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
Guidelines for Prevention and Treatment of Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults Opportunistic Infections in HIV-Infected Adults and Adolescentsand Adolescents
Progressive Multifocal Leukoencephalopathy Progressive Multifocal Leukoencephalopathy (PML) Slide Set(PML) Slide Set
May 2013 www.aidsetc.org2
About This PresentationAbout 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Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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
May 2013 www.aidsetc.org3
PML: PML: EpidemiologyEpidemiology
Opportunistic infection, caused by the polyoma virus JC virus
Characterized by focal demyelination in the CNS
Worldwide distribution, seroprevalence of 39-69% in adults
Primary infection usually in childhood No recognized acute JC virus infection
Likely asymptomatic chronic carrier state
May 2013 www.aidsetc.org4
PML: PML: Epidemiology Epidemiology (2)(2)
Before use of potent ART, PML developed in 3-7% of persons with AIDS
Substantially lower incidence in countries with wide access to ART
High mortality rate
Usually occurs with low CD4 count, but may occur with CD4 count >200 cells/μL and in those on ART
Rarely occurs in HIV-uninfected immuno-compromised persons Reported in persons treated with immunomodulatory
humanized antibodies (eg, natalizumab, efalizumab, infliximab, rituximab)
May 2013 www.aidsetc.org5
PML: PML: Clinical ManifestationsClinical Manifestations Focal neurologic deficits, usually with insidious onset, steady
progression over several weeks/months Demyelinating lesions may involve any region of the brain
Common: occipital lobes (hemianopsia), frontal and parietal lobes (aphasia, hemiparesis, hemisensory deficits), cerebellar peduncles and deep white matter (dysmetria, ataxia)
Spinal cord involvement is rare
Lesions often multiple, though one may predominate Headache and fever not characteristic (except in severe
IRIS) Seizures in 20% Cognitive dysfunction may occur but diffuse encephalopathy
or dementia is rare
May 2013 www.aidsetc.org6
PML:PML: Diagnosis Diagnosis
Compatible clinical syndrome and radiographic findings allow presumptive diagnosis in most cases Clinical: steady progression of focal
neurological deficits
Imaging: MRI is preferred
May 2013 www.aidsetc.org7
PML:PML: Diagnosis Diagnosis (2)(2)
MRI distinct white matter lesions in brain areas corresponding to clinical deficits Usually hyperintense on T2 and FLAIR, hypointense on T1
Usually no mass effect
Contrast enhancement in 10-15% but usually sparse
IRIS PMN may have different appearance
Diffusion-weighted imaging and MR spectroscopy may give additional diagnositic information
CT scan: single or multiple hypodense, nonenhancing white matter lesions
May 2013 www.aidsetc.org8
PML:PML: Diagnosis Diagnosis (3)(3)
PML, CT scan PML, MRI scan
Credit: Images courtesy AIDS Images Library (www.aids-images.ch)
May 2013 www.aidsetc.org9
PML: PML: Diagnosis Diagnosis (4)(4)
Definitive diagnosis: valuable, especially for atypical cases CSF evaluation for JC virus DNA (by PCR):
helpful if positive; 70-90% sensitive in patients who are not on ART (lower in those on ART)
Brain biopsy: identification of JC virus; visualization of oligodendrocytes with intranuclear inclusions, bizarre astrocytes, lipid-laden macrophages
Serologic testing generally not useful, butnewer approaches under investigation
May 2013 www.aidsetc.org10
PML: PML: PreventionPrevention
Preventing exposure No known way to prevent exposure
Preventing disease ART is the only effective way to prevent PML
Prevention of progressive immunosuppression caused by HIV
May 2013 www.aidsetc.org11
PML:PML: Treatment Treatment
No specific therapy Main approach: ART to reverse immune
suppression Start ART immediately for those not on ART; optimize
ART in all on ART without suppression of HIV viremia Effectiveness of ARVs with better CNS penetration is not
established – likely that systemic efficacy is most important, via restoration of anti-JCV immunity
Effective ART stops PML progression in approximately 50%
Neurologic deficits often persist
May 2013 www.aidsetc.org12
PML:PML: Treatment Treatment
Targeted treatments: no proven effective therapies Cytarabine, cidofovir: studies show no clinical benefit;
not recommended
5HT2a receptor inhibitors: clinical trial data lacking; cannot be recommended
Interferon-alfa: no clinical benefit; cannot be recommended
Topotecan: limited data; not recommended
May 2013 www.aidsetc.org13
PML:PML: Starting ART Starting ART
ART should be started immediately upon diagnosis of PML
For persons on ART with HIV viremia, optimize ART to achieve HIV suppression
May 2013 www.aidsetc.org14
PML:PML: Monitoring and Adverse Events Monitoring and Adverse Events
Monitor treatment response with clinical exam and MRI
If detectable JCV DNA in CSF before ART, may repeat quantitation of CSF JCV to assess treatment response (no clear guidelines)
If stable or improving, repeat MRI 6-8 weeks after ART initiation
If clinical worsening, repeat MRI promptly
May 2013 www.aidsetc.org15
PML: PML: Monitoring and Adverse Events Monitoring and Adverse Events (2)(2)
PML IRIS (inflammatory PML) PML may present within first weeks/months after ART initiation, associated with immune reconstitution
Both unmasking of cryptic PML and paradoxical worsening of known PML may occur
Features may be atypical, may include mass effect, edema, contrast enhancement on MRI, more rapid clinical course; perivascular mononuclear inflammatory infiltration on histopathology
May 2013 www.aidsetc.org16
PML:PML: Monitoring and Adverse Events Monitoring and Adverse Events (3)(3)
IRIS management: Corticosteroids may be helpful if substantial
inflammation, edema or mass effect, or clinical deterioration Dosage not established; consider starting with 3- to
5-day course of methylprednisolone 1 g IV QD, followed by prednisone 60 mg PO QD tapered over 1-6 weeks, according to clinical response
Contrast-enhanced MRI at 2-6 weeks – document status of inflammation and edema
ART should be continued
May 2013 www.aidsetc.org17
PML:PML: Treatment Failure Treatment Failure
Clinical worsening and detection of JCV (without significant decrease) at 3 months
Optimize ART, if detectable HIV RNA and poor CD4 response
Consider unproven therapies (see “Treatment”)
May 2013 www.aidsetc.org18
PML:PML: Preventing Recurrence Preventing Recurrence
Effective ART regimen
May 2013 www.aidsetc.org19
PML:PML: Considerations in Pregnancy Considerations in Pregnancy
Diagnosis as in nonpregnant adults
Treatment: optimal ART
May 2013 www.aidsetc.org20
Websites to Access the GuidelinesWebsites to Access the Guidelines
http://www.aidsetc.org
http://aidsinfo.nih.gov
May 2013 www.aidsetc.org21
This presentation was prepared by Susa Coffey, 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
About This Slide SetAbout This Slide Set