Starting HAART: When to Take the First Step?

1. Starting HAART: When to Take the First Step? Tuesday 20 July from 11:00 – 12:30 Session Room 1 Dr. Peter Mugyenyi Joint Clinical Research Centre Kampala, Uganda

2. Staring HAART: When to Take the First Step? Scientific Perspectives from a developing country Peter Mugyenyi FRCP Joint Clinical Research Centre Kampala, Uganda

3. Number of people receiving antiretroviral therapy in low- and middle-income countries, by region, 2002–2008 Source UNAIDS progress report 2009

4. Source UNAIDS progress report 2009

5. Background Higher mortality has been observed in the first 2-3 months on ART in adults initiating ART in low-income compared to high income settings unadjusted (LMIC:HIC) adjusted for age, sex, baseline CD4, stage, regimen 5

6. HAART started being scaled up in 2004 at a peak of the crisis • Priority given to the very sick • Starting CD4 was < 200 • Mortality and morbidity was high especially within the first 1 year • Resource-constrained countries still faced a dilemma of choosing between providing HIV treatment to more patients and focusing on more severely ill patients.

7. Evidence for late ART initiation from DART study

8. Morbidity and mortality observed in DART study was mainly due to late start of HAART

9. Deaths among DART study participants Adapted from Sarah Walker’s CROI presentation 9

10. Late initiation of HAART after eligibility determination in South Africa Study conducted in two outpatients government-subsidised hospitals in Kwazul-Natal South Africa (2008) Bassett IV. et. al. Who starts antiretroviral therapy in Durban, South Africa?... not everyone who should. AIDS 2010

11. Late initiation of HAART after eligibility determination in South Africa Fig: Mortality among antiretroviral therapy-eligible subjects, based on ART initiation status (N = 108 deaths among 536 ART-eligible subjects). (White) On ART; (Gray) unknown ART status; (Black) pre-ART. Bassett IV. et. al. Who starts antiretroviral therapy in Durban, South Africa?... not everyone who should. AIDS 2010

12. The Preventive role of HAART • Results from the study involving 3381 discordant couples in Africa: • Transmission rateInitiated HAART: • 0.37 per 100 person years • HAART not initiated: • 2.24 per 100 person years 92% risk reduction with HAART Donnell D et al hetrosexual HIV-1 transmission after initiating antiretroviral therapy: A prospective cohort analysis. Lancet 2010 June 12/18

13. The Preventive role of HAART • Among HIV infected individuals not on HAART, rate of HIV transmission highest : • CD4 < 200 • Viral load > 50,000 copies/ml Donnell D et al

14. When to Take the First Step? • Evidence for starting ART early is abundant and clear: Interim review led to early end of Clinical Trial known as CIPRA HT 001 in Haiti: starting ART at CD4 between 200 and 350 mm3 improves survival compared with deferring treatment until CD4 drops below 200 cells/mm3.

15. When to start • Optimum time to start is dependant on • Resources—these need to increase to cope with the rising numbers and as an “investment” for eventual control • continuing ART roll out • Success requires commitment to Universal access.

16. Is early start of ART cost effective? • Early start and sustained viral suppression: • Restores and preserves immune function • Role in “control of immune activation linked to chronic inflammation, end organ failure and comorbid conditions previously not thought to be linked to HIV” –from US new recommendation • decreases incidence of Malaria and debilitating OIs including TB : • HIV transmission • It ultimately delivers the best possible treatment outcome

17. Implication of DART results to Africa • Treatment can be scaled up to rural and hard to reach areas in Africa. (80% Ugandans live in rural areas) • Treatment may start and successfully scaled up while capacity building is going on. • Priority is to train health care providers in good clinical practice to ensure adherence. • With good clinical monitoring, the vast majority of patients can be maintained on first line therapy for many years (projected beyond 10 years)

18. Initiating HAART: Current practice in Resource limited countries - a mixed picture • Uganda: Start ART at CD4 250 as a “compromise because of resource constraints”. • A few countries in Africa use the current level of CD4 350 • Some donor programs and countries have come up with “priority patients” including pregnant women and HIV-TB co-infected people to be started on ART at CD4 350 • The reality is that many still use CD4 200 level but are not able to providing treatment to all.

19. AIDS crisis in Africa is getting worse in both treatment and prevention • The majority of patients in dire need of ART are not accessing it and the numbers in need are growing. • In SSA people on ART rose from 2.1 million in 2007 to 3.2 million by end of 2009 • Over 7 million in immediate need of ART but are not accessing it. • In less than a decade numbers in need of treatment are projected to double • Implication of raising thresholds for initiating treatment from CD4 200 to CD4 350: • “need for adults could be substantial – up to two times more than those currently estimated” (UNAIDS). .

20. ART programs are facing uncertain future. The main threats are: • Inadequate funding: • PEPFAR which implemented a highly successful treatment program showed what can be achieved if resources were availed. • Funds from Global fund for AIDS, TB and Malaria are grossly insufficient. • Clinton Foundation which supplements the programs is soon winding up, with no sign of replacement • Funder’s changed policies and priorities: • Donors are emphasizing “strengthening Health Systems” above treatment • Plans to transition AIDS programs to the mainly unprepared Ministries of health for integration into the continuum of care

21. Conclusion • Current WHO recommendation of starting ART 350 CD4 should be considered only the minimum interim start level, while awaiting further evidence from ongoing trials evaluating the benefits of starting earlier and the “Test and Treat” model

22. World Leaders made commitment to “Universal access” by the year 2010

23. Acknowledgements • DART and ARROW Trial Teams • Sarah Walker for providing the data and graphic illustrations • Others recognised on individual slides

24. End

25. WHO Recommendations for initiating ART in HIV infected infants and children according to clinical stage and immunological markers (May 2010)

26. WHO Recommendations for initiating ART in infants and children (May 2010)