Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents


Human Herpesvirus-8

Last Updated: May 7, 2013; Last Reviewed: July 25, 2017

NOTE: Update in Progress


Human herpesvirus-8 (HHV-8) seroprevalence among the general population in the United States is 1% to 5%. The seroprevalence is greater among men who have sex with men (20%–77%),1 regardless of HIV infection, and is also higher in certain Mediterranean countries (10%–20%) and in parts of sub-Saharan Africa (30%–80%).2 HHV-8 is etiologically associated with all forms of Kaposi’s sarcoma ([KS] i.e., classic, endemic, transplant-related, and AIDS-related) and certain rare neoplastic disorders (such as primary effusion lymphoma)  and lymphoproliferative disorders (multicentric Castleman’s disease) The precise pathogenesis is unclear even though seroconversion to HHV-8 precedes the development of these tumors.3 Patients who are HHV-8 seropositive and have HHV-8 viremia have an increased risk (approximately nine-fold) for developing KS compared with HHV-8 seropositive men without HHV-8 viremia.4 HHV-8 viremia almost always accompanies symptomatic episodes of multicentric Castleman’s disease.5 

The overall prevalence of KS was as high as 30% among patients with AIDS before the advent of effective antriretroviral therapy (ART).6 The incidence of KS, which increased nearly 10-fold in the United States between 1981 and 1987, began to gradually decline in 1987.7 Reasons for this reduction in KS incidence prior to the widespread availability of ART are likely to be multiple, including the deaths of patients with advanced AIDS who were most susceptible to KS, and the increasing use by HIV-infected individuals of antiviral drugs that may have activity against HHV-8 (zidovudine for the treatment of HIV; ganciclovir, foscarnet, and cidofovir use for treatment of CMV disease).8 Supporting the latter hypothesis, observational studies indicate that patients receiving ganciclovir or foscarnet (but not acyclovir) develop KS at a reduced rate.9-12 A more marked reduction in KS incidence occurred in 1996, shortly after the introduction of protease inhibitor-containing ART in the United States. Today the incidence of KS in the United States remains approximately 3-fold higher than before the HIV pandemic, and notably KS incidence has not declined in regions of sub-Saharan Africa where ART coverage is increasing but incomplete.13 Primary effusion cell lymphoma and multicentric Castleman’s disease remain rare.14 

KS and primary effusion lymphoma are described most frequently among HIV-infected persons with more advanced immunosuppression (CD4 T lymphocyte [CD4] cell counts <200 cells/µL), although they can occur at any CD4 cell count. Multicentric Castleman’s disease can present at any CD4 cell count. Recent reports of KS occurring at higher CD4 cell counts in the United States15,16 suggest that clinicians caring for patients with HIV should be vigilant for the clinical manifestations of KS in patients at risk of HHV-8 infection, regardless of CD4 cell count.

Clinical Manifestations

Most individuals with chronic HHV-8 infection are asymptomatic.17 Acquisition of HHV-8 in immunocompetent children and organ transplant recipients has been associated with a primary infection syndrome consisting of fever, rash, lymphadenopathy, bone marrow failure, and occasional rapid progression to KS.18,19 KS manifestations vary widely, but most patients have nontender, purplish, indurated skin lesions. Intraoral lesions are common and visceral dissemination can occur, occasionally without the presence of skin lesions. Multicentric Castleman’s disease manifests with generalized adenopathy and fever and can progress to multi-organ failure.14 Primary effusion lymphoma characteristically presents with effusions of the pleural, pericardial, or abdominal spaces; mass lesions can be seen but are less common manifestations.


The diagnoses of KS, multicentric Castlemans disease and primary effusion lymphoma depend on cytologic and immunologic cell markers, as well as histology. Routine screening for HHV-8 by polymerese chain reaction (PCR) or serologic testing for HHV-8 antibody is not indicated for HIV-infected persons. Use of PCR to quantify HHV-8 in the peripheral blood has no established role in the diagnosis of KS, multicentric Castleman’s disease and primary effusion lymphoma.5

Preventing Exposure

Asymptomatic HHV-8 infection is often associated with HHV-8 shedding in the saliva and occasional shedding in genital secretions.1,17,20 Viral shedding may result in HHV-8 transmission to uninfected partners through behaviors associated with exposure to saliva or genital secretions. Recommendations related to preventing exposure to HHV-8 do not exist; screening patients for HHV-8 serostatus and recommending behavioral modifications based on such information is not likely to be highly effective, has not been validated, and is not currently recommended (CIII).

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 (BIII). Because the strongest risk factor for the development of KS in HIV-positive individuals is a low CD4 cell count,21 early initiation of ART is likely to be the most effective measure for the prevention of KS.

Treating Disease

Although ganciclovir, foscarnet, and cidofovir have in vitro activity against HHV-8 and limited studies indicate these agents may be associated with reduced KS disease progression or lesion regression, larger and more definitive studies are needed to determine whether antiviral therapy has a useful role in managing HHV-8-associated diseases. KS regression has been documented after ganciclovir or foscarnet therapy, although one study indicated cidofovir was ineffective.22 

The use of IV ganciclovir or oral valganciclovir is an option for treatment of multicentric Castleman’s disease (CII). A 3-week course of twice-daily IV ganciclovir or oral valganciclovir was associated with remissions in multicentric Castleman’s disease in one report,23 and a combination of valganciclovir and high-dose zidovudine given for 7 to 21 days led to durable clinical remissions of the disease (CII).24 Rituximab also is an effective alternative to antiviral therapy in the treatment of multicentric Castleman’s disease (CII),25,26 though up to one-third of patients treated with rituximab may have subsequent exacerbations or emergence of KS.27,28 

Chemotherapy, in combination with ART, should be administered to patients with primary effusion cell lymphoma or visceral KS (AI) and is likely to be a useful adjunctive therapy in individuals with widely disseminated cutaneous KS (BIII). Some clinicians recommend valganciclovir as adjunctive therapy in the treatment of primary effusion lymphoma but there are no convincing data that it is useful (CIII).29,30 

Detailed recommendations for treatment of HHV-8 malignancies (including chemotherapy and radiation therapy) are beyond the scope of these guidelines. Treatment should be undertaken in consultation with an experienced specialist (AIII).

Special Considerations When Starting ART

Early initiation of ART is likely to prevent incident KS and primary effusion cell lymphoma, though no studies have confirmed this hypothesis to date. ART that suppresses HIV replication should be administered to all HIV-infected patients with KS, primary effusion cell lymphoma, or multicentric Castleman’s disease (AII), although insufficient evidence exists to support using one ART regimen over another.

Monitoring of Response to Therapy and Adverse Events (Including IRIS)

Immune reconstitution inflammatory syndrome (IRIS) has been a reported complication among HHV-8-infected patients initiating ART. 

KS: In one series, new onset KS or exacerbations of previously stable disease were the most common IRIS syndrome in a cohort of HIV-infected patients in Seattle.31 Over half of Ugandan patients with mild-to-moderate KS experienced an exacerbation when initating ART.32 Reliable predictors of KS-IRIS have not been identified.

Multicentric Castleman’s disease: A small number of patients with HIV-associated multicentric Castleman’s disease were also observed to have a clinical decompensation upon initiation of ART.33,34

Primary effusion lymphoma: No data exist on the frequency with which initiation of ART complicates the course of primary effusion lymphoma.

Taken together, it is clear that neither the incidence nor predictors of HHV-8-associated IRIS are well-described, but suppression of HIV replication and immune reconstitution are key components of therapy and initiation of ART should not be delayed (AIII).

Preventing Recurrence

Effective suppression of HIV replication with ART in HIV-infected patients with KS may prevent KS progression or occurrence of new lesions, and because KS is an AIDS-defining cancer, ART is indicated for all patients with active KS (AII). Suppression of HIV replication also is recommended for patients with multicentric Castleman’s disease (AIII) and those with malignant lymphoproliferative disorders (AIII).

Special Considerations During Pregnancy

The seroprevalence of HHV-8 infection among HIV-infected pregnant women varies by geographic area, ranging from 1.7% among U.S.-born and 3.6% among Haitian-born women in New York City to 11.6% among pregnant women from 4 other U.S. cities.35 Pregnancy does not appear to affect the prevalence of antibodies to HHV-8 or the antibody levels,36 although levels of HHV-8 DNA in the peripheral blood may increase late in pregnancy.37 HHV-8 seropositivity does not appear to influence pregnancy outcome. Routine screening for HHV-8 by PCR or serology is not indicated for HIV-infected pregnant women (AIII). Antiviral therapy for HHV-8 infection in pregnancy is not recommended (AIII).

In vitro models suggest that beta-human chorionic gonadotropin induces regression of KS tumors, but clinical reports on the incidence and natural history of KS in pregnancy are conflicting.38-41 

Perinatal transmission of HHV-8 occurs infrequently. Evidence supporting vertical transmission during pregnancy or the intrapartum period includes cases of KS occurring in the infant shortly after birth,42,43 higher risk for transmission with higher maternal antibody titer (and, by inference, higher maternal levels of HHV-8),44 and detection of similar strains of HHV-8 DNA by PCR in specimens drawn at birth from HHV-8-seropositive mothers and their infants.45 Data indicate increased mortality through age 24 months among HIV-infected infants born to HHV-8-seropositive compared with HHV-8-seronegative mothers,42-44,46-51 but these studies could not completely account for other confounding factors affecting HIV-infected infants. The majority of studies document a substantially higher rate of HHV-8 seropositivity among children born to HHV-8 antibody-positive compared with HHV-8 antibody-negative women.46-51 

Recommendations for Treating HHV-8 Diseases—Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL), Multicentric Castleman’s Disease (MCD)
Mild-to-Moderate KS:
  • Initiation or optimization of ART (AII)
Advanced KS:
  • Chemotherapy (in consultation with specialist) + ART [visceral KS (AI) or widely disseminated KS (BIII)]
  • Chemotherapy (in consultation with specialist) + ART (AI)
  • Oral valganciclovir or IV ganciclovir might be used as adjunctive therapy (CIII)
Preferred Therapy (in consultation with a specialist):
  • Valganciclovir 900 mg PO BID (CII) for 3 weeks, or
  • Ganciclovir 5 mg/kg IV q12h (CII) for 3 weeks, or
  • Valganciclovir 900 mg PO BID + zidovudine 600 mg PO q6h for 7–21 days (CII)
Alternative Therapy for MCD:
  • Rituximab 375 mg/m2 given weekly for 4–8 weeks, may be an alternative to, or used adjunctively with, antiviral therapy (CII)
Other Considerations:
  • Patients who received rituximab for treatment of MCD may experience subsequent exacerbation or emergence of KS
Key to Acronyms: ART = antiretroviral therapy; BID = twice daily; IV = intraveneously; KS = Karposi Sarcoma; MCD = multicentric Castleman’s disease; PEL = primary effusion lymphoma; PO = orally; q(n)h = every ”n” hours


  1. Pauk J, Huang ML, Brodie SJ, et al. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med. Nov 9 2000;343(19):1369-1377. Available at
  2. Dollard SC, Butler LM, Jones AMG, et al. Substantial regional differences in human herpesvirus 8 seroprevalence in sub-Saharan Africa: Insights on the origin of the “Kaposi's sarcoma belt”. International Journal of Cancer. 2010;127(10):2395-2401. Available at
  3. Gao SJ, Kingsley L, Hoover DR, et al. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med. Jul 25 1996;335(4):233-241. Available at
  4. Lennette ET, Blackbourn DJ, Levy JA. Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet. Sep 28 1996;348(9031):858-861. Available at
  5. Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood. Sep 15 2000;96(6):2069-2073. Available at
  6. Beral V. The epidemiology of cancer in AIDS patients. AIDS. 1991;5 Suppl 2:S99-103. Available at
  7. Eltom MA, Jemal A, Mbulaiteye SM, Devesa SS, Biggar RJ. Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer Inst. Aug 21 2002;94(16):1204-1210. Available at
  8. Casper C. Defining a role for antiviral drugs in the treatment of persons with HHV-8 infection. Herpes : the journal of the IHMF. Aug 2006;13(2):42-47. Available at
  9. Martin DF, Kuppermann BD, Wolitz RA, Palestine AG, Li H, Robinson CA. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl J Med. Apr 8 1999;340(14):1063-1070. Available at
  10. Ioannidis JP, Collier AC, Cooper DA, et al. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis. Aug 1998;178(2):349-359. Available at
  11. Mocroft A, Youle M, Gazzard B, Morcinek J, Halai R, Phillips AN. Anti-herpesvirus treatment and risk of Kaposi's sarcoma in HIV infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group. AIDS. Sep 1996;10(10):1101-1105. Available at
  12. Glesby MJ, Hoover DR, Weng S, et al. Use of antiherpes drugs and the risk of Kaposi's sarcoma: data from the Multicenter AIDS Cohort Study. J Infect Dis. Jun 1996;173(6):1477-1480. Available at
  13. Casper C. The increasing burden of HIV-associated malignancies in resource-limited regions. Annual review of medicine. 2011;62:157-170. Available at
  14. Casper C. The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care. British journal of haematology. Apr 2005;129(1):3-17. Available at
  15. Maurer T, Ponte M, Leslie K. HIV-associated Kaposi's sarcoma with a high CD4 count and a low viral load. N Engl J Med. Sep 27 2007;357(13):1352-1353. Available at
  16. Mani D, Neil N, Israel R, Aboulafia DM. A retrospective analysis of AIDS-associated Kaposi's sarcoma in patients with undetectable HIV viral loads and CD4 counts greater than 300 cells/mm(3). J Int Assoc Physicians AIDS Care (Chic). Sep-Oct 2009;8(5):279-285. Available at
  17. Casper C, Krantz E, Selke S, et al. Frequent and asymptomatic oropharyngeal shedding of human herpesvirus 8 among immunocompetent men. J Infect Dis. Jan 1 2007;195(1):30-36. Available at
  18. Andreoni M, Sarmati L, Nicastri E, et al. Primary human herpesvirus 8 infection in immunocompetent children. JAMA. Mar 13 2002;287(10):1295-1300. Available at
  19. Luppi M, Barozzi P, Schulz TF, et al. Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med. Nov 9 2000;343(19):1378-1385. Available at
  20. Casper C, Redman M, Huang ML, et al. HIV infection and human herpesvirus-8 oral shedding among men who have sex with men. J Acquir Immune Defic Syndr. Mar 1 2004;35(3):233-238. Available at
  21. Lodi S, Guiguet M, Costagliola D, et al. Kaposi sarcoma incidence and survival among HIV-infected homosexual men after HIV seroconversion. J Natl Cancer Inst. Jun 2 2010;102(11):784-792. Available at
  22. Little RF, Merced-Galindez F, Staskus K, et al. A pilot study of cidofovir in patients with kaposi sarcoma. J Infect Dis. Jan 1 2003;187(1):149-153. Available at
  23. Casper C, Nichols WG, Huang ML, Corey L, Wald A. Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood. Mar 1 2004;103(5):1632-1634. Available at
  24. Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood. Jun 30 2011;117(26):6977-6986. Available at
  25. Bower M, Newsom-Davis T, Naresh K, et al. Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease. J Clin Oncol. Jun 20 2011;29(18):2481-2486. Available at
  26. Marcelin AG, Aaron L, Mateus C, et al. Rituximab therapy for HIV-associated Castleman disease. Blood. Oct 15 2003;102(8):2786-2788. Available at
  27. Gerard L, Berezne 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. August 1, 2007 2007;25(22):3350-3356. Available at 
  28. Bower M, Powles T, Williams S, et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med. Dec 18 2007;147(12):836-839. Available at
  29. Aboulafia DM. Interleukin-2, ganciclovir, and high-dose zidovudine for the treatment of AIDS-associated primary central nervous system lymphoma. Clin Infect Dis. Jun 15 2002;34(12):1660-1662. Available at
  30. Crum-Cianflone NF, Wallace MR, Looney D. Successful secondary prophylaxis for primary effusion lymphoma with human herpesvirus 8 therapy. AIDS. Jul 13 2006;20(11):1567-1569. Available at
  31. Achenbach CJ, Harrington RD, Dhanireddy S, Crane HM, Casper C, Kitahata MM. Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection. Clin Infect Dis. Feb 1 2012;54(3):424-433. Available at
  32. Martin D, Gutkind JS. Kaposi's sarcoma virally encoded, G-protein-coupled receptor: a paradigm for paracrine transformation. Methods Enzymol. 2009;460:125-150. Available at
  33. Aaron L, Lidove O, Yousry C, Roudiere L, Dupont B, Viard JP. Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin Infect Dis. Oct 1 2002;35(7):880-882. Available at
  34. Achenbach C, Kitahata MM. Recurrence or Worsening of AIDS-defining Opportunistic Infection (OI) due to Immune Reconstitution Inflammatory Syndrome (IRIS) During Initial HAART Among a Clinic-Based Population. Paper presented at: 48th ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC.
  35. Goedert JJ, Kedes DH, Ganem D. Antibodies to human herpesvirus 8 in women and infants born in Haiti and the USA. Lancet. May 10 1997;349(9062):1368. Available at
  36. Huang LM, Huang SY, Chen MY, et al. Geographical differences in human herpesvirus 8 seroepidemiology: a survey of 1,201 individuals in Asia. J Med Virol. Mar 2000;60(3):290-293. Available at
  37. Lisco A, Barbierato M, Fiore JR, et al. Pregnancy and human herpesvirus 8 reactivation in human immunodeficiency virus type 1-infected women. J Clin Microbiol. Nov 2006;44(11):3863-3871. Available at
  38. Berger P, Dirnhofer S. Kaposi's sarcoma in pregnant women. Nature. Sep 7 1995;377(6544):21-22. Available at
  39. Lunardi-Iskandar Y, Bryant JL, Zeman RA, et al. Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone. Nature. May 4 1995;375(6526):64-68. Available at
  40. Rabkin CS, Chibwe G, Muyunda K, Musaba E. Kaposi's sarcoma in pregnant women. Nature. Sep 7 1995;377(6544):21; author reply 22. Available at
  41. Schulz TF, Weiss RA. Kaposi's sarcoma. A finger on the culprit. Nature. Jan 5 1995;373(6509):17-18. Available at
  42. Gutierrez-Ortega P, Hierro-Orozco S, Sanchez-Cisneros R, Montano LF. Kaposi's sarcoma in a 6-day-old infant with human immunodeficiency virus. Archives of dermatology. Mar 1989;125(3):432-433. Available at
  43. McCarthy GA, Kampmann B, Novelli V, Miller RF, Mercey DE, Gibb D. Vertical transmission of Kaposi's sarcoma. Archives of disease in childhood. May 1996;74(5):455-457. Available at
  44. Sitas F, Newton R, Boshoff C. Increasing probability of mother-to-child transmission of HHV-8 with increasing maternal antibody titer for HHV-8. N Engl J Med. Jun 17 1999;340(24):1923. Available at
  45. Mbulaiteye S, Marshall V, Bagni RK, et al. Molecular evidence for mother-to-child transmission of Kaposi sarcoma-associated herpesvirus in Uganda and K1 gene evolution within the host. J Infect Dis. May 1 2006;193(9):1250-1257. Available at
  46. Mantina H, Kankasa C, Klaskala W, et al. Vertical transmission of Kaposi's sarcoma-associated herpesvirus. Int J Cancer. Dec 1 2001;94(5):749-752. Available at
  47. Serraino D, Locatelli M, Songini M, et al. Human herpes virus-8 infection among pregnant women and their children: results from the Sardinia-IDDM Study 2. Int J Cancer. Mar 1 2001;91(5):740-741. Available at
  48. Gessain A, Mauclere P, van Beveren M, et al. Human herpesvirus 8 primary infection occurs during childhood in Cameroon, Central Africa. Int J Cancer. Apr 12 1999;81(2):189-192. Available at
  49. Bourboulia D, Whitby D, Boshoff C, et al. Serologic evidence for mother-to-child transmission of Kaposi sarcoma-associated herpesvirus infection. JAMA. Jul 1 1998;280(1):31-32. Available at
  50. Whitby D, Smith NA, Matthews S, et al. Human herpesvirus 8: seroepidemiology among women and detection in the genital tract of seropositive women. J Infect Dis. Jan 1999;179(1):234-236. Available at
  51. Plancoulaine S, Abel L, van Beveren M, et al. Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population. Lancet. Sep 23 2000;356(9235):1062-1065. Available at

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