Charlotte Schutz

Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis

BACKGROUND Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered. METHODS We assessed survival at 26 weeks among 177 human immunodeficiency virus-infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole. RESULTS The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups. CONCLUSIONS Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.).

Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial.

Background:Interferon-gamma (IFN&ggr;) is of key importance in the immune response to Cryptococcus neoformans. Mortality related to cryptococcal meningitis remains high, and novel treatment strategies are needed. We performed a randomized controlled trial to determine whether addition of IFN&ggr; to standard therapy increased the rate of clearance of cryptococcal infection in HIV-associated cryptococcal meningitis. Methods:Patients were randomized to amphotericin B 1 mg/kg per day and 5FC 100 mg/kg per day for 2 weeks (standard therapy), standard therapy and IFN&ggr;1b 100 &mgr;g days 1 and 3 (IFN&ggr; two doses), or standard therapy and IFN&ggr;1b 100 &mgr;g days 1, 3, 5, 8, 10 and 12 (IFN&ggr; six doses). Primary outcome was rate of clearance of cryptococcus from the cerebrospinal fluid (CSF) (early fungicidal activity, EFA) calculated from serial quantitative cultures, previously shown to be independently associated with survival. Results:Rate of fungal clearance was significantly faster in IFN&ggr; containing groups than with standard treatment. Mean EFA [log colony forming unit (CFU)/ml per day] was −0.49 with standard treatment, −0.64 with IFN&ggr; two doses, and −0.64 with IFN&ggr; six doses. Difference in EFA was −0.15 [confidence interval (95% CI) −0.02 to −0.27, P = 0.02] between standard treatment and IFN&ggr; two doses, and −0.15 (95% CI −0.05 to −0.26, P = 0.006) between standard treatment and IFN&ggr; six doses. Mortality was 16% (14/88) at 2 weeks and 31% (27/87) at 10 weeks, with no significant difference between groups. All treatments were well tolerated. Conclusion:Addition of short-course IFN&ggr; to standard treatment significantly increased the rate of clearance of cryptococcal infection from the CSF, and was not associated with any increase in adverse events. Two doses of IFN&ggr; are as effective as six doses.

Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome.

Tuberculous meningitis (TBM) immune reconstitution inflammatory syndrome is a severe complication of antiretroviral therapy in human immunodeficiency virus–associated TBM. We found that high cerebrospinal fluid neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation characterize, and cytokine concentrations predict, this syndrome.

Multisite Validation of Cryptococcal Antigen Lateral Flow Assay and Quantification by Laser Thermal Contrast

This assay is a major advance in the diagnosis of cryptococcal meningitis.

The Effect of Therapeutic Lumbar Punctures on Acute Mortality From Cryptococcal Meningitis

Intracranial pressure management with repeat lumbar puncture (LP) was investigated in patients with cryptococcal meningitis in sub-Saharan Africa. Conducting at least 1 additional LP soon after cryptococcal diagnosis was related to decreased risk of acute mortality regardless of initial pressure.

Corticosteroid Therapy, Vitamin D Status, and Inflammatory Cytokine Profile in the HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome

Vitamin D deficiency is common in human immunodeficiency virus–tuberculosis coinfected patients in Cape Town. Those who develop tuberculosis-immune reconstitution inflammatory syndrome have a further reduction in circulating 25-hydroxyvitamin D levels 2 weeks into combined antiretroviral therapy with a concomitant increase in inflammatory cytokines and chemokines.

Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting.

Background Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM. Methods A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009–August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions. Results TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08–0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4+ count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03–1.96) per 50 cells/µL drop in CD4+ count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45–15.87). Interpretation Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.

HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

Neutrophil-Associated Central Nervous System Inflammation in Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome

Tuberculous meningitis immune reconstitution inflammatory syndrome (TBM-IRIS) is characterized by severe, compartmentalized cerebral inflammation, involving mediators of innate and adaptive immune responses. A high baseline cerebrospinal fluid bacillary load predisposes to recurrent inflammation during antiretroviral therapy, manifesting as TBM-IRIS.

Rapid microbiological screening for tuberculosis in HIV-positive patients on the first day of acute hospital admission by systematic testing of urine samples using Xpert MTB/RIF: a prospective cohort in South Africa

BackgroundAutopsy studies of HIV/AIDS-related hospital deaths in sub-Saharan Africa reveal frequent failure of pre-mortem diagnosis of tuberculosis (TB), which is found in 34–64 % of adult cadavers. We determined the overall prevalence and predictors of TB among consecutive unselected HIV-positive adults requiring acute hospital admission and the comparative diagnostic yield obtained by screening urine and sputum samples obtained on day 1 of admission with Xpert MTB/RIF (Xpert).MethodsTo determine overall TB prevalence accurately, comprehensive clinical sampling (sputum, urine, blood plus other relevant samples) was done and TB was defined by detection of Mycobacterium tuberculosis in any sample using Xpert and/or mycobacterial liquid culture. To evaluate a rapid screening strategy, we compared the diagnostic yield of Xpert testing sputum samples and urine samples obtained with assistance from a respiratory study nurse in the first 24 h of admission.ResultsUnselected HIV-positive acute adult new medical admissions (n = 427) who were not receiving TB treatment were enrolled irrespective of clinical presentation or symptom profile. From 2,391 cultures and Xpert tests done (mean, 5.6 tests/patient) on 1,745 samples (mean, 4.1 samples/patient), TB was diagnosed in 139 patients (median CD4 cell count, 80 cells/μL). TB prevalence was very high (32.6 %; 95 % CI, 28.1–37.2 %; 139/427). However, patient symptoms and risk factors were poorly predictive for TB. Overall, ≥1 non-respiratory sample(s) tested positive in 115/139 (83 %) of all TB cases, including positive blood cultures in 41/139 (29.5 %) of TB cases. In the first 24 h of admission, sputum (spot and/or induced samples) and urine were obtainable from 37.0 % and 99.5 % of patients, respectively (P <0.001). From these, the proportions of total TB cases (n = 139) that were diagnosed by Xpert testing sputum, urine or both sputum and urine combined within the first 24 h were 39/139 (28.1 %), 89/139 (64.0 %) and 108/139 (77.7 %) cases, respectively (P <0.001).ConclusionsThe very high prevalence of active TB and its non-specific presentation strongly suggest the need for routine microbiological screening for TB in all HIV-positive medical admissions in high-burden settings. The incremental diagnostic yield from Xpert testing urine was very high and this strategy might be used to rapidly screen new admissions, especially if sputum is difficult to obtain.