HIV

1. HIV

2. Learning Objectives: At the end of the this Unit the student will be able to • 1. Define HIV disease and AIDS • 2. Understand the basic virology of the etiologic agent • 3. Describe the mode of transmission of HIV • 4. Understand the epidemiology of HIV • 5. Describe the pathophysiology of HIV/AIDS • 6. Identify the clinical manifestations of HIV/AIDS • 7. List the complications and Organ systems affected by HIV/AIDS • 8. Describe the most commonly investigations for the diagnosis of HIV

3. Definition: HIV disease is a chronic infectious disease caused by the Human Immuno Deficiency Virus.

4. Historical Back Ground • 1981: AIDS was first recognized in USA among Homosexual males PCP was seen among 5 homosexuals Kaposi’s sarcoma was diagnosed in 26 homosexuals with • 1983: HIV virus was isolated from a patient with lymphadenopathy • 1984: HIV virus was clearly demonstrated to be the causative agent for AIDS

5. Epidemiology • ♦ Sub-Saharan Africa is the worst affected by the pandemic with 25.7 million living with HIV, Out of which 2.1 million are children < 15 years. • Our country Ethiopia is the second most populous country in Sub-Saharan African • suffering from the brunt of HIV/AIDS. In Ethiopia HIV was first detected in collected sera • in 1984. The first two AIDS cases were reported to the Ministry of Health in1986.

6. Mode of Transmission of HIV • 1. Sexual Transmission: • Is the major mode of transmission worldwide ( 90 % ) • 2. Transmission through blood and blood products • 3. Mother to Child Transmission • .. Without any intervention, the risk of mother to child transmission is 30-45% in the developing world and 15-45% in developed world.

7. Etiology • HIV-1 & HIV-2 HIV-1 • Responsible for the global pandemic. • Contains 2 copies of single stranded RNA inside a capsid. • Has outer double lipid layer which contains gp120(surface protein) & gp41(transmembrane protein). • gp 41: highly immunogenic • gp 120:carries the binding site for CD4 molecules

8. Enzymes: RT, protease, Integrase. • Co-receptors: CxCR-4 & CCR-5 • CxCR-4: fusion inducing molecule, facilitates attachment of HIV to lymphocyte. • CCR-5: facilitates entry of HIV to Macrophage • Susceptible cells for infection are cells with CD4: • T lymphocytes, macrophages, microglia, astrocytes, Hofbaure cells on placenta. • Other cell surface receptors: Mannose binding protein on Mac & DC-SIGN on dendritic cells.

9. HIV -1 has subtypes: A,B,C,D,E • Subtype A & E: in East & Central Africa • Subtype C: 90% of the southern Africa • High transcription rate • Faster disease progression & with higher MTCT rates • HIV-2 • Less pathogenic and has little contribution to PAIDS. • Mostly found in west Africa, Mozambique, Angola. • But new cases in Europe & S.Asia.

10. Pathogenesis • Involves binding, fusion, entry, transcription, integration, replication, budding, maturation. • Binding: to cells expressing CD4 molecules • Fusion • gp120 binds to host cell receptor and co-receptor on the outside of host cell. • gp41 is inserted to the cell membrane of host cell with the fusion of the two membranes.

11. Entry • Virus particle released into the cytoplasm of host cell. • Host cell enzyme interacts with viral particle, resulting in release of viral enzymes. • Reverse transcription • Integration Provirus • Replication • Using host cell as a machine

12. Budding • The provirus gather at the membrane of the host cell & pushes through the membrane by budding taking the lipid bilayer with it. • Maturation • The gp160,embedded in the cell membrane, is cleaved by protease enzyme to produce functional gp120 & gp41 to form mature virus ready to infect a new cell.

14. Pathogenesis: • ♦ HIV virus has special affinity to CD4 T-cells and infects them • ♦ HIV infection is characterized by a profound immunodeficiency from progressive decline of T-helper cells • ♦ The pathogenic mechanism of HIV disease is multi-factorial and multiphasic and it differs in different stage of the disease

16. Relative Control of HIV: Viral Set Points • Predictor for: • Disease progression • Risk of transmission Viral load High set point = faster disease progression Low set point = slower disease progression Year 1

17. Patterns of HIV Disease Progression 7-10 years Typical Progressors 90 % HIV Infection <5 % Rapid Progressors <3 years Long-term Non-progressors <10 % >10-15 yr Normal, Stable CD4

19. WHO Clinical Staging System • The WHO clinical staging system includes: • A clinical classification system • A laboratory classification to categorize the immunosuppression of adults by their total lymphocyte counts or CD4 • This staging system has proven reliable for predicting morbidity and mortality in infected adults • The WHO Clinical Staging System is based on clinical markers believed to have prognostic significance resulting in four categories The WHO staging system is not 100% sensitive and specific!

20. Classification Systems for HIV Infectionand Disease • Require a positive HIV test • Reflect the progressive nature of HIV disease from asymptomatic to AIDS • Hierarchical: once in a stage cannot go back to an earlier stage • Staging reflective of prognosis and CD4 counts (level of immunity)

21. WHO Clinical Staging System Clinical Stage 1 Asymptomatic infection Persistent generalized lymphadenopathy (PGL) Definition of PGL: swollen or enlarged lymph nodes > 1cm, in 2 or more non-contiguous extra-inguinal sites, in absence of known cause

22. Clinical Stage 2 • Unexplained Weight loss <10% of presumed body weight • Minor mucocutaneous manifestations: • Papular pruritic eruptions • Seborrhoeic dermatitis • Angular chelitis • Fungal nail infections of fingers • Recurrent oral ulcerations (≥ 2 x/6months) • Herpes zoster (current or in last 2 years) • Recurrent upper respiratory tract infections (sinusitis, otitis media, bronchitis, pharyngitis)

23. Stage 2 Herpes Zoster

24. Stage 2 Papular pruritic eruption Always exlcude scabies, insect bites

25. Stage 2 Seborrhoeic dermatitis Itchy scaly skin condition, especially affecting scalp, face, upper trunk (also common in non-HIV)

26. Angular stomatitis Splits or cracks on lips at angle of mouth

27. Clinical Stage 3 Oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis in the last 2 yrs Unexplained Weight loss >10% Unexplained chronic diarrhoea > 1 month

28. Clinical Stage 3 Unexplained prolonged fever(intermittent or constant for >1 month) Severe presumed bacterial infections(e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteremia) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis

29. Clinical Stage 3 • Unexplained: • Anaemia (<8g/dl) or • Neutropenia (<500/mm³) or • Thrombocytopenia (<50 000/mm³) For > 1 month

30. Oral thrush

31. Oral hairy leukoplakia

32. Necrotising stomatitis

33. Clinical Stage 4 Recurrent severe bacterial pneumonia Chronic herpes simplex infection orolabial, genital, or anorectal of > 1 month duration Cytomegalovirus infection (other than liver, spleen, LN) CNS toxoplasmosis

34. Clinical Stage 4 HIV wasting syndrome Pneumocystis pneumonia Candidiasis of the oesophagus Extrapulmonary tuberculosis Kaposi's sarcoma Cryptococcal meningitis (or other extra pulmonary crypto)

35. Clinical Stage 4 Invasive cervical carcinoma Cryptosporidiosis, Isosporiasis HIV encephalopathy Progressive multifocal leukoencephalopathy (PML) Candidiasis of trachea, bronchi, or lungs Any disseminated endemic mycosis Histoplasmosis, Coccidiomycosis, Penicilliosis

36. Clinical Stage 4 Disseminated Mycobacterial diseases other than tuberculosis Recurrent non-typhoidal salmonella septicaemia (2 or >episodes in one year) Lymphoma (cerebral or B-cell non-Hodgkin) Leishmaniasis, visceral Visceral Herpes simplex

37. HIV wasting: definition Weight loss > 10% PLUS Unexplained chronic diarrhoea > 1 month OR Unexplained prolonged fever > 1 month

38. PCP

39. Cerebral toxoplasmosis

40. Kaposis Sarcoma

41. Kaposis Sarcoma

42. Kaposis

43. Kaposis Sarcoma

44. Lymphoma

45. Chronic extensive genital HSV

46. Laboratory Tests for Diagnosis • Direct detection of virus • Viral culture • Viral Load • DNA PCR • ANTIGEN (Ag) in plasma/serum (p24) • Detection of Antibody • Rapid tests • ELISA • Western blot AVAILABLE IN MOST SETTINGS

47. Window Period • Time period between acquisition of HIV infection and formation of detectable levels of ANTIBODIES (Ab) • At 6 weeks: 80% will have detectable antibodies • At 12 weeks almost 100% • Rare cases will take longer

48. Interpretation of HIV Testing An initial negative rapid test can be accepted as true true negative = not HIV infected Note that you need to consider that the patient may be in the window period. Positive rapid test Needs to be confirmed Only if a positive test is confirmed, can you report result to patient!

49. Why use Rapid Tests? • Easier to use, no need for expensive lab equipment or highly skilled staff • Same day result: useful for prophylactic regimens for transmission e.g. PEP • Increases the number of people that receive the test result  less transmission!

50. Antiretroviral Drugs (ARTs) • ARTs are the corner stone of medical management of HIV infection. • Classes of Antiretroviral Drugs • 1) Nucleoside reverse transcriptase inhibitors ( NRTIs) • Lamivudine (3TC) Stavudine ( d4t ) • Zidovudine (AZT ) Abacavir ( ABC) • Didanosine (DDI ) Zalcitabin ( DDC ) • Emtricitabine (FTC) Tenofovir (TDF ),