Efficacy of valaciclovir in preventing herpes zoster in patients receiving anifrolumab

Abstract

The objectives of this study were to assess the prevalence of HZ in real-life settings and to investigate the potential benefit of valaciclovir as prophylaxis against HZ. Despite these limitations, it confirms data from clinical trials, showing that a significant proportion of patients without prophylaxis experience HZ under anifrolumab.3 It also suggests that prophylactic treatment with valaciclovir is effective for preventing HZ infection in SLE patients treated with anifrolumab. Ethics approval This retrospective non-interventional study used patient information collected for routine clinical care, and according to French Public Health Laws, approval from an Institutional Review Board and written consent are not required for non-interventional human studies. X @crichez33 Contributors LT, FC, AM and ZA contributed to the conception and design of the study; LT, FC, MJ, CL, TB, SF, JH, GRC, NFM, SR, RM, KC, AL, EL, MC, NB, CR, CC, LS, SAA, JDLR, JC, AAV, TM, NA, NCC, CL, DB, DK, CSPT, PYJ, SL, JH, PS, MA, JDB, AM and ZA were involved in the acquisition of data; LT, FC, AM and ZA contributed to the analysis and interpretation of data.

Correspondence to Dr Ludovic Trefond; [email protected]

Systemic lupus erythematosus (SLE) is associated with an increased risk of herpes zoster (HZ), with a relative risk of 2.5 times higher than in the general population.¹ This risk is particularly increased in younger patients¹ and in those with immunosuppressant or neutralising anti-interferon-alpha antibodies.² Anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, also increases the risk of HZ in SLE. In phase 2 and 3 trials, patients treated with anifrolumab (300 mg monthly) had an increased risk of HZ compared with those receiving placebo (6.1% and 1.3%, respectively; exposure-adjusted incidence rate risk difference 5.4 (95% CI 2.8 to 8.4)), especially in the first year of treatment.^{3 4} Although a recombinant vaccine for HZ has been developed, it is not available worldwide. Currently, no specific recommendations exist for HZ prevention in patients receiving anifrolumab, including the potential prophylactic use of valaciclovir.

This multicentre observational study included patients with SLE treated with anifrolumab for at least 3 months from November 2021 to July 2024 in departments of internal medicine, dermatology and rheumatology in France. The objectives of this study were to assess the prevalence of HZ in real-life settings and to investigate the potential benefit of valaciclovir as prophylaxis against HZ. The decision to add valaciclovir was made at the discretion of the physician and the patient.

We included 132 patients (92% of women), with a mean (SD) age of 42.0 (12.4) years treated with anifrolumab. Of these, 87 (65.9%) patients received prophylactic valaciclovir (69 with 500 mg/day and 18 with 1000 mg/day), while 45 (34.1 %) did not. Two patients had received the live attenuated vaccine, and none had received the recombinant vaccine. 13 (9.8%) patients had a history of HZ before starting anifrolumab. The main demographic and clinical characteristics of patients according to the treatment with valaciclovir are presented in online supplemental table 1. The two groups were similar in demographic and clinical characteristics, including age, glucocorticoids and immunosuppressant treatment. However, patients treated with valaciclovir more frequently had a history of HZ (14.9% vs 0%, p=0.004). Fourteen patients discontinued anifrolumab because of ineffectiveness (n=10), desire for pregnancy (n=2) and infection (n=2). The median (IQR) follow-up duration under anifrolumab treatment was 234 days (158–287.5) days.

Four patients in the group without valaciclovir developed HZ at 31, 164, 276 and 432 days after starting anifrolumab. The corresponding HZ frequencies were 2.2% (n=1/45) at 3 months, 6.2% (n=2/32) at 6 months and 23% (n=3/13) at 12 months. None of the patients treated with valaciclovir developed an HZ during the survey period. Univariate survival analysis showed that the risk of HZ was lower in the group treated with valaciclovir (HR 0.08, 95%CI: 0.01 to 0.59, p=0.01) (figure 1). The locations of HZ were lumbar (n=2), cervical (n=1) and intercostal (n=1). In addition to anifrolumab, these patients were treated with HCQ alone (n=2) or associated with prednisone (n=2) and mycophenolate mofetil (n=2). None of the HZ was considered severe, and no patients were hospitalised or discontinued anifrolumab due to HZ. One patient experienced HZ neuralgia.

Figure 1. Kaplan-Meier estimates of the cumulative probability of herpes zoster (HZ) for patients in valaciclovir-treated and valaciclovir-untreated groups. Patients undergoing anifrolumab treatment for SLE under valaciclovir preventive treatment (red line) were compared with patients not receiving valaciclovir (blue line). Each corner in the curve represents a HZ infection. Curves were compared using log-rank tests. Crude HR was calculated using a proportional risk Cox model.

This study is limited by its observational design and the low incidence of zoster events during the follow-up. Despite these limitations, it confirms data from clinical trials, showing that a significant proportion of patients without prophylaxis experience HZ under anifrolumab.³ It also suggests that prophylactic treatment with valaciclovir is effective for preventing HZ infection in SLE patients treated with anifrolumab. This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

This retrospective non-interventional study used patient information collected for routine clinical care, and according to French Public Health Laws, approval from an Institutional Review Board and written consent are not required for non-interventional human studies. However, patients were informed that data collected in medical records might be used for research in accordance with privacy rules. The study’s protocol conforms to the ethics guidelines of the 1975 Declaration of Helsinki. Our study involves personal health data and was declared to the Commission Nationale de l’Informatique et des Libertés.

Footnote

X @crichez33

Contributors LT, FC, AM and ZA contributed to the conception and design of the study; LT, FC, MJ, CL, TB, SF, JH, GRC, NFM, SR, RM, KC, AL, EL, MC, NB, CR, CC, LS, SAA, JDLR, JC, AAV, TM, NA, NCC, CL, DB, DK, CSPT, PYJ, SL, JH, PS, MA, JDB, AM and ZA were involved in the acquisition of data; LT, FC, AM and ZA contributed to the analysis and interpretation of data. LT is the guarantor. All authors contributed to drafting and/or revising the manuscript. AM and ZM contributed equally as co-last authors.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests LT received support for attending meetings and/or travel from GSK, AstraZeneca, Otsuka and CSL VIFOR. FC has received grant/research support from AstraZeneca, BMS and GSK; participated in an advisory board related to lupus for AstraZeneca, GSK, Celgene, Merck, Horizon Therapeutics and Principabio; and received speaking fees and honoraria from AstraZeneca and GSK BMS related to lupus. AM has received grant/research support from Sobi; participated in advisory board related to lupus for AstraZeneca; received payment for expert testimony for GSK; received support for attending meetings and/or travel from AstraZeneca, GSK, Novartis and Otsuka; and received consulting fees, speaking fees and honoraria from AstraZeneca, GSK, Novartis and Otsuka. ZA has received grant/research support from GSK, AstraZeneca, Roche, Novartis and Amgen; participated in advisory board related to lupus for GSK, AstraZeneca, Kezar, Amgen, Otsuka, Novartis; and received consulting fees, speaking fees and honoraria from AstraZeneca and GSK. MJ participated in an advisory board and received speaking fees from AstraZeneca and GSK related to lupus. JLR received support for attending meetings and/or travel from GSKNB has participated in an advisory board related to lupus for AstraZeneca and received speaking fees and honoraria from AstraZeneca and GSK related to lupus. NCC participated in an advisory board related to lupus for BMS and received a grant to her institution from Roche and AstraZeneca. SF has participated in an advisory board for CSL Vifor, Sanofi–Genzyme, Novartis, Alexion and AstraZeneca. EL has received a grant/research support from AstraZeneca, SOBI, NOVARTIS and GSK; participated in an advisory board related to lupus for AstraZeneca and GSK; and received speaking fees and honoraria from AstraZeneca and GSK BMS related to lupus. MA received support for attending meetings and/or travel from Novartis and CSL VIFOR. JDB received consulting fees, speaking fees and grants from Astra Zeneca. CSPT received support for attending meetings and/or travel from AstraZeneca, GSK, Novartis and Abbvie. MS is a consultant for Abbvie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Fresenius Kabi, Galapagos, Innate Pharma, Nordic Pharma, Novartis and Sandoz. CL received speaking fees from GSK, Astrazenaca and BMSCR and has acted as a consultant for Abbvie, AstraZeneca, Biogen, BMS, GSK, Lilly, Novartis, and Pfizer.

Provenance and peer review Not commissioned; externally peer reviewed.

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References

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² Mathian A, Breillat P, Dorgham K, et al. Lower disease activity but higher risk of severe COVID-19 and herpes zoster in patients with systemic lupus erythematosus with pre-existing autoantibodies neutralising IFN-α. Ann Rheum Dis 2022; 81: 1695–703. doi:10.1136/ard-2022-222549

³ Tummala R, Abreu G, Pineda L, et al. Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials. Lupus Sci Med 2021; 8. doi:10.1136/lupus-2020-000464

⁴ Kalunian KC, Furie R, Morand EF, et al. A Randomized, Placebo-Controlled Phase III Extension Trial of the Long-Term Safety and Tolerability of Anifrolumab in Active Systemic Lupus Erythematosus. Arthritis Rheumatol 2023; 75: 253–65. doi:10.1002/art.42392