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Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy.

ABSTRACT: To determine the incidence, clinical manifestations and risk factors for immune reconstitution inflammatory syndrome (IRIS) in young children initiating highly active antiretroviral therapy (HAART).A prospective cohort of antiretroviral-naïve HIV-infected children less than 24 months of age enrolled in a treatment strategies trial in Johannesburg, South Africa.Among 169 HIV-infected children initiating HAART, April 2005 to November 2006, the records of 83 children suspected to have IRIS within 6 months of starting treatment were reviewed to determine whether they met criteria for IRIS. Seven were excluded due to incomplete follow-up. Pretreatment and post-treatment characteristics of children with and without IRIS were compared.Overall, 34/162 (21%) children developed IRIS at a median of 16 days (range 7-115 days) post-HAART initiation. Bacille Calmette-Guérin reaction was most common occurring in 24/34 (71%) children, primarily injection site lesions and/or ipsilateral axillary lymphadenitis with abscess. Other IRIS conditions (not mutually exclusive) included Mycobacterium tuberculosis (n = 12), cytomegalovirus pneumonia (n = 1), Streptococcus pneumonia sepsis (n = 1), and severe seborrheic dermatitis (n = 1). Children with IRIS were younger (median age 7 vs. 10 months, P = 0.007) with a lower CD4 cell percentage (median 13.9 vs. 19.2, P = 0.009) at HAART initiation than controls. After 24 weeks on HAART, 62% of IRIS cases vs. 28% of controls had HIV RNA more than 400 copies/ml (P = 0.001), odds ratio = 2.88 (95% confidence interval = 1.14-7.29) after adjusting for baseline factors.Infants and young children with advanced HIV disease initiating HAART are at high risk for developing IRIS, leading to additional morbidity and possibly impairing virologic response to antiretroviral treatment.

SUBMITTER: Smith K

PROVIDER: S-EPMC2810152 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy.

Smith Kelly K Kuhn Louise L Coovadia Ashraf A Meyers Tammy T Hu Chih-Chi CC Reitz Cordula C Barry Gillian G Strehlau Renate R Sherman Gayle G Abrams Elaine J EJ

AIDS (London, England) 20090601 9

<h4>Objectives</h4>To determine the incidence, clinical manifestations and risk factors for immune reconstitution inflammatory syndrome (IRIS) in young children initiating highly active antiretroviral therapy (HAART).<h4>Design</h4>A prospective cohort of antiretroviral-naïve HIV-infected children less than 24 months of age enrolled in a treatment strategies trial in Johannesburg, South Africa.<h4>Methods</h4>Among 169 HIV-infected children initiating HAART, April 2005 to November 2006, the reco ...[more]

PMID: 19417581

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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:BACKGROUND:Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. METHODS:CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir-ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960. FINDINGS:377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16-25). Time to restarting of ART after interruption was 33 weeks (26-45) in ART-40W and 70 weeks (35-109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38-0·93, p=0·02) for ART-40W and 0·47 (0·27-0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. INTERPRETATION:Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. FUNDING:US National Institutes of Health.

Project description:Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation.We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ?21 years) with advanced HIV (CD4 cell counts ?125 cells per ?L) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or ?(2) tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls.Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18-0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0-80·0]) and tumour necrosis factor (TNF)? (7·8 [1·1-55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2-2·5]) and TNF? (1·5 [1·0-2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3-6·1]), IL-12p40 (1·8 [1·0-3·4]), and IL-15 (2·0 [1·1-3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006).Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis.National Institutes of Health and the Penn Center for AIDS Research.

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Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy.

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Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy.

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