2008 Guidelines for Prevention and
Treatment of Opportunistic
Infections in HIV-Infected Adults
and Adolescents : Part 4
C...
Human Herpesvirus-8 Disease
2
HHV-8: Epidemiology
• Seroprevalence
– General population: 1-5%
– MSM: 20%–77%
– sub-Saharan Africa: 30%–80%
• Associated ...
HHV-8: Epidemiology
• HHV-8 viremia associated with a nine-fold
increased risk for KS compared with HHV-8
seropositive men...
HHV-8: Epidemiology
• Ganciclovir, foscarnet, and cidofovir use
inhibit the replication of HHV-8 in vitro
• Patients recei...
KSHV Genome
6
HHV-8: Clinical Manifestations
• Most with chronic infection are asymptomatic
• Primary infection syndrome consisting of f...
HHV-8: Clinical Manifestations
• Asymptomatic HHV-8 infection is often
associated with HHV-8 shedding in the saliva
and oc...
HHV-8: Diagnosis
• Routine screening for HHV-8 by PCR or
serologic testing for HHV-8 antibody is not
indicated
• Quantifyi...
KSHV and LANA in MCD
10
LANA: 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
14
Before Chemotherapy After Chemotherapy
HHV-8: Preventing Disease
• Despite observational evidence supporting a
role for anti-HHV-8 therapy in preventing the
deve...
HHV-8: Treating Disease
• KS regression has been documented after
ganciclovir or foscarnet therapy
– although one small st...
HHV-8: Treating Disease
• Highly active ART that suppresses HIV
replication should be administered to all HIV-
infected pe...
HHV-8 IRIS
• Fatal IRIS has been reported in persons
initiating ART with pre-existing KS and MCD
• The frequency of HHV-8-...
HHV-8: Pregnancy
• Routine screening for HHV-8 by PCR or serology is not
indicated for pregnant women
• Perinatal transmis...
Progressive Multifocal
Leukoencephalopathy (JC Virus)
20
PML: Epidemiology
• Caused by the polyoma virus JC virus (JCV) and
characterized by focal demyelination
• 85% of adults ar...
PML: Epidemiology
• Incidence of PML has decreased substantially
in HAART era
• PML may still appear in with CD4 > 200 as ...
PML: Clinical Manifestations
• Focal neurological deficits, usually with
insidious onset and steady progression
• Any regi...
PML: Clinical Manifestations
• The time course of this evolving demyelination,
with clinical progression over several week...
PML: Prognostic Factors
• CD4 at presentation
– OR (death) 2.71 if CD4<100 (reference:>=100)
• Contrast enhancement at pre...
Survival with PML
26
Falco 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
– M...
PML
28
Inflammatory PML: IRIS
• Reported to present within the first weeks to
months after initiating ART
• Atypical features tha...
Inflammatory PML: IRIS
• The cellular immune response against JCV,
mediated by CD8+ T-lymphocytes, is key in the
containme...
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
• Eff...
PML: Treatment
• Not recommended
– cytarabine
– cidofovir
– interferon-alpha
– topotecan
• Serotonergic 5HT2a receptor ant...
IRIS PML: Treatment
• No evidence supporting the routine use of
corticosteroids in HIV-related PML without an
inflammatory...
PML: Treatment Failure
• Working definition
– continued clinical worsening and continued
detection of CSF JCV at 3 months
...
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  • 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. KS—Kaposi&apos;s sarcoma; KSHV—Kaposi&apos;s sarcoma-associated herpesvirus; MCD—multicentric Castleman&apos;s disease; PEL—primary effusion lymphoma.
  • Expression of KSHV proteins in primary effusion lymphoma (PEL) and multicentric Castleman&apos;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&apos;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) &quot;Ground glass&quot; viral inclusion in oligodendrocyte with inflammatory cells (arrow). Hematoxylin–eosin (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.
  • 2008 guidelines for_prevention_and_treatment_of_opportunistic_4

    1. 1. 2008 Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents : Part 4 CDC NIH HIVMA/IDSA 1
    2. 2. Human Herpesvirus-8 Disease 2
    3. 3. 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
    4. 4. 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
    5. 5. 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
    6. 6. KSHV Genome 6
    7. 7. 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
    8. 8. 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
    9. 9. 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
    10. 10. KSHV and LANA in MCD 10 LANA: latency associated nuclear antigen
    11. 11. Multicentric Castleman Disease 11
    12. 12. Kaposi’s Sarcoma 12
    13. 13. Kaposi’s Sarcoma 13KS with lymphedema Extensive Pulmonary KS
    14. 14. Pulmonary Kaposi’s Sarcoma 14 Before Chemotherapy After Chemotherapy
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. 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
    19. 19. 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
    20. 20. Progressive Multifocal Leukoencephalopathy (JC Virus) 20
    21. 21. 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
    22. 22. 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 22 Giancola et al. AIDS Res Hum Retroviruses. 2008 Feb;24(2):155-62
    23. 23. 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
    24. 24. 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
    25. 25. 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 25 1. Giancola et al. AIDS Res Hum Retroviruses. 2008 Feb;24(2):155-62
    26. 26. Survival with PML 26 Falco et al. J Acquir Immune Defic Syndr. 2008 Sep 1;49(1):26-31
    27. 27. 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
    28. 28. PML 28
    29. 29. 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
    30. 30. 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
    31. 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. 32. Martinez, J. V. et al. Neurology 2006;67:1692-1694 Inflammatory PML
    33. 33. 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
    34. 34. 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
    35. 35. 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
    36. 36. PML: Treatment Failure • Working definition – continued clinical worsening and continued detection of CSF JCV at 3 months • Optimize ART • Experimental options 36

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