HIV/AIDS and Treatment
Manado, Indonesia
16 november
HIV [e] EDUCATION
HIV is a…
s
vir
u
RN
A-
0%
as
ite
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Pa
r
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s
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vir
u
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DNA-virus
DNARNA--virus
RNA
Parasite
DN
A-
1.
HIV
HIV is a RNARNA-virus.
virus.
HIV is an RNA virus which uses DNA for its
replication.
A virus is unable to replicate (reproduce) on its
own and must first infect a living cell in order to
replicate.
HIV has to infect living cells in order
to replicate…
What kind of cells?
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Ly
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ph
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yt
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oc
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th
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Erythrocytes
Lymphocytes
Thrombocytes
Er
y
1.
The lifecycle of HIVHIV-1…
Cellular CD4 receptor
Human DNA chromosome
CD4 ( T Helper) Cell
Reverse transcriptase
Cellular CD4 receptor
gp41
HIV
HIV RNA chromosome
Human DNA chromosome
CD4 ( T Helper) Cell
1. HIV approaches CD4
cell
2. HIV-CD4 interaction
4. Fusion of cell and
virus
3. Connection gp41
Cellular CD4 receptor
HIV RNA chromosome
Human DNA chromosome
CD4 ( T Helper) Cell
Cellular CD4 receptor
RNA
nucleotides
HIV RNA chromosome
Human DNA chromosome
CD4 ( T Helper) Cell
Reverse transcriptase
Cellular CD4 receptor
RNA
nucleotides
DNA
nucleotides
HIV RNA chromosome
Human DNA chromosome
CD4 ( T Helper) Cell
Reverse transcriptase
Cellular CD4 receptor
HIV RNA chromosome
HIV DNA provirus
Human DNA chromosome
CD4 ( T Helper) Cell
Integrase
Cellular CD4 receptor
Reverse transcriptase
HIV RNA chromosome
HIV DNA provirus
Human DNA chromosome
CD4 ( T Helper) Cell
Reverse transcriptase
Cellular CD4 receptor
HIV RNA chromosome
HIV DNA provirus
Human DNA chromosome
CD4 ( T Helper) Cell
Cellular CD4 receptor
HIV
HIV RNA chromosome
HIV DNA provirus
Human DNA chromosome
CD4 ( T Helper) Cell
Acute HIVHIV-infection
From HIVHIV- exposure at mucosal
surface to spreading to organs….
organs….
How long does it take?
take?
m
on
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Th
re
e
11
1d
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da
ys
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ay
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te
s
4.
in
u
3.
m
2.
10 minutes
1 day
11 days
Three months
10
1.
Day 0
Exposure to HIV at
mucosal surface (sex)
Day 0-2
Virus collected by
dendritic cells, carried
to lymph node
Day 3-11
HIV replicates in
CD4 cells, released
into blood
Day 11 on
Kahn JO, Walker BD. N Engl J
Med. 1998;339:33-39.
Virus spreads to
other organs
29 year old man, no medical history
2 weeks of malaise, myalgia and since a couple days
a rash
Four weeks ago unprotected sex
Complaints of severe fatigue, no weight loss or
mouth sores
1week ago his GP gave him antibiotics with no
effect
Physical exam: temperature of 38.3 C, diffuse
adenopathy, maculopapular rash
Rash
Test results
HIV RNA: 63.700 copies/ml
HIV antibody: negative
What is your diagnosis?
Acute HIVHIV-infection
Primary HIV Infection: Signs &
Symptoms
80
80--90% of patients will be symptomatic
A mononucleosismononucleosis-like illness of nonnon-specific
signs and symptoms
Signs and symptoms typically begin 11-4 weeks
post--exposure
post
Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.
Schacker T, et al. Ann Intern Med. 1996;125:257-264.
Primary HIV Infection:
Common Signs & Symptoms
fever
86
lethargy
74
myalgias
59
rash
57
headache
55
pharyngitis
N = 160 patients with PHI in
Geneva, Seattle, and Sydney
52
adenopathy
44
0
10
20
30
40
50
60
% of patients
70
Vanhems P et al. AIDS 2000; 14:0375-0381.
80
90
100
Typical Risk of Unprotected
Exposures
Estimated Average Per Contact Transmission Risk (%)
Shared Needles
Occupational Needlestick
Male to female, vaginal sex
Female to male, vaginal sex
Receptive oral sex with male
0.7%
0.3 %
0.2%
0.1%
0.03%
How long is your diagnostic window?
The current HIVHIV-antibody screening tests are able to
recognise almost 99.5 % of HIV–
HIV– infections……
A.
B.
C.
D.
2 weeks
1 month
3 months
1 year
0%
0%
0%
0%
3
ar
ye
1
m
on
th
1
m
ks
w
ee
2
on
th
s
….after primary HIV infection
90
How long is your diagnostic
window?
The current HIVHIV-antibody screening tests are able
to recognise almost 99.5% of HIVHIV-infections…
A.
B.
C.
D.
2 weeks
1 month
3 months
1 year
…..after primary infection with HIV
Typical Course of Primary HIV
HIV RNA
HIV-1 Antibodies
1 mil
HIV
RNA
100,000
10,000
1,000
100
Ab
+
Exposure
_
Symptoms
10
0
3
14
21
Days
28
35
HIV--markers and disease
HIV
progression
HIV Disease Progression
Progression can be monitored by:
Clinical markers:
markers:
HIV/AIDS
HIV/AIDS--related conditions
Laboratory markers
Increase in blood virus load
Decrease in CD4 cell count
CD4 Count, Viral Load, and Clinical Course
Primary
Infection
Seroconversion
10.000.000
AIDS
Plasma HIV RNA
1.000.000
100.000
10.000
Plasma RNA Copies
1.000
CD4 Cell Count
Intermediate Stage
1,000
CD4 Cells
100
500
10
1
4-8 Weeks
Up to 12 Years
2-3 Years
HIV Infection is characterized by a steady
decline in the number of CD4 cells
CD4 Cell Count (cells/mm³)
Acute
Infection
Asymptomatic HIV Infection
AIDS
1,000
CD4 cell count
500
200
high risk of opportunistic infections
4-8 Weeks
Up to 12 Years
Time
2-3 Years
Association between opportunistic
infections and CD4+-lymphocyte count
CD4+-lymphocyte count
(cells/µ
µl)
400
Herpes Zoster
Tuberculosis
300
Oral candidiasis
Pneumocystis carinii pneumonia
Esophageal candidiasis
200
Toxoplasmosis, cryptococcosis
Mycobacterium avium complex
100
50
Cryptosporidiosis, PML
time
Antiretroviral therapy
What is antiretroviral therapy?
ART
Anti
ntirretroviral Therapy
ARV
Anti
ntirretro
etrovviral
cART
HAART
combination Anti
ntirretroviral Therapy
Highly Active Anti
ntirretroviral Therapy
What kind of classes do we have?
NRTI’s
NNRTI’s
PI’s
(Entry inhibitors)
(Fusion inhibitors)
(Integrase inhibitors)
Available FDA approved drugs
Classes
NRTIs
NNRTI
Protease inhibitors
AZT
NVP
Saquinavir
DDI
Etravirine
Darunavir
DDC
EFV
Indinavir
D4T
3TC
ABC
Nelfinavir
Fusion inhibitors
Enfuvirtide
AZT/3-TC
ZT/3TC/ABC
TDF
Amprenavir
Lopinavir/rtv
Atazanavir
CCR5 antagonist
Maraviroc
FTC
3TC/ABC
Integrase inhibitor
TDF/FTC
Raltegravir
Fosamprenavi
Tipranavir
PI
NRTI
NRTI
(the “NRTI backbone”)
+
or
NNRTI
Combination of at least 3 drugs, usually:
2 NRTIs (the “NRTI backbone”), plus:
1 NNRTI or 1-2 PIs
Therapy with only one or two agents allows
HIV to overcome therapy through resistance
mutations
Goals of HAART
Prolong life and improve quality of life
Achieve maximal suppression of HIV
Low (undetectable) viral load
Reverse immune system damage
Increase CD4-count
Initiation of Antiretroviral
Therapy: Key Considerations
Symptoms & Opportunistic Infections
CD4 count
Anticipated Adherence - patient ‘readiness’
CDC
A:
Asymtomatic
Lymphaden.
B:
Symptomatic
C:
AIDS defining
illness
1
>500 CD4
Deferal
treatment
start
treatment
Start
treatment
2
200
200--499 CD4
200
200--350 start
treatment
Start
treatment
Start
treatment
3
<200 CD4
Start
treatment
Start
treatment
Start
treatment
When to start?
DHHS Guidelines 2008 update january
Male 28 years, HIV+
CD4 cell count: 150/µl,
150/µl, retrosternal pain
Start HAART?
o
0%
N
0%
es
2.
Yes
No
Y
1.
90
o
0%
N
0%
es
2.
Y
1.
Male 28 years, HIV+
CD4 cell count: 370/µl,
370/µl, retrosternal pain
Start HAART?
Yes
No
90
Male 42 years, HIV+, dry cough since three
weeks, breathing frequency 40
40/min
/min
CD4
CD4 cell count: 170
170/
/µl
X-thorax:
Start HAART?
o
0%
N
0%
es
2.
Yes
No
Y
1.
90
Male 42 years, HIV+, dry cough since three
weeks, breathing frequency 40
40/min
/min
CD4
CD4 cell count: 220
220/
/µl
X-thorax:
Start HAART?
o
0%
N
0%
es
2.
Yes
No
Y
1.
90
Male 42 years, HIV+, dry cough since three weeks,
breathing frequency 40/min, CD4 cell count: 170/µl
170/µl
X-thorax:
When to start HAART?
0%
3
m
on
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ee
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0%
28
3.
ow
2.
Now
2-8 Weeks
3 months
N
1.
90
Woman 34 years old; HIV+, Unexplained weight
loss; 66 kg 46 kg, CD4 cell count: 410/µl
410/µl
Start HAART?
o
0%
N
0%
es
2.
Yes
No
Y
1.
90
The treatment of patients with
symptomatic conditions (CDC B)
or an AIDS defining illness (CDC C)
should not depend on a CD4 cell
count!
Pfffffffff
finished!