ATAC CCG TeachIn

1
ATAC / CCG Teach-In

• Evolution of Treatment Activism, Structure of the
  US AIDS Research Program, and
• Current Challenges
• 26 July 2002
• Mark Harrington
• Treatment Action Group
• New York, NY USA

2
The charge

• Whos who NIAID, NIH, DAIDS, CPCRA, AACTG,
  HVTN and who is doing what, including WIHS, MACS,
  et al., and a history of community involvement in
  creating and working within these structures.

3
The response

• Evolution of treatment activism in the U.S.
• Structure of the U.S. AIDS research program,
  particularly NIH
• Current challenges

4
Evolution of AIDS Treatment Activism

• Origins of AIDS
• The Denver Principles
• US Government Inaction
• Discovery of AZT
• Foundation of ACT UP

5
History of Activism (II)

• ACT UP seizes control of the FDA
• Expanded Access, Parallel Track, Accelerated
  Approval
• ACT UP storms the NIH
• Treatment activism in the ACTG
• Drug company campaigns
• Strengthening NIH
• Activism after HAART

6
The Denver Principles (I)

• The first national meeting of people with AIDS
  (PWAs) occurred in Denver, Colorado, in 1983.
• This meeting was important because it resulted in
  the creation of the first PWA self-empowerment
  document, the so-called Denver Principles.

7
The Denver Principles (1983)

• We recommend that people with AIDS
• 1. Form caucuses to choose their own
  representatives, to deal with the media, to
  choose their own agenda, and to plan their own
  strategies.
• 2. Be involved at every level of decision-making
  and specifically serve on the boards of directors
  of provider organizations.
• 3. Be involved in all AIDS forums with equal
  credibility as other participants, to share their
  own experiences and knowledge.
• 4. Substitute low-risk sexual behaviors for those
  that could endanger themselves or their partners.
  We feel that people with AIDS have an ethical
  responsibility to inform their potential sexual
  partners of their health status.

8
US Government Inaction

• The US government failed to respond to the new
  epidemic.
• President Ronald Reagan didnt mention the word
  AIDS until 1987.
• Congress was forced to allocate resources for
  research on the new emergency.

9
Community-Based Organizations Respond to AIDS

• Gay Mens Health Crisis (GMHC), 1982
• Project Inform, 1985
• AIDS Coalition to Unleash Power (ACT UP), 1987
• Treatment Action Group (TAG), 1992
• And thousands of others (1982-2002)

10
AZT Discovered

• In 1985 researchers at the National Cancer
  Institute (NCI) and Burroughs-Wellcome discovered
  that an old, discarded cancer compound,
  azidothymidine (AZT) was active against HIV in
  the test tube. Studies in people with AIDS were
  begun.
• In 1986 the phase II study of AZT was stopped
  early when after 19 weeks just one person on AZT
  had died, versus 19 people on placebo
• AZT was distributed to 15,000 people on a
  treatment investigational new drug (treatment
  IND) program for the next eight months.

11
AZT Approved

• In March 1987 the US Food Drug Administration
  granted approval for BW to market AZT (Retrovir)
  as a treatment for people with AIDS.
• BW sold AZT at 10,000/year, then the most
  expensive drug ever marketed.
• US and British French researchers began studying
  earlier AZT to see if it delayed progression to
  AIDS and death (ACTG 019 study, Concorde study).

12
ACT UP

• Outraged by the high price of AZT, and by
  government inaction on AIDS, activists in New
  York City founded ACT UP in March 1987 to force
  the countrys leaders to deal with AIDS.
• ACT UP quickly spread around the country and
  abroad e.g., France.
• ACT UP used direct street protests and targeted
  zaps to highlight injustice, prejudice, and
  abandonment of people with AIDS, and to demand
  government resources for fighting the disease.

13
ACT UP Seizes Control of the FDA

• Outraged by slow FDA regulation of clinical
  trials for new drugs for AIDS and HIV, ACT UP
  mobilized a national demonstration at FDA
  headquarters on 11 October 1988. Over 1,500
  activists surrounded and shut down the FDA.
  Seize Control of the FDA made front page
  headlines across the country.
• As a result, FDA began to show new flexibility
  when it came to the testing, distribution, and
  approval of HIV/AIDS drugs.

14
Parallel Track / Expanded Access

• In 1989, FDA and NIH approved the first parallel
  track program providing wide pre-approval access
  to a new AIDS drug for people failing AZT. Over
  35,000 people ultimately Bristol-Myers ddI
  (didanosine, later Videx) under this first
  parallel track program.
• Later parallel track/expanded access programs
  were developed for d4T (stavudine, Zerit), 3TC
  (stavudine, Epivir), the protease inhibitors,
  etc..
• The Coalition for Salvage Therapy (CST) continues
  to press FDA and drug companies to provide
  expanded access programs for new ARVs for people
  failing current therapy. Current US expanded
  access programs include BMS atazanavir and
  Roche/Trimeris T-20.

15
Accelerated Approval

• In 1992, FDA established the accelerated
  approval program under which new AIDS drugs
  could be approved on the basis of beneficial
  changes in surrogate markers such as changes in
  CD4 counts or HIV viral load reductions. Drugs
  receiving accelerated approval included ddC
  (1992), d4T (1994), 3TC (1995), saquinavir
  (Invirase, 1995), indinavir (Crixivan, 1996),
  nevirapine (Viramune, 1996), efavirenz
  (Sustiva/Stocrin, 1998), and tenofovir (Viread,
  2001).
• Drugs are given accelerated approval based on
  favorable changes in viral load at 24 weeks, and
  full approval based on favorable changes in viral
  load at 48 weeks (formerly full approval was
  based on proof of clinical benefit).

16
ACT UP Storms the NIH

• In 1990, the AIDS Clinical Trials Group (ACTG)
  was unwilling to let AIDS activists and people
  with AIDS attend its meetings. Activists wanted
  the ACTG to have a broader agenda, including OI
  research, and to broaden eligibility criteria for
  trials to include more women, people of color,
  injecting drug users, etc.
• On 21 May 1990 ACT UP Stormed the NIH with a
  massive demonstration to demand that NIH tell the
  ACTG to enable community participation.
• As a result, NIH forced the ACTG to let in the
  activists, forming the Community Constituency
  Group (CCG) and allowing activists and people
  with AIDS to participate as full members on all
  ACTG committees and protocol teams and opening
  up the ACTG meetings to public participation.

17
Results of Storm the NIH

• Activists successfully pushed the ACTG to invest
  much more in studies of drugs to prevent or treat
  AIDS-related opportunistic infections and
  cancers, resulting in FDA approval for Bactrim
  (cotrimoxazole) for PCP prevention (1990),
  ganciclovir for CMV retinitis (1989), fluconazole
  for crytpococcal meningitis (1990), rifabutin,
  clarithromycin, and azithromycin for prevention
  of Mycobacterium avium complex (MAC) (1990-94),
  etc.
• Since 1990, activists have been an integral if
  not always a fully empowered and equal
  participant within the ACTG and other NIH
  supported clinical trials systems in the USA.
  Similar models have been adopted elsewhere.

18
Strengthening the NIH Office of AIDS Research
(OAR)

• In 1992, AIDS research was stalled. The NIH
  program, conducted at 18 different institutes,
  lacked coordination, planning, evaluation.
• Groups such as TAG called for greatly expanded
  resources for basic research on HIV pathogenesis,
  to provide a stronger scientific framework for
  the development of new drug targets and effective
  vaccine candidates.
• In addition, TAG called on Congress and the
  President to strengthen the NIH Office of AIDS
  Research (OAR), giving it power to budget, plan,
  coordinate and evaluate the then 800 million NIH
  AIDS research program, which was carried out by
  17 un-coordinated institutes.

19
Strengthening Basic Research on AIDS

• As a result of TAGs recommendations, in 1993
  Congress passed, and President Clinton signed,
  legislation creating a stronger OAR.
• In the first years of the Clinton administration
  the NIH AIDS research budget increased by over
  25.
• Under the leadership of immunologist Bill Paul,
  the OAR commissioned a major external review of
  the NIH AIDS research program, which resulted in
  the 1996 Levine Committee report recommending
  sweeping reforms of the NIH AIDS program.
• By 2002, the NIH AIDS research budget is 2.7
  billion, while the NIH as a whole has doubled in
  size since 1997, to 28 billion.
• Support for basic research increased by many
  hundreds of millions of dollars.
• The new basic research helped lead to a better
  understanding of HIV pathogenesis but better
  treatments, a vaccine and a cure are still many
  years away.

20
The HAART Revolution

• In 1996 the advent of the protease inhibitors,
  the use of viral load testing to monitor
  treatment, and the use of three drugs in
  combination (HAART) led to a dramatic decrease in
  AIDS and death rates among people in the
  industrialized world.

21
Impact of ART

• U.S. AIDS deaths peaked at 50,000/year in
  1994-1995.
• In 2000, there were 16,000 AIDS deaths.
• AZT used in pregnancy has reduced perinatal HIV
  transmission from 1,000 cases/year to 100
  cases/year.

22
Treatment Activism Post-HAART

• HAART increased the need for
• -- Treatment education
• -- Adherence training support
• -- Research on side effects
• -- Research on resistance
• -- Research on treatment strategies

23
Long-Term Effectiveness Research

• After HAART (1996) and the new U.S. DHHS HIV
  treatment guidelines (1997), activists pushed for
  NIH to sponsor studies looking at treatment
  strategies and long-term effectiveness of ART,
  including
• -- When to start (WTS)
• -- When to change (WTC)
• -- Structured treatment interruptions
• (STIs) intermittent therapy

24
Structure of the U.S. AIDS Research Program

• In 2002, the U.S. government is spending 14.7
  billion on HIV/AIDS.
• -- 59 on care
• -- 18 on research
• -- 11 on assistance
• -- 7 on prevention
• -- 6 on international programs
• -- KFF 2002

25
U.S. AIDS Research 2002

• In 2002, the U.S. is spending 2.6 billion on
  HIV/AIDS research.
• Of this, NIH spends 2.5 billion (up from 800
  million in 1991).
• Of this, NIAID spends 1.192 billion.
• 24 other NIH institutes spend the rest.
• The NIH Office of AIDS Research (OAR) is supposed
  to coordinate the entire NIH AIDS research effort.

26
Structure (II)

• Department of Health Human Services
• -- CDC
• -- FDA
• -- NIH
• NIH Director
• -- OAR
• NIAID
• -- Division of AIDS (DAIDS)
• NCI
• (25 other institutes)

27
NIH AIDS Program Areas

• Natural history/epidemiology 271 million
• Etiology/pathogenesis 719 million
• Therapeutics 702 million
• Vaccines 334 million
• Behavioral/social science 345 million
• Training/infrastructure 104 million
• Information dissemination 35 million

28
NIAID AIDS Clinical Trials Programs

• Adult AIDS Clinical Trials Group (AACTG)
• Pediatric AIDS Clinical Trials Group (PACTG)
• Community Programs for Clinical Research on AIDS
  (CPCRA)
• Acute HIV Infection Early Disease Research
  Program (AIEDRP)
• Evaluation of Subcutaneous Proleukin in a
  Randomized International Trial (ESPRIT)

29
What is the Structure of the AACTG?

• 95 million/year
• Leadership Executive Committee
• All studies must be approved by the Scientific
  Agenda Steering Committee (SASC)
• Three other committees can propose studies
• -- HIV Research Agenda Committee
• -- Immunology Research Agenda Committee
• -- Complications Research Agenda Committee
• Plus, there are a lot of support committees
  Pharmacology, Quality of Life, Womens Health,
  etc.

30
What is the Agenda of the AACTG?

• How is the AACTG agenda addressing crucial
  clinical questions related to the treatment of
  HIV among the 1 million HIV infected people
  living in the USA?
• Are they addressing questions such as
• -- When to start/switch/suspend ART?
• -- When to treat HCV in coinfected people?
• -- How to treat (or avoid) lipodystrophy?
• -- How to treat (or avoid) resistance?

31
Other NIAID AIDS Networks

• Centers for AIDS Research (CFARs)
• Comprehensive International Program of Research
  on AIDS (CIPRA)
• HIV Prevention Trials Network (HPTN)
• HIV Vaccine Trials Network (HVTN)
• Multicenter AIDS Cohort Study (MACS)
• Women Infants Transmission Study (WITS)
• Womens Interagency Health Study (WIHS)

32
Other NIH Clinical Trials Programs

• AIDS Malignancies Consortium (AMC), NCI
• Studies of the Ocular Complications of AIDS
  (SOCA), NEI
• Neurology AIDS Research Consortium (NARC), NINDS
• PACTG (part), NICHD

33
Community involvement

• All of the NIH supported clinical trials
  programs, including prevention, treatment, and
  vaccine trials, are supposed to have meaningful
  community involvement through a CCG, a CAB, or
  community people on their steering committees.
• Do they??

34
Some challenges for treatment activists

• Are the NIH programs well-coordinated?
• Are their agendas well-designed and executed?
• Are their research agendas relevant to a changing
  epidemic?
• Is community input and involvement real or is it
  symbolic?

35
Some more challenges for treatment activists

• How do community activists ensure continuity,
  train and mentor new advocates, and provide for
  exchanging and publicizing important issues and
  initiatives in the NIH AIDS research program?
• How are the NIH programs responding to the
  changing domestic research priorities?
• How are the NIH programs responding to the
  changing international research priorities?
• How can activists ensure that these programs
  continue to address both the domestic epidemic
  and the international pandemic?

36
6 Questions for DAIDS (1)

• Domestic long-term effectiveness research. How
  is NIAID/DAIDS going to ensure that the key
  unanswered questions about the use of ART are
  going to be addressed? Is there a game plan? If
  so, what is it? If not, why not? These are the
  long-term clinical effectiveness questions
  include when to start, when to switch, stop, but
  also questions with little commercial appeal such
  as head-to-head comparisons of regimens that
  contain drugs from different companies, studies
  of various forms of structured intermittent
  therapy, etc.

37
6 Questions for DAIDS (2)

• Whats going on at the AACTG? The Adult AIDS
  Clinical Trials Group (AACTG) receives 95
  million/year for its national clinical trials
  infrastructure. What recent or current studies
  are they doing to address and answer questions
  relevant to the standard of care for people with
  HIV in the USA? Why does it take over a year
  from study approval to first patient enrollment?
  Why is accrual into the AACTG HIV Research Agenda
  Committee (RAC) studies so slow?

38
6 Questions for DAIDS (3)

• What is the international treatment research
  agenda? If there is no game plan for this kind
  of operational/effectiveness research
  domestically, how does DAIDS or the AACTG expect
  to answer these kinds of questions
  internationally on optimal ART regimens, when
  to start, what forms of laboratory or clinical
  monitoring are necessary, improving MTCT
  regimens, developing and expanding model pilot
  projects, conducting larger-scale cohort studies,
  etc.

39
6 Questions for DAIDS (4)

• What is being done to foster new anti-HIV drug
  targets? How is DAIDS ensuring that the
  translational research on "new targets" like vif,
  gag, RNAseH gets done? This has generally been
  ignored by industry and academia thus far because
  it's too basic for industry and too applied for
  molecular biologists.

40
6 Questions for DAIDS (5)

• What is the HIV Vaccine Trials Network (HVTN) up
  to? What is DAIDS proposing to do with the VTN,
  now that the big canarypox (ALVAC/gp120 HVTN
  study 501) trial that was to occupy their time
  has been cancelled?

41
6 Questions for DAIDS (6)

• Are there plans for the post-doubling era? What
  are OAR and NIAID doing to plan for the post-NIH
  budget doubling era, projected to begin after FY
  2003, when annual increases for NIH as a whole
  and for AIDS research will go from double to
  single digits? How will this impact on program
  flexibility necessary to respond to new and
  emerging challenges in AIDS research,
  particularly those listed above?

42
Some activist principles

• Knowledge is power.
• Mobilize communities.
• Form coalitions with researchers and
  policy-makers.
• Be flexible.
• Use the media.
• Hold political leaders accountable.
• Communicate your goals accomplishments.
• Build sustainable movements.