A 40-year-old patient, known to be HIV-infected since 1990 but who had always been a poor adherent to follow-up and treatment, was referred for Pneumocystis jiroveci pneumonia in March 2005. In addition to fever (38.2°C), dyspnea and diffuse crackles raises, a 1-cm purplish tumefaction of the left lower eyelid was noticed, which had appeared a few days earlier, without any visual impairment. The rest of the cutaneous examination was normal. CD4 count was 11/μl (2%) and viral load was 190 000 RNA copies/ml (5.28 log). The patient received cotrimoxazole for his pneumonia, and an antiretroviral therapy was started combining lamivudine, tenofovir disoproxil fumarate and ritonavir-boosted lopinavir. The patient was cured of his pneumonia and was discharged from the hospital. He missed the follow-up appointments and neglected the eyelid lesion. Two months later, the lesion had evolved to a 3-cm tumor. An orbital invasion was documented by computed tomography scan (Fig. 1). The hypothesis of a Kaposi's sarcoma of the eyelid was raised. The patient refused orbital exenteration, and subsequently conservative surgery was performed. The pathologic examination of the tumor confirmed the diagnosis of Kaposi's sarcoma. As the surgical treatment was not optimal, especially regarding margins of resection, the patient was started with adjuvant chemotherapy consisting in weekly docetaxel 25 mg/m2, according to previously described regimens [1].Fig. 1: Orbital computed tomography scan, showing the invasion of the orbital cavity.Eight days after the first infusion of docetaxel, the patient developed neutropenic fever, with a neutrophil count of 450/μl and a C-reactive protein of 196 mg/mlL. He was rehospitalized and received intravenous antibiotics. Microbiological tests were negative, and the neutropenia resolved in the following week. We hypothesized that ritonavir-induced inhibition of CYP3A4, the main enzyme that metabolizes docetaxel [1,2], was responsible for an increased plasma exposure to docetaxel, and thus may have caused this febrile neutropenia. Hence, docetaxel was stopped, and the patient remained under highly active antiretroviral therapy (HAART). During the following 6 months, the CD4 count reached 130/μl (10%), and the viral load remained below 40 RNA copies/ml. No local recurrence of the Kaposi's sarcoma of the eyelid was noticed during the following 2 years. Kaposi's sarcoma of the eyelid is a rare manifestation of AIDS, which was first reported in 1989 in the setting of HIV infection [3], while other ocular manifestations of AIDS were known since the very beginning of the pandemia [4]. Before the HIV era, this manifestation of Kaposi's sarcoma was scarcely reported in the English literature [5,6], with a poorer prognosis than in other sites [7]. Some HIV-infected patients, even with a good immune restoration after the introduction of HAART, still display aggressive Kaposi's sarcoma, and therefore require chemotherapy. Anthracyclines and taxanes are active in this setting. In patients with Kaposi's sarcoma of the eyelid, the first line of treatment should be orbital exenteration [3]. However, in this patient, a conservative surgical treatment was decided, and we assumed that adjuvant chemotherapy together with HAART could improve disease control. The patient developed a febrile neutropenia while undergoing a HAART containing ritonavir, concomitantly to weekly docetaxel. Weekly docetaxel is a well tolerated and feasible regimen in Kaposi's sarcoma patients, with limited toxicities: in a recent phase II study in 12 patients [1], no grade 4 neutropenia or neutropenic fever was observed. It is worth noting that patients included in this study received HAART without ritonavir pharmacoenhancement. Ritonavir is a protease inhibitor that potently inhibits CYP3A4, and is subsequently prescribed in HAART as a booster for other protease inhibitors metabolized by CYP3A4 [8]. Moreover, preclinical data indicate that the inhibition of CYP3A4 indiced by ritonavir can cause a significant increase in exposure to docetaxel [9]. In addition, the concomitant administration of docetaxel and ketoconazole, another potent inhibitor of CYP3A4, resulted in a major reduction in plasma clearance of docetaxel [10]. Hence, we postulate that ritonavir may cause a decrease in docetaxel plasma clearance through inhibition of CYP3A4, and therefore induce acute toxicity of docetaxel, including febrile neutropenia as described in the present case. According to the drug interaction probability scale [11], the interaction between ritonavir and docetaxel was possible (score = 2). In conclusion, we hypothesize that ritonavir may decrease the plasma clearance of docetaxel through inhibition of CYP3A4. Therefore, we suggest avoiding the concomitant administration of ritonavir and docetaxel. Hence, Kaposi's sarcoma patients undergoing a HAART including ritonavir should receive anticancer drugs that are not metabolized by CYP3A4 instead of docetaxel. For instance, paclitaxel would be a valuable option since it is mainly metabolized by CYP2C8 [12] with a minor contribution of CYP3A4.
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Sep 3, 2008
Upender Velaparthi + 20
Open Access