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DR MD TIPU SULTAN
Associate Professor
Department of Microbiology
Chittagong Medical College
1
HIV
Human Immunodeficiency Virus
2
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
HIV and AIDS
4
“The greatest single public
health challenge that
humanity has ever faced.”
5
HIV/AIDS Historical
Perspective
1979
CDC reported unexplained 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
HIV/AIDS Historical
Perspective
1983
Virus isolated.Then it 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
HIV/AIDS Historical
Perspective
1985
ELISA test developed
Today:
Broad spectrum of disease
Asymptomatic infection
Clinical latency
Clearly
sexually transmitted, and
transmitted through blood products
8
In Bangladesh, HIV positive
cases was 1st detected in
1989 in Chittagong
9
Global summary of the HIV and AIDS epidemic
The ranges around the estimates in this table define the boundaries within which the actual numbers lie, based on the best available information.
10
HIV/AIDS
BANGLADESH SITUATION, END 2012
11
Prevalence Among High Risk
Population in Bangladesh
12
Important
Bangladesh was the first among the SAARC
Countries to take the threat of HIV epidemic
seriously & initiated a national response in 1985.
13
Retrovirus
RNA virus
Enveloped
Reverse
transcriptase
enzyme
HIV, HTLV
14
Unique Characteristics of Retroviruses
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.
Viral Matrix
Core
Image from
http://www.brown.edu/Courses/Bio_160/Projects1999/hiv/images/Virion2.jpg
16
HIV structure 17
Types of HIV
HIV 1
Subtypes- A to I and O
Subtype A & D – found in sub Sahara
Africa
Subtype B – found in US & Canada
India
Subtype E – found in south east Asia
Central Africa
Subtype I – found in Cyprus
HIV 2
18
HIV-1 and HIV-2
• HIV-1 and HIV-2 are
• Transmitted through the same routes
• Associated with similar opportunistic
infections
and Angola
19
HIV-1 and HIV-2
• HIV-2 is less easily transmitted
20
Important antigens:
1) Group-Specific Antigens
p24: nucleocapsid
p9: nucleocapsid associated with RNA
GAG gene
21
2) Type -Specific envelope glycoprteins
ENV gene
22
3. Enzymes
• Polymerase (reverse
transcriptase)
• Integrase
• Protease
• POL gene
23
Transmission
of HIV
24
Transmission of
HIV
HIV is transmitted 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
HIV enter the body via the bloodstream either during
sexual intercourse
needle drug abuse
transfusion with contaminated blood products
or via the placenta
26
Blood
Up to 10,000 infectious particles per
ml
Shared drug/drug-injecting
equipment
needles, syringes
Blood
Transfusions
plasma, whole blood, platelets
clotting factors (decreased since 1985)
28
Sexual Contact
STD’s increase risk of transmission
epidemiological trend
exposed to one, may mean exposed to others
inflammation make person more
vulnerable to HIV invasion
Sexual Contact
vaginal:
oral:
Sexual Contact
Semen: only 10-50 infectious virons per
ml
artificial insemination a risk
During delivery
Breast-feeding
low incidence
Risk Factors
33
High risk groups
1) homosexual/bisexual men
2) IV drug use/abuse
3) hemophiliacs
4) sex partners in abuse groups
5) infants of above groups
34
Transmission of HIV
HIV is not transmitted by
35
Important properties:
36
Which cells does HIV-1 infect?
Identification of molecular
targets.
38
HIV
chemokine
Mutant
CD4 CCR5 CCR5
CCR5 CD4
CD4
macrophage
Chemokine receptors are necessary co-receptors along with CD4 antigen
39
Provirus
40
41
Pathogenesis
42
43
Reduction in the numbers of CD4 T cells may result from
HIV-infected cytolysis, cytotoxic T-cell immune cytolysis.
44
Macrophage-lineage cells express both the CCR5 & CXCR4
chemokine receptors and can be infected by M-& L-tropic HIV.
47
Steps for pathogenesis of
HIV:
rapid early dissemination of virus
seeding of virus in lymphoid tissue
partial host immune responses that down-
regulates 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
Steps for pathogenesis of
HIV:(cont.)
destruction of lymphoid tissue
escape of viral elements into peripheral
blood cells
direct killing of CD4 cells
49
Potential mechanism of CD4 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
Three mechanisms by which
HIV evades immune system
1. Integration of viral DNA into host cell
DNA
resulting in a persistent infection.
52
Initially, large burst of virus production &
viremia, which corresponds to the occurrence
of a mononucleosis-like syndrome.
53
Virus levels in the blood decrease during a
clinically latent period, but viral replication
continues in the lymph nodes.
54
Late in the disease, virus levels in the blood
increase, CD4 levels are significantly decreased.
55
Clinical
Manifestations
56
Initial infection
Fever and other flu-like symptoms
lympadenopathy
57
Prolonged Asymptomatic
Infection
person is HIV+ but asymptomatic
lasts for several years (subclinical)
viral replication occurring
up to 10 billion virons per day
chronic lymphadenopathy
58
Early Symptomatic
Disease
CD4 counts drop to 500-600 cells/ml
symptoms: recurrent fever, night
sweats, malaise, headache
59
Opportunistic Infection
infection by a pathogenic organism
thatis normally present but not harmful
becomes infectious in
immunocompromised person
60
AIDS
AIDS vs. HIV positive
61
Average time between infection and
AIDS was 10 years
− fatigue/malaise
− lymphadenopathy
− weight loss
− fever
− night sweats
− diarrhea
63
AIDS
CD4 count less than 200/mm
majority of manifestations due to opportunistic
infections due to immunosuppression
rather than direct injury by virus
64
Clinical Course of
HIV/AIDS
HIV Infection
Virus deposited on mucosal surface
Acute infection (mono-like symptoms)
Viral dissemination
Replication of virus
Latent Period
65
Clinical Course of
HIV/AIDS
AIDS
Immunologic dysregulation
Opportunistic infections and cancers
66
WHO classification of clinical
stages of infection
67
WHO Clinical stage I
in Children
Asymptomatic
Generalized lymphadenopathy
68
WHO Clinical stage II
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
WHO Clinical stage III
in Children
AIDS – defining opportunistic
infections
Severe failure to thrive
Progressive encephalopathy
Malignancy
Recurrent septicaemia or meningitis
70
WHO Clinical stage I
in Adults & Adolescents
Asymptomatic
Persistent generalized
lymphadenopathy
Performance scale 1:
asymptomatic, normal activity
71
WHO Clinical stage II
in Adults & Adolescents
76
AIDS in Children
Infants who are seropositive at 18
months are infected
Infants progress to AIDS more rapidly,
usually in 3 years
77
AIDS in Children
Transmission is 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
Opportunistic infections
− pneumocystic carinii 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
Opportunistic tumors
− Kaposi’s sarcoma
− primary CNS lymphoma
− certain high-grade B-cell lymphoma
80
Diagnosis
81
Laboratory diagnosis
Evidence of HIV 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
1.Virus isolation :
HIV can be cultured from lymphocytes
in peripheral blood.
83
2. Detection of viral Nucleic Acid :
By RT-PCR
Branched-chain DNA
84
Viral RNA Assay -
Dynamics of HIV-
billions of viruses produced and
destroyed daily
86
87
Therefore utility of HIV RNA
assays include:
therapy
Typically 109-1010 virions are produced daily
88
3. Detection of HIV
Antigen
89
3. Detection of viral p24 Antigens:
90
4. Detection of antibody
Seroconversion:
Development of evidence of
antibody response to a disease.
Viral Load:
The amount of HIV in the blood.
93
“Window Period”
A period of 4-6 weeks after HIV exposure
when antibodies to HIV are not detectable
in the blood
ELISA false-positive:
immunologic abnormalities
neoplasms
multiple transfused
pregnancy
99
Western blot to be considered positive
102
Selection of the HIV
Test
Is site-specific based on:
National/local policies
Availability of supplies and laboratory
support
Availability of trained personnel
Costs
103
The Testing Process
• Test sample
• Blood, saliva, urine
• Obtain results
• Keep confidential
• Method determined by clinic protocols and
client
• Provide results to client
105
Guiding principles
(contd.)
• Pre-test Group education
• Informed Consent
• Identifies:
• Respects
• Individual’s autonomy and right to confidentiality
106
Counseling and Testing as an
Entry Point to MCH/HIV
Prevention
Primary
prevention of new
Community action HIV infection Prevention of
to reduce Stigma unintended
& discrimination pregnancy
VCT
Post - delivery and its links Safer obstetric
care and support with other practices
services
107
Pre-test Information
Group education 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
Post-Test
Counselling
Provide the woman with 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
Post-Test
Counselling
HIV-negative
110
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
Diagnosing HIV in HIV-
Exposed Infant
ARV prophylaxis reduces but does not eliminate
Mother to child transmission of HIV infection
• Identify support
115
CURRENT TESTING FACILITIES
IN BANGLADESH
Screening Purposes :
Latex agglutination
Immunochromatography
Particle agglutination
ELISA
For Confirmation :
BSMMU, Dhaka-Western blot AFIP,
Dhaka-Western blot
ICDDR,B-Dhaka-Western blot IEDCR,
Dhaka-Western blot Dhaka
Medical College-Line immunoassy, ELISA
Chittagong Medical College-Line immunoassy, ELISA
Sylhet Medical College-Line immunoassy, ELISA
116
EXISTING DIAGNOSTIC FACILITIES ( CONTD)
Screening tests for HIV [ PAT and ELISA ] are also carried
out in blood transfusion centres to ensure safe blood
transfusion
117
Treatment
118
Types of HIV Drugs
Entry inhibitors
Reverse Transcriptase inhibitors
Integrase inhibitors (On study)
Protease inhibitors
Assembly & budding inhibitors
(On study)
120
Attacking HIV with antiretroviral drugs
Protease
Attachment
inhibitors
inhibitors
Assembly
inhibitors
RT
inhibitors
Integration
inhibitors
121
Entry inhibitors
Fusion inhibitor
Fuzeon (enfuvirtide, or T-20)
122
Reverse Transcriptase
Inhibitors
Didanosine (ddl)
Stavudine (d4T)
Lamivudine (3TC)
Abacavir (ABC)
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
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
Therapy might be started 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
Highly Active
Antiretroviral Therapy
(HAART)
Combination of three
or more drugs
127
Why is HIV so hard to
treat?
1. HIV-1 and other lentiviruses have the unique
property among retroviruses to replicate in
nondividing cells.
128
4 Questions that Need Answers
for HIV Therapy
129
When to Initiate Therapy?
2001
Recommended for patients with RNA > 30,000
copies/ml
CD4 cell counts < 350/µl irrespective of RNA level.
130
What Drugs should be
Initiated in Newly Diagnosed
HIV + Patient?
131
Two strategies to maximize
benefits/minimize toxicities:
Alternating therapies
Combination therapy-demonstrated
more beneficial than monotherapy
Decreased emergence of resistance
Decreased risk of toxicity
132
HIV infected Pregnant Female
133
Reduced transmission of
HIV from mother to infant
Proportion of infants of HIV (+) mothers
who acquired HIV
40
30 33
% 20
10
8
0
No ARV With ARV
134
Pediatric Patients with HIV
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
Reasons to Change Regimen?
137
Goal of Therapy
Suppressing viremia 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
139
Prevention
140
Prevention of HIV
Infections
Vaccines
Pre-clinical work 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
Why is HIV so hard to
fight?
Some antibodies that the body produces actually
work to enhance HIV replication.
142
Vaccine development is difficult
145
New DNA vaccines on 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
SURVEILLANCE
SYSTEM
IN BANGLADESH
Surveillance is carried 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
MOST PRESSING ISSUES
IN HIV/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
A Short Preview Of The Existing Guideline On
HIV/AIDS And STD Related Issues :
150