Resolution of painful trichodysplasia spinulosa with topical cidofovir: case report.

Purpose: Trichodysplasia spinulosa (TS) is a rare, disfiguring skin condition which presents with widespread asymptomatic or pruritic, skin-colored papules with white protruding keratin spiculations in immunocompromised individuals. Due to its rarity, there is little data to guide treatment decisions. The purpose of this article is to report a case of TS that completely resolved after treatment with topical cidofovir.Materials and methods: A 19-year-old immunosuppressed female presented with widespread painful, itchy bumps on the nose and face. Upon examination, there were erythematous papules with hyperkeratinized spicules affecting the central face. Biopsy of the lesions was consistent with TS which was confirmed via PCR analysis. The tenderness of this patient's eruption was highly atypical for TS. Once daily topical application of compounded 1% cidofovir cream was prescribed.Results: The patient's symptoms resolved completely after 4 weeks of therapy with topical cidofovir 1% cream, without reduction of immunosuppression.Conclusions: Topical cidofovir 1% cream may be a valuable treatment for this rare disease.

Clinical evaluation of pediatric patients with recurrent respiratory papillomatosis.: A longitudinal study at a Saudi Arabian tertiary care center.

OBJECTIVES: To study the clinical evaluation of recurrent respiratory papillomatosis (RRP) patients and the factors associated with the improvement in the Derkay's score as a measure of disease severity. METHODS: A retrospective cohort that included all juvenile RRP patients who were admitted to King Abdulaziz University Hospital, Riyadh, Saudi Arabia, between September 2015 and June 2022 and underwent surgical debulking. RESULTS: A total of 16 patients were eligible to join our study. Among them, 7 patients were males. Hoarseness of voice was the most frequent symptom. The median period of the follow-up was 56 months. Complete remission was achieved in 31.3%. The univariate linear regression model revealed that the cidofovir-treated patients had a significant reduction in the change value of Derkay's score compared to those without treatment (regression coefficient= -5.83, 95% confidence interval [CI]: [-11.5 to -0.143], p=0.045). Also, the increased first Derkay's score decreased the change value and subsequently increased the improvement chance of the disease (regression coefficient= -0.424, 95% CI: [-0.764 to -0.083], p=0.018). However, in the multivariate regression model, both variables showed non-significant results. CONCLUSION: cidofovir treatment and higher Derkay's scores affected the disease improvement.

A Fulminant Case of Adenovirus Genotype C108 Infection in a Pediatric Stem Cell Transplant Recipient with x-Linked Lymphoproliferative Syndrome Type 1.

A 3-year-old male with X-linked lymphoproliferative syndrome type 1 underwent an unrelated umbilical cord blood transplant (UUCBT). The week prior to transplant the patient tested positive for adenovirus (HAdV) with a viral load of <190 copies/mL and was started on cidofovir. UUCBT proceeded as scheduled, and the patient engrafted on day +19. The patient's HAdV load in serum continued to rise with resulting hepatic dysfunction, despite ongoing therapy with cidofovir and HAdV specific T-cell infusions. The patient died 6 months after transplantation having never cleared the virus. Next generation whole genome sequencing and sequence data analyses identified an intertypic recombinant HAdV-C P1H2F2 closely related (99.6% similarity) to genotype C108 in the isolates from three blood specimens obtained during the last week of life. Incidentally, the de novo assembly strategy enabled the detection of an adeno-associated virus type 2 (AAV2) genome in the DNA purified from the plasma isolates. Proteotyping analysis revealed minor differences in the predicted amino acid sequences for E1A, E1B 19K, E1B 55K, DNA polymerase, penton base, and fiber. None of the mutations previously described for HAdV-C5 variants resistant to cidofovir were identified. In silico restriction enzyme analysis revealed a distinct Sac I profile for the identified virus, supporting its designation as a C108 variant.

Oral USC-093, a novel homoserinamide analogue of the tyrosinamide (S)-HPMPA prodrug USC-087 has decreased nephrotoxicity while maintaining antiviral efficacy against human adenovirus infection of Syrian hamsters.

Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. Presently, there is no drug specifically approved for the treatment of adenovirus infections by the FDA. The state-of-the-art treatment of such infections is the off-label use of cidofovir, an acyclic nucleotide phosphonate. While cidofovir inhibits adenovirus replication, it has dose-limiting kidney toxicity. There is an apparent need for a better compound to treat adenovirus infections. To this end, we have been developing acyclic nucleotide phosphonate prodrugs that utilize an amino acid scaffold equipped with a lipophilic modifier. Here, we compare the antiviral potential of two prodrugs of HPMPA that differ only in the amino acid-based promoiety: USC-087, based on an N-hexadecyl tyrosinamide, and USC-093, based on an N-hexadecyl serinamide. Oral administration of both compounds was very efficacious against disseminated HAdV-C6 infection in immunosuppressed Syrian hamsters, suppressing virus replication and mitigating pathology even when treatment was withheld until 4 days after challenge. We saw only marginal efficacy after respiratory infection of hamsters, which may reflect suboptimal distribution to the lung. Importantly, neither compound induced intestinal toxicity, which was observed as the major adverse effect in clinical trials of brincidofovir, a prodrug of cidofovir which also contains a C-16 modifier. Notably, we found that there was a significant difference in the nephrotoxicity of the two compounds: USC-087 caused significant kidney toxicity while USC-093 did not, at effective doses. These findings will be valuable guidepoints in the future evolution of this new class of potential prodrugs to treat adenovirus infections.

Intralesional cidofovir vs. bevacizumab for recurrent respiratory papillomatosis: a systematic review and indirect meta-analysis.

BACKGROUND: Specific HPV types cause recurrent respiratory papillomatosis (R.R.P.). When administered intralesionally, cidofovir, an antiviral agent, has shown favorable outcomes in reducing papilloma. Bevacizumab, an angiogenesis inhibitor, has demonstrated improved R.R.P. However, both treatments lack FDA approval for R.R.P. Our study aims to evaluate the efficacy and safety of intralesional Cidofovir and Bevacizumab for R.R.P. and compare the two interventions. METHODS: We searched five electronic databases to find relevant studies. After the screening, data were extracted from the included studies. Pooled ratios with 95% confidence intervals (CIs) were used for categorical outcomes, and mean difference (MD) was used for continuous outcomes. Statistical heterogeneity was evaluated using the chi-squared test for I2 statistics. The Cochrane Risk of Bias assessment tool was used to assess the methodological quality of randomized controlled trials (RCTs), while the National Institutes of Health's tool was used for observational studies. Analysis was done by Review Manager software. RESULTS: In our comprehensive meta-analysis of 35 articles involving 836 patients, cidofovir demonstrated an overall remission ratio of (0.90 [95% CI: 0.83, 0.98], p = 0.01), while bevacizumab (0.92 [95% CI: 0.79, 1.07]), p = 0.3). The complete remission ratio for cidofovir was (0.66 [95% CI: 0.57, 0.75], p > 0.0001), while bevacizumab was (0.29 [95% CI: 0.12, 0.71], p = 0.07). In partial remission, Bevacizumab showed a higher ratio than Cidofovir 0.74 [0.55, 0.99] vs. 0.40 [0.30, 0.54]. Bevacizumab had a pooled ratio of 0.07 [95% CI: 0.02, 0.30] in terms of no remission, indicating better outcomes compared to Cidofovir with a ratio of 0.28 [95% CI: 0.16, 0.51]. Additionally, Cidofovir showed a favorable decrease in the Derkay Severity Score (DSS) with a mean difference (MD) of 1.98 [95% CI: 1.44, 2.52]. CONCLUSION: Cidofovir had a higher impact on complete remission compared to Bevacizumab. Both showed partial remission, with Bevacizumab having a higher ratio. Moreover, Cidofovir showed a significant decrease in DSS. Bevacizumab had lower rates of no remission and recurrence and fewer adverse events compared to Cidofovir. However, the difference between the two treatments was not significant, except for partial remission.

Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis.

BACKGROUND: The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. METHODS: We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. RESULTS: A total of 33 published studies involving 986 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I2 = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I2 = 83%), 71% (95% CI: 0.63-0.78; I2 = 0), 87% (95% CI: 0.82-0.93; I2 = 45%), and 80% (95% CI: 0.59-1.00; I2 = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. CONCLUSIONS: Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.

Cidofovir in the Management of Non-Genital Warts: A Review.

INTRODUCTION: Cutaneous warts are one of the most frequent reasons for visits to the dermatologist. While there are many treatment options available and commonly used to treat warts, recurrence of lesions is common and complete clearance is rarely achieved. Cidofovir is an antiviral agent that has activity against various DNA viruses, including HPV, the virus that results in verrucae. OBJECTIVE: We examined the literature on the use of cidofovir in the treatment of non-genital warts to further assess its safety and efficacy.  Methods: A review of the literature using PubMed and Google Scholar databases was conducted to find relevant case reports and studies on the use of cidofovir in the treatment of non-genital warts.  Results: Thirteen case reports, five case series, six retrospective chart reviews, and one clinical study were reviewed and included. There were a total of 603 patients, 46.2% males and 53.7% females. Of 603 patients included in this review, 212 (35.2%) were treated with topical cidofovir for their warts. Clearance was achieved in 55.2%. There was no recurrence of lesions after clearance at two months to three years post-treatment (mean of 15.8 months). Of the 212 patients treated with topical cidofovir, 37 (17.4%) reported local side effects such as erythema, pruritus, and burning.  Discussion/Conclusion: Treatment options for recalcitrant non-genital warts are limited and have varying efficacy. Topical cidofovir may serve as an effective, safe, and affordable alternative for the clearance of recalcitrant non-genital warts, but controlled clinical trials are needed.J Drugs Dermatol. 2023;22(10):1009-1016  doi:10.36849/JDD.7258.

Monkeypox: Virology, laboratory diagnosis and therapeutic approach.

Monkeypox infection outbreaks have been observed sporadically in Africa, usually as a result of interaction with wildlife reservoirs. The genomes of the new strain range in size from 184.7 to 198.0 kb and are identified with 143-214 open reading frames. Viral cores are rapidly carried on microtubules away from the cell's perimeter and deeper into the cytoplasm once the virus and cell membranes fuse. Depending on the kind of exposure, patients with monkeypox may experience a febrile prodrome 5-13 days after exposure, which frequently includes lymphadenopathy, malaise, headaches, and muscle aches. A different diagnostic approach is available for monkeypox, including histopathological analysis, electron microscopy, immunoassays, polymerase chain reaction, genome sequencing, microarrays, loop-mediated isothermal amplification technology and CRISPR (i.e., "clustered regularly interspaced short palindromic repeats"). There are currently no particular, clinically effective treatments available for the monkeypox virus. An initial treatment is cidofovir. As a monophosphate nucleotide analog, cidofovir is transformed into an inhibitor of viral DNA polymerase by cellular kinases, which is analogous to cidofovir's function in inhibiting viral DNA synthesis. The European Medicine Agency and the Food and Drug Administration have both granted permission for IMVAMUNE, a replication-deficient, attenuated third-generation modified vaccinia Ankara vaccine, to be used for the prevention of smallpox and monkeypox in adults.

Effectiveness of topical cidofovir for treatment of refractory anal high-grade squamous intraepithelial lesion.

OBJECTIVES: Ablative electrocautery is effective treating anal high-grade squamous intraepithelial lesions (HSILs). However, persistence or recurrence of the HSIL despite ablative sessions is not uncommon. The aim of this study is to assess the feasibility of topical cidofovir as salvage therapy for the management of refractory HSIL. DESIGN: A prospective uncontrolled unicenter study of men and transgender people who have sex with men with HIV who had a refractory intra-anal HSIL after ablative treatments and who received topical cidofovir (ointment at 1%, auto-applicated, three times a week, a total of 8 weeks) as salvage therapy. Effectiveness was evaluated on-treatment defining response as resolution or regression to low-grade lesion of HSIL in the biopsy posttreatment. Tolerance and recurrences were recorded. RESULTS: From 2017 to 2022, 23 patients with refractory intra-anal HSIL (78.3% persistent lesions, 39% affecting > 50% of circumference, and a median of six previous ablative sessions) were treated with topical cidofovir. A response was observed in 16 of 23 patients [69.5% (95% confidence interval (95% CI) 50.8-88.4)]. Local tolerance was reported as regular or bad in 13 patients (52.2%), requiring modification of the treatment in eight patients (three early discontinuation and five dose reduction). Non-serious side effects were reported. After a median follow-up of 30.3 months, two of the 16 patients with a response developed recurrent HSIL [recurrence rate, 25.4% at 12 months (95% CI, 0-35)]. CONCLUSION: Topical cidofovir could be a good option in the management of anal HSIL due to its good effectiveness, low recurrence rate, and acceptable tolerance even in difficult-to-treat lesions.

Use of cidofovir in a patient with severe mpox and uncontrolled HIV infection.

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.

Evaluation of compounded cidofovir, famciclovir, and ganciclovir for the treatment of feline herpesvirus ocular surface disease in shelter-housed cats.

OBJECTIVE: To assess the efficacy of compounded cidofovir, famciclovir, and ganciclovir for the treatment of feline herpesvirus type 1 (FHV-1) ocular surface disease. ANIMALS STUDIED: 132 shelter-housed cats qPCR positive for FHV-1. PROCEDURES: A masked placebo-controlled study design was utilized. Animals were enrolled in one of four treatment groups: topical ocular placebo + oral placebo (n = 32), compounded cidofovir 0.5% ophthalmic solution + oral placebo (n = 32), compounded famciclovir oral solution (90 mg/kg) + topical ocular placebo (n = 32), and compounded ganciclovir 0.15% ophthalmic solution + oral placebo (n = 36). Cats were treated with each medication twice daily for 7 days and were evaluated on Day 1 and Day 8 using an ocular scoring system, body weight, and qPCR for FHV-1 viral load. RESULTS: Cidofovir significantly decreased viral load from Day 1 to Day 8 compared with placebo (p = .024). Neither famciclovir nor ganciclovir decreased viral load compared with placebo (p = .14, p = .41). There was no significant improvement of ocular scores for any drug group compared with placebo (p = .62). In all groups, 65%-75% of cats improved from Day 1 to Day 8. Juvenile cats had a significant increase in weight gain compared with placebo for cidofovir (p = .025) and ganciclovir (p = .023). All corneal ulcers in placebo animals failed to heal whereas 77% of ulcers in antiviral group animals healed. CONCLUSIONS: Topical ophthalmic cidofovir significantly decreased ocular FHV-1 viral shedding and increased weight gain in juvenile cats. Ganciclovir increased weight gain in juvenile cats. Compounded famciclovir demonstrated limited efficacy for the treatment of FHV-1 ocular surface disease in shelter-housed cats.

Therapeutic strategies for human poxvirus infections: Monkeypox (mpox), smallpox, molluscipox, and orf.

Therapeutic and vaccine development for human poxvirus infections (e.g., monkeypox (mpox) virus, variola virus, molluscum contagiosum virus, orf virus) has been largely deserted, especially after the eradication of smallpox by 1980. Human mpox is a self-limited disease confined to Central and West Africa for decades. However, since April 2022, mpox has quickly emerged as a multi-country outbreak, urgently calling for effective antiviral agents and vaccines to control mpox. Here, this review highlights possible therapeutic options (e.g., tecovirimat, brincidofovir, cidofovir) and other strategies (e.g., vaccines, intravenous vaccinia immune globulin) for the management of human poxvirus infections worldwide.

Nasal monkeypox virus infection successfully treated with cidofovir in a patient newly diagnosed with HIV.

Monkeypox (MPXV) usually causes a mild and self-limited infection. To date there are no data about cidofovir for the treatment for MPXV in humans. We report a case of a 25 years-old Brazilian man with a concurrent diagnosis of acute HIV (human immunodeficiency virus) infection, primary syphilis and MPXV infection with a nasal lesion successfully treated with intravenous cidofovir.

Endovesical instillation of Cidofovir in the treatment of BK polyomavirus hemorrhagic cystitis after allogeneic hematopoietic cell transplantation.

BACKGROUND: Hemorrhagic cystitis (HC) with BK polyomavirus (BKPyV) is a common complication after allogeneic hematopoietic cell transplantation (alloHCT) that may lead to severe discomfort for the patient and significant morbidity (urinary obstruction, increased transfusion requirements and prolonged hospitalization). So far, there is no clear consensus on how to manage this complication. PATIENTS AND METHODS: Here, we report a single-center case series of 9 patients (4 children and 5 adults) treated with cidofovir endovesical (EV) instillation(s) for BKPyV-HC after alloHCT. EV Cidofovir was administered at a dose of 5 mg/kg, for 1 to 3 instillations (with a minimum delay between 2 successive doses of 5 days). RESULTS: Eight out of the 9 treated patients with EV Cidofovir achieved a complete resolution of HC after 1-3 instillation(s), without recurrence of symptomatic infection within the next 3 months. Only 1 adult patient did not improve after treatment and developed severe morbidity (emphysematous cystitis). CONCLUSION: Although this single-center case series of EV cidofovir for BKPyV HC after alloHCT shows encouraging results, only large prospective studies will definitively establish the effectiveness of this therapy.

The use of antivirals in the treatment of human monkeypox outbreaks: a systematic review.

OBJECTIVES: Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant literature available on the use of antivirals in MPXV infection. This systematic review compiles all evidence of various antivirals used on their efficacy and safety and summarizes their mechanisms of action. METHODS: A review was done of all original studies mentioning individual patient data on the use of antivirals in patients with MPXV infection. RESULTS: Of the total 487 non-duplicate studies, 18 studies with 71 individuals were included. Tecovirimat was used in 61 individuals, followed by cidofovir in seven and brincidofovir (BCV) in three individuals. Topical trifluridine was used in four ophthalmic cases in addition to tecovirimat. Of the total, 59 (83.1%) were reported to have complete resolution of symptoms; one was experiencing waxing and waning of symptoms, only one (1.8%) had died, and the others were having a resolution of symptoms. The death was thought unrelated to tecovirimat. Elevated hepatic panels were reported among all individuals treated with BCV (leading to treatment discontinuation) and five treated with tecovirimat. CONCLUSION: Tecovirimat is the most used and has proven beneficial in several aggravating cases. No major safety concerns were detected upon its use. Topical trifluridine was used as an adjuvant treatment option along with tecovirimat. BCV and cidofovir were seldom used, with the latter often being used due to the unavailability of tecovirimat. BCV was associated with treatment discontinuation due to adverse events.

In Vitro efficacy of cyclosporine a and various antiseptics and antiviral drugs on adenovirus genotype 8, a common cause of epidemic keratoconjunctivitis.

PURPOSE: To evaluate the in vitro efficacy of cidofovir, ganciclovir, povidone-iodine, chlorhexidine, and cyclosporine A on adenovirus genotype 8. METHODS: Conjunctival samples were collected from patients with adenoviral conjunctivitis and cultured in A549 cells. Adenovirus diagnosis was confirmed by RT-PCR. For each drug, the 50% cytotoxic concentration (CC 50 ) was determined. Subsequently, the antiviral activity was tested at concentrations below CC 50, and the 50% inhibitor concentration (IC 50 ) of drugs was determined RESULTS: While the IC 50 of cidofovir against adenovirus genotype 8 was 3.07 ± 0.8 µM, ganciclovir, povidone-iodine, chlorhexidine, and cyclosporine A were not found to be effective against adenovirus genotype 8 at concentrations below the CC 50 value. CONCLUSIONS: Cidofovir was found effective and the IC 50 value was within the ranges in the literature. Ganciclovir and cyclosporine A were found to be ineffective at doses below the cytotoxic dose, povidone-iodine and chlorhexidine was found to be highly cytotoxic.