9.HIV[AIDS] infection for nurrse sir.ppt
mekulecture
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Jun 16, 2024
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About This Presentation
d
Slide Content
1
Pharmacotherapy of Human
immunodeficiency virus infection
Tesh A (Bpharm,MSc)
(HIV/AIDS)
Pharmacotherapy of Human
immunodeficiency virus infection
Tesh A (Bpharm,MSc)
(HIV/AIDS)
About HIV/AIDS
1.All are true except one?
A.It is chronic viral infection
B.It is both treatable and curable disease
C.It is the disease of immune system
D.Usually a combination therapy is used
E.HAART drugs work at gene level, and hence are toxic
2.First line ART is a combination of?
A.2NRTIs and 1-2PIs
B.1NNRTI and 2NRTIs
C.2NRTIs AND 2PIs
2
D.2NRTIs and 1PI
E.All except D
1.All are true except one?
A.It is chronic viral infection
B.It is both treatable and curable disease
C.It is the disease of immune system
D.Usually a combination therapy is used
E.HAART drugs work at gene level, and hence are toxic
2.First line ART is a combination of?
A.2NRTIs and 1-2PIs
B.1NNRTI and 2NRTIs
C.2NRTIs AND 2PIs
2
D.2NRTIs and 1PI
E.All except D
Characteristics of HIV
•A chronic retro-viral infection with no cure
•HIV infects cells that express CD4 receptor molecules
T4-lymphocytes(T-helper cells)
Monocyte-macrophage cell lines
•T4-lymphocytes are type of white blood cell that
‘switch on’ the immune system to fight disease
•HIV uses CD4 cells for reproduction
•As CD4 cells are destroyed, a person’s immunity is
impaired and opportunistic infections increase
3
•A chronic retro-viral infection with no cure
•HIV infects cells that express CD4 receptor molecules
T4-lymphocytes(T-helper cells)
Monocyte-macrophage cell lines
•T4-lymphocytes are type of white blood cell that
‘switch on’ the immune system to fight disease
•HIV uses CD4 cells for reproduction
•As CD4 cells are destroyed, a person’s immunity is
impaired and opportunistic infections increase
3
Etiology and virology
HIV -an RNA virus
HIV has two major types and several subtypes/strains:
HIV 1-Pandemic:
HIV M (A,B,C,D,E,F,..K,& others)->95% Global burden
HIV O
HIV N
HIV 2 –mainly in West Africa .
Subtype C viruses(of the M group) are the most common, accounting for
50% of infections worldwide.
Subtype C-the majority of sub-Saharan Africa infections.
Subtype B viruses are predominant in Americas, western Europe, and
Australia accounting for 12–13% of global infections.
4
HIV -an RNA virus
HIV has two major types and several subtypes/strains:
HIV 1-Pandemic:
HIV M (A,B,C,D,E,F,..K,& others)->95% Global burden
HIV O
HIV N
HIV 2 –mainly in West Africa .
Subtype C viruses(of the M group) are the most common, accounting for
50% of infections worldwide.
Subtype C-the majority of sub-Saharan Africa infections.
Subtype B viruses are predominant in Americas, western Europe, and
Australia accounting for 12–13% of global infections.
4
Etiology and virology
5
5
6
Pathophysiology of HIV/AIDS
Pathophysiology of HIV/AIDS
Natural history of HIV infection
oModes of infection/transmission
•Sexual transmission-at genital or colonic mucosa
•Blood transfusion (95%)
•Mother to infant (13% and 40%)
•Accidental occupational exposure
oViral tropism
•A fusion co-receptor is designated CXCR4 for T-cell tropic
strain and CCR5 for monocyte-macrophage tropic strains
•Transmitted viruses are usually macrophage-tropic
•Patients homozygous for the CCR5 mutation are relatively
resistant to transmission
7
oModes of infection/transmission
•Sexual transmission-at genital or colonic mucosa
•Blood transfusion (95%)
•Mother to infant (13% and 40%)
•Accidental occupational exposure
oViral tropism
•A fusion co-receptor is designated CXCR4 for T-cell tropic
strain and CCR5 for monocyte-macrophage tropic strains
•Transmitted viruses are usually macrophage-tropic
•Patients homozygous for the CCR5 mutation are relatively
resistant to transmission
7
8
Mechanism of spared
Mechanism of spared
HIV dissemination
•One of the cell types first encountered HIV-1 following sexual
transmission are dendritic cells (DC)
•DC capture HIV-1 through C-type lectin receptors, of which the
best studied example is DC-SIGN(CD209), which mediates
HIV-1 internalization
•DC can keep the virus infectious for several days and are able
to transmit HIV-1 to CD4 T cells.
•Subsequent transmission to T cells takes place via an
“infectioussynapse,” but avirus that has not been internalized
can also be transmitted to T cells
9
•One of the cell types first encountered HIV-1 following sexual
transmission are dendritic cells (DC)
•DC capture HIV-1 through C-type lectin receptors, of which the
best studied example is DC-SIGN(CD209), which mediates
HIV-1 internalization
•DC can keep the virus infectious for several days and are able
to transmit HIV-1 to CD4 T cells.
•Subsequent transmission to T cells takes place via an
“infectioussynapse,” but avirus that has not been internalized
can also be transmitted to T cells
9
Target cells of HIV
•Numerous organ systems are infected by HIV:
–Brain: microglial cells
–Lymph nodes and thymus: lymphocytes and dendritic cells
–Blood, semen, vaginal fluids: macrophages, dendritic cells
–Bone marrow: lymphocytes
–Skin: Langerhans cells
–Colon, duodenum, rectum: chromaffin cells
–Lung: alveolar macrophages
10
•Numerous organ systems are infected by HIV:
–Brain: microglial cells
–Lymph nodes and thymus: lymphocytes and dendritic cells
–Blood, semen, vaginal fluids: macrophages, dendritic cells
–Bone marrow: lymphocytes
–Skin: Langerhans cells
–Colon, duodenum, rectum: chromaffin cells
–Lung: alveolar macrophages
10
Cell free HIV
Skin or mucosa
24 hours 48 hours
1.HIV co-receptors,
CD4 + chemokine
receptor CCR5
Immature
Dendritic cell
3.Mature Dendritic cell in
regional LN undergoes a
single replication, which
transfers HIV to T-cell
Via lymphatics or
circulation
T-cell
PEP
Burst of HIV
replication
2.Selective of
macrophage-
tropic HIV
Early phases of HIV infection of mucosal
surfaces
11
Skin or mucosa
24 hours 48 hours
1.HIV co-receptors,
CD4 + chemokine
receptor CCR5
Immature
Dendritic cell
3.Mature Dendritic cell in
regional LN undergoes a
single replication, which
transfers HIV to T-cell
Via lymphatics or
circulation
T-cell
PEP
Burst of HIV
replication
2.Selective of
macrophage-
tropic HIV
Early phases of HIV infection of mucosal
surfaces
11
Primary HIV Infection
•About 4 to 11 days after infection, characterized by high level
of viremia (>1 million) for a duration of a few weeks
•Associated with a transient fall in CD4
•Nearly half of patients experience some mononucleosis-like
symptoms (fever, rash, swollen lymph glands)
•Primary infection resolves as body mounts HIV-specific
adaptive immune response
•Cell-mediated response (CTL) followed by humoral
•Patient enters “clinical latency”
12
•About 4 to 11 days after infection, characterized by high level
of viremia (>1 million) for a duration of a few weeks
•Associated with a transient fall in CD4
•Nearly half of patients experience some mononucleosis-like
symptoms (fever, rash, swollen lymph glands)
•Primary infection resolves as body mounts HIV-specific
adaptive immune response
•Cell-mediated response (CTL) followed by humoral
•Patient enters “clinical latency”
12
Window Period: untreated clinical course
13
--------------------------------------------PCR
P24
ELISA
0 234
Weeks since infection
a bTime from a to b is the window period
Viremia
Antibody
Asymptomatic
Acute HIV syndrome
Primary HIV
infection
Source: S Conway and J.G Bartlett, 2003
years
Clinical latency
13
--------------------------------------------PCR
P24
ELISA
0 234
Weeks since infection
a bTime from a to b is the window period
Viremia
Antibody
Asymptomatic
Acute HIV syndrome
Primary HIV
infection
Source: S Conway and J.G Bartlett, 2003
years
Clinical latency
0
100
200
300
400
500
600
700
800
900
1000
0369121234567891011
weeks years
CD4+ cells
modified after Pantaleo et al., NEJM, 1993
Primary HIV infection
Acute HIV Syndrome
(Acute RetroviralS~)
Clinical latency*
constitutional
symptoms
Plasma viremia
AIDS
very
early disease
early disease
advanced disease
* high rate of replication
in lymphoid tissue
steady state
14
HIV disease progression
100
200
300
400
500
600
700
800
900
1000
0369121234567891011
weeks years
CD4+ cells
modified after Pantaleo et al., NEJM, 1993
Primary HIV infection
Acute HIV Syndrome
(Acute RetroviralS~)
Clinical latency*
constitutional
symptoms
Plasma viremia
AIDS
very
early disease
early disease
advanced disease
* high rate of replication
in lymphoid tissue
steady state
14
HIV disease progression
Relative control of HIV: viral set points
15Year 1
Predictor for:
•Disease progression
•Risk of transmission
Low set point = slower
disease progression
(Long term/non progressors)
High set point = faster
disease progression
More rapid CD4 fall
•Viral loadof a person infected withHIV, which
stabilizes after a period of acute HIV infection
(<3 years,<5%)
(7-10 years,90%)
(>15-20year,10%)
Typical progressors
15Year 1
Predictor for:
•Disease progression
•Risk of transmission
Low set point = slower
disease progression
(Long term/non progressors)
High set point = faster
disease progression
More rapid CD4 fall
•Viral loadof a person infected withHIV, which
stabilizes after a period of acute HIV infection
(<3 years,<5%)
(7-10 years,90%)
(>15-20year,10%)
Typical progressors
Mechanisms of HIV pathogenesis
•Direct injury[Inflammation, hypersensitivity/Autoimmunity]
–Nervous (encephalopathy and peripheral neuropathy)
–Kidney (HIVAN = HIV-associated nephropathy)
–Cardiac (HIV cardiomyopathy)
–Endocrine (hypogonadism in both sexes)
–GI tract (dysmotility and malabsorption)
•Indirect injury
–Opportunistic infections and tumors as a consequence of
immunosuppression
16
•Direct injury[Inflammation, hypersensitivity/Autoimmunity]
–Nervous (encephalopathy and peripheral neuropathy)
–Kidney (HIVAN = HIV-associated nephropathy)
–Cardiac (HIV cardiomyopathy)
–Endocrine (hypogonadism in both sexes)
–GI tract (dysmotility and malabsorption)
•Indirect injury
–Opportunistic infections and tumors as a consequence of
immunosuppression
16
1.Cellular activation
•HIV induces immune activation
–Which may seem paradoxical because HIV ultimately
results in severe immunosuppression
•Activated T-cells support HIV replication
–Intercurrent infections are associated with transient
increases in viremia
–The magnitude of this increase correlates inversely with
stage of HIV disease
–Accounts for why TB worsens underlying HIV disease
17
•HIV induces immune activation
–Which may seem paradoxical because HIV ultimately
results in severe immunosuppression
•Activated T-cells support HIV replication
–Intercurrent infections are associated with transient
increases in viremia
–The magnitude of this increase correlates inversely with
stage of HIV disease
–Accounts for why TB worsens underlying HIV disease
17
2.Cytokine dysregulation
•HIV is associated with increased expression of pro-
inflammatory cytokines
–TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma
–Responsible for up-regulation of HIV replication
•HIV results in disruption and loss of immunoregulatory
cytokines
–IL-2, IL-12
–Necessary for modulating effective cell-mediated immune responses
(Cytotoxic T Lymphocytes and natural killer cells)
18
•HIV is associated with increased expression of pro-
inflammatory cytokines
–TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma
–Responsible for up-regulation of HIV replication
•HIV results in disruption and loss of immunoregulatory
cytokines
–IL-2, IL-12
–Necessary for modulating effective cell-mediated immune responses
(Cytotoxic T Lymphocytes and natural killer cells)
18
3.Immune dysfunction
•All elements of immune system are affected
•Advanced stages of HIV are associated with
substantial disruption of lymphoid tissue
Impaired ability to mount immune response to new
antigen
Impaired ability to maintain memory responses
Loss of containment of HIV replication
Susceptibility to opportunistic infections
19
•All elements of immune system are affected
•Advanced stages of HIV are associated with
substantial disruption of lymphoid tissue
Impaired ability to mount immune response to new
antigen
Impaired ability to maintain memory responses
Loss of containment of HIV replication
Susceptibility to opportunistic infections
19
4.Cell-mediated immune dysfunction
•Inability to respond to intracellular infections
and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
As the CD4 count declines over time, patients will develop
opportunistic infections
•Develop in a sequence predictable according to CD4 count
20
•Inability to respond to intracellular infections
and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
As the CD4 count declines over time, patients will develop
opportunistic infections
•Develop in a sequence predictable according to CD4 count
20
21
CD4 t-cell count and disease progression
CD4 t-cell count and disease progression
22
Clinical presentation of
HIV/AIDS
Clinical presentation of
HIV/AIDS
WHO clinical staging
•Stage I -asymptomatic
•Stage II -mild disease
•Stage III -moderate disease
•Stage IV -advanced immunocompromise
23
HIV disease staging
To assess disease severity, and to monitor disease progression
T-staging:
Staging while on ART to asses progress or response.
Up and down staging is possible .
Guides when to change treatment
•Stage I -asymptomatic
•Stage II -mild disease
•Stage III -moderate disease
•Stage IV -advanced immunocompromise
23
HIV disease staging
To assess disease severity, and to monitor disease progression
T-staging:
Staging while on ART to asses progress or response.
Up and down staging is possible .
Guides when to change treatment
WHO Clinical Stage I
•Asymptomatic or persistent generalized lymphadenopathy
(PGL)
Bilaterally swollen lymph nodes in accessible areas.
Usually not painful (“Rule of 1,2,3”>1cm,>2 sites, >3 months)
Performance scale 1: able to carry on normal activity.
24
•Asymptomatic or persistent generalized lymphadenopathy
(PGL)
Bilaterally swollen lymph nodes in accessible areas.
Usually not painful (“Rule of 1,2,3”>1cm,>2 sites, >3 months)
Performance scale 1: able to carry on normal activity.
24
WHO Clinical Stage II
•Moderate unexplained weight loss
(<10% of presumed or measured
body weight)
•Recurrent upper respiratory tract
infections
•Herpes zoster
•Papular pruritic eruptions
•Seborrheic dermatitis
•Fungal fingernail infections
•Angular cheilitis
•Recurrent oral ulcerations
25
•Performance scale 2: symptomatic, able to carryout normal activity
with effort, unable to do active work, requires occasional assistance but is
able to care for most needs.
•Moderate unexplained weight loss
(<10% of presumed or measured
body weight)
•Recurrent upper respiratory tract
infections
•Herpes zoster
•Papular pruritic eruptions
•Seborrheic dermatitis
•Fungal fingernail infections
•Angular cheilitis
•Recurrent oral ulcerations
25
•Performance scale 2: symptomatic, able to carryout normal activity
with effort, unable to do active work, requires occasional assistance but is
able to care for most needs.
WHO Clinical Stage II
26
Courtesy of Dr. R. Ojoh, www.thachers.org
Seborrheic dermatitis (dandruff)
Apthous Ulcer
Pruritic papular eruption
26
Courtesy of Dr. R. Ojoh, www.thachers.org
Seborrheic dermatitis (dandruff)
Apthous Ulcer
Pruritic papular eruption
Dermatomal Herpes (Varicella) Zoster
27
Image courtesy of Tom Thacher, MD
WHO Clinical Stage II
27
Image courtesy of Tom Thacher, MD
WHO Clinical Stage II
WHO Stage III
Conditions where a presumptive diagnosis can be made
on the basis of clinical signs or simple investigations
•Severe weight loss (>10% of presumed or measured body
weight)
•Unexplained chronic diarrhoea for longer than one month
•Unexplained persistent fever (intermittent or constant for longer
than one month)
•Persistent Oral candidiasis
•Oral hairy leukoplakia
•Pulmonary tuberculosis (TB)
•Severe bacterial infections (e.g. pneumonia, empyema,
pyomyositis, bone or joint infection, meningitis, bacteraemia)
•Acute necrotizing ulcerative stomatitis, gingivitis or
periodontitis
28
Conditions where a presumptive diagnosis can be made
on the basis of clinical signs or simple investigations
•Severe weight loss (>10% of presumed or measured body
weight)
•Unexplained chronic diarrhoea for longer than one month
•Unexplained persistent fever (intermittent or constant for longer
than one month)
•Persistent Oral candidiasis
•Oral hairy leukoplakia
•Pulmonary tuberculosis (TB)
•Severe bacterial infections (e.g. pneumonia, empyema,
pyomyositis, bone or joint infection, meningitis, bacteraemia)
•Acute necrotizing ulcerative stomatitis, gingivitis or
periodontitis
28
Oral hairy leukoplakia
29
Oral candidiasis
29
Oral candidiasis
WHO Stage III …
•Conditions where confirmatory diagnostic testing
is necessary:
•Unexplained anaemia (<8 g/dl), and or
•Neutropenia (<500/mm
3
) and or
•Thrombocytopenia (<50 000/ mm
3
) for more than one month
•Performance scale 3: bedridden more than normal, but <
50% of the day during last month
30
•Conditions where confirmatory diagnostic testing
is necessary:
•Unexplained anaemia (<8 g/dl), and or
•Neutropenia (<500/mm
3
) and or
•Thrombocytopenia (<50 000/ mm
3
) for more than one month
•Performance scale 3: bedridden more than normal, but <
50% of the day during last month
30
WHO Stage IV
•HIV wasting syndrome
•Pneumocystis pneumonia
•Recurrent severe bacterial pneumonia
•Oesophageal candidiasis (or candidiasis of trachea,
bronchi or lung)
•Extrapulmonary TB
•Kaposi’s sarcoma
•Cytomegalovirus infection (retinitis or infection of organs
other than liver, spleen or lymph nodes)
31
•HIV wasting syndrome
•Pneumocystis pneumonia
•Recurrent severe bacterial pneumonia
•Oesophageal candidiasis (or candidiasis of trachea,
bronchi or lung)
•Extrapulmonary TB
•Kaposi’s sarcoma
•Cytomegalovirus infection (retinitis or infection of organs
other than liver, spleen or lymph nodes)
31
Wasting syndrome
32
© ITECH India, 2005
Weight loss >10% body weight
plus
Unexplained chronic diarrhea
(>1 month) or
Unexplained fever (>1 month)
plus chronic weakness
32
© ITECH India, 2005
Weight loss >10% body weight
plus
Unexplained chronic diarrhea
(>1 month) or
Unexplained fever (>1 month)
plus chronic weakness
Kaposi’s Sarcoma (KS)
•Usually, multiple dark
raised lesions
•Lesions themselves
are not itchy and
are rarely painful
33
Courtesy of Tom Thacher, MD
•Usually, multiple dark
raised lesions
•Lesions themselves
are not itchy and
are rarely painful
33
Courtesy of Tom Thacher, MD
Esophageal Candidiasis
•HIV infected patient
with oral candidiasis
and chest (sub-sternal)
pain with swallowing
has presumed Candida
esophagitis
•Endoscopy would
prove the diagnosis
but is unnecessary if the patient responds to antifungal therapy
34
•HIV infected patient
with oral candidiasis
and chest (sub-sternal)
pain with swallowing
has presumed Candida
esophagitis
•Endoscopy would
prove the diagnosis
but is unnecessary if the patient responds to antifungal therapy
34
WHO Stage IV …
•Central nervous system (CNS) toxoplasmosis
•HIV encephalopathy
•Disseminated non-tuberculous mycobacteria infection
•Progressive multifocal leukoencephalopathy (PML)
•Dessiminate mycosis (extra-pulmunary Histoplasmosis
etc.)
•Chronic herpes simplex infection (orolabial, genital or
anorectal of more than one month’s duration)
•Chronic Cryptosporidiosis
•Chronic Isosporiasis
35
•Central nervous system (CNS) toxoplasmosis
•HIV encephalopathy
•Disseminated non-tuberculous mycobacteria infection
•Progressive multifocal leukoencephalopathy (PML)
•Dessiminate mycosis (extra-pulmunary Histoplasmosis
etc.)
•Chronic herpes simplex infection (orolabial, genital or
anorectal of more than one month’s duration)
•Chronic Cryptosporidiosis
•Chronic Isosporiasis
35
Severe chronic herpes simplex ulcers
36
WHO Stage IV …
36
WHO Stage IV …
WHO Stage IV…
•Recurrent septicemia
•Extrapulmonary cryptococcosis including meningitis
•Lymphoma (cerebral or B cell nonHodgkins)
•Invasive cervical cancers
•Atypical disseminated Leishmaniasis
•Symptomatic HIV associated nephropathy or cardiomayopathy
Performance Scale 4: bedridden > 50% of the day during the
last month
37
•Recurrent septicemia
•Extrapulmonary cryptococcosis including meningitis
•Lymphoma (cerebral or B cell nonHodgkins)
•Invasive cervical cancers
•Atypical disseminated Leishmaniasis
•Symptomatic HIV associated nephropathy or cardiomayopathy
Performance Scale 4: bedridden > 50% of the day during the
last month
37
Disseminated cutaneous cryptococcosis
38
38
Diagnosis of HIV/AIDS
A.Clinical:
HIV/AIDS can manifest with a spectrum of illnesses and diseases as a
result of the:
1.Direct effect of HIV infection:
[Inflammation, hypersensitivity/Autoimmunity];
Encephalopathy, cardiomyopathy, enteropathy, nephropathy,….
2. Indirect effects:
Opportunistic diseases
Drug related
Psychological
These manifestations, with lab. abnormalities, are used for disease
classification and staging.
39
A.Clinical:
HIV/AIDS can manifest with a spectrum of illnesses and diseases as a
result of the:
1.Direct effect of HIV infection:
[Inflammation, hypersensitivity/Autoimmunity];
Encephalopathy, cardiomyopathy, enteropathy, nephropathy,….
2. Indirect effects:
Opportunistic diseases
Drug related
Psychological
These manifestations, with lab. abnormalities, are used for disease
classification and staging.
39
Diagnosis …
B.LaboratoryFindings:
Specifictests:antibodyandantigendetection.
ConventionalHIVantibodytestingisdonebyELISA.
Westernblot:confirmatoryforpositivespecimens
Thesensitivityofscreeningserologictestsisgreaterthan
99.5%.
Thespecificityofpositiveresultsbytwodifferent
techniquesapproaches100%eveninlow-riskpopulations.
Antibodiesthataredetectablebyscreeningserologictests
willdevelopin95%ofpersonswithin6weeksafter
infection.
40
B.LaboratoryFindings:
Specifictests:antibodyandantigendetection.
ConventionalHIVantibodytestingisdonebyELISA.
Westernblot:confirmatoryforpositivespecimens
Thesensitivityofscreeningserologictestsisgreaterthan
99.5%.
Thespecificityofpositiveresultsbytwodifferent
techniquesapproaches100%eveninlow-riskpopulations.
Antibodiesthataredetectablebyscreeningserologictests
willdevelopin95%ofpersonswithin6weeksafter
infection.
40
Diagnosis …
Test
ELISA
Western blot
HIV rapid antibody test
Significance
Screening test for HIV infection.
50% are positive within 22 days
95% are positive within 6 weeks.
Sensitivity > 99.9%;
Must be confirmed with Western blot.
Confirmatory test for HIV.
> 99.99% specificity if combined with ELISA;
Indeterminate results with early HIV infection,
HIV-2 infection, autoimmune disease,
pregnancy, and immunization.
Screening test for HIV.
Produces results in 10-20 minutes.
Can be performed by personnel with limited
training.
Positive results must be confirmed with ELISA
and Western blot.
41
Test
ELISA
Western blot
HIV rapid antibody test
Significance
Screening test for HIV infection.
50% are positive within 22 days
95% are positive within 6 weeks.
Sensitivity > 99.9%;
Must be confirmed with Western blot.
Confirmatory test for HIV.
> 99.99% specificity if combined with ELISA;
Indeterminate results with early HIV infection,
HIV-2 infection, autoimmune disease,
pregnancy, and immunization.
Screening test for HIV.
Produces results in 10-20 minutes.
Can be performed by personnel with limited
training.
Positive results must be confirmed with ELISA
and Western blot.
41
Diagnosis…
Test
Absolute CD4 lymphocyte
count and CD4 lymphocyte
percentage.
HIV viral load tests
Significance
Predictor of HIV progression.
Percentage may be more reliable
than the absolute CD4 count.
Risk of progression to an AIDS is
high with CD4 < 200 cells/µL or
CD4 % < 20 in the absence of
treatment.
Measure the amount of actively
replicating HIV virus.
Correlate with disease progression
and response to antiretroviral drugs.
Diagnostic for acute HIV infection
(prior to seroconversion).
42
Test
Absolute CD4 lymphocyte
count and CD4 lymphocyte
percentage.
HIV viral load tests
Significance
Predictor of HIV progression.
Percentage may be more reliable
than the absolute CD4 count.
Risk of progression to an AIDS is
high with CD4 < 200 cells/µL or
CD4 % < 20 in the absence of
treatment.
Measure the amount of actively
replicating HIV virus.
Correlate with disease progression
and response to antiretroviral drugs.
Diagnostic for acute HIV infection
(prior to seroconversion).
42
Diagnosis…
Nonspecific laboratory findings with HIV infection
may include :
Anemia, leukopenia (particularly lymphopenia), and
thrombocytopenia in any combination
Elevated ESR
Polyclonal hypergammaglobulinemia.
43
Nonspecific laboratory findings with HIV infection
may include :
Anemia, leukopenia (particularly lymphopenia), and
thrombocytopenia in any combination
Elevated ESR
Polyclonal hypergammaglobulinemia.
43
Diagnosis …
False negative results may result from:
Window period
Agammaglobulinemia
Seroreversion (loss of HIV antibodies due to extreme
immune system destruction) in late disease
Technical error
Type N or O strains, or HIV-2
False positive results may result from:
Autoantibodies e.g., SLE
HIV vaccines
Technical error
44
False negative results may result from:
Window period
Agammaglobulinemia
Seroreversion (loss of HIV antibodies due to extreme
immune system destruction) in late disease
Technical error
Type N or O strains, or HIV-2
False positive results may result from:
Autoantibodies e.g., SLE
HIV vaccines
Technical error
44
Anti-retroviral therapy (ART)
45
45
46
Pre-Cautions to be taken before
starting ART !!
Time is needed to:
•EducatepatientaboutART,
•Identifypotentialadherencebarriers
•Addressemergencyinfectionsand/or
conditions
Pre-Cautions to be taken before
starting ART !!
Time is needed to:
•EducatepatientaboutART,
•Identifypotentialadherencebarriers
•Addressemergencyinfectionsand/or
conditions
Convincing Patients
•Educate patients on the reasons that ART is not always an
emergency
•ART has side effects
•There is potential for resistance development
•ART is not an emergency except PEP, i.e., HIV does not progress
overnight to AIDS or from AIDS to death
47
•Educate patients on the reasons that ART is not always an
emergency
•ART has side effects
•There is potential for resistance development
•ART is not an emergency except PEP, i.e., HIV does not progress
overnight to AIDS or from AIDS to death
47
Initiating ART
48
48
What is HAART (ART)?
•HAART = Highly Active Antiretroviral Therapy
•The HAART and ART acronyms may be used interchangeably
•ART is not a cure. ART cannot eliminate HIV completely
•ART includes at least three compatible antiretroviral agents
•Treatment:
•Controls HIV
•Allows the body to rebuild its immune system (its ability to fight
infections)
•Reduces the chance that a mother will pass HIV to her baby during
pregnancy, birth or breastfeeding
•If treatment is stopped, the virus will start replicating
49
•HAART = Highly Active Antiretroviral Therapy
•The HAART and ART acronyms may be used interchangeably
•ART is not a cure. ART cannot eliminate HIV completely
•ART includes at least three compatible antiretroviral agents
•Treatment:
•Controls HIV
•Allows the body to rebuild its immune system (its ability to fight
infections)
•Reduces the chance that a mother will pass HIV to her baby during
pregnancy, birth or breastfeeding
•If treatment is stopped, the virus will start replicating
49
Goals of ART
1.Clinical goal
•Prolong and improve quality of life
2.Virological goal
•Reduce viral load
•HIV RNA < 50 copies/mL or “undetectable” within 4-6 months
of ART initiation is good achievement
3.Immunologic goal
•Immune reconstitution(quantitative (CD4) & qualitative(pathogen
specific immune response))
•Increase in CD4 count of 50 to 150cells/mm
3
/year
4.Therapeutic goal
•Maintain treatment options
5.Epidemiological goal
•Reduce HIV transmission
50
1.Clinical goal
•Prolong and improve quality of life
2.Virological goal
•Reduce viral load
•HIV RNA < 50 copies/mL or “undetectable” within 4-6 months
of ART initiation is good achievement
3.Immunologic goal
•Immune reconstitution(quantitative (CD4) & qualitative(pathogen
specific immune response))
•Increase in CD4 count of 50 to 150cells/mm
3
/year
4.Therapeutic goal
•Maintain treatment options
5.Epidemiological goal
•Reduce HIV transmission
50
When to initiate
51
Ethiopian ART guideline 2014
•Children <15 years: All children with HIV infection regardless
of CD4 count and WHO clinical stage.
51
Ethiopian ART guideline 2014
•Children <15 years: All children with HIV infection regardless
of CD4 count and WHO clinical stage.
When to initiate (WHO 2015)
52
52
What to initiate
•Combination of at least 3 drugs, usually:
2 NRTIs
and
1 NNRTI or 1-2 PIs
Rarely Triple NRTIs
•Therapy with only one or two agents allows HIV to
overcome therapy through resistance mutations
•Treatment regimen is developed based on:
Efficacy, maintaining therapeutic options for future,
Safety and tolerability
Convenience for patient, realistic in terms of probability of adherence,
Availability
53
•Combination of at least 3 drugs, usually:
2 NRTIs
and
1 NNRTI or 1-2 PIs
Rarely Triple NRTIs
•Therapy with only one or two agents allows HIV to
overcome therapy through resistance mutations
•Treatment regimen is developed based on:
Efficacy, maintaining therapeutic options for future,
Safety and tolerability
Convenience for patient, realistic in terms of probability of adherence,
Availability
53
54
What to initiate…
What to initiate…
HIV drug targets
55
55
Nucleoside reverse transcriptase inhibitors (NRTIs)
•Lamivudine (3TC)
•Stavudine (d4T)
•Zidovudine (ZDV, AZT)
•Didanosine (ddI)
•Tenofovir (TDF)
•Abacavir (ABC)
•Emtricitabine (FTC)
56
•Lamivudine (3TC)
•Stavudine (d4T)
•Zidovudine (ZDV, AZT)
•Didanosine (ddI)
•Tenofovir (TDF)
•Abacavir (ABC)
•Emtricitabine (FTC)
56
Zidovudine (AZT or ZDV)
1.Dosing: 300mg BID
•Reduce ZDV dose for patients with renal compromise
and hepatic failure
•Metabolized by liver to 5’-glucuronyl zidovudine, which is
renally excreted.
2.Food interactions
•None –with or without food is ok
•Food decreases ZDV-related nausea
57
1.Dosing: 300mg BID
•Reduce ZDV dose for patients with renal compromise
and hepatic failure
•Metabolized by liver to 5’-glucuronyl zidovudine, which is
renally excreted.
2.Food interactions
•None –with or without food is ok
•Food decreases ZDV-related nausea
57
Zidovudine…
3.Drug interactions
•Avoid use with:
•D4T (competitive antagonism)
•Compete for activation by thymidine kinase.
•Other bone marrow suppressing drugs
•TMP/SMX
•Pyrimethamine
•Ganciclovir
•Dapsone
•Sulfadiazine
•Amphotericin B
58
3.Drug interactions
•Avoid use with:
•D4T (competitive antagonism)
•Compete for activation by thymidine kinase.
•Other bone marrow suppressing drugs
•TMP/SMX
•Pyrimethamine
•Ganciclovir
•Dapsone
•Sulfadiazine
•Amphotericin B
58
Zidovudine …
4.Toxicity
1.Nausea
2.Bone marrow suppression
•Anemia(fatigue)(1-2weeks)
Monitor Hgb
•Headache
•Thrombocytopenia(low platelet count)(4-6months)
•Neutropenia(low white blood cell [neutrophils] count)
59
4.Toxicity
1.Nausea
2.Bone marrow suppression
•Anemia(fatigue)(1-2weeks)
Monitor Hgb
•Headache
•Thrombocytopenia(low platelet count)(4-6months)
•Neutropenia(low white blood cell [neutrophils] count)
59
Zidovudine…
4.Toxicity….
•Myalgia
•Myopathy
•Insomnia
•Pigmentation of nail beds
•Lactic acidosis, fatty liver
60
With increased LDH (Lactic acid dehydrogenase)
and CPK (Creatine phosphokinase)
•Improved within 2-4 weeks
4.Toxicity….
•Myalgia
•Myopathy
•Insomnia
•Pigmentation of nail beds
•Lactic acidosis, fatty liver
60
With increased LDH (Lactic acid dehydrogenase)
and CPK (Creatine phosphokinase)
•Improved within 2-4 weeks
Lamivudine (3TC)
1.Dosing: 150mg BID or 300mg QD
•Reduce dose with renal compromise
2.Food Interactions:
•No food interactions
3.Toxicity:
•Very rare
•Headache
•Occasional nausea
•Lactic acidosis, fatty liver
•The safest ever known ART
61
1.Dosing: 150mg BID or 300mg QD
•Reduce dose with renal compromise
2.Food Interactions:
•No food interactions
3.Toxicity:
•Very rare
•Headache
•Occasional nausea
•Lactic acidosis, fatty liver
•The safest ever known ART
61
Lamivudine (3TC)
4.Resistance
•Low barrier to resistance: a single point mutation (M184V) is
sufficient for loss of effectiveness
•Advantages of the M184V mutation:
•Improves the susceptibility of certain ZDV-resistant viruses in
some patients
•Impairs viral fitness
•Appears to increase susceptibility to D4t
•Keeping 3TC as part of a combination despite proven resistance is
therefore sensible because this drug will continue reduce the
replicative capacity of HIV
62
4.Resistance
•Low barrier to resistance: a single point mutation (M184V) is
sufficient for loss of effectiveness
•Advantages of the M184V mutation:
•Improves the susceptibility of certain ZDV-resistant viruses in
some patients
•Impairs viral fitness
•Appears to increase susceptibility to D4t
•Keeping 3TC as part of a combination despite proven resistance is
therefore sensible because this drug will continue reduce the
replicative capacity of HIV
62
Stavudine (d4T)
1.Dosing
•30 mg BID
•Reduce dose in patients with renal compromise
2.Food Interactions:
•None
3.Toxicity
•Peripheral Neuropathy (5-15%, pain, tingling, and
numbness in extremities –Stop drug
•Within 2 to 6 months of starting theray
•Removed from guidelines recently
63
1.Dosing
•30 mg BID
•Reduce dose in patients with renal compromise
2.Food Interactions:
•None
3.Toxicity
•Peripheral Neuropathy (5-15%, pain, tingling, and
numbness in extremities –Stop drug
•Within 2 to 6 months of starting theray
•Removed from guidelines recently
63
Stavudine…
3.Toxicities
•Lipoatrophy
•Lactic acidosis, fatty liver
•Pancreatitis (do not re-
challenge)
•Hypertriglyceridemia
4.Drug interactions
•Do NOT use with ZDV
(competitive antagonism)
•Use with caution: Other ‘D’
drugs, INH, phenytoin,
ethambutol
64
3.Toxicities
•Lipoatrophy
•Lactic acidosis, fatty liver
•Pancreatitis (do not re-
challenge)
•Hypertriglyceridemia
4.Drug interactions
•Do NOT use with ZDV
(competitive antagonism)
•Use with caution: Other ‘D’
drugs, INH, phenytoin,
ethambutol
64
Facial lipoatrophy
•Discontinue the offending agent and use an alternate
medication
•Facial wasting is usually not reversible
65
•Discontinue the offending agent and use an alternate
medication
•Facial wasting is usually not reversible
65
Didanosine (ddI)
1.Dosing
•1 x 400mg enteric coated capsule QD (if <60kg: 250mg
QD)
or
•2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg:
125 mg BID or 250mg QD)
•NOTE: If using buffered tablets, 2 or more tablets must be used at each
dose to provide adequate buffer(need basic environment).
or
•250mg reconstituted buffered powder BID (if <60kg:
167mg BID)
66
1.Dosing
•1 x 400mg enteric coated capsule QD (if <60kg: 250mg
QD)
or
•2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg:
125 mg BID or 250mg QD)
•NOTE: If using buffered tablets, 2 or more tablets must be used at each
dose to provide adequate buffer(need basic environment).
or
•250mg reconstituted buffered powder BID (if <60kg:
167mg BID)
66
Didanosine…
2.Food Interactions: take on empty stomach
•If taken with tenofovir (TDF), can take with or without food
•Reduce dose to 250 mg qd with tenofovir (inhibit purine nucleotide phosphorylase)
3.Drug interactions
•Alcohol: risk of pancreatitis
•Other ‘D’ drugs: risk of peripheral neuropathy, pancreatitis
•Drugs that require gastric acidity for absorption:
ketoconazole
•INH: risk of peripheral neuropathy
67
2.Food Interactions: take on empty stomach
•If taken with tenofovir (TDF), can take with or without food
•Reduce dose to 250 mg qd with tenofovir (inhibit purine nucleotide phosphorylase)
3.Drug interactions
•Alcohol: risk of pancreatitis
•Other ‘D’ drugs: risk of peripheral neuropathy, pancreatitis
•Drugs that require gastric acidity for absorption:
ketoconazole
•INH: risk of peripheral neuropathy
67
Didanosine…
4.Toxicity
•Peripheral Neuropathy (5-12%) (2 to 6 months )
•Stop DDI or reduce dose to 250mg QD for patients that
develop peripheral neuropathy
•GI intolerance
•Pancreatitis (7%, fatal in 2%) (do not re-challenge)
•Lactic acidosis, fatty liver
68
4.Toxicity
•Peripheral Neuropathy (5-12%) (2 to 6 months )
•Stop DDI or reduce dose to 250mg QD for patients that
develop peripheral neuropathy
•GI intolerance
•Pancreatitis (7%, fatal in 2%) (do not re-challenge)
•Lactic acidosis, fatty liver
68
Tenofovir disoproxil fumarate (TDF)
•Actually, a nucleoTIDE
1.Dosing: 1 x 300mg tablet QD
•Reduce dose with renal compromise
2.Active against Hepatitis B
•Dosed 300mg QD
3.Food interactions:
•Can be taken with or without food
•Bioavailability improves with food, especially high-
fat meals.
69
•Actually, a nucleoTIDE
1.Dosing: 1 x 300mg tablet QD
•Reduce dose with renal compromise
2.Active against Hepatitis B
•Dosed 300mg QD
3.Food interactions:
•Can be taken with or without food
•Bioavailability improves with food, especially high-
fat meals.
69
Tenofovir Disoproxil Fumarate…
4.Drug interactions:
•TDF increases DDI levels (AUC levels by 40%-60%)
•TDF reduces ATZ levels(Combine ATZ with RTV)
•LPV/r increases TDF levels 30%, no dosage adjustment is necessary
5.Toxicity
•Very well tolerated, side effects are minimal
•Headache
•Nausea, diarrhea
•Lactic acidosis, fatty liver
•Renal insufficiency (rare)
•Reduce bone mineral density (rare)
70
4.Drug interactions:
•TDF increases DDI levels (AUC levels by 40%-60%)
•TDF reduces ATZ levels(Combine ATZ with RTV)
•LPV/r increases TDF levels 30%, no dosage adjustment is necessary
5.Toxicity
•Very well tolerated, side effects are minimal
•Headache
•Nausea, diarrhea
•Lactic acidosis, fatty liver
•Renal insufficiency (rare)
•Reduce bone mineral density (rare)
70
Abacavir (ABC)
1.Dosing: 1 x 300mg tablet BID or 600 mg QD
2.Food Interactions:
•No food interactions
•No dose adjustment for renal failure
3.Toxicity
•Hypersensitivity (appear 1-2 weeks after initiation)
•Occurs up to 6 weeks of therapy
•GI intolerance
•Rash
•Flu-like symptoms
71
1.Dosing: 1 x 300mg tablet BID or 600 mg QD
2.Food Interactions:
•No food interactions
•No dose adjustment for renal failure
3.Toxicity
•Hypersensitivity (appear 1-2 weeks after initiation)
•Occurs up to 6 weeks of therapy
•GI intolerance
•Rash
•Flu-like symptoms
71
Hypersensitivity to Abacavir…
•Observed in
approximately 5%
•Multi-organ system
involvement
•NEVER rechallenge*—
may be fatal
•Most common signs and
symptoms:
•Fever (>80%)
•Rash (maculopapular or urticarial)
(70%)
•Fatigue (>70%)
•Flu-like symptoms (50%)
•GI (nausea, vomiting, diarrhea,
abdominal pain) (50%)
72
•*Re-challenge :hypotension, bronchoconstriction, and/or renal failure and
treatment is supportive with IV fluids, dialysis.
•Steroids and antihistamines are not usually effective.
•Linked to the genetic variant HLA B5701
•About 55% of patients with the reaction are carriers of this SNP
•Observed in
approximately 5%
•Multi-organ system
involvement
•NEVER rechallenge*—
may be fatal
•Most common signs and
symptoms:
•Fever (>80%)
•Rash (maculopapular or urticarial)
(70%)
•Fatigue (>70%)
•Flu-like symptoms (50%)
•GI (nausea, vomiting, diarrhea,
abdominal pain) (50%)
72
•*Re-challenge :hypotension, bronchoconstriction, and/or renal failure and
treatment is supportive with IV fluids, dialysis.
•Steroids and antihistamines are not usually effective.
•Linked to the genetic variant HLA B5701
•About 55% of patients with the reaction are carriers of this SNP
Emtricitabine (FTC)
•Fluorinated version of lamivudine, have reduced toxicity and prolonged half-
life.
1.Dosing: 1 x 200mg capsule QD
•Dose should be reduced for patients with renal compromise
2.Food interactions:
•No food interactions
3.Toxicity
•Mild abdominal discomfort
•Occasional nausea
•Lactic acidosis, fatty liver
73
T1/2: 3-6 hours
Intracellular T1/2: 12 hours
T1/2: 8-9 hours
Intracellular T1/2: >20 hours
Vs.
•Fluorinated version of lamivudine, have reduced toxicity and prolonged half-
life.
1.Dosing: 1 x 200mg capsule QD
•Dose should be reduced for patients with renal compromise
2.Food interactions:
•No food interactions
3.Toxicity
•Mild abdominal discomfort
•Occasional nausea
•Lactic acidosis, fatty liver
73
T1/2: 3-6 hours
Intracellular T1/2: 12 hours
T1/2: 8-9 hours
Intracellular T1/2: >20 hours
Vs.
7474
NRTI class side effects
1.Nausea
2.Headache
3.Peripheral Neuropathy
(D4T/DDI)Vs.HIV
4.Lipoatrophy
5.Pancreatitis (DDI > D4T)
6.Lactic Acidosis, fatty liver
•D4T > DDI > ZDV
•Rare with ABC, TDF, 3TC and
FTC
•All ART, side effects worst during the first 1 to 2 weeks of therapy
•Reassure the patient that most SEs improve over time
NRTI class side effects
1.Nausea
2.Headache
3.Peripheral Neuropathy
(D4T/DDI)Vs.HIV
4.Lipoatrophy
5.Pancreatitis (DDI > D4T)
6.Lactic Acidosis, fatty liver
•D4T > DDI > ZDV
•Rare with ABC, TDF, 3TC and
FTC
•All ART, side effects worst during the first 1 to 2 weeks of therapy
•Reassure the patient that most SEs improve over time
NRTI mitochondrial toxicity
1.Inhibition of
mitochondrial DNA
polymerase-
•oxidative metabolism →
ATP generation
•In vitro D4T/DDI worse than
ZDV/3TC/FTC/ABC
2.Implicated in lactic
acidosis with hepatic
steatosis
3.Other possible
manifestations:
•Neuropathy (D4T, DDI)
•Lipoatrophy (D4T)
•Pancreatitis (DDI)
•Myopathy (ZDV)
•Cardiomyopathy (D4T, ZDV)
75
1.Inhibition of
mitochondrial DNA
polymerase-
•oxidative metabolism →
ATP generation
•In vitro D4T/DDI worse than
ZDV/3TC/FTC/ABC
2.Implicated in lactic
acidosis with hepatic
steatosis
3.Other possible
manifestations:
•Neuropathy (D4T, DDI)
•Lipoatrophy (D4T)
•Pancreatitis (DDI)
•Myopathy (ZDV)
•Cardiomyopathy (D4T, ZDV)
75
Non-nucleoside reverse
transcriptase inhibitors (NNRTIs)
1.Nevirapine (NVP)
2.Efavirenz (EFV)
3.Delavirdine*
4.Etravirine * (ETV)-New drug
76
transcriptase inhibitors (NNRTIs)
1.Nevirapine (NVP)
2.Efavirenz (EFV)
3.Delavirdine*
4.Etravirine * (ETV)-New drug
76
Nevirapine (NVP)
1.Dosing: 200 mg QD x 2 weeks, then 200 mg BID
2.Food Interactions:
•None
3.Pregnancy
•Prevention of perinatal transmission but use is limited
•A single oral dose of 200mg is given at the onset of labor, and a single
dose (2mg/kg) is given to the infant at 48-72 hours.
4.Drug interactions (induces liver enzymes)
•Reduces plasma level of certain drugs (ethinyl estradiol,
ketoconazole, PIs, etc)
5.Toxicity
•Rash (17%)
•Hepatitis (8–18%)
77
1.Dosing: 200 mg QD x 2 weeks, then 200 mg BID
2.Food Interactions:
•None
3.Pregnancy
•Prevention of perinatal transmission but use is limited
•A single oral dose of 200mg is given at the onset of labor, and a single
dose (2mg/kg) is given to the infant at 48-72 hours.
4.Drug interactions (induces liver enzymes)
•Reduces plasma level of certain drugs (ethinyl estradiol,
ketoconazole, PIs, etc)
5.Toxicity
•Rash (17%)
•Hepatitis (8–18%)
77
Moderate rash
78
•Prednisone and antihistamines are not effective in preventing
nevirapine rash, but can be used to treatment itching.
78
•Prednisone and antihistamines are not effective in preventing
nevirapine rash, but can be used to treatment itching.
Severe rash
79
•Severe itching + constitutional
symptoms (fever, myalgia/arthralgia,
conjunctivitis, facial edema, or oral
lesions)
•Blistering/peeling on the skin, or
steven-johnson syndrome (SJS), or
toxic epidermal necrolysis (TEN).
•Can also be accompanied by organ
dysfunction or have rash along with
increased liver function tests.
•Discontinue therapy and do not re-
challenge.
79
•Severe itching + constitutional
symptoms (fever, myalgia/arthralgia,
conjunctivitis, facial edema, or oral
lesions)
•Blistering/peeling on the skin, or
steven-johnson syndrome (SJS), or
toxic epidermal necrolysis (TEN).
•Can also be accompanied by organ
dysfunction or have rash along with
increased liver function tests.
•Discontinue therapy and do not re-
challenge.
Efavirenz (EFV)
1.Dosing: 600mg tablet QHS
2.Food Interactions
•Take with low-fat meal -High-fat meals increase absorption 50%
increases side effects (especially early in therapy)
3.Use in pregnancy including first trimester
•No Known to cause birth defects
4.Drug interactions (induces liver enzymes)
•Changing from a EFV to a PI, may need to increase dose of PI for first
two weeks
80
1.Dosing: 600mg tablet QHS
2.Food Interactions
•Take with low-fat meal -High-fat meals increase absorption 50%
increases side effects (especially early in therapy)
3.Use in pregnancy including first trimester
•No Known to cause birth defects
4.Drug interactions (induces liver enzymes)
•Changing from a EFV to a PI, may need to increase dose of PI for first
two weeks
80
Efavirenz…
4.Toxicity
•CNS Changes (52%), (discontinuation rate 2%-5%)
•Insomnia,
•Nightmares
•Poor concentration
•Mood change
•Dizziness
•Dysequilibrium,
•Depression, and psychosis
•Gynecologic side effects??
•Rash (15-27%),(in the first 2 weeks of therapy)
•Nausea
81
•Onset is usually at start of therapy
andresolves after 2 to 4 weeks.
4.Toxicity
•CNS Changes (52%), (discontinuation rate 2%-5%)
•Insomnia,
•Nightmares
•Poor concentration
•Mood change
•Dizziness
•Dysequilibrium,
•Depression, and psychosis
•Gynecologic side effects??
•Rash (15-27%),(in the first 2 weeks of therapy)
•Nausea
81
•Onset is usually at start of therapy
andresolves after 2 to 4 weeks.
82
NNRTIclass effects
Side effects
•Rash
•EFV > DLV > NVP
•Rate of discontinuation: NVP (7%) > DLV (4.3%) > EFV (1.7%).
•Hepatotoxicity manifested by elevated transaminase
•Frequency and severity (NVP>EFV)
Cross resistance across entire class
•Essentially a one chance class of drugs (K103N mutation)
•Except Etraverine
NNRTIclass effects
Side effects
•Rash
•EFV > DLV > NVP
•Rate of discontinuation: NVP (7%) > DLV (4.3%) > EFV (1.7%).
•Hepatotoxicity manifested by elevated transaminase
•Frequency and severity (NVP>EFV)
Cross resistance across entire class
•Essentially a one chance class of drugs (K103N mutation)
•Except Etraverine
Protease Inhibitors (PI)
•Lopinavir + ritonavir
•Atazanavir*
•Nelfinavir*
•Indinavir*
•Saquinavir-SGC*
•Ritonavir*
•Saquinavir-HGC*
•Amprenavir*
•Fosamprenavir*
•Tipranavir*
83
•Lopinavir + ritonavir
•Atazanavir*
•Nelfinavir*
•Indinavir*
•Saquinavir-SGC*
•Ritonavir*
•Saquinavir-HGC*
•Amprenavir*
•Fosamprenavir*
•Tipranavir*
83
Lopinavir/ritonavir (LPV/r)
1.Dosing: 250mg tabs and BID 500mg BID
•Each tablet contains LPV 200 mg/RTV 50 mg
2.Food Interactions:
•The tablet can be taken without food
3.Toxicity
•Nausea, diarrhea
•Lipid abnormalities
•Hyperglycemia
•Pancreatitis has been reported in adults,(high triglyceride
levels)
4.Tablets can be stored at room temperature
84
1.Dosing: 250mg tabs and BID 500mg BID
•Each tablet contains LPV 200 mg/RTV 50 mg
2.Food Interactions:
•The tablet can be taken without food
3.Toxicity
•Nausea, diarrhea
•Lipid abnormalities
•Hyperglycemia
•Pancreatitis has been reported in adults,(high triglyceride
levels)
4.Tablets can be stored at room temperature
84
Lopinavir/ritonavir…
5.Interactions with other ARVs
•EFV and NVP decrease LPV/r levels
•Increase LPV/r to 4 caps bid or 3 tablets bid
•LPV/r decreases fosamprenavir levels
•This combination is not recommended
85
5.Interactions with other ARVs
•EFV and NVP decrease LPV/r levels
•Increase LPV/r to 4 caps bid or 3 tablets bid
•LPV/r decreases fosamprenavir levels
•This combination is not recommended
85
Atazanavir/ritonavir (ATZ/r)
1.Dosing: 2 x 200mg capsules QD
•Dosed with ritonavir 100mg QD, ATZ dose = 2 x 150mg QD (for PI
experienced patients)
2.Food Interactions: Take with food
3.Toxicity:
•Nausea
•Diarrhea
•Elevated bilirubin
•ATZ:minimal effect on lipid profile and does not induce insulin
resistance
86
1.Dosing: 2 x 200mg capsules QD
•Dosed with ritonavir 100mg QD, ATZ dose = 2 x 150mg QD (for PI
experienced patients)
2.Food Interactions: Take with food
3.Toxicity:
•Nausea
•Diarrhea
•Elevated bilirubin
•ATZ:minimal effect on lipid profile and does not induce insulin
resistance
86
Atazanavir/r …
•ATZ: competitively inhibits the uridine diphosphate-
glucuronosyl transferase (UDP-GT) 1A1 enzyme [catalyzes
conjugation of bilirubin]
•Use in UGT deficiency: hyperbilirubinemia.
•DC ATZ in jaundiced patient (including yellow eyes)
•Hyperbilirubinemia will resolve following discontinuation.
Asymptomatic hyperbilirubinemia (60%)
Grade 3 to 4 bilirubin elevation (40%)
Jaundice (typically occurs with a BiliT= 2 to 4 (6%)
87
•ATZ: competitively inhibits the uridine diphosphate-
glucuronosyl transferase (UDP-GT) 1A1 enzyme [catalyzes
conjugation of bilirubin]
•Use in UGT deficiency: hyperbilirubinemia.
•DC ATZ in jaundiced patient (including yellow eyes)
•Hyperbilirubinemia will resolve following discontinuation.
Asymptomatic hyperbilirubinemia (60%)
Grade 3 to 4 bilirubin elevation (40%)
Jaundice (typically occurs with a BiliT= 2 to 4 (6%)
87
Atazanavir/r …
4.Pregnancy
•Potential for ATZ to cause hyperbilirubinemia in neonates or young infants.
•Do not use in child <3 month
5.Drug interactions
•Inhibits liver enzymes
•If used with RTV, decrease dose to 300 mg qd + RTV 100 mg qd
•TDF decreases ATZ levels
Use boosted ATZ with TDF
•Use boosted ATZ with any NNRTI
•H2 receptor antagonists: separate doses by 12 hours
•Antacids: give ATZ 2 hours before or 1 hour after.
•Estradiol increase AUC 48% and norethindrone increase AUC 110%; use
lowest dose or alternative.
88
4.Pregnancy
•Potential for ATZ to cause hyperbilirubinemia in neonates or young infants.
•Do not use in child <3 month
5.Drug interactions
•Inhibits liver enzymes
•If used with RTV, decrease dose to 300 mg qd + RTV 100 mg qd
•TDF decreases ATZ levels
Use boosted ATZ with TDF
•Use boosted ATZ with any NNRTI
•H2 receptor antagonists: separate doses by 12 hours
•Antacids: give ATZ 2 hours before or 1 hour after.
•Estradiol increase AUC 48% and norethindrone increase AUC 110%; use
lowest dose or alternative.
88
89
PI Class Side Effects
1.Metabolic Disorders
•Hepatotoxicities
•Hyperglycemia, insulin
resistance
•Lipid abnormalities
•Fat redistribution
2.GI intolerance
3.Drug interactions
•Due to CYP450 3A4 Inhibition
4.Bone Disorders
•Avascular necrosis
•Osteoporosis and Osteopenia
PI Class Side Effects
1.Metabolic Disorders
•Hepatotoxicities
•Hyperglycemia, insulin
resistance
•Lipid abnormalities
•Fat redistribution
2.GI intolerance
3.Drug interactions
•Due to CYP450 3A4 Inhibition
4.Bone Disorders
•Avascular necrosis
•Osteoporosis and Osteopenia
PIs induced hepatotoxicity
•RTV use linked to increased risk of severe hepatotoxicity
•Increased LFT’s observed with all PI’s
•More common in patients with chronic viral hepatitis (HBV, HCV)
•Data do not, however, support withholding PI’s from patients co-
infected with HBV or HCV
90
•RTV use linked to increased risk of severe hepatotoxicity
•Increased LFT’s observed with all PI’s
•More common in patients with chronic viral hepatitis (HBV, HCV)
•Data do not, however, support withholding PI’s from patients co-
infected with HBV or HCV
90
9191
Laboratory monitoring: baseline labs,pre ART
•HIV antibody test
•Full blood count and
differential
•AST or ALT
•Serum creatinine or blood
urea nitrogen
•Serum glucose
•Pregnancy tests for
women
•Urine dipstick
•Hep B surface antigen
•Serum amylase (for
patients on D4T or DDI)
•Serum lipids (for patients
with other cardiac risk
factors or to receive PIs or
EFV)
•CD4 lymphocyte count
Laboratory monitoring: baseline labs,pre ART
•HIV antibody test
•Full blood count and
differential
•AST or ALT
•Serum creatinine or blood
urea nitrogen
•Serum glucose
•Pregnancy tests for
women
•Urine dipstick
•Hep B surface antigen
•Serum amylase (for
patients on D4T or DDI)
•Serum lipids (for patients
with other cardiac risk
factors or to receive PIs or
EFV)
•CD4 lymphocyte count
92
ART class advantages vs. disadvantages
ART class advantages vs. disadvantages
Reasons for changing ART
•ART should not be changed unless absolutely
necessary!
•ART may be changed because of:
Treatment Failure
Toxicity or intolerance
Co-morbid conditions
Non-adherence/compromised quality of life
93
•ART should not be changed unless absolutely
necessary!
•ART may be changed because of:
Treatment Failure
Toxicity or intolerance
Co-morbid conditions
Non-adherence/compromised quality of life
93
Treatment failure
•Treatment failure is defined by
1.Clinical failure
2.Immunologic failure
3.Virologic failure
1.Clinical failure
•New or recurrent WHO stage 3/4 condition
Note: Should not be confused with immune
reconstitution inflammatory syndrome
94
•Treatment failure is defined by
1.Clinical failure
2.Immunologic failure
3.Virologic failure
1.Clinical failure
•New or recurrent WHO stage 3/4 condition
Note: Should not be confused with immune
reconstitution inflammatory syndrome
94
Treatment failure…
2.Immunologic failure
•Fall of CD4 count by >50% from the on treatment peak
•Return of the CD4 count to pretherapy baseline or below
•Persistent CD4 levels below 100 cells/mm
3
3.Virologicfailure:
•Reappearance of detectable virus after a period of undetectability (loss of
virologic control)
•Less than one log (10-fold) decrease in viral load from baseline after 8-
12 weeks of ART
•Plasma viral load above 5,000 copies/ml in duplicates after six months
on ART
95
2.Immunologic failure
•Fall of CD4 count by >50% from the on treatment peak
•Return of the CD4 count to pretherapy baseline or below
•Persistent CD4 levels below 100 cells/mm
3
3.Virologicfailure:
•Reappearance of detectable virus after a period of undetectability (loss of
virologic control)
•Less than one log (10-fold) decrease in viral load from baseline after 8-
12 weeks of ART
•Plasma viral load above 5,000 copies/ml in duplicates after six months
on ART
95
Clinical grading of adverse events
96
Item Grade 1Grade 2Grade 3Grade 4
96
Item Grade 1Grade 2Grade 3Grade 4
Toxicity: changing one drug
1.Regimen: AZT/3TC/NVP
•AZT-related anemia or neutropenia : Switch ZDVto TDF loose therapy
•NVP-related rash or hepatotoxicity:
Switch NVP to EFZ
Switch NVP to PI’s (in cases of severe adverse effect)
2.Regimen: AZT/3TC/EFV
•EFZ-related persistent CNS toxicity: Switch EFV to NVP
3.Regimen: TDF/3TC/EFV
•TDF-related renal problem: switch TDF to ABC
97
1.Regimen: AZT/3TC/NVP
•AZT-related anemia or neutropenia : Switch ZDVto TDF loose therapy
•NVP-related rash or hepatotoxicity:
Switch NVP to EFZ
Switch NVP to PI’s (in cases of severe adverse effect)
2.Regimen: AZT/3TC/EFV
•EFZ-related persistent CNS toxicity: Switch EFV to NVP
3.Regimen: TDF/3TC/EFV
•TDF-related renal problem: switch TDF to ABC
97
98
Pharmacotherapy of the common
opportunistic infections
Pharmacotherapy of the common
opportunistic infections
Opportunistic infections
•Infections that develop as a result of damage to the
immune system
•AIDS is characterized by the gradual erosion of immune
competence and the development of OIs and malignancies.
•These infectionstake advantage of the opportunity
provided by a weakened immune system
•Predominant causes of morbidity an mortality
•Tend to appear at predictable stages of immune
deterioration
99
•Infections that develop as a result of damage to the
immune system
•AIDS is characterized by the gradual erosion of immune
competence and the development of OIs and malignancies.
•These infectionstake advantage of the opportunity
provided by a weakened immune system
•Predominant causes of morbidity an mortality
•Tend to appear at predictable stages of immune
deterioration
99
100
Principles of OIs with HIV
1.Caused by defect in cell-mediated immunity, so common
viral and bacterial infections are not increased
•Exceptions: S. pneumoniaeand Salmonella
2.Nearly all OIs were highly responsive to ART
•Exception: PML (progressive multifocal
leukoencephalopathy)
3.Immune Reconstitution Inflammatory Syndrome (IRIS)
•Paradoxical or unmasking illness associated with improving
immunity
•Most common with CD4 <50, following initiation of
effective HAART
•Treatment: continue ART and OI treatment +/-steroids
101
1.Caused by defect in cell-mediated immunity, so common
viral and bacterial infections are not increased
•Exceptions: S. pneumoniaeand Salmonella
2.Nearly all OIs were highly responsive to ART
•Exception: PML (progressive multifocal
leukoencephalopathy)
3.Immune Reconstitution Inflammatory Syndrome (IRIS)
•Paradoxical or unmasking illness associated with improving
immunity
•Most common with CD4 <50, following initiation of
effective HAART
•Treatment: continue ART and OI treatment +/-steroids
101
Pneumocystis carini pneumonia
102
102
Pneumocystis carini pneumonia
Its taxonomy has been changed and
•P.carinii –only infects rats
•P. jirovecii -infects humans
•Most humans infected early in life
103
Its taxonomy has been changed and
•P.carinii –only infects rats
•P. jirovecii -infects humans
•Most humans infected early in life
103
Clinical manifestations
Most common manifestations of PJP
•Sub-acute onset of progressive dyspnoea
•Gradual fever
•Non-productive cough
•Chest discomfort that worsens within days to weeks
Hypoxemia, the most characteristic laboratory
abnormality, can range from
•Mild(room air arterial oxygen [pO2] >70 mm Hg or
alveolar-arterial O2 difference, [A-a] DO2) <35 mm Hg)
to moderate([A-a] DO >35 and <45 mm Hg) to severe
([A-a] DO >45 mm Hg)
104
Most common manifestations of PJP
•Sub-acute onset of progressive dyspnoea
•Gradual fever
•Non-productive cough
•Chest discomfort that worsens within days to weeks
Hypoxemia, the most characteristic laboratory
abnormality, can range from
•Mild(room air arterial oxygen [pO2] >70 mm Hg or
alveolar-arterial O2 difference, [A-a] DO2) <35 mm Hg)
to moderate([A-a] DO >35 and <45 mm Hg) to severe
([A-a] DO >45 mm Hg)
104
Clinical manifestations…
Elevated lactate dehydrogenase
•Almost >500 mg/dl is common but non-specific
Chest radiograph typically demonstrates
•Diffuse, bilateral, symmetrical interstitial infiltrates emanating
from the hila in a butterfly pattern
•May be normal in patients with early disease
•Atypical radiographic presentations
•Nodules, blebs and cysts, asymmetric disease, upper lobe
localization, and pneumothorax.
105
Elevated lactate dehydrogenase
•Almost >500 mg/dl is common but non-specific
Chest radiograph typically demonstrates
•Diffuse, bilateral, symmetrical interstitial infiltrates emanating
from the hila in a butterfly pattern
•May be normal in patients with early disease
•Atypical radiographic presentations
•Nodules, blebs and cysts, asymmetric disease, upper lobe
localization, and pneumothorax.
105
Diagnosis
•Diagnosis via induced sputum or bronchoalveolar
lavage (bronchoscopy)
•Histopathologic or cytopathologic demonstration of organisms in
tissue, bronchoalveolar lavage (BAL) fluid, or induced sputum
samples is required for a definitive diagnosis.
•Polymerase chain reaction (PCR) is an emerging method for
diagnosing PCP.
•Treatment can be initiated before making a definitive
diagnosis because organisms persist in clinical
specimens for days or weeks after effective therapy is
initiated
106
•Diagnosis via induced sputum or bronchoalveolar
lavage (bronchoscopy)
•Histopathologic or cytopathologic demonstration of organisms in
tissue, bronchoalveolar lavage (BAL) fluid, or induced sputum
samples is required for a definitive diagnosis.
•Polymerase chain reaction (PCR) is an emerging method for
diagnosing PCP.
•Treatment can be initiated before making a definitive
diagnosis because organisms persist in clinical
specimens for days or weeks after effective therapy is
initiated
106
Treatment
:http://aidsinfo.nihgov./guidelines2015 107
:http://aidsinfo.nihgov./guidelines2015 107
Adjunctive corticosteroids
:http://aidsinfo.nihgov./guidelines2015
NB:
No benefit for salvage therapy or mild episodes
Begin within 72 hours of specific antipneumocystis therapy
Use cautiously if diagnosis is not confirmed, and watch for other OIs
108
:http://aidsinfo.nihgov./guidelines2015
NB:
No benefit for salvage therapy or mild episodes
Begin within 72 hours of specific antipneumocystis therapy
Use cautiously if diagnosis is not confirmed, and watch for other OIs
108
PJP Benefit of Corticosteroids
Survival in PCP depends on patient’s level of oxygenation
Adjunctive corticosteroids can have a significant effect
Clinical outcome
Survival
Caution should be taken in treating patients with tuberculosis,
fungal pneumonia, or pulmonary Kaposi's sarcoma
Steroids can have detrimental effect
Vigorous attempts to confirm a diagnosis of PCP should be made rather
than initiating adjunctive corticosteroids empirically
109
Survival in PCP depends on patient’s level of oxygenation
Adjunctive corticosteroids can have a significant effect
Clinical outcome
Survival
Caution should be taken in treating patients with tuberculosis,
fungal pneumonia, or pulmonary Kaposi's sarcoma
Steroids can have detrimental effect
Vigorous attempts to confirm a diagnosis of PCP should be made rather
than initiating adjunctive corticosteroids empirically
109
Primary prophylaxis indications
http://aidsinfo.nihgov./guidelines2015
110
http://aidsinfo.nihgov./guidelines2015
110
Secondary prophylaxis
:http://aidsinfo.nihgov./guidelines2015
111
:http://aidsinfo.nihgov./guidelines2015
111
Toxoplasmosis
112
112
Toxoplasmosis
The two major routes of transmission
•Oral
•Congenital.
•Seroprevalence of anti-Toxoplasma antibody varies
substantially among different geographic locales
Ethiopia reaches 80%???
United States 11%
50% to 80% in certain European, Latin American, and
African countries.
113
The two major routes of transmission
•Oral
•Congenital.
•Seroprevalence of anti-Toxoplasma antibody varies
substantially among different geographic locales
Ethiopia reaches 80%???
United States 11%
50% to 80% in certain European, Latin American, and
African countries.
113
Toxoplasmosis
•The incidence is low in seronegativepatients
•In truly seronegatives,Toxoplasmosis could be due to
1.Primary infection
2.Re-activation of latent disease in individuals who cannot
produce detectable antibodies, or
3.Testing with insensitive assays
114
•The incidence is low in seronegativepatients
•In truly seronegatives,Toxoplasmosis could be due to
1.Primary infection
2.Re-activation of latent disease in individuals who cannot
produce detectable antibodies, or
3.Testing with insensitive assays
114
Toxoplasmosis
•Appears to occur exclusively because of reactivationof latent
tissue cysts.
•With CD4 <100mm
3
& focal neurologicsigns, cerebral
toxoplasmosis isthe most likely diagnosis
•Primary infection occasionally is associated with acute
cerebral or disseminated disease
115
•Appears to occur exclusively because of reactivationof latent
tissue cysts.
•With CD4 <100mm
3
& focal neurologicsigns, cerebral
toxoplasmosis isthe most likely diagnosis
•Primary infection occasionally is associated with acute
cerebral or disseminated disease
115
Clinical manifestations
•Most common clinical presentation
Focal encephalitis with headache, confusion, or motor weakness
and fever
•Non-focal manifestations, including only non-specific headache and
psychiatric symptoms
•Disease progression results in seizures, stupor, and coma.
•Can manifest as a single brain lesion or diffuse encephalitis
without evidence of focal brain lesions on imaging studies
•This latter presentation tends to be rapidly progressive
and fatal.
116
•Most common clinical presentation
Focal encephalitis with headache, confusion, or motor weakness
and fever
•Non-focal manifestations, including only non-specific headache and
psychiatric symptoms
•Disease progression results in seizures, stupor, and coma.
•Can manifest as a single brain lesion or diffuse encephalitis
without evidence of focal brain lesions on imaging studies
•This latter presentation tends to be rapidly progressive
and fatal.
116
Diagnosis
CT or MRI of the brain
•Multiple lesions usually ring-enhancing and have a predilection
for the basal ganglia [in the grey matter of the cortex or basal
ganglia], often with associated oedema.
•MRI more sensitive
•HIV patients are almost uniformly seropositive for
anti-toxoplasma IgG antibodies.
Definitive diagnosis requires a compatible clinical
syndrome;
•Identification of one or more mass lesions by CT, MRI, or
•Other radiographic testing
•And detection of the organism in a clinical sample.
117
CT or MRI of the brain
•Multiple lesions usually ring-enhancing and have a predilection
for the basal ganglia [in the grey matter of the cortex or basal
ganglia], often with associated oedema.
•MRI more sensitive
•HIV patients are almost uniformly seropositive for
anti-toxoplasma IgG antibodies.
Definitive diagnosis requires a compatible clinical
syndrome;
•Identification of one or more mass lesions by CT, MRI, or
•Other radiographic testing
•And detection of the organism in a clinical sample.
117
Diagnosis…
Brain biopsy is reserved for patients with:
•Symptoms of encephalitis who are
seronegative and
•Those who do not respond to presumptive
antitoxoplasmosistherapy.
118
Brain biopsy is reserved for patients with:
•Symptoms of encephalitis who are
seronegative and
•Those who do not respond to presumptive
antitoxoplasmosistherapy.
118
119
Diagnosis…
Diagnosis…
Treatment
•The presentation is so characteristicthat many guidelines
suggest routine treatment for toxoplasmosis
•A lack of response to such therapy (symptoms and MRI
changes) within 1-2 weeks indicates other possible conditions:
•Central nervous system lymphoma
•Tuberculoma
•Cryptococcoma
•Progressive multifocalleukoencephalopathy, rarely, cerebral
infarcts,varicella zoster infection,and other bacterial and parasitic
infections
•In patients who are seronegative for toxoplasmosis or are on prophylactic
therapy for toxoplasmosis, other diagnoses should be considered
120
•The presentation is so characteristicthat many guidelines
suggest routine treatment for toxoplasmosis
•A lack of response to such therapy (symptoms and MRI
changes) within 1-2 weeks indicates other possible conditions:
•Central nervous system lymphoma
•Tuberculoma
•Cryptococcoma
•Progressive multifocalleukoencephalopathy, rarely, cerebral
infarcts,varicella zoster infection,and other bacterial and parasitic
infections
•In patients who are seronegative for toxoplasmosis or are on prophylactic
therapy for toxoplasmosis, other diagnoses should be considered
120
Treatment …
•With empiric treatment for Toxoplasmosis:
•Most patients respond clinically within days of starting
therapy
•CT and MRI scans show improvement (14 days of
treatment) occur before clinical improvement
•In patients who have movement disorders with cerebral
toxoplasmosis, radiologic improvement may occur despite
no apparent improvement in the movement disorder.
•Repeat MRI scans after 14 days of therapy to assess
response to treatment
•Duration of treatment is 6 weeks, 3 weeks after complete
resolution of lesions on CT
121
•With empiric treatment for Toxoplasmosis:
•Most patients respond clinically within days of starting
therapy
•CT and MRI scans show improvement (14 days of
treatment) occur before clinical improvement
•In patients who have movement disorders with cerebral
toxoplasmosis, radiologic improvement may occur despite
no apparent improvement in the movement disorder.
•Repeat MRI scans after 14 days of therapy to assess
response to treatment
•Duration of treatment is 6 weeks, 3 weeks after complete
resolution of lesions on CT
121
Treatment
122
122
Chronic maintenance therapy
123
Corticosteroids (dexamethasone 4mg PO or IV q6hrs)
http://aidsinfo.nihgov./guidelines2015
123
Corticosteroids (dexamethasone 4mg PO or IV q6hrs)
http://aidsinfo.nihgov./guidelines2015
Indication for steroids
1.Substantial mass effect and the mental status is
significantly depressed.
•Such patients are at risk for cerebral herniation.
2.The diagnosis of PCNSL has already been
established
•since steroids can cause false negative results on a
subsequent brain biopsy in patients with lymphoma
124
1.Substantial mass effect and the mental status is
significantly depressed.
•Such patients are at risk for cerebral herniation.
2.The diagnosis of PCNSL has already been
established
•since steroids can cause false negative results on a
subsequent brain biopsy in patients with lymphoma
124
Primary prophylaxis
Indications
•Positive serology + CD4 <100/mm
3
•CD4 < 100/mm
3
•WHO Stage II, III, or IV
•HIV-associated oral candidiasis
•Unexplained fever
•What is used?
TMP-SMX: in addition covers PCP also
125
Indications
•Positive serology + CD4 <100/mm
3
•CD4 < 100/mm
3
•WHO Stage II, III, or IV
•HIV-associated oral candidiasis
•Unexplained fever
•What is used?
TMP-SMX: in addition covers PCP also
125
Primary prophylaxis …
126
126
Cryptococcal meningitis
•Most HIV-associated infections are caused by C.neoformans,
but occasionally C. gattii.
•Infection acquired through inhalation
•Occurs in advanced disease (CD4<100)
•Rarely, presents as pneumonitis, or as disseminated disease that
includes skin (umbilicated vesicles, like molluscum)
127
•Most HIV-associated infections are caused by C.neoformans,
but occasionally C. gattii.
•Infection acquired through inhalation
•Occurs in advanced disease (CD4<100)
•Rarely, presents as pneumonitis, or as disseminated disease that
includes skin (umbilicated vesicles, like molluscum)
127
Clinical presentation
•Commonly presents as a
•Sub acute meningitis or
•Meningoencephalitis with fever, malaise, and headache.
•Classic meningeal symptoms and signs:
•Neck stiffness and photophobia, occur in 1/4
th
to1/3
rd
of patients.
•Some patients experience encephalopathic symptoms:
•Lethargy, altered mentation, personality changes, and memory loss
that are usually a result of increased ICP
128
•Commonly presents as a
•Sub acute meningitis or
•Meningoencephalitis with fever, malaise, and headache.
•Classic meningeal symptoms and signs:
•Neck stiffness and photophobia, occur in 1/4
th
to1/3
rd
of patients.
•Some patients experience encephalopathic symptoms:
•Lethargy, altered mentation, personality changes, and memory loss
that are usually a result of increased ICP
128
Clinical…
•Any organ of the body can be involved, and
•Skin lesions may show myriad different manifestations,
including umbilicated skin lesions mimicking molluscum
contagiosum.
•Pulmonary cryptococcosis may present as acute respiratory
distress syndrome and mimic Pneumocystis pneumonia
129
•Any organ of the body can be involved, and
•Skin lesions may show myriad different manifestations,
including umbilicated skin lesions mimicking molluscum
contagiosum.
•Pulmonary cryptococcosis may present as acute respiratory
distress syndrome and mimic Pneumocystis pneumonia
129
Diagnosis
Analysis of cerebrospinal fluid (CSF)
•Mildly elevated levels of serum protein, low to-normal glucose
concentrations,
•Pleocytosis consisting mostly of lymphocytes.
•The opening pressure in the CSF elevated, with pressures ≥25 cm
H2O occurring in 60% to 80% of patients
Gram’s stain preparation, or an India ink preparation if
available
•May demonstrate numerous yeast forms
Cryptococcal disease can be diagnosed through culture, CSF
microscopy, or by cryptococcal antigen (CrAg) detection.
130
Analysis of cerebrospinal fluid (CSF)
•Mildly elevated levels of serum protein, low to-normal glucose
concentrations,
•Pleocytosis consisting mostly of lymphocytes.
•The opening pressure in the CSF elevated, with pressures ≥25 cm
H2O occurring in 60% to 80% of patients
Gram’s stain preparation, or an India ink preparation if
available
•May demonstrate numerous yeast forms
Cryptococcal disease can be diagnosed through culture, CSF
microscopy, or by cryptococcal antigen (CrAg) detection.
130
Treatment
131
•Treatment for cryptococcosis consists of 3 phases: induction,
consolidation, and maintenance therapy
http://aidsinfo.nihgov./guidelines2015
131
•Treatment for cryptococcosis consists of 3 phases: induction,
consolidation, and maintenance therapy
http://aidsinfo.nihgov./guidelines2015
Treatment
132
http://aidsinfo.nihgov./guidelines2015
132
http://aidsinfo.nihgov./guidelines2015
Mucocutaneous candidiasis
133
133
Clinical manifestations
1.Oropharyngeal candidiasis
•Painless, creamy white, plaque-like lesions that can occur on the
buccal surface, hard or soft palate, oropharyngealmucosa, or
tongue surface
2.Esophageal candidiasis
•Generally present with retrosternal burning pain or discomfort
along with odynophagia
•Occasionally esophagealcandidiasis can be asymptomatic
134
1.Oropharyngeal candidiasis
•Painless, creamy white, plaque-like lesions that can occur on the
buccal surface, hard or soft palate, oropharyngealmucosa, or
tongue surface
2.Esophageal candidiasis
•Generally present with retrosternal burning pain or discomfort
along with odynophagia
•Occasionally esophagealcandidiasis can be asymptomatic
134
Clinical manifestations
3.Candida vulvovaginitis
•Early
•white adherent vaginal discharge associated with mucosal
burning and itching of mild-to-moderate severity and sporadic
recurrences
−Advanced disease
•Episodes may be more severe and recur more frequently.
•In contrast to oropharyngealcandidiasis, vulvovaginal
candidiasis is less common and rarely refractory to azole
therapy.
135
3.Candida vulvovaginitis
•Early
•white adherent vaginal discharge associated with mucosal
burning and itching of mild-to-moderate severity and sporadic
recurrences
−Advanced disease
•Episodes may be more severe and recur more frequently.
•In contrast to oropharyngealcandidiasis, vulvovaginal
candidiasis is less common and rarely refractory to azole
therapy.
135
Diagnosis
1.Oropharyngeal candidiasis
•Clinically based on the characteristic appearance of lesions
•Microscopic examined for characteristic yeast or hyphal forms,
using a potassium hydroxide preparation is confirmatory.
2.Esophageal candidiasis
•Direct endoscopic visualization of lesions with histopathologic
demonstration of characteristic Candida yeast forms in tissue
and confirmation by fungal culture and speciation.
136
1.Oropharyngeal candidiasis
•Clinically based on the characteristic appearance of lesions
•Microscopic examined for characteristic yeast or hyphal forms,
using a potassium hydroxide preparation is confirmatory.
2.Esophageal candidiasis
•Direct endoscopic visualization of lesions with histopathologic
demonstration of characteristic Candida yeast forms in tissue
and confirmation by fungal culture and speciation.
136
Diagnosis…
3.Vulvovaginal candidiasis
•Clinical presentation coupled with the demonstration of
characteristic blastosphere and hyphal yeast forms in vaginal
secretions when examined microscopically after potassium
hydroxide preparation
•Microscopic and culture confirmation is required to avoid
unnecessary exposure to treatment.
137
3.Vulvovaginal candidiasis
•Clinical presentation coupled with the demonstration of
characteristic blastosphere and hyphal yeast forms in vaginal
secretions when examined microscopically after potassium
hydroxide preparation
•Microscopic and culture confirmation is required to avoid
unnecessary exposure to treatment.
137
Treatment
138
138
Treatment…
139
139
Herpes (Varicella) Zoster
•Occurs due to reactivation of varicella zoster
•Frequency of disease is highest with CD4 <200
cells/μl
•In HIV:
•Often multi-dermatomal
•May be recurrent
•Occurs early in disease; first episode usually in patients with
CD4 count>350 cells /mm
3
•If treated with acyclovir within 72 hrs of the first
appearance of symptoms (pain, redness, papular rash)
the progress/appearance of vesicular lesions may be
arrested
140
•Occurs due to reactivation of varicella zoster
•Frequency of disease is highest with CD4 <200
cells/μl
•In HIV:
•Often multi-dermatomal
•May be recurrent
•Occurs early in disease; first episode usually in patients with
CD4 count>350 cells /mm
3
•If treated with acyclovir within 72 hrs of the first
appearance of symptoms (pain, redness, papular rash)
the progress/appearance of vesicular lesions may be
arrested
140
Herpes (Varicella) Zoster
141
141
Varicella Zoster Treatment
•Superimposed bacterial infection should be treated with
antibiotics.
•Zoster Ophthalmicus can cause blindness
•Treatment -Acyclovir 800mg po 5x daily, plus
•Topical acyclovir ointment applied 5x daily with topical
midriatics to prevent synechae formation and corneal opacity
142
•Superimposed bacterial infection should be treated with
antibiotics.
•Zoster Ophthalmicus can cause blindness
•Treatment -Acyclovir 800mg po 5x daily, plus
•Topical acyclovir ointment applied 5x daily with topical
midriatics to prevent synechae formation and corneal opacity
142
Mycobacterium avium complex
143
143
Mycobacterium avium…
•Poor prognostic indicators include
•Prior MAC
•High plasma HIV RNA levels
•Previous colonization of the respiratory or GI tract with
MAC
•Reduced in vitro lymphoproliferative immune
responses to M. Avium antigens.
144
•Poor prognostic indicators include
•Prior MAC
•High plasma HIV RNA levels
•Previous colonization of the respiratory or GI tract with
MAC
•Reduced in vitro lymphoproliferative immune
responses to M. Avium antigens.
144
Clinical presentation
•Common presenting symptoms
•Fever
•Night sweats
•Anorexia
•Malaise
•Profound weight loss (> 10% body weight),
•Anaemia
•Lymphadenopathy, and
•Diarrhoea
145
•Common presenting symptoms
•Fever
•Night sweats
•Anorexia
•Malaise
•Profound weight loss (> 10% body weight),
•Anaemia
•Lymphadenopathy, and
•Diarrhoea
145
Diagnosis
•Disseminated MAC is best diagnosed by peripheral blood
cultures.
•AFB on a blood smear.
•Acid-fast smears of lymph node, liver, or bone marrow
biopsies.
•Because these organs are rich in monocytes (the target cells for
MAC infection)
•Culture methods using solid media may have a turnaround
time of as long as 8 weeks.
•Biochemical methods for organism identification may take weeks
to months.
•Even with the availability of all of these laboratory tests, results
generally are not available for 2 to 3 weeks.
146
•Disseminated MAC is best diagnosed by peripheral blood
cultures.
•AFB on a blood smear.
•Acid-fast smears of lymph node, liver, or bone marrow
biopsies.
•Because these organs are rich in monocytes (the target cells for
MAC infection)
•Culture methods using solid media may have a turnaround
time of as long as 8 weeks.
•Biochemical methods for organism identification may take weeks
to months.
•Even with the availability of all of these laboratory tests, results
generally are not available for 2 to 3 weeks.
146
Treatment
Principles
1.Two-drug or three-drug MAC regimen,
2.At least one of these drugs must be a macrolide.
•Clarithromycin(500 mg PO BID) is the preferred agent;
azithromycin is an alternative.
3.Ethambutol (15 to 25 mg/kg/day PO) is recommended
as the second agent
4.Rifabutin (300 mg/day), amikacin (10-15 mg/kg/day)
and fluoroquinolones can be used as the third agent
147
Principles
1.Two-drug or three-drug MAC regimen,
2.At least one of these drugs must be a macrolide.
•Clarithromycin(500 mg PO BID) is the preferred agent;
azithromycin is an alternative.
3.Ethambutol (15 to 25 mg/kg/day PO) is recommended
as the second agent
4.Rifabutin (300 mg/day), amikacin (10-15 mg/kg/day)
and fluoroquinolones can be used as the third agent
147
Treatment
Recommendations
•Clarithromycin +Ethambutol + Ciprofloxacin
•MAC is resistant to the usual anti-tuberculosis drugs INH, PZA
•Add 3rd or 4th drug if: CD4 count <50; high mycobacterial
loads; or absence of effective ART
•Ciprofloxacin 500-750 mg bid po
•Levofloxacin 500 mg qd po
•Amikacin IV 10-15mg/kg qd
148
Recommendations
•Clarithromycin +Ethambutol + Ciprofloxacin
•MAC is resistant to the usual anti-tuberculosis drugs INH, PZA
•Add 3rd or 4th drug if: CD4 count <50; high mycobacterial
loads; or absence of effective ART
•Ciprofloxacin 500-750 mg bid po
•Levofloxacin 500 mg qd po
•Amikacin IV 10-15mg/kg qd
148
Treatment
The choice of the third agent depends
•The severity of the illness including
•High mycobacterial loads
•CD4+ count less than 50
•Drug interactions
•Hepatic and renal function
•Patient tolerability
•Patient compliance, and cost.
149
•Treatment is lifelong unless 12 months treatment & asymptomatic
with CD4 lymphocyte count >100 x 3-6 months
The choice of the third agent depends
•The severity of the illness including
•High mycobacterial loads
•CD4+ count less than 50
•Drug interactions
•Hepatic and renal function
•Patient tolerability
•Patient compliance, and cost.
149
•Treatment is lifelong unless 12 months treatment & asymptomatic
with CD4 lymphocyte count >100 x 3-6 months
Treatment
150
150
Treatment
151
•Empiric therapy should be initiated as quickly as possible
151
•Empiric therapy should be initiated as quickly as possible
Prophylaxis
152
152
Quiz 4 (5%)
Prophylactic indication for MAC
153
Prophylactic indication for MAC
153
154
Management of infection in
Neutropenic patients
Management of infection in
Neutropenic patients
Neutropenia:
155
ANC=(neutrophils + Bands) x WBC
Fever is defined by a single oral temperature greater than or equal to 38.3°C
(101°F) or temperature greater than 38°C (100.4°F) for more than 1 hour
•Duration of the neutropenia significantly impacts on the risk of
developing complications; in particular, patient with an ANC < 500
cells/mm for > 7 days will likely develop febrile neutropenia (FN)
155
ANC=(neutrophils + Bands) x WBC
Fever is defined by a single oral temperature greater than or equal to 38.3°C
(101°F) or temperature greater than 38°C (100.4°F) for more than 1 hour
•Duration of the neutropenia significantly impacts on the risk of
developing complications; in particular, patient with an ANC < 500
cells/mm for > 7 days will likely develop febrile neutropenia (FN)
Neutropenia
156
ESMO and EORTC guidelines FN definition,
•Oral temperature > 38.5 °C or two consecutive readings of >
38.0 °C for 2 h and an ANC < 500 cells/mm or expected to
fall below this threshold.
156
ESMO and EORTC guidelines FN definition,
•Oral temperature > 38.5 °C or two consecutive readings of >
38.0 °C for 2 h and an ANC < 500 cells/mm or expected to
fall below this threshold.
Febrile neutropenia
157
CTCAE have graded neutropenia into 4 severity classes following the ANC:
•In a large prospective registry, 37% of the BC patients experienced
an absolute neutrophil count (ANC) lower than 500 cells/mm over
the first 4 cycles of treatment, and approximately 70% of the initial
episodes occurred in cycle 1
Common Terminology Criteria for Adverse Events (CTCAE) NCCN,2013
157
CTCAE have graded neutropenia into 4 severity classes following the ANC:
•In a large prospective registry, 37% of the BC patients experienced
an absolute neutrophil count (ANC) lower than 500 cells/mm over
the first 4 cycles of treatment, and approximately 70% of the initial
episodes occurred in cycle 1
Common Terminology Criteria for Adverse Events (CTCAE) NCCN,2013
Risk factors for FNP
158
AHS:CLINICAL PRACTICE GUIDELINE ,2014:SUPP-004
158
AHS:CLINICAL PRACTICE GUIDELINE ,2014:SUPP-004
Febrile neutropenia
159
MCCN Acute Oncology Guidelines (2014) Version 2.0
159
MCCN Acute Oncology Guidelines (2014) Version 2.0
Etiology
•Bacteremia(approximately 25% of febrile neutropenic patients) –
Aerobic gram negative bacilli
•Pseudomonas aeruginosa
•Escherichia coli, and
•Klebsiella pneumonia e) or
Aerobic gram-positive cocci
Coagulase-negative staphylococci,
S. Aureus,
Enterococci,
Viridans streptococci.
Clostridium difficile
160
•Bacteremia(approximately 25% of febrile neutropenic patients) –
Aerobic gram negative bacilli
•Pseudomonas aeruginosa
•Escherichia coli, and
•Klebsiella pneumonia e) or
Aerobic gram-positive cocci
Coagulase-negative staphylococci,
S. Aureus,
Enterococci,
Viridans streptococci.
Clostridium difficile
160
Management guideline
161
161
Febrile neutropenia
162Scottish Guidelines for the Management of Oncologic Emergencies in Adult Cancer Patients2014
Principle: Target polymicrobial
Door to antibiotic administration=60min
162Scottish Guidelines for the Management of Oncologic Emergencies in Adult Cancer Patients2014
Principle: Target polymicrobial
Door to antibiotic administration=60min
F neutropenia…prevention
CSFs(primary or secondary prophylaxis)
Two recombinant products, G-CSF (granulocyte colony-stimulating factor)
•Filgrastim stimulates the production of neutrophilic
granulocytes
GM-CSF (granulocyte macrophage colony-stimulating factor)
•Sargramostim promotes the proliferation of granulocytes (neutrophils and eosinophils),
monocytes and macrophages.
Findings:
•No or only minimal clinical benefit from use of CSFs in treating neutropenia;
•Therefore, should not be routinely used in patients with established neutropenia
regardless of the presence of fever
163
Pharmacotherapy A Pathophysiologic Aproach,2014: 9
TH
Edn.
CSFs(primary or secondary prophylaxis)
Two recombinant products, G-CSF (granulocyte colony-stimulating factor)
•Filgrastim stimulates the production of neutrophilic
granulocytes
GM-CSF (granulocyte macrophage colony-stimulating factor)
•Sargramostim promotes the proliferation of granulocytes (neutrophils and eosinophils),
monocytes and macrophages.
Findings:
•No or only minimal clinical benefit from use of CSFs in treating neutropenia;
•Therefore, should not be routinely used in patients with established neutropenia
regardless of the presence of fever
163
Pharmacotherapy A Pathophysiologic Aproach,2014: 9
TH
Edn.
F neutropenia…prevention
164
164
Quiz 3 (5%)
Out line the principle ofinfectionmanagement of in neutropenic
patient:
165
Out line the principle ofinfectionmanagement of in neutropenic
patient:
165
166
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