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Elizabeth V. Robilotti et al


Fig. 1. Infection control workflow for review of clinical trials involving potentially infectious agents.


TVEC-treated melanoma patients, care givers, and HCWs started in August 2017. Completion of enrollment and evaluation of this observational cohort of nearly 1,000 patients in the United States and Europe is anticipated in late 2024.


Transmission to HCWs


Limited data are available on the transmission of HSV viral infec- tions to HCWs involved in TVEC administration or subsequent care of patients. A self-reported survey from 82 HCWs across 36 study sites with 4,100 treatment visits, reported 5 occurrences of accidental exposure to TVEC by needlestick injury or mucosal splash. The most notable among these was an HCW who devel- oped herpetic whitlow that resolved after acyclovir treatment. Also, 2 other treatment-related exposures included an accidental needlestick during drug preparation (treated with antiviral agent) and conjunctival splash without any reported clinical consequence. None of the cases inHCWs resulted in secondary transmission.No cases of secondary or tertiary transmission from patient to HCW have been reported. Postexposure prophylaxis with acyclovir is recommended in case of accidental exposure of HCWs to TVEC, and serious disease has not been described among those exposed.


Transmission from TVEC recipient to household contacts


As part of the viral surveillance program for one of the pivotal tri- als, 1,217 surveillance questionnaires from 177 subjects identified 15 individuals (8.4%) who reported signs and symptoms possibly related to TVEC treatment among their close contacts.12,19 Suspected herpetic lesions among household contacts were not completely characterized as wild type versus secondary to TVEC transmission, although none of these reported events were severe.20 The incidence of this potential risk to close household contacts is being addressed in an ongoing postmarketing trial.12


Practical concerns: Transmission from TVEC recipient to immunocompromised contacts, including HCWs


No documented transmission of HSV infection from TVEC- treated patients to other immunocompromised contacts has been reported, although studies on viral shedding indicate that there is a nonzero risk of this occurring. Pregnant patients and HCWs or those with immunocompromising conditions are precluded from receipt or direct administration of the agent and are advised cau- tion during direct patient care due to theoretical risk of transmis- sion of TVEC across the placenta. Pregnant HCWs are instructed not to perform dressing changes or provide direct care to patients


through the duration of shedding. This recommendation is extrapolated from adverse events associated with transplacental HSV infection rather than TVEC-specific data.17


TVEC: Summary and recommendations for infection prevention


At MSK, TVEC administration guidelines were developed by a multidisciplinary team of key stakeholders from infection control, nursing, oncology, and pharmacy departments after evaluating available clinical and viral shedding data from early phase trials. These data indicated that most detectable virus from evaluated sites waned by 7 days postexposure.14,22 TVEC is classified as a BSL2-level agent at MSK, in accordance with FDA guidance, and this dictates preparation and environmental management for TVEC. Agent preparation by trained pharmacy personnel occurs in a negative-pressure room biosafety cabinent (BSC) using a closed transfer system. Post preparation, the BSC is cleaned with a 2-step process including high-level disinfectant and sterile alco- hol and remains unavailable for other preparations pending recommended contact time. Personal protective equipment is required for preparation and administration of the agent in agree- ment with BSL2 recommendations. Practically, this results in the use of gowns, gloves and eye shields for TVEC preparation and ad- ministration, which complies with the manufacturer’s prescribing information.23 Post injection, the treated site is covered with an occlusive dressing with a red alert sticker to indicate to staff that TVEC was administered. Electronic practice alerts and learning modules were developed to educate staff. Additionally, a dedicated contact isolation precaution indicator is placed in the patient’s electronic medical record, which serves to alert staff to recent treat- ment withTVECand the need for contact precautions.22 Entry and removal of the indicator is undertaken by the clinical support teams. Precautions are instituted until all lesions are healed or scabbed as determined by direct observation at follow-up or day 7 following injection of TVEC, whichever is longer.


Other investigational oncolytic viruses


Since TVEC approval, >15 clinical protocols and 9 unique viral oncolytic agents have been evaluated for transmission-based pre- cautions. The current process for trial evaluation evolved out of the TVEC experience and is conducted under the auspices of the Institutional Biosafety Committee (IBC), which is tasked with reviewing clinical and laboratory research protocols involving infectious agents and recombinant or synthetic DNA in accor- dance with National Institutes of Health (NIH) guidelines. The 3 phases of our process include (1) preapproval review, (2)


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