HAART in advanced phases of HIV-1 infection may induce immune reconstitution inflammatory syndrome (IRIS), requiring brief corticosteroid therapy in severe cases [1,2]. Clinical manifestations in ‘paradoxal IRIS’ are primarily a worsening of clinical signs or the appearance of new events in patients with a known infection after starting HAART, most often without detectable or viable opportunistic infection and despite a successful suppression of HIV plasma viremia . More rarely, in a form called ‘unmasking IRIS’, in which the opportunistic infection preexisted but was clinically silent, symptoms develop after the introduction of HAART. A switch from a type 2 helper T cell (Th2) to a Th1 immune response after HAART introduction is suspected, as suggested by increased levels of interferon gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in tuberculosis-associated IRIS , and the successful use of monoclonal TNF-α antagonist antibodies [5,6]. Thalidomide has shown in-vitro inhibition of TNF-α production , benefit during experimental tuberculosis meningitis , and response in a case of cryptococcal-associated IRIS .
We have report three cases of HIV-infected patients with refractory, corticosteroid-dependent and life-threatening paradoxal IRIS for whom thalidomide administration resulted in rapid clinical remission. The first case is a 33-year-old HIV-infected man who was admitted in April 2008 with cryptococcal meningitis. The CD4 cell count was 15 cells/μl and HIV-1 plasma viral load was 96 600 copies/ml. The clinical course was favorable after antifungal therapy and introduction of HAART at day 28. In September 2009, the patient presented symptoms of meningitis and cerebellar ataxia despite fluconazole prophylaxis (400 mg per day), undetectable plasma viral load and a CD4 cell count of 273 cells/μl. An extensive infectious work-up analysis revealed no active infection, an increased cerebral spinal fluid (CSF) opening pressure and CSF encapsulated yeast-like fungi with sterile cultures. Cerebral MRI results are shown in Fig. 1a. Paradoxal IRIS was suspected and intravenous (i.v.) methylprednisolone 250 mg per day was administered for 3 days, followed by oral prednisolone (1 mg/kg per day) with progressive tapering to 15 mg per day in the following 8 weeks. Fluconazole (800 mg per day) was continued. The patient presented three other IRIS relapses uncovered by cephalalgia and diplopia when corticosteroids were tapered to a daily dose of 12.5–15 mg. Thalidomide was initiated at 100 mg per day with aspirin 75 mg per day in August 2010, allowing complete cessation of corticosteroids in March 2012 with no following relapse (Fig. 1b).
The second case was a 47-year-old man who was admitted in December 2004 with cryptococcal meningitis and HIV infection (CD4 cell count was 19 cells/μl and HIV-1 plasma viral load was 462 292 copies/ml). Initial evolution was favorable for antifungal therapy and introduction of HAART at day 21 and fluconazole maintenance therapy (400 mg per day). In December 2006, he was admitted with encephalitis. HIV viral load was undetectable and CD4 cell count was 353 cells/μl. An extensive infectious work-up analysis of active infections, including a neurosurgical biopsy of right parietal-frontal meninges, was negative. Cerebral MRI showed right parietal-temporal hyperintensity in fluid-attenuation inversion recovery sequences and T1-weighted subarachnoid space enhancement intensity with gadolinium. Paradoxal IRIS was suspected and high dose of i.v. methylprednisolone (500 mg per day) was administered for 3 days followed by oral prednisolone (1 mg/kg per day) progressively tapered, in association with fluconazole (400 mg per day). Corticosteroids and fluconazole were interrupted in January and March 2009 respectively. In May 2009, the patient presented with a first relapse of IRIS treated with prednisone (60 mg per day) and fluconazole (400 mg per day). Two successive episodes, despite 15 mg per day of prednisolone, justified thalidomide introduction (100 mg per day) with aspirin in December 2010. In June and October 2011, prednisone and fluconazole were successfully interrupted. Thalidomide was interrupted in March 2012 with no relapse at the time of writing (June 2012).
In December 2007, the third case, a 19-year-old HIV-infected girl was diagnosed with disseminated tuberculosis in the context of immunovirologic failure despite HAART (CD4 cell count was 15 cells/μl and HIV-1 plasma viral load was 259 327 copies/ml). Antimycobacterial therapy was introduced and HAART optimized. Seven months later, she was admitted for abdominal pain and acute renal insufficiency (CD4 cell count of 104 cells/μl and HIV viral load of 567 copies/ml). Renal biopsies revealed gigantocellular and epithelioid granuloma without caseous necrosis. Cultures were negative. Paradoxal IRIS was suspected, and high doses of prednisone were introduced (2 mg/kg per day for 3 days, progressively tapered), resulting in rapid biological and clinical improvement at day 9. However, the patient presented two relapses of IRIS despite tuberculosis therapy after 4 and 23 months, the first when prednisone was tapered to 20 mg per day and the second 1 month after corticosteroid interruption, with intensive, transfixing abdominal pain linked to mesenteric necrotic lymph nodes (Fig. 1c). Thalidomide was introduced (100 mg per day) with prednisone (40 mg per day), aspirin and effective contraception measures, inducing rapid clinical and MRI responses (Fig. 1d). Prednisone and thalidomide were respectively interrupted 10 and 14 months later, with no sign of relapse in June 2012.
We retrospectively quantified the cytokine concentrations of TNF-α, eotaxin, MIP-1β, MIG, IL-15, IL-17, IL-1RA, IL-2R, GM-CSF, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, MCP-1, MIP-1α, RANTES, IP-10, IFN-γ and IFN-α in serum using a multiplexed microbead assay (cytokine human 25 plex Panel, Life Technologies, Saint Aubin, France) and a Luminex 100 apparatus (Luminex, Oosterhout, The Netherlands) during and after introduction of thalidomide. The local ethical committee approved the protocol and consent was obtained from all patients. No specific pattern of cytokine concentration and evolution could be identified.
We have described three cases of HIV-infected patients with severe and corticosteroid-dependent IRIS for whom thalidomide allowed steroid tapering. Both the underlying physiopathological immune mechanisms and the analogy with tuberculosis-related IRIS justified the initial administration of high-dose methylprednisolone. Rapid clinical remission followed steroid therapy, though clinical remissions were steroid dose-dependent in both cases of cryptoccocal-related IRIS. Thalidomide has been used in other IRIS-like syndromes such as treatment of erythema nodosum leprosum . Thalidomide (2 mg/kg per day) seemed beneficial in two HIV-infected children in a case series of four tuberculous meningitis complicated by IRIS . However, one randomized trial of thalidomide in childhood tuberculous meningitis had to be interrupted prematurely due to important adverse events in the thalidomide arm , but thalidomide doses were very important (24 mg/kg per day), and thalidomide was introduced after randomization independently of IRIS presence. In our cases, clinical responses were rapid under thalidomide and cortisone therapy and were maintained after tapering of corticosteroids, arguing for a direct and strong anti-inflammatory effect of thalidomide. The drug was also well tolerated at low doses, with only mild dizziness and constipation reported in two patients. No clear immunomodulatory effect of thalidomide on cytokine levels could be observed. Similarly, the effect of thalidomide on TNF-α synthesis was not confirmed in two randomized clinical trials of oral aphtous ulcers and Kaposi sarcoma in HIV-infected patients treated with thalidomide or placebo [12,13].
In conclusion, thalidomide may be an interesting salvage treatment in patients with cortico-dependent or refractory IRIS, and should be further studied in clinical trials.
Conflicts of interest
There are no conflicts of interest.
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