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Clinical experience with use of oral Tecovirimat or Intravenous Cidofovir for the treatment of Monkeypox in an Italian reference hospital

Published:November 05, 2022DOI:https://doi.org/10.1016/j.jinf.2022.11.001

      Keywords

      Dear Editor,
      We read with interest the manuscript by Li D. and colleagues, recently published in this Journal, in which the authors revealed the potential binding mode for tecovirimat with a poxvirus phospholipase from monkeypox (MPX) virus [
      • Li D
      • Liu Y
      • Li K
      • Zhang L.
      Targeting F13 from monkeypox virus and variola virus by tecovirimat: Molecular simulation analysis.
      ].
      Tecovirimat and cidofovir are potential options for severe cases of MPX, but limited data on their efficacy and safety are available [
      • Adler H
      • Gould S
      • Hine P
      • et al.
      Clinical features and management of human monkeypox : a retrospective observational study in the UK.
      ,
      • Desai A
      • George T
      • Neumeister S
      • Arutyunova A
      • Stuart C.
      Compassionate Use of Tecovirimat for the Treatment of Monkeypox Infection.
      ,
      • Matias WR
      • Koshy JM
      • Nagami EH
      • et al.
      Tecovirimat for the Treatment of Human Monkeypox: An Initial Series From Massachusetts, United States.
      ,
      • Tarín-Vicente EJ
      • 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.
      ,
      • Mailhe M
      • Beaumont A-L
      • Thy M
      • et al.
      Clinical characteristics of ambulatory and hospitalised patients with monkeypox virus infection: an observational cohort study.
      ].
      Here we retrospectively describe clinical presentation, evolution, management and viral kinetics of the first 19 MPX cases treated with antivirals at the INMI Lazzaro Spallanzani IRCCS in Rome, Italy. The decision regarding treatments was based on international medical consensus and availability of drugs.
      Viral DNA was extracted by the automatic extractor QIAsymphony (Qiagen, Hilden, Germany), and amplified using the real-time PCR method targeting the tumor necrosis factor receptor gene, G2R. Monkeypox virus (MPXV) DNA concentration was measured using threshold cycles (Ct) values of the MPXV-specific PCR. To obtain an absolute quantification of MPXV DNA in the clinical samples, the PCR assay was adapted to run in digital droplet PCR (ddPCR). The nucleic acid extracted from each sample was loaded into specific nanoplate and distributed, amplified and read in each one of the 26,000 partitions of each well, with a detection limit of the assay of 5 copies/µL.
      The study was conducted as a part of biological studies on emerging infections approved by the Ethical Committee of the Lazzaro Spallanzani Institute (approval number 14/2015 and amendments). Patients provided written informed consent.
      As of September 19, 2022, 19/128 (15%) diagnosed cases of MPXV infection at INMI L. Spallanzani received antiviral treatment. All patients were males aged between 27 and 50 years, all but one patients self-identified as men who have sex with men or bisexual and seven patients (37%) were HIV-positive. Systemic symptoms were reported in all but one patient. Muco-cutaneous lesions were observed in all patients (skin lesions in 89% and mucosal lesions in 95%) and in half of them preceded systemic symptoms.
      The majority (79%) of patients complained of a painful lymphadenopathy. Patients were admitted to hospital within a median of 8 days (IQR 5-10) from date of symptoms onset (OD), mainly for mucosal inflammation caused by MPXV and/or superinfection of the lesions and/or management of severe pain due to the lesions. Specifically, proctitis was diagnosed in four patients (21%) and severe pharyngo-tonsillitis in six patients (32%). One patient presented ocular localization complicated by periorbital edema and conjunctival hyperemia. Nine patients (47%) presented with superinfection of the soft tissues, one of which was complicated by abscess of a finger. Finally, one patient was admitted and treated for worsening of genital lesions.
      Antiviral treatment was started with a median time of 11 days (IQR 8-12) from OD with oral tecovirimat in 15 (79%) patients and intravenous (IV) cidofovir in 4 (21%) patients All patients treated with oral tecovirimat completed a 14-day course of therapy. Similarly, IV cidofovir was well tolerated. Symptoms improvement and no new lesion appearance were observed 72 hours after the start of treatment in all but one patient treated with cidofovir.
      No significative alterations of blood tests were observed, apart from a transient increase of alanine aminotransferase after cidofovir. Complete recovery was observed in all patients with a median of 15 days (IQR 11-19) from treatment start. Three patients had still persistence of signs of MPX-mucosal involvement after the resolution of lesions (Table 1).
      Table 1Patients’ characteristics and clinical course.
      PT1PT2PT3PT4PT5PT6PT7PT8PT9PT10PT 11PT 12PT 13PT 14PT 15PT 16PT 17PT 18PT 19
      Gender/Age/ EthnicityM/28 y/ CaucasianM/33 y/CaucasianM/35 y/CaucasianM/46 y/ CaucasianM/33 y/ CaucasianM/33 y/HispanicM/42y/AsianM/40y/ CaucasianM/47y/ CaucasianM/27y/CaucasianM/36 y/ CaucasianM/38y/HispanicM/48y/ CaucasianM/45y/CaucasianM/35y/ CaucasianM/50y/AfricanM/36y/HispanicM/38y/ CaucasianM/47y/ Caucasian
      Sexual orientationBisexualMSMMSMMSMMSMMSMMSMMSMMSMMSMMSMMSMMSMMSMMSMHetero-sexualMSMMSMMSM
      HIV status

      (ART; last CD4 (cell/mm3)/VL)
      NegNegNegPos(BIC/

      TAF/FTC;

      1622/ND)
      Pos

      (3TC/DT;

      872 /ND)
      Pos*

      (TDF/FTC

      +DTG;526/26 cp/mL)
      NegNegPos

      (3TC/DTG;

      828 /ND)
      Pos**(BIC/

      TAF/FTC;140/

      <30cp/mL)
      NegNegNegNegNegNegPos(TAF/

      FTC/DRV/

      c+DTG;

      253/22 cp/mL)***
      Pos(TDF/

      FTC/EFV;

      1323; ND)
      Neg
      HbsAg/HCVAbNeg/NegNeg/NegNeg/NegNeg/NegNeg/NegNA/NegNeg/NegNeg/NegNeg/NegNeg/NegNeg/NegNeg/NegNeg/NAPos/NegNA/NANeg/NegNeg/NegNA/NegNeg/Neg
      PREPNoYesYesNoNoNoNoYesNoNoNoYesNoNoNoNoNoNoNo
      Smallpox vaccinationNoNoNoNoNoNoNoNoNoYesNoNoYesNoNoNoNoNoNo
      Systemic symptomsFever, headacheFever, sore throat, myalgias, diarrhoeaFeverFever, myalgias, rectal pain with discharg, bleedingFever, headache, sore throatFeverFever, sore throat, odynophagiaFever, sore throat, odynophagia, myalgias, headacheFever, sore throat, odynophagia, diarrhoeaNoFever, headacheFever, rectal pain, discharge and bleedingFever, sore throat; odynophagiaFeverFeverFever, myalgiasfever, sore throat myalgias, headache, rectal pain, diarrhoeafever, headache,

      rectal pain
      fever, sore throat, headache
      Cutaneous lesionHead, trunk, right leg, suprapubic and perinealTrunk, limbs including handsHead, trunk, limbsTrunk, legsHead, trunk, limbsHead, trunk, limbsHead, trunk, limbs, including palms and solesHead, trunk, limbsNoHead including eyelids, trunk, limbs including palms and solesHead, trunk, limbsHead, trunk, limbsNoTrunkUpper lipHead including scalp, trunk, arms including handsHead, trunk, legsFeet, trunkHead including upper lip and scalp, limbs, trunk
      Mucosal lesionEyelidsPenisPenis, scrotum, perianalPerianal and oropharyngealOropha-

      ryngeal

      Penis, oropharyngealOropha-

      ryngeal

       penis and perianal
      Orophar-

      yngeal

      Oropha-ryngeal

      Penis, scrotum, perianalPenisPenis, scrotum, perianalPenis; oropharyngealPenisNoPenisPerianal, scrotumPerianalPenis, oropharyngeal
      Number of lesions11-2011-2011-20<5<511-20≥2011-20<5≥205-10≥20<55-10<5≥20≥20<55-10
      Systemic symptoms onset after lesionsYesYesYesNoNoYesYesYesNo-NoYesYesYesNoNoYesNoYes
      Lymphad-enopathyInguinalInguinalInguinalNoNeckInguinalInguinalNeckNeckInguinalInguinalNoNeckAxillaryNoYesInguinal, neckInguinalNeck
      Localized diseaseOcularNoNoProctitisPhary-ngoton-sillitisNoPhary-

      ngoton-

      sillitis
      Phary-

      ngoton-

      sillitis
      Phary-

      ngoton-

      sillitis
      NoNoProctitisPhary-

      ngoton-

      sillitis
      NoNoNoProctitisProctitisPhary-ngoton-sillitis
      Type of treatmentCidofovirTeco-virimatTeco-virimatTeco-virimatTeco-virimatTeco-virimatCidofovirCidofovirTeco-virimatCidofovirTeco-virimatTeco-virimatTeco-virimatTeco-virimatTeco-virimatTeco-virimatTeco-virimatTeco-virimatTeco-virimat
      Reason for treatmentOcular involvementSuper-infection of cutaneous lesionSoft-tissue superinfectionProctitisPhary-ngotons-illitisSoft-tissue superinfectionPhary-

      ngotons-

      illitis, pain management
      Compli-

      cated pharyn-

      goton-

      sillitis (right peritonsillar abscess)
      Phary-

      ngoton-

      sillitis
      Super-infection of cutaneous lesions, pain managementPain managementCompli-

      cated proctitis
      Phary-

      ngoton-

      sillitis
      Super-

      infection of cut-

      aneous lesions
      Soft-tissue superinfection

      (upper lip)
      Super-infection of cut-aneous lesionsSuper-infection of cut-aneous lesions/ProctitisProctitisSoft-tissue superinfection

      (upper lip)
      Days from OD to admission/treatment5/1210/187/109/1111/136/73/69/124/118/1111/1210/119/107/95/69/910/127/85/7
      Days from treatment to recovery13

      102191211144

      718621

      1420718172715
      * HIV diagnosis 2 months before MPX; ** AIDS presenters with HIV/AIDS diagnosis six months before MPX (multidrug resistant disseminated tuberculosis on treatment); *** recent virological failure. Abbreviations: M, male; y, years, MSM men who have sex with men; Neg, negative; Pos, positive; Unk, unknown; ART, antiretroviral therapy; VL, viral load; ND, not detectable, PREP, pre-exposure prophylaxis; BIC, bictegravir; TAF, tenofovir alafenamide fumarate; FTC, emtricitabine; 3TC, lamivudine; DTF dolutegravir, TDF, tenofovir disoproxil fumarate; DRV/c, darunavir/cobicistat; EFV, efavirenz; NA, not available; STD, sexual transmitted disease; CT computed tomography; OD, onset date.
      Finally, viral kinetics have been evaluated in 12 patients (Fig. 1). In all of them, MPXV-DNA was detected in at least one sample from at least one compartment. Particularly, during the follow-up, MPXV-DNA was detected by real-time PCR in: 10/12 patients on oropharyngeal swab (OPS), including 9 at the start of antiviral treatment, with a median Ct of 36 (IQR 33-41); 8/9 patients on blood samples with a median Ct of 41 (IQR 37-41); 6/6 patients on feces with a median Ct of 41 (IQR 36-41); 3/3 patients on saliva with a median Ct of 38 (IQR 32-40); 3/3 patients on seminal fluids with a median Ct of 39 (IQR 37-41). In almost all patients, a progressive decline in viral load was observed over the course of treatment. Most biological samples were negative at the last available observation. DdPCR results approximately mirrored the viral shedding expressed with real-time PCR. It is worth noting that, given the low threshold used for the ddPCR, several samples with high Ct values in real-timePCR, resulted negative in ddPCR.
      Figure 1:
      Fig. 1Kinetics of MPXV DNA shedding in different biological samples from starting of the antiviral therapy. A) MPXV DNA levels detected in different longitudinal samples are shown for the 12 MPX patients followed up during infection. B) MPXV DNA levels detected in the different type of samples: blood, oropharyngeal swabs (OPS), stool, sperm and saliva. MPXV DNA levels are expressed as cycle threshold (Ct) values. In grey are shown digital droplet PCR (ddPCR) results express as Log10 copies/µL with a detection limit of the assay of 5 copies/µL.
      Limited data on clinical effectiveness of tecovirimat are available, however, several recent reports on its use has shown good tolerability and no evolution versus severe disease in treated subjects [
      • Adler H
      • Gould S
      • Hine P
      • et al.
      Clinical features and management of human monkeypox : a retrospective observational study in the UK.
      ,
      • Desai A
      • George T
      • Neumeister S
      • Arutyunova A
      • Stuart C.
      Compassionate Use of Tecovirimat for the Treatment of Monkeypox Infection.
      ,
      • Matias WR
      • Koshy JM
      • Nagami EH
      • et al.
      Tecovirimat for the Treatment of Human Monkeypox: An Initial Series From Massachusetts, United States.
      ,
      • O'Laughlin K
      • Tobolowsky FA
      • Elmor R
      • et al.
      Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol — United States.
      ]. Additionally, preliminary results from the first 549 MPX-positive patients treated with tecovirimat in United States (US), showed median time to subjective improvement of 3 days [
      • O'Laughlin K
      • Tobolowsky FA
      • Elmor R
      • et al.
      Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol — United States.
      ]. To the best of our knowledge, this is the first report of the use of antivirals for MPX with both clinical and virological results in this current outbreak. One case series of patients treated in 2018-2021 reported viral decay in one patient during tecovirimat treatment showing a shorter duration of viral shedding compared to the other patients [
      • Adler H
      • Gould S
      • Hine P
      • et al.
      Clinical features and management of human monkeypox : a retrospective observational study in the UK.
      ]. Additionally, in a pre-print publication, outcomes, including viral kinetics, of 14 patients treated before February 2022 with tecovirimat were reported [

      Festus Mbrenga, Emmanuel Nakouné, Christian Malaka, Josephine Bourner, J ake Dunning, Guy Vernet, Peter Horby PO. Monkeypox treatment with tecovirimat in the Central African Republic under an Expanded Access Programme Author. medRxiv Prepr doi:10.1101/2022.08.24.22279177.

      ]. In contrast to that report, where rate of appearance of lesions decreased during treatment with a median of 5 days from treatment start [

      Festus Mbrenga, Emmanuel Nakouné, Christian Malaka, Josephine Bourner, J ake Dunning, Guy Vernet, Peter Horby PO. Monkeypox treatment with tecovirimat in the Central African Republic under an Expanded Access Programme Author. medRxiv Prepr doi:10.1101/2022.08.24.22279177.

      ], in our patients clinical improvement and no new lesions were reported in almost all patients 72 hours after tecovirimat initiation. The longer time elapsed from symptoms onset to treatment start (21 days) compared to our study (12 days) might partially explain this different result. Of note, in our case series, 15% of MPX cases diagnosed received antiviral treatment, consistently with US data [].
      Concerning viral kinetics, it should be noted that low viral loads were observed. Additionally, some patients had all available samples negative in ddPCR since antiviral starting, in line with previous evidence showing that viral shedding occurs mainly during the first two weeks of the disease [
      • Peiro-Mestres A
      • Fuertes I
      • Camprubi-Ferrer D
      • et al.
      Frequent detection of monkeypox virus DNA in saliva, semen, and other clinical samples from 12 patients, Barcelona, Spain, May to June 2022.
      ]. Due to the median time of 12 days from symptoms onset to starting treatment in this series, we cannot exclude a reduced impact of antiviral therapy on viral shedding or clinical resolution.
      The main limitations of this study was the lack of control group, so that any conclusions on the effectiveness of antiviral therapy cannot be drawn, the small number of patients included, the heterogeneity of samples and the impossibility to collect samples for all the patients at each timepoint.
      Data collected on observational studies such as this can help improve our knowledge of the use of antivirals for MPXV, waiting more robust results from the placebo-controlled randomized trial of tecovirimat for MPX.

      Funding

      This study was supported by Ricerca Corrente Linea 1 and 2, funded by the Italian Ministry of Health.

      Conflicts of interests

      The authors declare no conflict of interest for the present study.

      Acknowledgments

      INMI Monkeypox Study Group: Isabella Abbate, Alessandro Agresta, Camilla Aguglia, Alessandra Amendola, Andrea Antinori, Francesco Baldini, Tommaso Ascoli Bartoli, Alessia Beccacece, Rita Bellagamba, Giulia Berno, Aurora Bettini, Nazario Bevilacqua, Licia Bordi, Marta Camici, Priscilla Caputi, Fabrizio Carletti, Angela Corpolongo, Stefania Cicalini, Francesca Colavita, Alessandra D'Abramo, Angela D'Urso, Gabriella De Carli, Patrizia De Marco, Federico De Zottis, Silvia Di Bari, Lavinia Fabeni, Francesca Faraglia, Valeria Ferraioli, Carla Fontana, Federica Forbici, Concetta Maria Fusco, Marisa Fusto, Roberta Gagliardini, Anna Rosa Garbuglia, Saba Gebremeskel Teklé, Maria Letizia Giancola, Giuseppina Giannico, Emanuela Giombini, Enrico Girardi, Giulia Gramigna, Elisabetta Grilli, Susanna Grisetti, Cesare Ernesto Maria Gruber, Eleonora Lalle, Simone Lanini, Daniele Lapa, Gaetano Maffongelli, Fabrizio Maggi, Alessandra Marani, Andrea Mariano, Ilaria Mastrorosa, Giulia Matusali, Silvia Meschi, Valentina Mazzotta, Sabrina Minicucci, Claudia Minosse, Klizia Mizzoni, Martina Moccione, Annalisa Mondi, Vanessa Mondillo, Giorgia Natalini, Nicoletta Orchi, Sandrine Ottou, Jessica Paulicelli, Elisabetta Petrivelli, Maria Maddalena Plazzi; Carmela Pinnetti, Silvia Pittalis, Gianluca Prota, Vincenzo Puro, Silvia Rosati, Alberto Rossi, Gabriella Rozera, Martina Rueca, Laura Scorzolini, Eliana Specchiarello, Maria Virginia Tomassi, Massimo Tempestilli, Francesco Vaia, Francesco Vairo, Beatrice Valli, Alessandra Vergori, Serena Vita.

      Appendix. Supplementary materials

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