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Hemodiafiltration with online regeneration of ultrafiltrate for severe nevirapine intoxication in a HIV-infected patient

Hougardy, Jean-Michela,c; Husson, Cécilec; Mackie, Nicola E.d; Van Vooren, Jean-Paulb; Gastaldello, Karinea; Nortier, Joëlle L.a,c; Goffard, Jean-Christopheb

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doi: 10.1097/QAD.0b013e3283509770

A 41-year-old HIV-1-infected white patient was switched to a regimen containing ritonavir-boosted lopinavir and nevirapine (NVP) because of virological failure. The NVP lead-in dose was 200 mg/day. At the time of switch, CD4+ T-cell count was 236/μl and viral load was 783 copies/ml. Renal function was normal. Nine days later, painful erythematous rash developed on the back, soles, and palms. NVP was withdrawn immediately and methylprednisolone (1 mg/kg daily) was started. Seventy-two hours later, severe and diffuse bullous desquamations were observed, establishing the diagnosis of toxic epidermal necrosis (TEN). Given the life-threatening situation, hemopurification was started using hemodiafiltration with online regeneration of ultrafiltrate (HFR). After 3 h of HFR, progression of TEN was dramatically halted and skin lesions started to regress significantly during the following days. The patient was discharged after 48 h of favorable clinical observation. The NVP blood levels were monitored during the HFR session (Fig. 1). Plasma concentrations of NVP were determined by a fully validated method [1]. We compared this rate of blood elimination to that of the spontaneous elimination reported among nine HIV-infected patients [1]. During HFR, the NVP plasmatic elimination rate was −21.82 ± 4.94 ng/ml per h. NVP blood levels were, therefore, decreased by 36.5% after 3 h of HFR. The rate of spontaneous plasmatic NVP clearance was significantly slower (−4.55 ± 1.31 ng/ml per h; n = 9), which is five times slower than hemopurification (P = 0.039). In vitro, HFR resin adsorbed unbound NVP very efficiently with a rate of elimination equal to −3494 and −2357 ng/ml per h for 40 and 20 μg/ml NVP, respectively. Moreover, after only 1 h of incubation in the presence of HFR resin in vitro, levels of NVP were undetectable.

Fig. 1
Fig. 1:
Evolution of nevirapine plasma levels during hemodiafiltration with online regeneration of ultrafiltrate session (0–3 h) and after (9 and 16 h) illustrating the dramatic reduction in plasma levels in comparison to nine HIV-infected patients (controls) (for details, see text).

HFR is a blood purification procedure developed by Bellco (Mirandola, Italy). It is based on a paired filtration procedure. Blood first passes through a high permeability hemofilter (convective section). Then, the generated ultrafiltrate circulates through an adsorbing specific hydrophobic styrene resin cartridge (Selecta, Bellco Srl, Mirandola, Italy) and is reinfused after the hemofilter. This procedure is followed by hemodialysis on a low flux dialyzer (diffusive section). Small studies with HFR have shown significant reductions of chronic inflammation and oxidative stress in comparison to conventional hemodialysis [2–5]. However, no data are published on the role of HFR in drug removal in case of acute intoxication and poisoning.

HIV-infected individuals show high incidence of drug hypersensitivity reactions, which is up to 100 times in comparison to HIV-negative population [6]. The most common NVP-related adverse reactions such as the development of mild rash, severe hepatotoxicity, and/or TEN, including fatal cases, may occur in 1–4% of NVP-treated patients [7]. NVP toxicity could rely on excessive formation of reactive quinone methide, alkylating cellular macromolecules and causing cell death [8–10]. Hypersensitivity to NVP is multifactorial, involving several trigger factors such as concurrent infections, immune dysregulation, or oxidative stress [11]. Elevated NVP plasma concentrations are a risk factor for NVP-related skin toxicity [12]. Interestingly, our patient showed the highest blood levels of NVP before HFR (630 vs. 258.4 ± 195.8 ng/ml; mean ± SD; n = 7). The other identified risk factors for the development of adverse reactions to NVP are as follows: female, low BMI (<18.5), concomitant use of glucocorticoids or antihistamines, pregnancy, previous NVP-induced rash, high CD4 cell count, elevated liver enzymes, and HLA allelic variants (i.e., HLA-B*3505, HLA-B*5701) [13–17].

Conventional treatment of severe NVP hypersensitivity is mainly supportive after discontinuation of NVP and few effective therapeutic strategies are proposed [18,19]. Extracorporeal therapies, including hemodialysis or hemofiltration, are useful adjuncts in the treatment of acute poisoning [20]. NVP is a small but lipophilic molecule (molecular weight 266.30), mainly bound to plasma proteins (60%, predominantly albumin) and shows a long plasma elimination half-life (between 25 and 45 h) [12]. NVP is extensively metabolized in the liver and its renal elimination is minimal (<3%) [21]. Accordingly, hemodialysis alone is not a valuable therapeutic option in the case of NVP intoxication [22]. In contrast, the present technique of HFR, combining adsorptive properties of a large-surface-area column of resin and hemodialysis, seems to be efficient in removing drugs with molecular weights around 20 000 Da, even if lipophilic and/or protein-bound as NVP is [23].

In conclusion, we report the first successful use of HFR in a case of NVP-induced TEN in a HIV-infected patient. Although careful follow-up of all patients initiating NVP and prompt removal of the causative agent if TEN is suspected remains paramount, this observation points to the potential interest of this novel blood purification technique in the field of clinical toxicology.


Conflicts of interest

There are no conflicts of interest.


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