2008 Guidelines for Prevention and Treatment of Opportunistic

Infections in HIV-Infected Adults and Adolescents : Part 4

CDCNIH

HIVMA/IDSA

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Human Herpesvirus-8 Disease

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HHV-8: Epidemiology

• Seroprevalence– General population: 1-5%– MSM: 20%–77%– sub-Saharan Africa: 30%–80%

• Associated with– KS (i.e., classic, endemic, transplant related, and

AIDS related) – Primary effusion lymphoma (PEL)– Multicentric Castleman disease (MCD)

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HHV-8: Epidemiology

• HHV-8 viremia associated with a nine-fold increased risk for KS compared with HHV-8 seropositive men without HHV-8 viremia

• HHV-8 viremia almost always accompanies symptomatic episodes of MCD

• KS and PEL most frequently among HIV-infected persons with CD4+ counts of <200 cells/μL– although they can occur at any CD4+ count

• Episodes of MCD may present at any CD4+ count.

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HHV-8: Epidemiology

• Ganciclovir, foscarnet, and cidofovir use inhibit the replication of HHV-8 in vitro

• Patients receiving ganciclovir or foscarnet (but not acyclovir) have a reduced rate for developing KS

• Incidence of KS has declined dramatically after the introduction of PI drugs and highly active ART

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KSHV Genome

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HHV-8: Clinical Manifestations• Most with chronic infection are asymptomatic• Primary infection syndrome consisting of fever, rash,

lymphadenopathy, bone marrow failure, and occasional rapid progression to KS

• MCD presents with generalized adenopathy and fever and may progress to multi-organ failure

• KS – mucocutaneous– lymph node– visceral (occasionally without the presence of skin lesions )

•

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HHV-8: Clinical Manifestations

• Asymptomatic HHV-8 infection is often associated with HHV-8 shedding in the saliva and occasional shedding in genital secretions– these may result in HHV-8 transmission to

uninfected partners

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HHV-8: Diagnosis

• Routine screening for HHV-8 by PCR or serologic testing for HHV-8 antibody is not indicated

• Quantifying HHV-8 in the peripheral blood by PCR is helpful in the diagnosis and management of persons with MCD

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KSHV and LANA in MCD

10LANA: latency associated nuclear antigen

Multicentric Castleman Disease

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Kaposi’s Sarcoma

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Kaposi’s Sarcoma

13KS with lymphedema

Extensive Pulmonary KS

Pulmonary Kaposi’s Sarcoma

14Before Chemotherapy After Chemotherapy

HHV-8: Preventing Disease

• Despite observational evidence supporting a role for anti-HHV-8 therapy in preventing the development of KS, the toxicity of current anti-HHV-8 therapy outweighs the potential benefits of administration

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HHV-8: Treating Disease

• KS regression has been documented after ganciclovir or foscarnet therapy – although one small study indicated cidofovir was

ineffective • The use of IV ganciclovir or oral valganciclovir

is, however, recommended in the treatment of MCD and may be useful adjunctive therapy in the treatment of PEL

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HHV-8: Treating Disease

• Highly active ART that suppresses HIV replication should be administered to all HIV-infected persons with KS, PEL, or MCD

• Chemotherapy, in combination with ART, should be considered for patients with PEL or visceral/extensive cutaneous KS

• Rituximab also appears to be an effective alternative to antiviral therapy in the treatment of MCD

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HHV-8 IRIS

• Fatal IRIS has been reported in persons initiating ART with pre-existing KS and MCD

• The frequency of HHV-8-associated IRIS is not known – but suppression of HIV replication and immune

reconstitution are key components of therapy and initiation of ART should not be delayed.

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HHV-8: Pregnancy• Routine screening for HHV-8 by PCR or serology is not

indicated for pregnant women • Perinatal transmission of HHV-8 may infrequently

occur– cases of KS developing in the infant shortly after birth – higher risk of transmission with higher maternal HHV-8

antibody titer– substantially higher rate of HHV-8 seropositivity among

children born to HHV-8 antibody-positive compared with HHV-8 antibody-negative women

– increased mortality through 24 months among HIV-infected infants born to HHV-8-seropositive compared with HHV-8-seronegative mothers

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Progressive Multifocal Leukoencephalopathy (JC Virus)

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PML: Epidemiology• Caused by the polyoma virus JC virus (JCV) and

characterized by focal demyelination • 85% of adults are seropositive for JCV • Primary JCV infection usually occurs in childhood

– asymptomatic• Chronic asymptomatic carrier – frequent virus detection in urine (30%) and tonsils

(40%) of immunologically normal adults • PML associated with immunosuppression– natalizumab , rituximab– HIV

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PML: Epidemiology

• Incidence of PML has decreased substantially in HAART era

• PML may still appear in with CD4 > 200 as well as in those on ART

• PML may develop in the setting of initiating ART and immune reconstitution

• The overall probability of survival at 6 months was 61.5% in HAART era 1

22Giancola et al. AIDS Res Hum Retroviruses. 2008 Feb;24(2):155-62

PML: Clinical Manifestations

• Focal neurological deficits, usually with insidious onset and steady progression

• Any region of the CNS may be involved but more favored are – the occipital lobes (with hemianopia) – frontal and parietal lobes (hemiparesis and

hemisensory deficits)– cerebellar peduncles and deep white matter

(dysmetria and ataxia)

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PML: Clinical Manifestations

• The time course of this evolving demyelination, with clinical progression over several weeks, often provides a clue to diagnosis – cerebral toxoplasmosis and primary CNS lymphoma

characteristically progress more rapidly over hours or just a few days

– cerebral infarcts begin even more abruptly • Headache and fever are not part of the disease • Seizures in 20%

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PML: Prognostic Factors

• CD4 at presentation– OR (death) 2.71 if CD4<100 (reference:>=100)

• Contrast enhancement at presentation (favorable)

• Radiological improvement at 6 months on ART1

– OR 14.0 (2.2-87.2), p = 0.003

251. Giancola et al. AIDS Res Hum Retroviruses. 2008 Feb;24(2):155-62

Survival with PML

26Falco et al. J Acquir Immune Defic Syndr. 2008 Sep 1;49(1):26-31

PML: Diagnosis

• Combination of clinical and neuroimaging findings– steady progression of focal neurological deficits – MRI almost always confirms distinct white matter

lesions • hyperintense (white) on T2-weighted and FLAIR sequences• hypointense (dark) on T1-weighted sequences• usually no mass effect or displacement of normal structures • Contrast enhancement unusual unless IRIS

– PCR to identify JCV DNA in CSF (+ in 70-90%)– Brain biopsy (rarely necessary)

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PML

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Inflammatory PML: IRIS

• Reported to present within the first weeks to months after initiating ART

• Atypical features that include mass effect of the PML lesions with surrounding edema and sometimes striking contrast enhancement on MRI

• Likelihood of detecting JCV in CSF may be reduced in these patients compared to “classical” PML

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Inflammatory PML: IRIS

• The cellular immune response against JCV, mediated by CD8+ T-lymphocytes, is key in the containment of PML progression and has been associated with a favorable clinical outcome

• However, an “excessive” response related to IRIS may be lethal as a consequence of the inflammatory reaction or, rarely, brain swelling and herniation

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Martinez, J. V. et al. Neurology 2006;67:1692-1694

PML: Before (A,B) and After HAART (1 month: C-E; 3 months: F-G)

Martinez, J. V. et al. Neurology 2006;67:1692-1694

Inflammatory PML

PML: Treatment

• ART should be started immediately • ART should be changed to an effective

regimen if already on ART• Effectiveness of an ART-intensification

strategy in patients with undetectable plasma HIV requires further study

• More than half of patients with PML experience a remission after initiating effective ART

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PML: Treatment

• Not recommended– cytarabine– cidofovir– interferon-alpha– topotecan

• Serotonergic 5HT2a receptor antagonists (e.g. mirtazapine) not justified for routine use– 5HT2a receptor can serve as the cellular receptor

for JCV in a glial cell culture system

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IRIS PML: Treatment• No evidence supporting the routine use of

corticosteroids in HIV-related PML without an inflammatory response on neuroimaging

• In those with progressing clinical deficits and neuoroimaging features suggesting inflammatory disease (edema, swelling, and contrast enhancement), corticosteroid treatment is justified

• Although some have suggested stopping ART in the face of PML-IRIS, this is likely counterproductive in the longer run and is not recommended

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PML: Treatment Failure

• Working definition – continued clinical worsening and continued

detection of CSF JCV at 3 months• Optimize ART• Experimental options

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