1. CD4 and VL Monitoring: Research and Development needs and Policy implications Monitoring ART session XVIII IAC Vienna 2010 Prof Charles Gilks UNAIDS India

2. CD4 and VL Monitoring: Research and Development needs and Policy implications 1.Core concepts 2.Review of evidence 3.Policy and R&D implications

3. Monitoring ART: different guidelines and approaches WHO guidelines for Public Sector ART Public Health Approach to treatment First then second line regimens Maximise Survival and clinical benefit US DHHS; IAS USA; BHIVA; etc Physician/specialist-led ART Initial regimen then multiple options Maximal viral suppression

4. Monitoring to support Public Sector roll-out of ART and Universal Access Improve outcome of ART –Maximise benefit and survival –Promote adherence –Reduce emergence of HIV DR Be accessible –Long-term, decentralised chronic care Be a good investment for Programmes –Optimal resource allocation

5. Monitoring for ART outcome Guide when to change therapy Substitute within class – Toxicity monitoring – First-line to alternate first-line regimen(s) Switch to second line –To identify failure –Early versus late switch

6. Identifying failure No gold standard for monitoring ART to identify failure and trigger the switch to second line Three different domains for failure: –Clinical using WHO clinical staging –Immunological using CD4 counts –Virological using HIV PCR These domains measure different parameters and are NOT congruent Limited evidence on frequency of monitoring and what constitutes threshold for failure

7. Trials/Models to compare ART monitoring strategies Baseline against which different strategies can be compared – clinical monitoring Immunological (CD4) and virological (VL) monitoring are compared to baseline Incrementally added: CD4 then VL. Uncertainty about threshold value Usually 3-monthly schedule

8. DART: Switch to second-line DART trial team, Lancet 2010: 375; 23 - 31 Proportion switched to second-line 0.0 0.1 0.2 0.3 0.4 0.5 012345 Years from randomisation (ART initiation) CDM LCM HR(CDM:LCM) = 0.84 (95% CI 0.72-0.98), p=0.03

9. 9 DART Survival 0.90 0.87 0.08 0.92 0.90 0.18 0.95 0.94 0.55 012345 0.0 0.2 0.4 0.6 0.8 1.0 Proportion alive Years from randomisation (ART initiation ) LCM CDM Entebbe Cohort: pre-ART, median CD4 75 at start DART trial team, Lancet 2010: 375; 23 - 31

10. DART Survival 0.90 0.87 0.08 0.92 0.90 0.18 0.95 0.94 0.55 012345 0.0 0.2 0.4 0.6 0.8 1.0 Proportion alive Years from randomisation (ART initiation) LCM CDM Entebbe Cohort: pre-ART, median CD4 75 at start CEA: CD4 costs below about $3.80 to be cost-effective

11. HBAC Study: interim 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 economically preferable to viral load monitoring Abstract 125, CROI 2008; and unpublished

12. 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 Cost-effectiveness of Laboratory monitoring in Sub-Saharan Africa: A review of current literature. Walensky et al. CID 2010: 51; 123-127

13. VL as “tie-break” for cost savings Substantial numbers of patients with clear clinical or CD4 immunological failure and who switch ART are not failing virologically VL being considered as “tie-breaker” to confirm failure or to suggest continuation of first-line ART This is NOT virological monitoring of ART – it is a strategy to identify those who will benefit from switching to second line and to save costs.

14. Evidence-based policy CD4 over CDM improves survival – Costs below $4 with parsimonious monitoring More survival benefit from using costs of CD4 monitoring to start patients in need on ART Viral load monitoring not cost effective VL essential for EID and paediatric care VL likely to be cost-saving to confirm failure

15. Research & Development needs Low-cost POC assays for CD4 and VL –Support prevention and decentralised chronic care delivery Establish threshold for viral load failure and switching –DART has defined CD4 and clinical thresholds Efficacy of VL monitoring –Randomised trials of VL versus CD4 –Clinical consequences of detectable viral replication –transmissibility of DR versus wild-type Costs and Cost-effectiveness of different strategies –real data and PHA for modelling

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