Human monkeypox outbreak: Epidemiological data and therapeutic potential of topical cidofovir in a prospective cohort study

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.

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.