Purpose: To report a case of severe mpox in a newly diagnosed HIV patient concerning for Immune Reconstitution Inflammatory Syndrome (IRIS) and/or tecovirimat resistance and to describe the management approach in the setting of refractory disease. Case: 49-year-old man presented with 2 weeks of perianal lesions. He tested positive for mpox PCR in the emergency room and was discharged home with quarantine instructions. Three weeks later, the patient returned with disseminated firm, nodular lesions in the face, neck, scalp, mouth, chest, back, legs, arms, and rectum, with worsening pain and purulent drainage from the rectum. The patient reported being on 3 days of tecovirimat treatment, which was prescribed by the Florida department of health (DOH). During this admission, he was found to be HIV positive. A pelvic CT scan revealed a 2.5 cm perirectal abscess. Treatment with tecovirimat was continued for 14 days, along with an empiric course of antibiotics for treatment of possible superimposed bacterial infection upon discharge. He was seen in the outpatient clinic and initiated antiretroviral therapy (ART) with TAF/emtricitabine/bictegravir. Two weeks after starting ART, the patient was readmitted for worsening mpox rash and rectal pain. Urine PCR also returned positive for chlamydia, for which the patient was prescribed doxycycline. He was discharged on a second course of tecovirimat and antibiotic therapy. Ten days later, the patient was readmitted for the second time due to worsening symptoms and blockage of the nasal airway from progressing lesions. At this point, there were concerns for tecovirimat resistance, and after discussion with CDC, tecovirimat was reinitiated for the third time, with the addition of Cidofovir and Vaccinia, and showed an improvement in his symptoms. He received three doses of cidofovir and two doses of Vaccinia, and the patient was then discharged to complete 30 days of tecovirimat. Outpatient follow-up showed favorable outcomes and near resolution. Conclusion: We reported a challenging case of worsening mpox after Tecovirimat treatment in the setting of new HIV and ART initiation concerning IRIS vs. Tecovirimat resistance. Clinicians should consider the risk of IRIS and weigh the pros and cons of initiating or delaying ART. In patients not responding to first-line treatment with tecovirimat, resistance testing should be performed, and alternative options should be considered. Future research is needed to establish guidance on the role of Cidofovir and Vaccinia immune globulin and the continuation of tecovirimat for refractory mpox.

Progressive multifocal leukoencephalopathy (PML), presenting as immune reconstitution inflammatory syndrome (IRIS), is a known complication of antiretroviral therapy (ART) in people living with HIV (PLWH). Typically preceded by ART initiation, IRIS may appear simultaneously/unmasked (PML-s-IRIS) or as a delayed/worsening/paradoxical (PML-d-IRIS) presentation of known PML disease. Primary cerebellar tropism continues to be a rare presentation, and paradoxical cerebellar involvement of PML-IRIS syndrome can be a challenge for both diagnosis and management. Steroids have been suggested as a possible therapy in severe cases but the duration of steroid therapy remain elusive. Our case is that of a 34-year-old man with newly diagnosed HIV simultaneously found to have cerebellar PML. His PML lesions however worsened after initiation of ART (PML-d-IRIS) with evidence of increased intracranial pressure. Despite initial favorable response to a short duration of steroids, he had multiple recurrence of his PML lesions after steroids were discontinued. The presence of predominant cerebellar lesions and the question of how long steroids should be provided to prevent or minimize PML recurrence is the highlight of our case. This report emphasizes the need for more controlled studies to assist clinicians in the optimal diagnosis and management of PML-IRIS in PLWH.