1 / 31

Potential Role of Phidisa in the Global HIV Clinical Research Agenda

Potential Role of Phidisa in the Global HIV Clinical Research Agenda. Phidisa Conference Richards Bay, South Africa. Jim Neaton 26 July 2004. Some Points for Discussion. Global epidemic = global research.

xanto
Download Presentation

Potential Role of Phidisa in the Global HIV Clinical Research Agenda

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Potential Role of Phidisa in the Global HIV Clinical Research Agenda Phidisa Conference Richards Bay, South Africa Jim Neaton 26 July 2004

  2. Some Points for Discussion • Global epidemic = global research. • The optimal designs for addressing many questions are large, long-term, randomized studies. • Research requires an infrastructure. • Potential roles for Phidisa.

  3. Discussion Point 1:Motivation for Global Research • Major public health problem (no country will be spared) • Large studies can be quickly enrolled • Faster translation of research globally

  4. Adults and children estimated to be living with HIV/AIDS at the end of 2003 Eastern Europe & Central Asia 1.2 – 1.8 million Western Europe 520 000 – 680 000 North America 790 000 – 1.2 million East Asia & Pacific 700 000 – 1.3 million North Africa & Middle East 470 000 – 730 000 Caribbean 350 000 – 590 000 South & South-East Asia 4.6 – 8.2 million Sub-Saharan Africa 25.0 – 28.2 million Latin America 1.3 – 1.9 million Australia & New Zealand 12 000 – 18 000 Total: 38 million

  5. Large Studies Are Required Because… • Clinical outcomes are important. • Clinical event rates are low, but not low enough. • Considering the millions that are infected, treatments that result in moderate improvements in morbidity and mortality are very important from a public health point of view. The goal is optimization of clinical management.

  6. Side Effects of Global Research • Better trained work force. • Efficiency – some replication is good but too much is wasteful. • Familiarity and personal experience with treatments results in faster adoption in practice.

  7. Additional Motivations for a Global Research Agenda • Participating in research is good for those with the disease – it is not fair that some do not have access to research. • Many research questions are common to sites around the world.

  8. Participating in Research is Good • For those with the condition being studied • additional medical monitoring • personal awareness/reassurances • case management and social services • For researchers • access to new treatments • improved knowledge of research

  9. Example: A Research Question of Broad Interest • DHHS and IAS guidelines recommend an NNRTI-based regimen (efavirenz) or a ritonavir-boosted regimen (lopinavir/ritonavir) as an initial treatment regimen. • It is not clear which is best. • A large trial is needed!

  10. PHIDISA II: Relevant to Many Sites Around the World 2,800 HIV-infected participants withCD4+ < 200 cells/mm3 or AIDS AZT + ddI + EFV AZT + ddI + r/LPV d4T + 3TC + EFV d4T + 3TC + r/LPV

  11. Other Relevant, Large Ongoing Trials • ESPRIT: Does the addition of an immunomodulator to optimal ART prolong AIDS-free survival? • SMART: Does episodic compared to continuous use of ART prolong AIDS-free survival and reduce the incidence of major toxicities associated with treatment?

  12. ESPRIT HIV-infected patients on ART with CD4+ > 300 cells/mm3 • 10% 5-year event rate among controls • 27% difference in AIDS/death • Follow-up until 320 AIDS/death events SC rIL-2 7.5 MIU (N = 2,090) No rIL-2 (N = 2,060)

  13. SMART HIV-infected patients with CD4+ > 350 n = 3000 n = 3000 Virologic Suppression (VS) Strategy [Use ART to maintain viral load as low as possible throughout follow-up] Drug Conservation (DC) Strategy [Stop or defer ART until CD4 < 250; then episodic ART based on CD4 cell count to increase counts to > 350] • 15% 7-year event rate among controls (VS) • 17% difference in AIDS/death • Follow-up until 910 AIDS/death events

  14. Other Research Ideas Relevant to Sites Around the World • Management of OIs for participants starting therapy • Management of treatment failures • ART sparing strategies -- when to start and stop treatment (antiretroviral drugs and other treatments) • Prevention of complications

  15. Discussion Point 2:Many Questions Require Both a Large Quantity of Patients and Patience • Why randomized? • Why large? • Why long-term?

  16. Why Randomization? • Conscious and unconscious bias eliminated from treatment assignment • Known and unknown confounders balanced on average Moderate treatment effects cannot be reliably established in the presence of moderate bias.

  17. Why Large? Patients Randomized* Chance of CommentsEvents(Risk = 10%)Type II Error** on Sample Size 0-50 < 500 > 0.9 Utterly inadequate 50-150 1000 0.7-0.9 Probably inadequate 150-350 3000 0.3-0.7 Possibly inadequate 350-650 6000 0.1-0.3 Probably adequate > 650 10000 < 0.1 Adequate ** More than twice needed for 1/6 risk reduction instead of 1/4 * Probability of failing to achieve P < 0.01 if risk reduction = 25% Progress in CVD Dis 1985; Vol XXVII:335-371

  18. Why Long-Term? • Risks versus benefits of therapy on morbidity and mortality (the outcomes that count) cannot be assessed in the short term • “Some things you can count don’t matter; some things that matter, you can’t count” (Einstein) • Findings based on short follow-up may be wrong!

  19. Pooled Analysis of Immediate vs. Deferred AZT 0- 209 0.52 (0.39 - 0.68) 1- 357 0.94 (0.76 - 1.16) 2- 440 1.05 (0.87 - 1.27) 3- 369 1.12 (0.91 - 1.38) 4- 307 0.98 (0.78 - 1.23) 5+ 226 1.10 (0.84 - 1.43) No. AIDS/Death Events Year ofFollow-up Hazard Ratio* *Immediate vs. deferred AZT

  20. Protease Inhibitor versus Combination Nucleoside Therapy in Advanced Patients Interval ofFollow-up(months) 0 - 6 167 0.49 0.49 6 - 12 141 0.33 0.41 12 - 18 137 0.13 0.30 18 - 24 94 0.15 0.26 24 - 30 86 0.20 0.25 30 - 36 54 0.16 0.24 Hazard Ratio* No. AIDS/Death Events Cum. Interval *PI regimen vs. nRTIs adjusted for baseline CD4+

  21. Discussion Point 3:Infrastructure is Key: Defining the Question is Usually Easier Than Doing the Study Right • Training and coordination of interdisciplinary teams. • Data collection and management. • Data monitoring and analysis.

  22. Structure for Cooperative Studies(The Greenberg Report, 1967) (Independent DSMB) Policy Board or Advisory Committee National Advisory Heart Council Initialreviewgroup Institute staff (Sponsor) Executive Committee or Steering Committee CoordinatingCenter Participatingsites

  23. CopenhagenRCC MinneapolisRCC ESPRIT MODEL Minnesota Coordinating Center LondonRCC SydneyRCC Khon Kaen University, Srinagarind Hospital Israel Argentina Chulalongkorn University Hospital Siriraj Hospital Thailand NTCC Sydney RCC Thailand NTCC Australia Chiangrai Regional Hospital Chonburi Regional Hospital Singapore Japan

  24. PHIDISA Coordination Umtata Phalaborwa Mil 3 DMCOC Mil 2 Mtubatuba Mil 1 A future National Trial Coordinating Center in a global network?

  25. Role of Phidisa in the Fight Against AIDS • PHIDISA I and II • More Phidisa protocols done in the SANDF • NTCC in “Beyond ESPRIT” network • Catalyst for research in the region (coordinating center capabilities)

  26. Whatever You Decide, Remember • Keep it simple • Be flexible • Have fun!

  27. Keep it simple because it allows broaderparticipation “What a wonderful difference it would make if tens of thousands of physicians could report once in their lifetime how they had reshaped a fact of medical science.” Kornberg A. For Love of Enzymes. The odyssey of a biochemist, Harvard Univ Press, 1991.

  28. Be flexible because “Individualism – thinking for oneself - is highly desirable but can make a multi-center trial impossible.” Mainland D. J New Drugs, 1:197-205, 1961

  29. Have fun when you can because “Clinical trials lack glamour, they strain our resources and patience, and they protract to excruciating limits the moment of truth.” Frederickson DS, Bull NY Acad Med, 44:985-993, 1968

  30. Summay You can make a difference in the fight against AIDS!

More Related