3. HHV-8: Epidemiology
โข Seroprevalence
โ General population: 1-5%
โ MSM: 20%โ77%
โ sub-Saharan Africa: 30%โ80%
โข Associated with
โ KS (i.e., classic, endemic, transplant related, and
AIDS related)
โ Primary effusion lymphoma (PEL)
โ Multicentric Castleman disease (MCD)
3
4. HHV-8: Epidemiology
โข HHV-8 viremia associated with a nine-fold
increased risk for KS compared with HHV-8
seropositive men without HHV-8 viremia
โข HHV-8 viremia almost always accompanies
symptomatic episodes of MCD
โข KS and PEL most frequently among HIV-infected
persons with CD4+ counts of <200 cells/ฮผL
โ although they can occur at any CD4+ count
โข Episodes of MCD may present at any CD4+ count.
4
5. HHV-8: Epidemiology
โข Ganciclovir, foscarnet, and cidofovir use
inhibit the replication of HHV-8 in vitro
โข Patients receiving ganciclovir or foscarnet (but
not acyclovir) have a reduced rate for
developing KS
โข Incidence of KS has declined dramatically after
the introduction of PI drugs and highly active
ART
5
7. HHV-8: Clinical Manifestations
โข Most with chronic infection are asymptomatic
โข Primary infection syndrome consisting of fever, rash,
lymphadenopathy, bone marrow failure, and
occasional rapid progression to KS
โข MCD presents with generalized adenopathy and fever
and may progress to multi-organ failure
โข KS
โ mucocutaneous
โ lymph node
โ visceral (occasionally without the presence of skin lesions )
โข
7
8. HHV-8: Clinical Manifestations
โข Asymptomatic HHV-8 infection is often
associated with HHV-8 shedding in the saliva
and occasional shedding in genital secretions
โ these may result in HHV-8 transmission to
uninfected partners
8
9. HHV-8: Diagnosis
โข Routine screening for HHV-8 by PCR or
serologic testing for HHV-8 antibody is not
indicated
โข Quantifying HHV-8 in the peripheral blood by
PCR is helpful in the diagnosis and
management of persons with MCD
9
10. KSHV and LANA in MCD
10
LANA: latency associated nuclear antigen
15. HHV-8: Preventing Disease
โข 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
15
16. HHV-8: Treating Disease
โข KS regression has been documented after
ganciclovir or foscarnet therapy
โ although one small study indicated cidofovir was
ineffective
โข 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
16
17. HHV-8: Treating Disease
โข Highly active ART that suppresses HIV
replication should be administered to all HIV-
infected persons with KS, PEL, or MCD
โข Chemotherapy, in combination with ART,
should be considered for patients with PEL or
visceral/extensive cutaneous KS
โข Rituximab also appears to be an effective
alternative to antiviral therapy in the
treatment of MCD
17
18. HHV-8 IRIS
โข Fatal IRIS has been reported in persons
initiating ART with pre-existing KS and MCD
โข The frequency of HHV-8-associated IRIS is not
known
โ but suppression of HIV replication and immune
reconstitution are key components of therapy and
initiation of ART should not be delayed.
18
19. HHV-8: Pregnancy
โข Routine screening for HHV-8 by PCR or serology is not
indicated for pregnant women
โข Perinatal transmission of HHV-8 may infrequently
occur
โ cases of KS developing in the infant shortly after birth
โ higher risk of transmission with higher maternal HHV-8
antibody titer
โ substantially higher rate of HHV-8 seropositivity among
children born to HHV-8 antibody-positive compared with
HHV-8 antibody-negative women
โ increased mortality through 24 months among HIV-
infected infants born to HHV-8-seropositive compared
with HHV-8-seronegative mothers
19
21. PML: Epidemiology
โข Caused by the polyoma virus JC virus (JCV) and
characterized by focal demyelination
โข 85% of adults are seropositive for JCV
โข Primary JCV infection usually occurs in childhood
โ asymptomatic
โข Chronic asymptomatic carrier
โ frequent virus detection in urine (30%) and tonsils
(40%) of immunologically normal adults
โข PML associated with immunosuppression
โ natalizumab , rituximab
โ HIV
21
22. PML: Epidemiology
โข Incidence of PML has decreased substantially
in HAART era
โข PML may still appear in with CD4 > 200 as well
as in those on ART
โข PML may develop in the setting of initiating
ART and immune reconstitution
โข The overall probability of survival at 6 months
was 61.5% in HAART era 1
22
Giancola et al. AIDS Res Hum Retroviruses. 2008 Feb;24(2):155-62
23. PML: Clinical Manifestations
โข Focal neurological deficits, usually with
insidious onset and steady progression
โข Any region of the CNS may be involved but
more favored are
โ the occipital lobes (with hemianopia)
โ frontal and parietal lobes (hemiparesis and
hemisensory deficits)
โ cerebellar peduncles and deep white matter
(dysmetria and ataxia)
23
24. PML: Clinical Manifestations
โข The time course of this evolving demyelination,
with clinical progression over several weeks,
often provides a clue to diagnosis
โ cerebral toxoplasmosis and primary CNS lymphoma
characteristically progress more rapidly over hours or
just a few days
โ cerebral infarcts begin even more abruptly
โข Headache and fever are not part of the disease
โข Seizures in 20%
24
25. PML: Prognostic Factors
โข CD4 at presentation
โ OR (death) 2.71 if CD4<100 (reference:>=100)
โข Contrast enhancement at presentation
(favorable)
โข Radiological improvement at 6 months on
ART1
โ OR 14.0 (2.2-87.2), p = 0.003
25
1. Giancola et al. AIDS Res Hum Retroviruses. 2008 Feb;24(2):155-62
27. PML: Diagnosis
โข Combination of clinical and neuroimaging
findings
โ steady progression of focal neurological deficits
โ MRI almost always confirms distinct white matter
lesions
โข hyperintense (white) on T2-weighted and FLAIR sequences
โข hypointense (dark) on T1-weighted sequences
โข usually no mass effect or displacement of normal structures
โข Contrast enhancement unusual unless IRIS
โ PCR to identify JCV DNA in CSF (+ in 70-90%)
โ Brain biopsy (rarely necessary)
27
29. Inflammatory PML: IRIS
โข Reported to present within the first weeks to
months after initiating ART
โข Atypical features that include mass effect of
the PML lesions with surrounding edema and
sometimes striking contrast enhancement on
MRI
โข Likelihood of detecting JCV in CSF may be
reduced in these patients compared to
โclassicalโ PML
29
30. Inflammatory PML: IRIS
โข 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
โข However, an โexcessiveโ response related to
IRIS may be lethal as a consequence of the
inflammatory reaction or, rarely, brain
swelling and herniation
30
31. 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)
32. Martinez, J. V. et al. Neurology 2006;67:1692-1694
Inflammatory PML
33. PML: Treatment
โข ART should be started immediately
โข ART should be changed to an effective
regimen if already on ART
โข Effectiveness of an ART-intensification
strategy in patients with undetectable plasma
HIV requires further study
โข More than half of patients with PML
experience a remission after initiating
effective ART
33
34. PML: Treatment
โข Not recommended
โ cytarabine
โ cidofovir
โ interferon-alpha
โ topotecan
โข Serotonergic 5HT2a receptor antagonists (e.g.
mirtazapine) not justified for routine use
โ 5HT2a receptor can serve as the cellular receptor
for JCV in a glial cell culture system
34
35. IRIS PML: Treatment
โข No evidence supporting the routine use of
corticosteroids in HIV-related PML without an
inflammatory response on neuroimaging
โข In those with progressing clinical deficits and
neuoroimaging features suggesting inflammatory
disease (edema, swelling, and contrast enhancement),
corticosteroid treatment is justified
โข Although some have suggested stopping ART in the
face of PML-IRIS, this is likely counterproductive in the
longer run and is not recommended
35
36. PML: Treatment Failure
โข Working definition
โ continued clinical worsening and continued
detection of CSF JCV at 3 months
โข Optimize ART
โข Experimental options
36
Editor's Notes
Schematic representation of KSHV genome showing some of the genes involved in the pathogenesis of KSHV-related neoplasias. The differential transcriptional pattern found in KS, MCD, and PEL in a signigicant number of cells is shown. Transcripts in brackets refer to occasional lytic (virus replicating) cells in KS lesions. KSโKaposi's sarcoma; KSHVโKaposi's sarcoma-associated herpesvirus; MCDโmulticentric Castleman's disease; PELโprimary effusion lymphoma.
Expression of KSHV proteins in primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) is shown. A, KSHV latency-associated nuclear antigen (LANA) is expressed in almost all PEL cells. Inset depicts the speckled nuclear localization of LANA. B, A few tumor cells from a peritoneal biopsy with invasive PEL are immunopositive for viral IL-6. C, Lymph node biopsy from a plasma cell variant of KSHV-associated MCD displays hyalinization of germinal centers, targetoid mantle zone, and increased vascularity. D, Only a subpopulation of mantle zone lymphocytes from an MCD lymph node biopsy stains positive for KSHV LANA with a nuclear staining pattern
Lymph node biopsy from a plasma cell variant of KSHV-associated MCD displays hyalinization of germinal centers, targetoid mantle zone, and increased vascularity.
E , Extensive cutaneous epidemic/AIDS KS that is cosmetically disfiguring in an East African patient. F , Extensive oral mucosal epidemic/AIDS KS in an East African patient. Oral lesions are also common and frequently involve the gingivae.
Chemotherapy response. Patients with symptomatic visceral Kaposi's sarcoma (KS) may benefit significantly from chemotherapy. A , Chest radiograph from a patient with extensive pulmonary KS before chemotherapy. B , After chemotherapy, the patient shows marked improvement of bilateral pulmonary lesions.
Progressive multifocal leukoencephalopathy (PML). This unenhanced CT of an HIV-infected boy aged 9 years with PML shows hypodensity of the periventricular white matter in both frontal regions. No mass effect occurs on adjacent structures. Mild dilatation of the lateral ventricles because of brain atrophy is seen. PML is uncommon in children. It is the only disease caused by the JC virus and occurs most frequently as a devastating neurologic syndrome with insidious onset and progression over weeks or months.
Figure 1. (A and B) Initial brain nuclear MR (NMR), July 2004. Axial fluid-attenuated inversion recover (FLAIR) fast spin echo (FSE) (repetition time [TR]/echo time [TE] = 8,000/120 milliseconds, inversion time [TI] = 2,200 milliseconds) image (A) shows high signal intensity lesion in the white matter of the right frontal and parietal lobes and left centrum semiovale without mass effect. No enhancement was present on contrast enhanced T1-weighted (500/15 milliseconds) image (B). (C through E) Follow-up brain NMR, October 2004 (1 month after initiation of highly active antiretroviral therapy). Axial FLAIR FSE (TR/TE = 8,000/120 milliseconds, TI = 2,200 milliseconds) image (C) shows progression of white matter abnormalities with mass effect and compression of the right ventricle. On T1-weighted (500/15 milliseconds) images (D and E), diffuse enhancement of white matter abnormalities is present. (F and G) Subsequent brain MRI, January 2005 (3 months after immune reconstitution inflammatory syndrome). Axial FLAIR FSE (TR/TE = 8,000/120 milliseconds, TI = 2,200 milliseconds) image (F) shows white matter abnormalities without mass effect; no enhancement is observed in coronal T1-weighted (500/15 milliseconds) image (G).
Figure 2. (A) "Ground glass" viral inclusion in oligodendrocyte with inflammatory cells (arrow). Hematoxylinโeosin (HE); x400. (B) Inflammatory cells around vessel wall and within the brain parenchyma (arrows). HE; x400. (C) In situ hybridization to JC virus. The arrow shows oligodendrocyte nuclei. Original magnification, x1,000. Positive reaction for JC.