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![EXISTING DIAGNOSTIC FACILITIES ( CONTD)
Screening tests for HIV [ PAT and ELISA ] are also carried
out in blood transfusion centres to ensure safe blood
transfusion
Currently, 98 safe blood transfusion centres are present
in our country [ Medical Colleges- 13, Specialized hospitals
- 6, District hospitals- 53, CMH- 13, Other big hospital- 10,
Red crescent- 3 ]
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HIV (AIDS)
- 1. HIV/AIDS DR MD TIPUSULTAN Associate Professor Department of Microbiology Chittagong Medical College 1
- 2. HIV Human Immunodeficiency Virus H= Infects only Human beings I = Immunodeficiency virus weakens the immune system and increases the risk of infection V = Virus that attacks the body 2
- 3. AIDS Acquired Immune Deficiency Syndrome A= Acquired, not inherited I = Weakens the Immune system D = Creates a Deficiency of CD4+ cells in the immune system S = Syndrome, or a group of illnesses taking place at the same time 3
- 4. HIV and AIDS •When the immune system becomes weakened by HIV, the illness progresses to AIDS • Some blood tests, symptoms or certain infections indicate progression of HIV to AIDS 4
- 5. “The greatest singlepublic health challenge that humanity has ever faced.” Dr. Robert Lue, Harvard University 5
- 6. HIV/AIDS Historical Perspective 1979 CDC reportedunexplained PCP in 5 previously healthy, homosexual men CDC reported Kaposi’s sarcoma in 26 previously healthy, homosexual men Initially,then the disease was named as GRID (Gay related immune deficiency) 1981- AIDS was recognized as separate disease 1981-1982 Increased association with IV drug use, recipients of blood transfusions, hemophiliacs 6
- 7. HIV/AIDS Historical Perspective 1983 Virus isolated.Thenit was 1st named as LAV(Lymphadenopathy associated virus) 1984 Virus was named as HTLV-III (Human T-cell Lymphotrophic Virus) 1985 Virus was named as ARV (AIDS related Virus) 1986 Virus was named as HIV by the International committee on the taxonomy of viruses 7
- 8. HIV/AIDS Historical Perspective 1985 ELISA testdeveloped Today: Broad spectrum of disease Asymptomatic infection Clinical latency Advanced disease (AIDS) Clearly sexually transmitted, and transmitted through blood products 8
- 9. In Bangladesh, HIVpositive cases was 1st detected in 1989 in Chittagong 9
- 10. Global summary ofthe HIV and AIDS epidemic Number of people living with HIV Total 39.4 million (35.9– 44.3 million) 37.2 million (33.8–41.7 million) Adults Women 17.6 million (16.3– 19.5 million) Children under 15 years 2.2 million (2.0– 2.6 million) People newly infected with HIV Total 4.9 million (4.3 – 6.4 million) Adults 4.3 million (3.7 – 5.7 million) Children under 15 years 640 000 (570 000 – 750 000) AIDS deaths Total 3.1 million (2.8 – 3.5 million) Adults 2.6 million (2.3 – 2.9 million) Children under 15 years 510 000 (460 000 – 600 000) The ranges around the estimates in this table define the boundar within which the actual numbers lie, based on the best avail ble information. ies a 00003-E-1 – December 2004 10
- 11. HIV/AIDS BANGLADESH SITUATION, END2012 Total HIV-positive people - 2384 People living with AIDS - 676 Deaths due to AIDS - 263 Sources:DGHS, MOH&FW, December 1, 2012. WHO: Estimated to have 13,000 to 21,000 people are likely to be infected with HIV. 11
- 12. Prevalence Among HighRisk Population in Bangladesh •The highest prevalence is among IDUs 4%. • Street and Hotel based CSWs– 0.2% each. •Brothel based CSWs– 0.2% to 0.7% • MSMs – 0.2% 12
- 13. Important Bangladesh was thefirst among the SAARC Countries to take the threat of HIV epidemic seriously & initiated a national response in 1985. According to WHO, Bangladesh is one of the fortunate 111 countries where the infection rate has not yet reached 1 adult / 1000. 13
- 14.
- 15. Unique Characteristics ofRetroviruses Enveloped and encloses a capsid containing two copies of RNA genome. RNA-dependent DNA polymerase (reverse transcriptase) and integrase enzymes are carried in the virion. Replication proceeds through a DNA intermediate, termed the provirus. The provirus integrates randomly into the host chromosome and becomes a cellular gene. Simple retroviruses encode gag, pol, and env genes. Complex viruses also encode accessory genes (e.g., tat, rev, nef, vif, vpu for HIV). Virus assembles and buds from the plasma membrane. Final morphogenesis of HIV requires protease cleavage 15 of gag and gag-pol polypeptides.
- 16. HIV Structure HIV iscomposed of three main layers: Envelope Viral Matrix Core Image from http://www.brown.edu/Courses/Bio_160/Projects1999/hiv/images/Virion2.jpg 16
- 17.
- 18. Types of HIV HIV1 Subtypes- A to I and O Subtype A & D – found in sub Sahara Africa Subtype B – found in US & Canada Subtype C – found in South Africa & India Subtype E – found in south east Asia Subtype G & H - found in Russia & Central Africa Subtype I – found in Cyprus HIV 2 18
- 19. HIV-1 and HIV-2 •HIV-1 and HIV-2 are • Transmitted through the same routes • Associated with similar opportunistic infections • HIV-1 is more common worldwide • HIV-2 is found in West Africa, Mozambique, and Angola 19
- 20. HIV-1 and HIV-2 •HIV-2 is less easily transmitted • HIV-2 is less pathogenic • Duration of HIV-2 infection is shorter 20
- 21. Important antigens: 1) Group-SpecificAntigens p17: inner surface p24: nucleocapsid p9: nucleocapsid associated with RNA GAG gene 21
- 22. 2) Type -Specificenvelope glycoprteins gp120 & gp41 ENV gene 22
- 23. 3. Enzymes • Polymerase (reverse transcriptase) •Integrase • Protease • POL gene 23
- 24.
- 25. Transmission of HIV HIV istransmitted by • Direct contact with infected blood • Sexual contact: oral, anal, or vaginal • Direct contact with semen or vaginal and cervical secretions • HIV-infected mothers to infants during pregnancy, delivery, or breastfeeding 25
- 26. HIV enter thebody via the bloodstream either during sexual intercourse needle drug abuse transfusion with contaminated blood products or via the placenta During sexual intercourse, HIV 1 infects Langerhans dendritic cells in the epithelium and these can then travel to lymph nodes. On injection of virus into blood, the virus is likely to infect dendritic and other monocyte-macrophage lineage cells. 26
- 27. Blood Up to 10,000infectious particles per ml Shared drug/drug-injecting equipment needles, syringes
- 28. Blood Transfusions plasma, whole blood,platelets clotting factors (decreased since 1985) 28
- 29. Sexual Contact STD’s increaserisk of transmission epidemiological exposed trend to one, may mean exposed to others inflammation make person more vulnerable to HIV invasion
- 30. Sexual Contact Intercourse (withoutbarrier) anal: vaginal: oral:
- 31. Sexual Contact Semen: only10-50 infectious virons per ml artificial insemination a risk Vaginal/cervical secretions: less than 1 viron per ml
- 32. Perinatally In utero (maternal-fetalcirculation) HIV crosses the placenta During delivery Breast-feeding low incidence
- 33. Risk Factors What youdo not who you are 33
- 34. High risk groups 1) 2) 3) 4) 5) homosexual/bisexualmen IV drug use/abuse hemophiliacs sex partners in abuse groups infants of above groups 34
- 35. Transmission of HIV HIVis not transmitted by • Coughing, sneezing • Insect bites • Touching, hugging • Water, food • Kissing • Public baths • Handshakes • Work or school contact • Using telephones • Sharing cups, glasses, plates, or other utensils 35
- 36. Important properties: •HIV primarilyinfects CD4 T cells and cells of the macrophage lineage •Monocytes •Macrophages CD4 proteins on their surface •Dendritic cells (skin) •Microglial cells (CNS) 36
- 37. Which cells doesHIV-1 infect? Identification of molecular targets. Lymphocytes Receptor: CD4+, Coreceptor: CXCR4 Macrophages: Receptor: CD4+ Coreceptor: CCR5 Dendritic cells (DC): DC recognized by gp120 on HIV DC: primary target of mucosal infection! DC present HIV antigen to resting lymphocytes Microglial cells: Receptor: Galactosyl ceremide 37
- 38.
- 39. HIV chemokine CD4 CD4 CCR5 CCR5 CD4 Mutant CCR5 macrophage Chemokine receptors arenecessary co-receptors along with CD4 antigen 39
- 40.
- 41.
- 42.
- 43.
- 44. Reduction in thenumbers of CD4 T cells may result from HIV-infected cytolysis, cytotoxic T-cell immune cytolysis. The increased release of virus into the blood as the numbers of CD4 cells decrease gives development of symptoms. Macrophages may be spared the cytolytic action of HIV because they express less CD4 than T cells. 44
- 45. Macrophage-lineage cells expressboth the CCR5 & CXCR4 chemokine receptors and can be infected by M-& L-tropic HIV. The virus reaches the lymph node within 2 days of infection and there the CD4 T cells are infected. Macrophages are persistently infected with HIV and are probably the major reservoirs. Continuous replication of the virus occurs in the lymph nodes, with subsequent release of the virus and infected T cells into the blood 45
- 46. Pathogenesis(contd) The hallmark ofpathogenesis is the profound immunodeficiency, primarily affecting CMI HIV infect any cells bearing CD4 receptor -Severe depletion of CD4+ T-cell -Impairment of function of surviving CD4+ T-cell 46
- 47. Pathogenesis(contd) Monocyte/Macrophage abnormalitiesRelatively resistantto cytolytic effect of HIV and the consequences are *Acts as reservoir of virus *Transport the virus to different part of the body B-cell abnormalitiesPolyclonal activation leads to hypergammaglobulinaemia Unable to mount antibody response to a new antigen due to lack of T cell help 47
- 48. Steps for pathogenesisof HIV: rapid early dissemination of virus seeding of virus in lymphoid tissue partial host immune responses that downregulates viral replication sequestration of extracellular virus into germinal center of lymph nodes chronic activation of T lymphocytes and secretion of immune system activating cytokines 48
- 49. Steps for pathogenesisof HIV:(cont.) destruction of lymphoid tissue escape of viral elements into peripheral blood cells direct killing of CD4 cells 49
- 50. Potential mechanism ofCD4 T cell depletion/dysfunction Direct HIV mediated cytopathic effect HIV mediated formation of syncytia Virus specific immune response Autoimmune mechanism Anergy-Inappropriate cell signaling (gp120-CD4 interaction Superantigen Apoptosis 50
- 51. Three mechanisms bywhich HIV evades immune system 1. Integration of viral DNA into host cell DNA resulting in a persistent infection. 2. A high rate of mutation of the env gene. 3. Production of the Tat and Nef proteins that downregulate class I MHC proteins required for cytotoxic T cells to recognize and kill HIV-infected cell 51
- 52. Progression of HIVin the Body Image from http://www.hivaidssearch.com/hiv-aids-links.asp?id=936 52
- 53. Initially, large burstof virus production & viremia, which corresponds to the occurrence of a mononucleosis-like syndrome. 53
- 54. Virus levels inthe blood decrease during a clinically latent period, but viral replication continues in the lymph nodes. 54
- 55. Late in thedisease, virus levels in the blood increase, CD4 levels are significantly decreased. the structure of the lymph nodes is destroyed, and the patient becomes immunosuppressed 55
- 56.
- 57. Initial infection Fever andother flu-like symptoms lympadenopathy 57
- 58. Prolonged Asymptomatic Infection person isHIV+ but asymptomatic lasts for several years (subclinical) viral replication occurring up to 10 billion virons per day chronic lymphadenopathy 58
- 59. Early Symptomatic Disease CD4 countsdrop to 500-600 cells/ml symptoms: recurrent fever, night sweats, malaise, headache physical findings: lymphadenopathy, spleen enlarged, rash, weight loss 59
- 60. Opportunistic Infection infection bya pathogenic organism that is normally present but not harmful becomes infectious in immunocompromised person 60
- 61. AIDS AIDS vs. HIVpositive 61
- 62. Average time betweeninfection and AIDS was 10 years time has increased with new protease inhibitors
- 63. Symptoms of HIV- “classic 6” − − − − − − fatigue/malaise lymphadenopathy weight loss fever night sweats diarrhea 63
- 64. AIDS CD4 count lessthan 200/mm majority of manifestations due to opportunistic infections due to immunosuppression rather than direct injury by virus It is a condition in which common curable infectious disease turned into incurable form due to immunodeficiency, caused by HIV infection 64
- 65. Clinical Course of HIV/AIDS HIVInfection Virus deposited on mucosal surface Acute infection (mono-like symptoms) Viral dissemination HIV-specific immune response Replication of virus Destruction of CD4+ lymphocytes Rate of progression is correlated with viral load Latent Period 65
- 66. Clinical Course of HIV/AIDS AIDS Immunologic dysregulation Opportunistic infections and cancers Risk of infections is correlated with number of CD4+ lymphocytes Average patient with AIDS dies in 1-3 years 66
- 67. WHO classification ofclinical stages of infection Children – Three stages Adults & Adolescents – Four stages 67
- 68. WHO Clinical stageI in Children Asymptomatic Generalized lymphadenopathy 68
- 69. WHO Clinical stageII in Children Unexplained chronic diarrhoea Severe persistent or recurrent candidiasis outside the neonatal period Weight loss or failure to thrive Persistent fever Recurrent severe bacterial infection 69
- 70. WHO Clinical stageIII in Children AIDS – defining opportunistic infections Severe failure to thrive Progressive encephalopathy Malignancy Recurrent septicaemia or meningitis 70
- 71. WHO Clinical stageI in Adults & Adolescents Asymptomatic Persistent generalized lymphadenopathy Performance scale 1: asymptomatic, normal activity 71
- 72. WHO Clinical stageII in Adults & Adolescents Weight loss, <10% of the body weight Minor mucocutaneous manifestations Herpes Zoster within the last 5 years Recurrent upper respiratory tract infections Performance scale 2: symtomatic, normal activity 72
- 73. WHO Clinical stageIII in Adults & Adolescents Weight loss, >10% of the body weight Unexplained chronic diarrhoea >1 month Unexplained prolonged fever (interminant or constant) >1 month Oral candidiasis (thrush) Pulmunary tuberculosis Severe bacterial infection Performance scale 3: bed-ridden, >50% of the day during the last month 73
- 74. WHO Clinical stageIV in Adults & Adolescents HIV wasting syndrome Pneumocystis carinii pneumonia Toxoplasmosis of the brain Cryptosporidiosis with diarrhoea Cryptococcosis, extra pulmonary Atypical mycobacteriosis Salmonella septicaemia Progressive multifocal leukoencephalopathy Performance scale 4: bed-ridden, >50% of the day during the last month 74
- 75. WHO Clinical stageIV in Adults & Adolescents (Cond.) Cytomegalovirus disease of an organ other than liver, spleen or lymph nodes. Hepes simplex virus infection, mucateneous >1 month, or visceral any duration Progressive multifocal leukoencephalopathy Any disseminated endemic mycosis (I.e. histoplasmosis, coccidiodomycosis) Candidiasis of the oesophagus, trachea, bronchi or lungs Lymphoma 75
- 76.
- 77. AIDS in Children Infantswho are seropositive at 18 months are infected Infants progress to AIDS more rapidly, usually in 3 years HIV testing during pregnancy 77
- 78. AIDS in Children Transmissionis usually perinatal 100% are HIV+ at birth 25% are actually infected 1 in 4 chance of passing on virus less if mother is treated 78
- 79. Opportunistic infections − pneumocysticcarinii pneumonia (PCP) − candida esophagitis -- cryptococcal meningitis − chr. mucocutaneous Herpes simplex -- toxoplasmosis − disseminated Mycobacterium avium or kansasii − disseminated CMV -- chronic Cryptosporidial enterentis − disseminated stronyoidiasis -- Histoplasmosis − bronchopulmonary candidiasis -- Isosporiasis -- disseminated TB -- disseminated Coccidioidomycosis − recurrent Salmonella septicemia 79
- 80. Opportunistic tumors − Kaposi’ssarcoma − primary CNS lymphoma − certain high-grade B-cell lymphoma 80
- 81.
- 82. Laboratory diagnosis Evidence ofHIV infection Virus isolation Measurement of viral nucleic acid Detection of viral antigen Detection of viral antibody Recognition of immunodeficiency CD4+ T cell count Recognition of AIDS related disease 82
- 83. 1.Virus isolation : HIVcan be cultured from lymphocytes in peripheral blood. (Co-culture of patients T-cell with Leukaemic or mitogen stimulated CD4+ Tcell line). 83
- 84. 2. Detection ofviral Nucleic Acid : By RT-PCR Branched-chain DNA To detect viral RNA in clinical specimens. 84
- 85. Viral RNA AssayDynamics of HIVbillions of viruses produced and destroyed daily Rate of viral replication stabilizes after primary infection at a “set point: in each individual. (102-106 HIV RNA copies/ml) of plasma Remains stable over months and possibly years 85
- 86. Viral RNA Assay(cont.) Viral RNA - indirect reflection of the number productively infected cells in the body as a whole Appears to be a proportion between plasma viral RNA and the amount of viruses in the fixed lymphoid tissues Set point associated with the rate of disease progression and time of death HIV RNA levels appear more predictive of progression than CD counts 4 86
- 87.
- 88. Therefore utility ofHIV RNA assays include: Assessing baseline status in newly diagonal HIV patient Assessing response to therapy Assessing development of resistance to current therapy Typically 109-1010 virions are produced daily Reductions in plasma viremia correlates with increased CD4 cells and AIDS-free survival 88
- 89. 3. Detection ofHIV Antigen HIV antigen tests detect the presence of HIV in blood P24 antigen tests measure one of the proteins found in HIV The antigen often becomes undetectable after antibodies develop and may reappear at low levels intermittently during the period of clinical latency and in some people as infection progresses 89
- 90. 3. Detection ofviral p24 Antigens: Low levels of circulating HIV p24 antigen can be detected in the plasma by ELISA soon after infection. usually disappeared by 8-10 weeks after exposure. It can be a useful marker in individuals who have been infected recently but have not had time to mount an antibody response 90
- 91. 4. Detection ofantibody measuring antibodies by ELISA. HIV antibody may develop slowly, 4-8 wks in most patients. A positive test in a serum sample must be confirmed by a repeat test If the repeat ELISA test is reactive, a confirmation test is performed. By immunofluorescence, Western blot technique or Line immunoblot assay 91
- 92. Detection of IgGantibody to envelope components(gp120 and its subunits) This is the most commonly used marker of infection The routine tests used for screening are based on ELISA techniques, which may be confirmed with Western blot assays. Up to 3 months may elapse from initial infection to antibody detection (serological latency, or window period). IgG antibody to p24 (anti-p24) This can be detected from the earliest weeks of infection and through the asymptomatic phase. It is frequently lost as disease progresses. 92
- 93. Window period: Early ininfection when the blood of an infected person can contain HIV but antibodies are not detectable. Seroconversion: Development of evidence of antibody response to a disease. Viral Load: The amount of HIV in the blood. 93
- 94. “Window Period” Aperiod of 4-6 weeks after HIV exposure when antibodies to HIV are not detectable in the blood A person at high risk who initially tests negative should be retested at 3 months to confirm diagnosis 94
- 95. “Window Period” Time betweeninfection with HIV and detection of HIV antibodies in the serum (time to seroconvert) “Seropositive”: detectable antibodies to HIV in the serum person becomes infectious within 2 weeks of exposure
- 96. Seroconversion : detectableantibody response96
- 97. Tests which detect antibodies Enzymelinked immunosorbent assay (ELISA) Particle agglutination test (PAT) Screening tests Latex agglutination test Indirect fluorescence antibody test (IFAT) Radio immunoprecipitation assay (RIA) Immunochromatographic test (ICT) Line immunoblot assay (LIA) Western Blot assay (WB) Confirmatory tests 97
- 98. ELISA for HIVantibody ELISA false-positive: immunologic abnormalities neoplasms multiple transfused pregnancy Microplate ELISA for HIV antibody: colored wells indicate reactivity 98
- 99. Western Blot HIV-1 WesternBlot Lane1 : Positive Control Lane 2 : Negative Control Sample A: Negative Sample B: Indeterminate Sample C: Positive 99
- 100. Western blot tobe considered positive At least two bands including p24, gp41, or gp120/gp160 should be present. (antibodies to HIV proteins of specific molecular weight can be detected) Western blot is confirmatory test for HIV antibody detection, because the test can detect all the HIV-specific antibodies according to their molecular weight 100
- 101.
- 102. 5. CD4:CD8 cellcount: Absolute number of CD4+ cell and ratio of helper cell to inducer cell are abnormally low. 102
- 103. Selection of theHIV Test Is site-specific based on: National/local policies Availability of supplies and laboratory support Availability of trained personnel Evaluation of specific tests in the country Costs 103
- 104. The Testing Process •Test sample • Blood, saliva, urine • Process the sample, on-site or in lab • Obtain results • Keep confidential • Method determined by clinic protocols and client • Provide results to client • Provide post-test counselling, support and 104
- 105. Guiding Principles for Counsellingand Testing Information on HIV status kept private Information shared only with providers directly involved in care—and only on a “need to know” basis Medical records kept in safe place 105
- 106. Guiding principles (contd.) • Pre-testGroup education • Informed Consent • Identifies: • Purpose of testing and processes involved • Benefits and risks of testing • Available treatment and support • Respects • Individual’s autonomy and right to confidentiality 106
- 107. Counseling and Testingas an Entry Point to MCH/HIV Prevention Community action to reduce Stigma & discrimination Post - delivery care and support Safer infant feeding Primary prevention of new HIV infection VCT and its links with other services Prevention of unintended pregnancy Safer obstetric practices Antiretroviral prophylaxis 107
- 108. Pre-test Information Groupeducation in Relevant HIV and AIDS information Transmission and prevention STIs and HIV HIV testing and test result interpretation Implications of both positive and negative results Benefits and risks of HIV testing Individual counselling and risk assessment Identification of supportive services Privacy and Confidentiality 108
- 109. Post-Test Counselling Provide the womanwith her HIV test result Help her understand what the result means Provide support, information, and referral when indicated Encourage risk- reducing behavior Encourage disclosure and partner testing 109
- 110. Post-Test Counselling HIV-negative Reviewwindow period if indicated • Prevent future infection • Review risk with new infection • Educate partner and encourage partner testing 110
- 111. Post-Test Counselling HIV-positive result •Clarify understanding • Acknowledge feelings • Review benefits of knowing HIV status • Address immediate concerns • Schedule follow-up visit • Provide support ,name and telephone number of contact person 111
- 112. Diagnosing HIV inHIVExposed Infant ARV prophylaxis reduces but does not eliminate Mother to child transmission of HIV infection Since maternal antibodies cross the placenta, antibody testing is not recommended prior to 18 months of age Infants who are breastfeeding require additional testing 6 weeks after complete cessation of breastfeeding HIV viral assays are not used for diagnosis of HIV infection in the infant 112
- 113. Summary • Pre-test information,HIV testing, and post-test counselling should be available to all pregnant women • The need for pre-test counselling should be determined on an individual basis • The healthcare provider and the facility must maintain confidentiality of HIV status. • Partner testing and couples counselling should be encouraged 113
- 114. Summary (contd.) Rapid testswith same day results are the recommended procedure for most settings. Infant diagnosis is complex but important for clinical management • Standard diagnosis is done by antibody test at 18 months • Earlier diagnosis is possible with PCR testing Post-test counseling is important for all women, including HIV-negative women 114
- 115. Disclosure • Ensure confidentiality •Respect woman’s choices • Encourage partner testing • Review prevention of transmission • Identify support 115
- 116. CURRENT TESTING FACILITIES INBANGLADESH Screening Purposes : Latex agglutination Immunochromatography Particle agglutination ELISA For Confirmation : BSMMU, Dhaka-Western blot Dhaka-Western blot ICDDR,B-Dhaka-Western blot Dhaka-Western blot Medical College-Line immunoassy, ELISA Chittagong Medical College-Line immunoassy, ELISA Sylhet Medical College-Line immunoassy, ELISA AFIP, IEDCR, Dhaka 116
- 117. EXISTING DIAGNOSTIC FACILITIES( CONTD) Screening tests for HIV [ PAT and ELISA ] are also carried out in blood transfusion centres to ensure safe blood transfusion Currently, 98 safe blood transfusion centres are present in our country [ Medical Colleges- 13, Specialized hospitals - 6, District hospitals- 53, CMH- 13, Other big hospital- 10, Red crescent- 3 ] 117
- 118.
- 119. Types of HIVDrugs Entry inhibitors Reverse Transcriptase inhibitors Integrase inhibitors (On study) Protease inhibitors Assembly & budding inhibitors (On study) 120
- 120. Attacking HIV withantiretroviral drugs Protease inhibitors Attachment inhibitors Assembly inhibitors RT inhibitors Integration inhibitors 121
- 121. Entry inhibitors Fusion inhibitor Fuzeon(enfuvirtide, or T-20) 122
- 122. Reverse Transcriptase Inhibitors Nucleoside reversetranscriptase inhibitors (NsRTIs) Zidovudine(ZDV, AZT) Didanosine (ddl) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) 123
- 123. Reverse Transcriptase Inhibitors(contd) Non -nucleoside reverse transcriptase inhibitors (NsRTIs) Nevirapine (NVP) Efavirenz (EFZ) Delavirdine Nucleotide reverse transcriptase inhibitors (NtRTIs) Tenofovir disoproxil fumarate 124
- 124. Protease Inhibitors Indinavir(IDV) -Crixivan Nelfinavir(NFV) - Viracept Ritonavir(RTV) - Norvir Saquinavir(SQV) - Invirase or Fortovase Amprenavir(APV) – Agenerase Lopinavir/Ritonavir(LPV/r) - Kaletra 125
- 125. Therapy might bestarted when PVL is over 10,000. If therapy is in progress, several PVL tests a year monitor the status. If PVL goes up, medication needs to be changed, quite obviously. The goal is to clear detectable virus from the blood in 16-24 weeks. 126
- 126. Highly Active Antiretroviral Therapy (HAART) Combinationof three or more drugs 127
- 127. Why is HIVso hard to treat? 1. HIV-1 and other lentiviruses have the unique property among retroviruses to replicate in nondividing cells. 2. Mutation rate is maximum permissible 3. Latent period of incubation 4. Integration into host genome unpredictable 128
- 128. 4 Questions thatNeed Answers for HIV Therapy When to initiate therapy? Which types of drugs to use? When to change therapy? Which drugs to use when changing therapy? 129
- 129. When to InitiateTherapy? 2001 Recommended for patients with RNA > 30,000 copies/ml CD4 cell counts < 350/µl irrespective of RNA level. RNA levels 5000-30,000 and CD4 between 350500/µl 130
- 130. What Drugs shouldbe Initiated in Newly Diagnosed HIV + Patient? AZT + 3TC + either PI or NNRTI 131
- 131. Two strategies tomaximize benefits/minimize toxicities: Alternating therapies Combination therapy-demonstrated more beneficial than monotherapy Decreased emergence of resistance Decreased risk of toxicity 132
- 132. HIV infected PregnantFemale Standard antiretroviral therapy should be used in the HIV infected pregnant female Possible risk of premature delivery (highest in non-treated individuals) 133
- 133. Reduced transmission of HIVfrom mother to infant Proportion of infants of HIV (+) mothers who acquired HIV 40 30 33 % 20 10 0 8 No ARV With ARV 134
- 134. Pediatric Patients withHIV Therapy: AZT + 3TC + either PI (nelfinavir) or NNRTI (efavirenz) Expanded access of liquid formulations ddC zalcitabine (from Roche), efavirenz (from Dupont), Kaletra (from Abbott) Not recommended: overlapping toxicities or undesirable effects Monotherpay d4T and AZT ddC and ddI ddC and d4T ddC and 3TC 135
- 135. Reasons to ChangeRegimen? Plasma HIV RNA levels measured on 2 separate occasions CD4 count (changes in these counts) Remaining treatment options for potency Potential resistance patterns from prior antiretroviral therapies Potential for adherence/tolerance Potential for side effects, drug interactions, possible need to alter concomitant medications 136
- 136. 3 Patient Populations Identifiedas Needing Therapeutic Changing Patients receiving incompletely suppressive therapy (single or double NRTI) with detectable or undetectable plasma viral load Patients who have been on potent combination therapy and whose viremia was initially suppressed to undetectable levels but has again become detectable Patients receiving potent combination therapy and whose viremia was never suppressed to below detectable limits 137
- 137. Goal of Therapy Suppressingviremia to below detectable levels as consistently as possible. Requires a level of commitment to be adherent even a low level of non-adherence will result in the development of resistance which could render the therapy useless. 138
- 138.
- 139.
- 140. Prevention of HIV Infections Vaccines Pre-clinicalwork in animals is promising Education, Counseling & Behavior mod. Worked in the US for homosexual men Free needles for IV drug users Societal debate Improved blood supply Greatly decreased risk for hemophiliacs Screening and treating pregnant women Area where interventions are well accepted 141
- 141. Why is HIVso hard to fight? Some antibodies that the body produces actually work to enhance HIV replication. Some antibodies that work to neutralize HIV replication can become enhancing antibodies when the virus mutates. Cells other than helper T-cells can be infected, therefore the virus can colonize many tissues of the body. HIV can kill cells that it doesn’t even infect. 142
- 142. Vaccine development isdifficult 1. HIV mutates rapidly 2. Not expressed in all cells that are infected & is not completely cleared by the host immune response after primary infection. 3. Protective immunity are not known 4. Vaccine based on attenuated or inactivated HIV or in simian isolates don’t ensure safety against possible vector-induced disease 5. Lack of appropriate animal modal for HIV. 143
- 143. AIDS Vaccine Two vaccineson trial AIDSVAX B/B – tested in North America & Amsterdam AIDSVAX B/E – tested in Thailand Each mixed the surface proteins (gp120) from two strains of HIV 144
- 144. New vaccines onhuman trial tgAAC09 – begun in Belgium Single shot vaccine Uses Targeted Genetics ‘ rAAV (recombinant adeno associated viral vector) Technology 145
- 145. New DNA vaccineson human trial Vaccine - ADVAX Vaccine is tailored for C strain of HIV Worked by The Aron Diamond AIDS ResearchCenter & International AIDS Vaccine initiative Trail in New York & Rochester Developed on synthetic DNA based on the genetic material available Safe to use 146
- 146. SURVEILLANCE SYSTEM IN BANGLADESH Surveillance iscarried out in phases. Currently 4th round of HIV surveillance has been done : -Surveillance on high risk population -Surveillance on mass population No case has been detected on mass population So emphasis should be given on high risk population. 147
- 147. MOST PRESSING ISSUES INHIV/AIDS CONTROL MEASURE IN BANGLADESH High numbers of migrant workers Low socio-economic condition & illiteracy High prevalence rate of STI among sex workers Unsafe sex practice by sex workers Sharing of needles by the IDUs 148
- 148. A Short PreviewOf The Existing Guideline On HIV/AIDS And STD Related Issues : The government of Bangladesh has Formulated Guidelines On The Following Specific Areas Related To HIV/AIDS : Epidemiological surveillance, Testing policy, Infection management, Counseling , Safe blood transfusion , Education , Information , Awareness development , Promotion of preventive measures , Social science and behavioral research , Clinical vaccine trial , Ethical and legal aspects 149
- 149.
Editor's Notes
- #15 The establishment that the disease is caused by a virus and therefore the ability to produce antibodies against viral antigens led to the first tests for HIV, the ELIZA and Western blot tests. However, there is a 1 to 2 month time lag before antibodies are produced. This can be overcome by using a test that identifies viral RNA rather than antibodies produced against viral protein e.g PCR. The very fact that we can use an antibody test shows us that there is a good immune response and it is neutralizing antibody which gives hope for a vaccine. But the virus is not completely neutralized which argues that a vaccine may be difficult to develop. The virus goes underground within the cells and because it is a retrovirus, is prone to genetic drift. As it changes it overcomes the immune system. As we shall see retroviral vaccines pose special problems and HIV is more complicated than other retroviruses
- #30 Bacterial Infection Increases HIV Infection Through Upregulation of Viral Co-Receptors WESTPORT, CT (Reuters Health) Oct 18 - Concurrent bacterial infection can stimulate HIV replication through upregulation of the chemokine receptors CXCR4 and CCR5 on CD4+ T cells, researchers from the Netherlands report. "Intercurrent febrile diseases are associated with a transient rise in HIV replication," Dr. Tom van der Poll explained in an interview with Reuters Health. To see if this could be explained by upregulation of CXCR4 and CCR5, he and colleagues from the University of Amsterdam injected eight HIV-negative volunteers with the bacterial cell wall component lipopolysaccharide. As the researchers report in the October 15th issue of Blood, the injection increased the surface levels of CXCR4 and CCR5 per CD4+ T cell, in addition to increasing the fraction of CD4+ T cells expressing CXCR4. The increase in CXCR4 levels correlated with an increase in infectability with a T-tropic HIV-1 strain, but the increase in CCR5 did not correlate with increased infectability with an M-tropic HIV-1 strain. "We were surprised," Dr. van der Poll said. He suggested that bacterial infection could stimulate the release of CCR5 ligands such as RANTES and MIP-1-beta, which were indeed elevated, and could counteract the enhancing effect of increased CCR5 levels on HIV replication. Similar in vitro experiments, where the researchers stimulated blood cells with antigens from Mycobacterium tuberculosis and Staphylococcus aureus, produced similar increases in the levels of CXCR4 and CCR5 on CD4+ T cells. The upregulation appeared to be due in part to tumor necrosis factor and interferon-gamma. In addition, interleukin-10 specifically upregulated CCR5 but not CXCR4. "Pathogens commonly found in HIV-infected patients may increase viral burden in blood by upregulation of CXCR4," Dr. van der Poll and colleagues write. "Moreover, intercurrent infections may contribute to the selection of CXCR4-using viruses during the course of disease progression." "This is more a mechanistic study that needs confirmation in patient populations," Dr. van der Poll noted in the interview. "Possibly, blocking of CXCR4 may reduce the transient upregulation of HIV replication during intercurrent febrile illnesses." In the journal, he and colleagues suggest that intercurrent disease should be closely monitored and aggressively treated in HIV-infected patients. "For some pathogens, adequate antibiotic prophylaxis may reduce the HIV load." Blood 2000;96:2649-2654.
- #33 92% of children reported to be infected with HIV in 1996 were infected through vertical transmission- transmission from infected mother to baby. Vertical transmission can take place in several ways: (1) the virus can be transmitted to the fetus while it is still in the uterus; (2) the infection can take place in the birth process during which the baby comes in direct contact with large quantities of the infected blood of the mother; or (3) the virus can be passed on through breast milk.The chance of infection through breastfeeding, however, is small
- #35 Because HIV is transmitted by sex or contaminant blood, the groups that are at increased risk of contracting the disease are listed in this slide. Men, practicing unsafe sex are at high risk if they are homosexual or bisexual. If a patient uses IV drugs and shares needles with another that is HIV positive, this is another means of contracting the disease. The other groups are self-evident. Certain patient may have had a blood transfusion between 1987 and 1992 and became infected by that route also.
- #49 This slide details some of the steps that are necessary for HIV pathogenesisity. After HIV entry into the body by the different routes, within 2-4 weeks, the patient will have the peak viremia. However, the patient will be negative by HIV serology. This means that a patient can be infected with HIV and if tested too soon, the patient will have a negative HIV test however, the patient may still be HIV-positive. HIV will enter lymph tissue after infecting CD4 cells as early as 5 days after acute infection. After the initial peak plasma viremia, virus-specific immune responses can be detected and may contribute to both the control of the initial peak of virus replication and the reduction in plasma viremia. The immune response lack the ability to control HIV and block progression of the disease. This is different than other viruses such as Epstein-Barr virus where the immune response will stop progression of the disease. Soon after the acute infection, a pool of latently infected CD4 cell contain the virus and is capable of replicating. This is the key to the immunopathogenesis of HIV. This stable reservoir remains sheltered from the effects of host response and drug therapy.
- #50 Certainly with these mechanisms in place, HIV can then destroy lymph tissue and directly kill CD4 cells leading to immune suppression and opportunistic infections and neoplastic diseases.
- #63 time has increased with new protease inhibitors must be used in combination with other drugs
- #64 This slide details the classic 6 symptoms of patients in the primary HIV infection period. These symptoms can continue and may be the reason why patients seek medical attention. Therefore, physicians and other health care practitioners must be aware of these symptoms for adequate identification of the high risk patient. Certain questions should be asked of all patients between 17 and 30 regarding sexual preferences and activity when patients present to outpatient clinics with these symptoms.
- #80 This slide indicates the laundry list of opportunistic infections that patients can experience with a reduction in the numbers of CD4 cells. Most occur with CD4 cells < 200/mm3.
- #81 Additionally, patients can develop HIV associated cancers as this slide indicates.
- #86 The key element in HIV pathogenesis is the high rate of viral replication and infected CD4 cell. The rate of viral replication stabilizes after primary infection and remains stable over months or years.
- #87 At steady-state in the untreated state, the amount of virus produced and cleared each day are roughly equal. The quantity of virus in the blood of an infected patient is a function of the rate of virus production in that patient. The rate of CD4 destruction is also proportional to the rate of virus production. Measurements of plasma HIV RNA levels provide an estimate of the rate at which the immune system is being depleted. Studies have shown that the quantitative measurement of plasma HIV RNA is correlated to disease state. During therapy, the decline in plasma RNA levels is strongly associated with a decreased risk of disease progression. Therefore, monitoring plasma HIV RNA levels provides a direct correlation to risk of disease progression and ultimately mortality.
- #89 Plasma HIV RNA levels should be determined in all patients who have HIV infection as part of their initial evaluation. Results can be used to assess the patient’s risk of disease progression and help make decisions regarding therapy. If viral RNA levels are > 30,000 copies/ml, treatment should be highly recommended. Patients who have titers < 10,000 copies/ml and CD4 counts > 500/l are at very low risk of progression. Treatment in this case may be deferred and virus load monitored every 3-6 months. Plasma RNA assay should be repeated within 4-6 weeks of either initiating therapy or changing therapy. A minimum of a 1-log decrease in plasma RNA should be observed within this time frame. If not, presence of drug resistance, poor treatment adherence or an insufficiently potent regimen should be considered.
- #130 This slide helps to determine the questions that need to be answered when faced with a patient that requires therapy. Let’s review the discussion points associated with these questions.
- #131 This slide indicates the patients that therapy is recommended. Therapy should be highly recommended to patients with RNA levels > 30,000 copies/ml regardless of their CD4 cell counts. Additionally, therapy should be highly recommended for patients with CD4 cell counts < 350/l irrespective of viral RNA level. Therapy should be encouraged in patients with viral RNA levels between 5,000-30,000 copies/ml or with CD4 cell counts between 350 and 500/l.
- #132 Dual NRTIs are used in most 3 to 4-drug regimens. There are no current data regarding preferred sequencing of NRTI however, AZT and D4T should not be used together because of drug-drug antagonism. ddC plus ddI or D4T is not recommended due to overlapping toxicities. Lamivudine should be reserved for regimens that maximally suppress replication as M184V mutation results in loss of lamivudine activity. AZT + 3TC use results in loss of abacavir effectiveness. Abacavir is useful in initial regiments but its effectiveness with NRTI combinations other than AZT + 3TC is not well characterized. Efavirenz+3TC+AZT produced HIV suppression and CD4 cell count elevation is at least comparable to that with indinavir+3TC+AZT. Remember it is contraindicated in the 1st trimester of pregnancy. Potential for high-level resistance as a result of a single reverse transcriptase mutation suggests that NNRTI should be used only in regimens designed to maximally suppress HIV. Dual protease inhibitors (PI) are increasingly being used because of pharmacokinetic advantages of low-dose ritonavir inhibiting P4503A metabolism of the other PI improving the plasma concentrations of these drugs. May offer increased potency and reduced pill counts.
- #133 The present objective of antiretroviral therapy is to prevent disease progression and prolong survival while maintaining quality of life. The use of combinations of antiretrovirals with no overlapping toxicity and demonstrated antiviral synergy is recommended.
- #136 Currently, pediatric patients represent a minority of patients but are more difficult due to both toxicities and formulation problems. This slide shows recommended and non-recommended therapies for pediatric patients. If a patient received chemoprophylaxis with AZT, and now is determine to be HIV +, then immediate starting of therapy would be recommended. Risk of mortality is primarily viral loads > 100,000 copies/uL.
- #137 This slide details reasons to change therapy in a patient that has not met the goal of therapy. A patient that has detectable levels of viral RNA and/or their CD4 cell counts are not increasing, may need a change in therapy. The goal would be a target level of < 50 copies/ml by 16-24 weeks should raise concern in either poor adherence, inadequate drug absorption, or drug resistance.
- #138 This slide details the patient populations that require a therapeutic change.
- #139 This slide details the goal of therapy. If for whatever reason, this goal can not be reached, some investigators admit that withholding therapy until the patient can meet these expectations may be necessary for some patients.
- #140 This slide details the changes that have been made to ascertain how therapy has impacted the virus and patient’s well-being. During the early part of this disease in the late 1980s, when monotherapy was all we had to offer patient, the viral load would go down over time and then return to pre-treatment levels after the virus developed resistance to AZT. In the early 1990s, when patients received dual NRTIs the viral load would go down and then stay down longer than monotherapy. However, eventually, the viral load would come back up and CD4 cells would be killed. Since 1998, we now have HAART and this includes triple drug combinations and now we can see that viral load go down and remain at non-detectable levels unless patient are nonadherent to their therapy regimen.