1. Outcomes in ART treatment programmes with and without access to routine viral load monitoring Olivia Keiser on behalf of IeDEA Southern Africa okeiser@ispm.unibe.ch

2. 2 Debate on place of routine viral load monitoring in scale-up programmes South Africa: routine VL monitoring part of national programme Malawi and Zambia: no routine viral load monitoring Background

3. 3 Site Country Routine VLPatients Lighthouse Malawi CIDRZ Zambia no 9,604 71,333 Gugulethu Khayelitsha South Tygerberg Africa Thembalethu yes 2,658 7,230 1,361 7,457 Treatment naïve patients > 15 years, NNRTI-based ART regimen. Selection of patients/ programmes All sites participate in IeDEA Southern Africa see: www.iedea-sa.org

4. Mortality 0.00 0.05 0.10 0123 Years since HAART start No viral load monitoring (Malawi and Zambia) Routine viral load monitoring (South Africa) Cumulative mortality

5. 5 1) Differences in patient characteristics ?

6. 6 Patient characteristics at start of ART Non VL sitesVL sites Age35 (30-42)34 (30-41) CD4 count 132 (66-203)93 (39-159)

7. 7 Sites with and without (reference) VL monitoring Hazard ratio (95% CI) P value Crude0.81 (0.76-0.87)<0.001 Adjusted * 0.74 (0.69-0.80)< 0.001 Competing risk regression with loss to follow-up and start of second- line therapy as competing events *Adjusted for age, sex, CD4 cell count and clinical stage of disease

8. 8 2) Differences in loss to follow-up ?

9. 9 Adjusted* Hazard Ratio (95% CI) P value Mortality0.74 (0.69-0.80)< 0.001 Loss to follow-up0.70 (0.65-0.75)< 0.001 Competing risk regression *Adjusted for age, sex, CD4 cell count and clinical stage of disease Sites with < 15% loss to follow-up 2 years after ART start Sites with and without (reference) VL monitoring

10. 10 3) Differences in background mortality?

11. 11 Expected non-HIV-related death rate per 100 pyrs Setting Observed rate/ 100 pyrs Assuming identical non-HIV-related mortality* VL sites2.12 (1.93-2.34) Non VL sites3.10 (2.99-3.20)2.92 (2.82-3.02) Rate ratio0.68 (0.62-0.76)0.73 (0.65-0.81) * Based on South African rates

12. 12 4) Delayed/missed detection of treatment failure and switching in non-VL sites?

13. Six months after ART start Treatment failure - virologic (viral load sites) - immunologic (non viral load sites) Switch Death Loss to follow-up Multistate model Putter et al., Stat Medicine 2007

14. From 6 months after ART start 0200400600 800 0200400600 800 Non VL sitesVL sites Loss to follow-up Second-line therapy Death CD4 criteria for switching Remaining on first-line ART Time (days) 1 0.75 0.5 0.25 Proportion of patients 0

15. From failure Non VL sitesVL sites 80002004006008000200400600 Loss to follow-up Second-line therapy Death CD4 criteria for switching Time (days) 1 0.75 0.5 0.25 Proportion of patients 0

16. From switch Non VL sitesVL sites 0200400600 800 0200400600 800 Time (days) Loss to follow-up Second-line therapy Death 1 0.75 0.5 0.25 Proportion of patients 0

17. From switch Non VL sites VL sites (linkage with death registry) 0200400600 800 Time (days) Loss to follow-up Second-line therapy Death 0200400600 800 1 0.75 0.5 0.25 Proportion of patients 0

18. 18 Conclusions Mortality rate higher in sites without routine viral load monitoring Difference probably not explained by differences in - Patient characteristics - Loss to follow-up - Background mortality Alternative explanations: - Delayed/missed switching - Diagnostic and treatment capacities (for OIs), other differences in patient management

19. 19 Diagnostic capacities Non VL sitesVL sites SiteLHCITLTBGUKH Tuberculosis Culture MTb/other M. Cryptococcus Culture Ag test Amphotericin treatment Not generally available or off site yesno

20. 20 Limitations - Few sites and countries included - Mortality in patients lost to follow-up unknown in many sites - Linkage with death registry only possible for patients with South African ID number available - Estimates of HIV-free mortality might be inaccurate This is an observational study - Ideally one would need a randomized trial

21. 21 Acknowledgement University of Bern: Matthias Egger, Thomas Gsponer, Janne Estill, Gilles Wandeler, Franziska Schöni-Affolter, Martin Brinkhof, Fritz Käser, Claire Graber Data center Cape Town: Andrew Boulle, Morna Cornell, Leigh Johnson, Nicola Maxwell Site investigators: Benjamin Chi, Matt Fox, Mhairi Maskew, Catherine Orrell, Hans Prozesky, Ralf Weigel, Andrew Westfall