E1 ReplicatedModerate confidencePEM unclearRCTPeer-reviewedMachine draft
Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial.
Straus, S E, Dale, J K, Tobi, M et al. · The New England journal of medicine · 1988 · DOI
Quick Summary
Researchers tested whether acyclovir, an antiviral drug, could help people with ME/CFS who had signs of past Epstein-Barr virus infection. In this carefully controlled study of 27 patients, about half received the real drug and half received a placebo (fake treatment). After 37 days of treatment, similar numbers of people felt better in both groups—suggesting the drug itself wasn't the reason for improvement.
Why It Matters
This study addresses a historically important hypothesis—that ME/CFS might result from persistent EBV infection amenable to antiviral therapy. As one of the first rigorous trials to evaluate this mechanism, it provides evidence that targeting EBV alone is insufficient and helps redirect research toward other pathophysiological mechanisms in ME/CFS.
Observed Findings
- Eleven of 24 patients (46%) on acyclovir reported subjective improvement versus ten of 24 (42%) on placebo—not statistically different
- Three patients experienced acyclovir-induced nephrotoxicity requiring study withdrawal
- Neither acyclovir treatment nor clinical improvement correlated with EBV antibody titers, circulating immune complex levels, or leukocyte 2',5'-oligoadenylate synthetase activity
- Subjective improvement correlated with various measures of mood rather than viral or immunological parameters
Inferred Conclusions
- Acyclovir, administered as intravenous then oral therapy, does not ameliorate ME/CFS symptoms
- Clinical improvement in both treatment and placebo groups likely reflects placebo effect or spontaneous disease remission rather than antiviral efficacy
- Abnormal EBV serology alone does not identify a patient population responsive to antiviral therapy, suggesting other mechanisms merit investigation
Remaining Questions
- Do other antiviral agents or different acyclovir dosing regimens produce different outcomes?
- Are there biological or clinical subgroups of ME/CFS patients more likely to benefit from antiviral therapy?
- What role, if any, does persistent viral replication play in ME/CFS pathophysiology if not amenable to acyclovir?
What This Study Does Not Prove
This study does not prove that EBV plays no role in ME/CFS pathogenesis, only that acyclovir treatment does not improve symptoms in patients with abnormal EBV serology. It also does not establish whether different dosing regimens, patient subgroups, or earlier intervention might have different effects. The correlation between improvement and mood suggests subjective reporting bias rather than ruling out biological mechanisms entirely.
Tags
Symptom:Fatigue
Biomarker:AutoantibodiesBlood Biomarker
Method Flag:PEM Not DefinedWeak Case DefinitionSmall Sample
Metadata
- DOI
- 10.1056/NEJM198812293192602
- PMID
- 2849717
- Review status
- Machine draft
- Evidence level
- Replicated human evidence from multiple independent studies
- Last updated
- 8 April 2026
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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