Integrase Strand Transfer Inhibitors and the Emergence of Immune Reconstitution Inflammatory Syndrome (IRIS)

Psichogiou, Mina; Basoulis, Dimitrios; Tsikala‐Vafea, Maria; Vlachos, Stefanos; Kapelios, Christos; Daikos, Georgios

doi:10.2174/1570162x15666171122155708

Cited by 30 publications

(34 citation statements)

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“…First-line INSTI ART regimens are associated with a higher incidence of immune reconstitution immunodeficiency syndrome (IRIS) (142, 143). IRIS, that can worsen existing opportunistic infections or unmask previously subclinical infections, very commonly M.tb , is associated with redistribution and restoration of functional memory T cells within the first months of ART (144).…”

Section: Specific Considerations/limitationsmentioning

confidence: 99%

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

et al. 2019

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Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4 + T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4 + T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4 + T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4 + T cells from naïve cells, it is essential for the further transition of effectors to memory CD4 + T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4 + T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127 + CD4 + memory T cells increases, indicating restoration of effector to memory transition in CD4 + T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4 + T cells transition to long-lived, CD127 + CD4 + T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4 + T cell memory formation will limit the generation of long-lived HIV-infected CD4 + T cells and reduce the overall size of the stable HIV-1 reservoir.

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Section: Specific Considerations/limitationsmentioning

confidence: 99%

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

et al. 2019

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“…5 One factor that may have contributed to the high incidence of PML-IRIS was the high proportion of all patients who were treated with integrase strand transfer inhib-itors (INSTIs; 11 of 26, 42%), which have been previously shown to be associated with higher incidence of IRIS, felt to be related to the rapid decline in plasma HIV viral load. 19 INSTIs have been observed to have excellent CNS penetrance, 20 which has been shown to be associated with improved rates of HIV viral suppression within the CSF. 21 Unfortunately, viral suppression in the CSF has not correlated well with incident AIDS-defining neurological conditions, 22 so the adjustment of an ART regimen based on concern for PML or PML-IRIS is not supported at this time.…”

Section: Discussionmentioning

confidence: 99%

Not a Disease of the Past: A Case Series of Progressive Multifocal Leukoencephalopathy in the Established Antiretroviral Era

Summers

Kelley

Armstrong

et al. 2019

AIDS Research and Human Retroviruses

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Progressive multifocal leukoencephalopathy (PML) and PML immune reconstitution inflammatory syndrome (PML-IRIS) can be devastating neurological processes associated with HIV, but limited knowledge of their characteristics in the established antiretroviral therapy (ART) era is available. We conducted a case series to evaluate the clinical course of PML and PML-IRIS at our urban safety-net hospital in Atlanta, GA. All HIV-positive individuals with a positive John Cunningham virus DNA polymerase chain reaction in the spinal fluid between were identified from the electronic health records (EHRs) using the HIV Disease Registry. Demographics, symptom presentation, laboratory data, imaging results, treatment, and outcomes were abstracted from the EHR. PML and PML-IRIS were defined using the American Association of Neurology criteria. Of the 32 individuals identified, 6 (19%) were felt to have asymptomatic positive results. Of the remainder, 15 (58%) HIV-positive patients had PML and 11 (42%) PML-IRIS (2 with an unmasking presentation and 9 with a paradoxical presentation). The most common presenting symptoms were motor weakness (18, 69%), cognitive deficits (15, 58%), and dysarthria (11, 42%). Corticosteroids were used in 12 patients and maraviroc in 3 patients. Outcomes were dismal with 7 (47%) patients with PML and 9 (82%) with PML-IRIS dying or being referred to hospice, with median survival times of 266 days in the PML group and 109 days in the PML-IRIS group. Despite widespread access to ART, patients with PML continue to have poor outcomes, particularly among those who develop PML-IRIS. More research is needed to understand the risks for and prevention of PML-IRIS.

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“…The question of whether integrase inhibitors increase the risk of paradoxical TB-IRIS as they result in a more rapid decline in HIV viral load has arisen with increasing use of integrase inhibitors in first-line ART regimens. Observational studies have reported an association with all-cause IRIS [ 22 , 23 ]. A recent meta-analysis addressing Dolutegravir use did not find an association with IRIS [ 24 ].…”

Section: Paradoxical Tuberculosis-associated Immune Reconstitution Inmentioning

confidence: 99%

The tuberculosis-associated immune reconstitution inflammatory syndrome

Walker

Stek

Wasserman

et al. 2018

Current Opinion in HIV and AIDS

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Purpose of reviewAntiretroviral therapy (ART) is an essential, life-saving intervention for HIV infection. However, ART initiation is frequently complicated by the tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in TB endemic settings. Here, we summarize the current understanding highlighting the recent evidence.Recent findingsThe incidence of paradoxical TB-IRIS is estimated at 18% (95% CI 16–21%), higher than previously reported and may be over 50% in high-risk groups. Early ART initiation in TB patients increases TB-IRIS risk by greater than two-fold, but is critical in TB patients with CD4 counts less than 50 cells/μl because it improves survival. There remains no validated diagnostic test for TB-IRIS, and biomarkers recently proposed are not routinely used. Prednisone initiated alongside ART in selected patients with CD4 less than 100 cells/μl reduced the risk of paradoxical TB-IRIS by 30% in a recent randomized-controlled trial (RCT) and was not associated with significant adverse effects. Effective also for treating paradoxical TB-IRIS, corticosteroids remain the only therapeutic intervention for TB-IRIS supported by RCT trial data. TB-IRIS pathogenesis studies implicate high antigen burden, innate immune cell cytotoxicity, inflammasome activation and dysregulated matrix metalloproteinases in the development of the condition.SummarySpecific biomarkers would aid in identifying high-risk patients for interventions and a diagnostic test is needed. Clinicians should consider prednisone for TB-IRIS prevention in selected patients. Future research should focus on improving diagnosis and investigating novel therapeutic interventions, especially for patients in whom corticosteroid therapy is contraindicated.

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Integrase Strand Transfer Inhibitors and the Emergence of Immune Reconstitution Inflammatory Syndrome (IRIS)

Abstract: The use of INSTIs and especially DTG and EVG is associated with a higher probability for the development of IRIS in the background of late presentation and the presence of OIs. These data highlight the need for further research.

Cited by 30 publications

References 0 publications

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

Not a Disease of the Past: A Case Series of Progressive Multifocal Leukoencephalopathy in the Established Antiretroviral Era

The tuberculosis-associated immune reconstitution inflammatory syndrome

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