Antiviral Therapy 2015; 20:773–777 (doi: 10.3851/IMP2961)
Short communication Raltegravir plus two nucleoside analogues as combination antiretroviral therapy in HIV-infected patients who require cancer chemotherapy José L Casado1*, Isabel Machuca1, Sara Bañón1, Ana Moreno1, José Moltó2, Miguel A Rodriguez3 Department of Infectious Diseases, Ramon y Cajal Hospital, Madrid, Spain Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 3 Department of Pharmacy, Ramon y Cajal Hospital, Madrid, Spain 1 2
*Corresponding author e-mail:
[email protected]
Background: There are few data on the best combination antiretroviral therapy in patients with HIV infection who need cancer chemotherapy because of drug–drug interactions and increased risk of toxic effects. Methods: We evaluated the safety, efficacy and interactions of a raltegravir (RAL)-based regimen in 30 HIV-infected patients who received antineoplastic agents. Results: A total of 17 patients had a non-AIDS-defining malignancy (7 with Hodgkin disease) and 13 had an HIVrelated cancer (9 non-Hodgkin lymphoma, 2 Kaposi sarcoma and 2 anal cancer). Overall, they received 49 cycles of chemotherapy with 19 different antineoplastic drugs, including antimetabolites in 4 patients (5-FU, gemcitabine), alkylating agents in 10 cases (cyclophosphamide, ifosfamide), vinca alkaloids in 17 patients (vincristine,
vinblastine), anti-tumour antibiotics in 18 cases (doxorubicin), cisplatin or carboplatin in 6, and monoclonal antibodies in 13 patients (rituximab, trastuzumab, cetuximab). Six patients modified the doses of antineoplastic agents due to toxicity not related to raltegravir. During a median follow-up of 67.8 patient-years (median 170 days in concomitant therapy) there was only 1 case of virological failure and no patient discontinued RAL. Geometric mean trough levels of RAL were 143 ng/ml (79–455). There were no opportunistic infections, median CD4+ T-cell count increased by 49 cells/ml and four (13%) patients died during the study (not related to AIDS progression). Conclusions: Our results show that a RAL-based regimen is safe and effective in patients requiring chemotherapy, irrespective of type and of duration of chemotherapy.
Introduction The incidence of malignancies is significantly increasing in the HIV-infected population and cancer has become one of the most common causes of death [1]. In these patients, the concomitant use of combination antiretroviral therapy (cART) has been demonstrated to reduce morbidity and to improve overall survival [2–4]. However, clinically significant drug–drug interactions between antineoplastic agents and cART have been described. For example, both HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), are either potent inhibitors or inducers of the cytochrome P450 (CYP) enzyme system, which can lead to changes in antineoplastic drug concentrations with lower efficacy or an increase in the rate of chemotherapy toxicity. The HIV-1 integrase inhibitor raltegravir (RAL) has demonstrated clinical efficacy and it is well-tolerated ©2015 International Medical Press 1359-6535 (print) 2040-2058 (online)
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in treatment-experienced and treatment-naive patients with HIV-1 infection [5,6]. RAL is primarily eliminated through glucuronidation by UGT1A1 and has no clinically significant effects on the CYP system, limiting its potential to cause drug interactions [7]. We followed up a cohort of HIV-infected patients with a recent diagnosis of malignancy who required chemotherapy and who initiated or switched to RAL as third drug in the cART, to evaluate safety, efficacy and pharmacokinetics parameters of RAL in this situation.
Methods This was an observational cohort study of HIV-infected patients who started or switched to a regimen of RAL (400 mg twice daily) plus two nucleoside analogues from January 2011 to July 2014 because of a 773
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diagnosis of cancer and the need of chemotherapy. No patient had evidence of resistance to RAL or nucleoside analogues, as defined on the basis of the 2009 International Antiviral Society USA (IAS-USA). The study was approved by our institutional review board and patients gave written informed consent to clinical and analytical follow-up. Demographic data, HIV-related data (risk practice, time of infection, previous cART and reason for discontinuation) and HCV coinfection status were recorded for each patient. Routine physical examination and laboratory tests, including CD4+ T-cell counts and HIV-1 RNA levels (Versant HIV-1 RNA 1.0 [kPCR]; Siemens Diagnostics, Munich, Germany; quantification limit 37 copies/ml), were performed at baseline and at each follow-up visit, every 3 months. Information regarding CD4+ T-cell count, HIV RNA, adverse events or reasons for discontinuing the RALbased regimen was recorded. RAL concentration was determined in frozen plasma by high-performance liquid chromatography (HPLC) with fluorescence detector (2475 Multi l Fluorescence Detector; Waters Corporation, Milford, MA, USA) according to the method described by Poirier et al. [8]. Antineoplastic regimen was chosen by the responsible oncologist without considering interactions with cART. Patients were followed until loss to followup, death or September 2014, whichever came first. Survival was calculated from the day of cancer diagnosis (overall survival). Treatment failure was defined as virological failure (HIV RNA level above 37 copies/ ml in two successive determinations) or discontinuation of RAL. Toxicities were graded using the WHO criteria. The primary study end point was the proportion of patients who were free of cART treatment failure during 48 weeks at the intention-to-treat analysis (with patients discontinuing treatment counted as failures). Continuous variables were compared using Student’s t-test for normal distribution and the Mann–Whitney U test. Categorical variables were analysed with the c2 test or Fisher’s test, when applicable. Survival and efficacy duration curves were plotted according to the method of Kaplan–Meier. All P-values
