Abstract: We included seven RCTs with a total of 333 participants in our review. Three trials studied hospitalised patients, two trials were conducted in an outpatient setting, while the trial setting was unclear in two studies. Participants' ages ranged from two years to young adults. The type of antiviral, administration route, and treatment duration varied between the trials. The antivirals in the included studies were acyclovir, valomaciclovir and valacyclovir. Follow-up varied from 20 days to six months. The diagnosis of IM was based on clinical symptoms and laboratory parameters. The risk of bias for all included studies was either unclear or high risk of bias. The quality of evidence was graded as very low for all outcomes and so the results should be interpreted with caution. There were statistically significant improvements in the treatment group for two of the 12 outcomes. These improvements may be of limited clinical significance. There was a mean reduction in 'time to clinical recovery as assessed by physician' of five days in the treatment group but with wide confidence intervals (CIs) (95% CI -8.04 to -1.08; two studies, 87 participants). Prospective studies indicate that clinical signs and symptoms may take one month or more to resolve and that fatigue may be persistent in approximately 10% of patients at six-month follow-up, so this may not be a clinically meaningful result. Trial results for the outcome 'adverse events and side effects of medication' were reported narratively in only five studies. In some reports authors were unsure whether an adverse event was related to medication or complication of disease. These results could not be pooled due to the potential for double counting results but overall, the majority of trials reporting this outcome did not find any significant difference between treatment and control groups. There was a mean reduction in 'duration of lymphadenopathy' of nine days (95% CI -11.75 to -6.14, two studies, 61 participants) in favour of the treatment group. In terms of viral shedding, the overall effect from six studies was that viral shedding was suppressed while on antiviral treatment, but this effect was not sustained when treatment stopped. For all other outcomes there was no statistically significant difference between antiviral treatment and control groups. The effectiveness of antiviral agents (acyclovir, valomaciclovir and valacyclovir) in acute IM is uncertain. The quality of the evidence is very low. The majority of included studies were at unclear or high risk of bias and so questions remain about the effectiveness of this intervention. Although two of the 12 outcomes have results that favour treatment over control, the quality of the evidence of these results is very low and may not be clinically meaningful. Alongside the lack of evidence of effectiveness, decision makers need to consider the potential adverse events and possible associated costs, and antiviral resistance. Further research in this area is warranted.

Plain-language summary: We included seven studies that involved a total of 333 people; two were conducted in Europe and five in the USA. Three studies took place in hospitals, one each in a student health centre and a children's clinic, but the setting was unclear in two studies. Three different antiviral drugs were studied: acyclovir, valomaciclovir and valacyclovir, as well as dosage, comparison treatment (fake or no treatment), and how long people were treated and followed up. One study did not report study funding, but the other six studies appeared to have some industry support. None declared conflicts of interest, but one included two authors from a drug company. We wanted to investigate several outcomes: time to recovery; medication side effects; duration of: fever, sore throat, swollen lymph nodes, enlarged spleen and liver; development of glandular fever complications; how long it took to eliminate the virus from the throat; health-related quality of life; days off school or work; and economic outcomes. We found improvements in participants who received antiviral for two outcomes. There was an improvement of five days in time taken to recover among people who received antiviral treatment, but this result was not very precise, and the way it was measured was not clearly defined. Other studies show that glandular fever symptoms can take a month or more to get better, and tiredness may occur in about one in every 10 of patients six months later. This improvement may be of limited clinical significance. Most studies that examined adverse effects did not find any differences between people who received antivirals and those who did not. Time taken to resolve lymph node swelling improved to nine days when antivirals were used. However, studies that reported on this, measured lymph node swelling in different ways so we cannot be sure about the accuracy of the result. Evidence quality was rated as very low for all results, which means that we cannot know the exact effect of using antivirals for glandular fever. Better studies are needed so we can draw firm conclusions.