NPP-669, a prodrug of cidofovir, is highly efficacious against human adenovirus infection in the permissive Syrian hamster model.

Human adenoviruses can cause serious, disseminated infections in immunocompromised patients. For pediatric allogeneic stem cell transplant patients, the case fatality rate can reach 80%. Still, there is no available antiviral drug that is specifically approved by the Food and Drug Administration for the treatment of adenovirus infections. To fill this pressing medical need, we have developed NPP-669, a prodrug of cidofovir with broad activity against double-stranded DNA viruses, including adenoviruses. Here, we report on the in vivo anti-adenoviral efficacy of NPP-669. Using the immunosuppressed Syrian hamster as the model, we show that NPP-669 is highly efficacious when dosed orally at 1 mg/kg and 3 mg/kg. In a delayed administration experiment, NPP-669 was more effective than brincidofovir, a similar compound that reached Phase III clinical trials. Furthermore, parenteral administration of NPP-669 increased its efficacy approximately 10-fold compared to oral dosing without apparent toxicity, suggesting that this route may be preferable in a hospital setting. Based on these findings, we believe that NPP-669 is a promising new compound that needs to be further investigated.

Treatment and Vaccination for Smallpox and Monkeypox.

The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins.

The successful treatment of mpox with brincidofovir in renal transplant recipients-a report of 2 cases.

An mpox outbreak was declared in July 2022 by the world health organization (WHO). It causes a mild self-limiting disease however; in immunosuppressed hosts, it tends to cause severe disseminated infection. Most cases of mpox in sold organ transplant (SOT) recipients reported in the literature were treated with tecovirimat. Here we report two cases of severe disseminated mpox infection in renal transplant recipients that were successfully treated with brincidofovir. Both patients were discharged from the hospital with no immediate significant side effects from brincidofovir reported until the submission of this report.

Monkeypox: A re-emerging disease.

ABSTRACT: The virus known as monkeypox is the source of the zoonotic disease monkeypox, which was historically widespread in Central Africa and West Africa. The cases of monkeypox in humans are uncommon outside of West and Central Africa, but copious nonendemic nations outside of Africa have recently confirmed cases. People when interact with diseased animals, then, they may inadvertently contact monkeypox. There are two drugs in the market: brincidofovir and tecovirimat and both of these drugs are permitted for the cure of monkeypox by the US Food and Drug Administration. The present review summarizes the various parameters of monkeypox in context with transmission, signs and symptoms, histopathological and etiological changes, and possible treatment. Monkeypox is clinically similar to that of smallpox infection but epidemiologically, these two are different, the present study also signifies the main differences and similarities of monkeypox to that of other infectious diseases. As it is an emerging disease, it is important to know about the various factors related to monkeypox so as to control it on a very early stage of transmission.

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.

Computational analysis of antiviral drugs using topological descriptors.

Many health challenges are attributed to viral infections, which represent significant concerns in public health. Among these infections, diseases such as herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV) infections have garnered attention due to their prevalence and impact on human health. There are specific antiviral medications available for the treatment of these viral infections. Drugs like Cidofovir, Valacyclovir, and Acyclovir are commonly prescribed. These antiviral drugs are known for their efficacy against herpesviruses and related viral infections, leveraging their ability to inhibit viral DNA polymerase. A molecular descriptor is a numerical value that correlates with specific physicochemical properties of a molecular graph. This article explores the calculation of distance-based topological descriptors, including the Trinajstic, Mostar, Szeged, and PI descriptors for the aforementioned antiviral drugs. These descriptors provide insights into these drugs' structural and physicochemical characteristics, aiding in understanding their mechanism of action and the development of new therapeutic agents.

Brincidofovir for disease progression due to suspected tecovirimat resistance in association with advanced HIV.

A man with advanced HIV presented with verrucous plaques 2-3 months after initial mpox infection. He received two courses of tecovirimat without resolution of initial mpox lesions and development of new lesions raising concern for resistance. He was treated with two doses of brincidofovir and demonstrated improvement 6 months later.

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.

Brincidofovir inhibits polyomavirus infection in vivo.

Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases, there are no currently approved antivirals for treating polyomavirus infection. Brincidofovir (BCV) is an antiviral approved for the treatment of poxvirus infections and has shown activity against other double-stranded DNA viruses. In this study, we tested the efficacy of BCV against polyomavirus infection in vitro and in vivo using mouse polyomavirus (MuPyV). BCV inhibited virus production in primary mouse kidney cells and brain cortical cells. BCV treatment of cells transfected with MuPyV genomic DNA resulted in a reduction in virus levels, indicating that viral inhibition occurs post-entry. Although in vitro BCV treatment had a limited effect on viral DNA and RNA levels, drug treatment was associated with a reduction in viral protein, raising the possibility that BCV acts post-transcriptionally to inhibit MuPyV infection. In mice, BCV treatment was well tolerated, and prophylactic treatment resulted in a reduction in viral DNA levels and a potent suppression of infectious virus production in the kidney and brain. In mice with chronic polyomavirus infection, therapeutic administration of BCV decreased viremia and reduced infection in the kidney. These data demonstrate that BCV exerts antiviral activity against polyomavirus infection in vivo, supporting further investigation into the use of BCV to treat clinical polyomavirus infections. IMPORTANCE: Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating polyomavirus infections, management of polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection in vivo using mouse polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic.

Avaliação da eficácia do cidofovir na papilomatose respiratória recorrente juvenil / Efficacy of cidofovir in recurrent juvenile respiratory papillomatosis

O uso do cidofovir para papilomatose respiratória recorrente juvenil (PRRJ) ainda não tem estudos caso-controle suficientes que comprovem sua eficácia em literatura. OBJETIVO: Avaliar fatores que influenciem o prognóstico da PRRJ, e observar a atuação do cidofovir na erradicação da PRRJ. DESENHO DO ESTUDO: Retrospectivo. MATERIAIS E MÉTODOS: 22 crianças com PRRJ foram avaliadas num centro terciário. Todas as crianças foram submetidas ao tratamento cirúrgico, seguido (Grupo 2) ou não (Grupo 1) pelo uso do cidofovir. A idade ao diagnóstico foi correlacionada ao escore de Derkay e à evolução da doença. Os Grupos 1 e 2 tiveram suas evoluções comparadas entre si. RESULTADOS: Quinze crianças foram consideradas curadas, 8 no Grupo 2 e 7 no Grupo 1. Houve uma correlação negativa entre idade e Escores Total e Clínico (P<0,05). O número médio de cirurgias necessárias para controlar a doença foi semelhante entre os Grupos, mas a duração do tratamento até remissão foi significativamente maior no Grupo 1 quando comparado ao Grupo 2 (P<0,05). CONCLUSÕES: A PRRJ é mais agressiva quanto mais nova a idade do paciente ao diagnóstico. Pacientes tratados com cidofovir apresentaram duração significativamente menor de tratamento até erradicação da PRRJ do que os submetidos apenas ao tratamento cirúrgico.

The efficacy of cidofovir in juvenile recurrent respiratory papillomatosis (JRRP) remains uncertain due to the lack of published case-control studies. AIM: To establish factors affecting the progression of JRRP prognosis, and to evaluate cidofovir for eradicating JRRP. STUDY DESIGN: Retrospective. METHODS: 22 children with JRRP were evaluated at a referral center. All children underwent surgical debulking, followed by cidofovir injection (Group 2) or not (Group 1). Age at diagnosis was correlated with the Derkay score and disease outcome. Disease progression was compared between groups 1 and 2. RESULTS: fifteen children were considered disease-free; 8 were in Group 2 and 7 in Group 1. Age and total and clinical scores (P<0.05) were negatively correlated. The mean number of surgeries required to control the disease was identical in both groups; the duration of treatment until remission was significantly higher in Group 1 (P<0,05). CONCLUSION: JRRP is more aggressive in earlier onset disease. The duration of treatment was significantly lower in patients treated with cidofovir until eradication of JRRP compared to patients treated with surgery only.

Uso de cidofovir en la papilomatosis respiratoria recurrente / Use of cidofovir in recurrent respiratory papillomatosis

La Papilomatosis Respiratoria Recurrente (PRR) es una enfermedad causada por el virus papiloma humano (VPH) que se caracteriza por la presencia de tumores epiteliales en la vía aérea. Su principal mecanismo de contagio es por contacto directo, la zona más frecuentemente afectada es la laringe, pero puede comprometer cualquier lugar de la vía aéreo-digestiva. Sus manifestaciones van desde la disfonía a la obstrucción completa de la vía aérea, causando incluso la muerte. En algunas ocasiones los papilomas pueden malignizarse y transformarse en carcinoma epidermoide. El tratamiento existente es sólo paliativo y consiste en la excisión quirúrgica de los papilomas para mantener la vía aérea sin obstrucción y mejorar la calidad de la voz, pero tiene una alta tasa de recidiva y habitualmente se requieren múltiples intervenciones quirúrgicas, resultando un tratamiento de alto costo. En los últimos tiempos se ha usado el cidofovir, un nucleósido fosfanato acíclico, administrado en forma intralesional para el tratamiento de la papilomatosis laríngea obteniéndose promisorios resultados, observándose remisión completa en un alto porcentaje de los casos y disminución de las recidivas.

Recurrent respiratory papillomatosis (RRP) is a disease caused by infection with the human papillomavirus (HPV), and is characterized by the presence of epithelial tumors in the airway. It is most commonly spread by direct contact, and it usually affects the larynx, but it may involve any region of the airway. Its symptoms vary from dysphonia to complete obstruction of the airway, and it may even cause death. in some cases, papillomas can become malignant and transform into epidermoid carcinoma. Current treatments are only palliative, and consist of the papillomas surgical resection in order to maintain the airway unobstructed and to improve voice quality; but it has a high recurrency rate, and usually several surgical procedures are needed, resulting in a high-cost treatment. Recently, cidofovir, an acyclic nucleoside phosphonate, has been used for the intralesional treatment of laryngeal papillomatosis with promising results, including complete remission in a high percentage of cases, and decreased recurrence.

Sida en Bélgica, Europa y Africa / AIDS in Belgium, Europe and Africa

El SIDA es causado por un Retrovirus llamado HIV. Se distinguen 2 tipos de Retrovirus: HIV I y HIV II; el primero se encuentra en Europa, U.S.A. y Africa Central, especialmente en Zaire, Burundi, Rouana, Uganda y recientemente en Kenya. El HIV II, se encuentra fundamentalmente en Africa Occidental: Senegal, Costa de Marfil, etc.