The PEARLS Study: A Multinational Clinical Trial of HIV Treatment Prospective Evaluation of Antiretrovirals in Resource Limited Settings

UNAIDS 2001 Worldwide HIV Prevalence (2001)

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 Protease Inhibitors (PIs) Saquinavir Ritonavir Indinavir Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine 2NRTIs + PI 2NRTIS + NNRTI 3NRTIs

UNAIDS and WHO, 2008 Worldwide AIDS Deaths ( )

North America1 Caribbean5.6 Latin America2.5 Western Europe0.3 North Africa & Middle East4.6 Sub-Saharan Africa5.7 Eastern Europe & Central Asia1.4 East Asia & Pacific3.0 South & South-East Asia4.8 Australia & New Zealand0.3 Risk of Death from HIV vs Availability of ARV Data from WHO 2003

"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 Read my lips, Sadam. Baghdad, here we come

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

UNAIDS 2008 Antiretroviral Rollout ( )

Ann Intern Med. 2009;150:

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

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?

ACTG International Therapeutic Initiative (2002) Elucidate the most effective approaches to HIV-1 therapy in resource limited international settingsElucidate 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 settingsInform 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 settingsTransfer technology and develop infrastructure to conduct clinical trials in resource limited settings Support prevention research effortsSupport prevention research efforts Accelerate access to state-of-the-art care in resource limited settings through training, technology transfer and infrastructure developmentAccelerate access to state-of-the-art care in resource limited settings through training, technology transfer and infrastructure development

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)

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

ACTG Clinical Trials Units (2001) ACTG International Clinical Trials Units (2005) UNAIDS 2001

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

PEARLS Study Design Development of research objectives that are locally relevantDevelopment 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

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

Protocol Development : 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

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

N Engl J Med 2004;350:

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)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 regimensPEARLS 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

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

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

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

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

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

PEARLS Accrual

Participant Characteristics ( N = 1,571 ) Female47% Median age (IQR)34 (29-41) Race Black African Asian White Other Mestizo African American 34% 23% 16% 10% 8% 6% Median CD4 cells/mm 3 (IQR)172 (91-231) Median log 10 HIV viral load (IQR)5.0 c/mL ( ) History of TB20%

PEARLS DSMB Reviews 1DesignJune Safety onlyNovember Efficacy and SafetyJuly Safety OnlyNovember Efficacy and SafetyMay Efficacy and SafetyMay Efficacy and SafetyMay 2009

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

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

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

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

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

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)

Technology Transfer 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 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”

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

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

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

Thank You!