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EPIDEMIOLOGY 200B
Methods II – Prediction and
Validity
Scott P. Layne, MD
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PART 3
Human Immunodeficiency virus
Epidemic Between Hosts
March 2010
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TWO EPIDEMICS
Between people
HIV is a risk-based disease
Not all individuals are at equal risk
Within people
HIV-1 & HIV-2 disable the immune system
Predisposes to opportunistic infections & cancer
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GLOBAL VIEW
2.0 M HIV/AIDS deaths (2007)
male-to-female ratio ~ 1
30 - 36 M living with infection (2007)
male-to-female ratio ~ 1
2.0 million children < 15 years
2.7 M new infections (2007)
male-to-female ratio ~ 1
0.4 million children < 15 years
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GLOBAL VIEW
Becoming #1 infectious disease killer in the world
In the US, HIV is #2 cause of death in men 25 - 44 years
Millions to billions of viral genotypes
Antiviral therapies expensive
Antiviral resistance increasing
Vaccine trials underway but promise unclear
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CLINICAL FEATURES
HIV progressive, chronic disease
Infections irreversible, not curable
Progression associated with HIV loads
Higher viral loads cause faster CD4 cell declines
Lower viral loads cause slower CD4 cell declines
Viral loads < 102 associated with slower declines
Viral loads > 104 associated with faster declines
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CELLULAR MARKER
Normal CD4 counts (range)
900 - 1800 per mm3
Untreated HIV infection
Decline is 50 - 80 per year
AIDS diagnosis at 180 per mm3 on average (MACS).
Immunodeficiency
CD4 counts < 200 per mm3
Opportunistic infections
CD4 counts < 50 per mm3
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DISEASE PHASES
Acute retroviral syndrome
50 – 90% of cases
Occurs 2 – 4 weeks post exposure
Asymptomatic period
50% develop significant disease within 10 years
Symptomatic period
1. Persistent generalized lymphadenopathy (PGL)
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DISEASE PHASES
Symptomatic period (cont.)
2. AIDS related complex (ARC)
Fever
Fatigue
Diarrhea
Weight loss
Night sweats
3. Full blown AIDS
Opportunistic infections
Malignancies
Progressive wasting
Encephalopathy
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OPPORTUNISTIC INFECTIONS
Pneumocystis carinii
Toxoplasmosis
pneumonia
encephalopathy
Cryptosporidia
Cryptococcus neoformans
Candida albicans
Histoplasmosis
profuse diarrhea
meningitis
esophagitis
disseminated
Mycobacterium tuberculosis
Mycobacterium avium
Herpes simplex
pneumonia, disseminated
pneumonia
mucocutaneous ulcers
Cytomegalovirus
pneumonia, retinitis,
gastroenteritis
localized, disseminated12
Varicella-zoster
FURTHER MANIFESTATIONS
Malignancies
Kaposi’s Sarcoma
Non-Hodgkin’s lymphoma
Neurological
AIDS dementia
Memory Loss
Depression
Seizures and Coma
Wasting
Slim disease
Severe intractable wasting & diarrhea
More common in Africa
Associated with mix of opportunistic infections
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OUTCOMES
AIDS Mortality, pre-antiretrovirals
75% mortality within 2 years after AIDS diagnosis
Today
Drug treatments have slowed progression to AIDS
Recent advances have not reduced mortality rates
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EPIDEMIOLOGY
Transmission routes
Overall by intimate contact
Primarily heterosexual contact worldwide
No evidence of airborne, vector transmission
Transmission probabilities
Sexual (per contact)
0.001 – 0.004 (developed countries)
0.041 – 0.075 (female-to-male in Thailand)
Sexual (per partner)
0.1 – 0.2 (homosexual)
Perinatal (per birth)
0.25 – 0.40 for HIV-positive mothers
Parenteral (per needle-stick)
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0.002 – 0.004 for health workers
EPIDEMIOLOGY
Transmission probability increased by
Breaks in epithelial surface
Presence of ulcerative STDs
Lack of circumcision
Receptive anal intercourse
Multiple partners
Fragile mucosa of rectum
Various HIV phenotypes / genotypes ?
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EPIDEMIOLOGY
Human ID-50
Undefined
Cell-free vs cell-associated virus
Relative contributions of each are not determined
May depend on the particular route of transmission
HIV found in body fluids
Plasma
Semen
Cervical secretions
Breast milk
Saliva
Tears
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MODEL DEVELOPMENT
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KEY CONCEPTS
Initial growth of the AIDS epidemic in the United States
Rate that people become infected with HIV
Rate that people progress to AIDS
Prior to antiretrovirals
Prior to opportunistic infection prophylaxis
Why is this easier than today?
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Cumulative AIDS cases plotted as the cube root versus
time as reported by the CDC. Race: 1) White; 2) Black; 3)
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Hispanic; 4) Unknown.
KEY CONCEPTS
Risk-based disease
Risk is not distributed equally among the population
Behavorial mixing
People with similar risk tend to interact among themselves
Biased mixing
People interact equally with others
Unbiased mixing
Which one is it?
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Distribution of new partner rate for homosexual men
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attending sexually transmitted disease clinics in London.
The distribution of males (adolescent to 30) versus sexual
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outlet frequency. Data from Kinsey, 1948.
HIV —> AIDS
6% per year
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Probability of developing AIDS over time.
Source: San Francisco Hepatitis B Study, 1988
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T=0
Biased mixing
vs
Unbiased mixing
Risk
Susceptible
Infection
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T=1
Risk
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T=2
Saturate
Risk
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T=3
Saturate
Risk
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T=4
Infection Wave
Risk
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T=5
Risk
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Calculation of fraction infected versus risk behavior when
mixing is biased at various times (t = 5, 10, 15, ... 40 units)
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Homogenous Mixing
The fastest growth of infection of
infection occurs in average risk group
Early growth is nearly exponential and
larger than biased mixing case
Calculation is not consistent with CDC
observations
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Calculation of fraction infected when mixing is
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homogeneous at various times (t = 5, 10, 15, ... 40 units)
Biased Mixing
Infection grows to saturation in the
highest risk group and moves
progressively to lower risk groups
Calculation is consistent with CDC
observations
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IMPLICATIONS & INSIGHTS
Vaccines
Define efficacy as probability of preventing infection
Vaccine shifts or rescales peoples' position in risk-space
Even with highly effective vaccines, high-risk people will
maintain transmission
STDs and core groups
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Vaccine given at T = 5
Risk
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T=6
Infection Wave
Risk
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PREVENTION
HIV transmission is risk-based
Identify the risks that are associated
with transmission
Intervene and modify the risks that
facilitate transmission
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PREVENTION
Modify sexual behavior
Number of partners
Type of practices
Safe sex practices and failure rates (condoms)
Reduce co-factors
Sexually transmitted diseases
Programs to identify and treat STDs
Intravenous drugs
Reduce abuse
Reduce sharing of injection equipment
Promote disinfection of injection equipment
Provide clean injection equipment
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PREVENTION
Disruption of family and tribal units
Education to modify behaviors
Technology
Reduce cost of HIV testing
Make HIV testing more widely available
Rapid testing
Vaccines
Phase III trials underway / promise?
Variability of the viral genome is a problem
Selecting viral strain for vaccine is a problem
Not clear which immune responses are protective
False sense of protection that increases infection
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READING
Stirling A. Colgate, et al. 1989. Risk behavior-based
model of the cubic growth of acquired immunodeficiency
syndrome in the United States. Proc. Natl. Acad. Sci. USA
86, 4793 – 4797.
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