Venous Thromboembolism Among People With HIV: Design, Implementation, and Findings of a Centralized Adjudication System in Clinical Care Sites Across the United States.

BACKGROUND: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era. METHODS: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking. RESULTS: We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common. CONCLUSIONS: We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common.

An updated systematic review of HIV-associated cryptococcal meningitis treatment strategies.

BACKGROUND: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines. METHODS: We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021. RESULTS: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001). CONCLUSIONS: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.

Prevalence and Sequelae of Cryptococcal Antigenemia in Antiretroviral Therapy-Experienced Populations: An Evaluation of Reflex Cryptococcal Antigen Screening in Botswana.

BACKGROUND: Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among ART-experienced populations is lacking. We performed a study evaluating the utility of reflex CrAg screening in Gaborone, Botswana. METHODS: CD4 count data were collected from the HIV reference laboratory from 2014-2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency of repeat CrAg testing described. Analyses ascertained the impact of ART status on CrAg prevalence and outcomes, and whether CrAg titers could be used for risk stratification. RESULTS: Overall, 5.6% (3335/59 300) of individuals tested had CD4 ≤100 cells/µL; 2108 samples with CD4 ≤100 cells/µL from 1645 unique patients were CrAg tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART and 12.1% (255) defaulters; 22% (463) of CrAg tests were on repeat samples. CrAg prevalence was 4.8% (72/1494; 95% CI, 3.8-6.0%) among outpatients and 21.9% (32/151; 95% CI, 15.3-28.5%) among inpatients. CrAg prevalence rates did not differ by ART status, but 6-month mortality was significantly lower in CrAg-positive individuals on ART at screening. Ten CrAg positives were identified through repeat testing. A CrAg titer cutoff ≥1:80 provided the best discrimination for 6-month survival. CONCLUSIONS: CrAg-positivity rates in an ART-experienced population were comparable to those seen in ART-naive populations. Repeat screening identified individuals who seroconverted to CrAg positivity and were at risk of cryptococcal disease. CrAg titers ≥1:80 can help identify the individuals at highest risk of death for more intensive management.

Outcomes of Reflex Cryptococcal Antigen (CrAg) Screening in Human Immunodeficiency Virus (HIV)-Positive Patients With CD4 Counts of 100-200 Cells/µL in Botswana.

Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 cells/µL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101-200 and 6.2% ≤100 cells/µL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 ≤100 cells/µL and 3.2% (1/31) in CrAg-positive CD4 101-200 cells/µL.

Diagnostic Accuracy of the Biosynex CryptoPS Cryptococcal Antigen Semiquantitative Lateral Flow Assay in Patients with Advanced HIV Disease.

High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and mortality in CrAg-positive individuals with advanced HIV disease (AHD). We evaluated a novel semiquantitative lateral flow assay (LFA), CryptoPS, that may be able to identify individuals with high CrAg titers in a cohort of AHD patients undergoing CrAg screening. In a prospective cohort of patients with AHD (CD4 cell count, ≤200/µl) receiving CD4 count testing, whole blood was tested for CrAg by CryptoPS and the IMMY LFA; the two assays were conducted by two different operators, each blind to the results of the other assay. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CryptoPS were assessed against the IMMY LFA as a reference. CryptoPS low-titer (T1 band) and high-titer (T2 band) results were compared with IMMY LFA titers obtained through serial dilution. A total of 916 specimens were tested. The sensitivity of the CryptoPS assay was 61.0% (25/41) (95% confidence interval [95% CI], 44.5 to 75.8%), its specificity was 96.6% (845/875) (95% CI, 95.1 to 97.7%), its PPV was 45.5% (95% CI, 32.0 to 59.4%), and its NPV was 98.1% (95% CI, 97.0 to 98.9%). All (16/16) CryptoPS false-negative results were obtained for samples with IMMY titers of ≤1:160. Of 29 patients (30 specimens) who tested positive by CryptoPS but negative by the IMMY LFA, none developed cryptococcal meningitis over 3 months of follow-up without fluconazole. Median CrAg titers were 1:20 (interquartile range [IQR], 0 to 1:160) in CryptoPS T1-positive samples and 1:2,560 (IQR, 1:1,280 to 1:10,240) in T2-positive samples. We conclude that the diagnostic accuracy of the CryptoPS assay was suboptimal in the context of CrAg screening, with poor sensitivity at low CrAg titers. However, the CryptoPS assay reliably detected individuals with high titers, which are associated with poor outcomes.

Reduction in Baseline CD4 Count Testing Following Human Immunodeficiency Virus "Treat All" Adoption in Uganda.

Baseline CD4 testing rates declined from 73% to 21% between 2013 and 2018 with adoption of "Treat All" in Uganda. Advanced human immunodeficiency virus (HIV) disease (CD4 count < 200 cells/µL) remained common (24% of those tested in 2018, 83% of whom had World Health Organization stage I/II disease). Despite frequent presentation with advanced HIV disease, CD4 testing has declined dramatically.

Evaluation of a Novel Semiquantitative Cryptococcal Antigen Lateral Flow Assay in Patients with Advanced HIV Disease.

Higher cryptococcal antigen (CrAg) titers are strongly associated with mortality risk in individuals with HIV-associated cryptococcal disease. Rapid tests to quantify CrAg levels may provide important prognostic information and enable treatment stratification. We performed a laboratory-based validation of the IMMY semiquantitative cryptococcal antigen (CrAgSQ) lateral flow assay (LFA) against the current gold standard CrAg tests. We assessed the diagnostic accuracy of the CrAgSQ in HIV-positive individuals undergoing CrAg screening, determined the relationship between CrAgSQ scores and dilutional CrAg titers, assessed interrater reliability, and determined the clinical correlates of CrAgSQ scores. A total of 872 plasma samples were tested using both the CrAgSQ LFA and the conventional IMMY CrAg LFA, of which 692 were sequential samples from HIV-positive individuals undergoing CrAg screening and an additional 180 were known CrAg-positive plasma samples archived from prior studies. Interrater agreement in CrAgSQ reading was excellent (98.17% agreement, Cohen's kappa 0.962, P < 0.001). Using the IMMY CrAg LFA as a reference standard, CrAgSQ was 93.0% sensitive (95% confidence interval [CI] 80.9% to 98.5%) and 93.8% specific (95% CI, 91.7% to 95.6%). After reclassification of discordant results using CrAg enzyme immunoassay testing, the sensitivity was 98.1% (95% CI, 90.1% to 100%) and specificity 95.8% (95% CI, 93.9% to 97.2%). The median CrAg titers for semiquantitative score categories (1+ to 4+) were 1:10 (interquartile range [IQR], 1:5 to 1:20) in the CrAgSQ 1+ category, 1:40 (IQR, 1:20 to 1:80) in the CrAgSQ 2+ category, 1:640 (IQR, 1:160 to 1:2,560) in the CrAgSQ 3+ category, and 1:5,120 (IQR, 1:2,560 to 1:30,720) in the CrAgSQ 4+ category. Increasing CrAgSQ scores were strongly associated with 10-week mortality. The IMMY CrAgSQ test had high sensitivity and specificity compared to the results for the IMMY CrAg LFA and provided CrAg scores that were associated with both conventional CrAg titers and clinical outcomes.

Mortality from HIV-associated meningitis in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. METHODS: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months). RESULTS AND DISCUSSION: Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes. CONCLUSIONS: Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region.

Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Final Report.

BACKGROUND: E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosolized product to the user. Pulmonary illnesses related to e-cigarette use have been reported, but no large series has been described. In July 2019, the Wisconsin Department of Health Services and the Illinois Department of Public Health received reports of lung injury associated with the use of e-cigarettes (also called vaping) and launched a coordinated public health investigation. METHODS: We defined case patients as persons who reported use of e-cigarette devices and related products in the 90 days before symptom onset and had pulmonary infiltrates on imaging and whose illnesses were not attributed to other causes. Medical record abstraction and case patient interviews were conducted with the use of standardized tools. RESULTS: There were 98 case patients, 79% of whom were male; the median age of the patients was 21 years. The majority of patients presented with respiratory symptoms (97%), gastrointestinal symptoms (77%), and constitutional symptoms (100%). All case patients had bilateral infiltrates on chest imaging. A total of 95% of the patients were hospitalized, 26% underwent intubation and mechanical ventilation, and two deaths were reported. A total of 89% of the patients reported having used tetrahydrocannabinol products in e-cigarette devices, although a wide variety of products and devices was reported. Syndromic surveillance data from Illinois showed that the mean monthly rate of visits related to severe respiratory illness in June through August of 2019 was twice the rate that was observed in the same months in 2018. CONCLUSIONS: Case patients presented with similar clinical characteristics. Although the definitive substance or substances contributing to injury have not been determined, this initial cluster of illnesses represents an emerging clinical syndrome or syndromes. Additional work is needed to characterize the pathophysiology and to identify the definitive causes.

E-cigarette Product Use, or Vaping, Among Persons with Associated Lung Injury - Illinois and Wisconsin, April-September 2019.

In July 2019, the Illinois Department of Public Health and the Wisconsin Department of Health Services launched a coordinated epidemiologic investigation after receiving reports of several cases of lung injury in previously healthy persons who reported electronic cigarette (e-cigarette) use, or vaping (1). This report describes features of e-cigarette product use by patients in Illinois and Wisconsin. Detailed patient interviews were conducted by telephone, in person, or via the Internet with 86 (68%) of 127 patients. Overall, 75 (87%) of 86 interviewed patients reported using e-cigarette products containing tetrahydrocannabinol (THC), and 61 (71%) reported using nicotine-containing products. Numerous products and brand names were identified by patients. Nearly all (96%) THC-containing products reported were packaged, prefilled cartridges, and 89% were primarily acquired from informal sources (e.g., friends, family members, illicit dealers, or off the street). In contrast, 77% of nicotine-containing products were sold as prefilled cartridges, and 83% were obtained from commercial vendors. The precise source of this outbreak is currently unknown (2); however, the predominant use of prefilled THC-containing cartridges among patients with lung injury associated with e-cigarette use suggests that they play an important role. While this investigation is ongoing, CDC recommends that persons consider refraining from using e-cigarette, or vaping, products, particularly those containing THC. Given the diversity of products reported and frequency of patients using both THC- and nicotine-containing e-cigarette products, additional methods such as product testing and traceback could help identify the specific cause of this outbreak.

Causes of Pediatric Meningitis in Botswana: Results From a 16-Year National Meningitis Audit.

BACKGROUND: Central nervous system infections are an important cause of childhood morbidity and mortality in high HIV-prevalence settings of Africa. We evaluated the epidemiology of pediatric meningitis in Botswana during the rollout of antiretroviral therapy, pneumococcal conjugate vaccine and Haemophilus influenzae type B (HiB) vaccine. METHODS: We performed a cross-sectional study of children (<15 years old) evaluated for meningitis by cerebrospinal fluid (CSF) examination from 2000 to 2015, with complete national records for 2013-2014. Clinical and laboratory characteristics of microbiologically confirmed and culture-negative meningitis were described and incidence of Streptococcus pneumoniae, H. influenzae and cryptococcal meningitis was estimated for 2013-2014. RESULTS: A total of 6796 unique cases were identified. Median age was 1 year [interquartile range 0-3]; 10.4% (435/4186) of children with available HIV-related records were known HIV-infected. Overall, 30.4% (2067/6796) had abnormal CSF findings (positive microbiologic testing or CSF pleocytosis). Ten percent (651/6796) had a confirmed microbiologic diagnosis; including 26.9% (175/651) Cryptococcus, 18.9% (123/651) S. pneumoniae, 20.3% (132/651) H. influenzae and 1.1% (7/651) Mycobacterium tuberculosis. During 2013-2014, national cryptococcal meningitis incidence was 1.3 cases per 100,000 person-years (95% confidence interval, 0.8-2.1) and pneumococcal meningitis incidence 0.7 per 100,000 person-years (95% confidence interval, 0.3-1.3), with no HiB meningitis diagnosed. CONCLUSIONS: Following HiB vaccination, a marked decline in microbiologically confirmed cases of H. influenzae meningitis occurred. Cryptococcal meningitis remains the most common confirmed etiology, demonstrating gaps in prevention-of-mother-to-child transmission and early HIV diagnosis. The high proportion of abnormal CSF samples with no microbiologic diagnosis highlights limitation in available diagnostics.

Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey.

OBJECTIVES: Data on meningitis epidemiology in high HIV-prevalence African settings following antiretroviral therapy scale-up are lacking. We described epidemiology of adult meningitis in Botswana over a 16-year period. METHODS: Laboratory records for adults undergoing lumbar puncture (LP) 2000-2015 were collected, with complete national data 2013-2014. Cerebrospinal fluid (CSF) findings and linked HIV-data were described, and national incidence figures estimated for 2013-2014. Temporal trends in meningitis were evaluated. RESULTS: Of 21,560 adults evaluated, 41% (8759/21,560) had abnormal CSF findings with positive microbiological testing and/or pleocytosis; 43% (3755/8759) of these had no confirmed microbiological diagnosis. Of the 5004 microbiologically-confirmed meningitis cases, 89% (4432/5004) were cryptococcal (CM) and 8% (382/5004) pneumococcal (PM). Seventy-three percent (9525/13,033) of individuals undergoing LP with identifiers for HIV registry linkage had documented HIV-infection. Incidence of LP for meningitis evaluation in Botswana 2013-2014 was 142.6/100,000 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/100,000 (95%CI:23.2-26.9), and incidence of PM was 2.7/100,000 (95%CI:2.4-3.1). In contrast to previously reported declines in CM incidence with ART roll-out, no significant temporal decline in pneumococcal or culture-negative meningitis was observed. CONCLUSIONS: CM remained the predominant identified aetiology of meningitis despite ART scale-up. A high proportion of cases had abnormal CSF with negative microbiological evaluation.

Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus-associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial.

Background: We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods: Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results: Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions: Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration: ISRCTN 10248064.

Treatment for HIV-associated cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV-related deaths worldwide. The best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis is unclear, particularly in resource-limited settings where management of drug-related toxicities associated with more potent antifungal drugs is a challenge. OBJECTIVES: To evaluate the best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis; to compare side effect profiles of different therapies. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South-East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018. SELECTION CRITERIA: We included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV-associated cryptococcal meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random-effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10-week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta-analysis using multivariate meta-regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two-week and 10-week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node-splitting approach, and global inconsistency using design-by-treatment interaction modelling. For the network meta-analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10-week mortality. MAIN RESULTS: We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. All studies were carried out in adults, and all but two studies were conducted in resource-limited settings, including 11 of 12 studies with 10-week mortality data.In the direct pairwise comparisons evaluating 10-week mortality, one study from four sub-Saharan African countries contributed data to several key comparisons. At 10 weeks these data showed that those on the regimen of one-week amphotericin B deoxycholate (AmBd) and flucytosine (5FC) followed by fluconazole (FLU) on days 8 to 14 had lower mortality when compared to (i) two weeks of AmBd and 5FC (RR 0.62, 95% CI 0.42 to 0.93; 228 participants, 1 study), (ii) two weeks of AmBd and FLU (RR 0.58, 95% CI 0.39 to 0.86; 227 participants, 1 study), (iii) one week of AmBd with two weeks of FLU (RR 0.49, 95% CI 0.34 to 0.72; 224 participants, 1 study), and (iv) two weeks of 5FC and FLU (RR 0.68, 95% CI 0.47 to 0.99; 338 participants, 1 study). The evidence for each of these comparisons was of moderate certainty. For other outcomes, this shortened one-week AmBd and 5FC regimen had similar fungal clearance (MD 0.05 log10 CFU/mL/day, 95% CI -0.02 to 0.12; 186 participants, 1 study) as well as lower risk of grade three or four anaemia (RR 0.31, 95% CI 0.16 to 0.60; 228 participants, 1 study) compared to the two-week regimen of AmBd and 5FC.For 10-week mortality, the comparison of two weeks of 5FC and FLU with two weeks of AmBd and 5FC (RR 0.92, 95% CI 0.69 to 1.23; 340 participants, 1 study) or two weeks of AmBd and FLU (RR 0.85, 95% CI 0.64 to 1.13; 339 participants, 1 study) did not show a difference in mortality, with moderate-certainty evidence for both comparisons.When two weeks of combination AmBd and 5FC was compared with AmBd alone, pooled data showed lower mortality at 10 weeks (RR 0.66, 95% CI 0.46 to 0.95; 231 participants, 2 studies, moderate-certainty evidence).When two weeks of AmBd and FLU was compared to AmBd alone, there was no difference in 10-week mortality in pooled data (RR 0.94, 95% CI 0.55 to 1.62; 371 participants, 3 studies, low-certainty evidence).One week of AmBd and 5FC followed by FLU on days 8 to 14 was the best induction therapy regimen after comparison with 11 other regimens for 10-week mortality in the network meta-analysis, with an overall SUCRA ranking of 88%. AUTHORS' CONCLUSIONS: In resource-limited settings, one-week AmBd- and 5FC-based therapy is probably superior to other regimens for treatment of HIV-associated cryptococcal meningitis. An all-oral regimen of two weeks 5FC and FLU may be an alternative in settings where AmBd is unavailable or intravenous therapy cannot be safely administered. We found no mortality benefit of combination two weeks AmBd and FLU compared to AmBd alone. Given the absence of data from studies in children, and limited data from high-income countries, our findings provide limited guidance for treatment in these patients and settings.

Advanced Human Immunodeficiency Virus Disease in Botswana Following Successful Antiretroviral Therapy Rollout: Incidence of and Temporal Trends in Cryptococcal Meningitis.

Background: Botswana has a well-developed antiretroviral therapy (ART) program that serves as a regional model. With wide ART availability, the burden of advanced human immunodeficiency virus (HIV) and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis (CM), and describe characteristics of cases during 2000-2014 and temporal trends at 2 national referral hospitals. Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected from the period 2000-2014 to identify cases of CM. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers in the period 2004-2014. Results: A total of 5296 episodes of CM were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 (95% confidence interval [CI], 16.6-19.2) cases per 100000 person-years. In the HIV-infected population, incidence was 96.8 (95% CI, 90.0-104.0) cases per 100000 person-years; male predominance was seen across CD4 strata. At national referral hospitals, cases decreased during 2007-2009 but stabilized during 2010-2014. Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of CM comparable to pre-ART era rates in South Africa. Our findings suggest that a key population of individuals, often men, is developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.

C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings.

OBJECTIVE: The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. DESIGN: Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). METHODS: We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. RESULTS: Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. CONCLUSION: Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.