Epstein-Barr infection: Current treatment options


Epstein-Barr virus is one of the causes of known human cancers such as PLTD, BL and XLP. It is persistent in about 90% of the global population. Prevalent antiviral agents are not effective. A systematic review was undertaken to discuss current treatment options available for EBV infection. A search was made of PubMed to identify relevant papers published from 2000 to 2010 using various search indexes. The review is based on 11 articles included in the study. The result showed that there is no studies which analyzed antiviral agents in EBV infection. Combinational therapy using antiviral agents, immunotherapy and anticancer agents should be considered while antibiotic regimen should be considered to take care of any sepsis. Resistance to antiviral agents especially cross-resistance is burden in EBV infection Studies should be undertaken to evaluate resistance pattern in EBV infection. To assess the efficacy of EBV therapeutics. Viral load using molecular techniques should be used as biomarker of efficacy.

Keywords: Antiviral drugs, Epstein-Barr virus infection, resistance, treatment

How to cite this article:
Yaro A. Epstein-Barr infection: Current treatment options. Ann Trop Med Public Health 2013;6:10-3
How to cite this URL:
Yaro A. Epstein-Barr infection: Current treatment options. Ann Trop Med Public Health [serial online] 2013 [cited 2020 Oct 21];6:10-3. Available from: https://www.atmph.org/text.asp?2013/6/1/10/115167

Epstein-Barr virus (EBV) also known as Human Herpes virus 4 (HH4) was initially described as one of the causes of human cancers and in normal patients, it causes infective mononucleosis. It has also been associated with series of B-cells lymphoproliferative disorders such as post-transplant lymphoproliferative disorder (PLTD), Burkett’s Lymphoma (BL), Hodgkin’sand non-Hodgkin’s lymphoma and epithelial cancers such as Nasopharyngeal carcinoma (NPC) as well as associated with certain gastric carcinoma. [1] Further studies has associated EBV infection to lymphoma which are found in patients with congenital immunodeficiency like X-linked lymphoproliferative disorder (XLP) as well as prominently found in lymphoproliferative disorder found in people infected Human Immunodeficiency Virus (HIV) who are immuno-compromised. [2] Studies has confirmed that with Human Papillomavirus (HPV), Kaposi-sarcoma-associated herpes virus 8 (KSHV/HHV8), are the main three oncogenic viruses which are associated with human deficiency syndrome (HDS)-associated cancers. [3] EBV has also been found to be linked with several autoimmune disorders, [4] e.g. prospective seroepidemiological analysis has established a link between multiple sclerosis (MS) and EBV infection in which almost 100% of MS patients showed seropositive. [4],[5],[6],[7] EBV persistently infects more than 90% of the world population [8] and the conventional antiviral therapy used are acyclovir, ganciclovir or valganciclovir which has proved clinically ineffective but still been used as the first-line therapy. [9] Some have tried using intravenous immunoglobulin (IVIG) prophylaxis in patients with X-linked lymphoproliferative to attempt to prevent EBV infection. Despite this regimen, patients still die of EBV infection. [10] A report by Feranchak et al., showed that they successfully treated patients with fulminent EBV hepatitis using liver transplantation, antiviral therapy and EBV antibody. [11] Ganciclovir and acyclovir has been used to treat EBV associated hairy leukoplakia. [12],[13] Other licensed antiviral drugs used in treating EBV infections include penciclovir, valacyclovir, and famciclovir. [14],[15] However, the emergence of anti-resistance strains of EBV is of concern in the clinical settings.

This review was undertaken to evaluate the clinical effectiveness of current therapies available for EBV infection and antiviral drug resistance in EBV infection. An insight into albeit briefly of biomarker of treatment will be made.

Materials and Methods

A search of Pub Med databases was made for relevant studies published from January 2000 to March 2011 with the following index terms: “EBV infection”, “Antiviral drugs”, “Treatment”. Due to technical limitation only studies published in English Language were included in the studies but there was no age limitation. The relevant intervention was any antiviral or immunotherapy therapy either single or in combination. The measured outcome included the virological response during and after treatment as well as any adverse effects (AEs). Based on this on these only Randomized Controlled Trials (RCTs) and case reports were eligible for the review. Full papers of all potential relevant studies were screened and reference of all these studies were screened for relevant studies. A total of 3722 titles were obtained from Pub Med database search. All the abstracts were reviewed and 928 papers were selected in the first round of the review process. The full articles of the first round were extracted and critically reviewed. 12 met the inclusion criteria so were retained. The references of the extracted articles were screened and two of them met the inclusion criteria. Seventeen studies included in the final review process were published between January 2000 and 2011. Four of the studies focused on rituximab while the others focused on different interventions: romipdepin, acyclovir/valacyclovir, ganciclovir and in combination with arginine butyrate, foscarnet, valganciclovir, intravenous (IV) acyclovir, Immunochemotherapy and topical acyclovir in EBV-associate mycosis fungoides. Another search was made using the same database above for relevant studies using the following combinations: “EBV infection and drug resistance”, “in vivo drug resistance and EBV infection”, “in vitro drug resistance and EBV infection”. Only studies published in English language were included. All types of studies either in vivo or in vitro with identified outcome were included. There was no location limitation. A standard data extraction template was used to systematically assess and summarize the evidence. 109 titles were obtained from the search and 20 were selected for the first screening. None was viewed deem for inclusion so another search was made using “HHV-4 and in vitro drug resistance”, HHV-4 and in vivo drug resistance”, HHV-4 drug resistance”. 120 studies were retrieved from the search of which 13 were retained. The final screen saw 11 papers included.

Antiviral Drugs for EBV

EBV infection leads to different type of diseases as stated in the introduction of this article which range from IM to series of cancers as well as certain immunological pathologies. Therefore anti-EBV therapies should be the backbone of every treatment regimen associated with EBV-associated pathologies. The overall goal of such treatment is to selectively inhibit the replication cycle of the virus. [16] Based on this, the mode of action of antiviral agents can be divided into six classes: (1) Interfering with cellular process which the virus uses for its replication; (2) Bind to or get incorporated into the nucleic acid thereby inhibiting its function; (3) Modifies the viral envelope, this changes the viral protein resulting in preventing the virus infecting new cells; (4) Interfering with viral assembly thereby inhibiting the formation of new progeny; (5) Interferes with the viral enzyme and inhibits their function; (6) Prevents the processing of viral precursor polypeptide. [17] Currently, most of the antiviral agents used in EBV infection are used in inhibiting other herpes viruses. Drugs used in EBV infection can be grouped into three as nucleoside analog such as ganciclovir, [18],[19],[20],[21],[22] valganciclovir, [23] acyclovir, [24],[19],[22] valaciclovir; acyclic nucleotide analog such as cidofovir and adefovir; and pyrophosphate analog such as foscarnet. [20],[22] Others have also used histone-deacylase inhibitors such as Romidepsin [25] which are enzymes that deacetylate lysine residues of histone and other non-histone proteins and immunotherapy regimen using rituximab, [26],[19],[27],[28],[29] immunoglobulin [20] as well as immunochemotherapy such as etoposide. [30] The effect of some of the antiviral agents used in EBV infection is uncertain but the studies by Bossolasco et al,.(2006) showed ganciclovir associated with reduction of viral load in EBV-associated primary central nervous system lymphoma (PCNSL) [18] while Lysell (2009) described the antiviral effect of acyclovir. [24]

There have been reported cases of significant side effects in some of the regimen used during EBV therapy. Lysell (2009) reported of patient becoming irritable, hyperactive, restless, more tired and sleepy when acyclovir was given in high dose. This led to the patient’s parent refusing to accept further treatment with acyclovir. [24] The use of rituximab is associated with viral reactivation after 14 months of treatment. [19] This means it cannot be used for long term control of EBV infection in some patients like those with XLP. Interestingly, viral reactivation has been reported in Hepatitis B virus infection using rituximab. [31] A recommendation for EBV infection is challenging. However, there should be generalized goals of any EBV-associated antiviral therapy as follows: (1) To inhibit active replication of the virus; (2) Latent viral infection should be cured and (3) Cellular proliferation and transformation due to EBV should be interrupted. Though acyclovir, valganciclovir and ganciclovir are the recommended first line regimen, there is the need to develop more anti-EBV agents or optimize the available agents. Also combinational therapy involving antiviral agents, immunotherapy and anticancer agents should be carefully considered since EBV has been implicated in series of lymphoma cases while empiric antibiotics should be considered for potential sepsis. [32]

Mechanism of Antiviral Drug Resistance

Drugs used in EBV therapy act by either acting on the viral thymidine kinase (TK), e.g. acyclovir or directly inhibits DNA polymerase, e.g. foscarnet. Mutation in the TK and DNA polymerase are associated with mechanism of resistance to acyclovir [33] resulting in loss of TK activity and altered enzyme activity, respectively. [34] Three types of TK mutations have been described: TK-negative (TK N ), TK-altered (TK A ) and TK-partial (TK P ). [35] Different rate of mutational changes have been identified in herpes virus; e.g. human simplex virus-1 (HSV-1), 156 nucleotide changes have been identified of which 73.7% are silent mutation while HSV-2 had 51 nucleotide changes of which 51% are silent mutation. These are mutational changes which confer resistant to antiviral agents. However, there are other changes due natural polymorphisms as a result of changes several amino acids sequences [36] which occur either in the TK gene, e.g. S29A found in HSV-2 or DNA pol enzyme such as H98Y in HSV-1. [36] From this discussion, mutation can be either genotypic or phenotypic. [37],[38] Of late there have been reported cases of helicase-primase inhibitors such as BAY-57-1293 and BIL-22BS. A study showed that a single amino acids change in primase protein with no change in the UL5 helicase leads to moderate resistance while single change in UL5 helicase results in co-resistance to both agents. [39] A source of worry is cross resistance in antiviral therapy; [40] a study by Moira et al., showed that acyclovir resistant to HSV also confers resistant to the same agent in HSV/HIV co-infection. The resistant associated with HIV was due to mutation in the reverse transcriptase [41] while another studies established cross resistance in ACV-resistant strain and brivudin and penciclovir as well as foscarnet. [38]

Although a number of antiviral drugs are used in EBV infection, there are no specific studies that examined antiviral drug resistance in EBV infection. Taking into consideration that EBV affects a large number of global populations and the increasing number of diseases associated with it, should prompt the scientific world to undertake studies along this path.

Biomarkers of EBV Treatment

In most of EBV-associated morbidity, high levels of EBV DNA have been detected in blood samples of affected individuals. [42] In order to measure EBV load, the importance factors should be quantitative rather than qualitative. In PTLD, viral load which is measured by quantitative molecular analysis of the genome of the virus is used as marker for projecting the course of the disease and treatment. [32] The use of viral load can be used to measure the rate of therapeutic efficacy. [32],[43],[44],[45],[46] However, with the important role molecular techniques are playing in modern laboratories, the use of such techniques could be of great use in measuring treatment efficacy. [47],[48] Series of studies has elucidated this. In a study by Gandhi et al., showed that in HL patients, chemotherapy has effect on the viral load. [49] This finding was similar to the findings of Limaye et al., [50] If viral load is the biomarker of EBV treatment, the best technique to use is the nucleic acid Amplification Testing (NAT).


I thank the staff of Africa Health Research Organization (Ghana) for their immense support during this study and the authors whose works were used in this project.

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.115167

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