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The PEARLS Study: A Multinational Clinical Trial of HIV Treatment

The PEARLS Study: A Multinational Clinical Trial of HIV Treatment. P rospective E valuation of A ntiretrovirals in R esource L imited S ettings. Worldwide HIV Prevalence (2001). UNAIDS 2001.

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The PEARLS Study: A Multinational Clinical Trial of HIV Treatment

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  1. The PEARLS Study: A Multinational Clinical Trial of HIV Treatment ProspectiveEvaluation ofAntiretrovirals inResourceLimitedSettings

  2. Worldwide HIV Prevalence (2001) UNAIDS 2001

  3. Paradigm for Highly Active Antiretroviral Therapy (1995)Potent suppression of antiretroviral therapy with a combination of at least 3 drugs Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine Didanosine Stavudine Lamivudine Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine Protease Inhibitors (PIs) Saquinavir Ritonavir Indinavir 2NRTIs + PI 2NRTIS + NNRTI 3NRTIs

  4. Worldwide AIDS Deaths (1990-2001) UNAIDS and WHO, 2008

  5. Risk of Death from HIV vs Availability of ARV Eastern Europe & Central Asia 1.4 Western Europe 0.3 North America 1 East Asia & Pacific 3.0 North Africa & Middle East 4.6 Caribbean 5.6 South & South-East Asia 4.8 Latin America 2.5 Sub-Saharan Africa 5.7 Australia & New Zealand 0.3 Data from WHO 2003

  6. Read my lips, Sadam. Baghdad, here we come "I ask the Congress to commit $15 billion over the next five years, including nearly $10 billion in new money, to turn the tide against AIDS in the most afflicted nations of Africa and the Caribbean." State of the Union Address January 29, 2003

  7. Initiatives to Expand Global Access to ARV treatment • UN Global Fund to Fight AIDS, TB and Malaria • Announced 2001; Initial distribution of funds in 2003 • December 2005: 384,000 receiving ARVs in 65 countries • Presidents Emergency Plan For AIDS Relief (PEPFAR) • Announced January 2003: $10 billion in new funds over 5 years • 18 selected countries • December 2005: 471,000 people treated with ARVs • WHO 3 x 5 • Goal: 3 million people on ARVs in low/mid income countries by 2005 • Announced December 2003 (estimated 400,000 on ARVs) • June 2005: 1,000,000 people treated with ARVs

  8. Antiretroviral Rollout (2002-2007) UNAIDS 2008

  9. Ann Intern Med. 2009;150:688-695

  10. Rollout of antiretrovirals in resource-limited settings: Knowledge Gaps Most of what is known about the treatment of HIV comes from studies conducted in developed countries of N. America and Europe Factors that affect ARV efficacy may differ in other areas of the world: Drug toxicities Co-morbidities Diet/nutrition Human genetics

  11. Important Questions Related to the Global Treatment of HIV • Treatment Strategies • Which antiretroviral regimens should be used? • When during the course of HIV should ARVs be started? • Toxicities • Do ARV toxicities differ in different populations due to genetics, nutrition, co-morbidities? • Best strategies for monitoring toxicity and efficacy? • Co-infections • How do co-infections (TB, Hep B) influence decisions about what ARV regiment to start, when to start, toxicities, monitoring strategies? • How to best manage/prevent Immune Reconstitution Inflammatory Syndrome (IRIS)? • How to manage interactions between ARVs and anti-TB drugs, alternative/traditional medications?

  12. ACTG International Therapeutic Initiative (2002) Elucidate the most effective approaches to HIV-1 therapy in resource limited international settings Inform public policy though clinical trials research on treatment of persons with HIV-1 infection in resource limited settings Transfer technology and develop infrastructure to conduct clinical trials in resource limited settings Support prevention research efforts Accelerate access to state-of-the-art care in resource limited settings through training, technology transfer and infrastructure development

  13. Prospective Evaluation of Antiretroviral Therapy in Resource Limited Setting (PEARLS) Study • Multinational clinical trial funded by the NIAID through the AIDS Clinical Trials Group (ACTG) • Planning (2002 – 2005) • Accrual (2005 – 2007) • Follow-up and monitoring (2007 – present)

  14. PEARLS Study • Challenges • Study Design • Implementation • Opportunities • Knowledge gained • Transfer of clinical, pharmacy and laboratory expertise • Infrastructure development • Technology transfer

  15. ACTG Clinical Trials Units (2001) ACTG InternationalClinical Trials Units (2005) UNAIDS 2001

  16. Establishment of International Clinical Trials Units • Training in GCP • SOPs including pharmacy, lab, regulatory and clinical quality improvement • Laboratory: • GCLP compliant • Proficiency testing for each test • FDA-approved method (or validation study performed) • Accreditation Encouraged (CLIA or equivalent) • Pharmacy: • Appropriate storage requirements for product with limited access, vermin free • Refrigerator, Freezer if needed with continuous monitoring and alarm system • Controlled room temperature (15-30° C) with backup generator as appropriate to maintain temp and refrigeration

  17. PEARLS Study Design Development of research objectives that are locally relevant Avoid exploitation Use ARVs that are/will be available for use in the countries where the study is conducted

  18. Identification of Priority Research Questions • December 2001: Investigators from US and international communities were invited to submit research proposals • Spring 2002: Proposals evaluated by an international committee with representatives from each site • Priority questions: • Evaluation of PI- and NNRTI-sparing regimens • Evaluation of once-daily regimens

  19. Protocol Development • 2002-2003: Final study hypotheses and design formulated by a committee of US and international investigators from communities where the study would be conducted • During study design input solicited from community members at each site and community representatives joined study team

  20. PEARLS Design (May 2002) Hypothesis: An all nucleoside regimen is as safe and effective as a standard three drug regimen containing 2 NRTIs and efavirenz Sites: 12 ICTUs in 8 resource-limited countries Population: 1250 ARV naïve HIV-1-infected men and women with < 300 CD4+ cells/L Randomization: Zidovudine/lamivudine + efavirenz (2NRTI + NNRTI) Zidovudine/lamivudine + tenofovir (3NRTI) Zidovudine/lamivudine + didanosine (3NRTI) Treatment duration: 5 years

  21. N Engl J Med 2004;350:1850-61.

  22. PEARLS Redesign (March 2003) Planned DSMB interim review of A5095 found that ZDV/3TC/ABC (3 NRTI) provided inferior HIV suppression compared to ZDV/3TC/EFV (2NRTI + NNRTI) PEARLS team felt it was unethical to randomize participants to a comparison of all nucleoside reverse transcriptase inhibitors vs a non-nucleoside reverse transcriptase inhibitor regimens

  23. PEARLS Study Design • Step 1 (initial regimen) 1:1:1 randomization • Arm 1A: ZDV/3TC BID + EFV QD • Arm 1B: ddI QD + FTC QD + ATV QD • Arm 1C: TDF/FTC QD + EFV QD • Randomization stratified by country and screening plasma HIV RNA (> or < 100K) • Planned follow-up: the longer of 2.5 years or when at least 30% of participants have met the primary endpoint

  24. PEARLS Primary Endpoint • Time to treatment failure defined as the time from randomization to first occurrence of any of the following: • Death: any cause or • Disease progression - new or recurrent AIDS-defining OI or malignancy after 12 weeks of treatment or • Virologic failure - plasma HIV-1 RNA > 1,000 copies/mL after 16 weeks of treatment

  25. PEARLS Study Population 1520 HIV-1-infected persons Men and women > 18 years of age Naïve to antiretroviral therapy (< 7 days) CD4 < 300 At least 1200 subjects recruited from 12 sites in 8 resource-limited countries; Maximum of 320 subjects from ACTUs in the US

  26. Potential Safety Issues • Antiretroviral toxicities • Bone marrow, PN, liver, hypersensitivity rxn’s, renal and electrolyte, pancreatitis, myositis, lactic acidosis • Hep B co-infection • Pregnancy • Negative pregnancy test at study entry • Subjects who become pregnant while on study will be allowed to remain on study • EFV will be discontinued immediately • Subjects may remain on non-EFV study regimens or switch to a regimen provided outside of the study while pregnant • Breast-feeding • Permitted where formula-feeding is not an option • Breast-feeding women will be allowed to continue study drugs • ARV changes at discretion of site investigator • Biohazard containment

  27. PEARLS Implementation: Pilot Phase • PEARLS was the first ACTG clinical trial to be conducted at the participating international sites • Opened in a staged manner designed to identify and correct any deficiencies in good clinical practice (GCP) that may exist at the sites • Stage I: After 5 subjects begin treatment at a site, further enrollment at that site will be stopped until an outside monitor certified the site for further enrollment • Stage II: Full enrollment began after 6 sites successfully completed Stage I. Initially 100 spaces allocated to each international site

  28. PEARLS Accrual

  29. Participant Characteristics (N = 1,571)

  30. PEARLS DSMB Reviews

  31. 1.67 (1.02, 2.75) 1.77 (1.04, 3.03) 3.00 (0.61,14.87) 0.99 (0.23, 4.26) DSMB Findings (May 2008) Campbell et al, World AIDS 2008, Abstract THAB0404

  32. Response to DSMB Findings • Participants/Providers alerted to findings of DSMB (letters, dated May 23, 2008 distributed and posted) • 397 participants were still receiving the inferior regimen • Median time to starting an alternative antiretroviral regimen was 5 wks

  33. PEARLS Opportunities • Knowledge gained • Transfer of clinical, pharmacy and laboratory expertise • Infrastructure development • Technology transfer

  34. Knowledge Gained • Comparison of efficacy and safety of 3 different ARV regimens • Each has potential for use in resource-limited setting • Expected availability after study completion • Better understanding of how ARVs interface with unique features of each community: • Endemic co-infections • HIV strains (subtypes) • Nutrition • Human genetics • Human behavior • Traditional medications • Dissemination of knowledge to the communities

  35. Transfer of Expertise • Team-wide personnel training • Regional training programs geared toward issues relevant to Africa, Asia, South America • Each international site “twinned” with an experienced US site for training/mentoring • Training of community members for participation in Community Advisory Boards • Help to combat “brain drain” • Develop centers of expertise for future training and education of health care personnel in the community

  36. Infrastructure Development • Study implementation required investment in clinical, pharmacy and laboratory infrastructure at the sites • Infrastructure will be available for other research studies • Infrastructure may have multiple use (research and medical care)

  37. Technology Transfer Tertiary objective: “To assist with the transfer of immunologic, pharmacologic, and virologic technology and expertise relevant to the conduct of clinical studies of HIV-1 treatment in resource-limited settings” • Development of laboratory capacity at each site required implementation of technologies not previously available (i.e., HIV viral load tests) and/or more rigorous QA/QC of existing technologies • HIV drug resistance testing capacity developed at regional centers • Technology availability will assist with implementation of other research studies in the communities and will foster incorporation of improved technologies into patient care

  38. Access to Treatment after Study Completion • Antiretroviral therapy is life-long • Study sponsors will provide study antiretrovirals only during the duration of the study • Each site is responsible for identifying access to continued care and treatment after completion of study participation • The PEARLS team is developing a research objective to study the transition to local treatment

  39. PEARLS Summary • A multinational randomized clinical trial of HIV-1 treatment interventions was implemented in diverse resource-limited settings • The trial has been conducted with the same rigor as clinical trials conducted in the United States • PEARLS was designed to maximize benefits to resource-limited communities by: • Identifying priority research questions through interactions with the communities • Working to ensure that knowledge, expertise, infrastructure and technology used for the study will be available to the communities after the study is completed

  40. Acknowledgements • PEARLS study participants (N=1,571) and sites (N = 43) • PEARLS Study Team (N = 82) • PEARLS Co-Chairs: Tim Flanigan, James Hakim, N. Kumarasamy • SDAC - Laura Smeaton, Victor DeGruttola • ACTG Ops – Ron Barnett, Barbara Brizz, Barbara Bastow, Laura Moran, Lara Hosey • FSTRF – Apsara Nair, Ann Walawander • NIAID/DAIDS – Karin Klingman, Edith Swann, Anna Martinez, Eva Smith • Boehringer-Ingelheim Pharmaceuticals - Carolyn Conner, Marita McDonough • Bristol-Myers Squibb – Gary Thal, Jonathan Uy • Gilead Sciences – Jim Rooney, Audrey Shaw • GlaxoSmithKline – Keith Pappa, Elke Loeschel

  41. Thank You!

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