- Human herpesvirus-8 (HHV8): human gammaherpesvirus, also known as Kaposi’s sarcoma herpesvirus (KSHV).
- 20-30% of men who have sex with men (MSM) are HHV8 seropositive vs 1% of HIV-1 negative blood donors.
- Associated with receptive anal intercourse and the 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.
- 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 [Fig 1], mucous membranes [Fig 2] and/or viscera (e.g., GI tract and lungs).
- HIV-associated KS is seen mostly in MSM. 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 the skin [Fig 3] 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.
- The virus has been associated with KS as well as a febrile illness in the setting of bone marrow failure in transplant populations.
SITES OF INFECTION
- Mucocutaneous: skin, oropharynx.
- Endothelial and spindle cells contain HHV-8 DNA.
- Visceral organs
- 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.
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)
- The first line of therapy should probably be antiretroviral therapy (ART) 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 combination with HAART had a 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 the HHV-8 genes encodes a viral variant of this cytokine).
- A case series showed that the initiation of ART 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.
- 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
- Cesarman E, Damania B, Krown SE, et al. Kaposi sarcoma. Nat Rev Dis Primers. 2019;5(1):9. [PMID:30705286]
Comment: A comprehensive review of KS.
- Kaegi C, Wuest B, Schreiner J, et al. Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders. Front Immunol. 2019;10:1990. [PMID:31555262]
Comment: Reviews 8 trials of rituximab in Castleman disease. Most patients achieved remission
- Bhutani M, Polizzotto MN, Uldrick TS, et al. Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Semin Oncol. 2015;42(2):223-46. [PMID:25843728]
Comment: Review that describes current concepts and using immunomodulators as knowledge of oncologic pathogenesis expands.
- Uldrick TS, Polizzotto MN, Aleman K, et al. Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood. 2014;124(24):3544-52. [PMID:25331113]
Comment: This combination regimen was effective and well tolerated and 3 year survival rate was 81%
- Mosam A, Shaik F, Uldrick TS, 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. 2012;60(2):150-7. [PMID:22395672]
Comment: Patients treated with HAART and chemotherapy had higher KS response rate, but there was no difference in survival at 12 months
- Bower M. How I treat HIV-associated multicentric Castleman disease. Blood. 2010;116(22):4415-21. [PMID:20688959]
Comment: The authors advocate rituximab, and for aggressive disease adds chemotherapy.
- Nguyen HQ, Magaret AS, Kitahata MM, et al. Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: characterizing the predictors of clinical response. AIDS. 2008;22(8):937-45. [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.
- Bower M, Powles T, Williams S, et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med. 2007;147(12):836-9. [PMID:18087054]
Comment: Study showing 95% 2-year survival in 21 previously untreated patients with HIV-associated Castleman’s disease treated with rituximab.
- Gérard L, Bérezné A, Galicier 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. 2007;25(22):3350-6. [PMID:17664482]
Comment: Study showing that rituximab infusions after chemotherapy lead to prolonged sustained remission in HIV-infected patients with Castleman's disease.
- Hladik W, Dollard SC, Mermin J, et al. Transmission of human herpesvirus 8 by blood transfusion. N Engl J Med. 2006;355(13):1331-8. [PMID:17005950]
Comment: Study showing 2.8% excess risk of HHV-8 seroconversion following blood transfusion in Uganda.
- Blajchman MA, Vamvakas EC. The continuing risk of transfusion-transmitted infections. N Engl J Med. 2006;355(13):1303-5. [PMID:17005947]
Comment: Editorial on the risk of transmission of HHV-8 via blood transfusions.
- Stebbing J, Sanitt A, Nelson M, et al. A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet. 2006;367(9521):1495-502. [PMID:16679162]
Comment: Study defining positive and negative prognostic factors in AIDS-associated KS.
- Grabar S, Abraham B, Mahamat A, et al. Differential impact of combination antiretroviral therapy in preventing Kaposi's sarcoma with and without visceral involvement. J Clin Oncol. 2006;24(21):3408-14. [PMID:16849755]
Comment: Large retrospective study showing a dramatic decrease in the incidence of KS related to HAART. No difference in incidence was seen in pts on PI vs NNRTI based regimens.
- Little RF, Merced-Galindez F, Staskus K, et al. A pilot study of cidofovir in patients with kaposi sarcoma. J Infect Dis. 2003;187(1):149-53. [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 a progression of the disease with no decrease in HHV-8 viral load.
- Aaron L, Lidove O, Yousry C, et al. Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin Infect Dis. 2002;35(7):880-2. [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.
- Luppi M, Barozzi P, Rasini V, et al. Severe pancytopenia and hemophagocytosis after HHV-8 primary infection in a renal transplant patient successfully treated with foscarnet. Transplantation. 2002;74(1):131-2. [PMID:12134112]
Comment: A 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 the restoration of blood counts.
- Luppi M, Barozzi P, Schulz TF, et al. Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med. 2000;343(19):1378-85. [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
- Cordero E, López-Cortés LF, Viciana P, et al. Foscarnet and AIDS-associated Kaposi's sarcoma. AIDS. 1997;11(14):1787-8. [PMID:9386820]
Comment: Six 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.
- Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266(5192):1865-9. [PMID:7997879]
Comment: First identification of HHV-8 sequences in Kaposi Sarcoma lesions.
Typical cutaneous lesion that ranges in presentation from flatter to nodular, pigmented to violaceous/vascular.
Source: CDC/Dr. Steve Kraus
KS mucosal lesion
Intraoral KS in patient with AIDS. About 10% of patients with advanced AIDS will have mucosal lesions of KS. Lesions may be small to larger, nodular growths.
Source: CDC, S. Silverman DDS San Francisco
WIth endemic or classic KS, lesions often seen on ankle or foot region with flat, violaceous lesions.
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