COMBATING GLOBAL HEALTH CRISES: LESSONS FROM HIVAIDS

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COMBATING GLOBAL HEALTH CRISES LESSONS FROM
HIV/AIDS

• Howard S. Jaffe, MD
• Gilead Foundation

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Global HIV/AIDS

• 39 million people with HIV
• 5 million new infections per year (14,000/day)
• gt 50 women
• 50 15-24 years old
• gt 95 in lower income countries

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HIV Treatment History
NNRTIs introduced
Genotypic and phenotypic testing become widely
available
First cases reported
First once-daily fixed-dose combinations
introduced
HIV-1 genome sequenced
Viral load testing introduced
Drug-resistant HIV shown to be transmissible
1980
1985
1990
1995
2000
2005
First NtRTI introduced
First HIV treatment approved (AZT)
HAART begins protease inhibitors introduced
Metabolic complications of ARVs recognized
HIV-1 identified
Fixed-dose combinations for HIV therapy
Source Centers for Disease Control and
Prevention, GMHC, AEGiS, The New York Times
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Protease Inhibitors Saquinavir Ritonavir Indinavir
Nelfinavir Ampnavir Lopinavir/ritonavir
Atazanavir Fosamprenavir
Tipranavir
NRTIs Zidovudine (AZT) Didanosine (ddI) Stavudine
(d4T) Lamivudine (3TC) Abacavir (ABC) Tenofovir
(TDF) Emtricitabine (FTC)
NNRTIs Nevirapine Delavirdine Efavirenz
Fusion Inhibitors Enfuvirtide
Cellular DNA
Nucleus
HIV Virions
Reverse Transcriptase
Integrase
Unintegrated double stranded Viral DNA
gag-pol polyprotein
Integrated viral DNA
Viral mRNA
CCR5 or CXCR4 co-receptor
1
3
4
5
2
6
Assembly and Release
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AIDS Deaths and Persons Living with AIDS1982
2003 United States
Living with AIDS
AIDS Deaths
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ARV Regimens Are Increasingly Effective
AZT 3TC IDV (START II)
AZT 3TC ATV (AI424-034)
with HIV RNA
with HIV RNA
AZT 3TC EFV (AI424-034)
AZT 3TC ABC (CNA3005)
lt50 copies/
mL
lt50 copies/
mL
d4T ddI IDV (START II)
AZT 3TC IDV (DMP-006)
at 48 Weeks (ITT)
at 48 Weeks (ITT)
AZT 3TC IDV (AVANTI 2)
AZT ddI NVP (INCAS)
AZT 3TC NFV (AVANTI 3)
AZT 3TC IDV (CNA3005)
Regimen (trial)
Regimen (trial)
AZT 3TC IDV (START I)
d4T ddI 3TC (Atlantic)
d4T 3TC IDV (START I)
d4T ddI NVP (Atlantic)
2 NRTIs SQV (NV-15355)
d4T 3TC NFV (M98-863)
AZT 3TC ABC (CNAB3003)
d4T ddI IDV (Atlantic)
AZT 3TC EFV (EPV20001)
AZT 3TC EFV (DMP-006)
d4T 3TC LPV/RTV (M98-863)
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
Based on Bartlett. Presented at 7th CROI 2000
San Francisco, Calif. Poster 519.
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The Evolution of HAART
Dosing
Daily pill burden
Regimen
1996
10 pills, Q8H
Zerit/Epivir/Crixivan
1998
Combivir (Retrovir/Epivir)/ Sustiva
5 pills, BID
2002
3 pills, BID
Combivir/Sustiva
2003
3 pills, QD
Viread/Emtriva/Sustiva
2004
Truvada (Viread/Emtriva)/Sustiva
2 pills, QD
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Importance of Adherence
Relationship of adherence to virologic success1
P .00001
Patients reaching undetectable HIV RNA LOQ 400
()
Adherence Rates
Greatest danger zone for developing resistance
1Paterson. Ann Intern Med 200013321.
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Lessons Learned in the Developed World

• Progress is usually incremental, with notable
  exceptions
• Collaboration between multiple stakeholders is
  essential
• Community
• Regulators
• Academicians
• Industry
• Simplicity improves outcomes
• The battle still rages
• Successful prevention strategies remain elusive
• Complacency is dangerous

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HIV/AIDS 39 Million People Infected Globally
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Changes in Life Expectancy
65
60
Botswana
Uganda
55
South
-
Africa
Zambia
Life expectancy at birth, in years
50
Zimbabwe
45
40
35
1950
-
55
1955
-
60
1960
-
65
1965
-
70
1970
-
75
1975
-
80
1980
-
85
1985
-
90
1990
-
95
1995
-
00
Years
Source
United Nations Population Division, 1998
00001
-
E
-
45

27 June 2000
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3 x 5 InitiativeWHO - UNAIDS

• Plan to treat 3 million HIV-infected people in
  developing countries by end of 2005
• Ambitious goal
• 5,000 new patients to begin ARVs daily
• gt50,000 people need to be tested daily
• Estimated cost of gt4 billion USD per year
• Status 1 million people on ARVs by June 2005

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Presidents Emergency Plan for AIDS Relief
(PEPFAR)

• 15 billion over 5 years with focus on 15
  countries in Africa, Asia and Caribbean
• Central objectives
• Treat 2 million people with HAART
• Prevent 7 million new HIV infections
• Care for 10 million HIV-affected individuals
  (AIDS orphans and vulnerable children)
• PEPFAR funds distributed as follows
• 55 for treatment
• 20 for HIV/AIDS prevention
• 15 for palliative care
• 10 for aid to orphans and vulnerable children

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DHHS Initiatives to Support ARV Access and
Innovation

• FDA rapid review of branded and generic
  fixed-dose combinations and co-packaged ARVs
  provides standards for PEPFAR
• Reduces impediments to industry collaborations to
  create simpler ARV regimens
• Risk of re-importation considered
• Potential risks to public health
• Negative impact on new drug development and
  innovation

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Global HIV/AIDSGileads Response

• Innovation to improve treatment outcomes
• Once-daily, well-tolerated ARVs with high barrier
  to resistance
• Collaboration with BMS to create first all in
  one ARV
• In-country partnerships in Africa, Asia and
  Caribbean
• Gilead Access Program in least-developed
  countries (no-profit pricing)
• Volume-based discounting in middle-income
  countries
• Emphasis on clinical research to reduce cost of
  healthcare and prevent HIV infection

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Gilead Access Program

• Mali
• Mauritania
• Mauritius
• Moldova
• Mongolia
• Morocco
• Mozambique
• Myanmar
• Namibia
• Nepal
• Nicaragua
• Niger
• Nigeria
• Pakistan
• Papua New Guinea
• Rwanda
• Republic of Congo
• Saint Kitts and Nevis
• Saint Lucia

• Algeria
• Afghanistan
• Angola
• Antigua and
• Barbuda
• Bahamas
• Bangladesh
• Barbados
• Belize
• Benin
• Bhutan
• Bolivia
• Botswana
• Burkina Faso
• Burundi
• Cambodia
• Cameroon
• Cape Verde
• Central African

• Dominican Republic
• Egypt
• Equatorial Guinea
• Eritrea
• Ethiopia
• Gabon
• Gambia
• Ghana
• Grenada
• Guatemala
• Guinea
• Guinea-Bissau
• Guyana
• Haiti
• Honduras
• Indonesia
• Jamaica
• Kenya
• Kiribati

• Senegal
• Seychelles
• Sierra Leone
• Solomon Islands
• Somalia
• South Africa
• Sudan
• Suriname
• Swaziland
• Syria
• Tajikistan
• Tanzania
• Timor-Leste
• Togo
• Trinidad and Tobago
• Tunisia
• Tuvalu
• Uganda
• Uzbekistan

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Gilead Access Program Timeline
August 2005 Truvada and Viread prices reduced
318 and 208/year
July 2004 37 reduction 299/year
March 2005 Program expanded to 97 countries
manufacturing established in Bahamas to meet
increased demand
October 2001 Viread approved
April 2003 Gilead Access Program begins
No-profit pricing 68 countries 475/year
August 2004 Truvada added to Program 361/year
April 2005 Partnership with Aspen Pan-African
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Gilead Access Program Alternate Tradedress
Developing World
U.S. / Europe
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Clinical Trials Developing World

• Studies to determine best practices
• Supportive of healthcare infrastructure
• gt35,000 patient years of ARVs committed
• Treatment
• gt30 studies
• Includes DART study in Uganda and Zimbabwe,
  examining need for blood tests
• Prevention
• Mother-to-child
• Adults in high-risk populations

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Pre-Exposure HIV Prophylaxis Viread

• Randomized, placebo-controlled studies
• Multiple geographies and partners
• Family Health International and Gates Foundation
• Female sex workers (Ghana, Nigeria, Cameroon)
• Heterosexual men (Malawi)
• Centers for Disease Control
• MSM (United States)
• Heterosexual men and women (Botswana)
• IV drug users (Thailand)
• First results expected in 2006

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Lessons Learned in the Developing World

• Progress is incremental simplicity improves
  outcomes
• Multiple stakeholders create multiple hurdles
• Specific country regulatory requirements
• Complexity of controlled studies
• Special interest groups
• Scale of need is overwhelming
• Coordination between governments, industry and
  NGOs important
• Quality of ARVs must be ensured against the
  backdrop of HIV itself
• Do the right thing
• Dont be evil isnt good enough

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