Download Challenges in Global Health: HIV as a paradigm

Challenges in Global Health:
HIV as a paradigm for control
of infectious diseases worldwide
George W. Rutherford, M.D.
University of California, San Francisco
Global Health Sciences
International Health Interest Group
Stanford University School of Medicine
March 1, 2008
What I’ll talk about
• Placing HIV in the context of other
diseases and other infectious diseases
• HIV prevention
• HIV treatment
WHO’s definition of health:
“A state of complete physical,
mental and social well-being
and not merely the absence of
disease or infirmity”
WHO Constitution, April 1946
Reaffirmed in the Declaration of Alma-Ata, September 1978
Leading causes of death
worldwide
56.6 million deaths from all causes worldwide in 2001
Respiratory and
digestive
10%
Other
7%
Infectious
diseases
26%
14.8 million
Maternal
5%
Injuries
9%
Cancers
13%
Cardiovascular
disease
30%
In low-income countries, 45% of all deaths are from infectious diseases
Proportional distribution of
deaths by broad cause, 2001
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Low- and middleincome countries
High-income
countries
Group I
Group II
Group III
Group I = communicable, maternal, perinatal and nutritional conditions
Group II = non-communicable diseases
Group III = injuries
Deaths in millions
Leading causes of infectious disease
deaths by age group, 2001
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
3.5
2.3
2.2
1.5
1.1
Acute
respiratory
infections
(including
pneumonia and
influenza)
HIV/AIDS
Diarrhoeal
diseases
TB
Malaria
0.9
Measles
5 and over
Under 5
These six diseases cause 86% of infectious disease mortality in the World
10 leading causes of global burden
of disease, DALYs in millions, 2001
Rank Cause
DALYs in
millions
% of total
DALYs
1 Perinatal conditions
90.5
5.9%
2 Lower respiratory tract infections
85.9
5.6%
3 Ischemic heart disease
84.3
5.5%
4 Cerebrovascular disease
72.0
4.7%
5 HIV/AIDS
71.5
4.7%
6 Diarrheal diseases
59.1
39.%
7 Unipolar depressive illness
51.8
3.4%
8 Malaria
40.0
2.6%
9 Chronic obstructive pulmonary
disease
38.7
2.5%
36.1
2.3%
10 Tuberculosis
Top 10 causes of death by economic classification of
countries, DALYs in millions, 2001
Low- and middle-income countries
Cause
High-income countries
DALYs
%
Cause
DALYs
%
1
Perinatal conditions
89.1
6.4
1
Ischemic heart disease
12.4
8.3
2
Lower respiratory tract
infections
83.6
6.0
2
Cerebrovascular disease
9.4
6.3
3
Ischemic heart disease
71.9
5.2
3
Unipolar depressive
disorders
8.4
5.6
4
HIV/AIDS
70.9
5.2
4
Alzheimer’s and other
dementias
7.5
5.0
5
Cerebrovascular disease
62.7
4.5
5
Trachea, bronchus and
lung cancers
5.4
3.6
6
Diarrheal diseases
58.7
4.2
6
Hearing loss, adult onset
5.4
3.6
7
Unipolar depressive
disorders
43.4
3.1
7
Chronic obstructive
pulmonary disease
5.3
3.5
8
Malaria
40.0
2.9
8
Diabetes mellitus
4.2
2.8
9
Tuberculosis
35.9
2.6
9
Alcohol use disorders
4.2
2.8
Chronic obstructive
pulmonary disease
33.5
2.4
10
Osteoarthritis
3.4
2.5
10
Poverty and its consequences,
including poor nutrition and
sanitation, are the major factors
reducing years of healthy life in
the world
How does poverty affect health in
the developing world?
• Smaller proportion of population
educated; lack of education risk factor
for infant mortality
• Limited governmental funding for health
• Level of health infrastructure
development and access to health care
• Affordability and availability of health
technology
10/90 gap
• 90% of pharmaceutical research and
development is said to be targeted to diseases
that affect only 10% of the world’s population
• Only 13 of the 1,393 new drugs approved
between 1975 and 1999 were specifically
approved for a tropical disease
• High prevalence diseases: HIV, TB, malaria,
acute respiratory infections, vaccinepreventable diseases of children
• Neglected tropical diseases: leishmaniasis,
lymphatic filariasis, Chaga’s disease, leprosy,
dracunculiasis, onchocerciasis, schistsomiasis
Poverty and women’s health
• Maternal mortality in developing countries
is 500 per 100,000 compared to 7 per
100,000 in industrialized countries
annually
• Approximately 50 million pregnancies end
in abortion every year; 20 million are
carried out illegally or unsafely
• 100-200 million women who would like to
space or limit pregnancies are not using
contraceptives; primary means of spacing
is lactational amenorrhea
United Nations
Millennium Development Goals
•
•
•
•
•
•
•
•
Eradicate poverty and hunger
Achieve universal primary education
Promote gender equality and empower women
Reduce child mortality
Improve maternal health
Combat HIV/AIDS, malaria and other diseases
Ensure environmental sustainability
Develop a global partnership for development
While we focus on prevention and treatment
of diseases, what else is going on?
•
•
•
•
Consequences of population growth
Consequences of climate change
Consequences of a global economy
Consequence of continuing disparities






Food and water security
Biodiversity and species extinction
Conflict
Emerging epidemics
Energy security
Brain drain and health workforce shortages
Elements of global health
Health sciences, public health, biomedical
sciences, behavioral and social sciences
Economics, business,
international
development,
management
International relations,
political science, law, public
policy
Food security,
agriculture, animal
health, fisheries
Environmental sciences,
climatology, engineering,
oceanography, urban studies
HIV as a paradigm
for disease control
• Disease control - reduction of disease incidence,
prevalence, morbidity or mortality to an
acceptable level as a result of deliberate efforts
• Goals for HIV control
–
–
–
–
Reduce new infections (incidence)
Reduce HIV-related morbidity
Reduce HIV-related mortality
Minimize societal costs of HIV infection
• Needs
– Political commitment
– Funding for programs, evaluation and research
– Some relaxation of IP protections
Global summary of the HIV/AIDS
epidemic, December 2007
Number of people living with HIV/AIDS
Total
Adults
Women
Children under 15 years
33.2 million (30.6-36.1 million)
30.8 million (28.2-33.6 million)
15.4 million (13.9-16.6 million)
2.5 million (2.2-2.6 million)
People newly infected with HIV in 2007
Total
Adults
Children under 15 years
2.5 million (1.8 – 4.1 million)
2.1 million (1.4 – 3.6 million)
420 000 (350 000 – 540 000)
AIDS deaths in 2007
Total
Adults
Children under 15 years
2.1 million (1.9– 2.4 million)
1.7 million (1.6 – 2.1 million)
330 000 (310 000 – 380 000)
The ranges around the estimates in this table define the boundaries within which the actual numbers lie, based on the best available information. These ranges are
more precise than those of previous years, and work is under way to increase even further the precision of the estimates that will be published mid-2004.
Global HIV prevalence in
adults, June 2006
Why HIV and why Africa?
• HIV started in Africa
• Immune
amplification from
malaria
• High rates of STIs
• Lower age at
exposure for girls
• Sexual practices?
• Facilitators:
– Colonialism
– Rapid urbanization
following
decolonization
– Gender inequalities
– Poor access to health
care
– Conflicts and refugees
– Poverty
– Denial, stigma
Why is HIV so disruptive to
society?
• Increased mortality among most productive
age groups
• Economic destabilization due to lost
productivity (especially in agricultural sector)
• Orphans and burden on families leading to
decreased educational opportunities
• Reversal of health gains made from 1960s
• Destablilizes military
• Health care demands
What are risk factors for
transmission now?
• Uganda HIV Sero-Behavioural
• Serodiscordancy with
Survey (2006)
primary partner
 6.3% prevalence, 172 (16%) of
• Lack of circumcision
positive specimens recent
infections (incidence 1.9 per 100
• HSV-2
py)
• Concurrent partnerships
 106 (62%) sexually active married
persons with recent infection
• STDs


Non-modifiable risk factors:
female gender, widowed, live in
North-Central region
Modifiable risk factors: absence of
circumcision, HSV-2, STD in last
12 months, non-use of condoms
with extramarital partner in last 12
months
Risk factors in married persons
with incidenct HIV, UHSBS 2006
Non-use of condoms with
extramarital partner in last 12
months
HSV-2 infection
STD in last 12 months
Absence of circumcision
Behavioral interventions to prevent
sexual transmission of HIV
•
•
•
•
ABC = abstinence, be faithful, use condoms
Later age at first intercourse
Limit casual partners
Use condoms, especially with casual partners
and in discordant couples
• Make better sexual decisions
– Role of alcohol and drugs (disinhibition)
– Role of education
– Economic realities
Prevalence among pregnant women
in major urban areas, Uganda
35
Prevalence
30
25
20
15
10
5
0
1985 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000
Similar trends have now also been seen in Kenya and Zimbabwe
Source: Uganda National AIDS Programme
Uganda ANC vs. Zambia
35
Lusaka Zambia
Zambia other urban
Kampala Uganda
Uganda rural
Zambia rural
30
HIV prevalence (%)
25
20
15
10
5
0
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
If decline in HIV prevalence were related to increased
mortality and epidemic stage, one would expect similar
declines in neighbouring countries, which did not occur.
Comparative risk behaviors:
Uganda vs. Zambia, Kenya, Malawi
Condom use in casual sex
% reporting non-regular partner in last 12
months
60%
Men
49%
48%
50%
60
57%
56%
Women
40
30%
10%
30
19%
15%
Men
Women
50
40%
20%
% using condom with last non-regular
partner
“Casual” sex in past year
18%
20%
20%
42
40
36
24
34
27
20
20
7%
14
10
0%
Uganda
1995
Uganda
1989
Malawi 1996 Zambia 1996 Kenya 1998
Decline in casual sex in Uganda
since 1989 distinguishes Uganda
from other countries
0
Uganda 1995
Malawi 1996
Zambia 1996
Kenya 1998
Condom use levels in Uganda
similar to comparison countries.
Available evidence suggests HIV declines in Uganda related
to behaviour modification and in particularly partner reduction.
What went right in Uganda?
• Primary causes:
– Decrease in numbers of casual sexual partners
– Later age at first intercourse for girls
• Secondary causes:
– Increased condom use with casual partners
– Increased condom use with primary partners
• Contributing causes:
– Political openness and communication
– Broad personal knowledge of HIV/AIDS and its
prevention
– Lower levels of STIs
Biomedical interventions to prevent
sexual transmission of HIV
• Proven interventions


Male circumcision
Barrier methods (male
and female condoms)
• Proven in limited
circumstances


STI control
Voluntary counseling and
testing
• Disproven



Barrier methods
(diaphragms)
Herpes suppression
Several vaginal
microbicides
• Unproven



Antiretroviral therapy
Antiretroviral-containing
vaginal microbicides
Vaccines
Is male circumcision the new answer?
Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized,
controlled intervention trial of male circumcision for reduction onf HIV infection risk: The ANRS
1265 trial. PLoS 2005; 2:e298.
•
•
•
•
•
Randomized controlled trial of
male circumcision among
3,724 uncircumcised men, 1824 years old, in Gauteng
Province, South Africa
Intervention group circumcised
on entry to trial, control group
offered circumcision at end
Trial stopped at interim
analysis with average 18
month f/u
20 incident HIV infections in
intervention group and 49 in
control group (RR = 0.40, 95%
CI 0.24-0.68)
Risk reduction after adjustment
= 61%
Care prolongs productive life
Yearly Deaths as a Proportion of 1995 Values
The widening gap between North and South
2.5
AIDS deaths in Africa
2.0
1.5
1.0
AIDS deaths in Western Europe
0.5
HAART
0.0
1991
1992
1993
1994
1995
1996
Source: Adapted from WHO/UNAIDS Statistics, & HIV/AIDS Surveillance in
Europe, End- year report 2001, No. 66, CESES
1997
1998
1999
2000
2001
AIDS incidence and mortality rates,
Brazil, 1981 to 2000*
18
HAART
rate by 100,000 inhab.
16
14
12
10
8
6
4
2
0
81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00
years
Mortality rate
*estimated for 1999 and
2000
Incidence rate
Antiretroviral coverage in low- and
middle-income countries, June 2006
Geographic region
Sub-Saharan Africa
Number of persons Estimated Coverage
receiving ART
need
1,040,000 4,600,000
23%
Latin America and the
Caribbean
345,000
460,000
75%
East, South and
Southeast Asia
235,000 1,440,000
16%
Eastern Europe and
Central Asia
24,000
190,000
13%
North Africa and the
Middle East
4,000
75,000
5%
1,650,000 6,800,000
24%
Total
Antiretroviral therapy global
need, June 2006
5,000,000
70% of unmet need
4,500,000
4,000,000
3,500,000
3,000,000
Unmet need
2,500,000
Receiving ART
2,000,000
1,500,000
1,000,000
500,000
0
Sub-Sahara
Africa
Latin America
East, South
and the
and Southeast
Caribbean
Asia
Eastern
Europe and
Central Asia
North Africa
and the Middle
East
Treatment access among IDU,
Eastern Europe
100
90
80
70
60
IDU as % of persons
living with HIV
IDU as % of persons on
ART
50
40
30
20
10
0
Mo
ldo
Es
va
ton
ia
Uk
rai
ne
Se
rbi
a
Lit
hu
a
Cr
nia
oa
ti
a
Ru
ssi
Cz
ech
a
R
ep
Estimated total annual
resources available for AIDS,
1996-2005
9,000
US $ in millions
8,000
7,000
6,000
5,000
PEPFAR
4,000
3,000
Global Fund
World Bank MAP
launch
2,000
Signing of Declaration of
Commitment on HIV/AIDS
1,000
0
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
Antiretroviral treatment outcomes in
low- and middle-income countries
• Best-price scenario $130 per patient per year for first-line
generic ART
– Second-line therapy, pediatric formulations, diagnostics all add
to cost
• ART-CC examined 27,000 patients from developing and
industrialized countries*
– CD4+ and viral suppression were similar
– Overall 1-year mortality 6.4% in low-income (3.5 times higher
than in industrialized countries, especially in first month)
– 75% lower mortality in programs offering free access
– 40-60% lower mortality than in historical untreated cohorts
*Braitstein P, Brinkhof MW, Dabis F, et al. Mortality of HIV-1 infected patients in the first year of antiretroviral therapy: a comparison between low-income and high-income countries. Lancet 2006;
367:817-24.
Five clear care and
treatment priorities
1. Scale up HIV testing
2. Ensure minimum package of care, including
tuberculosis screening and treatment or preventive
therapy, co-trimoxazole prophylaxis and other simple
interventions
3. Ensure all patients with WHO stage III or IV disease
receive ART as early as possible
4. Strengthen laboratory capacity for CD4+ testing,
allowing earlier initiation of therapy based on
immunologic criteria
5. Define HIV/AIDS treatment as a global public good
requiring the abolition of user fees at point of care
Benefits = decreased morbidity, decreased mortality, return to
work, decreased orphans, possible decreased infectiousness
Policy and funding initiatives
• Global Fund to Fight AIDS, TB and
Malaria
• WHO initiatives (3 x 5 Initiative)
• US bilateral initiative (PEPFAR)
• Bill and Melinda Gates Foundation
• TRIPS amendment to WTA to allow
compulsory licensing and importation to
least developed countries
Global Fund to Fight AIDS, TB
and Malaria
• United Nations multi-donor trust fund overseen by
the World Bank
• $5.2 B disbursed through first seven rounds of
giving ($8.2 B in grants approved)
• 491 programs in 136 countries
• $9.8 B US in pledges to GFATM through 2008
– $9.3 B from governments, $500 M charities and private
sector, e.g., Gates, (PRODUCT) RED
• US has pledged $3.5 B through 2008 (currently
$841 M per year, statutorily limited to 1/3 of GF $)
Global Fund disbursements by
country through Round 6
US Initiatives
Presidential Emergency Plan for AIDS Relief
• $15B over 5 years, $10B new monies, $5B
previously committed for MTCT programs; $1B for
GFATM
• Proposed to increase to $30 B in 2009
reauthorization
• Countries of focus are: Botswana, Côte d’Ivoire,
Ethiopia, Guyana, Haiti, Kenya, Mozambique,
Namibia, Nigeria, Rwanda, South Africa,
Tanzania, Uganda, Vietnam and Zambia
• But, does it work? Are its effects measurable?
Botswana mortality,ages 10-59, 19942005 (2nd qtr annualized)
Botswana mortality ages 10-59, 1994-2005*
3000
2500
10 to 19
2000
deaths
20 to 29
30 to 39
1500
40 to 49
50 to 59
1000
500
)
nn
ua
li z
ed
(a
20
03
20
04
20
05
Annualized based on reports thru June 05
source: CSO vital registration statistics instiutional
deaths: Annual data pending for years 95,98,2002:
20
01
20
00
99
97
96
94
0
Botswana mortality, ages 0-9,19942005 (2nd qtr annualized)
Botswana mortality:ages 0-9, 1994-2005*
1600
infant
1400
1-4
5-9
1200
deaths
1000
800
600
400
200
20
)
al
iz
05
(a
n
nu
*Annualized based on reports thru June 05
source: CSO vital registration statistics instiutional
deaths: Annual data pending for years 95,98,2002:
ed
04
20
03
20
01
20
00
20
99
97
96
94
0
The Doctors
Without
Borders
clinic in
Khayelitsha,
South Africa,
has
used generic
drugs
successfully
in
treating AIDS.
Drugs are
prepared
at the clinic.
Francesco Zizola/Magnum, for Doctors Without Borders
State of the World’s health
Current
population
6,755,566,251
Births
133,201,704
Deaths
55,490,538
Natural
increase
+77,711,166
Top 10 causes of death in children
<5 years, Worldwide, 2000
Perinatal Conditions
Lower Respiratory Infections
Diarrheal Diseases
Malaria
Measles
Congenital Anomalies
HIV
Pertussis
Tetanus
Malnutrition
0
500
1000
1500
2000
Number of Deaths (thousands)
Paper No. 36, Global Burden of Disease, WHO, 2001
2500
Causes of 1.7 million vaccine -preventable
deaths among children, Worldwide, 2000
Measles
777,000
Hib
Neonatal
Tetanus
Yellow Fever
Source: World Health Report 2001
Pertussis
Diphtheria
Polio
Poverty
• Poverty is fundamental to all differences
• Poverty forces city dwellers in resource
poor countries to live in overcrowded
and unhygienic conditions, where lack
of water and sanitation provides a
breeding ground for infectious disease
and the development of drug-resistance
• Poverty correlates with rapid population
growth, thus tremendously affects the
health of women
What’s new in HIV/AIDS in Africa
• Epidemic continues to grow in southern and
eastern Africa, potential for major spread in
Ethiopia and Nigeria; now leading cause of death
in Africa
• New prevention technologies are being
evaluated, including male circumcision and
antiretroviral therapy; STD control, diaphragms,
vaginal microbicides and herpes suppression
unconvincing
• Variety of new policy initiatives and financing
mechanisms, especially for ARVs -- can we show
effects?
Vaginal microbicide current and
completed Phase III trials, 1
Drug (Trial
phase)
Site
Sponsor
Study
population
COL-1492 (III)
Benin, Côte
d’Ivoire, South
Africa,
Thailand
UNAIDS,
Columbia
Labs
Female sex
workers, ≥18
Cellulose
sulfate
(Ushercell®)
(III)
Benin, India,
South Africa,
Uganda,
Zimbabwe
(CONRAD)
USAID,
Gates
≥3 sexual
partners in last
3 mo, ≥18
1,333 Trial stopped, interim
analysis showed
evidence of harm.
Data unavailable.
Nigeria (FHI)
USAID
≥2 sexual
partners in last
3 mo, 18-35
1,644 Stopped because of
CONRAD data (no
evidence of harm).
Data unavailable.
South Africa
Pop Cncl,
USAID,
Gates
Sexually active
women, 16-40
6,203 Last follow up March
2007
Carrageenan
(Carraguard®)
(III)
N
Results
892 RR=1.5 (1.0-2.2)
Vaginal microbicide current and
completed Phase III trials, 2
Trial (phase)
Site
Sponsor
Study
population
N
Results
BufferGel +
PRO 2000
0.5% (IIb)
HPTN 035
Malawi, South
Africa, US,
Zambia,
Zimbabwe
NIAID,
Indevus,
ReProtect
Sexually
active
women, ≥18
3,100 Enrolling until July
31, 2007
PRO 2000/5
0.5% and 2%
(III) MDP301
South Africa,
Tanzania,
Uganda Zambia
Indevus,
MRC,
DFID
Sexually
active women
≥16
9,673 Enrolling. Expected
completion March
2009
C31G
(SAVVY) 1%
(III)
Ghana, Nigeria
Biosyn,
FHI,
USAID
≥2 sexual
partners in
last 3 months,
18-35
4,248 Ghana - RR=0.9
(0.3-2.3); Nigeria data analysis
pending
Dapivirine (III)
IPM009
Multiples sites
(Africa)
IPM
High-risk
women
Tenofovir 1%
(2 doses)(IIb)
CAPRISA 004
South Africa
CAPRISA, Sexually
CONRAD, active
USAID
women, 18-40
NA Not started
980 Not started
HIV transmission rate by serum
viral load
Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, Meehan MO, Lutalo T, Gray RH. Viral load and heterosexual
transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000 Mar 30;342(13):921-9.
.
Equity by age group and
gender
• No systematic bias against women in
treatment access; the proportion of ART
recipients who are women corresponds
to or exceeds the proportion infected
• Children account for 14% of all AIDS
deaths but only 6% of antiretroviral
recipients
• Less than 10% of HIV-infected pregnant
women benefit from antiretroviral
prophylaxis
How much of an effect on
transmission will ARVs
have?
• 75% coverage of
ARVs using DHHS
treatment criteria will result in 10%
decrease in size of HIV-infected population
in 20 years
• 75% coverage with a 50% effective
vaccine will result in 70% decrease in size
of HIV-infected population in 20 years
• 75% coverage of ARVs plus vaccine will
result in 85% decrease in size of HIVinfected population in 20 years
RH, Li X, Wawer MJ, et al. Stochastic simulation of the impact of antiretroviral therapy
and HIV vaccines on HIV transmission; Rakai, Uganda. AIDS 2003; 17:1941-51.
Global Fund expenditures through
Round 4
WHO’s 3 x 5 initiative
• 3 by 5:
provide 3
million
persons in
developing
countries on
antiretroviral
therapy by
Lack
of access
to antiretroviral therapy is a global health
2005
(needed
emergency. To deliver antiretroviral treatment to the millions
byneed
6 million)
who
it, we must change the way we think and change the
way we act.
US Initiatives
Presidential Emergency Plan for
AIDS Relief
• $15B over 5 years, $10B new monies, $5B
previously committed for MTCT programs;
$1B for GFATM
• Countries of focus are: Botswana, Côte
d’Ivoire, Ethiopia, Guyana, Haiti, Kenya,
Mozambique, Namibia, Nigeria, Rwanda,
South Africa, Tanzania, Uganda, Vietnam
and Zambia
World Trade Organization
• Recent compromise on Trade-Related
Aspects of Intellectual Property Rights
(TRIPS) agreement
• Previously had allowed pharmaceutical
production under compulsory licensing for
domestic market only, which effectively
limited countries’ ability to import cheaper
generics (Article 31(f))
• Now requirement waived to enable a
pharmaceutical product produced or
imported under a compulsory license to be
exported to least developed countries