BIOE 301

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BIOE 301

• Lecture Three
• Leading Causes of Mortality, Ages 15-44

Geoff Preidis MD/PhD candidate Baylor College of
Medicine preidis_at_post.harvard.edu
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Review of Lecture TwoLeading Causes of
Mortality, Birth-Age 4

• Developing world
• Perinatal conditions
• Lower respiratory infections
• Diarrheal diseases
• Malaria
• Developed world
• Perinatal conditions
• Congenital anomalies
• Lower respiratory infections
• Unintentional injuries

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1. Perinatal Conditions

• Question What is the 1 way to prevent
  septicemia in a newborn in the developing world?

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1. Perinatal Conditions
http//www.path.org/projects/clean-delivery_kit.ph
p
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2. Lower Respiratory Infections

• Question How can a busy health worker (or a
  parent) quickly screen for pneumonia in a child?

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2. Lower Respiratory Infections
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3. Diarrheal Diseases

• Question What is the 1 way to prevent diarrheal
  illness in a newborn?

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3. Diarrheal Diseases
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4. Malaria

• Questions
• 1. Why has malaria been eradicated from the
  southern U.S.? How can these principles be
  applied to less developed countries?

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4. Malaria

• Reduced human/insect contact
• Prevent mosquito breeding
• Use insect repellents, mats, coils
• Residual treatment of interior walls
• Wear long sleeves/pants
• Insecticide-treated mosquito bed nets
• Treatment of those who have malaria
• prevent its spread!

• Questions
• 2. What are the challenges for implementing this
  technology in developing countries?

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4. Malaria

• What are the challenges for implementing this
  technology in developing countries?
• Mapping areas that are difficult to access
• Poor communication
• Direction Transfer of vector control efforts
  from malaria control authorities to local primary
  health care center
• Financial support decreased standard of living
  from wars, environmental factors, migration
• Corruption, graft

• Questions
• 3. Where is the malaria vaccine?

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4. Malaria

• Where is the malaria vaccine?
• Funding
• Thousands of antigens presented to the human
  immune system -gt which ones are useful targets?
• Plasmodium has many life stages -gt different
  antigens at each stage
• Plasmodium has several strategies to confuse,
  hide, and misdirect the human immune system
• Multiple malaria infections of the different
  species and different strains of the same species
  may occur in one host!

http//www.cdc.gov/malaria/images/graphs/malaria_l
ifecycle.gif

• Questions
• 4. How does Chloroquine protect you when you
  travel?

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4. Malaria
http//sickle.bwh.harvard.edu
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Leading Causes of Mortality Ages 15-44

• Developing World
• HIV/AIDS
• Unintentional injuries
• Cardiovascular diseases
• Tuberculosis
• Developed World
• Unintentional injuries
• Cardiovascular diseases
• Cancer
• Self-inflicted injuries

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1. HIV/AIDS

• Burden of HIV/AIDS
• Pathophysiology of HIV
• Clinical course of HIV/AIDS
• Highly Active Antiretroviral Therapy
• Historical Perspective of HIV/AIDS
• Discussion Is HAART really feasible in
  developing countries?

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Burden of HIV/AIDS

• Worldwide
• 39.5 million people are living with HIV/AIDS
• 20 million people have been killed by the disease
• 2006
• 2.9 million deaths
• 4.3 million new HIV infections (400,000 more than
  in 2004)
• 40 of new infections occurred in young people
  (ages 15-24)
• 2/3 of those with AIDS and 3/4 of all AIDS deaths
  are in sub-Saharan Africa
• In the past 2 years, the number of HIV-infected
  people rose in every region in the world

Source 2006 AIDS Epidemic Update, UNAIDS/WHO
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AIDS has Reduced Life Expectancy
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Burden of HIV/AIDS

• United States
• 1.2 million people have HIV/AIDS (prevalence)
• 30,000-40,000 new infections per year (incidence)
• Only 7 countries in the world have more people
  living with HIV than the U.S.
• Routes of transmission
• Unsafe sex between men (44)
• Unprotected heterosexual intercourse (34)
• Non-sterile drug injection equipment (17)

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Burden of HIV/AIDS in the U.S.

• Racial and ethnic minorities are
  disproportionately affected
• 50 of AIDS diagnoses are in African-Americans
  (12 pop)
• 20 of AIDS diagnoses are in Hispanics (14 pop)
• The rate of new HIV diagnoses was 21x higher in
  African-American women than in white women
• Women are increasingly affected
• The proportion of of women among new HIV/AIDS
  diagnoses have risen from 15 to 27 in 10 years
• Question Why is the total number of HIV infected
  people in the U.S. continuing to increase?

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Burden of HIV/AIDS in the U.S.

• Anti-retroviral therapy has accounted for an 80
  decrease in AIDS death rates in the last decade
• Annual cost to treat 15 billion

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Pathophysiology of HIV/AIDS
HIV Structure
Envelope Proteins
gp120
Envelope
gp41
Matrix Proteins
p17
Core Proteins
p14
RT
RNA
Integrase
Protease
http//bayloraids.org/curriculum/
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Pathophysiology of HIV/AIDS
http//bayloraids.org/curriculum/
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Pathophysiology of HIV/AIDS
http//bayloraids.org/curriculum/
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Clinical Course of HIV/AIDS

• HIV Infection
• Spread by sexual contact with infected person or
  sharing needles with infected person or by
  transmission from mother to child
• Virus deposited on mucosal surface
• Acute infection (flu like symptoms)
• Viral dissemination
• HIV-specific immune response
• Replication of virus
• Destruction of CD4 lymphocytes
• Rate of progression is correlated with viral load
• Latent Period

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Clinical Course of HIV/AIDS
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Clinical Course of HIV/AIDS
http//hivinsite.ucsf.edu/topics/aids_basics
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Clinical Course of HIV/AIDS
http//bayloraids.org/curriculum/
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Clinical Course of HIV/AIDS

• AIDS
• Immunologic dysregulation
• Opportunistic infections and cancers
• Risk of infections is correlated with number of
  CD4 lymphocytes
• Average patient with AIDS dies in 1-3 years
• Within 10 years of infection (w/o Rx)
• 50 of patients develop AIDS
• 40 develop illness associated with HIV
• 5-10 remain asymptomatic

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Clinical Course of HIV/AIDS
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HIV/AIDS Therapy

• Reverse Transcriptase Inhibitor enzymes (1987)
• Enzyme is specific to HIV
• Combinations of RTIs appear effective
• HIV Protease Inhibitors (1995)
• HIV proteases are distinct from mammalian
  proteases
• Most significant advance in HIV therapy yet
• Highly Active Antiretroviral Therapy (HAART)
• Combination of three or more drugs
• Fusion inhibitors (2003)
• Subject of new research

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HIV/AIDS Therapy

• HIV can rapidly mutate to quickly develop
  resistance to a single drug
• Resistance develops much more slowly to drug
  combinations
• Goal of HAART
• Reduce viral levels
  to undetectable levels
• Has reduced death
  rate in US and Europe
  by 80

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HIV/AIDS Therapy
http//www.aids-ed.org
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6 million people living with AIDS in developing
countries are in need of HAART. 90 are in just
34 countries
http//www.npr.org/templates/story/story.php?story
Id4724368
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HIV/AIDS Therapy

• Prevention of Mother to Child Transmission
  (PMTCT)
• 3 routes of transmission
• Parentally (during pregnancy)
• Perinatally (during delivery)
• Breast feeding (through milk)
• 4 Core interventions
• HIV testing and counseling
• ARV prophylaxis (ZDV, NVP)
• Safer delivery practices
• Safer infant-feeding practices
• Reduces transmission from 30-40 to 4-6

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HIV/AIDS Historical Perspective

• 1981
• CDC reported unexplained PCP in 5 previously
  healthy, homosexual men
• CDC reported Kaposis sarcoma in 26 previously
  healthy, homosexual men
• 1981-1982
• Increased association with IV drug use,
  recipients of blood transfusions, hemophiliacs
• 1983
• Virus isolated

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HIV/AIDS Historical Perspective

• August 23, 1982
• Homosexual Plague Strikes New Victims
• Cites evidence from the CDC
• The 4-H Club

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HIV/AIDS Historical Perspective

• 1985
• ELISA approved, began screening U.S. blood supply
• 1987
• AZT (RTI) approved by FDA, costs 12,000 per year
• 1995
• First Protease Inhibitor approved, makes HAART
  possible
• 2003
• First Fusion Inhibitor approved
• 2005
• NIH funds CHAVI (Center for HIV/AIDS Vaccine
  Immunology)
• Today
• NRTIs, NNRTIs, Protease Inhibitors, Fusion
  Inhibitors
• Integrase Inhibitors??? Vaccine development???

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Discussion

• For the average AIDS patient in developing
  countries therapy is an inaccessible dream, and
  merely a diversion for developing country health
  ministries from more pressing concerns which
  threatens more cost-effective programs against
  HIV.... Since nothing will likely bridge this gap
  between poor and rich countries, only prevention
  and a vaccine will likely make a real difference
  for the poor in the battle against HIV/AIDS.
• --Hirschel B, Francioli P. Progress and problems
  in the fight against AIDS.
• NEJM 1998 Mar 26338(13)853-60.

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2. Unintentional Injuries
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2. Unintentional Injuries

• Burden of Unintentional Injuries
• Accident Physics
• Slowed Driver Reaction Time
• Prevention of Road Accidents

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Burden of Unintentional Injuries

• More than 1.25 million people ages 15-44 die from
  unintentional injuries each year
• 1 million deaths in developing countries, 1/4
  million in developed countries
• 40x this number are injured
• Major cause of disability
• Leading cause is road accidents
• 500,000 deaths per year in this age group
• 90 of these deaths occur in developing countries

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Burden of Road Accidents in the US

• Rates declining steadily
• A leading cause of potential years of life lost
• 2004
• 42,636 Americans killed
• 2,788,000 Americans injured
• Fatal accident rates gt4X higher for males than
  for females
• Motorcycles 40X higher death rate per mile
  traveled
• 39 of fatalities related to alcohol use

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Accident Physics

• Newtons 2nd Law
• F m a
• a dv/dt
• a initial velocity/time to come to rest
• In a crash
• Velocity slows to zero in a very short time
• Generates large forces
• How can we reduce these forces?
• Reduce initial velocity of impact
• Extend time that it takes passengers to come to
  rest

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Accident Physics

• 1. Reduce initial velocity of impact
• Excessive speed contributes to
• 30 of deaths in developed countries
• 50 of deaths in developing countries

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Slowed Driver Reaction Time

• When drivers anticipate a crash, they have time
  to brake and reduce initial velocity
• Factors which slow driver reaction time
• Alcohol use
• Mobile phone use
• Poor visibility
• Driver inexperience

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Slowed Driver Reaction Time

• Alcohol impaired drivers have 17X increased risk
  of being in fatal crash
• Alcohol use increases risk more in younger
  drivers
• 1 in 5 Americans will be involved in an
  alcohol-related crash at some time in their lives
• TX BAC limit
• 0.08 g/dl is illegal
• Approx 3 drinks in a
  140 lb individual
• Significant driving
  impairment at just
  0.04 BAC!

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Slowed Driver Reaction Time

• Mobile phone use
• At any given daylight moment in US
• 10 of drivers are using a cell phone
• Increases driver reaction time by 0.5-1.5
  sections
• Risk of crash is 4X higher when using a mobile
  phone
• Same as driving with a BAC of 0.09 g/ dl
• 4 states and D.C. have banned use of hand held
  phones while driving (NY, NJ, CT, CA)
• Partial bans in AR, AZ, FL, GA, IL, ME, MA, MN,
  NH, NM, OH, PA, TN, VA

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Prevention of Road Accidents

• 2. Extending Time to Come to Rest
• Crumple zones
• Allow passengers additional time to decelerate
• Seat belts
• Keep occupants in the passenger compartment
• Stretch during impact
• Reduce risk of death in crash by 40-60
• http//www.regentsprep.org/Regents/physics/phys01/
  accident/nobelt.htm
• http//www.regentsprep.org/Regents/physics/phys01/
  accident/withbelt.htm
• Air bags
• When combined with seat belts, reduce risk of
  serious and fatal injuries by 40-65
• http//www.nhtsa.dot.gov/staticfiles/DOT/NHTSA/Com
  munication2020Consumer20Information/Multimedia
  /Associated20Files/crashdum2.ram
• http//www.accidentreconstruction.com/movies/5thpe
  r.mov
• Child restraints
• Reduce risk of infant death by 71 and toddler
  death by 54
• http//www.nhtsa.dot.gov/staticfiles/DOT/NHTSA/Com
  munication2020Consumer20Information/Multimedia
  /Associated20Files/crashdum3.ram

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Prevention of Road Accidents

• Legislation
• Speed
• Seat belts, Car seats, Air Bags
• Alcohol use
• Motorcycle helmets
• Engineering
• Restraints
• Safety standards
• Education
• Seat belts, Car seats, Air Bags
• Alcohol use

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Prevention of Road Accidents

• Motorcycle helmets
• Layer of foam designed to crush upon impact,
  extending time for head to come to rest
• Laws in Texas
• Texas exempts riders 21 or older if they either
• 1) can show proof of successfully completing a
  motorcycle operator training and safety course
• Or
• 2) can show proof of having a medical insurance
  policy

http//www.iihs.org/laws/state_laws/helmet_current
.html2
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3. Cardiovascular Diseases

• 768,000 people ages 15-44 die as a result of
  cardiovascular disease every year
• Most common causes
• Ischemic heart disease (286,000 deaths)
• Cerebrovascular disease (159,000 deaths)
• Will be covered in depth in Lecture 4

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Tuberculosis
www.ohsu.edu/library/hom/exhibits/exhimages/200501
tb/openair_pavilions.jpg
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4. Tuberculosis

• Burden of Tuberculosis
• Natural History of TB Infection
• Diagnosis of Tuberculosis
• Drug Resistance
• Tuberculosis Treatment
• Directly Observed Therapy
• TB in This Century

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Burden of Tuberculosis

• Bacterial infection of the lungs caused by
  Mycobacterium tuberculosis
• Bacterium infects 1 in 3 people on the planet
• Drugs that cure TB were discovered in 1940s
• Results in death in 5 years in half of cases if
  untreated
• Kills 600,000 people ages 15-44 each year
• Estimated that TB will kill 35 million people in
  next 20 years if situation does not change
• 2004
• 8.9 million new cases (incidence)
• Growing 1/year
• 1.7 million deaths
• 98 of deaths occur in developing world

http//www.who.int/tb
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Burden of Tuberculosis

• 1/3 of worlds population is infected with TB
• Not all have active TB
• Most have latent TB - Immune system has walled
  off bacilli with waxy coat
• 5-10 of people with normal immune systems will
  go on to develop active TB
• Higher in people with compromised immune systems
  (10X higher in people with AIDS)
• TB is leading cause of death among people with
  HIV/AIDS
• http//www.npr.org/rundowns/segment.php?wfId15206
  99
• Follows poverty and urban crowding
• Particularly severe in
• AIDS patients
• Those who can't afford medical care
• Noncompliant patients.

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Natural History of TB Infection
http//www.health.vic.gov.au
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Natural History of TB Infection

• Primary TB
• Latent TB
• Secondary, or reactivation, TB

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Natural History of TB Infection

• TB and AIDS
• People with AIDS are 10x more likely to develop
  active TB once infected
• TB is the leading cause of death among HIV
  positive individuals, accounting for 13 of AIDS
  deaths worldwide

www.ourjeet.com/images/twinepidemics.gif
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Natural History of TB Infection

• Active TB
• Symptoms
• Fever
• Night sweats
• Weight loss
• Weakness
• Coughs (productive with bloody sputum)
• Airborne transmission
• Left untreated, one person with active TB can
  cough millions of infectious droplets into the air

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Diagnosis of Tuberculosis

• Skin test (PPD)
• Serum test
• CXR
• Shows nodules in active TB
• Sputum
• Acid-fast bacilli

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Drug Resistance

• Selective pressure Darwins theory of survival
  of the fittest
• Resistance is expected
• Factors can reduce development of resistance
• Finish a course of antibiotics
• Only those who need antibiotics
• Narrow spectrum

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Drug Resistance

• How does an organism acquire drug resistance?
• Mutation and selection
• Exchange of genes between strains and species

Source Essential Biochemistry
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Drug Resistance

• Multi-Drug Resistant (MDR) TB
• Can develop if patients do not take all medicine
• Growing problem
• Present in all countries
• 425,000 new cases per year
• In Russia and China, 14 of new cases are
  resistant
• Must be treated with second-line antibiotics
• Poorly supervised Rx is worse than no Rx
• Extensive Drug Resistant (XDR) TB
• Not only resistant to first-line drugs, but also
  to 3 or more of the 6 second-line drugs
• Identified in every region of the world, esp
  Russia
• High fatality rate
• 4 of MDR-TB cases in the US are XDR

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Tuberculosis Treatment

• Isoniazid
• 1 in 106 organisms is resistant to Isoniazid
• Adverse Effects liver toxicity
• Rifampin
• 1 in 108 organisms is resistant to Rifampin
• Adverse Effects liver toxicity, interactions
  with other meds, red bodily fluids (tears, urine)
• Ethambutol
• 1 in 106 organisms is resistant to Ethambutol
• Adverse Effects eye damage
• Poll Which drug(s)?
• How long? 2 weeks, 6 months or 2 years?

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Tuberculosis Treatment

• By treating with just one drug
• 2 weeks 25 chance of resistant organisms
• 6 months 60 chance of resistant organisms
• 2 years 80 chance of resistant organisms
• The probability of developing resistance to 2
  unrelated agents is the product of probabilities
• 1 in 106 x 1 in 108 1 in 1014
• Spontaneous evolution of MDR bacillus is
  exceedingly rare

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Tuberculosis Treatment

• Active TB
• Can almost always be cured by taking several
  antibiotics in combination
• Isoniazid, Rifampin, Ethambutol, etc
• Stay home for several weeks while contagious
• Take drugs for 6 months-2 years, depending on
  resistance
• If resistance develops, add at least 2 new drugs
• Latent TB
• Treated with Isoniazid for 9 months, prevents
  development of active TB

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Directly Observed Therapy (DOT)

• A health care worker watches and helps as the
  patient swallows anti-TB medicines in his/her
  presence.
• DOTS shifts responsibility for cure from patient
  to health care system
• Requires political commitment, accurate
  diagnosis, quality drugs, observation, follow up
• DOTS works well in many developing countries

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Directly Observed Therapy (DOT)

• 6 month supply is 10
• Cure rates of up to 95 even in poorest countries
• 17 million patients worldwide have been treated
  with DOT since 1995
• 25 of worlds population does not have access to
  DOT.

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Directly Observed Therapy (DOT)

• With HIV?
• Controversial
• Requiring DOT may impose substantial barriers to
  drugs in resource-poor countries
• HIV is more stigmatizing than TB
• Does directly observed therapy prevent more HIV
  mortality and transmission than self-administered
  therapy?

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Directly Observed Therapy (DOT)

• Clinical Trial
• Question Does combined directly observed therapy
  for HIV and TB decrease HIV mortality in a
  resource-limited developing country?
• NIH study in resource-poor Durban, South Africa
• 2 groups of patients Group 1 will undergo DOT
  for HIV and TB simultaneously. Group 2 will
  undergo DOTS for TB and HIV therapy without DOT
• Primary outcome Diagnosis of an AIDS-defining
  illness 18-month mortality

http//clinicaltrials.gov/show/NCT00091936
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TB in the Last Century

• TB incidence declined in the 1960s and 1970s.
  Incidence increased in the 1980s.
• Why?
• Drug prescription practices followed the
  previously mentioned guidelines.
• Why did therapy fail?

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Overlapping Epidemics

• TB and HIV
• TB is the leading killer of people with HIV
• In Africa, half of all TB cases are associated
  with HIV.
• Malaria and HIV
• For people with HIV, especially pregnant women,
  episodes of acute malaria are complicated and
  more serious.

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Discussion Pandemic control in Cuba

• Cubas early strategy to control HIV/AIDS
• Massive mandatory HIV testing
• Contact tracing
• Lifetime quarantine
• Public AIDS education
• How much deprivation of freedom are you willing
  to tolerate to eliminate the risknot the
  certaintythat someone will endanger others?
  Zonana VF. Los Angeles Times, 4 November 1988.

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Leading Causes of Mortality Ages 15-44

• Developing World
• HIV/AIDS
• Unintentional injuries
• Cardiovascular diseases
• Tuberculosis
• Developed World
• Unintentional injuries
• Cardiovascular diseases
• Cancer
• Self-inflicted injuries

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3. Cancer

• 580,000 people ages 15-44 die as a result of
  cancer every year
• Most common causes
• Liver Cancer (68,000 deaths per year)
• Leukemias (65,000)
• Stomach Cancer (58,000)
• Breast Cancer (57,000)
• Will be covered in depth in Lecture 4

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4. Self-Inflicted Injuries

• Burden of self-inflicted injuries
• Risk factors associated with suicide
• Methods of suicide
• Screening and prevention

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Burden of Self-Inflicted Injuries

• 480,000 people ages 15-44 take their own lives
  each year (4th leading cause of death)
• Unipolar depressive disorder ranks 1 for DALYs
  in this age group in developed countries
• Second to HIV/AIDS in developing countries
• Highest rate of completed suicides
• Men gt65 years old
• Highest rate of attempted suicides
• Men and women ages 20-24

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Risk Factors Associated with Suicide

• Psychiatric illness
• Affective, substance abuse, personality, other
  mental disorders
• Other risk factors
• Social adjustment problems
• Serious medical illness
• Living alone
• Recent bereavement
• Personal history of suicide attempt or completion
• Divorce or separation
• Unemployment

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Methods of Suicide

• Most common
• Firearms are used in 60 of suicides
• 2nd leading cause
• Men Hanging
• Women Drug overdose or poison
• Alcohol is involved in 25-40 of suicides
• Women attempt suicide more often men
  are more often successful

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Screening and Prevention

• 50-66 of all suicide victims visit physician lt1
  month before event
• 10-40 in the preceding week
• Hard to identify who is at risk
• Direct questioning has low yield
• General questions about sleep disturbance,
  depressed mood, guilt and hopelessness
• Survey instruments arent good at predicting what
  will happen

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Screening and Prevention

• How do we quantify the efficacy of such
  questionnaires?
• Goal of screening
• Catch as many positives as possible, even at the
  risk of some false positives
• Sensitivity
• Se probability of testing positive if you will
  commit suicide
• Sensitivity of best questionnaires 56 (low)

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Screening and Prevention

• How many false positives result?
• Positive predictive value
• PPVprobability of committing suicide if you test
  positive
• PPV of best questionnaires 3 (pathetic)

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Screening and Prevention
S IG E C A P S
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Selected Preventable Causes of Death

• HIV/AIDS 2,886,000
• TB 1,664,000
• Malaria 1,124,000
• Diarrheal diseases 2,001,000
• Perinatal conditions 2,504,000
• Childhood diseases 1,318,000
• Lung cancer 1,213,000
• Traffic accidents 1,194,000
• Suicide 849,000
• War 230,000
• Source The World Health Report 2002, WHO

87
Who is helping?

• Global Fund for AIDS, Tuberculosis and Malaria
  (GFATM)
• Responds to intertwining threats by underwriting
  expanded treatment programs
• Gates Foundation
• 186 million to fight malaria
• 200 million with NIH for childhood vaccines,
  insect control, nutrition, new treatments
• WHO/UNAIDS

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The Global Fund ARVs
90
Disease Burden and Funding
SOURCE MALARIA RD ALLIANCE
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Summary of Lecture 3

• Developing World
• HIV/AIDS
• Unintentional injuries
• Cardiovascular diseases
• Tuberculosis
• Developed World
• Unintentional injuries
• Cardiovascular diseases
• Cancer
• Self-inflicted injuries

92
Assignments Due Next Time

• HW3