Severe mpox has been observed in people with advanced human immunodeficiency virus (HIV). We describe clinical outcomes of 13 patients with advanced HIV (CD4 <200 cells/μL), severe mpox, and multiorgan involvement. Despite extended tecovirimat courses and additional agents, including vaccinia immune globulin, cidofovir, and brincidofovir, this group experienced prolonged hospitalizations and high mortality.

Monkeypox (mpox) is an orthopoxviral zoonotic disease with a similar, but less severe, clinical presentation as smallpox. However, immunocompromised patients such as solid organ transplant recipients are at higher risk of developing severe forms of the disease. Herein, we describe the case of a 43 years-old female kidney transplant recipient that manifested severe skin ulcers alongside nodular lung opacities and pleural effusion attributed directly to the Monkeypox virus. Notwithstanding the initiation of early treatment with tecovirimat, a satisfactory response was not achieved until a reduction in immunosuppression to everolimus monotherapy, coupled with the transition to cidofovir for antiviral treatment. In conclusion, mpox has the potential to produce a severe form of systemic infection in individuals who have undergone solid organ transplantation, demanding a meticulous approach involving sequential antiviral treatment and modifications to immunosuppressive regimens in order to achieve complete healing.

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.

Monkeypox is a zoonotic viral disease. Monkeypox was first reported in humans about 54 years ago. Prior to the global outbreak, monkeypox was endemic to the rainforests of central and western African countries. In the last three years, increasing numbers of human monkeypox have been reported from various countries. Responding to the severity, monkeypox was declared a Public Health Emergency of International Concern by the World Health Organization. In the absence of approved drugs or clinical studies, repurposed drugs and therapeutic medical countermeasures effective against other orthopoxviruses have been utilized to treat severe human monkeypox cases. Currently, clinical trials are underway exploring the potential therapeutic effectiveness of tecovirimate in human monkeypox cases. Monoclonal antibodies, IFN-β, resveratrol, and 15 triple-targeting FDA-approved drugs represent potential new drug targets for human monkeypox, necessitating further research.

OBJECTIVE: The 2022 global mpox outbreak disproportionately impacted people living with HIV. This review explores recent evidence on mpox in this group, focusing on clinical presentation, complications, treatment modalities and vaccine strategies.
RESULTS: Recent studies have suggested that people with HIV diagnosed with mpox have a greater risk of proctitis and hospitalization compared with people without HIV. In addition, those with advanced immunosuppression face an elevated risk of severe mpox infection, which can lead to mortality. Comprehensive and prompt supportive care using antiretrovirals and mpox antivirals is crucial in this group. Although results from randomized clinical trials are still forthcoming, recent studies suggest that early initiation of tecovirimat can prevent disease progression in people with HIV. The non-replicative attenuated smallpox vaccine is well tolerated and effective in preventing monkeypox virus infections in people with HIV. Further studies are needed regarding long-term vaccine effectiveness for this population.
CONCLUSIONS: Evaluating the risk of severe mpox in people living with HIV requires assessing the level of immune suppression and viral control. Universal access to vaccination is imperative to prevent the resurgence of future outbreaks.

This article delineates the systematic identification, synthesis, and impurity control methods used during the manufacturing process development of tecovirimat, an antiviral drug that treats monkeypox. Critical impurities were synthesized, and their chemical structure was confirmed through NMR analysis, GC, and HPLC mass spectrometry. The results established a thorough approach to identify, address, and control impurities to produce high-quality tecovirimat drug substance in accordance with International Conference on Harmonization (ICH)-compliant standards. This study is the first of its kind to evaluate both process and genotoxic impurities in tecovirimat, demonstrating effective control measures during commercial sample investigations and scaling up to a 60-kg batch size. The findings highlight the importance of critical impurity characterization and control in pharmaceutical development and production to ensure the safety and efficacy of the final product.

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UNASSIGNED: We conducted a multicentric national study (SEIMC-CEME-22), to describe the clinical and epidemiological profile of the mpox outbreak in Spain, including the management of the disease.
UNASSIGNED: This was a retrospective national observational study conducted by Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) and Foundation SEIMC-GESIDA. We included patients with a confirmed mpox diagnosis before 13 July 2022, and attended at the Spanish health network (the early phase of the outbreak). Epidemiological, clinical, and therapeutic data were collected.
UNASSIGNED: Of a total of 1472 patients from 52 centers included, 99% of them were cisgender men, mostly middle-aged, and 98.6% were residents in Spain. The main suspected route of transmission was sexual exposure, primarily among MSM. Occupational exposure was reported in 6 patients. Immunosuppression was present in 40% of patients, mainly due to human immunodeficiency virus (HIV). Only 6.5% of patients had been vaccinated against orthopoxvirus. Virus sequencing was performed in 147 patients (all B.1 lineage). Rash was the most frequent symptom (95.7%), followed by fever (48.2%), adenopathies (44.4%) myalgias (20.7%), proctitis (17%), and headache (14.7%). Simultaneously diagnosed sexually transmitted infections included syphilis (n = 129), gonococcal infection (n = 91), HIV (n = 67), chlamydia (n = 56), hepatitis B (n = 14), and hepatitis C (n = 11). No therapy was used in 479 patients (33%). Symptomatic therapies and antibiotics were used in 50% of cases. The most used therapy regimens were systemic corticoids (90 patients), tecovirimat (6 patients), and cidofovir (13 patients). Smallpox immunoglobulins were used in 1 patient. Fifty-eight patients were hospitalized, and 1 patient died.
UNASSIGNED: Mpox outbreak in Spain affected primarily middle-aged men who were sexually active and showed a high rate of HIV infection. A range of heterogeneous therapeutics options was performed.

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.

Monkeypox (now Mpox), a zoonotic disease caused by the monkeypox virus (MPXV) is an emerging threat to global health. In the time span of only six months, from May to October 2022, the number of MPXV cases breached 80,000 and many of the outbreaks occurred in locations that had never previously reported MPXV. Currently there are no FDA-approved MPXV-specific vaccines or treatments, therefore, finding drugs to combat MPXV is of utmost importance. The A42R profilin-like protein of the MPXV is involved in cell development and motility making it a critical drug target. A42R protein is highly conserved across orthopoxviruses, thus A42R inhibitors may work for other family members. This study sought to identify potential A42R inhibitors for MPXV treatment using computational approaches. The energy minimized 3D structure of the A42R profilin-like protein (PDB ID: 4QWO) underwent virtual screening using a library of 36,366 compounds from Traditional Chinese Medicine (TCM), AfroDb, and PubChem databases as well as known inhibitor tecovirimat via AutoDock Vina. A total of seven compounds comprising PubChem CID: 11371962, ZINC000000899909, ZINC000001632866, ZINC000015151344, ZINC000013378519, ZINC000000086470, and ZINC000095486204, predicted to have favorable binding were shortlisted. Molecular docking suggested that all seven proposed compounds have higher binding affinities to A42R (-7.2 to -8.3 kcal/mol) than tecovirimat (-6.7 kcal/mol). This was corroborated by MM/PBSA calculations, with tecovirimat demonstrating the highest binding free energy of -68.694 kJ/mol (lowest binding affinity) compared to the seven shortlisted compounds that ranged from -73.252 to -97.140 kJ/mol. Furthermore, the 7 compounds in complex with A42R demonstrated higher stability than the A42R-tecovirimat complex when subjected to 100 ns molecular dynamics simulations. The protein-ligand interaction maps generated using LigPlot+ suggested that residues Met1, Glu3, Trp4, Ile7, Arg127, Val128, Thr131, and Asn133 are important for binding. These seven compounds were adequately profiled to be potential antivirals via PASS predictions and structural similarity searches. All seven potential lead compounds were scored Pa > Pi for antiviral activity while ZINC000001632866 and ZINC000015151344 were predicted as poxvirus inhibitors with Pa values of 0.315 and 0.215, and Pi values of 0.052 and 0.136, respectively. Further experimental validations of the identified lead compounds are required to corroborate their predicted activity. These seven identified compounds represent solid footing for development of antivirals against MPXV and other orthopoxviruses.