Prevention of Recurrence of Herpes Simplex in Autoimmune Rheumatic Diseases

Official title

Prevention of Recurrence of Herpes Simplex in Patients With Autoimmune Rheumatic Diseases

Overview

The goal of this randomized, double-blind, placebo-controlled clinical trial is to evaluate the effectiveness and safety of oral suppressive therapy with acyclovir in preventing herpes simplex virus (HSV) reactivation in patients with autoimmune rheumatic diseases (ARDs) who have a history of recurrent HS episodes. The main questions this study aims to answer are: Does continuous oral acyclovir reduce the frequency of HSV reactivation in ARD patients compared to placebo? What is the safety profile of prolonged acyclovir use in this population? What are the main risk factors (clinical and treatment-related) associated with HSV reactivation in immunosuppressed patients. Participants will: Be randomly assigned (1:1) to receive oral acyclovir (400 mg BID) or placebo for 12 months; Be followed for a total of 24 months, with regular clinical evaluations (every 3 months) and laboratory monitoring (every 3 months); Be assessed for HSV recurrence based on clinical symptoms, detection of HSV DNA by polymerase chain reaction (PCR) in mucocutaneous swabs in doubtful cases, and standardized reporting forms; Undergo disease activity assessments and adverse event monitoring at regular intervals. The study includes adult and pediatric patients with confirmed diagnoses of one of the following ARDs: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), dermatomyositis/polymyositis (DM/PM), systemic sclerosis (SSc), systemic vasculitis, primary Sjögren's syndrome, Mixed connective tissue disease (MCTD), Chronic recurrent multifocal osteomyelitis (CRMO), Sarcoidosis and Behçet's Syndrome. All participants must have a documented history of recurrent HSV (oral and/or genital) before inclusion.

Detailed description

HSV-1 and HSV-2 are ubiquitous human pathogens that can establish lifelong latency, with the potential for frequent reactivation. Immunocompromised individuals, including patients with ARDs, are particularly vulnerable to more severe and disseminated HSV infections, which may result in significant morbidity and even mortality. Despite this, the true incidence and burden of HSV reactivation in ARD patients under immunosuppression remain underexplored.

Previous studies in solid-organ transplant recipients and people living with HIV have demonstrated that prophylactic or suppressive antiviral therapy with acyclovir can significantly reduce HSV-related complications. However, no randomized controlled trials to date have evaluated the efficacy and safety of this approach in ARD patients under frequent immunosuppressive drug use and recurrent HSV in this group.

This trial will enroll 62 participants with ARDs and prior recurrent HSV infection, randomly assigned to receive oral acyclovir or placebo for 12 months, followed by continued monitoring for an additional year. Primary outcomes include the number of clinically confirmed HSV reactivations in acyclovir and placebo groups. Secondary outcomes include safety (adverse events), treatment tolerability, and identification of clinical and therapeutic risk factors for HSV recurrence.

By providing high-quality evidence through a rigorously controlled methodology, this study seeks to fill a critical knowledge gap in rheumatology, offering practical guidance for antiviral prophylaxis in immunosuppressed ARD patients, ultimately improving patient safety and clinical outcomes in a vulnerable population.

Interventions

• Drug Acyclovir (ACV)
  Oral acyclovir 400 mg twice a day for 12 months. Acyclovir is a synthetic nucleoside analog with in vitro activity against HSV-1, HSV-2, VZV, and other herpesviruses.
• Other Placebo
  Matching oral placebo, administered twice a day for 12 months.

Primary outcome measures

• HSV Reactivation Rate [Time frame: Baseline to Month 24]

Secondary outcome measures (12)

• Safety Profile - Adverse Events (AEs) [Time frame: Day 1 through Month 12]
• Frequency of Serious Adverse Events (SAEs) [Time frame: Day 1 through Month 12]
• Treatment Discontinuation Due to AEs [Time frame: Day 1 through Month 12]
• Time to First HSV Reactivation [Time frame: Day 1 through Month 12]
• Factors Associated with HSV Reactivation [Time frame: Day 1 through Month 24]
• Disease Activity Flares - Systemic Lupus Erythematosus [Time frame: Day 1 through Month 12]
• Disease Activity Flares - Rheumatoid Arthritis [Time frame: Day 1 through Month 12]
• Disease Activity Flares - Juvenile Idiopathic Arthritis [Time frame: Day 1 through Month 12]
• Disease Activity Flares - Ankylosing Spondylitis [Time frame: Day 1 through Month 12]
• Disease Activity Flares - Psoriatic Arthritis [Time frame: Day 1 through Month 12]
• Disease Activity Flares - Dermatomyositis/Polymyositis [Time frame: Day 1 through Month 12]
• Disease Activity Flares - Systemic Sclerosis [Time frame: Day 1 through Month 12]

Eligibility criteria

Inclusion criteria

• Eligible participants must be >12 years old
• Any sex
• Have a confirmed diagnosis of an autoimmune rheumatic disease (ARD) based on internationally accepted classification criteria, including: rheumatoid arthritis (ACR/EULAR 2010), juvenile idiopathic arthritis (ILAR), axial spondyloarthritis (ASAS 2009), psoriatic arthritis (CASPAR 2012), systemic lupus erythematosus (SLICC 2012), systemic sclerosis (ACR 2013), dermatomyositis/polymyositis (Bohan \& Peter), systemic vasculitis (Takayasu arteritis, granulomatosis with polyangiitis, polyarteritis nodosa), primary Sjögren's syndrome (ACR/EULAR 2016), mixed connective tissue disease (Alarcón-Segovia or Kasukawa criteria), chronic recurrent multifocal osteomyelitis (Jansson et al., 2007), sarcoidosis (ATS/ERS/WASOG 2020 statement) and behçet's syndrome (International Study Group, 1990).
• Present serologic evidence of prior HSV infection (complement fixation titer ≥ 1:8)
• A clinical history of recurrent oral or genital herpes simplex virus infection, defined as at least four episodes in the past 12 months.

Exclusion criteria

-Participants will be excluded if they have a known hypersensitivity to acyclovir or any component of the study medication.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Prevention

Study locations

Brazil · 1 center

• Reumatology division of Hospital das Clinicas da Faculdade de Medicina da Universidade de — São Paulo

Publications

• Ioannidis JP, Collier AC, Cooper DA, Corey L, Fiddian AP, Gazzard BG, Griffiths PD, Contopoulos-Ioannidis DG, Lau J, Pavia AT, Saag MS, Spruance SL, Youle MS. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis. 1998 Aug;178(2):349-59. doi: 10.1086/515621. PMID 9697714
• Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007 Nov;57(5):737-63; quiz 764-6. doi: 10.1016/j.jaad.2007.06.027. PMID 17939933
• Beyar-Katz O, Bitterman R, Zuckerman T, Ofran Y, Yahav D, Paul M. Anti-herpesvirus prophylaxis, pre-emptive treatment or no treatment in adults undergoing allogeneic transplant for haematological disease: systematic review and meta-analysis. Clin Microbiol Infect. 2020 Feb;26(2):189-198. doi: 10.1016/j.cmi.2019.09.003. Epub 2019 Sep 16. PMID 31536817

Identifiers

NCT: NCT07341386 · 87204225.7.0000.0068

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗