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"EBV: The red haired stepchild that we should pay attention to!" by Steven P. LaRosa,M.D.

Epstein -Barr Virus (EBV), a member of the Herpes Virus family is often overlooked compared to its cousins HSV-1, HSV-2, VZV and CMV. As an Infectious Disease physician I suspect that this is in part due a taint that goes back to the days of patients complaining that they had "Chronic EBV" or chronic fatigue due to EBV (neither of which was true). Additionally, the currently available anti-virals Acyclovir, Valacyclovir, Ganciclovir and Valganciclovir have not demonstrated clinical improvement in patients with EBV infection.
EBV infects approximately 90 % of people during their lifetime. Approximately 30-40% of people infected will develop acute infectious mononucleosis (IM).The annual rate of IM in college students and military recruits is 1-5%. This is characterized by high fevers, lymphadenopathy, exudative pharyngitis, transaminitis, and splenomegaly. While acute IM from EBV is not associated with significant mortality  it is associated with a significant morbidity. Those with acute EBV are usually young and active, have a median duration of symptoms of 20 days and end up missing school or work during this time.A Cochrane review has been performed on 7 clinical trials of antivirals in IM involving 333 subjects. In 2 trials (acyclovir) there was a statistically significant reduction in time by 5 days in time to clinical recovery in the treatment arm (placebo recovery=20days). In 2 trials (acyclovir and valacyclovir) there was a statistically significant reduction in duration of lymphadenopathy by 9 days. Viral shedding was decreased by treatment but this effect was not sustained following treatment cessation. Treatment did not result in fewer lost days from school or work in 2 trials involving acyclovir.
Valomaciclovir (Epiphany Biosciences) is an experimental prodrug that is converted an active triphosphate. It has activity against HSV, VZV, HHV-6 and EBV. It has a 6X improvement in antiviral activity measure as IC50 relative to acyclovir against EBV. In a placebo-controlled trial in patients with IM, the 73% of patients in the Valmaciclovir 3gms po BID x 21days treatment arm had a 100X drop in oral supernatant EBV viral loads compared with 10% in the placebo group; p=0.008. Data on clinical recovery was not reported on this study. The enhanced activity of this agent against EBV warrants a larger trial in EBV.
Infection with EBV, like other members of the Herpes virus family, does not result in eradication but the conversion to a latent state. The virus can cycle between a latent and active lytic state depending on immunosuppression and comorbid illness. A large number of non-infectious illnesses have been associated with prior EBV infection. Malignancies attributable to EBV infection include nasopharyngeal carcinoma, post-transplant lymphoproliferative disease (PTLD), Burkitt's lymphoma, Hodgkin's lymphoma and gastric cancer. It is estimated that 1.8% of cancer deaths are due to EBV-attributable cancers with gastric cancer being the most rapidly increasing group. EBV has also been found within Glioblastoma multiforme brain tumors. Preliminary data suggest improvement with anti-viral therapy. As these malignancies are associated with latent EBV it is intriguing to consider combined approach of an induction agent to produce lytic EBV in combination with oral valomaciclovir.
Another intriguing association that deserves attention is that between multiple sclerosis (MS) and EBV. Multiple sclerosis is virtually unheard of in EBV seronegative individuals. As MS does occurs in only a minority of the 90% of the population with past EBV infection the answer must be found in the interplay between the immune system and EBV in infected individuals. Groups from Saudi Arabia and Stanford University have found EBV mostly in the latent stage in the brain samples of patients with MS. Infection with EBV involved not only B cells but astrocytes and microglia. There have been 3 trials of anti-virals (acyclovir and valacyclovir) in MS with a trend towards benefit in those with highly active disease. Valacyclovir levels in the CSF are 20% of those achieved in the serum and are typically below the IC50 for EBV 5 micro moles. Given Valomaciclovir’s increased potency against EBV compared with acyclovir and is worth testing in this disease As the majority of the EBV found in the brain of MS patients is in the latent phase an induction agent may need to be paired with Valmoaciclovir.
The association of EBV with numerous auto-immune diseases deserves merit. In Filipino patients EBV reactivation was more common in SLE cases than controls and EBV early antigen antibodies correlated with Lupus autoantibodies. An association of early antigen EBV antibodies and the presence of anti-Ro and anti-La antibodies have also been observed in Jorgen’s syndrome. In rheumatoid arthritis serum EBV DNA positive patients had higher disease activity. EBV increased in patients who were then treated with methotrexate and TNF inhibitors. Clinical trials of adjuvant treatment with Valomaciclovir in these diseases should be considered.
In conclusion, EBV causes Infectious Mononucleosis which results in considerable morbidity. A number of malignancies are EBV-attributable. A number of auto-immune disease are associated with EBV infection by causation has not been proven. The investigational agent Valomaclovir (Epiphany Biosciences) has significant EBV activity and should be investigated in these diseases.

Please contact me with questions, comments or interest
Steven P. LaRosa, M.D.
Phone: 401-575-1812


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