Transcript Treating Opportunistic Infections Among HIV

Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected Adults
and Adolescents
Cytomegalovirus 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 July 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become out of date quickly.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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CMV Disease: Epidemiology
 Double-stranded DNA virus, herpes virus family
 Disseminated or localized disease
 Occurs in patients with advanced
immunosuppression (CD4 count typically <50
cells/µL)
 Other risk factors: patient not on ART, previous
opportunistic infections, high level of CMV viremia,
high plasma HIV RNA (>100,000 copies/mL)
 Usually caused by reactivation of latent infection
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CMV Disease: Epidemiology (2)
 Before use of potent ART in the United States,
30% of AIDS patients developed CMV retinitis
 ART has decreased incidence by 75-80%
 In patients with established CMV retinitis,
recurrence rate much lower with ART, but may
occur even at high CD4 counts
 Regular ophthalmologic follow-up is needed
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CMV Disease: Clinical Manifestations
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Retinitis
Colitis, cholangiopathy
Esophagitis
Pneumonitis
Neurologic disease
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CMV Disease: Clinical Manifestations (2)
Retinitis
 Most common CMV end-organ disease
 Usually unilateral; if untreated, is likely to
progress to involve both eyes
 Symptoms:
 If peripheral: floaters, scotomata, visual field
defects, or may be asymptomatic
 If central or macular: decreased visual acuity,
central field defects
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CMV Disease: Clinical Manifestations (3)
Retinitis
 Examination: fluffy yellow-white retinal
infiltrates, with or without intraretinal
hemorrhage; little vitreous inflammation
unless immune recovery with ART
 Progresses unless treated; may cause
blindness
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CMV Disease: Clinical Manifestations (4)
CMV retinitis: funduscopic examinations showing hemorrhage and
retinal exudates
Credits: Left: P. Volberding, MD; UCSF Center for HIV Information Image Library
Right: D. Coats, MD; Pediatric AIDS Pictorial Atlas, Baylor International Pediatric
AIDS Initiative
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CMV Disease: Clinical Manifestations (5)
Colitis
 Second most common clinical
manifestation of CMV
 Occurs in 5-10% of persons
with CMV end-organ disease
 Weight loss, anorexia,
abdominal pain, severe
diarrhea, malaise, fever
 Mucosal hemorrhage and
perforation; can be life
threatening
 CT may show colonic
thickening
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Credit: P. Volberding, MD;
UCSF Center for HIV
Information Image Library
July 2013
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CMV Disease: Clinical Manifestations (6)
Esophagitis
 Infrequent in persons
with CMV end-organ
disease
 Odynophagia, nausea,
mid-epigastric or
retrosternal discomfort,
fever
Credit: P. Volberding, MD; UCSF
Center for HIV Information Image
Library
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CMV Disease: Clinical Manifestations (7)
Pneumonitis
 Uncommon
 CMV may be detected in bronchoalveolar lavage:
usually is not pathogenic; other causes should be
ruled out
 Shortness of breath, dyspnea on exertion,
nonproductive cough, hypoxemia
 CXR: interstitial infiltrates
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CMV Disease: Clinical Manifestations (8)
Neurologic disease
 Dementia: lethargy, confusion, fever, but may
mimic HIV-1 dementia
 CSF: lymphocytic pleocytosis, low-to-normal
glucose, normal-to-elevated protein
 Ventriculoencephalitis: more acute course;
cranial nerve palsies, nystagmus, other focal
neurologic signs, rapid progression to death
 CT or MRI: periventricular enhancement
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CMV Disease: Clinical Manifestations (9)
Neurologic disease
 Polyradiculomyelopathy: resembles GuillianBarré syndrome
 Urinary retention, progressive bilateral leg
weakness; progresses over weeks to loss of
bowel and bladder control, flaccid paraplegia
 Spastic myelopathy, sacral paresthesia possible
 CSF: neutrophilic pleocytosis, low glucose,
elevated protein
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CMV Disease: Diagnosis
 Blood tests (eg, PCR, antigen assays, blood
culture) not recommended for diagnosis of CMV
end-organ disease: poor positive and negative
predictive value
 CMV viremia usually present in end-organ
disease but may be present in absence of
end-organ disease
 Antibody levels not useful, though negative IgG
indicates CMV unlikely
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CMV Disease: Diagnosis (2)
 Retinitis: characteristic retinal changes on
funduscopy (by experienced ophthalmologist);
PCR of vitreous helpful if exam not diagnostic
 Colitis: mucosal ulcerations on endoscopy +
biopsy with characteristic intranuclear and
intracytoplasmic inclusions
 Esophagitis: ulceration of distal esophagus on
endoscopy + biopsy with intranuclear inclusion
bodies in endothelial cells
 CMV culture from biopsy or brushing of colon or
esophagus is not diagnostic
 In patients with low CD4 counts, viremia and positive
cultures may occur in absence of clinical disease
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CMV Disease: Diagnosis (3)
 Pneumonitis: interstitial infiltrates + compatible
clinical presentation + multiple CMV inclusion
bodies in lung tissue, and absence of other likely
pathogens
 Neurologic disease:
clinical syndrome +
CMV in CSF or brain
tissue; detection
enhanced by PCR
Brain biopsy with CMV inclusions
Credit: Images courtesy of AIDS Images
Library (www.aids-images.ch)
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CMV Disease: Preventing Exposure
 Patients from groups with low seroprevalence
rates for CMV exposure (no contact with MSM,
IDU, contact with children in day care) may be
tested for CMV IgG
 Counsel patients about exposure risks (semen,
cervical secretions, saliva) and prevention
(handwashing, latex gloves, condoms)
 CMV-seronegative patients needing
nonemergency blood transfusions should receive
CMV-negative blood products
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CMV Disease: Preventing Disease
 Use ART to suppress HIV VL and maintain CD4
count >100 cells/µL
 Primary prophylaxis with valganciclovir not
recommended (no preventive benefit in one
study)
 Recognition, treatment of early disease to prevent
progression
 Patient education: vigilance for increase in floaters,
decrease in visual acuity
 Some specialists recommend annual funduscopic
examinations by ophthalmologist if CD4 <50 cells/µL
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CMV Disease: Treatment
Retinitis
 Start or optimize ART for maximal viral
suppression and immune reconstitution
 Treat CMV retinitis in concert with ophthalmologist
experienced with diagnosis and management of
retinal disease
 Initial anti-CMV therapy followed by chronic
maintenance therapy
 Intravitreal therapy provides immediate high intraocular
drug levels and perhaps faster control of retinitis
 Systemic therapy important to prevent disease in
contralateral eye and improve survival
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CMV Disease: Treatment (2)
Retinitis (cont’d)
 Several effective treatments: few comparative
trials in recent years; no regimen proven to have
superior efficacy
 Individualize based on location and severity of
lesions, level of immunosuppression, other
factors
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CMV Disease: Treatment (3)
Retinitis (cont’d)
 Immediate sight-threatening lesions:
 Intravitreal injections of ganciclovir 2 mg/injection or
foscarnet 2.4 mg/injection for 1-4 doses over 7-10
days
 Ganciclovir ocular implant no longer available
PLUS systemic therapy:
 Preferred systemic therapy
 Valganciclovir 900 mg PO BID for 14-21 days, then QD
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CMV Disease: Treatment (4)
Retinitis (cont’d)
 Immediate sight-threatening lesions (cont’d):
 Alternative systemic therapy
 Ganciclovir 5 mg/kg IV Q12H for 14-21 days, then
5 mg/kg IV QD
 Ganciclovir 5 mg/kg IV Q12H for 14-21 days, then
valganciclovir 900 mg PO QD
 Foscarnet 60 mg/kg IV Q8H or 90 mg/kg IV Q12H
for 14-21 days, then 90-120 mg/kg Q24H
 Cidofovir 5 mg/kg/week IV for 2 weeks, then 5
mg/kg every other week (with pre- and postinfusion hydration and probenecid) (avoid in
patients with sulfa allergy)
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CMV Disease: Treatment (5)
Retinitis (cont’d)
 Small peripheral lesions:
 Preferred
 Systemic antiviral therapy as above
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CMV Disease: Treatment (6)
Colitis, esophagitis
 Preferred
 Ganciclovir 5 mg/kg IV Q12H, may switch to
valganciclovir 900 mg PO Q12H when patient can
absorb and tolerate PO therapy
 Alternative
 Foscarnet 60 mg/kg IV Q8H or 90 mg/kg IV Q12H – if
treatment-limiting toxicities or resistance to ganciclovir
 Oral valganciclovir if PO therapy can be absorbed
 For mild cases, if ART can be initiated or optimized
quickly, can consider withholding CMV therapy
 Duration: 21-42 days, or until signs and
symptoms have resolved
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CMV Disease: Treatment (7)
Pneumonitis
 Treat patients with histologic evidence of
CMV pneumonitis
 Limited experience: IV ganciclovir or
foscarnet is reasonable
 Oral valganciclovir not studied
 Duration of therapy not established
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CMV Disease: Treatment (8)
Neurologic disease
 Treatment not well studied
 Initiate treatment promptly
 Ganciclovir IV + foscarnet IV until symptoms
improve
 Combination treatment preferred as initial therapy,
to maximize response, but associated with high
rates of adverse effects
 Duration of therapy and role of oral
valganciclovir not established
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CMV Disease: Starting ART
 IRIS may cause retinal damage in patients with
active CMV retinitis, or recent or past CMV
retinitis
 Incidence or severity of IRIS may be reduced by
delaying ART until retinitis is controlled
 CMV replication usually controlled 1-2 weeks after
start of CMV therapy
 Weigh brief delay in ART initiation against risk of other
OIs
 Most experts would not delay ART for more than 2
weeks after starting CMV therapy for retinitis or other
CMV end-organ disease
 Use clinical judgment in case of neurologic disease
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CMV Disease: Monitoring
Retinitis
 Close monitoring by experienced
ophthalmologist
 Dilated exam at time of diagnosis, after induction
therapy, 1 month after initiation of therapy,
monthly thereafter while on treatment
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CMV Disease: Adverse Events
Immune recovery uveitis
 Inflammatory reaction to CMV after initiation of
ART and in setting of significant rise in CD4
counts 4-12 weeks after start of ART
 May cause macular edema and epiretinal
membranes, vision loss
 Treatment: periocular corticosteroids or short
course of systemic corticosteroids
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CMV Disease: Adverse Events (2)
 Ganciclovir: neutropenia, thrombocytopenia,
nausea, diarrhea, renal dysfunction, seizures
 Foscarnet: anemia, nephrotoxicity, electrolyte
abnormalities, neurologic symptoms including
seizures
 Monitor CBC, electrolytes, renal function twice
weekly during induction therapy, weekly
thereafter
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CMV Disease: Adverse Events (3)
 Cidofovir: nephrotoxicity, hypotony
 Check renal function, urinalysis before each
infusion
 Do not administer if renal dysfunction or proteinuria
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CMV Disease: Treatment Failure
 Retinitis: recurrence is likely unless immune
reconstitution with ART
 Early relapse: usually caused by limited
intraocular penetration of systemic treatments
 Drug resistance to ganciclovir, foscarnet, or
cidofovir can occur
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CMV Disease: Treatment Failure (2)
Treatment options for first relapse:
 Ganciclovir implant
 Reinduction with the same drug, followed by
maintenance therapy
 Changing to alternative drug at first relapse:
usually not more effective, unless drug
resistance or significant side effects
 Ganciclovir + foscarnet: superior to
monotherapy but greater toxicity
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CMV Disease: Treatment Failure (3)
Later relapse: often owing to drug resistance
 Resistance occurs in long-term therapy
(25-30% by 9 months of therapy)
 Similar rates for ganciclovir, foscarnet,
cidofovir
 Consider resistance testing in blood
 >90% correlation with virus in eye
 Can be done in <48 hours
 Most virus with high-level resistance to ganciclovir
(UL97 + UL54 mutations) respond to foscarnet
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CMV Disease: Treatment Failure (4)
Low-level ganciclovir resistance:
 Consider ganciclovir implant
(higher local levels of ganciclovir)
High-level ganciclovir resistance:
 Switch to alternative therapy
 Usually also resistant to cidofovir, sometimes
to foscarnet
 Consider repeated intravitreous fomivirsen
(combine with systemic therapy)
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CMV Disease: Preventing Recurrence
Retinitis:
 Chronic maintenance therapy (secondary
prophylaxis) for life, unless immune reconstitution
on ART
 Consult ophthalmologist regarding choice for
chronic maintenance therapy and the preferred
route (intravitreal, IV, oral, or combination),
consider anatomic location of retinal lesions,
vision in the contralateral eye, other factors
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CMV Disease: Preventing Recurrence (2)
Retinitis (cont’d):
 Preferred
 Valganciclovir 900 mg PO QD
 Alternative
 Ganciclovir 5 mg/kg IV 5-7 times weekly
 Foscarnet 90-120 mg/kg IV QD
 Cidofovir 5 mg/kg IV every other week (with preand post-infusion hydration and probenecid) (avoid
in patients with sulfa allergy)
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CMV Disease: Preventing Recurrence (3)
GI disease, pneumonitis, CNS disease:
 Chronic maintenance therapy not routinely
recommended, after resolution of acute CMV
syndrome and initiation of effective ART, unless
retinitis or relapses
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CMV Disease: Preventing Recurrence (4)
 Consider discontinuation of secondary
prophylaxis in patients with increase in CD4
count to >100-150 cells/µL for ≥6 months on ART
 For retinitis, consult with ophthalmologist;
consider location of retinal lesions, vision in
contralateral eye
 Close ophthalmologic monitoring
 Restart secondary prophylaxis if CD4 count decreases
to <100-150 cells/µL
 Relapses have occurred at high CD4 counts (≥1,250
cells/µL); relapse rate if secondary prophylaxis
discontinued for immune recovery is 3% per year
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CMV Disease: Considerations in Pregnancy
 Diagnosis as in nonpregnant women
 Treatment:
 For retinitis, consider retinal implants or
intravitreous therapy to limit fetal exposure to
systemic antivirals
 Ganciclovir: teratogenic in animals; limited data
in human pregnancy but is treatment of choice
during pregnancy
 No data on valganciclovir during pregnancy
 Monitor for hydrops fetalis after 20 weeks of
gestation
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CMV Disease: Considerations in Pregnancy (2)
 Foscarnet: skeletal abnormalities in animals;
no experience in early human pregnancy
 Monitor amniotic fluid volumes after 20 weeks of
gestation
 Cidofovir: embryotoxic and teratogenic in
animals; no experience in human pregnancy
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CMV Disease: Considerations in Pregnancy (3)
 In utero infection occurs most commonly among
infants born to mothers with primary CMV infection
during pregnancy
 >90% of HIV-infected women are CMV antibody
positive; no role for treatment of asymptomatic
women
 For pregnant women with primary CMV infection
or CMV end-organ disease, refer to maternal-fetal
specialist
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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, for the AETC National Resource Center in
July 2013.
 See the AETC NRC website for the most current
version of this presentation:
http://www.aidsetc.org
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