Epstein-Barr virus suppression in chronic obstructive pulmonary disease

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterised by progressive breathlessness and functional decline. This condition is now the third most common cause of global mortality and there are currently no treatments that can meaningfully alter disease progression. EBV has been demonstrated across the severity spectrum of COPD during exacerbations and stable disease using sputum qPCR and immunohistochemistry staining of airway biopsies. In this study we hypothesised that this herpesvirus could represent a novel therapeutic target in COPD. Methods: The EViSCO trial was a single-centre, double-blind, randomised, placebo-controlled trial to determine the safety and efficacy of valaciclovir (1 gram three times daily for 8 weeks) for the suppression of EBV in patients with moderate-to-severe COPD. The primary efficacy outcome was EBV suppression (as defined by a >90% reduction in sputum viral load) at week 8.  The primary safety outcome was the incidence of serious adverse reactions (SARs). Secondary outcomes were lung function (FEV₁) and drug tolerability. Exploratory outcomes were quality-of-life and sputum biomarkers (cell counts, cytokines, proteases and microbiota). EViSCO is registered on ClinicalTrials.Gov (NCT03699904). Results: In total, 84 participants were randomised (43 to valaciclovir, 41 to placebo), with 81 having sputum EBV formally quantified by PCR before and after treatment (41, valaciclovir). The intention-to-treat analysis found that a higher number of patients experienced sputum EBV suppression in the treatment group (36 (87.8%) vs. 17 (42.5%); p < 0.001). Treatment with valaciclovir was associated with a statistically significant reduction in sputum EBV qPCR titre at week 8 (valaciclovir -90404 copies/ml vs. placebo -3940 copies/ml, p=0.002). In the treatment group there was a 24mL numerical increase in the FEV₁ at week 8 compared to a 20mL reduction in the control group (difference 44mL (95% CI - 0.15 to 0.062);p=0.41) There were no statistically significant differences in quality-of-life or exacerbations. The mechanistic analysis indicated that a reduction in total sputum cell count over 8 weeks was significantly greater in the valaciclovir compared to the placebo group (difference 2.89; 95% CI 1.5 x106 to 7.4 x 106); (p=0.003). Furthermore, there were statistically significant reductions in sputum MCP-1 and IP-10 within the valaciclovir group at week 8. An exploratory sub-study demonstrated that valaciclovir was not associated with any significant alterations in the sputum microbiota at week 8 compared to placebo. The EViSCO trial was terminated early (08/04/20) due to safety concerns regarding ongoing participant recruitment during the COVID-19 pandemic (after 85 patients were recruited from a planned sample size of 88). In light of the COVID-19 pandemic it was not possible to conduct lung function testing due to infection control concerns. Conclusions: This phase 2 clinical trial demonstrates that valaciclovir (1 gram three times daily for 8 weeks) is safe and effective for the suppression of EBV in moderate-to-severe COPD. Furthermore, valaciclovir was associated with a modest increase in FEV₁ and appeared to attenuate the sputum inflammatory cell infiltrate at week 8. The study intervention was tolerable and the recruitment data from this trial suggest that a larger multi-centre study to evaluate the effect of EBV suppression on clinical outcomes in COPD would be feasible.