Transcript Sino-US ACTG - Harvard University

The PEARLS Study: A
Multinational Clinical Trial of
HIV Treatment
Prospective
Evaluation of
Antiretrovirals in
Resource
Limited
Settings
Worldwide HIV Prevalence (2001)
UNAIDS 2001
Paradigm for Highly Active
Antiretroviral Therapy (1995)
Potent suppression of antiretroviral therapy
with a combination of at least 3 drugs
Nucleoside Reverse
Non-Nucleoside
Protease
Transcriptase Inhibitors Reverse Transcriptase Inhibitors (PIs)
(NRTIs)
Inhibitors (NNRTIs)
Saquinavir
Zidovudine
Nevirapine
Ritonavir
Didanosine
Indinavir
Stavudine
Lamivudine
2NRTIs + PI
2NRTIS + NNRTI
3NRTIs
Worldwide AIDS Deaths (1990-2001)
UNAIDS and WHO, 2008
Risk of Death from HIV vs Availability of ARV
Western Europe
0.3
North America
Eastern Europe
& Central Asia
1.4
1
East Asia & Pacific
Caribbean
5.6
3.0
North Africa & Middle East
4.6
South & South-East Asia
4.8
Latin America
2.5
Sub-Saharan Africa
5.7
Australia
& New Zealand
0.3
Data from WHO 2003
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
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
Antiretroviral Rollout (2002-2007)
UNAIDS 2008
Ann Intern Med. 2009;150:688-695
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 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
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 International
ACTG Clinical Trials Units (2001)
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 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
• 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 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 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
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
1,571
1400
Domestic
International
Total
Accrual
1200
1000
800
600
400
200
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2005
2006
2007
Participant Characteristics (N = 1,571)
Female
Median age (IQR)
47%
34 (29-41)
Race
Black African
34%
Asian
23%
White
16%
Other
10%
Mestizo
8%
African American
6%
Median CD4 cells/mm3 (IQR)
Median log10 HIV viral load (IQR)
History of TB
172 (91-231)
5.0 c/mL (4.6-5.5)
20%
200
150
100
A5175 Accrual
300
Men
Women
250
50
0
S
ti
ai d
H lan
ai
Th il
az
Br
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Pe ab
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a ic
di fr
In h A
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So i
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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)
Favors Arm 1B
ddI + FTC + ATV
Favors Arm 1A
ZDV/3TC + EFV
Primary Endpoint
1.67 (1.02, 2.75)
Virologic Failure
1.77 (1.04, 3.03)
AIDS Progression
3.00 (0.61,14.87)
Death
0.99 (0.23, 4.26)
0.01
0.1
1
10
Hazard Ratio (+/- 99.8% CI)
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
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
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!