Treatment with tecovirimat of the first two cases of monkeypox in Japan

Abstract

Outbreaks of monkeypox in Europe and North America have been reported since May 2022. At the end of July, we encountered the first two cases of monkeypox diagnosed in Japan. Case 1 was a white man who traveled to Spain where he had sexual intercourse with men. He presented to our hospital with fever, rash, and tiredness, and was diagnosed with monkeypox based on positive PCR test results from the skin lesions. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 15. Case 2 involved a Japanese man who visited us because of fatigue, muscle pain, headache, and oral ulcers. He was living in New York and traveled to Japan one day before presentation. He had experienced sexual intercourse with men four times during the previous month. The patient was diagnosed with monkeypox based on positive PCR results from the blood. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 14. These were the first two cases of monkeypox diagnosed in Japan. Based on their history and epidemiology, the viruses seem to have been imported from Europe and North America, respectively. After initiation of tecovirimat, both patients showed mild symptoms and immediate disappearance of viral DNA. The second case was notable for being diagnosed without skin rash. Our report suggests that tecovirimat could decrease the viral load rapidly, and that our prompt diagnosis contributed to the prevention of a monkeypox outbreak in Japan.

1. Introduction

Monkeypox was first described in 1970, and sporadic outbreaks have been reported mainly in Africa [1]. In May 2022, an outbreak of monkeypox was reported in non-endemic areas, especially in Europe and North America. Most patients were men who have sex with men (MSM) and had no travel history to endemic areas of Africa [2].

The outbreak spread from Europe and North America to Asian countries, such as Singapore, Taiwan, Korea, and India, and finally reached Japan in July 2022 [3]. Tecovirimat is an antiviral drug against monkeypox approved by the European Medicines Agency [4], but so far it has not been approved in Japan or the United States. Therefore, our group launched a clinical study titled “A multicenter, open-label, double-arm trial to evaluate the efficacy and safety of oral tecovirimat therapy for patients with smallpox or monkeypox” (CRB3200011). Here, we report the first two cases of monkeypox in Japan and describe their clinical course under tecovirimat treatment.

2. Case report

2.1. Case 1

A Caucasian man in his 30s visited our hospital in late July because of a newly noticed skin rash on the right buttock. He had been feeling normal until he felt tiredness 10 days before his visit to our hospital. He attributed this symptom to jet lag because he had just returned to Japan from travelling abroad. Six days before his visit, he had a low-grade fever and headache that had lasted for one week. On the weekend, his symptoms improved but two days before his visit he discovered a single skin rash on the right buttock, and he was concerned that he was infected with monkeypox.

His medical history was notable for treated syphilis and episodes of recurrent pneumothorax, for which he had undergone surgery. He was an MSM who used emtricitabine and tenofovir alafenamide as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV). He had lived in Japan since 2020 with his partner. He did not smoke and was an occasional alcohol drinker.

He traveled to Spain alone from 27 to 11 days before his visit to our hospital. He boarded a 10-days cruise ship along the coast of Spain on the fourth day of travel. During the cruise, he had sexual intercourse with approximately 20 men. He had insertive, receptive, and oral intercourse. He did not notice that anyone had a skin lesion at that time, but two men were later diagnosed with monkeypox. No monkeypox cases had been reported previously in Japan, and he denied any sexual contact after returning to Japan. His partner had no symptoms when he visited our hospital. He denied any contact with animals in Japan or Spain.

On physical examination, the bilateral posterior neck and inguinal lymph nodes were swollen but non-tender. Erythema that was about 3 cm diameter with tender central umbilication was observed on the right buttock (Fig. 1 A). Two tiny umbilicated pustules were surrounded by erythema. There were no oral, penile, or perianal lesions. Blood tests showed normal liver and kidney function, normal electrolyte and blood glucose levels, and HIV and syphilis tests were negative. Polymerase chain reaction (PCR) tests for monkeypox of the blood and buttock skin lesions were performed; only the skin lesion test was positive.

Fig. 1.

Clinical images of case patients. A, erythema with central umbilicated lesion on the buttock of case 1. B, pustular lesion at the bottom of the penile shaft of case 2. A blue circle was added to emphasize the lesion in the original image. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

At that time, viral testing was done at the Tokyo Metropolitan Institute of Public Health. Viral DNA was extracted from the patient specimens using the QIAamp DNA Mini Kit (Qiagen), and was detected using QuantStudio 12K Flex (Thermo Fisher Scientific, Massachusetts, USA) with the QuantiTect Probe PCR Kit. Specific multiplex quantitative PCR (qPCR) based on a previous report was performed to measure the copy numbers of the monkeypox virus and varicella zoster virus genomic DNAs [5].

The patient was admitted to our hospital on the day of his visit (day 0), and the following day he began to receive tecovirimat 600 mg twice daily for 14 days. On day 1, viral DNA was detected in the throat and buttock, but it became undetectable after day 4 (Table 1 ). After admission, viral testing was performed at the National Institute of Infectious Diseases (NIID). Quantitative one-step RT-PCR for monkeypox virus, variola virus and varicella zoster virus was done as described above [5]. Total nucleic acids were extracted from the patient specimens using a High Pure Viral Nucleic Acid kit (Roche Applied Science, Basel, Switzerland) according to the manufacturer's protocols. For the qPCR assay, the extracted nucleic acid solution was added to the reaction mixture of the QuantiTect probe PCR kit (Qiagen, Hilden, Germany). The qPCR reaction was performed using a LightCycler 96 (Roche Applied Science). On day 8, aspartate transferase (AST), aminotransferase (ALT), and creatinine kinase (CK) levels were elevated to 176 U/L, 60 U/L, and 8723 U/L, respectively. Although he confessed that he had worked out doing push-ups one day before, we skipped two doses of tecovirimat because of concerns regarding adverse drug effects. The liver function test soon recovered and did not worsen after resuming tecovirimat. During his hospital stay, he seemed well and did not have any newly identified monkeypox lesions. His vital signs and laboratory findings were stable, except for the AST, ALT, and CK levels. On day 8, all skin lesions disappeared, and he was discharged on day 15.

Table 1.

The detected viral load from the body sites of cases 1 and 2.

	days after presentation	urine	throat (copies/mL)	blood (copies/mL)	skin (copies/mL)	skin site
case 1	1	N.D.	1.4x103	N.D.	7.5x106	buttock
	4	N.D.	N.D.	N.D.	N.D.	buttock
	8	N.D.	N.D.	N.D.	N.D.	buttock
	11	N.D.	N.D.	N.D.	N.D.	buttock
	14	N.D.	N.D.	N.D.	N.D.	buttock
case 2	1	N.D.	N.D.	N.D.	N.D.	back
	5	N.D.	N.D.	37	1.8x103	penis
	8	N.D.	N.D.	N.D.	N.D.	abdomen
	12	N.D.	N.D.	N.D.	N.D.	abdomen
	14	N.D.	N.D.	N.D.	N.D.	abdomen

N.D., not detected.

2.2. Case 2

A Japanese man in his 30s visited our hospital because of fatigue, muscle pain, headache, and mouth ulcers, as well as concern for monkeypox in late July. He was feeling normal until he felt tiredness, myalgia, and headache two days before his visit. His symptoms did not improve the next day, when he found a mouth ulcer.

His medical history was unremarkable, except for COVID-19 in December 2021. He was an MSM who used emtricitabine and tenofovir alafenamide as PrEP for HIV. He has been living in New York City (NYC) for a couple of years, he transiently traveled to Japan for business one day before his visit, and he was staying with his friend in Tokyo. He denied sexual contact with his roommate in NYC and his friend in Tokyo. He did not have a history of smallpox or monkeypox vaccination.

He remembered having receptive and orally unprotected sexual intercourse with four men in the last month of NYC. He did not notice any skin lesions on his partners and was unaware if they had been later diagnosed with monkeypox.

On physical examination, small, non-tender palpable bilateral inguinal lymph nodes were found on palpation, and two aphthous stomatitis lesions were found on the mucosa of the lower lip, as well as several acne-like lesions on the back. No remarkable rash was observed on the penis or perianal area.

Blood tests showed that liver and kidney function tests, electrolytes, and blood glucose levels were within normal limits, while blood cells were lower than the normal limit (3180 cells/μL, with 45% neutrophils, 43.4% lymphocytes, 6.9% monocytes, 4.4% eosinophils, and 0.3% basophils). HIV and syphilis tests were negative. We collected blood specimens, and monkeypox DNA was detected. In case 2, all specimens were sent to NIID for analysis.

He was admitted to our hospital the day after his visit (day 1) and received 600 mg of tecovirimat twice daily for 14 days. At the end of day 1, he noticed a newly identified skin rash on the bottom of the penile shaft (Fig. 1B). On day 4, we also discovered new blisters in both the brachia and periumbilical areas. On day 12, the skin rashes disappeared, and he was discharged on day 14. Viral DNA was not detected on day 1 but it was discovered again on day 4 in the blood and penile skin specimens, and then it disappeared after day 8 (Table 1). During the hospital stay, he had no fever, and his laboratory data were unremarkable.

2.3. Case contacts

People with close contact with the patients were invited to a clinical study titled “An open-label, single-arm study to investigate the efficacy and safety of smallpox vaccine as postexposure prophylaxis in monkeypox” (CRB3200011). We, healthcare workers, wore proper personal protective equipment at the first contact and the exposure risk was categorized as low. As long as we know, no secondary monkeypox cases were discovered from their contacts.

3. Discussion

We report the first two cases of monkeypox diagnosed by PCR in Japan. According to their travel histories, our patients were suspected as imported cases. Case 1 had a history of recent travel to Spain until one day before he felt the first symptom of tiredness, although it could be explained by jet lag. Before and after travel, he had lived in Japan, where no cases had been previously reported. Case 2 lived in the United States for years and had sexual intercourse there, and he first noticed symptoms such as headache, myalgia, and tiredness on the day he arrived in Japan. Therefore, he was presumed to be exposed to monkeypox in the United States because the incubation period of monkeypox is usually 3–17 days [6]. Our patients appeared to have mild disease and no apparent risk factors for developing severe disease. Both patients received tecovirimat 600 mg twice daily and viral DNAs were not detected after day 4 or day 8, respectively.

Tecovirimat is an antiviral drug developed for the treatment of smallpox, which inhibits the formation of extracellular enveloped virus by inhibiting membrane protein 37; tecovirimat is presumed to be safe and well tolerated in phase I and II studies [7]. Although evidence of the clinical efficacy and safety of tecovirimat against monkeypox is still limited, a case series of 25 monkeypox patients treated with tecovirimat demonstrated complete resolution of lesions in 40% of patients on day 7 of therapy, and none of the patients discontinued therapy [8]. A retrospective observational study reported that monkeypox patients with tecovirimat therapy had a shorter duration of viral shedding and illness compared with other patients [1]. While the viral PCR test became negative 17–76 days after the onset of rash in six patients treated with brincidofovir or supportive care only, the PCR test became negative 6 days after the onset of rash in a patient treated with tecovirimat [1].

Our cases also showed prompt disappearance of viral DNA copies within 7 days after treatment, supporting the hypothesis that tecovirimat reduces the viral load. An experimental study showed that monkeypox DNA levels correlate with infectivity, and low viral amount (Cq ≥ 35) predicts no or very low infectivity in cultured cells [9]. Therefore, a rapid decrease in viral load with tecovirimat could contribute to the prevention of disease transmission and infection control. However, its epidemiological impact is uncertain, and we have to keep in mind that excessive usage of antiviral drugs may lead to the development of drug-resistant strains; thus, this hypothesis requires further examination.

Case 2 was notable for the absence of skin rash at the time of diagnosis. Most of the patients with monkeypox have skin lesions [2] and to the best of our knowledge, only one report described a case of monkeypox diagnosed without skin lesions [10]. Our patient had malaise, myalgia, and fever before the rash occurred, which is consistent with prodromal symptoms [4]. These symptoms seem to be non-specific and rarely provide diagnostic clues. We suspected the diagnosis because he was an MSM that had sexual intercourse in an area where the monkeypox outbreak occurred, and there were no alternative diagnoses such as COVID-19, influenza, other respiratory viral infections identified with multiplex PCR, acute HIV infection, syphilis, or acute viral hepatitis. He was scheduled to work and visit friends during his stay in Japan, which might have resulted in a monkeypox outbreak in Japan if we had not promptly established the correct diagnosis. Thanks to his understanding and cooperation, he agreed to cancel his schedule and be hospitalized.

In conclusion, herein we describe the first two cases of monkeypox in Japan, which were thought to be imported cases. The patients were diagnosed promptly, hospitalized, and prescribed tecovirimat 600 mg twice daily. Both cases showed rapid viral clearance and no complications or apparent adverse drug effects. Our prompt diagnosis and management may have contributed to the prevention of monkeypox outbreaks in Japan. Healthcare professionals should be aware that monkeypox is an actual threat, especially for MSMs, and we should raise awareness among MSMs so that they can visit a medical facility if they suspect infection with monkeypox.

Ethical approval

This study was approved by the ethics committee of the NCGM (approval no: NCGM-C-004505-03) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patients for publication of this report.

Funding

This work was supported by Ministry of Health, Labour and Welfare “Research on Emerging and Re-emerging Infectious Diseases and Immunization” Program Grant Number 20HA2005. The funding source was not involved in the writing of this report.

Authorship statement

All authors meet the ICMJE authorship criteria. Author contributions are as described below:

Conceptualization: Makoto Inada, Sho Saito, Shinya Tsuzuki, Shinichiro Morioka.

Acquisition of data: Makoto Inada, Sho Saito, Nobumasa OkumuraORCID, Lubna SatoORCID, Kohei Kamegai, Mio Sanada, Mika Komatsubara, Shinichiro Morioka.

Sample analysis: Masayuki Shimojima, Hideki Ebihara, Fumi Kasuya, Mami Nagashima, Kenji Sadamasu.

Drafting the article: Makoto Inada, Sho Saito, Shinya Tsuzuki.

Supervision: Kei Yamamoto, Mugen Ujiie, Shinichiro Morioka, Norio Ohmagari.

All authors contributed to the writing of the final manuscript.

Declaration of competing interest

All authors declare no conflicts of interest regarding this study.