1. Cost-effectiveness of early infant HIV diagnosis and immediate antiretroviral therapy in HIV- infected children <24 months in Thailand IJ Collins 1,2, J Cairns 3, N Ngo-Giang-Huong 1, W Sirirungsi 4, P Leechanachai 4, S Le Coeur 1, 5, N Kamonpakor 6, J Mekmullica 7, S Shabbar 2, G Jourdain 1, M Lallemant 1, for the Programme for HIV Prevention and Treatment (PHPT) study team 1 Institut de Recherche pour le Développement (IRD) UMI 174-PHPT, France - Faculty of Associated Medical Sciences, Chiang Mai University, Thailand - Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, USA, 2 Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine (LSHTM), UK; 3 Faculty of Public Health and Policy, LSHTM, UK; 4 Faculty of Associated Medical Sciences, Chiang Mai University, Thailand, 5 Unité Mixte de Recherche 196 Centre Français de la Population et du Développement (INED-IRD-Paris V University), Paris, France, 6 Somdej Prapinklao Hospital, Thailand, 7 Bhuminbol Adulyadej Hospital, Thailand Program for HIV Prevention and Treatment IRD 174/PHPT

2. Background In 2012, 290,000 children were newly infected with HIV. Without ART, up to 50% will die by two years of age in resource limited settings. CHER trial: immediate ART in infants aged <12 weeks reduced mortality by 76% as compared to deferred treatment. WHO(2010) recommends immediate ART in HIV+ children <24 months. Early infant HIV diagnosis (EID) is essential for early ART. As maternal antibodies persist for up to 18 months, EID requires more complex and costly diagnosis tests. Estimated 35% of HIV-exposed infants received EID by 2 months-old. Coverage of ART in children is disproportionately low at 34%. No data on cost effectiveness EID and immediate ART. Important to inform decision makers facing competing health demands. WHO Progress Report 2013, Violari et al. NEJM 2008.

3. Objective To assess the cost effectiveness of early infant HIV diagnosis and immediate ART in HIV infected children, in a non-breastfed population in Thailand, comparing: 1)EID and immediate ART in HIV+ children <24 months (Early-Early) 2)EID and deferred ART based on immune/clinical criteria (Early-Late) 3)Clinical based diagnosis or serology at 18 months, and deferred ART based immune/clinical criteria (Late-Late, Reference)

4. Setting: Thailand Free ART under universal health coverage. Pilot EID programme from 2007, 68% coverage. DNA PCR using dried blood spot (DBS) accessible for rural hospitals and community health clinics. First test at 2 months or earlier if symptomatic. If test positive repeat immediately, if negative repeat at 4 months. Estimated cost EID: $32 per test (including infrastructure, human resources, QA etc.) Naiwatanakul et al. IAS 2012; Sirirungsi et al. Pead HIV Workshop 2013.

5. Methods Decision tree for EID and ART pathway: all HIV exposed children Markov cohort model: HIV infected who initiate ART Health care provider’s perspective, costs US$ 2011 (PPP) Time horizon: up to 40 years on ART. Discount rate 3%. Incremental cost effectiveness ratio (ICER) per life year gained = Incremental cost -------------------------------------- Incremental life year gained (LYG) ICER less than 1xGDP (US$ 4,420) was considered as cost effective. Univariate and Probabilistic Sensitivity Analysis (1000 runs).

6. Survival and cost estimates: PHPT cohort PHPT observational cohort study in a network of public hospitals. Two modes of entry: – Birth cohort: EID at birth and 6 weeks – Referred cohort: diagnosed after symptomatic at older ages  All children started ART based on immune/clinical criteria Mortality pre-ART and on ART at up to 5 years of follow up 1 Cost of ART: hospitalization 2 and ART drug costs 3. Base case: weighted average of children starting ART under and over 12 months. 1 Collins et al. CID 2008, 2. Collins et al. AIDS 2012, 3. Collins et al. JAIDS in press.

7. Survival and cost estimates: PHPT cohort PHPT observational cohort study in a network of public hospitals. Two modes of entry: – Birth cohort: EID at birth and 6 weeks – Referred cohort: diagnosed after symptomatic  All children started ART based on immune/clinical criteria Mortality pre-ART and on ART at up to 5 years of follow up 1 Cost of ART: hospitalization 2 and ART drug costs 3. Base case: weighted average of children starting ART under and over 12 months. 1 Collins et al. CID 2008, 2. Collins et al. AIDS 2012, 3. Collins et al. JAIDS in press. >> Early-Late >> Reference >> Early-Early: CHER study risk reduction in disease progression

9. Key parameters ParameterEstimate95% CISource Rate of MTCT3.9%2.2-6.6Plaipat 2003 Coverage of EID68%47-79Naiwatanakul 2012 Confirmation of EID78%47-85Naiwatanakul 2012 Linkage to HIV care within 3 months of EID73%64-82Sirirungsi 2013 Initiated ART within 3 months of linkage85%79-92Sirirungsi 2013 Sensitivity and specificity of DNA PCR100%Ngo 2008. Risk reduction in disease progression on ART in Early Early (apply for 12-months) 0.250.15-0.41Violari 2008

10. Results: Model validation PHPT cohort survival (95% CI)Model projected survival (95% CI) 1 year5 years1 year5 years Children <12 months at start of ART Early-Early--93.6%90.0% Early-Late84.1 (69.5-92.1)74.1 (58.0-92.1)82.0%73.6% Reference84.6 (51.2-95.9) 78.1%67.8% Children ≥12 months at start of ART Early-Early--97.4%95.0% Early-Late98.5 (89.6-99.8)96.7 (87.4-99.2)97.4%95.0% Reference95.3 (92.8-96.9)93.6 (90.4-95.6)96.0%92.5% Projected survival was within 2% of PHPT cohort estimate among older children. Poorer projections among infants in Reference arm, most likely due to small sample size.

11. Results: ICER Main benefit of Early-Early was reduced risk of pre-ART deaths and early mortality on ART. Over 90% of programme cost was lifetime cost of ART. Reductions in MTCT will substantially reduce programme cost. Programme modelEarly-EarlyEarly-LateReference Total Cost (All children) $4.0 million$3.1 million$2.4 million Mean LYG (undiscounted) of HIV+ child 17.8 years (29.1) 14.3 years (22.8) 13.3 years (21.0) Discounted mean life time costs of HIV+ child $17,128$13,441$10,426 ICER over Reference $1,489$2,929- ICER over Early-Late $1,067--

12. Change in ICER ($ per LYG)

14. Results: Probabilistic sensitivity analysis

15. Probability of cost effectiveness by defined threshold per LYG

16. Subgroup analysis: by risk of perinatal transmission

17. Limitations Generalizability: non breastfed population, context specific coverage, retention, costs and cost-effectiveness threshold. Quality of life: scarce data in children, not capture additional benefits e.g. preservation of immune function, avert neurodevelopmental damage, benefit of EID etc. Assumed 100% sensitivity and specificity of DNA PCR, unclear if this will vary with exposure to maternal HAART for PMTCT (Shapiro et al. IAS 2011).

18. Summary EID and immediate ART in HIV infected children <24 months was cost effective in the non-breastfed population in Thailand. Results were robust to sensitivity analyses and was cost effective even when low rates of MTCT. Supports efforts for continued scale up of EID and improved linkage with ART services.

19. Acknowledgements Program for HIV Prevention and Treatment (IRD-PHPT) Participating hospitals Faculty of Associated Medical Sciences, Chiang Mai University Global Fund to Fight AIDS, TB and Malaria Oxfam GB MRC DTA Studentship, UK

20. Decision tree : pathway for HIV diagnosis and referral for ART.