Valaciclovir for Epstein-Barr Virus Suppression in Moderate-to-Severe COPD

Abstract

BackgroundEpstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease.Research QuestionIs valaciclovir safe and effective for EBV suppression in COPD?Study Design and MethodsThe Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines.ResultsFrom November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P < .001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (–90,404 copies/mL [interquartile range, –298,000 to –15,200 copies/mL] vs –3,940 copies/mL [interquartile range, –114,400 to 50,150 copies/mL]; P = .002). A statistically nonsignificant 24-mL numerical FEV1 increase was shown in the valaciclovir group (difference, –44 mL [95% CI, –150 to 62 mL]; P = .41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P = .003).InterpretationValaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes.Trial RegistryClinicalTrials.gov; No.: NCT03699904; URL: www.clinicaltrials.gov Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease. Is valaciclovir safe and effective for EBV suppression in COPD? The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines. From November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P < .001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (–90,404 copies/mL [interquartile range, –298,000 to –15,200 copies/mL] vs –3,940 copies/mL [interquartile range, –114,400 to 50,150 copies/mL]; P = .002). A statistically nonsignificant 24-mL numerical FEV1 increase was shown in the valaciclovir group (difference, –44 mL [95% CI, –150 to 62 mL]; P = .41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P = .003). Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. ClinicalTrials.gov; No.: NCT03699904; URL: www.clinicaltrials.gov FOR EDITORIAL COMMENT, SEE PAGE 564Take-home PointsStudy Question: Is valaciclovir safe and effective for Epstein-Barr virus (EBV) suppression in COPD?Results: This study demonstrated that EBV infection, as indicated by shedding of the virus in the sputum, can be suppressed in patients with COPD using valaciclovir (1 g tid for 8 weeks); however, this was not associated with significant improvements in FEV1 or quality of life, despite a reduction in sputum total cell count.Interpretation: Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. FOR EDITORIAL COMMENT, SEE PAGE 564 Study Question: Is valaciclovir safe and effective for Epstein-Barr virus (EBV) suppression in COPD? Results: This study demonstrated that EBV infection, as indicated by shedding of the virus in the sputum, can be suppressed in patients with COPD using valaciclovir (1 g tid for 8 weeks); however, this was not associated with significant improvements in FEV1 or quality of life, despite a reduction in sputum total cell count. Interpretation: Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. COPD is increasingly recognized as a heterogenous condition.1Global Burden of Disease Chronic Respiratory Disease CollaboratorsPrevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet Respir Med. 2020; 8: 585-596Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar However, numerous cluster analyses have not led to a consensus regarding disease subtype definitions.2Castaldi P.J. Benet M. Petersen H. et al.Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts.Thorax. 2017; 72: 998-1006Crossref PubMed Scopus (60) Google Scholar, 3Castaldi P.J. Boueiz A. Yun J. et al.Machine learning characterization of COPD subtypes: insights from the COPDGene Study.Chest. 2020; 157: 1147-1157Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 4Burgel P.R. Paillasseur J.L. 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Bhowmik A. et al.Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2001; 164: 1618-1623Crossref PubMed Scopus (876) Google Scholar McManus et al16McManus T.E. Marley A.M. Baxter N. et al.High levels of Epstein-Barr virus in COPD.Eur Respir J. 2008; 31: 1221-1226Crossref PubMed Scopus (32) Google Scholar reported high levels of sputum Epstein-Barr virus (EBV) during COPD exacerbations with similar viral titers in most patients months later, suggesting persistence of infection. A cohort of patients showing negative sputum quantitative polymerase chain reaction (qPCR) results during exacerbation were subsequently shown to have high sputum EBV viral load during stable disease.16McManus T.E. Marley A.M. Baxter N. et al.High levels of Epstein-Barr virus in COPD.Eur Respir J. 2008; 31: 1221-1226Crossref PubMed Scopus (32) Google Scholar This may indicate cyclical virus shedding. In a separate study using immunohistochemistry, the number of airways showing positive staining for latent EBV antigens was increased significantly in severe COPD.17Polosukhin V.V. Cates J.M. Lawson W.E. et al.Bronchial secretory immunoglobulin a deficiency correlates with airway and of chronic obstructive pulmonary disease.Am J Respir Crit Care Med. PubMed Scopus Google Scholar In EBV detection was associated with secretory deficiency and CD8+ V.V. Cates J.M. Lawson W.E. et al.Bronchial secretory immunoglobulin a deficiency correlates with airway and of chronic obstructive pulmonary disease.Am J Respir Crit Care Med. PubMed Scopus Google Scholar that dendritic cells a in T. Morias Y. Hamrud E. et al.Human lung conventional dendritic cells orchestrate lymphoid neogenesis during chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2020; 202: 535-548Crossref PubMed Scopus (26) Google Scholar that this virus a novel therapeutic that be using have virus suppression in randomized that EBV shedding in associated in clinical C. J. et of of for the of acute 164: PubMed Scopus Google E. E. A. et and of acute a placebo-controlled PubMed Scopus Google Scholar EBV suppression with valaciclovir has been shown to clinical outcomes in et study of in PubMed Scopus Google Scholar Furthermore, et Epstein-Barr virus in and to with PubMed Scopus Google Scholar that valaciclovir g tid for 8 EBV with clinical of Valaciclovir is a of with to and may levels similar to of S. M. et of the valaciclovir after and to normal PubMed Scopus Google Scholar the of and the of the clinical response demonstrated by et to study valaciclovir using a of g tid for 8 weeks. The of this study was to evaluate the and clinical of valaciclovir for EBV suppression in This was a randomized double-blind placebo-controlled clinical trial conducted at Mater Hospital Belfast, Northern Ireland. and and was by the Northern The trial was by and Care and from the of Northern trial was by and The study safety were months by independent and The trial was and The trial and analysis completed are from were and had a of COPD to the Global for Chronic Disease to of < after were for trial The were sputum EBV detection by and or severe of were had a exacerbation the or had a of asthma, or lung disease. 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M. et al.The is in PubMed Scopus Google Scholar IP-10 is in are associated with COPD T. Morias Y. Hamrud E. et al.Human lung conventional dendritic cells orchestrate lymphoid neogenesis during chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2020; 202: 535-548Crossref PubMed Scopus (26) Google M. M. et expression of the CXCR3 and in airways of smokers with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2002; PubMed Scopus Google Scholar A study by et T. Morias Y. Hamrud E. et al.Human lung conventional dendritic cells orchestrate lymphoid neogenesis during chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2020; 202: 535-548Crossref PubMed Scopus (26) Google Scholar that dendritic cells are the most potent of T cells in dendritic cells a to immune cell during T. Morias Y. Hamrud E. et al.Human lung conventional dendritic cells orchestrate lymphoid neogenesis during chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2020; 202: 535-548Crossref PubMed Scopus (26) Google Scholar expression is in response to EBV M. R. E. Epstein-Barr virus induced PubMed Scopus Google Scholar suggesting that the virus may the of chronic adaptive immune in COPD during tertiary lymphoid study has is to the of antiviral of et V.V. Cates J.M. Lawson W.E. et al.Bronchial secretory immunoglobulin a deficiency correlates with airway and of chronic obstructive pulmonary disease.Am J Respir Crit Care Med. PubMed Scopus Google Scholar previously reported in to of airways in and valaciclovir has efficacy is for or be Valaciclovir has potent efficacy however, this is in of patients with stable T.E. Marley A.M. 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