3 4 Treat irrespective of CD 4 cell count Treat if CD 4 cell count < 200/mm 3 1 Women have lower CD 4 cell counts during pregnancy compared to postpartum, partly due to pregnancy-related haemodilution. The impact of this on using CD 4 350 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

HIV and infant feeding technical consultation Geneva, October 25 -27, 2006 CONSENSUS STATEMENT • 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 HIVinfected women is recommended. 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 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 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) 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. 16 6 wks NVP Control sd NVP AHR 0. 56, p<0. 001 14 wks NVP Control sd NVP AZT x 7 Swen Study Team, Lancet 2008; 372: 300 -13, Kumwenda NI et al NEJM 2008; 10. 1056, International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Research priorities Maternal triple ARV regimens for prophylaxis • • • Impact of stopping Research priorities Maternal triple ARV regimens for prophylaxis • • • Impact of stopping triple ARVs on women's health Optimal regimens differentiated by maternal CD 4 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Research priorities • Extended infant ARV prophylaxis – Optimal duration and safety of prolonged Research priorities • Extended infant ARV prophylaxis – Optimal duration and safety of prolonged nevirapine, or other ARVs e. g. 3 TC, 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? International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

‘PMTCT’ • As a term it has – Constrained our understanding of what is ‘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’ International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

‘Integration’ ANC + PMTCT and family planning PMTCT and A/N services PMTCT and Prevention ‘Integration’ ANC + PMTCT and family planning PMTCT and A/N services PMTCT and Prevention services ANC + PMTCT and postnatal services Integrated mother and child health cards PMTCT and ART services ‘ 6 characters in search of an author. ’ Luigi Pirandello. 1921 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 How can effective interventions be scaled up to reduce infections to children and protect women? ? International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

From proof of principle to implementation • Cannot simply extrapolate practices implemented at one 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 International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

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

Why do academics and funders not, more commonly, engage these questions? • Implementation research 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 Do. H – multidisciplinary team • Different skills and perspectives 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 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 HIVinfected adolescents in order to achieve risk-reduction interventions for other? International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009

Other ethical challenges in paediatric HIV research • What responsibility do research centres have 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? International AIDS Society, Industry Liaison Forum, Montreal, 8 th February 2009