Transcript HIV II - CareGate

HIV II
Update on Opportunistic
Infections
Prevention and Treatment
Pathophysiology
Depletion of CD-4
cells (T-helper)
HIV binds
Cell entry
cell death
CD4-deficiency
Direct mechanisms
– Accumulation of
unintegrated viral DNA
– Interference with cellular
RNA processing
– Intracellular gp 120-CD4
autofusion events
– Loss of plasma membrane
integrity because of viral
budding
– Elimination of HIV-infected
cells by virus-specific
immune responses
Indirect mechanisms
– Aberrant intracellular
signaling events
– Syncytium formation
– Autoimmunity
– Superantigenic stimulation
– Innocent bystander killing
of viral antigen-coated cells
– Apoptosis
– Inhibition of lymphopoiesis
CD4 depletion syndromes
HIV/AIDS
idiopathic CD4+ T lymphocytopenia
Iatrogenic
– Corticosteroids
– Immunosuppressants
Opportunistic infections
For patients taking potent combination antiretroviral
therapy (ART), beginning in 1996, there has been a
dramatic decline in the incidence of AIDS-related
opportunistic infections (OIs) such as Pneumocystis
carinii pneumonia (PCP), disseminated
Mycobacterium avium complex (MAC), and invasive
cytomegalovirus (CMV) disease
Treatment Guidelines
• Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected
Adults and Adolescents:
http://www.cdc.gov/mmwr/pdf/rr/rr5804.pdf
Major Changes in Guidelines
Increased emphasis on importance of ART
More information about IRIS
Information about using IGRAs for latent
TB diagnosis
More drug interactions data
Addition of section on Hepatitis B
treatment
Addition of section on malaria.
ART therapy in OI
Benefits of ART have been demonstrated
for cryptosporidiosis, PML,
microsporidiosis, KS and other relatively
untreatable OIs
– Recommend begin ART (AIII)
– KS essentially goes away
However, institution of ART during an OI
can result in an exuberant immune
response
Drug/drug interaction can also be difficult
ART therapy in OI
TB, MAC, PCP, crytococcal infection
– Highest association with IRIS
– Wait for clinical response to OI rx before
starting ART (CIII)
When OI develops within first 12 weeks of ART
initiation, begin OI rx and do not stop ART (AIII)
A RCT demonstrated a clinical and survival
benefit of starting ART withint the first 2 wks of
initiation of rx for OI, except for TB Zolopa A, Andersen J, Komarow
L, et al. Immediate versus deferred ART in the setting of acute AIDS-related OI: final results of a randomized
strategy trial, ACTG A5164. 15th CROI;2008; Boston, MA. Abstract 142.
Management of acute OI after
starting ART
First group: within 12 wks, may be
unmasked, therefore don’t represent
failure of ART
>/= 12 wks with high CD4 (IRIS vs failure
of ART?)
>/= 12wks after ART with virologic failure
HIV and fever
Disseminated MAC
– before HAART, most common cause of FUO
in advanced AIDS.
Disseminated histo
bartonellosis
CMV
cryptococcosis
Mycobacterium avium-intracellulare
complex (MAC)
Disseminated
– FUO
Fever, night sweats,
weight loss, diarrhea
Anemia, elevated
alkaline phosphatase
– GI
– Visceral
– pulmonary
Localized "immune
reconstitution" illnesses
– biopsies show a
granulomatous response
– lymphadenitis (mesenteric,
cervical, thoracic)
– can mimic Pott's disease
with disease presenting in
the spine or other
bones/joints
– Pulmonary
MAC
Findings
– Adenopathy
– Elevated alk phos
– anemia
Diagnosis
– Blood culture
– Tissue culture
– Histopathology
Treatment
– Macrolide +
ethambutol + rifabutin
– Amikacin
– ciprofloxacin
MAC
Sources
– Food
– Water
– soil
Stool screening not rec b/c no data for
benefit, although predicts disease
No recs for avoidance
MAC
prophylaxis
Primary CD4 < 50 until >100 3 mo. (AI)
– Clarithromycin
– Azithromycin
– Rifabutin (not combo-EI)
Exclude TB
DI’s
Secondary for 12 mo and until no sx and CD4
>100 6 mo (BCx neg)
– Macrolide + ethambutol, +/- rifabutin
– High dose clarithromycin asso. W/higher mortality (EI)
– Clofazimine too many ADR’s (DII)
Restart at CD4 <50-100
Drug Interactions
Azithromycin not
affected by c P450
Protease inhibitors
– Increase
clarithromycin levels
– Some contraindicated
w/rifabutin
NNRTIs (efavirenz)
– Induce clarithromycin
metabolism
– Some contraindicated
w/rifabutin
Bartonella
Manifestations
– Bacillary angiomatosis
(BQ)
– Lymphadenitis (BH)
– Hepatosplenic disease
(BH)
peliosis hepatis
– GI
– Brain
neuropsych
– bone
B. henselae and B.
quintana
Treatment
– Erythromycin
– Tetracycline deriv.
Bartonellosis
HIV-higher incidence
Older cats less likely to transmit
Control fleas
No rec for primary prophylaxis
Consider long-term suppression (C-III)
CMV
Risk groups
– MSM
– IDU
– Childcare exposure
Test IgG if lower risk
group
Not IDU/MSM
% IgG positive
– Varies by country
CMV
Manifestations
– FUO
– pancytopenia
– CNS
Retinitis
– Blurred vision
– scotomata
– field cuts
Encephalitis
Transverse myelitis
Radiculitis
– pneumonitis
– GI
Gastritis/GU
DU
colitis
CMV
Diagnosis
– Serology-not helpful
– Tissue histopathology
– Molecular diagnostics
Antigen
PCR
Treatment
– Valganciclovir
– Ganciclovir 5 mg/kg IV
bid × 14-21 days
– Foscarnet 60 mg/kg IV
q8h or 90 mg/kg IV
q12h × 14-21 days
– Cidofovir 5 mg/kg IV
weekly × 2 then every
other week
– Implants
CMV
prophylaxis
Primary
– Can consider if IgG (+)
and CD4 <50
– Oral ganciclovir or
valganciclovir
– Regular optho exams
– Discuss symptoms
– NOT
acyclovir/valacyclovir
Secondary
– Intraocular alone not
sufficient
– Valganciclovir
– Consider stopping when
CD4>100-150 6mo
– Continue regular f/u
CMV-neg or leukopoor
irradiated blood if CMV
(-)
HIV and diarrhea
Cryptosporidium
Microsporidiosis
Isospora
Giardia
bacterial enteric
infections
–
–
–
–
Salmonella
Shigella
campylobacter
Listeria
CMV
Cdiff
HIV and diarrhea
•Crampy abdominal pain, bloating, and nausea suggest small bowel
•Cryptosporidia
•Microsporidia
•Isospora
•Giardia
•cyclospora)
•MAC.
•High-volume, watery diarrhea with weight loss and electrolyte
disturbance is most characteristic of cryptosporidiosis
•bloody stools with abdominal cramping and fever ( invasive
bacterial pathogen)
•Clostridium difficile
•CMV colitis
HIV and diarrhea
Stool studies
–
–
–
–
–
O&P
Trichrome
AFB
Immunohisto
Cdiff
Thorough history
Medication review
Low threshold for flex sig
Given the availability of
effective treatment; more
aggressive evaluation
that often includes
endoscopy has replaced
the less invasive
approach.
Treatment
– Antimotility agents
Imodium, Lomotil
Opium
– Calcium
– octreotide
Bacterial Enteric Infections
Prevention
Seek vet care for animals
with diarrhea
WASH HANDS
Travel precautions
–
–
–
–
Bottled beverages
Avoid fresh produce
Avoid ice
Consider prophylaxis or
early empiric therapy
Cipro 500 qd
Bactrim
Avoid
– Reptiles, chicks and
ducklings
– Raw eggs
– Raw poultry, meat and
seafood
– Unpasteurized dairy
products/juices
– Raw seed sprouts
– Soft cheeses
– Deli counters unless can
reheat
– Refrigerated meat spreads
Cryptosporidium
coccidian protozoan (I.
belli, C. cayetanensis,
and Toxoplasma gondii)
5%-10% of diarrhea in
immunocompetent
Asymptomatic carriers
mammalian hosts-cattle,
horses, rabbits, guinea
pigs, mice.
transmission fecal-oral.
Waterborne outbreaks
due to contamination of
drinking water
thick-walled, highly
resistant oocyst
excysts in stomach
sporozoites infect
enterocytes and persist at
the apical pole of
intestinal epithelial cellsmicroscopic appearance
of extracellular, adherent
parasite
Cryptosporidiosis
prevention
biopsy
fecal examination
– Modifed AFB
– Immunohisto stains
Treatment
–
–
–
–
–
Azithromycin
Paromomycin
(Octreotide-now DII)
nitazoxanide
HAART
Clarithromycin/rifabutin
work, but no data.
Counsel regarding
exposure-avoid feces
–
–
–
–
–
Private room
Diapers
Animals with diarrhea
young animals (screen BIII)
water
boil water when suggested
(AI)
filters (CIII)
oysters
bottled (CIII)
Microsporidiosis
observed initially in
intestinal biopsy
specimens in 1982
No disease in normal
hosts
2 types
– Enterocytozoon bieneusi,
reproduces within
enterocytes
– Encephalitozoon (Septata)
intestinalis infects epithelial
cells and stromal cells of
the lamina propria and
causes systemic infection
Diagnosis
– Difficult to see by light
microscopy-order trichrome
stain
Treatment
– Albendazole (for
intestinalis)
– Atovaquone
– metronidazole.
– nitazoxanide
No recs for prevention
Isospora
no other known host
endemic in Brazil, Colombia, Chile, and
parts of equatorial Africa and southwest
Asia.
seen rarely in normals
fecal-oral route
Isospora
Immunocompetent
– watery diarrhea
– usually clear the infection
within about 2 weeks;
– may persist
HIV-chronic high-volume
watery diarrhea
Detection in stool
samples difficult, and
concentration or flotation
methods. AFB +
histologic sections
– Villus atrophy,
eosinophil infiltrates,
and disorganization of
the epithelium
shown better with
Giemsa on histo
Cipro better than
Bactrim
Cyclospora
first reported in the 1980s
endemic in tropical countries and other
areas w/poor standards of hygiene and
water purification
severity related to the degree of
immunosuppression
Rx Bactrim
Cyclospora
Epidemics attributed to contamination of
water supplies, fruits, and vegetables
similar to Cryptosporidium but larger (8 to
10 mum versus 4 to 5 mum) and AFB +
fecal-oral route
intermittent watery diarrhea for 3 > mo.
infect enterocytes and proliferate within a
supranuclear parasitophorous vacuole.
TABLE 3 -- Diagnostic Workup of HIVRelated Chronic Diarrhea
Stool tests
Bacterial culture (to detect Salmonella
species and so on)
Ova and parasite examination (Giardia
lamblia and so on)
C. difficile toxin assay
Modified acid-fast stain or
immunofluorescence kit (cryptosporidia)
Modified trichrome stain
(microsporidia)
Add blood cultures if febrile (bacteria,
mycobacteria)
Flexible sigmoidoscopy with mucosal
biopsies
Light microscopy (mycobacteria,
CMV, cryptosporidia)
Mycobacterial culture (mycobacteria)
Upper endoscopy with duodenal biopsies
Light microscopy (CMV,
mycobacteria, cryptosporidia,
microsporidia)
Mycobacterial culture (mycobacteria)
± electron microscopy (microsporidia)
HIV and pneumonia
PCP
histoplasmosis
cryptococcosis
rhodococcus
CMV
Pneumococcus
– 100-fold risk
Nontypable H. flu
Pseudomonas
– 40-fold risk
– Lowest CD4
HHV-8
Coccidiodomycosis
TABLE 1 -- CAUSES OF RESPIRATORY DISEASE IN PERSONS WITH HIV
Very Common
Pneumocystis carinii
S. pneumoniae
H. influenzae
MTB *
Somewhat Common
Rare
Pseudomonas aeruginosa
Nocardia asteroides
Staphylococcus aureus
Legionella spp.
Enteric GNR
M. avium complex
Histoplasma capsulatum
Toxoplasma gondii
C. neoformans
Cryptosporidium
Cytomeglovirus
R. equii
Kaposi's sarcoma
Primary pulmonary HTN
Aspergillusspp.
Lymphocytic interstitial
pneumonia (LIP)
Pulmonary lymphoma
Congestive heart failure
PCP
PCP
Symptoms
– Incidious onset
– SOB>cough
– pneumothorax
Findings
– diffuse infiltrates in a perihilar or bibasilar distribution
and a reticular or reticulonodular pattern
– No effusion
– Elevated LDH
– SX>>>CXR
Normal in 26%
– Extrapulmonary disease
PCP
Microbiology
–
–
–
–
P. jiroveci infects human
P. carinii infects rodents
Fungus with protozoal properties
Primary infection usually early childhood
Diagnosis (preferred)
–
–
–
–
–
Expectorated sputum much less sensitive
Sputum for DFA
Sputum cytology
BAL for same
Histopathology/stains
Mortality 60% in patients requiring mechanical vent
PCP
TMP 15 mg/kg/d + SMX 75 mg/kg/d po or IV × 21 days in 34 divided doses; for outpatient, 2 DS tablets po tid (AI)
rash, fever, gastrointestinal symptoms, hepatitis, hyperkalemia, leukopenia,
and hemolytic anemia
Steroid (pO2 < 70 or A-a gradient > 35)-21d taper (AI)
Alternatives
–
–
–
–
–
TMP-dapsone (BI)
Clinda/primaquine (BI)
Atovaquone (less effective in mild-mod) (BI)
Trimetrexate/folinic acid (keep fol for 3 d after last dose)-(AI)
Iv Pentam (BI)
nausea, infusion-related hypotension, hypoglycemia, hypocalcemia, renal
failure, and pancreatitis
PCP
prophylaxis
CD4<200 or history of
oral thrush (AII)
CD4%<14 or other OI
(BII)
Bactrim (AI)
– DS daily (toxo,
bacterial pathogens)
– SS daily
– DS TIW (BII)
– rechallenge if rash
(desens) - 70%
tolerate
PCP
prophylaxis
Dapsone
Dapsone +
pyrimethamine/leucov
orin
aerosolized pentam
(Respirgard II)pregnancy 1st term
atovaquone
All BI
Other aerosolized
Pentam
parenteral pentam
oral pyrimethamine/
sulfadoxine
oral clinda/primaquine
trimetrexate
All CIII
PCP
prophylaxis
Stop when CD4>200
for 3 mo.
Restart if CD4<200
Stop secondary
prophylaxis if
CD4>200 unless PCP
occurred at higher
CD4
Children of HIV
mothers need
prophylaxis
Children with PCP
can not stop
secondary
prophylaxis.
Histoplasmosis
THE MOST common
endemic mycosis
Pulmonary, mucosal,
disseminated or CNS
Respiratory culture
Blood culture
Bone marrow biopsy
Urine Ag
Mississippi valley and
Ohio valley + worldwide
Normal hosts usually
asympto or mild URI-no
rx
– Some cross reaction
– More sensitive in dissem
disease, esp HIV
Rx ampho, itra
Clin Chest Med - 01-DEC-1996; 17(4): 725-44
Histoplasmosis
Prevention
Routine skin testing
not predictive
Avoid
– Creating soil/old
building dust
– Cleaning chicken
coops
– Disturbing bird roosts
– Exploring caves
Secondary
prophylaxis
– Itraconazole
– No data-no rec for
stopping
Primary Prophylaxis
– No proven survival
benefit
– Consider in high risk
and CD4<100
Typical CAP
Increased mortality
with Pneumococcal
Increased incidence
of Pseudomonas
Bactrim and
macrolide prophylaxis
prevent resp
infections, but not rec
solely for this reason
Maintain normal
granulocyte count &
IgG
Prevention
– PCV-13 followed by
polysaccharide
vaccine
Tuberculosis
Low threshold of
suspicion
Lower CD4=atypical
presentation
Higher mortality
Tuberculin skin
testing (TST) negative
in 40% of patients
with disease
4-drug therapy initially
Drug interactions
major issue
Tuberculosis prevention
PPD for all new diagnoses
Consider annual if continued risk
– Employment
– Homeless
– Foreign travel
Tuberculosis
New guidelines
– Emphasize DOT and
provider responsibility
Louis Pasteur once
said, "The microbe is
nothing...the terrain
everything"
– Reculture at 2 mo of
trx
Extend if still + and
cavitary disease
INH--rifapentine once weekly
continuation phase (Regimens
1c and 2b) is contraindicated
CD4+ cell counts <100/µl
should receive daily or three
times weekly treatment
“paradoxical” flares occur
– Associated w/HAART
– Effusions, infiltrates,
enlargement of CNS
lesions, nodes, fever
– Steroids used
“Treatment of tuberculosis benefits both the
community as a whole and the individual patient,
thus and public health program or private provider
undertaking to treat a patient with tuberculosis is
assuming a public health function that includes not
only prescribing an appropriate regimen, but also
insuring adherence to the regimen until treatment is
completed.”
Tuberculosis
prevention
PPD on diagnosis of
HIV (5mm)
IGRA can also be
used
if positive treat
– INH/B6 9 months (AII)
– rifampin 4 months
(BIII)
– rif/PZA for 2 months
hepatic toxicity
– rifabutin can be sub’d
(less data)
Close contacts should
be treated if HIV+
if exposed to MDR TB
needs expert advice
and PH
BCG contraindicated
Vague guidelines for
repeating PPD
– yearly if “high risk”
– repeat when CD4>200
Coccidiocomycosis
Growth is enhanced by
bat and rodent droppings.
Exposure is heaviest in
the late summer and fall
Acute pulm, chronic pulm,
dissem, CNS
more severe in
immunosuppressed
individuals, African
Americans, and Filipinos
2/3 of immunosuppressed
have disseminated
disease
Avoid disturbing native
soil
Diagnose by serology or
biopsy
Blood cultures not usually
positive
Skin test not predictive
Often refractory to
treatement
Secondary prophylaxis
lifelong, too little data for
stopping (>100)
Coccidiomycosis
Treatment
– Amphotericin +/an azole
– Fluconazole for
CNS disease
Med Clin North Am - 01-Nov-2001; 85(6): 1461-91,
HIV and rash
Molluscum
HHV-8 (KS)
HPV
VZV
HSV
cryptococcus
Bartonella
Syphilis
Candida
Seborrheic dermatitis
Folliculitis
– Eosinophilic
– bacterial
Psoriasis
Onchomycosis
Prurigo nodularis
scabies
Molluscum contagiosum
Papular eruption
– Pearly
– umbilicated
Poxvirus
Usually CD4 < 200
Rx liquid nitrogen
HHV-8
Agent of Kaposi’s
sarcoma
Vertical transmission
occurs
No screening available
Antivirals may have some
effect
May be accelerated if
infected after HIV
– Advise about prevention
Manifestations
– Cutaneous
– Mucosal
– Visceral
GI
Pulmonary
other
Human papillomavirus
Manifestations:
–
–
–
–
Condyloma acuminata
Plantar warts
Facial
Periungual
– Genital epithelial
cancer
Twice yearly screening,
then annual in women
Follow NCI guidelines
Screening for men
being developed
Herpes
VZV
HSV
– Very common (>90%
of MSM sero+)
– Severe, erosive
disease, proctitis
– Some need chronic
suppression
(acyclovir/famcyclovir)
– Resistance occurs and
cross-res
w/ganciclovir.
– occurs at CD4
200-500
– Dermatomal,
ocular,
disseminated
– No effective
secondary
prevention recs
– Avoid exposure
– Vaccinate
relatives
– VZIG if exposed
and negative
Candida Infections
Manifestations
– Oral thrush
– Esophageal
candidiasis
– Candidal dermatitis
– vulvovaginal
Treatment
– fluconazole
– Clotrimazole
– Nystatin
– Itraconazole
– Amphotericin (po or iv)
Responds quickly to
therapy
Primary prophylaxis not
rec
Secondary is optional,
prefer early empiric rx
Azole resistance is an
issue
HIV and headache
Cryptococcus-meningitis
Toxoplasmosis-enhancing
PML
lymphoma
HIV
CMV (perivent)
EBV
nonenhancing
Cryptococcus
Meningitis
– Headache
– subtle cognitive effects.
– Occaasional meningeal
signs and focal
neurologic findings
– nonspecific presentation
is the norm
Pulmonary disease
Disseminated disease
– FUO
– Adenopathy
– Skin nodules
– Organ involvement
Diagnosis
– CSF Ag sens=100%
– Need opening pressure
Treatment
– Ampho + 5FC (GI, hem
toxicity)
– fluconazole
Cryptococcal meningitis
ICP management
– >250 mm H2O was seen in 119 out of 221
patients
higher titers of cryptococcal antigen
more severe clinical manifestations
–
–
–
–
–
– headache, meningismus, papilledema, hearing loss, and
pathologic reflexes
– shortened long-term survival
Desired OP < 200 mm H2 O or 50% of the initial pressure
Daily lumbar punctures until the pressure is stable
Lumbar drain
Ventriculoperitoneal shunting
Corticosteroids are not recommended
Cryptococcus
Prevention
Primary prophylaxis effective but generally
not rec
Secondary until CD4>100-200 6 mo. and
no sx (only CIII rec)
– Fluconazole (AI)
– Restart at <100-200
Toxoplasmosis
Encephalitis
– sensorimotor deficits,
seizure, confusion, ataxia.
– Fever, headache
common.
– Rare if CD4>200
– Multiple ring-enhancing
lesions
– Almost always due to
reactivation of latent
tissue cysts
Toxoplasmosis
Diagnosis
– IgG seropositivity with appropriate lesions on
MRI
– PCR is only 50% sensitive
– Biopsy is gold standard
Toxoplasma
Treatment
Pyrimethamine 100-200 mg then 50-100 mg/d
+ folinic acid 10 mg/d + sulfadiazine 4-8 g/d for
at least 6 weeks
Or sub clinda, azithro, clarithro or atovaquone
Steroids if mass effect
Anticonvulsants only if seizure activity (DIII)
Strongly consider biopsy if treatment failure
Toxoplasma
prophylaxis
Screen for IgG (BIII)
– if negative, aggressively counsel regarding
avoidance of cat litter, raw meat (165 deg)
– wash, wear gloves when gardening
– wash vegetables
– keep cats indoors, avoid raw meat foods
– getting rid of or testing the cat is an EIII
offense!
CD4 <100 if seropositive only
Toxoplasma
primary prophylaxis
Trim/sulfa DS qd (AII)
dapsone/pyrimethamine (BI)
atovaquone (CIII)
dapsone, macrolides, pyrimethamine don’t
work (DII)
Aerosolized pentam definitely doesn’t work
(EII)
Toxoplasma
primary prophylaxis
Stop primary when
CD4 > 200 for 3
months
restart when CD4
drops <100 again
Toxoplasma
secondary prophylaxis
After initial therapy completed
Pyrimethamine plus sulfadiazine
pyrimethamine plus clinda (not for PCP)
stop when CD4>200 for 6 months, no
symptoms and initial therapy completed
restart if drop below 200
Prevention of Exposure
Currently, there are no recommendations for
preventing exposure to:
– P jiroveci pneumonia (PCP) – no data to
support isolation
– M avium complex (MAC) – no data
– S pneumoniae and H influenzae – not
practical
– Candidiasis – not practical
– Cryptococcosis – not practical
Summary of stopping prophylaxis
Disease
PCP
MAC
Toxo
PCP
MAC
Type of
prophylaxis
Primary
CD4 limit
Length
200
100
200
>3 months
Secondary
200
100
>3months
> 6mo plus 12 months
HAART and no sx
>6 months, completed rx
and no sx
>6 months, completed rx
and no sx
toxo
200
Crypto
100-200
Strength of
rec
AI
AI
AI
BII
CIII
CIII
CIII