1. Monitoring ART in resource-limited settings: option or necessity ? Public Health Approach Prof Charlie Gilks UNAIDS Country Coordinator, India 5th IAS conference on Pathogenesis, Cape Town, 21 July 2009

2. 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

3. “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

4. 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

6. Harmonised ART Policy Guidance

7. 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

8. Core elements of ART monitoring ARV toxicity and SAEs ART efficacy HIV drug resistance Clinical monitoring Laboratory monitoring Individual and/or population level

9. Evidence base on laboratory monitoring strategies in PHA Clinical end-point trials including cost-effectiveness DART trial: preliminary data, IAS Cape Town ART toxicity and efficacy Clinically driven monitoring versus clinical + CD4 monitoring Modelling study: Phillips et al. Lancet 2008: 371 1443-51 HBAC trial: presented but as yet unpublished data ART efficacy Clinical monitoring; clinical + CD4; clinical and CD4 and/or + VL No end-point data on ART switch with detectable vl Targeted viral loads: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

10. IAS July 2009 10 0.0 0.2 0.4 0.6 0.8 1.0 Proportion event-free 012345 Years from randomisation (ART initiation) LCMCDM Grade 4 AE p=0.18 SAE p=0.20 ART- modifying AE p=0.85 DART routine toxicity monitoring Grade 3/4 AE p=0.52

11. 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 0.0 0.2 0.4 0.6 0.8 1.0 Proportion of patients alive on trial 012345 Years from randomisation (ART initiation) LCM CDM Second-line Original first-line Substituted first-line

12. 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 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 HR(CDM:LCM)0.580.480.770.901.351.10 heterogeneity p=0.001

13. IAS July 2009 13 Survival (secondary endpoint) 0.90 0.87 0.92 0.90 0.95 0.94 149414451395749CDM 16561552150114681436796LCM 012345 0.0 0.2 0.4 0.6 0.8 1.0 Proportion alive 16601542 HR(CDM:LCM)1.082.05het 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 LCM CDM Number needed to monitor = 130

14. IAS July 2009 14 Sensitivity Analysis: Minimal Monitoring LCM N = 1656 CDM N = 1660 Difference (LCM – CDM) Overall Mean Total Cost US$ 2008 Adjusted for censoring, discounted at 3% [95% Confidence Interval]* $2599$2382$217 [$95, $334] Overall survival days** Discounted at 3% [95% Confidence Interval]* 18631826+37 [-10, 83] Incremental Cost Effectiveness Ratio Adjusted 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 1 st 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.

15. 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

16. 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 economically preferable to viral load monitoring …

17. IAS July 2009 17 Sensitivity Analysis: CD4 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

18. 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

19. IAS July 2009 19 DART Survival using PHA 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 What more could VL monitoring add, and at what cost? CTXp – 50% reduction first 72 weeks of ART (MOPEB020)

20. 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

21. 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

22. 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

23. THANK YOU