1. HIV and AIDS PM2 PATHOPHYSIOLOGY

2. HIV is the causative agent of AIDS Human immunodeficiency virus Human immunodeficiency virus retrovirus retrovirus most common type: HIV-1 most common type: HIV-1 HIV-1: distributed worldwide HIV-1: distributed worldwide HIV-2:mainly endemic in west Africa HIV-2:mainly endemic in west Africa

5. When was it discovered? AIDS was first recognized in June 5,1981 AIDS was first recognized in June 5,1981

6. 107 cases of Pneumocystis carinii pneumonia United States, pre-AIDS epidemic AIDS epidemic has resulted in 166,368 cases up to 1999 HIV and AIDS Pneumocystis pneumonia

7. HIV and AIDS an 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

8. HIV and AIDS Two rare diseases in the gay community linked to IMMUNOSUPPRESSION OPPORTUNISTIC INFECTIONS

9. 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

10. Gay-Related Immune Deficiency Gay-Related Immune Deficiency Acquired Immune Deficiency Syndrome (AIDS) Acquired Immune Deficiency Syndrome (AIDS)

11. HIV and AIDS Clusters of infected men Apparent concentration within sexually interactive groups High numbers of sex partners Distinguishing characteristics Suggests an infectious agent

12. 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) HIV and AIDS Haitian origin

13. HIV and AIDS 1983: The 4H Club H omosexuality among males H emophilia H eroin use H aitian origin

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

15. 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 Statistics

16. Modes of transmission most common means in the world: most common means in the world: sexual contact blood or blood product transfusion (before routine testing) blood or blood product transfusion (before 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 (in utero) or by perinatal infection of neonates (breast milk) transplacental (in utero) or by perinatal infection of neonates (breast milk)

17. HIV entry into cells

18. Important HIV components Gp120 + CD4 RECEPTORS Gp120 + CD4 RECEPTORS Viral reverse transcriptase : produces complementary DNA using the viral RNA template Viral reverse transcriptase : produces complementary DNA using the viral RNA template Provirus: Viral DNA is transported into the nucleus and is integrated into the chromosome Provirus: Viral DNA is transported into the nucleus and is integrated into the chromosome

19. Function of T cells

20. Macrophages: The 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

21. Population Polymorphism EVERY new virus has at least one mutation ! EVERY new virus has at least one mutation ! The HIV that infects a patient is very different from that seen by the time AIDS appears

22. 4 stages of HIV infection Stage I: asymptomatic Stage I: asymptomatic Stage II: Stage II: minor mucocutaneous manifestations recurrent upper respiratory tract infections

23. 4 stages of HIV infection Stage III: Stage III: unexplained chronic diarrhea>1 month severe bacterial infections Stage IV: Stage IV: toxoplasmosis of the brain candidiasis of the esophagus, trachea, bronchi or lungs Kaposi's sarcoma

24. AIDS-defining diseases Candidiasis of bronchi, trachea, or lungs Candidiasis of bronchi, trachea, or lungs Candidiasis esophageal Candidiasis esophageal Cervical cancer (invasive) Cervical cancer (invasive) Coccidioidomycosis, disseminated or extrapulmonary Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal for longer than 1 month Cryptosporidiosis, chronic intestinal for longer than 1 month Cytomegalovirus disease (other than liver, spleen or lymph nodes) Cytomegalovirus disease (other than liver, spleen or lymph nodes)

25. AIDS-defining diseases Encephalopathy (HIV-related) Encephalopathy (HIV-related) Herpes simplex: chronic ulcer(s) (for more than 1 month); or bronchitis, pneumonitis, or esophagitis Herpes simplex: chronic ulcer(s) (for more than 1 month); or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extrapulmonary Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (for more than 1 month) Isosporiasis, chronic intestinal (for more than 1 month) Kaposi's sarcoma Kaposi's sarcoma Lymphoma Burkitt's, immunoblastic or primary brain Lymphoma Burkitt's, immunoblastic or primary brain Mycobacterium avium complex Mycobacterium avium complex

26. AIDS-defining diseases Mycobacterium, other species, disseminated or extrapulmonary Mycobacterium, other species, disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumocystis carinii pneumonia Pneumonia (recurrent) Pneumonia (recurrent) Progressive multifocal leukoencephalopathy Progressive multifocal 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

27. However, when an individual shows negative lab results for HIV infection, the diagnosis of AIDS is still considered if: 1) the patient has not undergone high-dose corticoid therapy,other immunosuppressive/cytotoxic therapy in the three months before the onset of the indicator disease OR 2) the patient has not been diagnosed with Hodgkin's disease, non-Hodgkin's lymphoma, lymphocytic leukemia, multiple myeloma, or any cancer of lymphoreticular or histiocytic tissue, or angioimmunoblastic lymphoadenopathy 2) the patient has not been diagnosed with Hodgkin's disease, non-Hodgkin's lymphoma, lymphocytic leukemia, multiple myeloma, or any cancer of lymphoreticular or histiocytic tissue, or angioimmunoblastic lymphoadenopathyOR 3)the patient does not have a genetic immunodeficiency syndrome atypical of HIV infection, such as one involving hypogamma globulinemia

28. AND the individual has had Pneumocystis carinii pneumonia the individual has had Pneumocystis carinii pneumoniaOR one of the above defining illnesses one of the above defining illnessesAND a CD4+ T-cell count <200 cells/µl or a CD4+percentage <14% a CD4+ T-cell count <200 cells/µl or a CD4+percentage <14%

29. TESTPurpose Serological tests: ELISAInitial Screening Latex AgglutinationInitial Screening Western Blot AnalysisConfirmation Test ImmunofluorescenceConfirmation Test Other tests: p24 antigen Early Marker of Infection (detection of a recent infection) Virion RNA RT-PCR Detection of virus in blood (detection of a recent infection) and to confirm treatment efficacy. CD4:CD8 T-cell Ratio Staging the disease and to confirm treatment efficacy. Isolation and culture of virusOnly available in research labs.

30. P24 antigen (nucleocapid) produced early in infection produced early in infection present in the patient's bloodstream present in the patient's bloodstream

31. Reverse Transcriptase Polymerase Chain Reaction (RT- PCR ) for VIRAL LOAD to detect HIV RNA in plasma to detect HIV RNA in plasma first 2-4 weeks of infection, when patients may be seronegative and yet are infective first 2-4 weeks of infection, when patients may be seronegative and yet are infective

32. Western blot: definitive diagnosis Antibody specific for HIV gp120 or gp160 (detectable within 4-8 weeks post-exposure) Antibody specific for HIV gp120 or gp160 (detectable within 4-8 weeks post-exposure) However in 5% of the patients antibodies may not be detectable for 6 months or more. However in 5% of the patients antibodies may not be detectable for 6 months or more.

33. CD4+, CD8+ counts CD4+ is monitored every 3-6 months CD4+ is monitored every 3-6 months -when to start PCP therapy -monitor antiviral therapy -when to start antiviral therapy -when to start antiviral therapy Normal CD4+ levels:500 to 1600 Normal CD4+ levels:500 to 1600 Normal CD8+ levels: 375 to 1100 Normal CD8+ levels: 375 to 1100

34. Abnormal values CD percentage: refers to the total lymphocytes; more reliable indicator of HIV; predictor of HIV disease progression CD percentage: refers to the total lymphocytes; more reliable indicator of HIV; predictor of HIV disease progression CD4+ CD4+ <200 = start PCP therapy <100= toxoplasmosis; crytpcoccosis <75= MAC CD4+ percentage CD4+ percentage>28%=normal 14-27%= intermediate <14%= clinical AIDS

35. Abnormal values CD4/CD8 ratio CD4/CD8 ratio Normal: 0.9 to 1.9 Normal: 0.9 to 1.9 In HIV, CD8 appears increased due to decrease of CD4 In HIV, CD8 appears increased due to decrease of CD4

36.  1. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)  2. Nucleoside Reverse Transcriptase Inhibitors (NRTIs),  3. Protease Inhibitors (PIs)  4. Fusion Inhibitors

37.  1. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)  2. Nucleoside Reverse Transcriptase Inhibitors (NRTIs),  3. Protease Inhibitors (PIs)  4. Fusion Inhibitors

38. HAART (Highly Active Antiretroviral Therapy) available since 1995 available since 1995 results in suppression of viral replication results in suppression of viral replication halts damage to the immune system halts damage to the immune system partially restores the immune system leading to partial restoration of immune function partially restores the immune system leading to partial restoration of immune function fewer opportunistic infections and longer life for the patients. fewer opportunistic infections and longer life for the patients.

39. When 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