Statins and the Risk of Herpes Zoster: A Population-Based Cohort Study

Antoniou, Tony; Zheng, Hong; Singh, Surinder; Juurlink, David N.; Mamdani, Muhammad; Gomes, Tara

doi:10.1093/cid/cit745

Cited by 38 publications

(52 citation statements)

References 37 publications

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“…A recent report showed that older persons treated with statins had an increased risk of herpes zoster infections compared to those not treated with statins. 26 Statins have been shown to inhibit inflammatory chemokine expression, leukocyte migration and adhesion, and proliferation of monocyte/macrophages, and facilitate Th2-polarization and regulatory T-cell expansion. 1, 2, 27-29 In our study, patients were severely immunocompromised by the HCT procedure and ongoing treatment with immunosuppressive drugs.…”

Section: Discussionmentioning

confidence: 99%

The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation

Seo

Boeckh

Storer

et al. 2015

Bone Marrow Transplant

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Recent studies have reported that statin use may be associated with improved outcomes in patients with sepsis or respiratory viral infections. In the setting of allogeneic hematopoietic cell transplantation (HCT), it has been shown that donor and recipient statin use are associated with reduced risks of graft-versus-host disease. We assessed in retrospective analysis whether donor or recipient statin use impacts infection risk after allogeneic HCT (n=1191). While recipient statin use was associated with increased incidence of gram-negative bacteremia (adjusted hazard ratio [aHR] 2.22, [95% CI 1.2 – 4.2], p=0.01) without affecting mortality, donor statin use was associated with increased incidence of respiratory viral infections in recipients (aHR 2.84 [95% CI 1.3 – 6.0], p=0.007). The overall incidence of invasive fungal infections, and CMV-reactivation and disease were not impacted by recipient or donor statin use. In conclusion, this study suggests that recipient or donor statin use may be associated with increased incidence of some infections without adversely affecting mortality.

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Section: Discussionmentioning

confidence: 99%

The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation

Seo

Boeckh

Storer

et al. 2015

Bone Marrow Transplant

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“…In addition to myopathies, a statin trial should collect data on adverse events related to immunosuppression and insulin resistance, 58–60 which may include incident infectious diseases, second primary cancers, changes in fasting insulin levels from baseline, and failure of glucose tolerance tests.…”

Section: A Clinical Trial Of Adjuvant Breast Cancer Therapy With Statmentioning

confidence: 99%

Statins and breast cancer prognosis: evidence and opportunities

Ahern

Lash

Damkier

et al. 2014

The Lancet Oncology

167

141

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SUMMARY Much preclinical and epidemiologic evidence supports anticancer effects of HMG-CoA reductase inhibitors (statins). Epidemiologic evidence does not support an association between statin use and reduced breast cancer incidence, but does support a protective effect of statins—particularly simvastatin—on breast cancer prognosis. We argue that the current evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins. We advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well-tolerated, and in expensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several design opportunities—including candidate predictive biomarkers of statin safety and efficacy—and offer solutions to key challenges to enrolment, follow-up, and analysis of such a trial.

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“…Our study offers the first comprehensive analysis of the effect of statins on chronic gammaherpesvirus infection, providing a potential insight into the modification of chronic herpesvirus infections in a significant number of individuals treated with statins. In spite of the prevalent use of statins, the status of herpesvirus activity in statintreated individuals has not been assessed, with the exception of a single study that found a small increase in the incidence of zoster in statin users (41). Importantly, markers of inflammation/immune activity were not taken into account in this study.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Lange

Darrah

Vonderhaar

et al. 2016

J Virol

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The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCEStatins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. population. Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity. I ntracellular cholesterol is acquired via two major mechanisms: internalization of exogenous cholesterol via the low-density lipoprotein receptor (LDLR) and endogenous cholesterol synthesis. The latter mechanism (Fig. 1A) operates in all cell types and is positively regulated by sterol regulatory element-binding protein 2 (Srebp2). Srebp2, a transcription factor synthesized as an inactive membrane-associated precursor, is cleaved by Golgi apparatus-specific proteases under conditions of low cholesterol to release an active product (1). This active cleaved product induces expression of most enzymes involved in cholesterol synthesis, including the rate-limiting enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) (2). Active Srebp2 also increases the expression of LDLR to promote the acquisition of exogenous cholesterol. Due to the critical role of cholesterol for cell viability, genetic disruption of Srebp2 leads to early embryonic lethality (3).Elevated plasma cholesterol levels are a potent risk factor for atherosclerosis, and the targeting of the cholesterol synth...

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Statins and the Risk of Herpes Zoster: A Population-Based Cohort Study

Abstract: Statins have immunomodulating properties that may increase the risk of varicella-zoster virus reactivation. We found that older patients treated with statins were at an increased risk of developing herpes zoster relative to individuals who were not prescribed to these drugs.

Cited by 38 publications

References 37 publications

The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation

The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation

Statins and breast cancer prognosis: evidence and opportunities

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

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