Rhinocerebral zygomycosis in an HIV-infected man during therapy with an investigational CCR5 inhibitor

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Rhinocerebral zygomycosis (RCZ) is uncommon in HIV/AIDS. Treatment with surgery, antifungal therapy and reversal of immunosuppression comprises the standard of care. We report a case of an HIV-infected man who developed RCZ while on a CCR5 inhibitor and prednisone. Declining surgical intervention, he responded well to posaconazole for 9 months before experiencing a rapid decline after the initiation of antiretroviral therapy. In December 2005, a 52-year-old HIV-infected nondiabetic man initiated open-label Vicriviroc (Schering Plough, Kenilworth, New Jersey, USA), an investigational CCR5 inhibitor, in combination with an optimized antiretroviral regimen. His CD4+ T cell count was 10 cells/μl and his HIV-1 viral load was 10 500 copies/ml (HIV Amplicor Monitor, version 1.5; Roche, Basel, Switzerland). One week later, he developed severe bilateral maxillary and ethmoid inflammation. The HIV-1 viral load was 26 374 copies/ml. Prednisone 40 mg and piperacillin/tazobactam were started. Ten days later, he developed right facial nerve paralysis and hypoesthesia of the right cheek. He was found to have progressive sinusitis and signs of necrosis of the right cheek and hard palate. Fungal stains of a palatal biopsy revealed broad, branching, nonseptate hyphae consistent with mucor and cultures grew Rhizopus species. His absolute neutrophil count was 3900 cells/μl, blood glucose = 100 mg/dl, anion gap = 11, HbA1C = 5.4 and CD4+ T cell count was 2 = cells/μl. Vicriviroc and prednisone were discontinued. The patient declined surgical debridement due to likely facial disfigurement, and he received liposomal amphotericin at 7 mg/kg/day for 7 days. Due to nephrotoxicity, therapy was switched to posaconazole (Schering Plough) orally at 800 mg total daily dose, provided on a compassionate use basis. He was discharged home on day 20 of hospitalization. Over the following months, he demonstrated improvement in both his physical appearance and sinusitis. He remained stable on posaconazole for 9 months when he was started on a salvage antiretroviral regimen. He developed right eye blindness of unclear etiology and died 1 month later with progressive wasting. Progression of zygomycosis was not documented. His HIV viral load was undetectable. This case adds important data to the limited body of literature describing RCZ in HIV-infected individuals (Table 1) [1–6]. In a review of 929 reported cases of zygomycosis, only 2% of patients had HIV as an underlying infection [7]. The commonest predisposing factors were diabetes, malignancy, solid organ transplantation and bone marrow transplantation seen in 36%, 17%, 7% and 5% of patients respectively [7]. Contrary to the rapid progression typically seen in patients with zygomycosis, our patient experienced an indolent disease course, as seen in previous reported cases of RCZ with underlying AIDS [1,5,6]. He declined surgical debridement due to the likelihood of facial disfigurement. Although he did not have the classic risk factors associated with RCZ, the short course of corticosteroid therapy and relative neutropenia (absolute neutrophil count 1000–2400) in the months preceding his disease likely contributed to disease susceptibility.Table 1: Summary of rhinocerebral zygomycosis in HIV-infected individuals.CCR5 inhibition has not previously been associated with an increased risk of fungal infection. It is an unlikely association, based on observations of individuals who do not express cellular CCR5 and short-term data from phase 1 and 2 trials of CCR5 inhibitors. However, mononuclear phagocytes (mostly CCR5+) play an important role in the host response to fungi and CCR5 expression is upregulated in cells exposed to Candida[8]. Also, CCR5 deficiency increases the risk of symptomatic West Nile virus infection [9]. Further study is warranted to assess the impact of CCR5 inhibition on risk for fungal infection. Although we doubt that CCR5 inhibition alone created significant risk for RCZ in our patient, we question whether it might have potentiated the immunosuppression caused by corticosteroids and/or low-grade neutropenia. Similarly, we are uncertain whether stopping the CCR5 inhibitor contributed to our patient's initial favorable response. It was hoped that the introduction of newer antifungal agents would alter the therapeutic options for invasive mucormycosis. Although two open-label, compassionate use trials in 24 patients treated with posaconazole as salvage therapy demonstrated successful outcomes in 79% of subjects, all patients without surgical resection died within 1 year of diagnosis [10]. Our case supports the role of surgical resection in an attempt at curative therapy, but also suggests that newer antifungal therapy can result in an acceptable quality of life for many months following RCZ diagnosis. Our patient's decline after apparent successful antiretroviral therapy suggests the possibility of an immune reconstitution reaction. This is an association not previously described for invasive zygomycete infection. Our patient's disease course raises important questions regarding the pathogenesis and medical management of rhinocerebral mucormycosis in a patient with HIV in the era of newer antifungal and successful antiretroviral therapies. Sponsorship: Supported in part by grants AI27658 and RR00044 from the National Institutes of Health, Bethesda, MD.