PEARLS is a Phase IV clinical trial evaluating the efficacy of once-daily antiretroviral regimens for the initial treatment of HIV-1 in resource-limited settings. The trial aims to enroll 1,520 adult patients naive to treatment with CD4 counts less than 300 from the US and resource-limited countries. Patients are randomized to receive one of three treatment combinations: two NRTIs plus an NNRTI twice daily; two NRTIs plus a PI once daily; or two NRTIs plus an NNRTI once daily. The primary endpoint is time from treatment initiation to treatment failure, defined as death, disease progression, or virologic failure. The trial has faced challenges establishing research infrastructure

1. PEARLS A P rospective E valuation of A nti R etroviral T reatment in R esource- L imited S ettings

3. “ Men wanted for hazardous journey. Small wages, bitter cold, long months of complete darkness, constant danger, safe return doubtful. Honor and recognition in case of success.”

4. PEARLS, an ongoing voyage on uncharted seas…

5. … launched from a mature clinical trials organization

6. ACTG proposes international initiative to NIAID - 1999

7. 06/06 e The greatest burden of the epidemic is outside the U.S., especially in resource-limited settings 2.4

8. WHO-UNAIDS Data Need for treatment far exceeds access

9. Organizational, funding & pharmaceutical provisions were provided

10. Despite uncertainties the PEARLS crew maintained a single intention of purpose…

11. … meeting biweekly via teleconferences & in person whenever possible…

12. … with leadership from the Co-Captains

13. 1520 adult patients “naïve” to treatment with CD4 T-cells <300 enroll, 270 from the U.S. and 1250 from resource limited settings

14. Three types of anti-HIV medication are used Nucleoside reverse transcriptase inhibitor (NRTI) Non-NRTI (NNRTI) Protease inhibitor (PI)

15. Hypothesis 1: three-drug regimens are given once vs. twice daily provide similar anti-HIV benefit

16. Hypothesis 2: a drug regimen containing a PI, given once a day, provides similar anti-HIV benefit versus a regimen containing an NNRTI given twice a day

17. Patients are randomized open label to either 2 NRTIs + NNRTI 2x/day or 2 NRTI + PI 1x/day or 2 NRTIs + NNRTI 1x/day

18. The time from initiation of treatment until the failure of treatment is the primary study endpoint and defined as either: Death any reason Disease progression medical condition that defines AIDS Virologic failure 2 viral loads >1,000 c/mL at wk 16 or later

19. 2002 04 05 06 07 May DSMB June Full accrual n = 1520 April Protocol development began May V1.0 May Accrual began November DSMB July DSMB October V2.0 November DSMB

20. Lima Rio de Janerio* Porto Alegre Johannesburg* Durban Harare Lilongwe Blantyre Chennai* Pune* Chiang Mai Port-au-Prince 21 Sites Data Center 33 clinical research sites implement PEARLS *Genotyping labs

21. PEARLS encounters challenges and uncertainties

22. Research infrastructure was limited in certain areas & was upgraded

23. Acquisition of study drugs were at times challenging

24. Changes in HIV clinical science and differing treatment guidelines necessitates adaptation

25. Conclusions

26. The voyage continues… Photo Credits: women & boy, UNAIDS/G. Pirozzi; woman & man, UNAIDS/W. Phillips; medications, UNAIDS/O. O’Hanlon