- Member of human gamma herpesvirus family. 90-95% in US infected by adult years. Most HIV+ individuals also harbor EBV.
- Establishes latent infection. Spread mostly by asymptomatic shedding of virus into salivary secretions.
- Virus also may be shed in semen and vaginal secretions.
- Primary infection: subclinical, especially in children or clinical (infectious mononucleosis, IM); peak incidence of IM in teens and early 20’s.
- Presence of EBV may be considered as a tumor marker in proper clinical context.
- May be the cancer promoter in certain types of non-Hodgkin lymphoma (NHL, e.g., Burkitt’s lymphoma [mostly in Africa], diffuse large B-cell, extra-nodal natural killer/T-cell nasal type) and nasopharyngeal carcinoma.
- Tumors more common in setting of low CD4 counts.
- EBV infection established in most individuals prior to HIV infection.
- EBV+ and HIV: >60x risk of NHL over general population, though overall risk remains small.
- In HIV, EBV most highly associated with primary CNS lymphoma (PCNSL).
- EBV CSF PCR + in ~ specific 100%, especially if using high copy number (e.g., in thousands instead of low hundreds).
- Studies suggest CSF PCR equivalent to brain Bx (sensitivity 83-100%, specificity 93-100%).
- In HIV, EBV most highly associated with primary CNS lymphoma (PCNSL).
- Primary CNS lymphoma: EBV PCR, if positive in proper clinical scenario.
- Role of EBV PCR (quantitative) of blood uncertain: conflicting data regarding correlation with risk of NHL.
- Significance of EBV PCR in other tissues and fluids less certain, though described with smooth muscle tumors in HIV+ pts.
- Clinical reliability depends on assay used.
- Infectious mononucleosis:
- Monospot (heterophile antibodies, serum) used to dx IM (~90% positive).
- 10% Monospot-negative and may require dx through EBV-specific serology, e.g., EBV capsid IgM, IgG, and EBNA antibodies.
- False positive Monospot may be caused by acute HIV infection, and Sx can be similar.
- Since EBV establishes latency within cells, eradication impossible.
SITES OF INFECTION
- HIV-related lymphomas:
- B cell lymphoma (~100% CNS, ~50% peripheral lymphomas associated w/ EBV)
- T/NK cell lymphoma (10-100% depending on histological grade)
- Sporadic Burkitts lymphoma (~25%),
- Primary effusion lymphoma (70-80%, but 100% also contain HHV-8).
- See Lymphoma, Non-Hodgkins (NHL), Lymphoma, Hodgkins, Lymphoma, Primary CNS (PCNSL).
- Nasopharyngeal carcinoma
- Leiomyosarcoma: mainly in children
- Oral hairy leukoplakia (OHL): painless, white/gray patches on lateral margins of tongue caused by intense lytic-phase replication of EBV. Patches may spread to other parts of tongue and oral cavity.
- DDx=thrush, squamous cell CA, leukoplakia. Dx by appearance and location, cannot scrape off, unlike Candida.
- Infectious mononucleosis: cardinal triad of fever, lymphadenopathy and pharyngitis. Unclear if presentation of primary EBV infection different in setting of HIV. More details about IM found in Epstein-Barr virus ABX Guide module.
Oral Hairy Leukoplakia
- Infection of epithelial cells, usually focused upon the tongue. Only seen in immunosuppression or immune-senescence.
- May be typically predictive of HIV infection, but may also occur in those with non-HIV malignancies, iatrogenic immunosuppression including post-transplant.
- Treatment: specific EBV therapy usually unnecessary.
- ART preferred as means to improve immune system and control lytic-phase EBV replication.
- EBV-specific anti-viral therapy:
- Topical treatments:
- Small studies have examined use of podophyllin (25%) resin, acyclovir (5%), penciclovir (1%). Most suggest healing of lesions with best success when combining podophyllin + acyclovir.
- Drugs may can limit EBV replication and may improve appearances; however, lesions recur with stopping therapy.
- Other options include cryotherapy, surgical removal and topical podophyllin with variable results.
- IM usually self-limited < 3 wks average, rest and supportive care.
- Corticosteroids (prednisone 40-60 mg/d) indicated for airway obstruction, severe thrombocytopenia or hemolytic anemia. Some give for severe pharyngitis or constitutional Sx (controversial).
- Acyclovir/ganciclovir: no role in IM. Reduces viral shedding in mouth, but no clinical benefit.
- Ganciclovir employed by some for EBV CNS disease, but little data backing this practice.
Selected Drug Comments
Acyclovir and other antivirals such as famciclovir, valacyclovir, foscarnet and val/ganciclovir can all limit acute phase replication and viral shedding. Can use to treat OHL, but will recur without treatment of immunosuppression. Clinical impact of these drugs on HIV-related lymphomas is uncertain.
Limited data suggestive ganciclovir lowers EBV viral load in vivo, especially for PCNSL, but clinical utility undefined.
Basis for recommendation
- Patton LL, Ramirez-Amador V, Anaya-Saavedra G, et al. Urban legends series: oral manifestations of HIV infection. Oral Dis. 2013;19(6):533-50. [PMID:23517181]
Comment: Practical and heavily referenced review addresses questions regrding oral lesions in HIV infected patients. Review includes topical therapies for OHL.
- Grulich AE, Vajdic CM. The Epidemiology of Cancers in Human Immunodeficiency Virus Infection and After Organ Transplantation. Semin Oncol. 2015;42(2):247-257. [PMID:25843729]
Comment: EBV-related malignancies among the top causes in HIV, along with HHV8 and non-Hodgkin’s lymphoma (NHL). EBV may be the promoter in certain types of Burkitt’s lymphoma (mostly in Africa), NHL (including diffuse large B-cel, extra-nodal natural killer/T-cell nasal type) and nasopharyngeal carcinoma.
- Yanagisawa K, Tanuma J, Hagiwara S, et al. Epstein-Barr viral load in cerebrospinal fluid as a diagnostic marker of central nervous system involvement of AIDS-related lymphoma. Intern Med. 2013;52(9):955-9. [PMID:23648713]
Comment: Authors using retrospective data suggest that a cut off of EBV copies of 200/ml predicted CNS lesions (sensitivity 70-73%, specificity 85-93%) with both PCNSL and AIDS-related lymphoma, respectively. Best specificity was acheived using a cut-off of 2,000 copies.
- Tsibris AM, Paredes R, Chadburn A, et al. Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211. Clin Infect Dis. 2009;48(5):642-9. [PMID:19191652]
Comment: Because 4 lymphomas developed during a phase II trial of vicriviroc (a CCR5 antagonist), plasma EBV DNA was monitored in 116 pts who did not experience increases in detectable levels, suggesting that CCR5 antagonism by this drug did not lead to EBV reactivation.
- Carbone A, Cesarman E, Spina M, et al. HIV-associated lymphomas and gamma-herpesviruses. Blood. 2009;113(6):1213-24. [PMID:18955561]
Comment: Thorough overview from an oncologic perspective points out that EBV-driven lymphomas often present with plasmablastic differentiation in HIV+ pts, and that ART appears improve outcomes with combined chemotherapy protocols.
- Corcoran C, Rebe K, van der Plas H, et al. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol. 2008;42(4):433-6. [PMID:18455472]
Comment: Some have questioned specificity of CSF EBV PCR in Dx of CNS lymphoma in HIV+ pts. This study suggests that addition of quantitative aspect (namely >10,000 c/ml) improves specificity and positive predictive value compared to qualitative result for Dx of PCNSL (96% vs. 66% and 50% vs. 10%, respectively).
- Aboulafia DM, Ratner L, Miles SA, et al. Antiviral and immunomodulatory treatment for AIDS-related primary central nervous system lymphoma: AIDS Malignancies Consortium pilot study 019. Clin Lymphoma Myeloma. 2006;6(5):399-402. [PMID:16640817]
Comment: Small study suggests that treatment with ganciclovir, AZT and IL-2 may have been helpful in 2/5 patients.
- Bossolasco S, Falk KI, Ponzoni M, et al. Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2006;42(4):e21-5. [PMID:16421782]
Comment: Along with Aboulafia ref, data suggesting that active replication of EBV may be playing role in PCNSL.
- Bonnet F, Jouvencel AC, Parrens M, et al. A longitudinal and prospective study of Epstein-Barr virus load in AIDS-related non-Hodgkin lymphoma. J Clin Virol. 2006;36(4):258-63. [PMID:16762591]
Comment: EBV PCR was not helpful diagnostically, but higher EBV PCR viral load correlated with poorer outcomes in HIV+ population with NHL.
- Suankratay C, Shuangshoti S, Mutirangura A, et al. Epstein-Barr virus infection-associated smooth-muscle tumors in patients with AIDS. Clin Infect Dis. 2005;40(10):1521-8. [PMID:15844077]
Comment: Case series describing an association.
- Cingolani A, Fratino L, Scoppettuolo G, et al. Changing pattern of primary cerebral lymphoma in the highly active antiretroviral therapy era. J Neurovirol. 2005;11 Suppl 3:38-44. [PMID:16540454]
Comment: Reviews largely anecdotal experience suggesting that ART is influencing both epidemiology and outcomes of PCNSL.
- Ivers LC, Kim AY, Sax PE. Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2004;38(11):1629-32. [PMID:15156453]
Comment: Small series refuting claimed high sensitivity/specificity of EBV CSF PCR. Here 26 pts studied with CNS processes, but PCR had only 29% positive predictive value, and specificity 79%. This study more likely reflects real-life statistics in evaluating a diffuse set of CNS conditions in HIV. Authors suggest test useful for ruling out lymphoma, but Dx requires brain Bx.
- Walling DM, Flaitz CM, Nichols CM. Epstein-Barr virus replication in oral hairy leukoplakia: response, persistence, and resistance to treatment with valacyclovir. J Infect Dis. 2003;188(6):883-90. [PMID:12964120]
Comment: Small RCT of 19 HIV+ pts. examining use of valacyclovir (with better bioavailability than acyclovir) in treatment of OHL. Most cases resolved, though in some cases productive EBV replication recurred after discontinuation of treatment. In a few treated cases, treatment failed, which authors attributed to drug-resistant EBV.
- Crawford DH, Swerdlow AJ, Higgins C, et al. Sexual history and Epstein-Barr virus infection. J Infect Dis. 2002;186(6):731-6. [PMID:12198605]
Comment: Study of university students in Scotland suggests EBV acquired more frequently in those sexually active. However, since kissing and intercourse are closely related behaviors, it is still unclear whether EBV is commonly acquired by other than salivary shedding.
- Vidrih JA, Walensky RP, Sax PE, et al. Positive Epstein-Barr virus heterophile antibody tests in patients with primary human immunodeficiency virus infection. Am J Med. 2001;111(3):192-4. [PMID:11530029]
Comment: Report describes 3 pts suspected of IM with positive heterophile (Monospot) testing who instead had acute HIV infection, with EBV-specific serologies not suggesting acute EBV infection. These cases add to other reports showing that the Monospot can be falsely positive in pts with primary HIV infection.
- Rosenberg ES, Caliendo AM, Walker BD. Acute HIV infection among patients tested for mononucleosis. N Engl J Med. 1999;340(12):969. [PMID:10094651]
Comment: Retrospective study examined unselected pts with suspected IM who had negative heterophile antibody tests. 2% had HIV disease by plasma HIV RNA testing. Of those, half had primary HIV infection, and half had chronic HIV disease.
- Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology. 1997;48(3):687-94. [PMID:9065549]
Comment: One of the better papers suggesting diagnostic utility of CSF EBV DNA PCR in patients with PCNSL. In 136 HIV+ pts with brain lesions, examining both EBV DNA or T. gondii-DNA tests, positive predictive value for PCNSL increased to >0.96. Regardless, authors suggested that brain Bx still necessary to establish Dx of PCNSL. However, brain Bx mortality may be ~2%, so this needs to be weighed against risks of inappropriately receiving brain irradiation.
- Beral V, Peterman T, Berkelman R, et al. AIDS-associated non-Hodgkin lymphoma. Lancet. 1991;337(8745):805-9. [PMID:1672911]
Comment: Report from pre-HAART era suggesting 60-fold increased risk of NHL in HIV+ pts and linking risks to EBV. From CDC-gathered information 1686 cases were immunoblastic lymphoma, 548 primary CNS lymphoma, and 590 Burkitts lymphoma, a condition not normally associated with immunosuppression.
- Dias EP, Israel MS, Silva Junior A, et al. Prevalence of oral hairy leukoplakia in 120 pediatric patients infected with HIV-1. Braz Oral Res. 2006;20(2):103-7. [PMID:16878201]
Comment: OHL described on subclinical (histopathological) basis in ~17% of HIV+ pediatric patients, which is higher than prior reports in adult populations.
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