Immune Reconstitution Inflammatory Syndrome Events Research Articles

Therapeutic effectiveness on early and delayed treatment of antiretroviral in TB-HIV patients: a literature review

Introduction: Indonesia is one of the countries with a high TB-HIV prevalence. Antiretroviral treatment (ART) is only being administered to approximately 42% of TB-HIV patients. The low utilization of ART can be attributed, in part, to the delayed initiation of treatment. Nonetheless, starting ART in these people at an early stage poses risks, owing to the increased likelihood of drug-drug interactions and the manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS) side effects when combined with anti-TB medication. Postponing ART, on the other hand, can hasten illness progression and increase the risk of death. Methods: A literature review was conducted to assess the effects of early ART (within four weeks of getting anti-TB) against delayed ART initiation (at least eight weeks after receiving anti-TB) in individuals co-infected with TB and HIV. The data was obtained by a comprehensive electronic search using the PubMed and Science Direct databases. Results: The findings of our study suggest that there was no statistically significant disparity in mortality rates between the early ART group and the delayed ART group. The initial ART cohort had a markedly elevated susceptibility to encountering an IRIS occurrence, particularly among individuals with a CD4 count below 50 cells per cubic millimeter. Conclusion: In summary, the strategy of delaying the initiation of ART in patients co-infected with TB-HIV is seen as preferable when compared to the approach of early treatment. The frequency of IRIS events is a significant determinant in determining the optimal timing of ART initiation in individuals co-infected with TB-HIV.

The Effect of Early vs. Deferred Antiretroviral Therapy Initiation in HIV-Infected Patients With Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Analysis in China.

Background: The optimal timing for initiation of antiretroviral therapy (ART) in HIV-positive patients with cryptococcal meningitis (CM) has not, as yet, been compellingly elucidated, as research data concerning mortality risk and the occurrence of immune reconstitution inflammatory syndrome (IRIS) in this population remains inconsistent and controversial.Method: The present multicenter randomized clinical trial was conducted in China in patients who presented with confirmed HIV/CM, and who were ART-naïve. Subjects were randomized and stratified into either an early-ART group (ART initiated 2–5 weeks after initiation of antifungal therapy), or a deferred-ART group (ART initiated 5 weeks after initiation of antifungal therapy). Intention-to-treat, and per-protocol analyses of data for these groups were conducted for this study.Result: The probability of survival was found to not be statistically different between patients who started ART between 2–5 weeks of CM therapy initiation (14/47, 29.8%) vs. those initiating ART until 5 weeks after CM therapy initiation (10/55, 18.2%) (p = 0.144). However, initiating ART within 4 weeks after the diagnosis and antifungal treatment of CM resulted in a higher mortality compared with deferring ART initiation until 6 weeks (p = 0.042). The incidence of IRIS did not differ significantly between the early-ART group and the deferred-ART group (6.4 and 7.3%, respectively; p = 0.872). The percentage of patients with severe (grade 3 or 4) adverse events was high in both treatment arms (55.3% in the early-ART group and 41.8% in the deferred-ART group; p=0.183), and there were significantly more grade 4 adverse events in the early-ART group (20 vs. 13; p = 0.042).Conclusion: Although ART initiation from 2 to 5 weeks after initiation of antifungal therapy was not significantly associated with high cumulative mortality or IRIS event rates in HIV/CM patients compared with ART initiation 5 weeks after initiation of antifungal therapy, we found that initiating ART within 4 weeks after CM antifungal treatment resulted in a higher mortality compared with deferring ART initiation until 6 weeks. In addition, we observed that there were significantly more grade 4 adverse events in the early-ART group. Our results support the deferred initiation of ART in HIV-associated CM.Clinical Trials Registration: www.ClinicalTrials.gov, identifier: ChiCTR1900021195.

High Levels of TNF-α and TIM-3 as a Biomarker of Immune Reconstitution Inflammatory Syndrome in People with HIV Infection.

Immune reconstitution inflammatory syndrome (IRIS) is an exacerbated immune response that can occur to HIV+ patients after initiating antiretroviral therapy (ART). IRIS pathogenesis is unclear, but dysfunctional and exhausted cells have been reported in IRIS patients, and the TIM-3/Gal-9 axis has been associated with chronic phases of viral infection. This study aimed to evaluate the soluble levels of TIM-3 and Gal-9 and their relationship with IRIS development. TIM-3, Gal-9, TNF-α, IFN-γ, IL-6, TNFR1, TNFR2, E-cadherin, ADAM10, and ADAM17 were measured to search for IRIS-associated biomarkers in plasma samples from 0-, 4-, 8-, 12-, and 24-weeks after ART initiation of 61 HIV+ patients (15 patients developed IRIS, and 46 did not). We found that patients who developed IRIS had higher levels of TIM-3 [median 4806, IQR: 3206–6182] at the time of the IRIS events, compared to any other follow-up time evaluated in these patients or compared with a control group of patients who did not develop IRIS. Similarly, IRIS patients had a higher TNF-α level [median 10.89, IQR: 8.36–12.34] at IRIS events than any other follow-up time evaluated. Other molecules related to the TIM-3 and TNF-α pathway (Gal-9, IL-6, IFN-γ, TNFR1, TNFR2, ADAM-10, and ADAM-17) did not change during the IRIS events. In conclusion, our data suggest that a high level of soluble TIM-3 and TNF-α could be used as an IRIS biomarker.

Prospective International Study of Incidence and Predictors of Immune Reconstitution Inflammatory Syndrome and Death in People Living With Human Immunodeficiency Virus and Severe Lymphopenia.

Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation. We investigated the clinical impact of IRIS in PLWH and CD4 counts <100 cells/μL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models. We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/μL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2; P = .004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2; P = .031). Being female (P = .004) and having a lower body mass index (BMI; P = .003), higher white blood cell count (P = .005), and higher D-dimer levels (P = .044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin <8.5 g/dL as predictive of IRIS and C-reactive protein (CRP) >106 μg/mL and BMI <15.6 kg/m2 as predictive of death. For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk.

An Exclusively Skewed Distribution of Pediatric Immune Reconstitution Inflammatory Syndrome Toward the Female Sex Is Associated With Advanced Acquired Immune Deficiency Syndrome.

In human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) patients with very low CD4 cell counts, there is a temporal relationship between administration of antiretroviral therapy (ART) and an increased inflammatory response state known as the immune reconstitution inflammatory syndrome (IRIS). The predominant clinical presentation of IRIS is an infectious disease that can be life-threatening. IRIS-related infectious events are distributed similarly between adult males and females, albeit a few studies have shown a skewing toward the male sex in pediatric IRIS. Here, we assessed sex-specific differences in the causes and extent of IRIS infectious events in HIV-infected pediatric patients on ART. We carried out a prospective clinical analysis (from 2000 to 2018) of IRIS-related infectious events after ART in a cohort of 82 Brazilian children and adolescents infected with HIV-1 through mother-to-child transmission as well as a comprehensive cross-referencing with public records on IRIS-related infectious causes in pediatric HIV/AIDS. Twelve events fulfilling the criteria of IRIS occurred exclusively in 11 females in our cohort. The median age at IRIS events was 3.6 years. The infectious causes included Mycobacterium bovis, varicella-zoster virus, molluscum contagiosum virus, human papillomavirus, cytomegalovirus, and Mycobacterium tuberculosis. In one female, there was regional bacillus Calmette-Guérin dissemination and cytomegalovirus esophagitis. There was complete health recovery after 10 IRIS events without the use of corticosteroids or ART interruption. One case of IRIS-associated miliary tuberculosis was fatal. The biological female sex was a significant risk factor for IRIS events (odds ratio: 23.67; 95% confidence interval 95%: 1.341–417.7; P = 0.0016 and P < 0.01 by the multivariable analysis). We observed an effect of the advanced HIV/AIDS variable in IRIS females as compared with non-IRIS females (mean CD4+ T cell percentage 13.36 vs. 18.63%; P = 0.0489 and P < 0.05 by the multivariable analysis), underpinning the exclusively skewed distribution toward the female sex of this cohort. Moreover, the IRIS females in our cohort had higher mean CD4+ T cell percentages before (13.36%) and after IRIS (26.56%) than those of the IRIS females (before IRIS, 4.978%; after IRIS, 13.81%) in previous studies conducted worldwide. The exclusively skewed distribution of pediatric IRIS toward the female sex in the cohort was not linked to preferential X-chromosome inactivation rates. We concluded that the exclusively skewed distribution of pediatric IRIS toward females is associated with more advanced AIDS.

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis.

BackgroundThere remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV‐positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced.ObjectivesTo compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV‐positive people with concurrent cryptococcal meningitis.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies.Selection criteriaWe included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV‐positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion.Data collection and analysisTwo review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time‐to‐death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach.Main resultsFour trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low‐ and middle‐income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used.Early ART initiation may increase all‐cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low‐certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low‐certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I2 = 54%; very low‐certainty evidence). We are uncertain if early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (RR 0.93, 95% CI 0.72 to 1.22; 205 participants, 2 trials; I2 statistic = 0%; very low‐certainty evidence).We were unable to pool results related to rate of fungal clearance for the two trials that reported this outcome; individual trial results indicated that there was no difference in cerebrospinal fluid fungal clearance between trial arms. Similarly, we were unable to pool results on adverse events for the trials reporting on this outcome; individual trial results indicated no difference in the occurrence of grade 3 to 5 adverse events between trial arms.Three of the four included trials had an overall low or unclear risk of bias related to the primary outcome of all‐cause mortality. However, we assessed one trial as at high risk of bias due to selective outcome reporting and other bias. This, in addition to the few clinical events and imprecision of effect estimates, led to downgrading of the evidence to low or very low certainty.Authors' conclusionsThe results of this review are relevant to HIV‐positive adults with cryptococcal meningitis in low‐ and middle‐income countries. These data suggest a higher risk of mortality among people who initiate ART within four weeks of cryptococcal meningitis diagnosis. However, it is unclear if this higher mortality risk is related to cryptococcal meningitis‐IRIS.11 April 2019Up to dateAll studies incorporated from most recent searchAll eligible published studies found in the last search (7 Aug, 2017) were included

Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease.

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

The Epidemiology of IRIS in Southern India: An Observational Cohort Study.

Immune reconstitution inflammatory syndrome (IRIS) is an uncommon but dynamic phenomenon seen among patients initiating antiretroviral therapy (ART). We aimed to describe incidence, risk factors, clinical spectrum, and outcomes among ART-naive patients experiencing IRIS in southern India. Among 599 eligible patients monitored prospectively between 2012 and 2014, there were 59.3% males, with mean age 36.6 ± 7.8 years. Immune reconstitution inflammatory syndrome incidence rate was 51.3 per 100 person-years (95% confidence interval: 44.5-59.2). One-third (31.4%) experienced at least 1 IRIS event, at a median of 27 days since ART initiation. Mucocutaneous infections and candidiasis were common IRIS events, followed by tuberculosis. Significant risk factors included age >40 years, body mass index <18.5 kg/m2, CD4 count <100 cells/mm3, viral load >10 000 copies/mL, hemoglobin <11 g/dL, and erythrocyte sedimentation rate >50 mm/h. Immune reconstitution inflammatory syndrome-related morality was 1.3% (8 of 599); 3 patients died of complicated diarrhea. These findings highlight the current spectrum of IRIS in South India and underscore the importance of heightened vigilance for anemia and treatment of diarrhea and candidiasis during ART initiation.

Risk Factors and Frequency of Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome among HIV/Tuberculosis Co-infected Patients in Southern India

Immune reconstitution inflammatory syndrome (IRIS) continues to be a complication in HIV/tuberculosis (TB) co-infected patients initiating highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the risk factors associated with developing IRIS to identify a possible biomarker to predict or diagnose IRIS in patients initiating HAART. A total of 175 HIV/TB co-infected patients initiating HAART were followed up longitudinally during September 2010 to May 2013 attending a HIV care clinic in Chennai. Patients were followed up longitudinally after HAART initiation and baseline demographic, laboratory parameters and treatment characteristics between patients with IRIS events and those without IRIS events were compared. Chi-square or Fisher’s exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables were performed using SPSS, version 12.0 software. Patients with IRIS had a significantly lower median baseline CD4+ T-cell count (P = 0.0039). There were no differences in terms of sex, CD4 T-cell %, plasma viral load, time interval between initiating ATT and HAART between the IRIS and non-IRIS patients. Low CD4+ T-cell count (<100 cells/μL) could be used as a marker to screen and monitor patients initiating HAART.

Biomarkers for Identifying Risk of Immune Reconstitution Inflammatory Syndrome

Biomarkers for Identifying Risk of Immune Reconstitution Inflammatory Syndrome

Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial

Immune Reconstitution Inflammatory Syndrome (IRIS) is a common complication of antiretroviral therapy (ART) in HIV-infected patients. IRIS is associated with an increased risk of hospitalization and death. We ascertained whether CCR5 blockade using maraviroc reduces the risk of IRIS. The CADIRIS study was a randomized, double-blind, placebo-controlled, clinical trial that accrued subjects from five clinical sites in Mexico and one in South Africa between November 2009 and January 2012, and followed them for one year. The primary outcome was occurrence of IRIS by 24 weeks. HIV-infected adults, naïve to ART, with CD4 cells <100/μL, and HIVRNA >1,000 copies/mL were eligible. We screened 362 subjects; 279 met inclusion criteria, 3 refused participation, and 276 were randomized. Participants received maraviroc 600 mg twice daily or placebo added to an ART regimen that included tenofovir, emtricitabine, and efavirenz for 48 weeks. There were 276 patients randomized (140 received maraviroc and 136 placebo). There was no difference in the time to IRIS events between treatment arms (HR 1·08, 95% CI (0·66, 1·77), log-rank test p=0·743). In total, 64 (23%) patients had IRIS events, 33 (24%) in the maraviroc arm and 31 (23%) in the placebo arm (p=0·88). Maraviroc had no significant effect on frequency, time or severity of IRIS events after ART initiation. Including a CCR5 inhibitor in an initial treatment regimen does not confer a meaningful protection from the occurrence of IRIS in persons with advanced HIV infection. The trial was funded as investigator initiated research by Pfizer Inc, New York, NY, USA. ClinicalTrials.gov. ID: NCT00988780 (http://clinicaltrials.gov/ct2/show/NCT00988780).

English

BACKGROUND & OBJECTIVES: It is estimated that 10-25% of patients who are started on HAART, experience Immune Reconstitution Inflammatory Syndrome (IRIS). This clinical deterioration is a result of an exuberant inflammatory response towards previously diagnosed or incubating opportunistic pathogens as well as response towards undefined antigens. Thus study was carried out with objectives to determine incidence, clinical spectrum & the risk factors of IRIS in HIV patients initiating HAART, registered in ART clinic. METHODS: Prospective study of 118 HIV positive patients (all HIV-1) attending ART clinic between Nov. 2006 & Aug. 2007 was carried out at Government medical college, Nagpur. Patients were investigated as per standard protocol. CD4 cell counts were performed on the blood samples (FACS calibur, Becton- Dickinson, Immunocytometry system). Clinical follow up was done every 15 days as per the NACO guidelines. Base line & follow up values of CD4 counts were compared to assess the IRIS events. The patients presented with opportunistic infections, they were first treated for opportunistic infections & subsequently HAART was initiated as per NACO guidelines. RESULTS: Out of 118 HIV positive patients, 112 patients were started on HAART. Out of Fifty nine patients who came for the regular clinical follow up when followed over a period of 10 months, 8 patients (13.56%) experienced IRIS infections. Mean+SEM of baseline CD4 count in IRIS was 85.75+20.84/μl at the time of initiation of HAART while for patients without IRIS was 151.7+12.45 cells/ μl (Significant 'p' value 0.0480). Mean+SEM of increase in CD4 count after HAART in IRIS patients was 76.88 + 29.13/μl while for patients without IRIS after HAART initiation was found to be 181.8+18.92/μl (Significant 'p' value 0.0379). Mean duration of development of IRIS in 8 cases after HAART was about 47.25 days. Infections in 8 IRIS patients were extra-pulmonary Mycobacterium tuberculosis, Cryptococcal meningitis, Herpes Zoster, Cytomegalovirus retinitis & oral candidiasis as single or in mixed form. Six IRIS cases experienced reactivation of dormant infection & 2 cases showed new infections. INTERPRETATION & CONCLUSION: In present study, high incidence of IRIS was found with male preponderance mostly with reactivation of occult infections. Risk factor for development of IRIS was found to be baseline CD4 cell count less than 100/ µl. So, we suggest that occurrence of IRIS infections can be prevented or reduced by initiating HAART before CD4 cell count drops below 100 cells/μl.

Early development of immune reconstitution inflammatory syndrome related to Pneumocystis pneumonia after antiretroviral therapy

Immune reconstitution inflammatory syndrome is a recognized complication after the initiation of combination antiretroviral therapy (cART). We report a patient who developed life-threatening pulmonary immune reconstitution inflammatory syndrome (IRIS) three days after initiation of cART. We reviewed published cases of IRIS after Pneumocystis pneumonia (PCP), in particular the time from initiation of cART to IRIS event. The median duration from the initiation of cART to the onset of IRIS was 15 days in the 33 patients reviewed. This report alerts clinicians to the rapidity of the development of pulmonary IRIS following PCP after the initiation of cART.

Impact of immune reconstitution inflammatory syndrome on antiretroviral therapy adherence

ObjectiveWe determined the impact of immune reconstitution inflammatory syndrome (IRIS) on antiretroviral therapy (ART) adherence in a cohort of 274 human immunodeficiency virus (HIV)-infected South African adults initiating ART.MethodsWe carried out a secondary analysis of data from a randomized controlled trial of partially supervised ART in Cape Town, South Africa. Monthly pill count adherence, viral suppression (HIV viral load < 50 c/mL), and IRIS events were documented. Poisson regression was used to identify variables associated with ART adherence below the median in the first 6 months of ART.ResultsWe enrolled 274 patients: 58% women, median age 34 years, median CD4 count 98 cells/μL, 46% World Health Organization clinical stage IV, and 40% on treatment for tuberculosis (TB). IRIS and TB-IRIS developed in 8.4% and 6.6% of patients, respectively. The median cumulative adherence at 6 months for those with an IRIS event vs no IRIS was 95.5% vs 98.2% (P = 0.04). Although not statistically significant, patients developing IRIS had a lower 6-month viral load suppression than those without IRIS (68% vs 80%, P = 0.32). ART adherence below the median of 98% was independently associated with alcohol abuse (relative risk [RR] 1.5; 95% confidence interval [CI] 1.2–1.9; P = 0.003) and IRIS events (RR 1.7; 95% CI 1.2–2.2; P = 0.001).ConclusionAlthough IRIS events were associated with slightly lower adherence rates, overall adherence to ART remained high in this study population. Concerns about IRIS should not deter clinicians from early ART initiation.

Incidence, Clinical Spectrum, Risk Factors and Impact of HIV-Associated Immune Reconstitution Inflammatory Syndrome in South Africa

BackgroundImmune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa.Methods and Findings498 adults initiating ART in Durban, South Africa were followed prospectively for 24 weeks. IRIS diagnosis was based on consensus expert opinion, and classified by mode of presentation (paradoxical worsening of known opportunistic infection [OI] or unmasking of subclinical disease). 114 patients (22.9%) developed IRIS (36% paradoxical, 64% unmasking). Mucocutaneous conditions accounted for 68% of IRIS events, mainly folliculitis, warts, genital ulcers and herpes zoster. Tuberculosis (TB) accounted for 25% of IRIS events. 18/135 (13.3%) patients with major pre-ART OIs (e.g. TB, cryptococcosis) developed paradoxical IRIS related to the same OI. Risk factors for this type of IRIS were baseline viral load >5.5 vs. <4.5 log10 (adjusted hazard ratio 7.23; 95% confidence interval 1.35–38.76) and ≤30 vs. >30 days of OI treatment prior to ART (2.66; 1.16–6.09). Unmasking IRIS related to major OIs occurred in 25/498 patients (5.0%), and risk factors for this type of IRIS were baseline C-reactive protein ≥25 vs. <25 mg/L (2.77; 1.31–5.85), haemoglobin <10 vs. >12 g/dL (3.36; 1.32–8.52), ≥10% vs. <10% weight loss prior to ART (2.31; 1.05–5.11) and mediastinal lymphadenopathy on pre-ART chest x-ray (9.15; 4.10–20.42). IRIS accounted for 6/25 (24%) deaths, 13/65 (20%) hospitalizations and 10/35 (29%) ART interruptions or discontinuations.ConclusionIRIS occurred in almost one quarter of patients initiating ART, and accounted for one quarter of deaths in the first 6 months. Priority strategies to reduce IRIS-associated morbidity and mortality in ART programmes include earlier ART initiation before onset of advanced immunodeficiency, improved pre-ART screening for TB and cryptococcal infection, optimization of OI therapy prior to ART initiation, more intensive clinical monitoring in initial weeks of ART, and education of health care workers and patients about IRIS.

859 Dermatologic Immune Reconstitution Inflammatory Syndrome (IRIS) In Children Receiving Art from a Community Outreach Program in Kampala

BackgroundOrikiriiza (2011) demonstrated that dermatological manifestations were the most common IRIS events in children receiving ART. We aimed to find the incidence of dermatological-IRIS in children receiving ART for at...

Immune reconstitution inflammatory syndrome in a large multicenter cohort study: case definition and comparability

Evaluation of: Novak RM, Richardson JT, Buchacz K et al.; HIV Outpatient Study (HOPS) Investigators. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS 26(6), 721–730 (2012).This study was nested within the HIV Outpatient Study cohort and investigated the incidence and risk factors for immune reconstitution inflammatory syndrome (IRIS) and the impact of IRIS on mortality. IRIS was defined as a new type B or C AIDS-defining condition or one of a range of mucocutaneous or autoimmune conditions diagnosed within 180 days of starting a new combination antiretroviral therapy regimen, provided there was a documented HIV viral load or CD4 response. IRIS occurred in 10.6% of the 2610 patients. Risk factors independently associated with IRIS included high HIV viral load and low CD4 count. IRIS related to type B or C AIDS-defining conditions was associated with subsequent mortality. Deaths among IRIS cases occurred over 3 years (median) after the IRIS event, making it unlikely that these deaths were directly attributable to IRIS. The IRIS case definition used has important differences when compared with previously published IRIS case definitions thereby affecting comparability of these findings, but this was a pragmatic definition for a large multicenter cohort study utilizing a central database.

Selective expansion of polyfunctional pathogen-specific CD4+ T cells in HIV-1–infected patients with immune reconstitution inflammatory syndrome

AbstractSince the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied. We hypothesized that there is a common mechanism underlying IRIS pathogenesis and investigated a patient group with IRIS related to different pathogens. Functional and phenotypic characterization of PBMC samples was performed by polychromatic flow cytometry after in vitro stimulation with relevant antigenic preparations. In most patients, IRIS events were characterized by the robust increase of preexisting polyfunctional, highly differentiated effector CD4+ T-cell responses that specifically targeted the antigens of the underlying co-infection. T-cell responses to HIV-1 or other underlying infections were not affected and did not differ between IRIS and non-IRIS patients. These data suggest that patients with IRIS do not have a generalized T-cell dysfunction; instead, IRIS represents a dysregulated CD4+ T-cell response against residual opportunistic infection antigen. These studies were registered at www.clinical-trials.gov as NCT00557570 and NCT00286767.

Integration of Antiretroviral Therapy with Tuberculosis Treatment

We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006). Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.).

Incidence and Predictors of Immune Reconstitution Inflammatory Syndrome in a Rural Area of Mozambique

BackgroundThere is limited data on the epidemiology of Immune Reconstitution Inflammatory Syndrome (IRIS) in rural sub-Saharan Africa. A prospective observational cohort study was conducted to assess the incidence, clinical characteristics, outcome and predictors of IRIS in rural Mozambique.MethodsOne hundred and thirty-six consecutive antiretroviral treatment (ART)-naïve HIV-1-infected patients initiating ART at the Manhiça district hospital were prospectively followed for development of IRIS over 16 months. Survival analysis by Cox regression was performed to identify pre-ART predictors of IRIS development.ResultsThirty-six patients developed IRIS [26.5%, incidence rate 3.1 cases/100 persons-month of ART (95% CI 2.2–4.3)]. Median time to IRIS onset was 62 days from ART initiation (IQR 35.5–93.5). Twenty-five cases (69.4%) were “unmasking”, 10 (27.8%) were “paradoxical”, and 1 (2.8%) developed a paradoxical worsening followed by the unmasking of another condition. Systemic OI (OI-IRIS) accounted for 47% (17/36) of IRIS cases, predominantly of KS (8 cases) and TB (6 cases) IRIS. Mucocutaneous IRIS manifestations (MC-IRIS) accounted for 53% (19/36) of IRIS events, mostly tinea (9 cases) and herpes simplex infection (3 cases). Multivariate analysis identified two independent predictors of IRIS development: pre-ART CD4 count <50 cells/µl (HR 2.3, 95% CI 1.19–4.44, p = 0.01) and body mass index (BMI) <18.5 (HR 2.15, 95% CI 1.07–4.3, p = 0.03). The pre-cART proportion of activated T-cells, as well as the immunologic and virologic response to ART were not associated with IRIS development. All patients continued on ART, 7 (19.4%) required hospitalization and there were 3 deaths (8.3%) attributable to IRIS.ConclusionsIRIS is common in patients initiating ART in rural Mozambique. Pre-ART CD4 counts and BMI can easily be assessed at ART initiation in rural sub-Saharan Africa to identify patients at high risk of IRIS, for whom close supervision is warranted.