Transaminitis prevalence among HIV-infected adults eligible for tuberculosis preventive therapy.

OBJECTIVE: To assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting. DESIGN/METHODS: We conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/µl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption. RESULTS: Among 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant. CONCLUSION: Prevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.

Point-of-care C-reactive protein and risk of early mortality among adults initiating antiretroviral therapy.

OBJECTIVES: In resource-limited settings, mortality in the initial months following antiretroviral therapy (ART) initiation remains unacceptably high. Novel tools to identify patients at highest risk of poor outcomes are needed. We evaluated whether elevated C-reactive protein (CRP) concentrations predict poor outcomes among people living with HIV (PLWH) initiating ART. METHODS: We enrolled and followed for 3-months consecutive PLWH with pre-ART CD4 T-cell counts 350 cells/µl or less initiating ART from two HIV clinics in Uganda. Pre-ART CRP concentrations were measured from capillary blood using a point-of-care (POC) assay. After excluding patients with prevalent tuberculosis - the leading cause of HIV death - we measured 3-month mortality rates using Kaplan-Meier curves, used Cox regression to compare differences in survival, and used logistic regression to compare differences in the odds of opportunistic infections, between patients with and without elevated POC CRP (≥8 mg/l). RESULTS: Of 1293 patients included [median CD4 T-cell count 181 (interquartile range 82-278)], 23 (1.8%) died within 3 months, including 19 of 355 (5.4%) with elevated POC CRP and four of 938 (0.4%) with nonelevated POC CRP. Eighty-six (6.7%) patients were diagnosed with opportunistic infections, including 39 of 355 (11.0%) with elevated POC CRP and 47 of 938 (5.0%) with nonelevated POC CRP. Elevated POC CRP was associated with mortality (adjusted hazard ratio 10.87, 95% confidence interval 3.64-32.47) and opportunistic infection (adjusted odds ratio 1.95, 95% confidence interval 1.23-3.07). CONCLUSION: Among PLWH with advanced HIV, elevated pre-ART POC CRP concentrations are associated with early mortality and opportunistic infections. Pre-ART POC CRP testing may reduce mortality by identifying patients at high risk for poor outcomes.

Yield and Efficiency of Novel Intensified Tuberculosis Case-Finding Algorithms for People Living with HIV.

RATIONALE: The recommended tuberculosis (TB) intensified case finding (ICF) algorithm for people living with HIV (symptom-based screening followed by Xpert MTB/RIF [Xpert] testing) is insufficiently sensitive and results in unnecessary Xpert testing. OBJECTIVES: To evaluate whether novel ICF algorithms combining C-reactive protein (CRP)-based screening with urine Determine TB-LAM (TB-LAM), sputum Xpert, and/or sputum culture could improve ICF yield and efficiency. METHODS: We compared the yield and efficiency of novel ICF algorithms inclusive of point-of-care CRP-based TB screening and confirmatory testing with urine TB-LAM (if CD4 count ≤100 cells/µl), sputum Xpert, and/or a single sputum culture among consecutive people living with HIV with CD4 counts less than or equal to 350 cells/µl initiating antiretroviral therapy in Uganda. MEASUREMENTS AND MAIN RESULTS: Of 1,245 people living with HIV, 203 (16%) had culture-confirmed TB including 101 (49%) patients with CD4 counts less than or equal to 100 cells/µl. Compared with the current ICF algorithm, point-of-care CRP-based TB screening followed by Xpert testing had similar yield (56% [95% confidence interval, 49-63] vs. 59% [95% confidence interval, 51-65]) but consumed less than half as many Xpert assays per TB case detected (9 vs. 4). Addition of TB-LAM did not significantly increase diagnostic yield relative to the current ICF algorithm but provided same-day diagnosis for 26% of TB patients with advanced HIV. Addition of a single culture to TB-LAM and Xpert substantially improved ICF yield, identifying 78% of all TB cases. CONCLUSIONS: Point-of-care CRP-based screening can improve ICF efficiency among people living with HIV. Addition of TB-LAM and a single culture to Xpert confirmatory testing could enable HIV programs to increase the speed of TB diagnosis and ICF yield.

Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study.

BACKGROUND: Symptom-based screening for tuberculosis is recommended for all people living with HIV. This recommendation results in unnecessary Xpert MTB/RIF testing in many individuals living in tuberculosis-endemic areas and thus poor implementation of intensified case finding and tuberculosis preventive therapy. Novel approaches to tuberculosis screening are needed to help achieve global targets for tuberculosis elimination. We assessed the performance of C-reactive protein (CRP) measured with a point-of-care assay as a screening tool for active pulmonary tuberculosis. METHODS: For this prospective study, we enrolled adults (aged ≥18 years) living with HIV with CD4 cell count less than or equal to 350 cells per µL who were initiating antiretroviral therapy (ART) from two HIV/AIDS clinics in Uganda. CRP concentrations were measured at study entry with a point-of-care assay using whole blood obtained by fingerprick (concentration ≥10 mg/L defined as screen positive for tuberculosis). Sputum samples were collected for Xpert MTB/RIF testing and culture. We calculated the sensitivity and specificity of point-of-care CRP and WHO symptom-based screening in reference to culture results. We repeated the sensitivity analysis with Xpert MTB/RIF as the reference standard. FINDINGS: Between July 8, 2013, and Dec 15, 2015, 1237 HIV-infected adults were enrolled and underwent point-of-care CRP testing. 60 (5%) patients with incomplete or contaminated cultures were excluded from the analysis. Of the remaining 1177 patients (median CD4 count 165 cells per µL [IQR 75-271]), 163 (14%) had culture-confirmed tuberculosis. Point-of-care CRP testing had 89% sensitivity (145 of 163, 95% CI 83-93) and 72% specificity (731 of 1014, 95% CI 69-75) for culture-confirmed tuberculosis. Compared with WHO symptom-based screening, point-of-care CRP testing had lower sensitivity (difference -7%, 95% CI -12 to -2; p=0·002) but substantially higher specificity (difference 58%, 95% CI 55 to 61; p<0·0001). When Xpert MTB/RIF results were used as the reference standard, sensitivity of point-of-care CRP and WHO symptom-based screening were similar (94% [79 of 84] vs 99% [83 of 84], respectively; difference -5%, 95% CI -12 to 2; p=0·10). INTERPRETATION: The performance characteristics of CRP support its use as a tuberculosis screening test for people living with HIV with CD4 count less than or equal to 350 cells per µL who are initiating ART. HIV/AIDS programmes should consider point-of-care CRP-based tuberculosis screening to improve the efficiency of intensified case finding and increase uptake of tuberculosis preventive therapy. FUNDING: National Institutes of Health; President's Emergency Plan for AIDS Relief; University of California, San Francisco, Nina Ireland Program for Lung Health.

Epidemiology of meningitis in an HIV-infected Ugandan cohort.

There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical.

Prevalence and outcomes of cryptococcal antigenemia in HIV-seropositive patients hospitalized for suspected tuberculosis in Uganda.

BACKGROUND: Cryptococcal infection occurs in HIV-seropositive patients and is associated with high mortality. However, limited information is available on the prevalence and outcomes of cryptococcal antigenemia among hospitalized HIV-seropositive patients in sub-Saharan Africa. OBJECTIVES: To determine the prevalence of and risk factors for cryptococcal antigenemia among HIV-seropositive patients presenting to Mulago Hospital (Kampala, Uganda) with unexplained cough ≥2 weeks and suspected tuberculosis (TB) and also to determine if antigenemia is associated with an increased mortality. METHODS: Between September 2009 and September 2010, we enrolled consecutive HIV-seropositive adults hospitalized at Mulago Hospital with cough ≥2 weeks and suspected TB. Banked serum was tested for cryptococcal antigen. We compared demographic and clinical characteristics, and 2-month mortality in patients with and without cryptococcal antigenemia. RESULTS: Of 563 HIV-seropositive patients, 32 (5.7%) were cryptococcal antigen (CrAg) positive. None had Cryptococcus neoformans detected on fungal culture of bronchoalveolar lavage fluid (n = 116). CrAg-positive patients had a lower median CD4 count compared with CrAg-negative patients (25 vs. 55 cells/µL, P = 0.02), and a substantial proportion of CrAg-positive patients also had concurrent TB (31%). A positive CrAg test was not associated with increased mortality during the 2-month follow-up period (hazard ratio: 0.99, 95% confidence interval: 0.63 to 1.54, P = 0.95) after adjusting for CD4 count and antiretroviral therapy use at enrollment and/or follow-up. CONCLUSIONS: Occult cryptococcal antigenemia occurs commonly among hospitalized HIV-seropositive patients with suspected TB. CrAg testing should be considered in hospitalized HIV-seropositive patients with CD4 count <50 cells/µL, coupled with longer follow-up to evaluate the diagnostic value of CrAg and therapeutic interventions in patients with asymptomatic cryptococcal antigenemia.