MICROBIOLOGY

  • Human herpesvirus-8 (HHV8): human gammaherpes virus, also known as Kaposi’s sarcoma herpesvirus (KSHV).
  • 20-30% of homosexual males HHV8 seropositive vs 1% of HIV-1 negative blood donors.
    • Associated with receptive anal intercourse and number of partners.
    • An unknown cofactor may be involved in transmission.
  • HHV-8 gene products promote spindle cell proliferation and angiogenesis and may therefore eventually lead to tumor transformation.

CLINICAL

  • Virus is either likely cause or has been associated with the following:
    • HIV-associated Kaposi sarcoma (KS): typically characterized by violaceous vascular lesions on skin, mucous membranes and/or viscera (e.g., GI tract and lungs).
      • HIV-associated KS is seen mostly in homosexual men. HHV-8 found in saliva and semen.
      • Pulmonary KS typically presents with dyspnea, cough, chest pain or hemoptysis.
      • Gastrointestinal KS can cause abdominal pain, intestinal obstruction or hemorrhage.
    • Classic KS (non HIV-associated): variant is usually limited to skin and typically affects elderly Mediterranean and East European men.
    • Endemic African KS: presentation varies from skin lesions only to aggressive systemic disease.
    • Multicentric Castleman’s disease: lymphoproliferative disorder mostly seen in HIV+ patients, characterized by B type symptoms, lymphadenopathy, hypergammaglobulinemia.
    • Primary effusion lymphoma: a non Hodgkin’s Disease B cell lymphoma mostly seen in HIV+ patients. Presents with body cavity based effusions in the absence of a solid tumor.
  • Virus has been associated with KS as well as a febrile illness in setting of bone marrow failure in transplant populations.

SITES OF INFECTION

  • Mucocutaneous: skin, oropharynx.
    • Endothelial and spindle cells contain HHV-8 DNA.
  • Visceral organs
  • Lung
  • Gastrointestinal tract
  • HHV-8 DNA found in saliva, semen, blood (viremia in HIV and transplant pts), B cells of primary effusion lymphoma and lymphoid tissue of multicentric Castleman’s disease.

TREATMENT

Kaposi Sarcoma (local disease <25 lesions)

  • Options include cryotherapy, radiation therapy or surgery.
  • Topical alitretinoin has been shown to have an approximately 35% partial response: apply 0.1% gel to affected site 2-4x/day.
  • Intralesional vinblastine injection: 0.2-0.3 mg/ml: 0.1ml/0.5 cm2 lesion; result in 60-90% clinical response rate.

Kaposi Sarcoma (Systemic Disease)

  • First line of therapy should probably be HAART in HIV infected patients or reduction of immunosuppressive therapy in transplant patients.
  • Combination chemotherapy often suggested.
    • Paclitaxel 100 mg/m2 every 2 weeks was associated with a 59% response rate.
    • Pegylated liposomal doxorubicin 40 mg/m2 q2wk has been shown to be more effective than chemotherapy with 58% response rate.
    • A regimen of bleomycin, doxorubicin and vincristine given in comination with HAART had better response rate than HAART alone.

Multicentric Castleman's Disease

  • Combination chemotherapy usual, consult oncology.
    • Rituximab (375 mg/m2, once weekly for 4 weeks) has been shown to be very effective
    • Rituximab in combination with liposomal doxorubicin has been effective in patients with severe disease
    • Etoposide 100-200mg/m2, once weekly for 4 weeks, can be given with rituximab to help prevent relapses
  • Anti-IL6 antibody has been useful in alleviating symptoms due to IL-6 overproduction (one of HHV-8 genes encodes a viral variant of this cytokine).
  • A case series showed that the initiation of HAART did not prevent relapse of disease, but may prolong survival.

Primary febrile illness with BM failure

  • A reduction in immunosuppressive therapy in conjunction with foscarnet 80 mg/kg twice-daily x 2 weeks was successful on a case report basis in a transplant patient.

OTHER INFORMATION

  • HHV-8 mostly causes disease mainly in immunocompromised individuals
  • Interferon-alpha probably is effective in KS because it has both antiviral and immunomodulatory effects.
  • Pulmonary KS can be life threatening and should be treated immediately.

Basis for recommendation

  1. Sullivan RJ et al: HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis 47:1209, 2008  [PMID:18808357]

    Comment: Recent review of HHV-8 associated diseases.

References

  1. Cordero E et al: Foscarnet and AIDS-associated Kaposi's sarcoma. AIDS 11:1787, 1997  [PMID:9386820]

    Comment: 6 patients with HIV associated KS were treated with foscarnet at 180 mg/Kg once-daily for a mean of 19.5 days. By 3 months after the end of treatment, the disease had progressed in all patients.

  2. Bhutani M et al: Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Semin Oncol 42:223, 2015  [PMID:25843728]

    Comment: Review that describes current concepts and using immunomodulators as knowledge of oncologic pathogenesis expands.

  3. Bower M: How I treat HIV-associated multicentric Castleman disease. Blood 116:4415, 2010  [PMID:20688959]

    Comment: Author advocates rituxamab, and for aggressive disease adds chemotherapy.

  4. Luppi M et al: Severe pancytopenia and hemophagocytosis after HHV-8 primary infection in a renal transplant patient successfully treated with foscarnet. Transplantation 74:131, 2002  [PMID:12134112]

    Comment: Case report of a kidney transplant patient who developed a febrile illness and BM failure in the setting of HHV-8 viremia. Treatment with foscarnet leads to restoration of blood counts.

  5. Aaron L et al: Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin Infect Dis 35:880, 2002  [PMID:12228826]

    Comment: Case series of 7 HIV infected patients with Castleman's disease who were treated with HAART. While relapse of disease occurred, mean survival (48 months) was longer than expected.
    Rating: Important

  6. Luppi M et al: Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med 343:1378, 2000  [PMID:11070102]

    Comment: Description of febrile illness and BM failure in the setting of primary or reactivation HHV-8 disease in 3 solid organ transplant patients

  7. Blajchman MA, Vamvakas EC: The continuing risk of transfusion-transmitted infections. N Engl J Med 355:1303, 2006  [PMID:17005947]

    Comment: Editorial on the risk of transmission of HHV-8 via blood transfusions.

  8. Chang Y et al: Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865, 1994  [PMID:7997879]

    Comment: First identification of HHV-8 sequences in Kaposi Sarcoma lesions.

  9. Little RF et al: A pilot study of cidofovir in patients with kaposi sarcoma. J Infect Dis 187:149, 2003  [PMID:12508160]

    Comment: Five patients with HIV-KS and 2 pts with non-HIV KS were treated with cidofovir at 5mg/kg q wk x 2 weeks then every other week. All 7 pts had progression of disease with no decrease in HHV-8 viral load.
    Rating: Important

  10. Grabar S et al: Differential impact of combination antiretroviral therapy in preventing Kaposi's sarcoma with and without visceral involvement. J Clin Oncol 24:3408, 2006  [PMID:16849755]

    Comment: Large retrospective study showing dramatic decrease in the incidence of KS related to HAART. No difference in incidence was seen in pts on PI vs NNRTI based regimens.

  11. Mosam A et al: A randomized controlled trial of highly active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa. J Acquir Immune Defic Syndr 60:150, 2012  [PMID:22395672]

    Comment: Patients treated with HAART and chemotherapy had higher KS response rate, but there was no difference in survival at 12 months
    Rating: Important

  12. Nguyen HQ et al: Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: characterizing the predictors of clinical response. AIDS 22:937, 2008  [PMID:18453853]

    Comment: Retrospective analysis showed that chemotherapy and HAART were the two factors associated with positive outcomes in 114 patients with KS. There was no difference in outcome seen in PI based vs NNRTI based HAART.
    Rating: Important

  13. Stebbing J et al: A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet 367:1495, 2006  [PMID:16679162]

    Comment: Study defining positive and negative prognostic factors in AIDS associated KS.

  14. Hladik W et al: Transmission of human herpesvirus 8 by blood transfusion. N Engl J Med 355:1331, 2006  [PMID:17005950]

    Comment: Study showing 2.8% excess risk of HHV-8 seroconversion following blood transfusion in Uganda.
    Rating: Important

  15. Bower M et al: Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med 147:836, 2007  [PMID:18087054]

    Comment: Study showing 95% 2 year survival in 21 previously untreated patients with HIV-associated Castleman's disease treated with rituximab.

  16. Gérard L et al: Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial. J Clin Oncol 25:3350, 2007  [PMID:17664482]

    Comment: Study showing that rituximab infusions after chemotherapy lead to prolonged sustained remission in HIV-infected patients with Castleman's disease.

  17. Uldrick TS et al: Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood 124:3544, 2014  [PMID:25331113]

    Comment: This combination regimen was effective and well tolerated and 3 year survival rate was 81%
    Rating: Important

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Last updated: November 17, 2015