Sonidegib in a patient with multiple basal cell carcinomas and HIV infection

Abstract

Treatment of patients with locally advanced or metastasizing basal cell carcinomas (BCC) represents a therapeutic challenge. We report on a HIV-infected patient with multiple unresectable BCC who was treated with a sonic hedgehog (SHH) inhibitor under antiretroviral triple therapy. The 51-year-old patient presented with numerous tumors on the whole integument that had evolved and successively enlarged during the last years. He was out of work and completely isolated from social contacts due to stigmatization. Concomitant diseases included a HIV infection diagnosed 21 years ago, healed hepatitis C and a history of polytoxicomania. His antiretroviral medication, consisting of ritonavir, daltegravir and darunavir, had been interrupted for 18 months due to social withdrawal and restarted two weeks ago. In the prior past, multiple BCC had been excised. Treatment attempts with imiquimod and photodynamic therapy had been without effect. A mutation analysis of the PTCH1 gene performed to exclude Gorlin-Goltz syndrome had been unremarkable. The patient had a history of occasional tanning bed use (circa once weekly over two years during winter), and he had spent a six-week vacation in Australia. Clinical examination showed > 100 tumors on the head, trunk (Figure 1a, 2a), upper and lower extremities (Figure 2b) many of which were ulcerated and superinfected. There were no clinical signs of Gorlin-Goltz syndrome. Mapping biopsies from of the right chest (Figure 1b), the right thigh and both lower legs confirmed ulcerated nodular BCC. Sonography of the cervical, axillary and inguinal lymph nodes and a CT scan of the thorax and abdomen gave no evidence of metastasis. Laboratory tests revealed reduced T helper cells (312/μL, normal range 404–1,612/μL) and 105,000 copies/ mL HIV-1 RNA. The resistogram showed sensitivity to ritonavir, daltegravir and darunavir, and the consulted infectiologist recommended continuing this medication. Following the consensus decision of the interdisciplinary tumor board, we initiated treatment with the SHH inhibitor sonidegib. Due to co-medication with the CYP3A4 inhibitor ritonavir, the dosage was reduced to sonidegib 200 mg every second day, as recommended in the medicinal product information. The treatment was satisfactorily tolerated and led to almost complete clinical remission of all BCC within nine months (Figure 2c, d). Adverse events were alopecia totalis, xerostomia grade 1 according to the Common Terminology Criteria for Adverse Events, dysgeusia grade 2 and weight loss of 5 kg. High-caloric energy drinks were offered, but not well tolerated. In addition, the patient suffered from occasional muscle cramps that were treated with magnesium 400 mg/day. Seven weeks after initiation of sonidegib, he experienced a one-time asymptomatic increase in creatine kinase grade 3 (1,035 U/l, normal range < 174 U/L) that was spontaneously reversible. The creatine kinase was within normal limits at all prior and subsequent controls. Overall, the patient reported good treatment satisfaction and wished to continue sonidegib. Excision of one remaining BCC on the right chest was recommended, but not desired by the patient. Under antiretroviral therapy the T helper cells increased to 378/μL, and the HIV-1 viral load decreased to 35 copies/mL. The lifetime risk of BCC is > 10 % for Central and Northern Europeans. Major risk factors are ultraviolet light exposure and immunosuppression. Patients with HIV have a circa 1.8-fold increased risk of BCC [1], which may be reduced by adequate control of the HIV infection [1, 2]. However, occurrence of dozens of BCC in patients with HIV but without additional risk factors is unusual [3]. Activation of the SHH signaling pathway plays a key role in the development of inherited and sporadic BCC [4]. A mutation in the SHH inhibitor patched (PTCH) leads to uncontrolled activation of smoothened (SMO), which renders Clinical Letter