Intralesional cidofovir for the treatment of recalcitrant periungual warts.

Purpose: Successful treatment of periungual warts presents a clinical challenge, as many are refractory or represent following conventional treatments. The use of destructive therapies, such as cryotherapy, may even cause permanent nail dystrophy. Materials and methods: Here, we present a series of nine cases in which intralesional cidofovir was used for recalcitrant periungual warts between July 2020 and July 2022 at the University of California, Los Angeles. Results: Following a mean of 2.7 treatments (SD = 0.87), 100% of patients (n = 9) saw improvement in the appearance of their warts, and 77.8% (n = 7) had near to complete resolution. Few self-resolving local reactions occurred, including pain, edema, erosion, blister formation, and discoloration at the proximal nail fold. All reactions resolved within weeks of treatment and required no additional treatment. Conclusions: Intralesional cidofovir treatment of recalcitrant periungual warts is well tolerated and provides unmatched results. Given the risks of traditional therapies to the nail, intralesional cidofovir should be considered as a first-line therapy for periungual warts. Randomized clinical trials are necessary, in the future, to adequately understand the effectiveness of intralesional cidofovir.

Assessment of Cidofovir for Treatment of Ocular Bovine Herpesvirus-1 Infection in Cattle Using an Ex-Vivo Model.

Bovine herpesvirus-1 (BoHV-1) infection contributes to keratoconjunctivitis, respiratory disease, and reproductive losses in cattle. The objective of this study was to determine the most appropriate ophthalmic antiviral agent for BoHV-1 inhibition using in-vitro culture and novel ex-vivo bovine corneal modeling. Half-maximal inhibitory concentrations of BoHV-1 were determined for cidofovir, ganciclovir, idoxuridine, and trifluridine via in-vitro plaque reduction assays. In-vitro cytotoxicity was compared amongst these compounds via luciferase assays. Trifluridine and cidofovir were the most potent BoHV-1 inhibitors in vitro, while trifluridine and idoxuridine were the most cytotoxic agents. Therefore, cidofovir was the most potent non-cytotoxic agent and was employed in the ex-vivo corneal assay. Corneoscleral rings (n = 36) from fresh cadaver bovine globes were harvested and equally divided into an uninfected, untreated control group; a BoHV-1-infected, untreated group; and a BoHV-1-infected, cidofovir-treated group. Virus isolation for BoHV-1 titers was performed from corneal tissue and liquid media. Histologic measurements of corneal thickness, epithelial cell density, and tissue organization were compared between groups. Substantial BoHV-1 replication was observed in infected, untreated corneas, but BoHV-1 titer was significantly reduced in cidofovir-treated (1.69 ± 0.08 × 103 PFU/mL) versus untreated (8.25 ± 0.25 × 105 PFU/mL, p < 0.0001) tissues by day 2 of culture. No significant differences in histologic criteria were observed between groups. In conclusion, cidofovir warrants further investigation as treatment for BoHV-1 keratoconjunctivitis, with future studies needed to assess in-vivo tolerability and efficacy.

Topical Astodrimer Sodium, a Non-Toxic Polyanionic Dendrimer, Demonstrates Antiviral Activity in an Experimental Ocular Adenovirus Infection Model.

There is no approved antiviral therapy for adenovirus (HAdV) ocular infections. Astodrimer sodium (SPL7013) is a polyanionic dendrimer with antiviral activity. The current study evaluated the ocular tolerability and anti-adenoviral efficacy of topical SPL7013 in rabbit ocular models. In a tolerability study, rabbits were treated with 3% SPL7013, vehicle, or 0.5% cidofovir. Their eyes were graded using the Draize scale. In antiviral efficacy studies, HAdV5 inoculated eyes were treated with 3% SPL7013, vehicle, or 0.5% cidofovir. Eyes were cultured for the virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. Viral titers were determined. There were no differences in Draize scores between 3% SPL7013 and vehicle on any day. Cidofovir produced significantly higher Draize scores on day 12 than SPL7013 and vehicle. The 3% SPL7013 and 0.5% cidofovir significantly reduced daily viral titers and positive cultures per total compared with vehicle on several different days. The 3% SPL7013 and 0.5% cidofovir significantly reduced the duration of HAdV5 shedding compared to vehicle. The 3% SPL7013 demonstrated significantly more antiviral activity compared with vehicle in the Ad5/NZW rabbit ocular model. The 3% SPL7013 induced "minimal" to "practically non-irritating" Draize scores in the ocular tolerability study. Further development of astodrimer sodium as a topical antiviral therapy for adenoviral ocular infections is indicated.

Cidofovir intravesical, uso en cistitis hemorrágica por poliomavirus BK tras un trasplante de progenitores hematopoyéticos: off-label / Cidofovir intravesical, use in BK poliomavirus associated haemorrhagic cystitis after a transplantation of hematopoyetic progenitors: Off-label

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Topical Treatment of Acyclovir-Resistant Herpes Simplex Virus Stomatitis after Allogeneic Hematopoietic Cell Transplantation.

INTRODUCTION: We report on patients who developed severe acyclovir-resistant (ACVr) herpes simplex virus 1 (HSV-1) stomatitis after allogeneic hematopoietic cell transplantation (HCT). PATIENTS: HCT patients suffering from HSV-1 stomatitis without response after 1 week of high-dose acyclovir (ACV) were tested for ACV resistance. Patients with proven ACV resistance were treated either topically with cidofovir solution and gel or with topical foscavir cream or with intravenous foscavir. RESULTS: Among 214 consecutive HCT patients, 6 developed severe ACVr HSV-1 stomatitis (WHO grade III n = 1, WHO grade IV n = 5). All 6 patients suffered from relapse of acute myeloid leukemia (AML) after HCT. ACVr stomatitis was treated topically with first-line (n = 4) or second-line (n = 2) cidofovir. Topical foscavir cream was applied as first-line (n = 1) or second-line (n = 1) therapy. Intravenous foscavir was used in 3 patients (first-line therapy, n = 1; second-line therapy, n = 2). Complete remission was reached by topical cidofovir (n = 3), topical foscavir (n = 1), and intravenous foscavir (n = 1), respectively. Five of the 6 patients died due to progression of leukemia. Only 1 patient survived. CONCLUSIONS: ACVr HSV-1 stomatitis is a severe complication in AML patients relapsing after HCT. It reflects the seriously impaired general condition of these patients. This analysis shows that topical treatment with cidofovir or foscavir might be a sufficient first-line therapy approach in ACVr HSV-1 stomatitis. It might serve as a less toxic alternative to intravenous foscavir.

BK virus encephalitis and end-stage renal disease in a child with hematopoietic stem cell transplantation.

BK virus encephalitis after HSCT is uncommon. Several reports of native kidney BKVN in patients with HSCT, hematologic malignancies, human immunodeficiency virus infection, and non-renal solid organ transplantation have been described. However, an uncommon combination of BK encephalitis and ESRD of native kidneys secondary to BK virus in a child with HSCT has not been described. We report a 10-year-old boy who presented with a gradually rising serum creatinine during treatment for severe autoimmune hemolytic anemia, which he developed 9 months after receiving an allogeneic HSCT for aplastic anemia. There was no proteinuria or hematuria present. Serum BK virus load was 5 × 106  copies/mL. A renal biopsy showed evidence of BKVN. He developed fever, seizures, and confusion, and the (CSF) showed significant presence of the BK virus (1 × 106  copies/mL) along with biochemical evidence of viral encephalitis. Cerebrospinal fluid cultures were negative. Despite significant clinical symptoms and presence of BK virus in CSF, the magnetic resonance brain imaging findings were minimal. With reduction of immunosuppression, there was resolution of BK encephalitis but BKVN remained resistant to multiple anti-BK virus agents, including leflunomide and cidofovir. He eventually became dialysis-dependent and, 6 years later, received a renal transplant from his mother. This case illustrates that BK virus in severely immunocompromised HSCT recipient may lead to BK encephalitis and BKVN of native kidneys, even without hemorrhagic cystitis, leading to ESRD. Knowledge of such is important for appropriate timely evaluation and management.

Use of intralesional cidofovir in the recurrent respiratory papillomatosis: a review of the literature.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is characterized by exophytic, benign, and papillary lesions infected by the virus in the epithelium of the upper aerodigestive tract. RRP is caused by persistent infection of the respiratory epithelium by human papillomavirus (HPV) HPV6 and-11. The clinical course of RRP is unpredictable, frequently relapsing, and may be lifelong. The aim of this study is to evaluate the efficacy and safety of the use of intralesional Cidofovir in the treatment of RRP. PATIENTS AND METHODS: We have selected articles on the use of cidofovir as adjuvant therapy in laryngeal papillomatosis. We reviewed 20 reports that enrolled 185 patients with "adult onset recurrent respiratory papillomatosis" (AORRP) and 85 patients with "juvenile onset recurrent respiratory papillomatosis" (JORRP). We evaluated concentration of cidofovir, number of injections, injection interval, therapeutic response, side effects, and progression to dysplasia. RESULTS: The mean concentration of cidofovir was 7.5 mg/ml at injection. The mean number of injections per patient is 6 with 26 days between injections. The percentage of patients with dysplasia after use of cidofovir is 1.48%. The AORRP response to cidofovir is better with a 74% complete response rate, compared to 56.5% of the JORRP. CONCLUSIONS: Intralesion use of cidofovir has a good adjuvant action in RRP increasing the complete remission of the disease. The treatment does not increase the risk of laryngeal dysplasia.

Evaluation of Safety of Intralesional Cidofovir for Adjuvant Treatment of Recurrent Respiratory Papillomatosis.

Importance: The use of intralesional cidofovir injections for recurrent respiratory papillomatosis (RRP) remains controversial owing to concern regarding the risks of its use, including increased risk of dysplasia or carcinogenesis. Objective: To describe the rates of dysplasia, development of malignant lesions, and adverse events associated with use of intralesional cidofovir injections as adjuvant treatment for RRP compared with patients treated without adjuvant cidofovir. Design, Setting, and Participants: In this case series performed at a tertiary care referral center, review of electronic medical records on all adult and pediatric patients (N = 154) treated for RRP with adequate follow-up from January 1, 2000, to December 31, 2016, was performed. Data were collected on the use of cidofovir, development and presence of dysplasia or malignant lesions, complications, and intersurgical interval. Exposures: Adjuvant intralesional cidofovir or surgical excision only. Main Outcomes and Measures: The main outcomes measured were the development of dysplasia, malignant lesions, and complications from treatment. These outcomes were determined before collection of data. Results: Of the 154 patients included in the analysis, 83 patients (53.9%) received adjuvant intralesional cidofovir and 71 patients (46.1%) underwent surgical excision only. One hundred patients (64.9%) were male; mean age was 27.7 (95% CI, 24.3-31.2) years. Patients were followed up for a median (interquartile range) of 70 (24-118) months in the noncidofovir group and 91 (47-152) months in the cidofovir group. There were no statistically significant differences in the rates of development of dysplasia (2.8%; 95% CI, -8.3% to 13.2%) or malignant lesions (2.2%; 95% CI, -5.3% to 11.2%) between the groups. No nephrotoxic effects were observed in the treated cohort, and only 5 minor complications that occurred in 628 injections were noted in the cidofovir group; 3 were related to direct laryngoscopy and 2 were related to needle malfunction. Conclusions and Relevance: In this cohort of patients with RRP, adjuvant intralesional cidofovir injections did not appear to cause major complications or an increased rate of development of dysplasia and cancer.

Low-dose cidofovir and conversion to mTOR-based immunosuppression in polyomavirus-associated nephropathy.

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) remains a relevant complication following kidney transplantation with allograft loss rates of up to 50%. Reduction in overall immunosuppression is a cornerstone of therapy, whereas no specific antiviral regimen has shown conclusive benefit to date. The present case series demonstrates the efficacy of a dual therapeutic approach with low-dose cidofovir and conversion to mTOR-based immunosuppression in PVAN. METHODS: Patients with biopsy-proven PVAN having received low-dose cidofovir (0.25 mg/kg) according to the Tübingen Cidofovir Protocol and been converted to mTOR-based immunosuppression were analyzed retrospectively. RESULTS: Twenty-three patients with a median follow-up of 2.24 [IQR 1.55-5.01] years were included in the analysis. Median time to PVAN diagnosis was 268 [IQR 153-869] days after transplantation. Polyomavirus clearance from plasma was achieved in 78% of patients after a median of 118 [IQR 76-293] days. Of the 23 patients, nine patients (39%) lost their allograft function during follow-up, but only three of these (13%) due to PVAN. Fourteen patients (61%) stabilized or improved allograft function. The cidofovir protocol allowed for specific antiviral therapy without adverse nephrotoxicity, even in patients with low allograft function. CONCLUSIONS: Low-dose cidofovir and conversion to mTOR-based immunosuppression allow for effective virus clearance and preservation of allograft function in a high proportion of patients with PVAN and progressive allograft dysfunction and may prolong allograft survival in these patients.

Successful treatment of genital warts with cidofovir cream in a pediatric patient with Fanconi anemia.

INTRODUCTION: Patients with Fanconi anemia have an increased susceptibility to malignancies associated with human papillomavirus, and thus prevention and early management of human papillomavirus infections in this patient population are crucial. CASE REPORT: A nine-year-old girl with Fanconi anemia developed genital warts about three years after undergoing haplo-identical stem cell transplant. The transplant was complicated by chronic graft-versus-host disease, and the patient had therefore received multiple immunosuppressants. The genital warts were treated with several creams, but minimal improvement was reported. MANAGEMENT AND OUTCOME: Cidofovir was extemporaneously compounded into an unscented 1% moisturizing cream and applied daily at bedtime to the genital warts. By the end of treatment, the warts had been successfully treated, and no adverse events were reported. The patient is still free of any lesions at six months after completing treatment. DISCUSSION: Although reports have been published on the use of cidofovir cream, most were in adults with non-genital warts. Cidofovir cream may be considered as a treatment option for refractory genital warts in pediatric patients. However, further studies are needed to better define the optimal preparation and dosing for such patient population.

Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis Following Hematopoietic Stem Cell Transplantation.

Background: BK virus hemorrhagic cystitis (BKV-HC) is a common complication following hematopoietic stem cell transplant (HSCT); optimal management remains uncertain. Supportive care (bladder irrigation and blood transfusions) and intravenous and intravesicular cidofovir have all been used with varying success. Objective: The purpose of this study was to determine the safety and effectiveness of intravesicular cidofovir for BKV-HC following HSCT. Methods: A retrospective analysis of all HSCT patients with BKV-HC prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were treated for BKV-HC. The median age was 50 years (range 23-73), and 18 (55%) were male. The median HC symptom severity was 2, with a median BK urine viral load pretreatment of 100,000,000 IU/mL. Patients received a median of 2 intravesicular treatments (range 1-7) at a dosage of 5 mg/kg per instillation. In all, 19 (59%) patients demonstrated complete clinical resolution of symptoms; 9 (28%) had a partial response; and 4 (13%) had no change in symptoms. Patients with a high pretreatment BK viral load (>100 million) and high HC grade (2-4) had a lower frequency of complete remission. The main side effect of intravesicular instillation was severe bladder spasms in 4 patients (12%). Conclusion and Relevance: This is the largest study of intravesicular cidofovir treatment of BKV HC reported to date; 88% of patients with BVK-HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for this treatment for BKV-HC.

Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers.

Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.

Neutropenia and renal dysfunction due to intravesical cidofovir for virus-associated hemorrhagic cystitis after kidney and allogenic hematopoietic stem cell transplantations.

We present a patient with virus-associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo-HSCT). Six months post-allo-HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.

Laser-Assisted Delivery of Topical Cidofovir in the Treatment of Plantar Warts

Recalcitrant plantar warts pose a therapeutic challenge. Cidofovir is a viral DNA polymerase inhibitor that has been used in treatment of verrucae with greater success than traditional treatments in some cases. Laser-assisted drug delivery enhances drug penetration beyond the epidermis and is particularly well-suited, though under-utilized, to target palmoplantar verrucae. We report the use of an erbium:yttrium-aluminum-garnet (Er:YAG) ablative fractional laser (AFL) followed by topical cidofovir in treating recalcitrant plantar warts. Two patients were treated with a 2940-nm Er:YAG laser at depths of 1.2-1.5 mm followed by topical application of cidofovir 75 mg/mL. Both patients exhibited a significant reduction in lesion size and improvement in symptoms. AFL-assisted delivery of topical cidofovir represents a promising therapeutic option for recalcitrant plantar warts. J Drugs Dermatol. 2019;18(7):663-665.

Intralesional Cidofovir for Treatment of Acyclovir-Resistant Laryngeal Herpes Manifesting as Supraglottic Mass.

INTRODUCTION:: Laryngopharyngeal herpes simplex virus infection is rare and presents typically in the supraglottis. Findings on presentation can range from small mucosal lesions to fungating obstructive masses mimicking neoplasm. Laryngopharyngeal herpes is a medically treated disease. OBJECTIVES:: Identify potential treatment in cases that are refractory to antiviral medications. METHODS:: Individual case with treatment adapted from other case report. CASE PRESENTATION:: We report a case of bulky, obstructive supraglottic and glottic herpes virus laryngitis that presented with dysphonia, dysphagia, and airway complaints resistant to acyclovir analogues that was treated effectively with intralesional cidofovir injection. CONCLUSIONS:: Our promising initial response suggests a potential novel treatment for this unusual condition.

Resistant Cytomegalovirus Infection in Solid-organ Transplantation: Single-center Experience, Literature Review of Risk Factors, and Proposed Preventive Strategies.

BACKGROUND: Cytomegalovirus (CMV) infection causes morbidity and mortality in solid-organ transplant recipients. Drug-resistant CMV is an emerging problem with poor survival outcomes and limited therapeutic options. In this study we comprehensively address the issue of drug resistance in CMV when compared with standard therapies, such as ganciclovir (GCV) and foscarnet. METHODS: We conducted a retrospective review of adult patients diagnosed with CMV after solid-organ transplant at our center between 2013 and 2017, and identified 7 resistant CMV cases. To study risk factors in the published literature, we performed an extensive database search. RESULTS: All patients had documented UL97 mutations, and 3 patients harbored both UL97 and UL54 mutations. For cases with increasing viral load or failure to achieve clinical improvement despite optimal therapy, genetic resistance testing was carried out. Patients received GCV and foscarnet combination therapy. As an adjunct, CMV immunoglobulin, cidofovir, and leflunomide were added. Risk factors, including donor+/recipient- serostatus, persistent high viral replication, prolonged therapeutic GCV exposure (>2.5 months), and allograft rejection, were assessed. CONCLUSION: Patients at risk, especially those with D+/R- serostatus, should be judiciously monitored for resistance. Prolonged intravenous GCV exposure increases the risk for development of drug resistance. Therefore, precise guidelines are required for prevention of long-term GCV/VGCV exposure. Investigation regarding interferon-gamma release assay and adoptive transfer of T cells in diagnosed CMV patients is warranted to improve future prophylactic and management strategies against CMV, with a potential to reduce the requirement for available toxic antiviral drugs.