HIV

HIV

• 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

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

Historical Back Ground

• 1981: AIDS was first recognized in USA among Homosexual males

PCP was seen among 5 homosexualsKaposi’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

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.

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.

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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

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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.

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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.

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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.

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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

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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.

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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Relative Control of HIV: Viral Set Points

Year 1

Vir

al lo

ad

Predictor for:-Disease progression-Risk of transmission

Low set point = slower disease progression

High set point = faster disease progression

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Patterns of HIV Disease Progression

HIV Infection

Long-term Non-progressors

Rapid Progressors

Typical Progressors

<3 years

7-10 years

>10-15 yr

Normal, Stable CD4

90 %

<5 %

<10 %

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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!

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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)

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WHO Clinical Staging System

Clinical Stage 1 Asymptomatic infectionPersistent 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

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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)

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Stage 2

Herpes Zoster

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Stage 2Papular pruritic

eruption

Always exlcude scabies, insect bites

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Stage 2Seborrhoeic dermatitis

Itchy scaly skin condition, especially affecting scalp, face, upper trunk (also common in non-HIV)

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Angular stomatitis

Splits or cracks on lips at angle of mouth

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Clinical Stage 3

Oral candidiasis Oral hairy leukoplakiaPulmonary tuberculosis in the last 2 yrsUnexplained Weight loss >10% Unexplained chronic diarrhoea > 1 month

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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

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Clinical Stage 3

Unexplained: Anaemia (<8g/dl) or Neutropenia (<500/mm³) or Thrombocytopenia (<50 000/mm³)

For > 1 month

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Oral thrush

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Oral hairy leukoplakia

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Necrotising stomatitis

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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

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Clinical Stage 4

HIV wasting syndrome Pneumocystis pneumoniaCandidiasis of the oesophagus Extrapulmonary tuberculosis Kaposi's sarcomaCryptococcal meningitis (or other extra pulmonary crypto)

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Clinical Stage 4Invasive cervical carcinomaCryptosporidiosis, IsosporiasisHIV encephalopathy Progressive multifocal leukoencephalopathy

(PML)Candidiasis of trachea, bronchi, or lungsAny disseminated endemic mycosis Histoplasmosis,

Coccidiomycosis, Penicilliosis

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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, visceralVisceral Herpes simplex

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HIV wasting: definition

Weight loss > 10%

PLUS

Unexplained chronic diarrhoea > 1 month

OR

Unexplained prolonged fever > 1 month

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PCP

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Cerebral toxoplasmosis

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Kaposis Sarcoma

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Kaposis Sarcoma

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Kaposis

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Kaposis Sarcoma

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Lymphoma

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Chronic extensive genital HSV

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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

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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

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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 confirmedOnly if a positive test is confirmed, can you report result to patient!

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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!

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 ),

• 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

• 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.

WHO clinicalstage

CD4 testing not available

CD4 testing available1

1 Don’t treat Start ART only if CD4count is < 200/mm3

2 ART may be started if TLC is <1200/mm3

3 If symptomatic initiate ARTirrespective of TLC

Start ART if CD4 is<350/mm3 and initiatebefore CD4 drops<200/mm3

4 Start ART irrespective of TLC

Start ART irrespective ofCD4 count

•Thank u•?????