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-Huong1, W Sirirungsi4, P Leechanachai4, S Le Coeur1, 5, N Kamonpakor6, J Mekmullica7, S Shabbar2, G Jourdain 1, M Lallemant 1,

for the Programme for HIV Prevention and Treatment (PHPT) study team1Institut 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, 2Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine (LSHTM), UK;3Faculty 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

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.

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)

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.

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).

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 up1 • Cost of ART: hospitalization2 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.

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 up1 • Cost of ART: hospitalization2 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

Key parametersParameter Estimate 95% CI Source

Rate of MTCT 3.9% 2.2-6.6 Plaipat 2003

Coverage of EID 68% 47-79 Naiwatanakul 2012

Confirmation of EID 78% 47-85 Naiwatanakul 2012

Linkage to HIV care within 3 months of EID 73% 64-82 Sirirungsi 2013

Initiated ART within 3 months of linkage 85% 79-92 Sirirungsi 2013

Sensitivity and specificity of DNA PCR 100% Ngo 2008.

Risk reduction in disease progression on ART in Early Early (apply for 12-months)

0.25 0.15-0.41 Violari 2008

Results: Model validationPHPT cohort survival (95% CI) Model projected survival (95% CI)

1 year 5 years 1 year 5 years

Children <12 months at start of ART

Early-Early - - 93.6% 90.0%

Early-Late 84.1 (69.5-92.1) 74.1 (58.0-92.1) 82.0% 73.6%

Reference 84.6 (51.2-95.9) 84.6 (51.2-95.9) 78.1% 67.8%

Children ≥12 months at start of ART

Early-Early - - 97.4% 95.0%

Early-Late 98.5 (89.6-99.8) 96.7 (87.4-99.2) 97.4% 95.0%

Reference 95.3 (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.

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 model Early-Early Early-Late Reference 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 - -

Rate of HIV infection

Coverage of Early HIV diagnosis

Confirmation of Early HIV Diagnosis

Initiate on ART in EE arm

Risk of developing symptoms <12mo

Risk of developing symptoms 12-24 mo

Risk reduction in disease progression

Cost of early HIV diagnosis

Cost ART Year 1-5

Cost of ART Y5+

Cost third line ART

Cost of ART monitoring

Hospitalization cost (>Y1)

Outcome discount

Cost discount

-600 -400 -200 0 200 400 600 800 1000 1200

Univariate Sensitivity Analysis: Effect of input parameter high and low estimate on ICER in Early-Early versus Reference arm

Low estimateHigh estimate

Change in ICER ($ per LYG)

Rate of HIV infection

Coverage of Early HIV diagnosis

Confirmation of Early HIV Diagnosis

Initiate on ART in EE arm

Risk of developing symptoms <12mo

Risk of developing symptoms 12-24 mo

Risk reduction in disease progression

Cost of early HIV diagnosis

Cost ART Year 1-5

Cost of ART Y5+

Cost third line ART

Cost of ART monitoring

Hospitalization cost (>Y1)

Outcome discount

Cost discount

-600 -400 -200 0 200 400 600 800 1000 1200

Univariate Sensitivity Analysis: Effect of input parameter high and low estimate on ICER in Early-Early versus Reference arm

Low estimateHigh estimate

Change in ICER ($ per LYG)

Results: Probabilistic sensitivity analysis

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00$0

$5,000

$10,000

$15,000

$20,000

$25,000

$30,000

Early LateEL Probabilistic meanEarly EarlyEE Probabilistic mean

Incremental LYS

Incr

em

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tal C

ost

(U

SD

)

$0 $1,000 $2,000 $3,000 $4,000 $5,000 $6,000 $7,0000.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Standard

Early-Late

Early Early

Value of ceiling ratio

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Probability of cost effectiveness by defined threshold per LYG

Subgroup analysis: by risk of perinatal transmission

$0 $500 $1,000 $1,500 $2,000 $2,500 $3,000 $3,500 $4,0000.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

No PMTCT (37.5%)

ZDV only (9.7%)

ZDV and other ARV (3.9%)

PHPT-2 (1.9%)

Cost effectiveness threshold

Pro

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co

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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).

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.

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

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