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. 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. 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. 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. 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. 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. 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

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

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

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19. 19  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 WHO Clinical Staging System The WHO staging system is not 100% sensitive and specific!

20. 20 Classification Systems for HIV Infection and 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. 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. 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. 23 Stage 2 Herpes Zoster

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

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

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

27. 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. 28 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 Clinical Stage 3

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

30. 30 Oral thrush

31. 31 Oral hairy leukoplakia

32. 32 Necrotising stomatitis

33. 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. 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. 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. 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. 37 HIV wasting: definition Weight loss > 10% PLUS Unexplained chronic diarrhoea > 1 month OR Unexplained prolonged fever > 1 month > 1 month

38. 38 PCP

39. 39 Cerebral toxoplasmosis

40. 40 Kaposis Sarcoma

41. 41 Kaposis Sarcoma

42. 42 Kaposis

43. 43 Kaposis Sarcoma

44. 44 Lymphoma

45. 45 Chronic extensive genital HSV

46. 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. 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. 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. 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 ),

51. Mechanism of Action: Structurally these drugs resemble naturally occurring nucleosides and break the formation of viral DNA by breaking the chain ( chain breakers ) 2) Non-nucleoside reverse transcriptase inhibitors ( NNRTIs) Nevirapine (NVP, Nevipan ® ) Efavirenz (EFV, Stocrin ® ) Mechanism of Action: inhibit the active site of Reverse transcriptase enzyme

52. 3) Protease Inhibitors Mechanism of Action: Inhibit viral assembly by blocking the PI PIs are mainly used as second line drugs in recourse limited settings as these drugs are expensive and most formulations need refrigeration.

53. WHO clinical stage CD4 testing not available CD4 testing available1 1Don’t treat Start ART only if CD4 count is < 200/mm 3 2 ART may be started if TLC is < 1200/mm 3 3 If symptomatic initiate ART irrespective of TLC Start ART if CD4 is< 350/mm 3 and initiate before CD4 drops <200/mm 3 4 Start ART irrespective of TLC Start ART irrespective of CD4 count

54. Thank u ?????