Portal de Periódicos da CAPES

Severe insomnia related to high concentrations of raltegravir

2011; Lippincott Williams & Wilkins; Volume: 25; Issue: 5 Linguagem: Inglês

10.1097/qad.0b013e32834465c8

1473-5571

Céline Eiden, Hélène Peyrière, Gilles Peytavin, Jacques Reynes,

HIV-related health complications and treatments

Raltegravir (RAL) is the first drug of the new class of HIV-1 integrase inhibitors. In phase II/III clinical trials, RAL was well tolerated overall [1–2]. We report three cases of HIV-infected adults who experienced severe insomnia and nightmares possibly related to RAL therapy. Patient 1 is a 50-year-old HIV-infected man, treated with monotherapy of lopinavir/ritonavir (Kaletra, 400/100 mg twice daily) since 2005. Because of diabetes associated with a lipodystrophy, metformine 850 mg twice daily was added. In February 2008, a new antiretroviral treatment was initiated with atazanavir/ritonavir (300/100 mg once a day), and RAL (Isentress 400 mg twice daily). At that time, plasma HIV-RNA was 98 copies/ml, and CD4 cell count was 890 cells/μl. In March 2008, the antiretroviral plasma concentrations were determined approximately 12 h after the last dose using the ultra-performance liquid chromatography/mass spectrometry (UPLC-MS/MS) method (Acquity UPLC-Acquity TQD, Waters) as previously described [3]: RAL trough concentration (Ctr) was 3107 ng/ml [expected value 63 ng/ml (range 29–118)] [4], atazanavir Ctr was 1564 ng/ml (range 200–800 ng/ml) [4]. Total serum bilirubin was 83 μmol/l (normal value 2–24), unconjugated serum bilirubin was 77 μmol/l (normal value 2–16). In June 2008, the patient reported the onset of a major insomnia reducing his sleep to 2 or 3 h by night, associated with nightmares. Because of this severe neuropsychic intolerance, atazanavir/ritonavir was replaced by darunavir/ritonavir (600/100 mg twice daily), the rest of therapy was unchanged. This modification has significantly improved the sleep time of the patient (5–6 h duration) without total recovery. Antiretroviral plasma concentrations after 1 month of treatment were: RAL Ctr 72 ng/ml, darunavir Ctr 1575 ng/ml [expected value 3539 ng/ml (range 1255–7368)] [4], and ritonavir Ctr 30 ng/ml. The symptoms resolved gradually in 2 months. Patient 2 is a 67-year-old HIV-infected man, treated with didanosine (Videx, 250 mg once a day), nevirapine (Viramune, 200 mg on morning and 100 mg on evening) and abacavir (Ziagen, 300 mg twice daily) since 1999. Because of a hypertension, a treatment with losartan and nebivolol was prescribed. In April 2010, because of a ptosis suspected to be related to HIV therapy, a switch to RAL (400 mg twice daily) and abacavir/lamivudine (Kivexa 600/300 once a day) was done. In June 2010, the patient reported severe insomnia, which resolved in 6 days after the discontinuation of RAL, replaced by nevirapine. At the discontinuation of RAL, RAL Ctr was 2350 ng/ml. Since 2009, the patient presented a moderate elevation of gamma-glutamyltransferase and alkaline phosphatase. Patient 3 is a 55-year-old HIV-infected man, co-infected with HBV, treated with tenofovir-emtricitabine (Truvada, 300/200 once a day) and atazanavir/ritonavir (Reyataz/Norvir 300/100 mg once a day) since 2009. Because of a dyslipidemia, fenofibrate 200 mg was also prescribed. In July 2010, a lipoma suspected to be related to HIV therapy, led to a switch of protease inhibitors to RAL (400 mg twice daily). Three months later, because of a suspected Fanconi syndrome [creatinine 131 μmol/l (53–106), proteinuria 0.88 g/l], Truvada was replaced by emtricitabine (Emtriva 200 mg once a day) and maraviroc (Celsentri 300 mg twice daily). RAL Ctr was 330 ng/ml. In November 2010, the patient related for the first time severe insomnia with diurnal drowsiness, which had appeared for a few weeks. RAL Ctr was 221 ng/ml, maraviroc was 56 ng/ml [expected value 37 ng/ml (range: 6–487)] [4] and emtricitabine was 797 ng/ml. Regarding the three patients, no proton pomp inhibitors were prescribed, no hypnotics were used to treat the insomnia, and plasma HIV-RNA remained undetectable according to the modifications of treatment. Available data suggest marked inter-individual and intra-individual variability of RAL pharmacokinetics [5,6]. RAL plasma trough concentrations ranged from 20 to 2470 ng/ml in 54 HIV-infected patients receiving salvage regimens based on RAL with and without maraviroc coadministration [6]. In patient 1, higher RAL Ctr associated with atazanavir/ritonavir therapy may reflect an inhibition of the UGT1A1 enzyme by atazanavir. Indeed, atazanavir is an inhibitor of both cytochrome P4503A4 and UGT1A1. RAL is predominantly metabolized by glucuronidation (UGT1A1) [7]. Multiple doses of atazanavir (boosted or not) are known to modestly increase plasma levels of RAL in healthy individuals [8]. However, a recent study in RAL HIV-infected patients showed that coadministration of atazanavir significantly increases RAL Ctr, especially in patients with high atazanavir exposure (506 ± 411 vs. 177 ± 262 ng/ml) [9]. Insomnia was reported in 3.6% of patients from the 96-week results from the STARTMRK study [2]. In the literature, four cases of exacerbation of pre-existing depression related to the start of RAL therapy are described [10], but the mechanism of such psychiatric decompensation remains unknown. Moreover, Gray and Young [11] reported two cases of insomnia associated with the initiation of RAL. In these two cases, RAL concentrations were not measured. Our patients have no previous history of psychiatric or neurological disorders, or severe insomnia. The pharmacologic mechanism for most drug-induced nightmares is not known [12]. Central adrenergic receptors may be involved in some cases; dopamine receptor stimulation may be another common mechanism [12]. Regarding human cerebrospinal fluid (CSF) or brain RAL penetration, some data have shown that RAL is present in CSF at low levels, as well as a correlation between CSF and plasma concentration (r2 = 0.24, P = 0.02) [13]. Thus, direct toxicity of RAL in the brain could be suspected. These cases of sleep disorders induced by RAL suggest a possible concentration–effect relationship and underline the importance of therapeutic drug monitoring for this new antiretroviral agent.