Cause-Specific Mortality and the Contribution of Immune Reconstitution Inflammatory Syndrome in the First 3 Years after Antiretroviral Therapy Initiation in an Urban African Cohort
ABSTRACT Although many studies have reported high early mortality among patients enrolled in antiretroviral therapy (ART) programs in sub-Saharan Africa-particularly among those individuals with advanced immunodeficiency-few studies have reported the most common causes of these early deaths.
We determined cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome (IRIS) in a well-characterized patient cohort in Kampala, Uganda, over a 36-month period of ART.
In a cohort of patients who initiated antiretroviral therapy in Uganda, we observed a high early mortality rate among patients with advanced disease. The most common causes of death were tuberculosis and cryptococcal meningitis. The contribution of immune reconstitution inflammatory syndrome to mortality was limited.
We show a significant early mortality in our ART cohort in resource-limited settings that is driven by advanced human immunodeficiency virus disease and characterized by low CD4 cell counts. In our experience, the contribution of IRIS to this observed early mortality is limited.
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ABSTRACT: Amphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa. Human immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001-2002, and universal in 2006-2012. In 2001-2009, serum potassium (K(+)) was monitored on days 1, 7, and 14 of treatment with replacement (K(+), Mg(2+)) per clinician discretion. In 2011-2012, K(+) was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K(+), Mg(2+)) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies. With limited intravenous fluids, the 14-day survival was 49% in 2001-2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006-2010 (P = .003). In 2011-2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006-2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011-2012 with universal supplementation (P < .001). Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K(+), Mg(2+)), as part of comprehensive amphotericin-based cryptococcal therapy.07/2014; 1(2):ofu070-ofu070. DOI:10.1093/ofid/ofu070
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ABSTRACT: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16- monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.PLoS Pathogens 10/2014; 10:e1004433. DOI:10.1371/journal.ppat.1004433 · 8.06 Impact Factor
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ABSTRACT: To demonstrate the feasibility of integrated screening for cryptococcal antigenemia and tuberculosis (TB) before antiretroviral therapy (ART) initiation and to assess disease specific and all-cause mortality in the first 6 months of follow-up. We enrolled a cohort of HIV-infected, ART-naive adults with CD4 counts ≤250 cells per microliter in rural Uganda who were followed for 6 months after ART initiation. All subjects underwent screening for TB; those with CD4 ≤100 cells per microliter also had cryptococcal antigen (CrAg) screening. For those who screened positive, standard treatment for TB or preemptive treatment for cryptococcal infection was initiated, followed by ART 2 weeks later. Of 540 participants enrolled, pre-ART screening detected 10.6% (57/540) with prevalent TB and 6.8% (12/177 with CD4 count ≤100 cells/μL) with positive serum CrAg. After ART initiation, 13 (2.4%) patients were diagnosed with TB and 1 patient developed cryptococcal meningitis. Overall 7.2% of participants died (incidence rate 15.6 per 100 person-years at risk). Death rates were significantly higher among subjects with TB and cryptococcal antigenemia compared with subjects without these diagnoses. In multivariate analysis, significant risk factors for mortality were male sex, baseline anemia of hemoglobin ≤10 mg/dL, wasting defined as body mass index ≤15.5 kg/m, and opportunistic infections (TB, positive serum CrAg). Pre-ART screening for opportunistic infections detects many prevalent cases of TB and cryptococcal infection. However, severely immunosuppressed and symptomatic HIV patients continue to experience high mortality after ART initiation.JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2015; 68(5):1. DOI:10.1097/QAI.0000000000000527 · 4.39 Impact Factor