Guidelines for Prevention and Treatment of Opportunistic Infections

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Progressive Multifocal Leukoencephalopathy (PML) 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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 2 May 2013 www. aidsetc. org

PML: Epidemiology § 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 3 May 2013 www. aidsetc. org

PML: Epidemiology (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 CD 4 count, but may occur with CD 4 count >200 cells/μL and in those on ART § Rarely occurs in HIV-uninfected immunocompromised persons 4 § Reported in persons treated with immunomodulatory humanized antibodies (eg, natalizumab, efalizumab, infliximab, rituximab) May 2013 www. aidsetc. org

PML: Clinical 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 5 May 2013 www. aidsetc. org

PML: Diagnosis § Compatible clinical syndrome and radiographic findings allow presumptive diagnosis in most cases § Clinical: steady progression of focal neurological deficits § Imaging: MRI is preferred 6 May 2013 www. aidsetc. org

PML: Diagnosis (2) § MRI distinct white matter lesions in brain areas corresponding to clinical deficits § Usually hyperintense on T 2 and FLAIR, hypointense on T 1 § 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 7 May 2013 www. aidsetc. org

PML: Diagnosis (3) PML, CT scan PML, MRI scan Credit: Images courtesy AIDS Images Library (www. aids-images. ch) 8 May 2013 www. aidsetc. org

PML: Diagnosis (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, lipidladen macrophages § Serologic testing generally not useful, but newer approaches under investigation 9 May 2013 www. aidsetc. org

PML: Prevention § 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 10 May 2013 www. aidsetc. org

PML: 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 11 May 2013 www. aidsetc. org

PML: Treatment § Targeted treatments: no proven effective therapies § Cytarabine, cidofovir: studies show no clinical benefit; not recommended § 5 HT 2 a receptor inhibitors: clinical trial data lacking; cannot be recommended § Interferon-alfa: no clinical benefit; cannot be recommended § Topotecan: limited data; not recommended 12 May 2013 www. aidsetc. org

PML: Starting ART § ART should be started immediately upon diagnosis of PML § For persons on ART with HIV viremia, optimize ART to achieve HIV suppression 13 May 2013 www. aidsetc. org

PML: 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 14 May 2013 www. aidsetc. org

PML: Monitoring and Adverse Events (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 15 May 2013 www. aidsetc. org

PML: Monitoring and Adverse Events (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 16 May 2013 www. aidsetc. org

PML: Treatment Failure § Clinical worsening and detection of JCV (without significant decrease) at 3 months § Optimize ART, if detectable HIV RNA and poor CD 4 response § Consider unproven therapies (see “Treatment”) 17 May 2013 www. aidsetc. org

PML: Preventing Recurrence § Effective ART regimen 18 May 2013 www. aidsetc. org

PML: Considerations in Pregnancy § Diagnosis as in nonpregnant adults § Treatment: optimal ART 19 May 2013 www. aidsetc. org

Websites to Access the Guidelines § http: //www. aidsetc. org § http: //aidsinfo. nih. gov 20 May 2013 www. aidsetc. org

About This Slide Set § 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 21 May 2013 www. aidsetc. org