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Received Aug 10, 2017; Revised Feb 28, 2018; Accepted Mar 13, 2018
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1. Introduction
Drug-induced adverse effects have been reported with the use of all antiretroviral (ARV) drugs [1]. Hepatotoxicity is a relatively common adverse drug reaction (ADR) leading to the treatment interruptions in human immunodeficiency virus- (HIV-) infected patients on different drug regimens [2], with consequent immunologic compromise [3]. The severity of the hepatic injury and drug-induced liver injury (DILI) depends upon the toxic molecules (reactive oxygen species) and the counterbalance of cytokines (TNF-α, IL-1β, IL-10, and IL-1RA) [4–6]. 10.8% in the efavirenz-treated group while 8.9% in the nevirapine-treated group reported having grade 3 or 4 hepatotoxicity [7]. While in another report, nevirapine use was associated with a higher incidence of hepatotoxicity than efavirenz use [8]. Nagpal et al. [9] reported a prevalence of nevirapine-induced hepatotoxicity (3.19%) in HIV-infected individuals in India. The activity of drug metabolizing enzymes was found to be altered in some infectious and inflammatory states such as bacterial pneumonia, viral infections, surgery, and trauma [10]. The effect of infection on the drug metabolizing enzymes is carried by the few cytokines such as IL-1β, IL6, tumor necrosis factor alpha (TNF-α), and interferon (INF) α or γ [11, 12]. IL-1 receptor antagonist (IL-1RA) restricted the induction of HIV replication in vitro [13–15], and the treatment with ARV drugs resulted in an increased level of circulating IL-1RA [16].
Interleukins (ILs) are proinflammatory cytokines produced by leukocytes, macrophages, monocytes, and epithelial cells. The IL-1 family consists of eleven members including IL-1 alpha (IL-1α), IL-1 beta (IL-1β), and IL-1 receptor antagonist (IL-1RA) [17]. IL-1α and IL-1β are the most influencing proinflammatory cytokines, and IL-1RN is a naturally occurring anti-inflammatory cytokine [18, 19]. The IL-1RA also regulates biological activity of IL-1α and IL-1β [19–21]. ILs promote the interaction of endothelial cells with circulating leukocytes and induce the proliferation of monocytes and macrophages.
IL-1 cytokine cluster spanning ~430 kb region which is located on chromosome 2q13-21, consists of IL-1α,