HIV and AIDS PM2 PATHOPHYSIOLOGY. HIV is the causative agent of AIDS Human immunodeficiency virus...

HIV and AIDSHIV and AIDS

PM2 PATHOPHYSIOLOGYPM2 PATHOPHYSIOLOGY

HIV is the causative HIV is the causative agent of AIDSagent of AIDS

Human immunodeficiency virus Human immunodeficiency virus retrovirusretrovirus most common type: HIV-1 most common type: HIV-1 HIV-1: distributed worldwideHIV-1: distributed worldwide HIV-2:mainly endemic in west AfricaHIV-2:mainly endemic in west Africa

When was it discovered?When was it discovered?

AIDS was first recognized AIDS was first recognized in June 5,1981in June 5,1981

107 cases of Pneumocystis carinii pneumonia United States, pre-AIDS epidemic

AIDS epidemic has resulted in 166,368 cases up to 1999


Pneumocystis pneumonia

HIV and AIDSHIV and AIDSan infectious agent – Kaposi’s Sarcomaan infectious agent – Kaposi’s Sarcoma

1981 - 26 cases of Kaposi’s sarcoma

• Young

• Male

• San Francisco and New York

• All Homosexuals

1981-1999: 46,684 definite cases in United States


Two rare diseases in the gay community linked to

IMMUNOSUPPRESSION IMMUNOSUPPRESSION OPPORTUNISTIC INFECTIONSOPPORTUNISTIC INFECTIONS

Lymphadenopathy cases

diffuse, undifferentiated non-Hodgkins lymphoma

1977- 1980: No cases in the young male (20 - 39 years old) population of the San Francisco area

March 1981 - January 1982: four cases within 10 months

Gay-Related Immune DeficiencyGay-Related Immune Deficiency

Acquired Immune Deficiency Acquired Immune Deficiency Syndrome (AIDS)Syndrome (AIDS)


• Clusters of infected men

• Apparent concentration within sexually interactive groups

• High numbers of sex partners

Distinguishing characteristics

Suggests an infectious agentSuggests an infectious agent

Female sex partners of AIDS-positive IV drug users and hemophiliacs

More evidence for an infectious agent

Different ways of getting a similar syndrome• Blood transfusions

• Intravenous drug use

• Hemophilia (clotting factor)


Haitian origin


1983: The 4H Club

• Homosexuality among males

• Hemophilia

• Heroin use

• Haitian origin

• AIDS is the end point of an infection that is continuous, progressive and pathogenic

AIDS DefinitionAIDS DefinitionAIDS DefinitionAIDS Definition• AIDS is currently defined as the presence of one of 25 conditions indicative of severe

immunosuppression

OR • HIV infection in an individual with a CD4+ cell count

of <200 cells per cubic mm of blood

• Approximately 40,000,000 people in the world are HIV-infected

•14,000 new HIV infections occur daily around the world

-Over 90% of these are in developing countries

-1000 are in children less than 15 years of age

-Of adult infections, 48% are in women

AIDS StatisticsAIDS Statistics

Modes of transmissionModes of transmission

most common means in the world:most common means in the world:

sexual contactsexual contact blood or blood product transfusion (before blood or blood product transfusion (before

routine testing) routine testing) transplanted tissue (before routine testing) transplanted tissue (before routine testing) IV drug use with shared needles IV drug use with shared needles transplacental (transplacental (in uteroin utero) or by perinatal ) or by perinatal

infection of neonates (breast milk)infection of neonates (breast milk)

HIV entry into cells

Important HIV Important HIV componentscomponents

Gp120 + CD4 RECEPTORSGp120 + CD4 RECEPTORS

Viral reverse transcriptase : produces Viral reverse transcriptase : produces complementary DNA using the viral RNA complementary DNA using the viral RNA templatetemplate

Provirus: Viral DNA is transported into the Provirus: Viral DNA is transported into the nucleus and is integrated into the nucleus and is integrated into the chromosomechromosome

Function of T cellsFunction of T cells

Macrophages:Macrophages:The Trojan HorseThe Trojan Horse

Macrophages:Macrophages:The Trojan HorseThe Trojan Horse

Carry virus into different organs (brain)

macrophages sustain HIV production for a long time without being killed by virus

Macrophages form a reservoir outside the blood

Population Population PolymorphismPolymorphism

Population Population PolymorphismPolymorphism

EVERY new virus has at least one mutationEVERY new virus has at least one mutation!!

The HIV that infects a patient is very different from that seen The HIV that infects a patient is very different from that seen by the time AIDS appearsby the time AIDS appears

4 stages of HIV infection4 stages of HIV infection

Stage I: asymptomaticStage I: asymptomatic

Stage II: Stage II:

minor mucocutaneous minor mucocutaneous manifestations manifestations recurrent upper recurrent upper respiratory tract respiratory tract infections infections

4 stages of HIV infection4 stages of HIV infection Stage III: Stage III:

unexplained chronic diarrhea>1 unexplained chronic diarrhea>1 monthmonth

severe bacterial infectionssevere bacterial infections

Stage IV: Stage IV: toxoplasmosis of the braintoxoplasmosis of the braincandidiasis of the esophagus, candidiasis of the esophagus,

trachea, trachea, bronchi or lungs bronchi or lungs Kaposi's sarcomaKaposi's sarcoma

AIDS-defining diseasesAIDS-defining diseases Candidiasis of bronchi, trachea, or Candidiasis of bronchi, trachea, or

lungs lungs Candidiasis esophageal Candidiasis esophageal Cervical cancer (invasive) Cervical cancer (invasive) Coccidioidomycosis, disseminated or Coccidioidomycosis, disseminated or

extrapulmonary extrapulmonary Cryptococcosis, extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal for Cryptosporidiosis, chronic intestinal for

longer than 1 month longer than 1 month Cytomegalovirus disease (other than Cytomegalovirus disease (other than

liver, spleen or lymph nodes) liver, spleen or lymph nodes)

AIDS-defining diseasesAIDS-defining diseases Encephalopathy (HIV-related) Encephalopathy (HIV-related) Herpes simplex: chronic ulcer(s) (for Herpes simplex: chronic ulcer(s) (for

more than 1 month); or bronchitis, more than 1 month); or bronchitis, pneumonitis, or esophagitis pneumonitis, or esophagitis

Histoplasmosis, disseminated or Histoplasmosis, disseminated or extrapulmonary extrapulmonary

Isosporiasis, chronic intestinal (for Isosporiasis, chronic intestinal (for more than 1 month) more than 1 month)

Kaposi's sarcoma Kaposi's sarcoma Lymphoma Burkitt's, immunoblastic or Lymphoma Burkitt's, immunoblastic or

primary brain primary brain Mycobacterium avium complex Mycobacterium avium complex

AIDS-defining diseasesAIDS-defining diseases Mycobacterium, other species, Mycobacterium, other species,

disseminated or extrapulmonary disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumocystis carinii pneumonia Pneumonia (recurrent) Pneumonia (recurrent) Progressive multifocal Progressive multifocal

leukoencephalopathy leukoencephalopathy Salmonella septicemia (recurrent) Salmonella septicemia (recurrent) Toxoplasmosis of the brain Toxoplasmosis of the brain Tuberculosis Tuberculosis Wasting syndrome due to HIV Wasting syndrome due to HIV

However, when an individual shows negative lab However, when an individual shows negative lab results for HIV infection, the diagnosis of AIDS is results for HIV infection, the diagnosis of AIDS is

still considered if:still considered if:

1) the patient has not undergone high-dose 1) the patient has not undergone high-dose corticoid therapy,other corticoid therapy,other immunosuppressive/cytotoxic therapy in the immunosuppressive/cytotoxic therapy in the three months before the onset of the three months before the onset of the indicator disease indicator disease

OROR 2) the patient has not been diagnosed with 2) the patient has not been diagnosed with

Hodgkin's disease, non-Hodgkin's Hodgkin's disease, non-Hodgkin's lymphoma, lymphocytic leukemia, multiple lymphoma, lymphocytic leukemia, multiple myeloma, or any cancer of lymphoreticular myeloma, or any cancer of lymphoreticular or histiocytic tissue, or angioimmunoblastic or histiocytic tissue, or angioimmunoblastic lymphoadenopathy lymphoadenopathy

OR OR 3)the patient does not have a genetic 3)the patient does not have a genetic immunodeficiency syndrome atypical of HIV immunodeficiency syndrome atypical of HIV infection, such as one involving hypogamma infection, such as one involving hypogamma globulinemia globulinemia

ANDAND the individual has had the individual has had Pneumocystis Pneumocystis

cariniicarinii pneumonia pneumonia

OR OR one of the above defining illnesses one of the above defining illnesses

AND AND a CD4+ T-cell count <200 cells/µl or a CD4+ T-cell count <200 cells/µl or

a CD4+percentage <14% a CD4+percentage <14%

TEST Purpose

Serological tests:

ELISA Initial Screening

Latex Agglutination Initial Screening

Western Blot Analysis Confirmation Test

Immunofluorescence Confirmation Test

Other tests:

p24 antigenEarly Marker of Infection (detection of a recent

infection)

Virion RNA RT-PCRDetection of virus in blood (detection of a recent

infection) and to confirm treatment efficacy.

CD4:CD8 T-cell RatioStaging the disease and to confirm treatment

efficacy.

Isolation and culture of virus Only available in research labs.

P24 antigen P24 antigen (nucleocapid)(nucleocapid)

produced early in infection produced early in infection present in the patient's present in the patient's

bloodstreambloodstream

Reverse Transcriptase Polymerase Chain Reverse Transcriptase Polymerase Chain

Reaction Reaction (RT-PCR(RT-PCR) for VIRAL ) for VIRAL LOADLOAD

to detect HIV RNA in to detect HIV RNA in plasmaplasma

first 2-4 weeks of infection, first 2-4 weeks of infection, when patients may be when patients may be seronegative and yet are seronegative and yet are infectiveinfective

Western blot: definitive Western blot: definitive diagnosisdiagnosis

Antibody specific for HIV gp120 or Antibody specific for HIV gp120 or gp160 (detectable within 4-8 weeks gp160 (detectable within 4-8 weeks post-exposure)post-exposure)

However in 5% of the patients However in 5% of the patients antibodies may not be detectable antibodies may not be detectable for 6 months or more. for 6 months or more.

CD4+, CD8+ countsCD4+, CD8+ counts

CD4+ is monitored every 3-6 months CD4+ is monitored every 3-6 months

-when to start PCP therapy-when to start PCP therapy

-monitor antiviral therapy-monitor antiviral therapy

-when to start antiviral therapy-when to start antiviral therapy

Normal CD4+ levels:500 to 1600Normal CD4+ levels:500 to 1600 Normal CD8+ levels: 375 to 1100Normal CD8+ levels: 375 to 1100

Abnormal valuesAbnormal values CD percentage: refers to the total CD percentage: refers to the total

lymphocytes; more reliable indicator of HIV; lymphocytes; more reliable indicator of HIV; predictor of HIV disease progressionpredictor of HIV disease progression

CD4+CD4+<200 = start PCP therapy<200 = start PCP therapy<100= toxoplasmosis; crytpcoccosis<100= toxoplasmosis; crytpcoccosis<75= MAC<75= MAC

CD4+ percentageCD4+ percentage>28%=normal>28%=normal14-27%= intermediate14-27%= intermediate<14%= clinical AIDS<14%= clinical AIDS

Abnormal valuesAbnormal values

CD4/CD8 ratioCD4/CD8 ratio Normal: 0.9 to 1.9Normal: 0.9 to 1.9 In HIV, CD8 appears increased due In HIV, CD8 appears increased due

to decrease of CD4to decrease of CD4

1. Nonnucleoside Reverse 1. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)Transcriptase Inhibitors (NNRTIs)

2. Nucleoside Reverse Transcriptase 2. Nucleoside Reverse Transcriptase Inhibitors (NRTIs),Inhibitors (NRTIs),

3. Protease Inhibitors (PIs)3. Protease Inhibitors (PIs)

4. Fusion Inhibitors4. Fusion Inhibitors

HAARTHAART (Highly Active (Highly Active Antiretroviral Therapy)Antiretroviral Therapy)

available since 1995available since 1995 results in suppression of viral results in suppression of viral

replicationreplication halts damage to the immune systemhalts damage to the immune system partially restores the immune system partially restores the immune system

leading to partial restoration of leading to partial restoration of immune functionimmune function

fewer opportunistic infections and fewer opportunistic infections and longer life for the patients. longer life for the patients.

When to start treatmentWhen to start treatment history of an AIDS-defining illness or

with a CD4 T-cell count <350 cells/mm3.

Antiretroviral therapy should also be initiated in the following groups of patients regardless of CD4 T-cell count:

a. Pregnant women b. Patients with HIV-associated

nephropathy c. Patients coinfected with HBV

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