Transcript 2008 Guidelines Opportunistic OIs house staff Nov 2010

2008 Guidelines for
Prevention and Treatment of
Opportunistic Infections in
HIV-Infected Adults and
Adolescents : Part 1
Major Changes Since 2008
(1) more emphasis on the importance of ART
for prevention and treatment of OIs,
especially those for which specific
chemoprophylaxis and treatment do not exist;
(2) information on diagnosis and
management of immune reconstitution
inflammatory syndromes (IRIS);
(3) information on interferon-gamma release
assays (IGRAs) for the detection of latent
Mycobacterium tuberculosis infection;
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Major Changes Since 2008
(4) updated information on drug
interactions affecting use of rifamycin
drugs for prevention and treatment of
tuberculosis (TB);
(5) the addition of a section on hepatitis B
virus (HBV) infection;
(6) the addition of a section on malaria to
the OIs of geographic interest.
3
Initiation of ART in the Setting of
an Acute OI (Treatment-Naïve
Patients)
No consensus has been reached
concerning the optimal time to start ART in
the setting of a recently diagnosed OI.
Recently completed RCT demonstrated a
clinical and survival benefit of starting ART
early, within the first 2 weeks, of initiation
of treatment for an acute OI, excluding TB
Zolopa A, et al., ACTG A5164. 15th CROI; 2008; Boston, MA. Abstract 142.
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Initiation of ART in the Setting of
an Acute OI (Treatment-Naïve
Patients)
Majority of OIs represented were PCP and
serious bacterial infections
Study Conclusion
– Unless there are other contraindications, early
initiation of ART near the time of initiation of
OI treatment should be considered for most
patients with an acute OI, excluding TB.
Zolopa A, et al., ACTG A5164. 15th CROI; 2008; Boston, MA. Abstract 142.
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Initiation of ART in the Setting of
an Acute OI (Treatment-Naïve
Patients)
In cases of cryptosporidiosis,
microsporidiosis, PML, KS, PCP, and
serious bacterial infections, the early
benefits of ART outweigh increased risk
related to these other factors and ART
should be started as soon as possible
Risks of early ART initiation may be
greatest in those with CNS IRIS leading to
increased ICP and brain shift (WCM
opinion)
Zolopa
A, et al., ACTG A5164. 15 CROI; 2008; Boston, MA. Abstract 142.
th
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Management of Acute OIs in
Patients Receiving ART: 3
Groups
OIs that occur shortly after initiating ART (within 12
weeks).
– “unmasking” IRIS
– Treat OI and continue ART
OIs occurring >12 weeks after initiation of ART among
patients with suppressed pVL and CD4+ >200 cells/μL
– IRIS vs incomplete immune restoration
– Continue ART
– No evidence that changing the ART regimen in this setting
will improve the CD4+ response
OIs that develop in setting of virologic and
immunologic failure while on potent ART
– Treat OI
– HIV resistance testing and regimen change
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Special Considerations During
Pregnancy
For pregnant women who have had an OI
diagnosed and are not on ART, immediate
initiation of ART with OI therapy should be
encouraged to minimize the risk of perinatal
transmission of HIV.
Decisions about immediate versus delayed
initiation of ART in pregnancy should take
into account gestational age, maternal HIV
RNA levels and clinical condition, and
potential toxicities and interactions between
ART and OI drugs.
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Pneumocystis Pneumonia
Epidemiology
– 90% of cases with CD4+ counts of <200 cells/μL
– Other risk factors
CD4+ cell percentage <14%
previous episodes of PCP
oral thrush
recurrent bacterial pneumonia
unintentional weight loss
higher plasma HIV RNA
– Mortality 20%–40% with profound
immunosuppression
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Pneumocystis Pneumonia
Clinical Manifestations
– subacute onset of progressive dyspnea, fever,
nonproductive cough, and chest discomfort
– Chest clear or “cellophane” rales
– Oxygenation variable
– LDH >500 mg/dL is common but nonspecific
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Pneumocystis Pneumonia
– CXR typically bilateral interstitial infiltrates or normal
(if mild)
– Atypical presentations: nodules, blebs and cysts,
asymmetric disease, upper lobe localization, and
pneumothorax occur.
– Pneumothorax in a patient with HIV infection should
raise the suspicion of PCP
– Cavitation, intrathoracic adenopathy, and pleural
effusion are uncommon
presence might indicate an alternative diagnosis.
– Approximately 13%–18% of patients with documented
PCP have another concurrent cause of pulmonary
dysfunction (e.g., TB, KS, or bacterial pneumonia)
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Mild Pneumocystis Pneumonia
PCP
Severe Pneumocystis Pneumonia
Residual Cyst 6 weeks after Rx of PCP
Pneumocystis Pneumonia:
Diagnosis
Expectorated sputum not useful
Sensitivity of
–
–
–
–
induced sputum <50%–>90%
bronchoalveolar lavage 90%–99%
transbronchial biopsy 95%–100%
open lung biopsy 95%–100%
Methods
–
–
–
–
Giemsa, Diff-Quik, and Wright stains
Gomori methenamine silver (GMS)
IFA
PCR sensitive but not specific
Other
– S-adenosylmethionine (which is lowered in cases of active PCP)
– (1→3)ß-D-glucan (levels increase with PCP)
15
Geimsa: left
GMS: below
16
Pneumocystis Pneumonia:
Treatment
Initiate presumptive treatment without
delay
TMP-SMX is the treatment of choice
Adjunctive corticosteroids
– pO2 <70 mm Hg or Aa O2 gradient >35 mm Hg
RA within 72 hours of starting PCP treatment
– Reduce Mortality about 50%
– “Rescue” steroids (after 72 h) of uncertain
benefit
Ventilatory support
– survival in up to 50% requiring ventilatory
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Pneumocystis Pneumonia:
Treatment
Many health care providers delay initiation
of ART until after the completion of antiPCP therapy, or until at least 2 weeks after
initiating anti-PCP therapy
– Additive/synergistic toxicities
– Rare IRIS
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Pneumocystis Pneumonia:
Treatment Failure
Important to wait at least 4–8 days before
switching therapy for lack of clinical
improvement
In the absence of corticosteroid therapy, early and
reversible deterioration within the first 3–5 days of
therapy is typical
Failure due to lack of drug efficacy occurs in
approximately 10% of those with mild-to-moderate
disease
Other concomitant infections must be excluded
(BAL)
use parenteral pentamidine or primaquine
combined with clindamycin for moderate-severe 19
Pneumocystis Pneumonia: Toxicity
Management
Treatment-limiting toxicities occurs in up to
one-third of patients
TMP-Sulfa
–
–
–
–
–
–
–
rash (30%–55%) (including SJS)
fever (30%–40%)
leukopenia (30%–40%)
thrombocytopenia (15%)
azotemia (1%–5%)
hepatitis (20%)
hyperkalemia.
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Pneumocystis Pneumonia: Toxicity
Management
Pentamidine (IV)
– azotemia, pancreatitis, hypo- or
hyperglycemia, leukopenia, electrolyte
abnormalities,hypotension during infusion,
and cardiac dysrhythmia
Dapsone and Primaquine
– Hemolysis with G6PD deficiency
– Methemoglobinemia
21
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Pneumocystis Prevention
Primary prophylaxis
– CD4+ count of <200 cells/μL or a history of oropharyngeal
candidiasis
– CD4+ cell percentage of <14% or a history of an AIDS-defining
illness
– Discontinuing primary prophylaxis
response to ART with increase CD4+ counts to >200 cells/μL for >3
months
reintroduced if the CD4+ count decreases to <200 cells/μL
Secondary prophylaxis
– chronic maintenance therapy with TMP-SMX unless immune
reconstitution occurs as a result of ART
– discontinued when CD4+ count increased from <200 cells/μL to
>200 cells/μL for >3 months as a result of ART
– If the episode occurred at a CD4+ count of ≥200 cells/μL,
continue PCP prophylaxis for life
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Primary Prophylaxis: PCP
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Toxoplasma gondii Encephalitis
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Toxoplasma Encephalitis (TE)
Epidemiology
– Seroprevalence 15% in the United States and
50%–75% in certain European countries
– Greatest risk with a CD4+ count <50 cells/μL
– Rare if CD4>200
– 12 month incidence if not receiving
prophylaxis with drugs active against T. gondii
approximately 33%
– incidence of toxoplasmosis in patients who
are seronegative for Toxoplasma is extremely
low
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TE: Clinical Manifestations
Focal encephalitis with headache,
confusion, or motor weakness and fever
CT scan or MRI of the brain will typically
show multiple contrast-enhancing lesions,
often with associated edema
Can manifest as single lesions, especially
by CT
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TE: Diagnosis
Almost uniformly seropositive for antitoxoplasma IgG in serum
Absence of IgG antibody makes a diagnosis
of toxoplasmosis unlikely but not impossible
Detection of T. gondii by PCR in CSF
disappointing
– Specificity is high (96%–100%),
– Sensitivity is low (50%) and the
– Usually negative once specific anti-toxoplasma
therapy started
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TE: Differential Diagnosis
Primary CNS lymphoma
– CD4 < 50
Tuberculomas
Fungal infection (e.g., cryptococcosis)
Chagas disease
Bacterial abscess
rarely PML (inflammatory form)
Neurocysticercosis
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TE: Prevention
Primary
– test for IgG antibody to Toxoplasma soon after
the diagnosis of HIV infection to detect latent
infection with T. gondii
– advise not to eat raw or undercooked meat,
including undercooked lamb, beef, pork, or
venison
– avoid cat litter
– Toxoplasma-seropositive patients who have a
CD4+ count of <100 cells/μL should be
administered prophylaxis against TE (TMP-SMX)
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TE: Prevention
Discontinuing Primary Prophylaxis
– patients who have responded to ART with
an increase in CD4+ counts to >200
cells/μL for >3 months
– reintroduced if the CD4+ count decreases
to <100–200 cells/μL
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TE: Primary Prophylaxis
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TE: Treatment
Initial therapy of choice for TE consists of
the combination of pyrimethamine plus
sulfadiazine plus leucovorin
Some treat severely ill patients initially
requiring parenteral therapy for TE with
parenteral TMP-SMX (oral pyrimethamine
could be considered in addition to IV TMPSMX) or oral pyrimethamine plus
parenteral clindamycin
33
TE: Treatment
Acute therapy for TE should be
continued for at least 6 weeks, if there
is clinical and radiologic improvement
Adjunctive corticosteroids
(dexamethasone) only for treatment of
a mass effect or associated edema
Anticonvulsants should not be
administered as prophylactics to all
patients
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TE: Treatment and Maintenance
35
TE: Treatment Failure
A brain biopsy should be strongly
considered for patients who fail to
respond to initial therapy for TE
– defined by clinical or radiologic
deterioration during the first week despite
adequate therapy OR
– lack of clinical improvement within 2
weeks.
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Cerebral toxoplasmosis
Cerebral Toxoplasmosis
TE: Secondary Prophylaxis
Pyrimethamine plus sulfadiazine plus
leucovorin is highly effective as
suppressive therapy for patients with TE
For sulfa intolerant patients,
pyrimethamine plus clindamycin
TMP-SMX could be used as a suppressive
regimen to reduce pill burden1
1. Duval, X et al., AIDS, 2004. 18(9): p. 1342-4.
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TE: Secondary Prophylaxis
Discontinuing maintenance therapy
– Consider if sustained increase in their CD4+
counts of >200 cells/μL after ART (e.g., >6
months)
– Reintroduced if the CD4+ count decreases to
<200 cells/μL
41
Disseminated Mycobacterium
avium Complex (dMAC)
42
dMAC: Epidemiology
Ubiquitous in the environment
The mode of transmission: inhalation, ingestion, or
inoculation via the respiratory or gastrointestinal
tract
MAC disease generally occurs among persons
with CD4+ counts <50 cells/μL (20-40%)
Overall incidence rate 2 cases per 100 personyears among those with
– CD4+ count <100 cells/μL receiving effective
prophylaxis or
– have responded to ART with a sustained increase in
CD4+ count to levels >100–200 cells/μL
43
dMAC: Clinical Manifestations
No ART
– Disseminated, multi-organ, mycobacteremia
– Fever, night sweats, weight loss, fatigue,
diarrhea, and abdominal pain
On ART
– Localized (cervical or mesenteric
lymphadenitis, pneumonitis, pericarditis,
osteomyelitis, skin or soft tissue abscesses,
genital ulcers, or CNS infection)
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dMAC: Clinical Manifestations
Disseminated
– Anemia
– Increased alkaline phosphatase
– Hepatomegaly
– Splenomegaly
– Lymphadenopathy
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MAC IRIS
Focal lymphadenitis with fever
Absent mycobacteremia
46
dMAC: Diagnosis
Isolation of MAC from cultures of blood,
lymph node, bone marrow, or other
normally sterile tissue or body fluids
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dMAC: Small Bowel
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dMAC IRIS
49
dMAC: Prevention
Chemoprophylaxis against disseminated
MAC disease if CD4+ count of <50
cells/μL
Primary MAC prophylaxis should be
discontinued when response to ART with
an increase in CD4+ counts to >100
cells/μL for ≥3 months
Reintroduced if the CD4+ count decreases
to <50 cells/μL
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dMAC: Prevention
51
dMAC: Treatment
Two or more antimycobacterial drugs to
prevent or delay the emergence of
resistance
Clarithromycin is the preferred first agent
– Azithromycin can be substituted for
clarithromycin for drug interactions or
clarithromycin intolerance
– Azithromycin should be used in pregnancy
EMB is the recommended second drug
Some clinicians would add rifabutin as a
third drug
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dMAC: Treatment
A third or fourth drug considered in settings in
which mortality is increased and emergence
of drug resistance is most likely
– advanced immunosuppression (CD4+ count <50
cells/μL),
– high mycobacterial loads (>2 log10 colony forming
units/mL of blood), or
– absence of effective ART
Based on data in non-HIV-infected patients,
the third or fourth drug might include an
injectable agent such as amikacin or
streptomycin
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dMAC Treatment
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dMAC: Monitoring
A repeat blood culture for MAC 4–8 weeks
after initiation of therapy only for patients
who fail to have a clinical response
Improvement in fever and a decline of
mycobacteria in blood or tissue can be
expected within 2–4 weeks
For those with more extensive disease or
advanced immunosuppression, clinical
response might be delayed.
55
dMAC: IRIS
Symptoms of moderate-to-severe intensity
due to IRIS in the setting of ART should
receive initial treatment with nonsteroidal,
anti-inflammatory agents
If IRIS symptoms fail to improve, shortterm (4–8 weeks) systemic corticosteroid
therapy, in doses equivalent to 20–40 mg
of oral prednisone daily, has been
successful in reducing symptoms and
morbidity
56
dMAC: Treatment Failure
Two new drugs to which the isolate is
susceptible: EMB, rifabutin, amikacin, or a
quinolone (moxifloxacin, ciprofloxacin, or
levofloxacin)
An injectable agent such as amikacin or
streptomycin should be considered
Optimizing ART is an important adjunct to
second-line or salvage therapy for MAC
disease
Clofazimine should not be used
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dMAC: Therapy Duration
Lifelong secondary prophylaxis (chronic
maintenance therapy) (AII), unless immune
reconstitution occurs as a result of ART
Discontinuing chronic maintenance therapy is
reasonable if
– completed a treatment course of ≥12 months
– asymptomatic with respect to MAC
– sustained increase (≥6 months) CD4+ to >100
Secondary prophylaxis reintroduced if the
CD4+ count decreases to <100 cells/μL
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