Scaling up WHO recommendations for HIV therapy in resource-limited settings: What to do first

1. Scaling up WHO recommendations for HIV therapy in resource-limited settings: What to do first Rochelle P. Walensky, MD, MPH Robin Wood, FCP, MMed, DTM&H Andrea L. Ciaranello, MD, MPH A. David Paltiel, PhD, MBA Sarah B. Lorenzana Xavier Anglaret, MD, PhD Adam Stoler, MA Kenneth A. Freedberg, MD, MSc for the CEPAC-International Investigators Supported by NIAID, NIDA, & Doris Duke Charitable Foundation

2. New WHO ART Guidelines (2009) Four Key Changes • Revised to better align standards in resource-limited settings with those in more developed nations • Include 4 key changes: • Routine CD4 counts (CD4) • ART initiation at CD4 <350/µl instead of <200/µl (ART at 350/µl) • Replacement of first-line stavudine with tenofovir (d4T to TDF) • Increased number of sequential ART regimens (2nd-line ART)

3. Implementation Challenges Countries still unable to meet 2006 guidelines Resource limitations make comprehensive implementation unlikely 2009 recommendations lead to important policy questions What to do first?

4. Objective To project the clinical and economic outcomes of alternative implementation approaches toward the 2009 WHO ART guidelines.

5. Options for Changing ART Standards of Care

6. Options for Changing ART Standards of Care

7. Options for Changing ART Standards of Care

8. Options for Changing ART Standards of Care

9. Analysis Evaluate each step-wise decision, choosing the one that maximizes life expectancy In step-wise fashion, evaluate the remaining options, again maximizing life expectancy Examine the cost-effectiveness of all 13 possible combinations of scale-up decisions

10. CEPAC-International • Cost-effectiveness of Preventing AIDS Complications (CEPAC)-International Model • Mathematical model of HIV disease & treatment • Adapted for resource-limited settings: • CD4 counts and/or HIV RNA may not be available • Clinical data are from South Africa • Representative of a resource-limited setting • Model provides outcomes in: • Mean projected life expectancy • Mean projected per person costs Funded by NIAID/DDCF

11. Outcomes examined 5-year survival Projected life expectancy Incremental cost-effectiveness Threshold for “very cost-effective” defined by WHO as <1x per capita GDP For South Africa, <$5,400/YLS

12. Model Input Parameters • 1. Hammond et al., Int J STD AIDS 2004 • Delfraissey et al., AIDS 2008 • Boulle et al., Antivir Ther 2007 • Gallant et al., NEJM 2006

13. Survival & Life Expectancy

14. Step #1: Survival & Life Expectancy

15. Step #2: Survival & Life Expectancy

16. Step #3: Survival & Life Expectancy

17. Survival Curves Status quo No ART

18. Survival Curves Status quo Step 1: CD4, ART <350/µl No ART

19. Survival Curves Status quo Step 1: CD4, ART <350/µl Step 2: 2nd-line ART No ART

20. Survival Curves Status quo Step 3: d4T to TDF Step 1: CD4, ART <350/µl Step 2: 2nd-line ART No ART

21. Costs and Effectiveness 2nd-line ART and CD4 monitoring available One-line ART, CD4 monitoring available Clinical criteria alone Legend = CD4 < 350/µl = CD4 < 200/ µl = d4T = TDF = Clinical criteria

22. Costs and Effectiveness TDF /<350/µl / 1-line d4T / WHO / 1-line

23. Incremental Cost-effectiveness* *Discounted at 3% per year South Africa 2008 GDP: $5,400

24. Sensitivity Analysis • Results are extremely sensitive to the price of tenofovir. • A decrease in the price of tenofovir from $135 to $51 per person per year would make tenofovir both more effective and less costly than stavudine.

25. Limitations Results are for individuals initiating ART; do not address ART programs with patients in ongoing care (1st line, 2nd line). While this analysis examines value for money, it does not project the implications of each component of the WHO recommendations on program budgets.

26. This decision depends on where a country’s policies currently stand. In countries without laboratory capacity, CD4 monitoring and ART at <350/µl is the most critical initial priority. Where ART at <350/µl is already available: Replacing stavudine with tenofovir and second-line ART will both provide survival benefits; both are cost-effective. Adding second-line ART will offer a larger survival advantage, but with substantial increases in total costs. What to do first with WHO Guidelines?

27. Tenofovir price reductions could end the debate about further use of stavudine in first-line therapy. What to do first with WHO Guidelines?

28. United States Kenneth Freedberg, MD, MSc Elena Losina, PhD Rochelle Walensky, MD, MPH Aima Ahonkhai, MD, MPH Ingrid Bassett, MD, MPH Melissa Bender, MD Andrea Ciaranello, MD, MPH Kenneth Freedberg, MD, MSc Sue Goldie, MD, MPH April Kimmel, PhD, MSc Julie Levison, MD, MPhil Ben Linas, MD, MPH Marc Lipsitch, PhD Zhigang Lu, MD Alethea McCormick, PhD Farzad Noubary, PhD A. David Paltiel, PhD Mai Pho, MD Erin Rhode, MS Paul Sax, MD Bruce Schackman, PhD Callie Scott, MSc George Seage, III, PhD Caroline Sloan, AB Adam Stoler, MA Lauren Uhler Milton Weinstein, PhD CEPAC Investigators India Nagalingeswaran Kumarasamy MD Timothy Flanigan, MD Kenneth Mayer, MD Malaisamy Muniyandi, PhD Soumya Swaminathan, MD South Africa Linda-Gail Bekker, MD, PhD Neil Martinson, MBBCh, MPH Robin Wood, MD Lerato Mohapi, MD Catherine Orrell, MBBCh, MMed Côte d’Ivoire Xavier Anglaret, MD, PhD Eugène Messou, MD Catherine Seyler, MD, MSc Christine Danel, MD, PhD Eric Ouattara, MD, MPH Siaka Touré, MD, MPH Hapsatou Touré, MD, MPH France Yazdan Yazdanpanah, MD, PhD Sylvie Deuffic-Burban, PhD Delphine Gabillard, PhD Francois Dabis, MD