The PEARLS Study: A Multinational Clinical Trial

of HIV TreatmentProspectiveEvaluation ofAntiretrovirals inResourceLimitedSettings

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 ReverseTranscriptase Inhibitors

(NRTIs)ZidovudineDidanosineStavudine

Lamivudine

ProteaseInhibitors (PIs)

SaquinavirRitonavirIndinavir

Non-NucleosideReverse Transcriptase

Inhibitors (NNRTIs)Nevirapine

2NRTIs + PI2NRTIS + NNRTI3NRTIs

UNAIDS and WHO, 2008

Worldwide AIDS Deaths (1990-2001)

North America11

Caribbean5.65.6

Latin America2.52.5

Western Europe0.30.3

North Africa & Middle East4.64.6

Sub-Saharan Africa5.75.7

Eastern Europe & Central Asia1.41.4

East Asia & Pacific3.03.0

South & South-East Asia4.84.8

Australia & New Zealand

0.30.3

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 AddressJanuary 29, 2003

Readmy 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 (2002-2007)

Ann Intern Med. 2009;150:688-695

Rollout of antiretrovirals in Rollout of antiretrovirals in resource-limited settings: resource-limited settings:

Knowledge GapsKnowledge 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 ACTG International Therapeutic Initiative (2002)Therapeutic Initiative (2002)

• Elucidate the most effective approaches to HIV-1 Elucidate the most effective approaches to HIV-1 therapy in resource limited international settingstherapy in resource limited international settings

• Inform public policy though clinical trials research on Inform public policy though clinical trials research on treatment of persons with HIV-1 infection in resource treatment of persons with HIV-1 infection in resource limited settingslimited settings

• Transfer technology and develop infrastructure to Transfer technology and develop infrastructure to conduct clinical trials in resource limited settingsconduct clinical trials in resource limited settings

• Support prevention research effortsSupport prevention research efforts

• Accelerate access to state-of-the-art care in resource Accelerate access to state-of-the-art care in resource limited settings through training, technology transfer limited settings through training, technology transfer and infrastructure developmentand 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 ACTG Clinical Trials Units (2001)(2001)

ACTG InternationalACTG InternationalClinical Trials Units (2005)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 DesignPEARLS Study Design

• Development of research objectives that Development of research objectives that are locally relevantare locally relevant

– Avoid exploitation Avoid exploitation

– Use ARVs that are/will be available for use in Use ARVs that are/will be available for use in the countries where the study is conductedthe 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

• 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

PEARLS Design (May PEARLS Design (May 2002)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;350:1850-61.

PEARLS Redesign (March PEARLS Redesign (March 2003)2003)

• Planned DSMB interim review of A5095 Planned DSMB interim review of A5095 found that ZDV/3TC/ABC (3 NRTI) provided found that ZDV/3TC/ABC (3 NRTI) provided inferior HIV suppression compared to inferior HIV suppression compared to ZDV/3TC/EFV (2NRTI + NNRTI)ZDV/3TC/EFV (2NRTI + NNRTI)

• PEARLS team felt it was unethical to PEARLS team felt it was unethical to randomize participants to a comparison of randomize participants to a comparison of all nucleoside reverse transcriptase all nucleoside reverse transcriptase inhibitors vs a non-nucleoside reverse inhibitors vs a non-nucleoside reverse transcriptase inhibitor regimenstranscriptase 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 PopulationPEARLS 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

May

Jul Sep

Nov

Jan M

ar

May

Jul Sep

Nov

Jan M

ar

May

Jul Sep

Acc

rual

200

400

600

800

1000

1200

1400DomesticInternationalTotal

2005 2006

1,571

2007

Participant Characteristics (N = 1,571)Female 47%

Median age (IQR) 34 (29-41)

Race

Black African

Asian

White

Other

Mestizo

African American

34%

23%

16%

10%

8%

6%

Median CD4 cells/mm3 (IQR) 172 (91-231)

Median log10 HIV viral load (IQR) 5.0 c/mL (4.6-5.5)

History of TB 20%

A51

75 A

ccru

al

0

50

100

150

200

250

300

Men Women

US South Africa

PeruM

alawi

IndiaZim

babwe

Thailand

HaitiBrazil

PEARLS DSMB Reviews

1 Design June 2003

2 Safety only November 2005

3 Efficacy and Safety July 2006

4 Safety Only November 2006

5 Efficacy and Safety May 2007

6 Efficacy and Safety May 2008

7 Efficacy and Safety May 2009

DSMB Findings (May 2008)

Hazard Ratio (+/- 99.8% CI)

0.01 0.1 1 10

Primary Endpoint

Virologic Failure

AIDS Progression

Death

Favors Arm 1AZDV/3TC + EFV

Favors Arm 1BddI + FTC + ATV

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!