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Monday, 24 November 2008
Small Tools for Big Problems: Microchips for Small Tools for Big Problems: Microchips for Global Health AIDS Diagnostics
Xuanhong Chengua o g C e gMaterials Science and Engineering
Bioengineering
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Overview of Presentation
1 Global Health Challenges
2 HIV/AIDS Statistics and Biology
3 HIV/AIDS Diagnostics
4 Mi hi T h l f HIV/AIDS Di i 4 Microchip Technology for HIV/AIDS Diagnostics
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Leading causes of death, Global
1 Ischemic heart disease 12.7
2 Cerebrovascular disease 9 9
Rank % of total
2 Cerebrovascular disease 9.9
3 Acute lower respiratory infections 7.1
4 HIV/AIDS 4.8
5 Chronic obstructive pulmonary disease 4.8
6 Perinatal conditions 4.2
7 Diarrheal diseases 4 07 Diarrheal diseases 4.0
8 Tuberculosis 3.0
11 Malaria 1.9
Source: WHO , The World Health Report 2000
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Leading causes of death, Africa
1 HIV/AIDS 20.6
2 Acute lower respiratory infections 10.3
Rank % of total
2 Acute lower respiratory infections 10.3
3 Malaria 9.1
4 Diarrheal diseases 7.3
5 Perinatal conditions 5.9
6 Measles 4.9
7 Tuberculosis 3 47 Tuberculosis 3.4
8 Cerebrovascular disease 3.2
9 Ischemic heart disease 3.0
10 Maternal conditions 2.4
Source: WHO , The World Health Report 2000
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Cell Bacteria(TB, Typhoid)
Virus(HIV, hepatitis, SARS, influenza)
.
HIV emerging from a cellHIV emerging from a cell
Cell
HIV
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Global diversity of different HIV-1 strains
Source: Los Alamos Database http://hiv-web.lanl.gov/
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39 million adults living with HIV/AIDS, 2006
Source: WHO
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Growth of the AIDS Epidemic
40
45
People With HIV/AIDS, Cumulative Regional TotalsMillions
25
30
35
40
15
20
25
0
5
10
1986 1988 1990 1992 1994 1995 1998 2000 2002 20041986 1988 1990 1992 1994 1995 1998 2000 2002 2004
Sub-Saharan Africa Asia Latin AmericaEurope & N. America* Eastern Europe & Central Asia North Africa & Middle EastCaribbean
*Western and Central Europe & North America.Source: UNAIDS/WHO, 2004.
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People With HIV/AIDS, by Region
Eastern Europe and Central Asia
Western and Central Europe
Latin America4%
Caribbean1%
4%
Oceania
North America3%
p2%
S th d S th
Oceania<1%
East Asia3%
Sub-Saharan Africa64%N h Af i d
South and South-East Asia
18%
64%North Africa and Middle East
1%
Source: UNAIDS, AIDS Epidemic Update 2004.
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Changes in Life Expectancy, 1950 - 2000
65
55
60
Botswana
Uganda
45
50South Africa
Uga da
Zambia
40
45Zimbabwe
351950 1960 1970 1980 1990 2000
Source: United Nations Population Division, 1998
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AIDS’ Toll on Population Structure, Botswana
Population Structure in 2020 (Projected)Thousands
Age80+
Males Females
80+75706560555550454035303025201510
150 100 50 0 50 100 150
With AIDS Without AIDS
50
With AIDS Without AIDS
Source: U.S. Census Bureau demographic estimates and projections, 2004.
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P t f A i lt l L b F L t t HIV/AIDS 1985 2020
AIDS’ Effect on African Agriculture
26Namibia
Percent of Agricultural Labor Force Lost to HIV/AIDS, 1985-2020 (Projected)
23
23
Botswana
Zimbabwe
20
20
Mozambique
South Africa
17
14
Kenya
Malawi
14
13
Uganda
Tanzania
Source: Food and Agriculture Organization (FAO), “AIDS—A Threat to Rural Africa: Fact Sheet” (www.fao.org/focus/e/aids/aids6-e.htm).
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HIV destroys immune defenses against TB
TuberculosisTuberculosis
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
HIVHIV
CD4
CD4 cell
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
CD4 Binding
Co-receptor
d g
CD4
p(CCR5 or CXCR4)
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Fusion
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Virion entryVirion entry
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Reverse transcription
HIV DNA
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Translocation to nucleus
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Integrationg
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Transcription / Translationof HIV mRNA / polyprotein/ p yp
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HIVHIV
HIV Pathophysiology Life CycleHIV Pathophysiology - Life Cycle
Protease processingand viral assembly
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HIV infection
HIV attacks CD4 cells, the generals of the immune system’s army
HIV inserts itself into our genes
HIV creates many different strainsHIV creates many different strains
CD4 cell
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HIV infection
Viral loadViral load
CD4
time Years Weeks
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Relationship Between CD4 count and Viral Load
Slow: <5,000, Fast: 50,000+
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WHO Stage 2 and 3:Symptomatic HIV infectionC 4 200 00
WHO Stage 1:Asymptomatic HIV infectionCD4 >500
1000CD4 200 - 500Mild infectionsWeight loss, fatigueTB Thrush
WHO Stage 4AIDSCD4 200
TB, Thrush
CD4Count
CD4 < 200TB, infectionsDeath ~18 months
200
642
Time(years)
642
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WHO Stage 1 - Asymptomatic HIV Disease
• Minimal symptoms
• Daily battle between virus and immune system; 10,000,000 new virus copies each dayday
• CD4 count drops gradually• CD4 count drops gradually
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WHO Stage 2 - Symptomatic HIV Disease
• Early signs of chronic HIV infection:– Weight loss (3-5 kg)– Skin rashes– Respiratory infections
Herpes zoster (“shingles”)– Herpes zoster (“shingles”)
– CD4 count =350-500
• Normal activity, able to work / attend school
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Opportunistic Infections - Côte d’Ivoire, Thailand
Prevalence• Tuberculosis 29-37%• Cryptococcosis 19-38%• Wasting syndrome 8-28%• Wasting syndrome 8-28%• Pneumocystis pneumonia 5-20%• Bacterial pneumonia 4%• Esophageal candidiasis 3-6%• Toxoplasmosis 2-3%
Cryptosporidiosis 1 2%• Cryptosporidiosis 1-2%
Sources: Chariyalertsak, 2001; Tansuphasawadikul, 1999; Lorsina, 2004
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Goals of HIV Treatment
• Improve quality of life
• Prevent opportunistic infections
• Prevent progression to AIDS
• Prevent death
d h l k l h d f h• Reduce the likelihood of transmission to others (“Secondary prevention”)
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HIV Treatment - Antiretrovirals
Fusion/EntryInhibitors (1) Maturation
Inhibitors (~2008)
ProteaseInhibitors(8)
Inhibitors ( 2008)
(8)
ReverseTranscriptaseInhibitors(11) Integration
Inhibitors (~2008)
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HIV Treatment - Antiretrovirals
25
30
20 No therapyMonotherapy
15Dual therapy
5
10
Triple therapy
0
5
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
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HIV Treatment - Timing of HIV Treatment
• Therapy is delayed until patients develop WHO Stage 3 or Stage 4 disease
Delaying therapy until Stage 3 or 4 if done carefully does not – Delaying therapy until Stage 3 or 4, if done carefully, does not decrease the likelihood of successful treatment
– Treatment is lifelong and expensive, do not want to start g p ,unnecessarily early
– Delayed therapy minimizes opportunity for side effects
– Delayed therapy minimizes opportunity for drug resistance
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CD4 and Mortality - Zimbabwe
1.00
y
CD4 > 200
0.75
0.50Prob
abili
ty
CD4 50-2000.50
0.25
Surv
ival
P
0
0 1 2 3 4
S
CD4 < 50
0 1 2 3 4Time from enrolment to death (years)
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Impact of Treatment
Before
AfterAfter
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Impact of Treatment
After 9 months
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Impact of Treatment
After 9 months
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Impact of Treatment
“I was a walking skeleton before I began therapy. I was afraid to gog g py gout of my house and no one would buy things from my shop. Butnow I am fine again… My wife has returned to me and now mychildren are not ashamed to be seen with me. I can work again.”
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Impact of Treatment
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Impact of Treatment
Begin ART
CD4
Viral load(HIV RNA level)
time Years Weeks
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Impact of Treatment - Society
Effective ARVs available
30
35
40Unintentionalinjury
Cancer
20
25
Deaths per 100,000 Population
Heart disease
Suicide
5
10
15
pHIV infection
Homicide
0
5
1982 1984 1986 1988 1990 1992 1994 1996 1998
Chronic liver
disease
Stroke
Diabetes
Source: Centers for Disease Control, 200
YearDiabetes
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Current Status of Treatment - December 2004
Source: WHO
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Current Status of Treatment - June 2005
Source: WHO
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Number of Individuals Receiving ART
Source: WHO
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Community-based Care
Care takes place pin the community. Reinforced in the
lclinic.
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Basic Water SupplyClinical Indicators
900900101088
‘Viral load’‘Viral load’
CD4 cell countCD4 cell count
800800
700700
10107 7
101066
HIV RNAHIV RNAlevellevel
(cells/(cells/μμL blood)L blood)600600
500500101055
101044
(copies/(copies/mL plasma)mL plasma)
400400
300300
1010
101033
200200
100100
101022
101011
Years Years
WeeksWeeks 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
00101000
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Basic Water SupplyState of the Art Technologies
BD FACSCalibur
CD4-countCD4 countstart treatment < 200 cells/ul
RT PCR
Viral load countViral load countmeasure resistance to treatment
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Basic Water SupplyLab Diagnostics in Resource Poor Settings
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What is Needed
• Low cost
• Easy to use
• Rapid and Robust
• Portable
S d f• Sensitive and specific
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Basic Water SupplyMicrochip Technology for Medicine
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Basic Water SupplyMicrochips for Bioseparation
–O –O–Si–(CH2)3–S––O
O O
N N–O
O
–O –O–Si–(CH2)3–S––O
O O
N N–O
O
–O –O–Si–(CH2)3–S––O
O O
N N–O
O
silane linker avidin anti-CD4
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Basic Water SupplyMicroelectrodes for Biosensing
3x10-14
K+ Cl-
Na+K+K+
Cl-
Cl-lysis3x10-14
K+ Cl-
Na+K+K+
Cl-
Cl-lysis3 0mole ions
Low
NaK K+Cl-
High
3 0mole ions
Low
NaK K+Cl-
Highoconductance
gconductance
oconductance
gconductance
(ohm
-1)
0.0015
0.0020
due
to C
ell L
ysis
(
0.0005
0.0010
ucta
nce
Cha
nge
d
-0.0005
0.0000
MSE Lunch and Learn, Oct 16, 2008Captured Cells on Chip by Optical Microscopy
0 2000 4000 6000 8000 10000 12000
Con
du
-0.0015
-0.0010
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Basic Water SupplyClinical Validation of the Microchip
S iti itTest Positive
N = 49R2 = 0.86
N = 49R2 = 0.86
Sensitivity =
Specificity =
Total PositiveTest NegativeTotal Negativey = x
y = 1.1x
y = x
y = 1.1x
Total Negative
SpecificitySensitivityCD4 Counts(cells/μL)y
0.970.90< 350
1.00.86< 200
(ce s/μ )
0.940.97< 500
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Basic Water SupplyCommercial Development