Monitoring ART in resource-limited settings: option or necessity ? Public Health Approach
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Monitoring ART in resource-limited settings: option or necessity ?
Public Health Approach
Prof Charlie GilksUNAIDS Country Coordinator, India
5th IAS conference on Pathogenesis,
Cape Town, 21 July 2009
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Outline
• The Public Health Approach and what it means in terms of lab monitoring
• Evidence of the impact of different ART monitoring strategies
• Options for resource-limited settings
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“Three by Five”
Initiative started in 2003
The target: three million people
on treatment by the end of 2005
The goal : universal access to anti-retroviral therapy (ART) as
a human right to health
•
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Public Health ART Strategy
Key elements for public sector ART
• First-line then second-line regimens
• Simple recommendations for when to start, toxicity substitutions & switch
• Tiered laboratory support for clinical decision-making
• Standard population-based HIVDR monitoring and surveillance
• Population-based Pharmacovigilance and toxicity monitoring
• Integrated and decentralised care with task shifting
• Chronic disease management
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Harmonised ART Policy Guidance
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Different guidelines for different populations and ART approaches
• Public sector ART• First then second line regimens • Limited number of ARVs used • Limited human resources• Limited laboratory services
• Physician/specialist-led ART • Initial regimen then multiple options• All ARVs available for use • Sophisticated labs to tailor regimen choice• Any detectable vl triggers regime change• Few cost constraints
Consider guidelines in their context
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Core elements of ART monitoring
• ARV toxicity and SAEs• ART efficacy• HIV drug resistance
• Clinical monitoring • Laboratory monitoring
• Individual and/or population level
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Evidence base on laboratory monitoring strategies in PHA
Clinical end-point trials including cost-effectiveness
• DART trial: preliminary data, IAS Cape TownART toxicity and efficacyClinically driven monitoring versus clinical + CD4 monitoring
• Modelling study: Phillips et al. Lancet 2008: 371 1443-51
• HBAC trial: presented but as yet unpublished dataART efficacy Clinical monitoring; clinical + CD4; clinical and CD4 and/or +
VL
• No end-point data on ART switch with detectable vl Targeted viral loads: July 2009 CID paper & editorial
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IAS July 2009 10
0.0
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1.0
Pro
port
ion
even
t-fr
ee
0 1 2 3 4 5
Years from randomisation (ART initiation)
LCM CDM
Grade 4 AEp=0.18
SAE p=0.20
ART-modifying AEp=0.85
DART routine toxicity monitoring
Grade 3/4 AEp=0.52
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DART: first-line ART received
• Median follow-up to 31 December 2008 4.9 years (IQR 4.5-5.3)• 98% and 99% of expected nurse and doctor visits attended
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1.0
Pro
port
ion o
f p
ati
ents
aliv
e o
n t
rial
0 1 2 3 4 5Years from randomisation (ART initiation)
LCMCDM
Second-line
Originalfirst-line
Substitutedfirst-line
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IAS July 2009 12
Switch to second-line
Note: Adjusted for competing risk of death before switch to second-line
Proportion switched
to second-line
0.0
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0.2
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0 1 2 3 4 5
Years from randomisation (ART initiation)
CDMLCM
HR(CDM:LCM) = 0.84 (95% CI 0.72-0.98), p=0.03
HR(CDM:LCM) 0.58 0.48 0.77 0.90 1.35 1.10heterogeneity p=0.001
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IAS July 2009 13
Survival (secondary endpoint)
0.90
0.87
0.92
0.90
0.95
0.94
1494 1445 1395 749CDM1656 1552 1501 1468 1436 796LCM
0 1 2 3 4 5
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1.0
Pro
port
ion
aliv
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1660 1542
HR(CDM:LCM) 1.08 2.05het p=0.004
(95% CI) (0.85-1.39) (1.43-2.93)
Years from randomisation (ART initiation)
HR(CDM:LCM) = 1.35 (1.10-1.65) p=0.004
LCMCDM
Number needed to monitor = 130
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IAS July 2009 14
Sensitivity Analysis: Sensitivity Analysis: Minimal MonitoringMinimal Monitoring
LCMN = 1656
CDMN = 1660
Difference(LCM – CDM)
Overall Mean Total Cost US$ 2008Adjusted for censoring, discounted at 3%[95% Confidence Interval]*
$2599 $2382 $217[$95 , $334]
Overall survival days** Discounted at 3%[95% Confidence Interval]*
1863 1826 +37[-10 , 83]
Incremental Cost Effectiveness RatioAdjusted for censoring, discounted at 3%[95% Confidence Interval]*
$2146[$721 , Dominated]
Modifications from Adjusted and Discounted Costs and Benefits: • 12-weekly CD4 cell count routinely performed after the 1st year on ART• No routine (12-weekly) Haematology and Biochemistry tests
* 95% CI estimated with bootstrapping percentile method.** Estimated through the area under the Kaplan-Meier survival curve, with censoring applied at the longest observed time of the arm whose maximum observed time occurs first.
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Although survival was slightly longer with viral load monitoring, this strategy was not the most cost-effective.
The benefits of Vl or CD4 over clinical monitoring are modest. Development of cheap and robust assays is important; meanwhile widening access to ARVs is the highest priority
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Interim HBAC Conclusions
• Adding CD4 to clinical monitoring ($831 - $838 per DALY averted) is about as cost-effective as putting another person on ART in Tororo ($600 per DALY).
• Adding viral load to CD4/clinical monitoring has a cost per DALY averted ($3,600 - $11,900) that is 4 to 20 times higher.
• HBAC analysis suggests that CD4 monitoring or starting a patient on ART are economicallypreferable to viral load monitoring …
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IAS July 2009 17
Sensitivity Analysis: Sensitivity Analysis: CD4 count costsCD4 count costs
• At current costs ($7.06 - $8.82), CD4 testing is not cost effective
• We sought to establish the cost per test at which CD4 monitoring would be cost effective
(ICER of $1200 ~3 times GDP per capita; WHO Commission on Macroeconomics and Health)
CD4 count would have to cost $3.8 or less for ART management with 12-weekly CD4 monitoring after 1st year to be cost effective
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Targeted viral loads at failure• 3 failure domains which are not the same:
– clinical; immunological and virological • 20% of clinical failures had high CD4 in DART• 15 – 40% switches with clinical/immunological failure unnecessary:
viral suppression or low-level replication
• Targeted viral load testing as “tie-break” to conserve use of second-line and reduce costs: policy in India
• Caveat: are “failing” patients not benefiting from early switch?
• Does not mean that routine viral load monitoring is a necessary or will be cost-effective in resource-limited settings in public sector:– What threshold for viral failure to trigger switch?
– Maximal suppression likely to be far too early
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IAS July 2009 19
DART Survival using PHA
0.90
0.87
0.08
0.92
0.90
0.18
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0.94
0.55
0 1 2 3 4 5
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Pro
port
ion a
live
Years from randomisation (ART initiation)
LCMCDM
Entebbe Cohort:pre-ART, median CD4 75 at start
What more could VL monitoring add, and at what cost?
CTXp – 50% reduction first 72 weeks of ART (MOPEB020)
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HIV drug resistance: population-based monitoring and surveillance
No scope in PHA for different first-line ART according to baseline resistance pattern
Cohort DR monitoring for programme effectiveness
Population DR monitoring for extent of transmitted HIV DR
Articles reporting results from HIVDR transmission surveys in 7 countries; all had <5% DR in incident cases
No need to change ARVs provided in public sector for first-line ART
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Summary and conclusions
• PHA is an extremely effective tool for ART scale-up and delivery of effective ART in resource-constrained settings
• (Quality) clinically-driven monitoring can deliver excellent outcomes for the individual
• Small outcome benefit from routine CD4 monitoring
• Likely only small additional outcome benefit from routine VL in addition to CD4 monitoring
• Neither laboratory-based strategies are cost-effective; getting people in need on to ART remains the priority
• Drug resistance monitoring and SAE/toxicity monitoring are best done at a population level to inform PHA ARV choices
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Future directions
• Drive for Quality clinical monitoring• CD4 testing for eligibility to start/thresholds• Targeted CD4 ART monitoring with much
cheaper and ideally POC tests • VL testing for Early Infant Diagnosis• Targeted vl as cost-saving tie-break for patients
with clinical or immunological failure• Drug resistance and pharmacovigilance at
population level or in cohort studies
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THANK YOU