Four cases of disseminated herpes simplex virus following talimogene laherparepvec injections for unresectable metastatic melanoma

To the Editor: In the article titled ‘‘Durable melanoma control following disseminated talimogene laherparepvec herpetic infection,’’ Shmuylovich et al presented a case of disseminated herpes simplex virus (HSV) following talimogene laherparepvec (T-VEC) intralesional therapy for unresectable locally advanced melanoma. We are aware of 1 other published case by Kimmis et al. Here, we describe 4 additional cases of disseminated HSV in immunocompetent patients following T-VEC therapy. The patients consented to having nonidentifying photographs taken and utilized for educational and research purposes as well as sharing of descriptions of their cases and nonidentifying information.


Four cases of disseminated herpes simplex virus following talimogene laherparepvec injections for unresectable metastatic melanoma
To the Editor: In the article titled ''Durable melanoma control following disseminated talimogene laherparepvec herpetic infection,'' Shmuylovich et al 1 presented a case of disseminated herpes simplex virus (HSV) following talimogene laherparepvec (T-VEC) intralesional therapy for unresectable locally advanced melanoma. We are aware of 1 other published case by Kimmis et al. 2 Here, we describe 4 additional cases of disseminated HSV in immunocompetent patients following T-VEC therapy. The patients consented to having nonidentifying photographs taken and utilized for educational and research purposes as well as sharing of descriptions of their cases and nonidentifying information.

CASE 1
A 76-year-old man with American Joint Committee on Cancer Stage III C 3 melanoma of the upper portion of the right arm was treated with 1.2 mL of 10 6 -plaque-forming units (PFU)/mL T-VEC divided among 4 in-transit lesions. On postinjection day (PID) 10, vesicles developed on the right side of the chest, right axilla, and right arm (Fig 1). Although both punch biopsies taken yielded negative results for HSV 1 and 2, as determined using immunohistochemistry, a diagnosis of HSV infection was made based on the pattern of inflammation and epidermal necrosis ( Fig 2) and a positive result of polymerase chain reaction for vesicular fluid HSV. T-VEC was discontinued, and a 10-day course of valacyclovir resolved the rash.

CASE 2
A 67-year-old man with stage IIID 3 melanoma of the right heel was treated with 0.5 mL of 10 6 -PFU/mL T-VEC divided among 24 in-transit lesions. On PID 1, he developed fever, arthralgias, and fatigue. On PID 7, he developed a nontender, nonpruritic, vesicular rash extending beyond the injection sites. On PID 8 (Fig 3), 1 of 2 biopsied lesions was HSV positive, as determined using immunohistochemistry (Fig Y).
T-VEC was discontinued, and a 10-day course of valacyclovir resolved the rash.

CASE 3
A 79-year-old man with stage IIIC 3 melanoma of the right plantar foot was treated with 0.3 mL of 10 6 -PFU/mL T-VEC divided among 3 in-transit lesions. On PID 3, he developed diffuse, mild erythema and fever, which progressed by PID 4 to a nonpruritic, nontender, and nonexudative violaceous eruption extending to the thigh. On PID 8, the patient presented with crusted, grouped erythematous papules (Fig 4); a punch biopsy yielded a positive result for HSV, as determined using immunohistochemistry. T-VEC was discontinued, and a 10-day course of valacyclovir resolved the rash.

CASE 4
A 73-year-old man with stage III 3 melanoma of the left calf was treated with 0.5 mL of T-VEC at 10 6 PFU/ mL in a region of subcutaneous metastasis of the left thigh. Between PIDs 7 and 8, he reported arthralgias, myalgia, fever, generalized weakness, severe fatigue, dyspnea, an injection-site vesicular rash, altered mentation, and imbalance requiring admission to the intensive care unit. Empiric intravenous acyclovir and broad-spectrum antibiotics were initiated, and polymerase chain reaction test of cerebral spinal fluid ultimately returned a positive result for HSV-1. A 3-week course of intravenous acyclovir and physical therapy resolved all symptoms. T-VEC was discontinued.

CONCLUSIONS
Our patients had no known immunocompromising factors or history of HSV infection and only received the initial 10 6 -PFU/mL dose of T-VEC. Two cases had received prednisone; however, T-VEC was initiated more than 1 month after prednisone discontinuation. Both the case described by Kimmis et al 2 and our case had received prior immune checkpoint inhibitor treatment. 2 Although it is possible that immune checkpoint inhibitors are associated with an increased risk of disseminated HSV, our patients had discontinued immune checkpoint inhibitors over 3 months prior to T-VEC treatment.
Our cases substantiate the risk of disseminated HSV in immunocompetent patients receiving T-VEC and demonstrate that immediate T-VEC cessation and antiviral therapy can truncate the disease course and lead to resolution, without permanent sequelae, even in the case of encephalitis.