Transcript Guidelines for Prevention and Treatment of Opportunistic

Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected
Adults and Adolescents
Parasitic Infections Slide Set
Prepared by the AETC National Resource Center
based on recommendations from the CDC,
National Institutes of Health, and HIV Medicine
Association/Infectious Diseases Society of America
About This Presentation
These slides were developed using recommendations
published in May 2013. The intended audience is
clinicians involved in the care of patients with HIV.
Users are cautioned that, because of the rapidly
changing field of HIV care, this information could
become out of date quickly. Finally, it is intended that
these slides be used as prepared, without changes in
either content or attribution. Users are asked to honor
this intent.
-AETC National Resource Center
http://www.aidsetc.org
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Parasites
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Toxoplasma gondii encephalitis
Cryptosporidiosis
Microsporidiosis
Malaria
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Parasites
Toxoplasma gondii encephalitis
Toxoplasma gondii Encephalitis:
Epidemiology
 Caused by the T gondii protozoan
 Disease almost always caused by reactivation of
latent tissue cysts
 Primary infection may be associated with acute
cerebral or disseminated disease
 Seroprevalence varies widely: 11% in the United
States, 50-80% in some European, Latin
American, and African countries
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Toxoplasma gondii Encephalitis:
Epidemiology (2)
 In advanced AIDS, 12-month incidence of TE
was 33% among Toxoplasma-seropositive
patients who were not on prophylaxis or ART
 Among seronegative persons, toxoplasmosis is
rare
 Occurs primarily in patients with CD4 counts of
<200 cells/µL, especially <50 cells/µL
 Incidence and mortality lower in United States
and Europe owing to widespread use of
prophylaxis and potent ART
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Toxoplasma gondii Encephalitis:
Epidemiology (3)
 Primary infection acquired from tissue cysts
in undercooked meat or raw shellfish, or
ingestion of sporulated oocysts (from cat
feces) in soil, water, or food
 No transmission by person-to-person
contact
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Toxoplasma gondii Encephalitis:
Clinical Manifestations
 Focal encephalitis with headache,
confusion, or motor weakness and fever
 May have nonfocal symptoms, including
nonspecific headache and psychiatric
symptoms
 May have focal neurological abnormalities;
may progress to seizures, altered mental
status, coma
 Retinochoroiditis, pneumonia, other organ
involvement are rare
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Toxoplasma gondii Encephalitis:
Clinical Manifestations
 CT or MRI:
 Typical findings are multiple contrast-enhancing
lesions in gray matter of cortex or basal ganglia,
often associated edema
 May show single brain lesion, or diffuse
encephalitis without focal lesions
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Toxoplasma gondii Encephalitis:
Diagnosis
 Serum anti-Toxoplasma IgG
 Positive in almost all patients with TE; negative
IgG makes diagnosis unlikely but not impossible
 IgM usually negative
 Definitive diagnosis: compatible clinical
syndrome + mass lesion(s) on imaging +
detection of organism in a clinical sample
(brain biopsy)
 CT, MRI of brain: typically multiple contrast-enhancing
lesions, often with edema
 MRI better than CT for radiological diagnosis
 PET or SPECT may help distinguish TE from
lymphoma
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Toxoplasma gondii Encephalitis:
Diagnosis (2)
 Check CSF (if safe and feasible) for T gondii
PCR, cytology, culture, cryptococcal antigen, PCR
for M tuberculosis, EBV, JC virus
 CSF PCR specificity for T gondii is 96-100%,
sensitivity 50%
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Toxoplasma gondii Encephalitis:
Diagnosis (3)
 Differential diagnosis of focal neurological
disease
 CNS lymphoma, PML, mycobacterial infection
(TB), fungal infection, Chagas disease,
abscess
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Toxoplasma gondii Encephalitis:
Diagnosis (4)
CT scan of the brain
showing contrastenhancing lesion of
toxoplasmosis
Credit: P. Volberding, MD; UCSF Center for HIV Information
Image Library
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Toxoplasma gondii Encephalitis:
Diagnosis (5)
 May initially make empiric diagnosis,
established on basis of clinical and
radiographic improvement to TE therapy,
in absence of a likely alternative diagnosis
 Brain biopsy if failure to respond to
therapy, or if initial studies suggest
etiology other than TE
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Toxoplasma gondii Encephalitis:
Preventing Exposure
 All HIV+ should be tested for IgG to
Toxoplasma at baseline, to detect latent
infection
 Toxoplasma seronegative: counsel about
sources of infection
 Patients: avoid eating raw or undercooked
meat or shellfish; wash hands after handling
raw meat and after contact with soil; wash
fruits/vegetables; clean cat-litter boxes daily
and wash hands afterward; cats should not
be fed raw/undercooked meats
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Toxoplasma gondii Encephalitis:
Primary Prophylaxis
For all Toxoplasma IgG positive with CD4 count <100
cells/µL
 Recommended:
 TMP-SMX 1 DS QD
 Alternative:
 TMP-SMX 1 DS PO TIW
 TMP-SMX 1 SS QD
 Dapsone* 50 mg PO QD + pyrimethamine 50 mg PO Q week +
leucovorin 25 mg PO Q week
 Dapsone* 200 mg PO Q week + pyrimethamine 75 mg PO Q
week + leucovorin 25 mg PO Q week
 Atovaquone 1,500 mg PO QD +/- pyrimethamine 25 mg PO QD
+ leucovorin 10 mg PO QD
* Avoid dapsone if patient has G6PD deficiency; screen before treatment
with dapsone, if possible.
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Toxoplasma gondii Encephalitis:
Primary Prophylaxis (2)
 Toxoplasma seronegative patients: retest
for Toxoplasma IgG if CD4 count declines
to <100 cells/µL, unless taking PCP
prophylaxis that also is active against TE
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Toxoplasma gondii Encephalitis:
Discontinuing Primary Prophylaxis
 Discontinue if on effective ART with CD4
count of >200 cells/µL for >3 months
 Restart prophylaxis if CD4 count decreases
to <100-200 cells/µL
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Toxoplasma gondii Encephalitis:
Treatment
 Preferred:
 Pyrimethamine 200 mg PO 1 dose, then:
 For weight ≤60 kg: pyrimethamine 50 mg PO QD
+ sulfadiazine 1,000 mg PO Q6H + leucovorin 1025 mg PO QD
 For weight >60 kg: pyrimethamine 75 mg PO QD
+ sulfadiazine 1,500 mg PO Q6H + leucovorin 1025 mg PO QD
 Duration: ≥6 weeks, longer if extensive disease
or incomplete response at 6 weeks
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Toxoplasma gondii Encephalitis:
Treatment (2)
 Alternative:
 Pyrimethamine as above + clindamycin 600 mg IV or
PO Q6H + leucovorin as above
 TMP-SMX (5 mg/kg TMP and 25 mg/kg SMX) IV or
PO BID
 Atovaquone 1,500 mg PO BID + pyrimethamine, as
above + leucovorin as above
 Atovaquone 1,500 mg PO BID + sulfadiazine (weightbased as above)
 Atovaquone 1,500 mg PO BID (variable absorption)
 Pyrimethamine as above + azithromycin 900-1,200
mg PO QD + leucovorin as above
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Toxoplasma gondii Encephalitis:
Treatment (3)
 Adjunctive corticosteroids only if
indicated for treatment of mass effect;
monitor closely and discontinue as soon
as possible
 Anticonvulsants if history of seizures;
continue at least through period of acute
therapy
 Should not be given prophylactically to all
patients
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Toxoplasma gondii Encephalitis:
ART Initiation
 No data to guide recommendation on
when to start ART
 Many recommend starting ART within 2-3
weeks after diagnosis of TE
 In one study, lower rate of AIDS progression
or death with early ART
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Toxoplasma gondii Encephalitis:
Monitoring and Adverse Events
 Follow clinical and radiologic improvement
 Ab titers not useful
 Monitor for adverse events
 Pyrimethamine: rash, nausea, bone marrow
suppression
 May be reversed with increase in leucovorin dosage
 Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea,
vomiting, diarrhea, renal insufficiency, crystalluria
 Clindamycin: rash, fever, nausea, diarrhea (including
Clostridium difficile colitis), hepatotoxicity
 TMP-SMX: rash, fever, leukopenia, thrombocytopenia,
hepatotoxicity
 Atovaquone: nausea, vomiting, diarrhea, rash,
headache, hyperglycemia, fever
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Toxoplasma gondii Encephalitis:
Monitoring and Adverse Events (2)
 IRIS appears to occur rarely
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Toxoplasma gondii Encephalitis:
Treatment Failure
 Clinical or radiologic deterioration during
first week of therapy, or lack of clinical
improvement within 10-14 days
 Brain biopsy, if not done previously
 If confirmed TE, consider switch to
alternative treatment regimen
 In patients who adhere to treatment,
recurrence is unusual during maintenance
therapy following initial clinical and
radiographic response
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Toxoplasma gondii Encephalitis:
Preventing Recurrence
 Secondary prophylaxis:
 Preferred:
 Pyrimethamine 25-50 mg PO QD + sulfadiazine 2,000-4,000
mg PO daily in 2-4 divided doses + leucovorin 10-25 mg PO
QD
 Alternative:
 Clindamycin 600 mg PO Q8H + pyrimethamine 25-50 mg PO
QD + leucovorin 10-25 mg PO QD (not effective as PCP
prophylaxis)
 TMP-SMX DS 1 tablet BID
 Atovaquone 750-1,500 mg PO BID + pyrimethamine 25 mg
PO QD (+ leucovorin 10 mg PO QD)
 Atovaquone 750-1,500 mg PO BID + sulfadiazine 2,000-4,000
mg PO daily in 2-4 divided doses
 Atovaquone 750-1,500 mg PO BID
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Toxoplasma gondii Encephalitis:
Preventing Recurrence (2)
 Discontinuing maintenance therapy: consider in
asymptomatic patients after successful initial
therapy for TE, resolution of signs and symptoms
of TE, and sustained increase in CD4 count to
>200 cells/µL for >6 months, on ART
 Consider brain MRI before treatment discontinuation;
continue therapy if mass lesions present or
enhancement persists
 Restart secondary prophylaxis if CD4 count
decreases to <200 cells/µL
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Toxoplasma gondii Encephalitis:
Considerations in Pregnancy
 Check T gondii IgG during pregnancy
 If suspected or confirmed T gondii
infection, evaluate and manage with a
maternal-fetal specialist
 Diagnostic considerations same as for
nonpregnant women
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Toxoplasma gondii Encephalitis:
Considerations in Pregnancy (2)
 Perinatal transmission usually occurs only with
acute maternal infection; case reports of
transmission with reactivation of chronic infection
in women with severe immunosuppression
 If toxoplasmosis during pregnancy (primary
infection or reactivation of chronic
toxoplasmosis):
 Detailed ultrasound of fetus
 Consider PCR of amniotic fluid in select circumstances
 Neonate should be evaluated for evidence of
congenital infection
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Toxoplasma gondii Encephalitis:
Considerations in Pregnancy (3)
 Primary prophylaxis: recommended
 TMP-SMX preferred
 Balance possible risks with expected benefits
 Treatment: as in nonpregnant adults
 Secondary prophylaxis: as in nonpregnant
women
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Toxoplasma gondii Encephalitis:
Considerations in Pregnancy (4)
 Pyrimethamine appears safe in human
pregnancy
 Sulfadiazine appears safe though, if given
around time of delivery, may increase risk of
neonatal kernicterus
 Clindamycin considered same in pregnancy
 Dapsone: risk of mild maternal hemolysis with
long-term therapy; low risk of hemolytic anemia
in exposed fetuses with G6PD deficiency
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Toxoplasma gondii Encephalitis:
Considerations in Pregnancy (5)
 Consider immediate initiation of ART, to
decrease risk of perinatal HIV transmission,
especially for women diagnosed with TE in 3rd
trimester
 Preconception care for women receiving TE
prophylaxis: discuss option of deferring
pregnancy until TE prophylaxis can be
discontinued safely
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Parasites
Cryptosporidiosis
Cryptosporidiosis: Epidemiology
 Caused by Cryptosporidium species
 Protozoan parasites
 Infect small intestine mucosa; in
immunosuppressed patients, also infect
large intestine and other sites
 Advanced immunosuppression (eg, CD4
<100 cells/µL) associated with prolonged,
severe, or extraintestinal disease
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Cryptosporidiosis: Epidemiology (2)
 Infection results from ingestion of oocysts
excreted in feces of infected humans or
animals
 Water supplies and recreational water
sources (oocysts may withstand standard
chlorination)
 Person-to-person transmission common, via
oral-anal contact, from infected children to
adults (eg, during diapering), or care of
patients with diarrhea
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Cryptosporidiosis: Epidemiology (3)
 Common cause of chronic diarrhea in AIDS
patients in developing countries
 In developed countries with low rates of
envrionmental contamination and
widespread use of effective ART, <1 case
per 1,000 person-years in AIDS patients
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Cryptosporidiosis: Clinical Manifestations
 Acute or subacute onset of profuse watery,
nonbloody diarrhea, often with nausea, vomiting,
and abdominal cramping
 Fever in 1/3 of patients
 Can be very severe, especially with immune
suppression
 Malabsorption is common; dehydration,
electrolyte abnormalities, malnutrition may result
 Biliary tract and pancreatic duct may be infected,
causing scleroding cholangitis and pancreatitis
 Pulmonary infection is possible
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Cryptosporidiosis: Diagnosis
 Microscopic identification of oocysts in
stool or tissue
 DFA very sensitive, specific, is current gold
standard for stool specimens
 Acid-fast staining often used
 PCR extremely sensitive
 ELISA or immunochromatographic tests
 Small intestine biopsy with identification of
Cryptosporidium organisms
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Cryptosporidiosis: Diagnosis (2)
 Single specimen usually sufficient in
profuse diarrhea
 Repeat stool sampling is recommended in
mild disease
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Cryptosporidiosis: Prevention
Preventing exposure
 Avoid exposure to infected contacts
 Contact with diarrhea
 Potential oral exposure to feces during sex
 Direct contact with farm animals, stool from
pets
 Scrupulous handwashing after potential
contact with feces (eg, after diapering), after
handling pets or other animals, gardening,
before preparing food or eating, before and
after sex
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Cryptosporidiosis: Prevention (2)
 Avoid exposure to contaminated water,
food
 Do not drink or swallow water from
recreational sources (lakes, streams, pools)
 Ice, fountain beverages, water fountains may
be contaminated
 Avoid raw oysters
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Cryptosporidiosis: Prevention (3)
 Boil tap water for ≥1 minute during
outbreaks or when community advisory is
issued
 Submicron water filters or bottled water may
reduce risk
 For non-outbreak settings, data are
inadequate to recommend that all persons
with low CD4 counts avoid drinking tap
water
 Consider drinking only filtered water
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Cryptosporidiosis: Prevention (4)
Preventing disease
 Primary prophylaxis:
 Appropriate initiation of ART before severe
immunosuppression should prevent disease
 Rifabutin and possibly clarithromycin are
protective, but data insufficient to recommend
as chemoprophylaxis
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Cryptosporidiosis: Treatment
 Preferred strategies
 ART with immune restoration (to CD4 count
>100 cells/µL)
 Usually results in complete resolution; should be
offered as part of initial management of
cryptosporidiosis
 Symptomatic treatment: antidiarrheals
 Tincture of opium may be more effective than
loperamide
 Octreotide usually not recommended (no more
effective than other antidiarrheals)
 Supportive care: aggressive hydration,
electrolyte repletion, nutritional support (IV
therapies may be needed)
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Cryptosporidiosis: Treatment (2)
 Alternative strategies
 No consistently effective antimicrobial therapy
in absence of ART
 Consider nitazoxanide or other antiparasitic
drugs in conjunction with ART, not instead of
ART
 Nitazoxanide 500-1,000 mg PO BID for 14 days +
ART and other measures above
 Some studies show clinical improvement with nitazoxanide
 Paromomycin 500 mg PO QID for 14-21 days + ART
and other measures above
 Limited data; may improve clinical response in conjunction
with ART
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Cryptosporidiosis: Starting ART
 ART should be offered as part of initial
management of this infection
 PIs inhibit Cryptosporidium in animal models –
some experts prefer PI-based ART
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Cryptosporidiosis: Monitoring and
Adverse Events
 Monitor closely for volume depletion, electrolyte
loss, weight loss, and malnutrition
 TPN may be indicated
 IRIS not reported
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Cryptosporidiosis: Treatment Failure
 Supportive treatment
 Optimization of ART
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Cryptosporidiosis: Prevention of Recurrence
 No effective prevention, other than
immune restoration with ART
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Cryptosporidiosis: Considerations in
Pregnancy
 Rehydration and ART initiation as with
nonpregnant adults
 Nitazoxanide not teratogenic in animals, but no
data in pregnant humans
 Use after 1st trimester in severely symptomatic women
 Paromomycin: limited information on
teratogenicity; minimal systemic absorption with
PO administration
 Use after 1st trimester in severely symptomatic
women
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Cryptosporidiosis: Considerations in
Pregnancy (2)
 Loperamide: possible risk of hypospadias with
1st-trimester exposure
 Avoid during 1st trimester, unless benefits expected to
outweigh risks
 Preferred antimotility agent during late pregnancy
 Tincture of opium not recommended during late
pregnancy
 Opiate exposure during late pregnancy associated with
neonatal respiratory depression; chronic exposure may
result in neonatal withdrawal
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Parasites
Microsporidiosis
Microsporidiosis: Epidemiology
 Protists, related to fungi
 Many species, including Enterocytozoon
bieneusi, Encephalitozoon cuniculi,
Encephalitozoon intestinalis
 Ubiquitous, may be zoonotic and/or
waterborne
 Risk greatest with CD4 count <100 cells/µL
 Incidence dramatically lower in areas with
widespread use of effective ART
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Microsporidiosis: Clinical Manifestations
 Most common: diarrheal illness
 Other manifestations: cholangitis, hepatitis,
encephalitis, ocular infection, sinusitis,
myositis, disseminated infection
 Clinical syndromes may vary by species
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Microsporidiosis: Diagnosis
 Microscopic identification of stool or tissue
samples
 Identification requires high magnification
(1,000×), selective stains to differentiate
spores from cellular debris
 Electron microscopy, PCR, Ab-specific stains can
determine species
 Evaluate 3 stool samples
 Small bowel biopsy if stool studies are
negative and suspicion is high
 Urine examination may be useful if cause is
Encephalitozoon or Trachipleistophora spp
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Microsporidiosis: Prevention
 Preventing exposure
 Handwashing; avoidance of undercooked
meat or seafood and exposure to infected
animals
 Patients with CD4 counts of <200 cells/μL
should avoid drinking untreated water
 Primary prophylaxis
 Appropriate initiation of ART before severe
immunosuppression should prevent disease
 No chemoprophylaxis known to be effective
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Microsporidiosis: Treatment
 ART with immune restoration (to CD4
count >100 cells/µL)
 Should be offered to all as part of initial
management
 If severe dehydration, malnutrition,
wasting: hydration, nutritional support (IV
therapies may be needed)
 Antimotility agents, if needed for diarrhea
control
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Microsporidiosis: Treatment (2)
 E bieneusi GI infections:
 ART and fluid support as above
 no specific antimicrobial;
 Fumagillin 60 mg PO QD or TNP-470: some evidence
of efficacy but not available in United States
 Nitazoxanide: limited data; cannot be recommended
with confidence
 Nonocular infection caused by microsporidial
other than E bieneusi and V corneae:
 Albendazole 400 mg PO BID
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Microsporidiosis: Treatment (3)
 Disseminated disease caused by
Trachipleistophora or Anncaliia
 Itraconazole 400 mg PO QD + albendazole 400 mg
PO BID
 Ocular infection: fumagillin (Fumidil B) eye
drops 70 mcg/mL + albendazole 400 mg PO
BID
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Microsporidiosis: Starting ART
 ART should be offered as part of initial
management of this infection
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Microsporidiosis: Adverse Events
 Albendazole: adverse effects are rare;
monitor hepatic enzymes
 Fumagillin
 Topical: no known substantial side effects
 Oral: thrombocytopenia
 IRIS: 1 report
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Microsporidiosis: Treatment Failure
 Supportive treatment
 Optimization of ART
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Microsporidiosis: Prevention of Recurrence
 Ocular:
 If CD4 >200 cells/µL on ART, consider
discontinuing treatment after ocular infection
resolves; restart if CD4 drops to <200 cells/µL
 Other manifestations:
 Safety of treatment discontinuation after
immune restoration with ART is not known
 Reasonable to discontinue maintenance
therapy in asymptomatic patients on ART with
increase in CD4 count to >200 cells/µL for ≥6
months (no data to support this approach)
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Microsporidiosis: Considerations in
Pregnancy
 Initiate ART to restore immune function
 Albendazole:
 Embryotoxic and teratogenic in animals
 Not recommended in 1st trimester, use during later
pregnancy only if benefits expected to outweigh risks
 Systemic fumagillin: growth retardation in rats:
should not be used with pregnant women
 Topical fumagillin appears safe
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Microsporidiosis: Considerations in
Pregnancy (2)
 Itraconazole: avoid in 1st trimester
 Loperamide: possible risk of hypospadias with
1st-trimester exposure
 Avoid in 1st trimester, unless benefits expected to
outweigh risks
 Preferred antimotility agent during late pregnancy
 Tincture of opium not recommended during late
pregnancy
 Opiate exposure during late pregnancy associated
with neonatal respiratory depression; chronic
exposure may result in neonatal withdrawal
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Websites to Access the Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
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About This Slide Set
 This presentation was prepared by
Susa Coffey, MD, and Oliver Bacon,
MD, for the AETC National Resource
Center in May 2013
 See the AETC NRC website for the
most current version of this
presentation:
http://www.aidsetc.org
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