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  • progression of the enhancing mass involving the left CN V, possibly the posterior left cavernous sinus, with mass effect on the pons and left middle cerebral penduncle, with associated edema. There was also new enhancement of CN V within left internal auditory canal.
  • KSHV is divided into 6 subtypes, A-E plus N, with A and C dominating in North America and Europe, B predominant in Sub Saharan Africa. The prevalence varies tremendously, from 50% in Sub Saharan Africa. But maps like these have to be interpreted with caution due to considerable variation in the assays.
  • There is extensive literature on modes of transmission, but little clarity has emerged. KSHV has been noted to be transmitted through sexual activity, deep kissing, organ transplant, and rarely mother to child. On top is the prevalence of KSHV in South Africa, bottom is in Uganda. HIV prevalence was roughly the same.

Idconference10 28final-091027054849-phpapp01 Idconference10 28final-091027054849-phpapp01 Presentation Transcript

  • Case Presentation: Progressive Neurological Deficits in a Patient with HIV Jason Andrews Harvard Joint ID Conference October 28, 2009
  • PW, 46 year old man with HIV
    • Diagnosed with HIV in 1988, on/off ARVs
    • Had CD4 of 159
    • Recently restarted Epzicom and Kaletra
    • Five days later presented to ER with left eyelid droop and numbness on the left side of his face
    • MRI Done - No abnormalities detected
  • HPI Continued
    • Over ensuing weeks, numbness spread from V2 to all three branches of facial nerve
    • He was treated with Valacyclovir without improvement
    • He developed numbness, ataxia, dysarthria and dysphagia
    • Also noted fatigue, weight loss, night sweats
  • Past Medical History
    • Dx with HIV in 1988, had cutaneous KS
    • VL 5/09 was 511,000
    • CD4 154, 7.5% (7/20)
    • CD4 240, 9.2% (8/18), VL 5130
    • CD4 110, 7.8% (9/22)
    • Cutaneous KS recurrence, 2005
    • IBD
    • Psoriasis
    • Unexplained Dermopathy (Morgellon’s syndrome)
    • Treated for ?primary syphilis 6/09, RPR/TPPA (-)
    • 30 sexual partners in past 3 years
    • No known TB contacts
    • Two months after onset of symptoms, seen in Neurology clinic
    • Initial MRI reviewed, though to be enhancement of Left Trigeminal Nerve involving V1, V2, V3 intradurally
    • MRI Repeated
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  • Admitted for Expedited Workup
    • Physical Exam:
    • Afebrile, VSS
    • Dysarthric
    • Left eye ptosis
    • Mild dysmetria on FTN
    • Left temporal wasting
    • Diminished hearing left
    • Sensation diminished on left side of face, particularly V1 distr.
    • Labs:
    • CSF: 106 WBC, 0 RBC
    • TP 205, Gluc 45
    • CSF Cytology - Atypical Cells
    • CSF Flow Cytometry Negative
    • CSF EBV negative
    • CSF IgH rearrangement neg
    • CSF VDRL neg
    • CSF VZV & HSV neg
    • RPR & TPPA negative
    • PPD negative
    • CrAg negative
    • Bartonella Serology neg
    • Serum LDH 150
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  • Dr. Jeremy Abramson Cancer Center Massachusetts General Hospital Questions: What HIV-associated malignancies should be considered? What are the next steps in the work-up?
  •  
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  • Myocardial Biopsy Pathology
    • Appearance: Large atypical lymphoid cells infiltrating the myocardium
    • Stains: HHV8 +
    • MUM1/IRF4 +
    • Rare CD79a + large cells CD20 negative
    • In situ hybridization for EBV encoded RNA Neg
    • Impression: HHV8(+) / EBV (-) Diffuse Large B Cell Lymphoma
  • Kaposi’s Sarcoma Herpes Virus
    • Epidemiology of KSHV
    • Expanding Array of Clinical Manifestations in Patients with HIV
    • New insights into treatment
  • Moritz Kaposi (1872): “Idiopathic multiple pigmented sarcoma of the skin”
  • “ Rare Cancer Seen in 41 Homosexuals” New York Times
  • Dukers NH and Rezza G. AIDS 2003, 17:1717-1730
  • Butler LM, et al. JID 2009; 200:430-8.
  • Clinical Manifestations of KSHV/HHV8
    • Kaposi’s Sarcoma
    • a. Classical
    • b. Endemic
    • c. Iatrogenic
    • d. AIDS-associated
    • Primary Effusion Lymphoma
    • Multicentric Castleman’s Disease
    • DLBCL arising from MCD
    • LBCL not arising from MCD**
  • Multicentric Castleman’s Disease
    • Presents with recurrent lymphadenopathy, fever, fatigue, hepatosplenomegaly.
    • KSHV identified in ~100% of HIV-associated and most non-HIV-associated cases
    • Associated with plasmablastic NHL
    • Treatment options:
        • Antiretroviral therapy - caution with IRIS
        • Combination chemotherapy +/- rituximab
        • Rituximab monotherapy
        • Antivirals (ganciclovir)
    Aaron L, et al. CID 2002. 35:880-82.
  • Is the incidence of MCD increasing? Perhaps MCD not related to immune suppression; unlike KS, not associated with paucity of HHV8-specific CD8+ T cells Powles T, et al. Annals of Oncology 2009, 20:775-79.
  • Primary Effusion Lymphoma (PEL)
    • Classic PEL: lymphomatous involvement of serosal surfaces, causing effusions (e.g. pleural, pericardial, peritoneal)
    • Phenotype: CD19 & CD20 (B cell markers) and CD2,CD3,CD5,CD7 (T cell markers) typically not seen
    • Solid PEL: solid lymphoma with PEL phenotypic features.
  • 24 patients, Median Survival: MCD 44 months, PEL 6 months, Solid Lymphoma 22 days. Simonelli C, et al. J Med Virol 2009;81:888-896.
  • What is the role of KSHV viral load?
    • Observational study of 21 patients with known AIDS-related KS.
    • 15/15 pts with KS VL < 1.5 log had non- progression or remission.
    • 5/6 pts with KS VL > 1.5 log had progression of their KS.
    • HIV VL and CD4 count were not predictive.
    • ART use was not reported
    • Quinlivan EB, et al. JID 2002; 185:1736-44.
  • KS viral load correlates with KS clinical stage KS viral load is higher in patients with HIV Campbell TB, et al. CID 2003; 36:1144-51.
  • Is there a role for antivirals?
    • RCT of ganciclovir for CMV retinitis, the six month incidence of KS was:
    • 11.3% in placebo group
    • 2.7% in oral ganciclovir group (+ ocular implant)
    • 1.5% in IV ganciclovir group
    • (N=377)
    • Randomized, double-blind, placebo controlled cross over trial of valganciclovir for 8 weeks significantly reduced viral shedding
    • (N=26, not designed for clinical endpoints)
    • Case series:
      • 3 patients at UW: clinical improvement, decline in HHV8 viral load in patients with MCD
      • Cidofovir was used in 5 patients with MCD and failed
      • Foscarnet used successfully in one case, unsuccessful in another
    • Martin D, et al. NEJM 1999;340:1063-70
    • Casper C, et al. JID 2008;198:23-30.
  • Antiretroviral Therapy
    • Most Studies Show Reduced Risk of KS and NHL
    • International Collaboration on HIV and Cancer (N=47,936)
    • For KS: ART - RR 0.32 (0.26-0.40)
    • For NHL ART - RR 0.58 (0.45-0.74)
    • French Hospital Database on HIV (N=52,278):
    • For KS: ART - RR 0.3 (0.2-0.4) (P<0.0001)
    • For NHL ART - RR 0.8 (0.6-1.0) (P=0.07)
    • J Natl Cancer Inst 2000 92(22);1823-30.
  • NHL Survival in HAART Era Bower MA, et al. Ann Int Med 2005; 143:265-273.
  • Developing NHL While on ART
    • Adjusted Risk of Death
      • No ART at Diagnosis Ref
      • ART < 90 Days 1.3
      • ART > 90 Days 2.0
  • EBV and KSHV in HIV-associated Lymphomas
    • Our Patient:
    • EBV (-)
    • KSHV (+)
    • Large B cell
    • Not arising from MCD
    • Extranodal
    • CD20 (-)
    Carbone A, et al. Blood 2009;113:1213-1224.
  • Take Home Points
    • KSHV is increasingly recognized as having a role in HIV-associated lymphoproliferative disorders
    • The Important Classes are:
        • Multicentric Castleman’s Disease
        • Primary Effusion Lymphoma / Solid PEL
        • DLBCL
    • There may be a role for antivirals.. awaiting further studies
    • ART: prevents, improves outcomes, but developing NHL on it bodes poorly
  • Thank you
    • Greg Robbins
    • Jeremy Abramson
    • Nesli Basgoz