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• W2464756024 abstract "12 July 2008 Dear Editor, SEVERELY IMMUNOCOMPROMISED HIV-INFECTED PAEDIATRIC PATIENT WITH DRUG-RESISTANT CYTOMEGALOVIRUS INFECTION TREATED WITH SUBCUTANEOUS INTERLEUKIN-2 Several studies have demonstrated substantial expansion of CD4 T cells in adult and paediatric HIV-infected patients treated with interleukin-2 (IL-2).1-3 None of these studies have included patients with other active infections; hence, the infection reactivation risk in patients receiving IL-2 remains unknown. We report the case of a 14-year-old HIV-infected boy with AIDS-associated wasting syndrome, severe malnutrition (height and weight at −6 SD below age- and sex-adjusted mean) and cytomegalovirus (CMV) disease with pulmonary and retinal involvement, under treatment with intravenous ganciclovir and foscarnet. Genotype resistance testing performed 1 year before starting IL-2 showed multiple mutations in the reverse transcriptase (M41L, D67N, K101E, V118I), protease (L10I, L33V, M46I, L63P, A71V, V82F, L90M) and envelope gene associated with resistance to entry inhibitors (V38M, N43D). Therefore, treatment with boosted darunavir and etravirine (dose-adjusted by pharmacokinetic studies) was started at that time. The patient presented undetectable HIV viral load 2 months after beginning this new regimen, but immunological restoration was never achieved. At that point, in addition to antiviral therapy, treatment with subcutaneous IL-2 (Proleukin, Novartis Pharmaceuticals Ltd., West Sussex, UK) at a dose of 4 MU/m2 given twice daily in 5-day courses every 8 weeks for 6 cycles3 was started, after obtaining authorisation for compassionate use by the Spanish Agency for Medicines and Healthcare Products (AEMPS). HIV viral load remained undetectable and CD4 cell count was 6% (105 cells/mm3). CMV viral load was 84 000 copies/mL at that time. During this period, HIV viral load remained undetectable and CD4 cell count exhibited a significant 11% increase (258 cells/mm3) 15 days after initiating therapy (Fig. 1). Evolution of cytomegalovirus viraemia, CD4 count and HIV viral load after IL-2 treatment. At the end of the first cycle, the patient presented capillary leak syndrome resulting in multiple organ failure (renal and respiratory failure, and hypotension), and CMV exacerbation in both the intestine and retina. He was admitted to the Paediatric Intensive Care Unit for 1 week, with progressive stabilisation. Due to these severe late-onset adverse reactions, IL-2 therapy was definitely discontinued. In the following month, CMV viral load increased 27-fold (from 84 000 to 6 130 037 copies/mL). Intestinal CMV progression resulted in uncontrolled rectorrhagia that led to the patient's death 34 days after starting IL-2. This adverse reaction was reported to the spontaneous notification programme for adverse drug reactions and the AEMPS. Resistance to both ganciclovir and foscarnet was demonstrated after the patient's death (M460V and K513R). IL-2 is a cytokine produced by T lymphocytes that promote lymphocyte proliferation and differentiation of CD4 and CD8 T cells. Several phase I/II clinical studies have demonstrated that intermittent subcutaneous or continuous intravenous administration of IL-2 in HIV-infected patients induces substantial expansion of CD4 T cells, as observed in our patient. These studies recommend the intermittent subcutaneous route to minimize drug-associated side effects. A major concern regarding the use of IL-2 is the theoretical risk that this cytokine could stimulate HIV replication, although this did not happen in our patient.1, 2 Although drug-related toxicities are described as common in most clinical trials, these events are limited to the period of drug administration and are resolved at the end of the cycle. In a paediatric series, more than 90% had fatigue, malaise or lethargy during the IL-2 administration cycle. Other common adverse events include headache or myalgia (66%); pruritis, generalized rash or urticaria (75%); nausea, emesis, anorexia and diarrhoea (83%); respiratory symptoms (33%); and oedema (25%).3 No severe adverse reactions such as those occurring in our patient have been reported. Capillary leak syndrome has been described as an adverse reaction associated with IL-2 administration. However, it usually appears shortly after initiation of therapy and is reported to be less severe with subcutaneous route.4 As to CMV exacerbation with the use of IL-2, this effect has not been described as such in the literature. Nevertheless, it should be mentioned that IL-2 use is contraindicated in patients with evidence of active infection.4 The decision to initiate IL-2 therapy in our patient was based on his critical status and the fact that CMV infection was partially controlled with intravenous antiviral therapy. In addition, according to Yu et al., the use of IL-2 restores the proliferative response of CMV-specific CD8+ T cells in patients with HIV.5 Despite subcutaneous IL-2 seems useful in increasing CD4 counts even in severely immunocompromised HIV-infected paediatric patients with concomitant uncontrolled infections, clinicians should be aware of the risk of serious late-onset adverse reactions with IL-2 even if the subcutaneous route is employed. Disease due to CMV may progress despite antiviral therapy and IL-2 in the face of CMV resistance mutations. We thank Ms Celine L. Cavallo for English language assistance." @default.
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• W2464756024 date "2009-04-01" @default.
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• W2464756024 title "Letters to the Editor" @default.
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• W2464756024 doi "https://doi.org/10.1111/j.1440-1754.2009.01480.x" @default.
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