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Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.

ABSTRACT: The risks of unmasking and paradoxical forms of immune reconstitution disease in HIV-infected patients starting antiretroviral therapy (ART) are fuelled by a combination of the late presentation of patients with advanced immunodeficiency, the associated high rates of opportunistic infections (OIs) and the need for rapid initiation of ART to minimize overall mortality risk. We review the risk factors and our current knowledge of the immunopathogenesis of immune reconstitution disease, leading to a discussion of strategies for prevention. Initiation of ART at higher CD4 counts, use of OI-preventive therapies prior to ART eligibility, intensified screening for OIs prior to ART initiation and optimum therapy for OIs are all needed. In addition, use of a range of pharmacological agents with immunosuppressive and immunomodulatory activity is being explored.

SUBMITTER: Lawn SD

PROVIDER: S-EPMC3252684 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.

Lawn Stephen D SD Meintjes Graeme G

Expert review of anti-infective therapy 20110401 4

The risks of unmasking and paradoxical forms of immune reconstitution disease in HIV-infected patients starting antiretroviral therapy (ART) are fuelled by a combination of the late presentation of patients with advanced immunodeficiency, the associated high rates of opportunistic infections (OIs) and the need for rapid initiation of ART to minimize overall mortality risk. We review the risk factors and our current knowledge of the immunopathogenesis of immune reconstitution disease, leading to ...[more]

PMID: 21504399

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Project description:BackgroundIntegrase inhibitors (INI) induce a rapid decline of HIV-RNA in plasma and CD4+ T-cell recovery in blood. Both characteristics are also associated with immune reconstitution inflammatory syndrome (IRIS). Whether the use of INI-containing combination antiretroviral therapy (cART) increases the risk of IRIS is being questioned.MethodsStudy within the Dutch ATHENA HIV observational cohort. HIV-1 infected late presenters initiating cART after March 2009 were included if they had <200 CD4+ T-cells per μL and were diagnosed with an opportunistic infection. IRIS was defined either according to the criteria by French et al. (IRISFRENCH) or by a clinical IRIS diagnosis of the physician (IRISCLINICAL). The primary outcomes were the association between INI and the occurrence of IRISFRENCH and IRISFRENCH+CLINICAL in multivariable logistic regression.Findings672 patients with a median CD4+ T-cell count of 35 cells per μL were included. Treatment with INI was independently associated with IRISFRENCH as well as IRISFRENCH+CLINICAL (OR 2·43, 95%CI:1·45-4·07, and OR 2·17, 95%CI:1·45-3·25). When investigating INI separately, raltegravir (RAL) remained significantly associated with IRISFRENCH (OR 4·04 (95%CI:1·99-8·19) as well as IRISFRENCH+CLINICAL (OR 3·07, 95%CI:1·66-5·69), while dolutegravir (DTG) became associated with IRISFRENCH+CLINICAL after it replaced RAL as preferred INI in the cohort after 2015 (OR 4·08, 95%CI:0·99-16·82, p=0·052). Too few patients used elvitegravir to draw meaningful conclusions. Steroid initiation for IRIS was more likely in those who initiated INI versus in those who did not, but no increased hospital (re)admission or mortality rates were observed.InterpretationIn HIV late presenters from a resource rich setting, INI based treatment initiation increased the risk of IRIS. This was observed for RAL and DTG when being initiated as preferential INI in the presence of specific AIDS-conditions, indicative of channeling bias. Although we controlled for all relevant measured confounders, we cannot exclude that the observed association is partially explained by residual confounding. INI use was not associated with mortality nor hospitalization. Therefore, our observation is no reason to avoid INI in late presenters.FundingThe ATHENA database is maintained by Stichting HIV Monitoring and supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment.

Project description:To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in gut-associated lymphoid tissue.Profibrotic changes within the secondary lymphoid organs and mucosa have been implicated in failed immune reconstitution following effective combination antiretroviral therapy (cART). Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are nonprofessional antigen-presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen.Duodenal biopsies, obtained from patients naive to cART, underwent trichrome staining and were examined for tissue growth factor-beta (TGF-?) expression. Combined immunostaining and second harmonic generation analysis were used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine IMF activation and Toll-like receptor (TLR)4 expression. Finally, primary IMF cultures were stimulated with lipopolysaccharide to demonstrate the expression of the inflammatory biomarkers.The expression of the fibrosis-promoting molecule, TGF-?1, is significantly increased in duodenal biopsies from HIV patients naïve to cART, and negatively correlated with subsequent peripheral CD4(+) recovery. The increase in TGF-?1 coincided with an increase in collagen deposition in the duodenal mucosa in the tissue area adjacent to the IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-?1, and interleukin-6.Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes, and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients.

Dataset Information

Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.

Publications

Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.

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