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As a consequence of the immunocompromised state of these individuals, the initial immune response to <jats:styled-content style=\"fixed-case\">CM<\/jats:styled-content> is predominantly type 2 T helper (Th2) \/Th17 rather than Th1, leading to inefficient fungal clearance at the time of antiretroviral initiation, and a subsequent overexaggeration of the Th1 response and life\u2010threatening <jats:styled-content style=\"fixed-case\">IRIS<\/jats:styled-content> development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An article\u2010based and clinical trial\u2010based search was conducted to investigate <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">CM IRIS<\/jats:styled-content> pathophysiology and current treatment practices.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Guidelines for <jats:styled-content style=\"fixed-case\">CM<\/jats:styled-content> treatment, based on the Cryptococcal Optimal Antiretroviral Timing (<jats:styled-content style=\"fixed-case\">COAT<\/jats:styled-content>) trial, recommend delayed antiretroviral therapy (<jats:styled-content style=\"fixed-case\">ART<\/jats:styled-content>) following antifungal treatment. The approach aims to decrease fungal burden and allow immune balance restoration prior to <jats:styled-content style=\"fixed-case\">ART<\/jats:styled-content> initiation. If the initial immune balance is not restored, the fungal burden is not sufficiently reduced and there is a risk of developing <jats:styled-content style=\"fixed-case\">IRIS<\/jats:styled-content> post\u2010<jats:styled-content style=\"fixed-case\">ART<\/jats:styled-content>, highlighted by a Th1 immune overcompensation, leading to increased mortality. The mainstay treatment for Th1\u2010biased <jats:styled-content style=\"fixed-case\">IRIS<\/jats:styled-content> is corticosteroids; however, this treatment has been shown to correlate with increased mortality and significant associated adverse events. We emphasize targeting a more specific Th1 mechanism via the tumour necrosis factor (<jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>)\u2010\u03b1 cytokine antagonist thalidomide, as it is the only <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\u2010\u03b1 antagonist currently approved for use in infectious disease settings and has been shown to decrease Th1 overreaction, restoring immune balance in <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">CM IRIS<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Although the side effects and limitations of thalidomide must be considered, it is currently being successfully used in infectious disease settings and warrants mainstream application as a therapeutic option for treatment of <jats:styled-content style=\"fixed-case\">IRIS<\/jats:styled-content> in HIV\u2010infected patients with 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