2008 guidelines for_prevention_and_treatment_of_opportunistic_4
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Transcript of 2008 guidelines for_prevention_and_treatment_of_opportunistic_4
2008 Guidelines for Prevention and Treatment of Opportunistic
Infections in HIV-Infected Adults and Adolescents : Part 4
CDCNIH
HIVMA/IDSA
1
Human Herpesvirus-8 Disease
2
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)
3
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.
4
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
5
KSHV Genome
6
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 )
•
7
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
8
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
9
KSHV and LANA in MCD
10LANA: latency associated nuclear antigen
Multicentric Castleman Disease
11
Kaposi’s Sarcoma
12
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
15
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
16
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
17
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.
18
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
19
Progressive Multifocal Leukoencephalopathy (JC Virus)
20
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
21
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)
23
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%
24
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)
27
PML
28
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
29
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
30
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
33
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
34
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
35
PML: Treatment Failure
• Working definition – continued clinical worsening and continued
detection of CSF JCV at 3 months• Optimize ART• Experimental options
36