Human Immunodeficiency Viru Sreal

HUMAN IMMUNODEFICIENCY VIRUS SUBMITTED BY- GROUP D1 MEDICAL WARD 25.4.2006

First described in 1981 Reported as lymphadenopathy associated virus (LAV) in paris 1983 at Pasteur Institute by Lue Montagrier and associates In U.S. , called human T lymphotropic virus type III (HTLV III) by Robert Gallo and colleagues at National Institute of Health Assigned a uniform name, the Human Immunodeficiency virus (HIV) by the International Committee on the Taxonomy of virus in 1986

Family – retrovirus RNA virus HIV 1 has widest distribution , world wide HIV 2 found mostly in western Africa HIV 2 less aggressive than HIV 1 Second leading cause of disease burden world-wide Leading cause of death in Africa( >20% of deaths

In 2000, WHO estimated that over 36 million people living with HIV/AIDS, 5.3 million new infection and 3 million deaths Rising alarmingly in heavily populated parts of the world including some Eastern European countries ( Ukraine , Russia) and South East Asian countries (Thailand , Myanmar)

Major mode of spreads Sexual (vaginal , anal ,oral) parenteral (blood and blood product recipients, injection drugs users and those experiencing occupational injury) Vertical transmission Major route of transmission (>70%) world-wide is hetrosexual

Transmission risk after exposure >90 % for blood and blood products 15-40 % for vertical transmission 0.5-1 % for injection drug users 0.2-0.5 % for genital mucous membrane <0.1 % non-genital mucous membrane

5-10% of new HIV infections are in children More than 90% of those are infected during pregnancy, birth and breast-feeding

In USA and northern Europe , predominant in homosexual man In southern and eastern Europe, Vietnam , Malaysia , North-east India and China , incidence is greatest in injection drug users In Africa, South America and much of Southeast Asia, predominant in vertical transmission

High risk persons Male homosexuals IVDUs CSWs Multiple transfusion recipients Highly promiscuous persons Offspring of HIV posistive mothers

Course of untreated HIV infection spans about a decade Stages include-Primary infection -Dissemination of virus to lymphoid organs -Clinical latency -Elevated HIV expression -Clinical disease -Death (within 2yrs after onset of clinical symptoms)

Immunological abnormalities in HIV infection T helper cells – reduced in number , abnormal function (e.g. diminished response to antigens and IL 2) B lymphocytes – abnormal function ( e.g. reduced response to antigens , polyclonal activation leading to increase in immunoglobulin ) Monocytes – defective function ( e.g. antigen presentation , phagocytosis)

Cardinal feature – depletion of T helper- inducer lymphocytes Major receptor – CD4 molecule for viral attachment to T lymphocytes These receptors bind with gp-120 on the viral envelope B lymphocytes – polyclonal activation of B cells with high immunoglobulin levels Monocytes and macrophages play a major role in dissemination and pathogenesis of HIV infection They serve as major reservior for HIV in the body Monocytes are refractory to the cytopathic effects of HIV

Main immune response to HIV infection consists of cytotoxic CD8 positive T lymphocytes Failure of these cells result in clinical picture of AIDS Antibodies against various HIV proteins , such as p24 , gp120 and gp41 are produced but they neutralize the virus poorly in vivo and appear to have little effects on the course of disease

Three mechanisms to evade immune system 1)- integration of viral DNA into host cell DNA , resulting in a persistent infection 2)- high rate of mutation of the envelope gene 3)- production of the Tat and Nef proteins that down regulates class I MHC proteins required for cytotoxic T cells to recognize and kill HIV infected cells

CD4 cells are pivotal in orchestrating the immune response , depletion renders the body susceptible to opportunistic infections and oncogenic virus-related tumors Reduction in number of CD4 cells circulating in peripheral blood is tightly correlated with the amount of plasma viral load Both are monitored closely in patients and are used as measures of disease progression

Neurological Maybe direct consequence of HIV infection or indirect result of CD4 cells depletion - Space occupying lesion , - AIDS dementia complex - encephalitis - Meningitis - Myelitis - Spinal root disease or neuropathy

Eye – cytomegalovirus retinitis,anterior uveitis (pneumocystis, toxoplasmosis, syphilis , and lymphoma can affect the eyes

Gastrointestinal Oesophagitis –candidiasis , herpes simplex virus , cytomegalovirus Gastric- nausea , vomitting , frequently due to drugs Small bowel – bacteria , viral, parasitic infection (diarrhoea, weight loss , abdominal pain Hepatitis –viral hepatitis A, B, C, cytomegalovirus , mycobacterium avium intracellulare

Respiratory Pulmonary disease very common(>half of patient ) (1) Pneumocystic carinii pneumonia – most common AIDS defining illness , rarely occur when CD4 counts more than 200cells/ mm3 (2)Mycobacterium tuberculosis –reactivating latent infection or acquired from open contact develop progressive primary disease , disseminated , miliary or extra pulmonary tuberculosis

Cardiac (3)Bacterial infection -S pneumoniae , H influenzae ,Staph aureus , pseudomonas and norcardia infection Myocarditis , cardiomyopathy (25 – 40 % of the patients ), pericardial effusion , congestive cardiac failure

Renal Endocrine HIV associated nephropathy is the most important renal condition usually present with nephrotic syndrome, chronic renal disease or combination of both. Reduced level of testosterone , abnormal adrenal function (hypoadrenalism in 25% of patients )

Mucocutaneous Seborrhoeic dermatitis (80%) Herpes infection (20%) Molluscum contagiosum ( 10%) Fungal infection ( candidiasis ) Drug allergy – Stephen Johnson’s syndrome Recurrent apthous ulceration

Haematology Disorders of all 3 major cell lines may occur in HIV Most frequent in late-stage disease Anaemia – 70 % Leucopenia – 50 % Thrombocytopenia – 40 %

Neoplasms Kaposi sarcoma and Non-Hodgkin’s lymphoma are most common opportunistic malignancies associated with HIV and are considered AIDS defining diagnosis Primary CNS lymphoma-usually complicate late stage HIV Genital cancer-anogenital (vulval, vaginal, anal, penile) and cervical cancer closely associated with HPV is more frequently observed in HIV

HIV associated lymphoma (non-Hodgkin’s lymphoma –it is late manifestation of HIV )

Opportunistic infection Protozoa – toxoplasmosis , cryptosporidiosis , microsporidiosis, Virus – CMV , Herpes , EBV , HPV , Papova virus , Fungus – PCP , Cryptococcus , Candida , Dermatophytes , Aspergillus , Histoplasma Bacteria – Mycobacteria ,Staphylococci , Non-typhoidal salmonellosis , Others – Disseminated strongyloidiasis , Giadiasis, Crustes ( Norwegian )scabes

Common AIDS defining condition Oesophageal candidiasis Cryptococcal meningitis Chronic cryptosporidial diarrhoea CMV retinitis Chronic mucocutaneous herpes simplex Disseminated Mycobacterium avium intracellulare Miliary or extrapulmonary tuberculosis PCP Progressive multifocal leuco-encephalopathy

Recurrent non-typhi salmonella septicaemia Cerebral toxoplasmosis Karposi’s sarcoma Non-Hodgkin’s lymphoma Primary cerebral lymphoma HIV associated wasting HIV associated dementia

Primary infection Mild in most patients and only identify by retrospective enquiry Symptoms appear 2 to 4 wks after exposure ( seroconversion illness) Manifest as fever , erythematous or maculopapular rash over the body , fatigue , pharyngitis , cervical lymphadenopathy , myalgia , arthralgia , retro-orbital headache, mucosal ulceration

Rarely present with aseptic meningitis, encephalitis, myelitis , polyneuritis Coincides with surge in plasma HIV RNA level and fall in CED4 count . Recover after 1- 2 wks associated with fall in viral load and rise in CD4 count but not to its previous value . HIV antibody appear at 3 – 12 wks

Asymptomatic infection (CD4> 500/cumm) Variable period in which infected individual remains well with no evidence of disease May present with persistent generalized lymphadenopathy ( PGL)( enlarged lymph nodes at two or more extra inguinal sites persists for 3 months without any other causes of generalized lymphadenopathy ) Sustained viraemia with decline in CD 4 counts

Mildly symptomatic disease ( ARC) ( CD4 200-500/cumm) Impaired cellular immunity median interval from infection is 7-10 yrs Chronic weight loss, fever , diarrhoea , oral or vaginal candidiasis , oral hairy leucoplakia , recurrent herpes zoster infection , severe pelvic inflammatory disease , bacillary angiomatosis , ITP and cervical dysplasia

Acquired immune deficiency syndrome Development of - 1) specified opportunistic infection , - 2) tumors , - 3) wasting and - 4) dementia Disease correlate with level of CD 4 count

CD 4 < 200 – PCP pneumonia , mucocutaneous herpes simplex , cryptosporidiosis , microsporidiasis, oesophageal candidiasis, miliary or extra pulmonary TB , wasting and peripheral neuropathy CD 4 < 100 – Cerebral toxoplasmosis , cryptococcal meningitis , primary CNS lymphoma , non Hodgkin’s lymphoma , dementia and progressive multifocal leucoencephalopathy CD 4 < 50 – Cytomegalovirus retinitis , gastrointestinal disease , disseminated mycobacterium avian intracellulare

Major signs weight loss >10 % Diarrhoea > 1 month Fever > 1 month CRITERIA USED IN MYANMAR

Minor signs Persistent cough > 1 month ( not due to tuberculosis ) Candidiasis ( oropharyngeal ) Herpes zoster ( recurrent ) Herpes simplex ( chronic progressive and disseminated) Generalized pruritic dermatitis Generalized lymphadenopathy

laboratory confirmation Serology test using ELISA antibody testing { false positive are rare but it is important that any (+)ve results are confirmed by using other immunoassays ,e.g. immunoblot } Seroconversion ( HIV antibody negative ) and vertical transmission ( HIV antibody positive ) , ELISA test is unhelpful and HIV RNA must be measured by using PCR ( reverse transcriptase ) , b DNA , NASBA technique Ag detection for P24 Ag

Pre and post test counselling Prior to HIV antibody testing , the patient must see a counsellor Pretest counselling – involve assessment of the risk of exposure and explore a person’s knowledge about HIV infection Post-test counselling ( return +ve)- to provide emotional support , organised continuous contact and medical follow up , safer sex and needle exchange

Baseline investigations all patients -CD4 count -viral load -HBV surface antigen -HCV antibody -HBV core antibody -HAV IgG antibody -Toxoplasma antibody -CMV IgG antibody -Treponema serology -Chest radiograph

CD 4<200 -chest radiograph -HCV RNA -cryptococcal antigen -HCV RNA -stool for ova , cysts and parasites

CD 4 < 100 -CMV-PCR -ECG -dilated fundoscopy -mycobacterial blood culture

Investigation for systemic diseases Skin ( muco-cutaneous leision ) -diagnosis is mainly clinical including Kaposi’s sarcoma -skin biopsy , histology and culture should be done

GI disease -Stool microscopy ( specific stain often necessary ) and culture , -Specific imaging and -Endoscopy with biopsy -Blood culture Respiratory disease -Gram stain and Ziehl – Neelsen stain for pathogen -Culture ( blood and sputum ) -chest X ray -Arterial gases

Nervous system If Lumbar puncture is not contraindicated, -CSF R.E -PCR analysis ( Herpes simplex, varicella zooster , CMV , EBV) Eye disease - fundoscopy Haematology - blood complete picture

Malignancy Genital cancer – cervical smear (annual) from all HIV infected women Regular anal smear considered for homosexual man Renal disease Urine RE Blood urea & electrolyte Ultrasound kidney -for nephrotic syndrome and chronic renal disease

Aims To reduce viral load to an undetectable level To improve CD4 counts above 200/cumm To improve quality of life To reduce transmission

Asymptomatic HIV positive patient Counselling and follow up CD4 count(monitoring of disease course) Prophylactic antibiotics Antiretroviral treatment

Symptomatic HIV infection 1 . Symptomatic relief and supportive care -treat diarrhoea , dehydration -anaemia ,bleeding -fits -counselling; psychological support , nutritional , social and nursing care -health education to the family and society

2 . Specific treatment of infection and tumors -PCP cotrimoxazole -TB combination chemotherapy (second line drugs) -candidiasis fluconazole -other fungal amphotericin B infection -herpes infection acyclovir -CMV infection gancyclovir -Toxoplasmosis pyrimethamine sulphadiazine -other infection appropriate antibiotics

3. Specific treatment of HIV infection Antiretroviral drugs are 1)Nucleoside reverse transcriptase inhibitors(NRTIs) 2)Non-nucleoside reverse transcriptase inhibitors(NNRTIs) 3)Protease inhibitors 4)Others

1)Nucleoside reverse transcriptase inhibitors(NRTIs) ddC(zalcitabine) ddI(didanosine) 3TC(lamivudine) ZDV(zidovudine) d4T(stavudine) Abacavir CNS penetration is good with all NRTIs and ZDV is benefit in AIDS dementia.

Side effect of NRTIs -peripheral neuropathy -pancreatitis -hepatic steatosis/lactic acidosis -anaemia/neutropenia -myopathy /cardiomyopathy -extremity fat loss

2)Non-nucleoside reverse transcriptase inhibitors(NNRTIs) Nevirapine Efavirenz Class specific side effect -rash -Stevens-Johnson syndrome

3)Protease inhibitors Indinavir Ritonavir Saquinavir Nelfinavir Lopinavir

Class specific side effect -GI intolerance -fat redistribution -hyperlipidaemia -insulin resistant /hyperglycaemia -bleeding in haemophilia -liver enzyme derangement

Antiretroviral drugs should be started after appropriate counselling and readiness because of expensiveness of drugs & life long treatment Decision to start therapy is a major one This dependent on - symptom status of patient - CD4 count - Viral load - wishes of patient

Indication to start HAART (Highly active antiretroviral therapy) Note; The higher the viral load; the earlier the treatment should be recommended Consider Monitor 2 monthly Monitor/ recommend based on viral load Recommend Seroconversion >350 200-350 <200 Decision CD4 count (cells/cumm)

Factors to consider when choosing HAART Ease of compliance Fit of drug regimen around the patient’s lifestyle Whishes of the patient Stage of disease Coexisting/ past medical history Possibility of additive side-effects Potential for drug interactions with non-HIV medications Antagonistic NRTI combinations CNS penetration Possibility of acquisition of resistance virus

Combination treatment for the naïve patient Standard (1) 2 NRTIs - d4T + 3TC - ZDV + 3TC - d4T + ddI - ZDV + ddI (2) PI or NNRTIs - Indinavir - Saquinavir - Ritonavir - Nelfinavir - Lopinavir - Efavirenz - Nevirapine

Alternative (1) 2 NRTIs - ZDV + ddC - ddI + 3TC - Abacavir + another RTI (2) PI or NNRTI - Ritonavir + Saquinavir - Ritonavir + Indinavir - Nelfinavir + Saquinavir

Other regimens (1) Equal potency - ZDV + 3TC + abacavir - NNRTI + PI + NRTI - 2 PI + 2 NRTI (2) Uncertain potency - NNRTI + PI - 2 NNRTI + 2 NRTI (3) Suboptimal potency - d4T + ddI + hydroxyurea - d4T + ddI + 3TC - Squinavir + 2 NRTI - Amprenavir + ZDV + 3TC

A change in antiretroviral therapy may be necessary because of - 1) drug side- effects (early or late ) , 2) difficulties in adherence or 3) virological failure In a patient with a previously undetectable viral load , virus rebound is usually first evidence of treatment failure

Causes of virological failure Insufficient drug activity (suboptimal potency, high baseline viral load) Insufficient plasma drug levels ( poor adherence, poor absorption, drug toxicity, drug interactions) Insufficient intracellular active drug ( drug competition) Viral resistance ( primary acquisition, insufficient drug activity, insufficient plasma drug level)

Enhancing immune mechanism HAART alone will not cure HIV patient because of long live cellular latency of virus Immune system can be enhance by 1) wild virus stimulation of immune mechanism 2) direct anti HIV cytotoxic T cell stimulation through immunization with viral protein But beneficial in long term is unknown

1) Sexual Comprehensive school sex education program Public awareness campaigns for HIV Easily accessible/ discreet testing centres Safe sex practices - avoidance of penetrative intercourse - correct/ consistent condom use - reduction of sexual partners Targeting safe sex methods to high risk groups Controlled of sexually transmitted diseases - condom usage, education, early treatment

2) Parenteral Blood product transmission - donor questionnaire - routine screening of donated blood - use of blood substitutes Injection drug users - education ( safe practices/ support services/ unprotected sex) - needle/ syringe exchange - avoidance of high risk situitations - support for detoxification/ drug rehabilitation services

3) Perinatal Routine antenatal HIV antibody testing Counselling about risks of pregnancy if HIV- seropositive Measure to reduce vertical transmission - HAART during pregnancy - perinatal antiretroviral prophylaxis - caesarean section - zidovudine to neonate - avoidance of breastfeeding

4) Occupational Educational training Universal precautions Needlestick avoidance Post-exposure prophylaxis

Prophylaxis of opportunistic infections Clarithromycin or rifabutin azithromycin <50/cumm MAI INH or rifampicin& pyrazinamide Rifampicin & INH (+) ve tuberculin test Tuberculosis Gancyclovir <50/cumm CMV Dapsone & pyrimethamine Co-trimoxazole <100/cumm Toxoplasmosis Dapsone, Co-trimoxazole <200/cumm Pneumocystis Alternative First-line Indication (CD4 count) Organisms/ infection

Post exposure prophylaxis (PEP) Initiate PEP as soon as possible, preferably 1-2 hr after exposure Selection of PEP regimen should consider type of exposure, as well as situation If HIV serostatus is unknown at the time of exposure, initiate two-drugs PEP regimen until laboratory results have been obtained

Basic & expanded post- exposure prophylactic regimen As above + Indinavir (Indivan) 800mg 8 hrly OR Efavirenz( Efavir) 600mg OD at night OR Nelfinavir 750mg tds Occupational HIV exposure that posses an increase risk of transmission( e.g. larger volume of blood or higher virus titer in blood) Expanded (28days) Zidovudine 300mg b.d +lamivudine 150mg b.d (Duovir) OR Stavudine 30/40 mg b.d + lamivudine 150mg b.d (Lamivir-s 30/40 ) Occupational HIV exposure for which there is a recognized risk Basic (28days) Drug regimen Indication Category

Follow up Workers with possible expoure to HIV infection should undergo HIV antibody testing for at least 6 months ( e.g. at base-line, 6 weeks, 12 weeks & 6 months) following the exposure HIV antibody testing using ELISA should be use to monitor for seroconversion Counselling & education is important aspect of post-exposure management Exposed workers should avoid behaviors that entail a risk of secondary transmission of infection for the duration of follow-up period

Q & A Programme All questionnaires are warmly welcomed .

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