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The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. Pan African Clinical Trials Registry PACTR201411000939962.

Brincidofovir is an oral antiviral in development for prevention of cytomegalovirus disease. Cytomegalovirus genotyping results from a phase 2 trial comparing brincidofovir to placebo for prophylaxis against cytomegalovirus infection in hematopoietic cell transplant recipients provided initial data on the clinical resistance profile for brincidofovir. In this study, no known resistance-associated mutations were detected in brincidofovir-treated subjects; identified genotypic substitutions did not confer resistance to cytomegalovirus antivirals in vitro, suggesting that these changes represent polymorphisms unrelated to brincidofovir resistance. Lack of evidence for genotypic resistance during prophylaxis suggests that first-line use of brincidofovir for prevention of cytomegalovirus infection may preserve downstream options for patients.

Objectives: We performed a prospective, double-blind, placebo-controlled, longitudinal adjuvant therapy trial to determine the efficacy of cidofovir in the treatment of severe recurrent respiratory papillomatosis (RRP). Although results of case series suggest that cidofovir may decrease the frequency and rapidity of papilloma regrowth, no blinded placebo-controlled studies have demonstrated efficacy. Methods: Adults and children (n = 19) with aggressive RRP received either active drug (cidofovir) or placebo. When surgical intervention was needed, drug or placebo was injected into affected areas after surgical removal of disease. The following measures were made at baseline and at 2-month intervals for the course of 12 months: Derkay papilloma severity grading scale, Voice Handicap Index, Health-Related Quality of Life, and total number of procedures performed over 12 months. Results: At 2- and 12-month follow-ups, there was a significant (p < .05) improvement in the Derkay Severity Score within the cidofovir and placebo groups, but no difference between groups, and no difference between groups in the number of procedures performed. Significant improvement was found in Voice Handicap Index scores in the cidofovir group at the 12-month follow-up. No differences were seen in Health-Related Quality of Life. Conclusions: A randomized, blinded, placebo-controlled trial is necessary in the study of RRP, because the natural history of the disease can include remissions and reactivations. We found a significant improvement in the Derkay Severity Score 12 months after the baseline assessment in patients treated with cidofovir. This effect, however, was also seen in the placebo group. Accordingly, we were unable to provide proof of efficacy of cidofovir in the treatment of RRP.

Genital condylomata acuminata are nonmalignant human papillomavirus (HPV)-induced tumors in which HPV types 6 and 11 are most commonly found. Usual treatments for condylomata acuminata are nonspecific and are based on the destruction or removal of infected tissue. These procedures are often painful and are characterized by a high relapse rate. We report here what is to our knowledge the first double-blind, placebo-controlled study of the use of cidofovir, a nucleotide analogue, for the treatment of genital papillomavirus infections. Thirty patients were enrolled in the study; 19 received cidofovir, and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine (47%) of 19 patients in the cidofovir group had a complete response (total healing), compared with 0 of the patients in the placebo group (P = .006). None of the patients in the cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable.

A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration.

The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were 01.84 versus 00.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.

Currently, mpox virus (MPXV) continues to pose a global public health challenge, with immunocompromised individuals often exhibiting more severe clinical symptoms. This study screens three male mouse models (ICR, IFNAR1 -/- , SCID) and identifies SCID mice as the optimal model for modeling severe patient symptoms, including pneumonia, rash, and localized inflammation, which is applied to evaluate the antiviral efficacy of tecovirimat and cidofovir. Both drugs prevent systemic MPXV spread when administered within two days post virus exposure. Local antiviral efficacy differs between the two drugs, particularly after intradermal infection. Prolonged treatment up to 28 days post infection results in 100% survival of SCID mice but fails to effectively suppress localized rash and inflammatory swelling, suggesting that the drugs have limited impact at later stages of the disease. These findings indicate that the therapeutic efficacy of tecovirimat and cidofovir depends on the timing of intervention initiation and the stage of disease progression. This study establishes MPXV clade IIb-infected SCID mouse models presenting with pneumonia, lesions, and localized inflammation that recapitulate key clinical manifestations observed in high-risk populations, and demonstrates that the timing of treatment initiation and the stage of disease progression critically influence the anti-MPXV efficacy of both tecovirimat and cidofovir.

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase Ijll study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens ⩾3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of20 patients had serum creatinine levels ⩾2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 rug/kg). The clinical efficacyof cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.

Background Brincidofovir (BCV) is a novel nucleoside phosphonate analogue with unique dual antiviral and anti-tumor properties. Methods The activity of BCV was evaluated in 44 cell-line models, including T/NK-cell non-Hodgkin lymphoma (T/NK-NHL, n  = 25) and B-cell lymphoma (BCL, n  = 19), and their respective NOD/SCID mice xenograft models. The potential immunogenic effects were examined in a syngeneic EL4-C57BL/6 murine lymphoma model. Results BCV demonstrated potent anti-tumor activity across the majority of cell lines regardless of EBV positivity, with IC50 values within clinically achievable human plasma concentrations (2 µg/ml) in 17 of 25 (68.0%) T/NK-NHL and in 13 of 19 (68.4%) BCL. In vivo treatment significantly inhibited tumor growth in all xenograft models compared to vehicle control. Notably, RNAseq analysis demonstrated BCV downregulated MYC-target pathways in T/NK-NHL models. BCV evoked S-phase cell cycle arrest, replication stress, DNA damage, and apoptosis while triggering STING pathway-mediated interferon responses, PD-L1 expression, and immunogenic cell death. In the EL4-C57BL/6 model, BCV in combination with anti-PD1 significantly inhibited tumor growth and triggered an immune reaction characterized by the highest scores for adaptive immune response, cytokines/chemokines and receptors, cytotoxic cells, dendritic cells, NK CD56dim cells, and neutrophils (NanoString Immunology Panel). Conclusions Taken together, these results demonstrate a novel role for BCV in lymphoma therapy and suggest potential for combination with checkpoint immunotherapy.