Thalidomide for IRIS? Optimal dose, duration unclear
Abstract & Commentary
Thalidomide for IRIS? Optimal dose, duration unclear
By Dean L. Winslow, MD, FACP, FIDSA, Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is a consultant for Siemens Diagnostic.
Synopsis: A case series of three patients with severe immune reconstitution inflammatory syndrome (IRIS) was presented (2 associated with cryptococcal meningitis, 1 with tuberculosis) where patients developed IRIS which recurred following discontinuation or tapering of glucocorticoid therapy. Remission of IRIS was sustained by treatment with thalidomide, allowing glucocorticoids to be tapered and discontinued.
Source: Brunel AS, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26: (epub ahead of print).
Three HIV-infected patients with refractory, corticosteroid-dependent and life-threatening IRIS were presented. The first patient with an initial CD4+ count of 15 cells/uL presented with cryptococcal meningitis which initially favorably responded to antifungal therapy and had HAART introduced on day 28.17 months later the patient presented with signs and symptoms of meningitis and cerebellar ataxia despite fluconazole suppressive treatment. At that time his CD4+ count was 273 cells/uL and his plasma HIV RNA was undetectable.
Lumbar puncture revealed raised intracranial pressure and was sterile on culture. MRI of the brain revealed bilateral cerebellar intensities on fluid-attenuation inversion recovery ( FLAIR) images. The patient was initially managed with aggressive doses of IV methylprednisolone followed by oral prednisolone and increase in fluconazole to 800 mg/day. The patient experienced 3 additional relapses characterized by headache and diplopia when his predisolone was tapered to 12.5-15 mg/day. Thalidomide instituted in August 2010 at 100 mg/day and ASA 81 mg/day allowed complete cessation of steroids by March 2012.
The second patient also had cryptococcal meningitis and had an initial CD4+ count of 19 cells/uL, had a good initial response to antifungal therapy, HAART was initiated on day 21 and the patient continued to receive suppressive PO fluconazole. Two years later he was admitted with an encephalitis-like picture and his CD4+ count had risen to 353 cells/uL. MRI showed right parietal-temporal hyperintensity in FLAIR images and T1-weighted subarachnoid space enhancement after gadolinium administration. In this case as well, aggressive IV followed by PO glucocorticoid therapy was initiated along with continued fluconazole. When steroid therapy was interrupted the patient developed relapse of his symptoms in approximately 5 months followed by 2 additional relapses when steroids were tapered below 15 mg/day. Thalidomide and ASA were started in December 2010 and prednisone was stopped in June 2011. Thalidomide was finally stopped in March 2012 with no relapse to date.
The third patient had disseminated TB and a CD4+ count of 15 cells/uL at time of diagnosis. Antimycobacterial therapy was started and her HAART was optimized. Seven months later she was admitted to the hospital with abdominal pain and acute kidney injury. At that time her CD4+ count had risen to 104 cells/uL. MRI of the abdomen showed a voluminous mass encircling the mesenteric vessels and renal biopsy showed granulomas without caseous necrosis and negative AFB cultures. Glucocorticoids were administered along with continued anti-TB therapy with resolution of her symptoms. However the patient presented with 2 relapses of IRIS when the prednisone was tapered to 20 mg/day at 4 months and when interrupted at 23 months. Thalidomide, prednisone, and ASA were instituted following the second IRIS relapse. Prednisone was stopped 10 months later and thalidomide was stopped 14 months later with no sign of relapse to date.
Commentary
IRIS occurring after institution of HAART in patients with HIV is felt to be related to a switch from a TH2 to a TH1 immune response and can be associated with increased levels of IFN-gamma and TNF-alpha. Thalidomide has been shown to inhibit production of TNF-alpha in vitro and is commonly used to treat both "reversal reactions" and erthyma nodosum leprosorum, which likely represent immune phenomena similar to HIV IRIS. Currently, systemic glucocorticoids remain the mainstay of treatment for severe life-threatening IRIS as illustrated in the 3 case reports included in this series. Obviously the use of steroids over long periods of time is problematic in patients due to glucocorticoid-related side effects.
This small case series suggests that thalidomide may be useful as a steroid-sparing agent in HIV IRIS. However, in addition to the problems with teratogenicity associated with thalidomide, the optimal dose and duration of thalidomide to treat IRIS is not clear.
For example, its efficacy even in the cases presented in this report is not clearly established since the patients all received long courses of glucocorticoids and it is possible that their IRIS may have eventually resolved whether or not thalidomide had been administered.
Although off-label use of thalidomide proved successful in this small case series, prospective, randomized controlled trials of thalidomide for IRIS should be conducted prior to the use of this agent routinely for this condition.
Three HIV-infected patients with refractory, corticosteroid-dependent and life-threatening IRIS were presented.Subscribe Now for Access
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