1. ART Scale-up Where to go in the next decade? Prof Charles Gilks Head of School of Public Health University of Queensland

2. Outline of talk ART scale-up: a decade of progress Advances in ARVs and ART Laboratory monitoring of ART The next decade – where to go?

3. The global treatment gap The treatment gap was declared a global health emergency on Sept 22 nd, 2003 at UNGASS (UN General Assembly Special Session) Global activism around increasing access to ART as a basic human right in resource- limited settings GFATM and PEPFAR established and resourced for ART scale-up JW Lee pledges to address global HIV inequity and close the treatment gap HOW?? Target-driven Public Health JW Lee Director General WHO 2003-2006 ‘The right of everyone to the enjoyment of the highest attainable standard of health’

4. “Three by Five” The target: three million people on treatment by the end of 2005 The goal : universal access to ART as a basic human right to health to all in need Public Health ART strategy WHO guidelines

5. Public Health ART Strategy Aim: Prolong survival Increase Quality of Life Core Elements of PHA Chronic disease management Practical case records and registers Decentralised care Task shifting Simplified and standardised approaches First-line and second line ART When to start; substitute; switch; stop/salvage Parsimonious laboratory monitoring Population-level HIV DR monitoring Users: Public sector planners & policy makers

6. Guidelines and Guidelines WHO guidelines for Public Sector ART Simple standard care packages First then second line regimens CD4 testing available; clinical monitoring Population level impact – survival; QOL US DHHS; IAS USA; BHIVA; ASHM; etc Physician/specialist-led ART Initial regimen then multiple options Access to all lab services Individual outcome – viral suppression

7. Global Access to Treatment Actual and projected numbers of people receiving antiretroviral therapy in low-and middle-income countries, and by WHO Region, 2003–2015 Nearly 10 million people on ART by end of 2012 1.6 million in one year African region shows the greatest rate of increase Coverage 68% for adults but only 34% for children Coverage not uniform - certain regions and populations left behind (Eastern Europe, IDUs) WHO, Global Treatment Report 2013

8. Impact of ART on survival Cumulative Life-Years Gained from Antiretroviral Therapy, 1996–2011 — Global total High-income countries Low- and middle income countries 25 Cumulative life-years gained (in millions) 0 1996 Source: Joint United Nations Programme on HIV/AIDS, 2012. 2011

9. 1 st and 2 nd line ARVs for adults StartSubstituteSwitch Stop 1 st Line2 nd line AZT, d4T, 3TC, NVP; EFV ABC, TDF ddI PI/r Recommended 1 st Line ARV Drugs Recommended as 2 nd Line Drugs Frequently Recommended as 2 nd line drugs, but also as alternative drugs in 1 st line regimens

10. Ceiling Prices of Major 1 st and 2 nd Line ARV Regimens Clinton Foundation, April 2008

11. 11 Evolution of ARV drugs: Moving towards better and safer options

12. Use of TDF in 1 st line Regimens AMDS, 2013 Market share of NRTIs (except 3TC and FTC) in low- and middle-income countries, 2004 – 2013 AZT

13. Changes in NVP and EFV use (2007-2013) 49% Between 4.6 to 5.8 million people using NVP containing regimen in 2012 WHO AMDS database, 2014 (preliminary data)

14. Relative market share (% of PYR) of protease inhibitors (2003-2013) AMDS, 2013 DRV

15. Public Health ART scale-up Provision of laboratory services Universal access to ART predicated on decentralised care Limited access and high cost of high technology hospital Laboratory Services

16. HIV disease and AIDS WHO CLINICAL STAGING OF HIV FOR ADULTS AND CHILDREN

17. Patient monitoring of ART When to switch first-line therapy to second-line – Clinical monitoring alone – Immunological (CD4) – Detectable virus (vl) Routine toxicity monitoring – Haematology – Liver Function – Renal function

18. VirologicClinicalImmunologic Viral load CD4 count Clinical criteria Early Switch Late Switch Failure / When to Switch The three failure domains are all different $$$ Costs /access universal coverage

19. DART Trial design 3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease, CD4<200 cells/mm 3 (median 86 cells/mm 3 ) initiating triple drug ART Laboratory and Clinical Monitoring (LCM) 12 weekly biochemistry, FBC & CD4 Other investigations & concomitant medications if clinically indicated Switch to second-line for new/recurrent WHO 4 (or multiple WHO 3) CD4<100 cells/mm 3 Clinically Driven Monitoring (CDM) 12 weekly biochemistry, FBC & CD4; FBC & biochemistry only returned if clinically indicated (or grade 4 toxicity); CD4 never returned Other investigations (not CD4) & concomitant medications if clinically indicated Switch to second-line for new/recurrent WHO 4 (or multiple WHO 3) randomise As per WHO guidelines, switching before 48 weeks discouraged in both arms 5 year follow-up

20. 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 study enrolment

21. IAS July 200921 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 Adverse events Grade 3/4 AE p=0.52

22. Durability of first-line ART

23. The DART trial Runner-up Lancet paper of the Year, 2009 The ARROW trial (babyDART) Published Lancet March 2013

24. HBAC trial: results Randomised 1000 Ugandan patients to clinical alone, clinical with CD4, or clinical with CD4 and vl monitoring In patients on ART routine laboratory monitoring associated with improved health and survival compared with clinical monitoring alone … There was no significant difference (p=0.31) between CD4 and vl arms

25. Stratall ANRS 12110/Esther trial: results 256 African patients were randomised to clinical or laboratory (CD4 and VL) monitoring and followed for two years Clinical monitoring was not non-inferior; supports WHO recommendations and suggests clinical monitoring alone useful

26. PHPT-3 study: results * 716 Thai patients on ART randomised to either CD4 or vl monitoring and followed for 3 years Rate of clinical failure was very low and did not differ between arms Viral load monitoring may be less important than regular safety, tolerability, adherence and immunological monitoring * Presented at 18 th CROI Boston 2011 abstract 44

27. IAS July 2009 27 CEA laboratory monitoring Routine laboratory monitoring for toxicity is particularly expensive and with the standard first-line regimens used in DART provided no measurable clinical benefit. Using routine haematology and biochemistry tests in ART roll- out needs to be questioned by policy makers CD4 monitoring provides clinical and survival benefit but the ICER remains high ($ 8313; 3867 – dominated) under most scenarios Threshold analysis suggests costs of CD4 tests need to drop below $3.78 to be cost effective in Uganda and Zimbabwe at 3-monthly frequency

28. The future is looking good for low-cost CD4 POC devices

29. Estill et al: CEA of POC viral load monitoring vs CD4 or clinical VL monitoring is not cost-effective - primarily due to the large number of unnecessary switches to second-line CEA of POC VL is improved by higher detection limit; by taking reduction in new HIV infections into account; and by assuming the failure of first- line ART is reduced by targeted adherence counselling

30. Hamers et al: modelling clinical, CD4 or vl monitoring Additional costs of laboratory monitoring balanced by cost- savings from unnecessary switches - but massive failure rates and many unnecessary switches ascribed to clinical monitoring strategy. Routine vl monitoring may be preferred as a replacement for CD4 counts – but no start-up costs to set up of vl network were included.

31. Gilks et al: DART re-analysis - single CD4 test tiebreaker >250 with clinical failure predicts vl suppression Multiple but not single WHO3 events and WHO4 events predict first-line failure A single CD4 threshold tiebreak of 250 for clinically monitored patients failing first-line would identify 80% with vl<400 who do not need to switch to second-line and thus avoids premature use of second-line

32. The next decade: WHO 2013 Guidelines Much earlier start (CD4 500) Routine toxicity monitoring Viral load monitoring is preferred Provision for Third-line ART More individualised; convergenge with DHHS approach Moving away from PHA: Decentralisation & task shifting Fourth guideline in a Decade; more are planned Aspirational when budgets flatlined and competing health priorities like NCDs Consolidate gains and achievements

33. If implement 2013 guidelines fully as compared to 2010 guidelines: 28 m eligible by 2025 Avert 3.0 m deaths (↓ 59%) Avert 3.1 m new infections (↓ 23%) Cost 1.8 B more in 2015, peaks at 3.3 B in 2020, 1.7 B in 2025 Highly cost effective at QALY 350 USD Figure 1 Figure 2 Figure 3

34. P aul Revill, Miqdad Asaria, Andrew Phillips, Di Gibb, Charles Gilks

35. What approach – who decides? Ministry of Health convene committee Donors and funders (PEPFAR, GFATM); WHO National experts (physicians) Community representatives; on ART Public Health professionals Health economists

36. Thank you