Abstract
Background
Human monkeypox has become increasingly frequent worldwide since the outbreak was first reported in May 2022.
Objectives
As cidofovir is effective against vaccinia and other Orthopoxvirus diseases, we hypothesize that its topical use could be an effective treatment for monkeypox skin lesions, avoiding the adverse effects of systemic administration.
Methods
We conducted a prospective study to collect data on the clinical and virologic course of patients with monkeypox. All patients were offered symptomatic treatment. They were also offered treatment with topical cidofovir on a compassionate use basis. Twelve patients received treatment with topical cidofovir 1%, while the others received only symptomatic treatment. Prospective visits were scheduled for the collection of clinical and virological data.
Results
Lesions cleared quicker in the cidofovir-treated group (hazard ratio, 4.572; P = .0039). The median time to resolution was 12 (11.5-15) and 18 (16-21) days, respectively. On day 14, polymerase chain reaction-positive skin lesions were detected in 10% of the cidofovir sample, compared with 62.5% of the non-treated group (P = .019). Local adverse effects were frequent (50%), especially in the anogenital region. No systemic adverse effects were reported.
Limitations
The study is not a clinical trial and lacks a placebo-controlled arm.
Discussion
Topical cidofovir is a potentially relevant therapy in patients with skin lesions but mild systemic involvement. Reducing time to resolution could shorten isolation time and improve the cosmetic impact in areas such as the face.
Key words: cidofovir, monkeypox, skin, topical
Capsule Summary.
-
•
Our study is the first to describe the use of topical cidofovir for monkeypox skin lesions, finding a shorter time to lesion resolution and negativization of viral polymerase chain reaction.
-
•
These results encourage the development of clinical trials to demonstrate the efficacy and safety of this novel treatment.
Introduction
Human monkeypox virus is a double-stranded DNA virus of the genus Orthopoxvirus that belongs to the family Poxviridae.1 Since monkeypox was first recognized in monkeys in 1958 and the first human cases were reported in Nigeria in 1970, it has been considered an endemic disease in some regions of Central and West Africa.2, 3, 4 The clinical picture consists of a skin rash formed by multiple vesicles and pustules that progress to dome shaped lesions with an umbilicated necrotic center, spreading in a cephalo-caudal direction. Cutaneous symptoms are accompanied by lymphadenopathies, fever, and arthromyalgia. The fatality rate is 1% to 10% in Africa.5 A possible zoonotic route of infection, through contact with apes, has been described, and the main inter-human routes of contagion comprise close contact and respiratory droplets.6
Since the disease was first described, several self-limiting outbreaks have occurred in the United Kingdom and the United States of America. The affected patients were travelers to endemic regions or persons who had contact with an imported reservoir.2, 3, 4 Since May 2022, a new outbreak has been spreading rapidly in non-endemic areas, especially in the Southern Europe. The cases reported to date in Europe are less symptomatic than previous descriptions of monkeypox in Africa.7
Data from recent series show that 98% of the cases involved men who have sex with men with a median age of 38 years. Of these, 41% are people living with HIV. Transmission was suspected to have occurred through direct cutaneous contact, mainly during sexual relations in 95%. Clinical manifestations include rash in 95% of patients and anogenital lesions in 73%. Concomitant sexually transmitted diseases (STDs) were reported in 29% of those tested. The median incubation period was 7 days (range, 3-20). Severe anorectal pain is a common finding and may lead to hospitalization.8, 9, 10
Current World Health Organization recommendations for management include respiratory and contact isolation for 21 days, treatment of symptoms, and use of tecovirimat in cases with significant systemic involvement.11 In the current outbreak of monkeypox, tecovirimat combined with intravenous cidofovir has been reported to be successful, although little evidence is available.8
Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine] is an acyclic nucleoside analog with an antiviral effect that was initially studied for treatment of cytomegalovirus retinitis in AIDS patients. Its effect is based on selective interaction of its diphosphoryl metabolite with viral DNA polymerases, which incorporate cidofovir by slowing or completely inhibiting DNA synthesis.12, 13, 14, 15
Cidofovir has been shown to be effective for the treatment and prophylaxis of poxvirus infection and can be used not only for the treatment of infection by orthopoxviruses,12 , 13 , 16 but also for infection by parapox (orf), molluscum (molluscum contagiosum), and Herpesviridae family viruses in cases of resistance to other antivirals.14 Of note, topical cidofovir has proven to be more effective than systemic cidofovir when treating vaccinia in animals.15
Administration has traditionally been intravenous, with nephrotoxicity being the most relevant adverse effect. However, the topical route has been widely used for off-label administration of 1% to 3% cream in the treatment of refractory herpesvirus and human papillomavirus lesions.15 , 17
While clinical data for cidofovir efficacy in monkeypox are scarce, cidofovir has been administered intravenously in disease outbreaks and successfully reduced morbidity and mortality in simian animal models.12 , 13
Given the rapid spread of the current outbreak, its potential disfiguring sequelae, the long isolation period required, and the low availability of tecovirimat, we prioritized the search for treatments that could shorten infectivity time (and therefore, the isolation period) and reduce potential cosmetic damage. In cases of low systemic severity, we consider that topical treatment will enable us to reach these objectives in patients with predominantly cutaneous symptoms.
Patients and methods
Study design
We designed a prospective study to collect data on the clinical and virologic course of patients with monkeypox at La Paz University Hospital, Madrid, Spain. The study was approved by the local ethics committee. All patients were offered symptomatic treatment with analgesia. They were also offered the option of treatment with topical cidofovir on a compassionate use basis, explaining that it is not an approved drug for this indication.
Inclusion criteria
-
1.
Age ≥18 years.
-
2.
Monkeypox confirmed with real time polymerase chain reaction (PCR).
-
3.
At least 1 skin lesion due to monkeypox.
-
4.
Signed informed consent for inclusion in the study and for off-label use of topical cidofovir.
Exclusion criteria
-
1.
Refusal to sign the informed consent document.
Study procedures
We studied the characteristics of 24 adult patients diagnosed with human monkeypox infection in the Madrid health area between May 26, 2022, and June 13, 2022. All 24 patients received symptomatic treatment, if needed, and 12 of the patients were treated with topical cidofovir off-label. The order of selection of the participants was only conditioned by the patient's willingness to participate in the study.
Cidofovir was extracted from vials of cidofovir solution and formulated to 1% using Beeler base as an excipient until a homogeneous composition was achieved. The preparation was stored and refrigerated (2-8 °C) until it was dispensed to the patient, who also stored the product refrigerated at home. Patients received oral and written instructions for self-application of cidofovir, application of a very thin layer on active lesions twice a day for 7 days.
At the baseline visit, all patients gave their written informed consent for collection of their medical data. Those receiving cidofovir also signed a separate consent document (compassionate use). A detailed clinical history was taken, including the date of onset of first lesion, presence or absence of systemic symptoms, sexual history, travel destinations, previous STDs, parameters relative to HIV infection and its treatment, and a visual analog scale (VAS) for pruritus/itch/stinging/pain, with scores ranging from 0 to 10, where greater values represent more intense symptoms. Each patient underwent a full physical examination in order to record the total number of lesions, the number of active lesions and crusts, anatomical location, presence or absence of lymphadenopathies, and mucosal involvement. Pharyngeal and skin swab samples were taken from an active lesion for genomic amplification. In addition, serology tests were performed for other STDs (syphilis, HIV, hepatitis B, and hepatitis C), as well as a second swab sample for amplification testing to detect herpes, syphilis, chlamydia, and mycoplasma.
All 24 patients were scheduled to attend 2 further visits (day 7 and day 14 after diagnosis), at which the clinical history was retaken and the physical examination and swab sampling from active lesions were repeated (except in the case of a previous negative result). The data recorded at each visit were appearance of new lesions, total number of lesions, number of lesions in the crusting phase, time until all lesions crusted, and pruritus and pain (VAS). For those patients receiving cidofovir, we also measured adherence (number of applications out of 14) and asked about adverse effects. Photographs were taken at each visit, with the patient's written informed consent.
Criteria for response
The primary endpoint was the time to resolution of the lesion, which was defined as crusting. The secondary endpoints were virological status measured by genomic amplification at days 7 and 14 in both the pharynx and the skin lesion, adherence to treatment, and percentage of patients with local adverse effects, which were rated as mild (irritation, erythema), moderate (skin erosion with moderate pain), and severe (ulceration, severe pain).
Statistical analysis
All data were analyzed using the R open-source software environment (4.1.2 version). The demographic characteristics of the patients studied are expressed as mean and standard deviation for normally distributed quantitative variables (assessed using the Shapiro-Wilk test). Differences in these variables between groups were assessed using the t test for independent samples. Non-normally distributed variables are expressed as median and interquartile range. Differences between groups were assessed using the Mann-Whitney test. The chi-square test was used to evaluate the differences in qualitative variables. The Kaplan-Meier method and Cox proportional hazards model were used to assess treatment efficacy of different groups. P values less than .05 were considered statistically significant.
Results
Demographic and clinical characteristics
The study sample comprised 24 men with a median age of 39.5 years (range 19-62). All of them reported at least 1 unprotected sexual encounter, which was with another man in 23 cases (96%). Thirteen patients (54.17%) were people living with HIV. The median maximum number of lesions was 5 (range, 1-60), and the median number of days since onset of first lesion was 3.5 (range, 0-14). Based on the VAS result (scale of 1-10), patients generally described lesions as slightly more itchy (3.90 ± 3.13) than painful (3.57 ± 2.22) or burning (3.48 ± 3.37). No statistically significant differences were found between the cidofovir-treated and the non-treated groups regarding age, history of smallpox vaccination, HIV infection, or median days from onset of first lesion to admission. We found statistically significant differences in the antecedent of chem-sex practice and oral-penile sexual relation. Further epidemiological and clinical data are collected in Table I .
Table I.
Demographic characteristics
n = 24 | Cidofovir (n = 12) | Non-treated (n = 12) | P value |
---|---|---|---|
Sex at birth | - | ||
Male | 12 (100%) | 12 (100%) | |
Female | 0 (0%) | 0 (0%) | |
Age (y, mean ± SD) | 40.75 ± 9.51 | 41.33 ± 12.23 | .897 |
History of smallpox vaccination | 3 (25.00%) | 3 (25.00%) | 1.000 |
HIV infection | 5 (41.57%) | 8 (66.67%) | .219 |
Median (IQR) days since first lesion at admission | 3.5 (2-6) | 3.5 (2.75-8) | .663 |
Sexual orientation | .307 | ||
MSM | 12 (100%) | 11 (91.67%) | |
Non-MSM | 0 (0.00%) | 1 (8.33%) | |
Median (IQR) sexual partners in the last 21 d | 8 (1.75-12.75) | 2.5 (1-4) | .111 |
Previous confirmed monkeypox contact | 6 (50.00%) | 2 (16.67%) | .189 |
Type of sexual contact | |||
Oral-penile | 11 (91.67%) | 4 (33.33%) | .003 |
Oral-anal | 8 (66.67%) | 4 (33.33%) | .408 |
Penile-anal | 11 (91.67%) | 7 (58.33%) | .059 |
Sexual habits | |||
One or more unprotected sexual contact | 12 (100%) | 11 (91.66%) | .307 |
Use of dating apps | 6 (50.00%) | 7 (58.33%) | .206 |
Sex in bars/saunas | 5 (41.67%) | 3 (25.00%) | .673 |
Group sex (≥3 people) | 4 (33.33%) | 1 (8.33%) | .132 |
Chemsex | 7 (58.33%) | 1 (8.33%) | .009 |
Features of the exposed areas | |||
Contact with others' body fluids | 8 (66.67%) | 7 (58.33%) | .653 |
Recently shaved | 3 (25.00%) | 3 (25.00%) | .386 |
Coinfection with other STDs | |||
Syphilis | 0 (0%) | 1 (8.33%) | .307 |
Chlamydia trachomatis | 1 (8.33%) | 1 (8.33%) | 1.000 |
Herpes simplex virus | 1 (8.33%) | 0 (0%) | .307 |
Hepatitis C virus | 0 (0%) | 1 (8.33%) | .307 |
Maximum number of skin lesions, median (IQR) | 5.5 (2.75-10) | 4.5 (2-9.25) | .466 |
Location of initial lesion | |||
Face | 6 (50.00%) | 4 (33.33%) | .408 |
Upper limbs | 2 (16.67%) | 0 (0%) | .139 |
Genital | 2 (16.66%) | 5 (41.67%) | .178 |
Perianal | 2 (16.66%) | 3 (25.00%) | .615 |
Initial lesion-related symptoms (mean ± SD) | |||
Pain (score from 0-10) | 3.73 ± 3.23 | 3.4 ± 3.37 | .616 |
Pruritus (score from 0-10) | 2.73 ± 1.95 | 5.2 ± 3.74 | .142 |
Burning (score from 0-10) | 2.82 ± 2.79 | 4.2 ± 3.94 | .388 |
Associated systemic signs and symptoms | |||
Fever | 6 (50.00%) | 6 (50.00%) | .408 |
Headache | 0 (0%) | 1 (8.33%) | .307 |
Myalgia | 1 (8.33%) | 2 (16.67%) | .537 |
Sore throat | 2 (16.67%) | 2 (16.67%) | 1.000 |
Proctitis | 3 (25.00%) | 2 (16.67%) | .615 |
Lymphadenopathies | 6 (50.00%) | 2 (16.67%) | .219 |
Numeric values are expressed as No. (%) unless otherwise specified. Bold indicates statistically significant differences in the antecedent of chem-sex practice and oral-penile sexual relation.
HIV, Human immunodeficiency virus; IQR, interquartile range; MSM, men who have sex with men; SD, standard deviation.
Effectiveness
The median number of days until lesion resolution was significantly lower (12 [11.5-15] vs 18 [16-21]; P = .006) in the cidofovir group. A Kaplan-Meier curve revealed a hazard ratio of 4.572 (1.55-13.47) (P = .0039) (Fig 1 ), which can be interpreted as a higher probability, in favor of the cidofovir-treated group, of skin lesions resolving in a given period of time. Table II summarizes these outcomes and presents significant differences in the percentage of skin lesions with a negative PCR result on day 14, again favoring the cidofovir group (P = .019). No significant differences were found in time to negative results in the pharynx PCR tests.
Fig 1.
Kaplan-Meier curve revealed a hazard ratio of 4.572 (1.55-13.47) (P = .0039), which can be interpreted as a higher probability, in favor of the cidofovir-treated group, of skin lesions resolving in a given period of time.
Table II.
Comparative results of clinical and microbiological outcomes
n = 24 | Cidofovir (n = 12) | Non-treated (n = 12) | P value |
---|---|---|---|
Orthopoxvirus PCR test in lesion on day 0 | - | ||
Positive | 12 (100%) | 12 (100%) | |
Negative | 0 (0%) | 0 (0%) | |
Orthopoxvirus PCR test in lesion on day +7 | (n = 11) | (n = 11) | .127 |
Positive | 7 (63.64%) | 10 (90.91%) | |
Negative | 4 (36.36%) | 1 (9.09%) | |
Orthopoxvirus PCR test in lesion on day +14 | (n = 10) | (n = 8) | .019 |
Positive | 1 (10.00%) | 5 (62.5%) | |
Negative | 9 (90.00%) | 3 (37.5%) | |
Orthopoxvirus PCR test in pharynx on day 0 | (n = 10) | (n = 12) | .696 |
Positive | 5 (50.00%) | 5 (41.67%) | |
Negative | 5 (50.00%) | 7 (58.33%) | |
Orthopoxvirus PCR test in pharynx on day +7 | (n = 11) | (n = 11) | 1.000 |
Positive | 6 (54.55%) | 6 (54.55%) | |
Negative | 5 (45.45%) | 5 (45.45%) | |
Orthopoxvirus PCR test in pharynx on day +14 | (n = 10) | (n = 8) | - |
Positive | 0 (0%) | 0 (0%) | |
Negative | 10 (100%) | 8 (100%) | |
Percentage of lesions in the scab phase | |||
Day 7 (%) | 83.97 ± 22.19 | 46.63 ± 37.42 | .247 |
Day 14 (%) | 100 ± 0.00 | 92.27 ± 10.72 | .342 |
Median (IQR) days until full recovery | 12 (11.5-15) | 18 (16-21) | .006 |
Numeric results are expressed as No. (%) and mean ± SD. Median values are expressed alongside the respective interquartile ranges. Bold indicates significant differences in the percentage of skin lesions with a negative PCR result on day 14, again favoring the cidofovir group (P = .019).
IQR, Interquartile range; PCR, polymerase chain reaction.
Adherence, measured as the number of applications out of 14, was excellent. Seven patients (58%) followed our recommendations strictly, applying cidofovir 14 times, 1 (8%) used 13 applications, 3 (25%) used 12 applications (skipping last doses), and only 1 (8%) discontinued treatment after 2 applications. Fig 2 shows the progress of skin lesions (A-C) before and 1 week after topical cidofovir was initiated (D-F). Fig 3 shows (A) Skin lesions in the back of a different patient, also treated with 14 applications of topical cidofovir during 7 days. On the left picture, (B) pseudovesicles with an umbilicated necrotic center and an erythematous surrounding base can be observed, while on the right, most skin lesions are scabs. Two patients withdrew after visit +7 due to the impossibility of attending review appointments.
Fig 2.
A-C, Skin lesions in the back of a different patient, also treated with 14 applications of topical cidofovir during 7 days. On the left picture, (D-F) pseudovesicles with an umbilicated necrotic center and an erythematous surrounding base can be observed, while on the right, most skin lesions are scabs.
Fig 3.
Progress of skin lesions (A) before and (B) 1 week after topical cidofovir was initiated.
Adverse events in the cidofovir-treated group
Six out of the 12 patients (50%) who received cidofovir experienced at least 1 adverse effect, which ranged from mild (1/6) to moderate (5/6). All 6 patients reported irritation or erosions on and around the site of application (4 of them on the penis or scrotum and 2 on the perianal region), producing local discomfort. In 5 of the 12 patients, the local adverse effects occurred during the last 2 days of treatment. These did not lead to discontinuation of therapy, although they did involve erosions that were managed locally with a borax poultice. In the sixth patient, topical cidofovir produced local irritation and intolerance from the first day, leading him to discontinue treatment after only 2 applications, being the only case of treatment abandonment due to adverse effects. No systemic adverse effects or other local lesions were observed.
Discussion
We found a statistically significant reduction in the median time to resolution of skin lesions in the cidofovir-treated group. All the lesions had reached the crusting phase in 50% of the patients on day 12; in the non-treated group, it took an average of 6 more days to reach this stage. Moreover, only 10% of the cidofovir-treated sample tested positive for skin lesions by PCR on day 14, compared with 62.5% in the non-treated group (P = .019). This faster crusting and consequent reduction of the infectivity period could be relevant, as it could reduce the risk of contagion and therefore shorten the 21-day isolation period. Recently, a study reported a negative result in the PCR of blood and pharyngeal samples 48 hours after starting intravenous tecovirimat, although its low availability could limit its widespread use.18
Half of the cidofovir-treated sample developed painful local erosions. As this effect was mainly observed in lesions located in the anogenital area, we hypothesize that reducing the dose in these areas could overcome this effect. Despite local irritation, positive results were observed in terms of crusting, even in patients who used fewer applications owing to adverse effects. Furthermore, the fact that onset during the last 2 days of treatment in 5 out of 6 patients suggests that wider dosing intervals would be better tolerated. No local adverse effects were observed in other areas of the skin, including facial areas such as the nose, where efficacy was remarkable, with rapid resolution of symptoms. Of note, no patients presented systemic adverse effects. In a study previously carried out by our group, no systemic adverse effects or abnormal blood count or creatinine levels were reported, even after application of cidofovir 1% to the anal mucosa.17 There is a risk of systemic toxicity if the drug is applied at an excessively high concentration over too large an area of abraded skin, as illustrated by the case of a patient treated with 4% cidofovir.19
In terms of epidemiology, consistent with published series, we found that most patients were men who have sex with men,8 , 9 who had recently engaged in unprotected sexual relations. Unlike other series, we did not have any cases of infection in women.10 People living with HIV with an undetectable viral load accounted for 50% of the sample. HIV coinfection did not seem to increase the severity of monkeypox (defined as requiring systemic treatment with tecovirimat or admission to hospital). No statistically significant differences were found between the cidofovir-treated and the non-treated group regarding most epidemiological variables, except for chem-sex practice and oral-penile sexual relation. Nevertheless, we do not believe that these differences influence the efficacy of cidofovir.
Most skin lesions first appeared in the anogenital area (50%) and to a lesser extent on the face, specifically the perioral area (29.17%), probably because 62.7% of patients reported contact with human fluids in these areas, underscoring the potential relevance for contagion by direct contact during sexual intercourse.
We detected 5 coinfections with STDs (20.84%), which must always be ruled out in the patient with monkeypox. These were caused by Herpesviridae (1), Chlamydia trachomatis (2), hepatitis C virus (1), and Treponema pallidum (1). Our finding for coinfection is lower than frequencies reported elsewhere (29%).8
Fever was the most common accompanying symptom (50%), followed by lymphadenopathies (33.34%) and proctitis (20.84%), compared with 54% to 62%, 54% to 56%, and 14% to 22%, respectively in other series.8, 9, 10
While the results of our study are encouraging, they are subject to limitations. As the study was not a clinical trial and lacks a placebo-controlled arm, the evidence generated should be confirmed in a well-designed clinical trial. Long-term data are not available, thus preventing us from assessing the potential cosmetic sequelae (scarring).
Conclusion
To our knowledge, this is the first study to assess topical cidofovir for treatment of monkeypox infection. This potentially relevant therapeutic option seems to accelerate healing of monkeypox lesions.
The patients who could benefit most from cidofovir are those with multiple lesions in uncovered areas but no major systemic involvement. Topical application prevents the potential severe adverse effects associated with systemic administration, although the drug should be applied with caution in the anogenital region.
Clinical trials are warranted to evaluate the efficacy of topical cidofovir for monkeypox skin lesions in different therapeutic regimens.
Conflicts of interest
None disclosed.
Acknowledgments
This study would not have been possible without the collaboration of all patients, medical, and nursery staff involved in this project. We would like to thank the pharmacy service, and particularly Dr Fátima Ros Castelar, for their collaboration in the elaboration of the topical cidofovir cream.
Footnotes
Funding sources: None.
IRB approval status: The study has received approval from the local ethics committee, which is available for submission to the journal.
Consent informed: Consent for the publication of recognizable patient photographs or other identifiable material has been obtained by the authors and are available for submission to the journal.
Reprints not available from the authors.
References
- 1.Petersen E., Kantele A., Koopmans M., et al. Human monkeypox. Infect Dis Clin North Am. 2019;33(4):1027–1043. doi: 10.1016/j.idc.2019.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Costello V., Sowash M., Gaur A., et al. Imported monkeypox from international traveler, Maryland, USA, 2021. Emerg Infect Dis. 2022;28(5):4. doi: 10.3201/eid2805.220292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rao A.K., Schulte J., Chen T.H., et al. Monkeypox in a traveler returning from Nigeria — Dallas, Texas, July 2021. MMWR Morb Mortal Wkly Rep. 2022;71(14):509–516. doi: 10.15585/mmwr.mm7114a1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hobson G., Adamson J., Adler H., et al. Family cluster of three cases of monkeypox imported from Nigeria to the United Kingdom, May 2021. Eurosurveillance. 2021;26(32) doi: 10.2807/1560-7917.ES.2021.26.32.2100745. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bunge E.M., Hoet B., Chen L., et al. The changing epidemiology of human monkeypox—a potential threat? A systematic review. PLoS Negl Trop Dis. 2022;16(2) doi: 10.1371/journal.pntd.0010141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Jezek Z., Szczeniowski M., Paluku K.M., Mutombo M. Human monkeypox: clinical features of 282 patients. J Infect Dis. 1987;156(2):293–298. doi: 10.1093/infdis/156.2.293. [DOI] [PubMed] [Google Scholar]
- 7.Antinori A., Mazzotta V., Vita S., et al. Epidemiological, clinical and virological characteristics of four cases of monkeypox support transmission through sexual contact, Italy, May 2022. Eurosurveillance. 2022;27(22):2200421. doi: 10.2807/1560-7917.ES.2022.27.22.2200421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Thornhill J.P., Barkati S., Walmsley S., et al. Monkeypox virus infection in humans across 16 countries — april–June 2022. N Engl J Med. 2022;387(8):679–691. doi: 10.1056/NEJMoa2207323. [DOI] [PubMed] [Google Scholar]
- 9.Català A., Clavo Escribano P., Riera J., et al. Monkeypox outbreak in Spain: clinical and epidemiological findings in a prospective cross-sectional study of 185 cases. Br J Dermatol. 2022;187(5):765–772. doi: 10.1111/bjd.21790. [DOI] [PubMed] [Google Scholar]
- 10.Tarín-Vicente E.J., Alemany A., Agud-Dios M., et al. Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study. Lancet. 2022;400(10353):661–669. doi: 10.1016/S0140-6736(22)01436-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Monkeypox [WHO, internet] https://www.who.int/news-room/fact-sheets/detail/monkeypox
- 12.De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002;55(1):1–13. doi: 10.1016/S0166-3542(02)00008-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Andrei G., Snoeck R. Cidofovir activity against poxvirus infections. Viruses. 2010;2(12):2803–2830. doi: 10.3390/v2122803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Smee D.F., Bailey K.W., Wong M., Wandersee M.K., Sidwell R.W. Topical cidofovir is more effective than is parenteral therapy for treatment of progressive vaccinia in immunocompromised Mice. J Infect Dis. 2004;190(6):1132–1139. doi: 10.1086/422696. [DOI] [PubMed] [Google Scholar]
- 15.Sadowski L.A., Upadhyay R., Greeley Z.W., Margulies B.J. Current drugs to treat infections with herpes simplex viruses-1 and -2. Viruses. 2021;13(7):1228. doi: 10.3390/v13071228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Siegrist E.A., Sassine J. Antivirals with activity against monkeypox: a clinically oriented review. Clin Infect Dis. 2023;76(1):155–164. doi: 10.1093/cid/ciac622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sendagorta E., Bernardino J.I., Álvarez-Gallego M., et al. Topical cidofovir to treat high-grade anal intraepithelial neoplasia in HIV-infected patients: a pilot clinical trial. AIDS. 2016;30(1):75–82. doi: 10.1097/QAD.0000000000000886. [DOI] [PubMed] [Google Scholar]
- 18.Adler H., Gould S., Hine P., et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 2022;22(8):1153–1162. doi: 10.1016/S1473-3099(22)00228-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Bienvenu B., Martinez F., Devergie A., et al. Topical use of cidofovir induced acute renal failure. Transplantation. 2002;73(4):661–662. doi: 10.1097/00007890-200202270-00033. [DOI] [PubMed] [Google Scholar]