HIV and AIDS

History

1950s: Blood samples from Africa have HIV antibodies.

1976: First known AIDS patient died.

1980: First human retrovirus isolated (HTLV-1). 1981: First reports of Acquired Immunodeficiency Syndrome in Los Angeles. 1983: Virus first isolated in France (LAV).

1984: Virus isolated in the U.S. (called HTLV-III and AIDS-Related Virus, ARV). 1985: Development and implementation of antibody test to screen blood donors

History
1986:

Consensus name Human Immunodeficiency Virus (HIV-1), first case in India was detected in Chennai

Related virus (HIV-2) identified 1992: AIDS becomes the leading cause of death

among adults ages 25-44 in the U.S. 1997: Mortality rates of AIDS starts to decline due to the introduction of new drug cocktails 2001: World Health Organization predicts up to 40 million infected individuals. More than 22 million have already died.

HIV Virus
RNA virus HIV-I: A,D: East, West, North, Central Africa B: US, Europe, East Asia, Brazil C: India, South Africa E: Thailand F: East Europe, Brazil HIV-II : West Africa, Brazil, South West Asia Less transmissible Associated with lower viral load , Slower rate of clinical progression Not susceptible to NNRTI, possible PI resistance

HIV Virus Srains

Three groups: "major" group M "outlier" group O "new" group N

Group O - west-central Africa Group N - discovered in 1998 in Cameroon - is extremely rare Group M - nine genetically distinct subtypes A, B, C, D, F, G, H, J and K

HIV Viral proteins

gag pol env (tat, rev, nef, vif, vpr, vpu) tev

Life cycle of HIV

Life cycle of HIV

Attachment:

Virus binds to surface molecule (CD4) of T helper cells and macrophages. - Coreceptors: Required for HIV infection - CXCR4 and CCR5 mutants are resistant to infection Fusion: Viral envelope fuses with cell membrane, releasing contents into the cell

Life cycle of HIV

Reverse Transcription: Viral RNA is converted into DNA by unique enzyme reverse transcriptase.

Reverse transcriptase

RNA ------------------------> DNA Reverse transcriptase is the target of several HIV drugs: AZT, ddI and ddC. Integration: Viral DNA is inserted into host cell chromosome by unique enzyme integrase. Integrated viral DNA may remain latent for years and is called a provirus.

Life cycle of HIV

Replication: Viral DNA is transcribed and RNA is translated, making viral proteins. Viral genome is replicated.
Assembly:

New viruses are made.

Release: New viruses bud through the cell membrane.

Life cycle of HIV

Replication: Viral DNA is transcribed and RNA is translated, making viral proteins. Viral genome is replicated.
Assembly:

New viruses are made

Release: New viruses bud through the cell membrane

High Risk Groups

Promiscuous heterosexual/ homosexual

Commercial sex worker

IV drug abuser Spouse of HIV infected Blood recipient

Transmission of HIV (Worldwide)

Sexual contact with infected individual: All forms of sexual intercourse (homosexual and heterosexual); 75% of transmission. Sharing of unsterilized needles by intravenous drug users and unsafe medical practices; 5-10% of transmission. Transfusions and Blood Products: Hemophiliac population was decimated in 1980s. Risk is low today; 3-5% of transmission. Mother to Infant (Perinatal): 25% of children become infected in utero, during delivery, or by breast-feeding (with AZT only 3%); 5-10% of transmission.

Transmission Categories
Transmission Categories
Sexual Perinatal Blood and blood products Injecting drug users Number of cases 93,964 3,957 2,201 2,661

%
85.93 3.62 2.01 2.43

Others (not specified)

Total

6,566
109,349

6.00
100%

Pathogenesis

Viral transmission
2-3 wks

Acute retroviral syndrome

2-3 wks

Recovery + Seroconversion
2-4 wks

Asymptomatic chronic HIV infection

avg 8 yrs

Symptomatic HIV infection/AIDS

1-3 yrs

Death

Natural History

Stages of HIV Infection

Global summary of the AIDS epidemic December 2006

Number of people living with HIV in 2006 Total Adults 39.5 million (34.1 - 47.1 million) 37.2 million (32.1 - 44.5 million)

Women
Children under 15 years

17.7 million (15.1 - 20.9 million)

2.3 million (1.7 - 3.5 million)

Source: Joint United Nations Programme on HIV AIDS (UNAIDS) and WHO 2006

Global summary of the AIDS epidemic December 2006

People newly infected with HIV in 2006 Total Adults Children under 15 years 4.3 million (3.6-6.6 million) 3.8 million (3.2-5.7 million) 5,30,000 (4,10,000-4,60,000)

AIDS deaths in 2006 Total Adults Children under 15 years 2.9 million (2.5-3.5 million) 2.6 million (2.2-3.0 million) 3,80,000 (2,90,000-5,00,000)

Source: Joint United Nations Programme on HIV AIDS (UNAIDS) and WHO 2006

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)

Primary HIV infection

Asymptomatic
Acute retroviral syndrome

Clinical stage 1

Asymptomatic
Persistent generalized lymphadenopathy

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 2

Moderate and unexplained weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections Herpes Zoster Recurrent oral ulcerations Papular pruritic eruptions

Seborrhoeic dermatitis
Fungal nail infections

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 3
Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations

Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever Severe weight loss (>10% of presumed or measured body weight) Oral candidiasis Oral hairy leukoplakia

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 3 Pulmonary tuberculosis (TB) diagnosed in last two years Severe bacterial infections Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Conditions where confirmatory diagnostic testing is necessary

Unexplained anaemia (< 80 g/l), and or neutropenia (<500/l) and or thrombocytopenia (<50 000/ l) for more than one month

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 4
Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations

HIV wasting syndrome Pneumocystis pneumonia Recurrent severe or radiological bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal of more than one months duration)

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 4 Oesophageal candidiasis Extrapulmonary Tuberculosis Kaposis sarcoma Central nervous system toxoplasmosis HIV encephalopathy
Conditions where confirmatory diagnostic testing is necessary

Extrapulmonary cryptococcosis including meningitis

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 4 Disseminated non-tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy Candida of trachea, bronchi or lungs Cryptosporidiosis Isosporiasis Visceral herpes simplex infection

Revised WHO clinical staging of HIV/AIDS for Adults and Adolescents (2005)
Clinical stage 4 Cytomegalovirus infection Any disseminated mycosis (e.g. histoplasmosis, coccidiomycosis, penicilliosis) Recurrent non-typhoidal salmonella septicaemia Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Visceral leishmaniasis

WHO revised Clinical staging

Laboratory Axis
Lymphocytes + CD 4 ++ Stage I Asymptomatic PGL IA IB IC

Clinical Axis
Stage II Early HIV 2A 2B 2C Stage III Intermediate (ARC) +++ 3A 3B 3C Stage IV late AIDS 4A 4B 4C

A >2000 B 1000-2000 C <1000

>500 200-500 <200

+ Reference range total Lymphocytes : 1500-11400/mm

++ Reference range CD 4 count : 450-1400/mm +++ ARC AIDS- related complex

Clinical Stages (CDC)

Primary illness: Oral candidiasis, lymphadenopathy, Maculopapular rash, Fever, URTI Early symptomatic: PTB, Recurrent herpes, Herpes zoster, Extragenital molluscum, Florid STD Late symptomatic: Septicaemia, Abscess, Wasting, Weight loss, Bacterial pneumonia, Amoebiasis, Drug eruption, Extrapulmonary TB, Seborrheic.dematitis, Psoriasis, Reiters disease

Clinical Stages (CDC)

AIDS : Oro-esophageal candidiasis, Cryptococcosis, Toxoplasmosis, PCP, Histoplasmosis, Penicilinosis, CMV, PML, Peripheral neuritis, Encephalopathy, Addisonian pigmentation, Drug rash, Extra pulmonary TB, Weight loss

Confirmation of HIV diagnosis

Asymptomatic : In Symptomatics with

Double ELISA

clinical marker of HIV/AIDS : Single ELISA

In Pediatrics :

ELISA, p-24, RT- PCR, Viral culture.

Laboratory Test in HIV

Screening Test Elisa/RIA Rapid HIV Test Confirmatory test Western Blot Immunoflorescence IFA Resistant testing Genotyping Phenotyping Monitoring CD4 Count Viral Load Viral Load and confirmation HIV DNA PCR HIV Culture Quantitative RT-PCR

Baseline investigations
To Rule Out Underlying O.Is X-ray chest Montoux test Sputum for AFB USG abdomen FNAC/Biopsy of lymphnodes VDRL HbsAg

Baseline investigations
For Monitoring ARV Hb CBC LFT RFT Blood sugar Urine & Stool S. Cholesterol S.Triglycerides S. Uric acid S.Creatinine S. Lactic acid S. Amylase Prognostic Investigations CD4 lymphocyte enumeration Plasma Viral load assays

Counselling for ART

Permanency of therapy Cost of ART

Side-effects of ART
Adherence & compliance Failure of therapy Extended counseling for relatives & friends Safe sex-practices

Aim of ART

Improve symptom free longevity by maximal, sustainable & durable suppression of viral replication (<50 copies/ml)

When to initiate ART?

New insights: Changing Guidelines

Early90s: HIV +ve?

1998 2001 CD4 count<500 Cd4 count 200-350

Indications of ART

AIDS defining HIV illness regardless of CD4 count and viral load levels - eg. esophageal candidiasis CD4 counts < 200; Viral load > 1,00,000 copies/ml Total lymphocyte count < 1200 cells/ml

WHO Guidelines
CD4 count available WHO stage IV WHO stage I / II / III CD4 <200/cu.mm CD4 count not available WHO stage IV WHO stage II / III TLC <1200 cells/cu.mm

Current Antiretroviral Medications

NRTI
Zidovudine Lamivudine Stavudine Didanosine Zalcitabine Abacavir Emtricitabine Tenofovir ZDV, AZT 3TC d4T ddI ddC ABC FTC TVF, TDF NVP EFV DLV

PI
Saquinavir soft gel hard gel Indinavir Ritonavir Nelfinavir Amprenavir Lopinavir Atazanavir Fosamprenavir SQV SGC HGC IDV RTV NFV APV LPV ATV f-APV

NNRTI
Nevirapine Efavirenz Delavirdine

Fusion Inhibitor
Enfuvirtide T-20

ART Regimens
3 Drug combination 2 NRTI + 1 NNRTI 2 NRTI + 1 PI 1 NRTI + 1 NNRTI + 1 PI 3 NRTI

4 Drug Combination (Double PI Therapy) d4T + 3tc + RTV + IDV/SQV

Mega Combinations: 5 - 6 drugs

Cause of ART failure:

Practical problems Influence of food Pill burden ADRs Drug interaction Lack of adherence & compliance Lack of counseling for ART Resistance

Cutaneous Manifestations of HIV

Infectious Inflammatory Neoplastic Hair and Nail disorders

Cutaneous Infections
Bacterial: Staphylococcus Aureus: Bullous Impetigo, Ecthyma, Folliculitis Bartonella: Bacillary Angiomatosis Pseudomonas Aeruginosa Mycobacterial Infection: Scrofuloderma, TB Gumma, Atypical mycobacterial infections

Cutaneous Infections
Viral: Herpes Simplex Virus Varicella Zoster: Multidermatomal, Recurrent, Bullous, Hemorrhagic and Necrotic Molluscum Contagiosum Human Papillomavirus (Warts) Acute HIV exanthem & enanthem

Cutaneous Infection: Fungal and Yeast Infections

Superficial Infections: Thrush, Dermatophytosis Deep (Systemic) Fungal Infections: Cryptococcosis, Histoplasmosis, Sporotrichosis, Aspergillosis, Candidiasis, Coccidioidomycosis, Actinomycosis, and Phaeohyphomycosis

Arthropods: Scabies Demodecidosis (Demodex folliculorum folliculitis)

Inflammatory conditions

Psoriasis Reiter's Syndrome Xerosis and Ichthyosis Seborrheic Dermatitis, Atopic Dermatitis Pruritic Papular Eruptions Eosinophillic Folliculitis Insect Bite Reactions Photosensitivity Porphyria Cutanea Tarda (PCT) Aphthosis

Drug Reactions

Morbilliform drug eruptions Urticaria Fixed drug eruption Erythema multiforme Stevens Johnson syndrome Toxic epidermal necrolysis Erythroderma

Drug Reactions

Morbilliform drug eruptions Urticaria Fixed drug eruption Erythema multiforme Stevens Johnson syndrome Toxic epidermal necrolysis Erythroderma

Neoplastic Disorders of skin

Kaposi's Sarcoma Basal cell carcinomas Squamous cell carcinomas HIV-associated lymphoma of either T or B cells

Hair and nail disorders

Diffuse alopecia, telogen effluvium, alopecia areata Elongation of the eyelashes and softening and straightening of the scalp hair Beau lines, pallor of the nail beds Longitudinal, transverse, or diffuse melanin pigmentation of the nails (Zidovudine or HIV associated) Proximal subungual onychomycosis

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