Restarting pre-exposure prophylaxis (PrEP) for HIV: a systematic review and meta-analysis.

Background: High coverage of pre-exposure prophylaxis (PrEP) will reduce HIV transmission and help end the HIV/AIDS pandemic. However, PrEP users face challenges, including long-term adherence. The study aimed to document the proportions of individuals who restart HIV PrEP after they stop and the reasons for restarting PrEP. Methods: This study is a systematic review and meta-analysis. We systematically searched CINAHL, Embase, Emcare, Global Health, Medline, Scopus, and PsychINFO for peer-reviewed with no date restrictions. A grey literature search was conducted through Google search, a search of abstract books of AIDS conferences and the websites of WHO and UNAIDS. The data search was conducted in April 2023 and updated in February 2024. Two authors extracted data on the proportion of people who stopped and then restarted PrEP, reasons for restarting, and strategies to support people restarting PrEP. Two authors appraised the data using the Joanna Briggs Institute Appraisal Tools. We used a random-effects meta-analysis to pool estimates of restarting. We conducted meta-regression to determine potential sources of heterogeneity. This study is registered with PROSPERO, CRD42023416777. However, we deviated from our original plan as we did not identify enough studies for strategies to support restarting PrEP (primary objective). Subsequently, we revised our plan to strengthen our secondary objective to quantify the proportion of people who stopped and restarted PrEP, and explore possible reasons for its heterogeneity. Findings: Of 988 studies, 30 unique studieswere included: 27 reported the proportion restarting PrEP, and of these, 7 also reported reasons for restarting PrEP, and 3 studies reported only on the reasons for restarting PrEP. No study evaluated interventions for restarting PrEP. For the meta-analysis, we included 27 studies. Most studies were from high-income countries (17/27, 63%) or the USA (15/27, 56%). Overall, 23.8% (95% CI: 15.9-32.7, I2 = 99.8%, N = 85,683) of people who stopped PrEP restarted PrEP. There was a lower proportion of restarting in studies from middle-income countries compared to high-income countries (adjusted odds ratio (aOR) 0.6, 95% CI: 0.50-0.73, p < 0.001). There was higher restarting in studies from Africa compared to the USA (aOR 1.55, 95% CI: 1.30-1.86), heterosexual populations compared to men who have sex with men or transgender women (aOR 1.50, 95% CI: 1.25-1.81, p < 0.001) and in studies defining restarting as those who had stopped PrEP for >1 month compared to those who stopped <1 month (aOR 1.20, 95% CI: 1.06-1.36, p < 0.001). Reasons for restarting PrEP included perceived higher risk for HIV acquisition and removal of barriers to access PrEP. In terms of quality assessment, overall, both randomised controlled trials had a low risk of bias, while the observational studies used in the meta-analysis had some potential risk of bias related to not explicitly addressing potential confounders (15/25, 60%) or not describing strategies to address incomplete follow-up (24/25, 96%). Interpretation: About a quarter of people who stopped PrEP would restart, with substantial variation across countries and populations. It is important to understand the motivations and contextual factors influencing restarting PrEP and the support systems to enable restarting PrEP for those at ongoing risk. Funding: Australian National Health and Medical Research Council.

Addressing gaps in AMR awareness in the public: an evidence-based policy brief to guide school curriculum review in Uganda.

The government of Uganda, through its Ministry of Health, previously adopted curriculum review as a mechanism to respond to public health threats such as HIV/AIDS and include content in primary and secondary schools. This approach contributes to raising public awareness, a key strategy recommended by the World Health Organization to support the global response to the threat of antimicrobial resistance (AMR). This policy brief, developed for policymakers related to school curricula, aims to advocate for and support integration of AMR content in Uganda's primary and secondary level school curricula. The policy brief supports efforts by the multisectoral National AMR Subcommittee to create awareness on this issue as part of its role in facilitating the operationalization of Uganda's National Action Plan on AMR.

Antimicrobial consumption surveillance in Uganda: Results from an analysis of national import data for the human health sector, 2018-2021.

BACKGROUND: The surveillance of antimicrobial consumption (AMC) is critical to developing appropriate antimicrobial stewardship interventions. It is a key component of World Health Organization's (WHO) Global Action Plan on Antimicrobial Resistance and the Uganda Antimicrobial Resistance National Action Plan 2018-2023. Our study's objective was to determine the national consumption of all antimicrobials. METHODS: Data on all imported antimicrobials were retrieved from paper-based records and entered in the web-based National Drug Authority (NDA) management information system from 2021. The import data for the year is a proxy for nationwide consumption because they account for 95% of all medical products. The NDA authorizes all imports to the country regardless of final distribution in the supply chain. The data were analyzed in accordance with WHO Anatomical Therapeutic Chemical codes and defined daily dose (DDD) methodology. We also retrieved consumption data for 2018, 2019, and 2020 that were previously submitted by Uganda to WHO's Global Antimicrobial Resistance and Use Surveillance System. RESULTS: In 2021, the average DDD per 1000 inhabitants was 29.02 for all antimicrobials; 80.7% of antimicrobials consumed were oral. Penicillins (27.6%) were the most consumed antimicrobial class, followed by sulfonamides and trimethoprim (15.5%). Based on WHO's Access, Watch, and Reserve (AWaRe) antibiotic classification, 62.91% of AMC was from the access class, with watch class averaging 14.51% in the period 2018-2021. Watch class AMC spiked in 2021 (34.2%) during COVID-19 pandemic compared to 2020 (24.29%). Azithromycin and ciprofloxacin were the most consumed watch class antimicrobials in 2021. CONCLUSIONS: The relatively high consumption of injectable antimicrobials and year over year increase in watch class AMC requires urgent stewardship interventions. Further work is needed to establish a system for longitudinal AMC surveillance that is well resourced and funded to overcome the challenges of estimation and provide more accurate data on consumption and use patterns.

Health care worker carriage of drug-resistant bacteria and infection control practices at a tertiary care hospital in Uganda: a cross-sectional survey.

Introduction: bacterial carriage by health care workers (HCWs) is a major risk factor for transmission of healthcare-associated infections (HAIs). Often, these pathogens are multiple drug resistant (MDR) and are transmitted from hospital environments. We aimed to study the carriage of pathogenic bacteria among HCWs at a tertiary care hospital in Uganda. Methods: a cross-sectional study was done at Naguru Regional Referral Hospital from June 2017 to August 2017. Five finger imprints of both hands-on blood and MacConkey agar were done. We assessed pathogenic bacterial carriage by HCWs and characterized drug sensitivity and relatedness of these isolates. Genotyping of extended-spectrum beta-lactamase (ESBL) and Methicillin-resistant Staphylococcus aureus (MRSA) positive isolates was done to determine intra-hospital transmission. A survey of the hospital's IPC de program was done. Results: one hundred and eight (108) HCWs were enrolled. Carriage of pathogenic bacteria was highest in surgical and emergency wards at 36% and 35.6% respectively, p-value of 0.00. The proportion of microbial carriage was highest among nurses 16 (34.8%) followed by medical officers 11 (23.9%). Among the isolated pathogenic bacteria, 25 (36.2%) were Gram-positive and 44 (63.8%) were Gram-negative. Fifty percent of Staphylococcus aureus were methicillin-resistant, and one isolate was vancomycin-resistant. Fifty-four percent (54.6%) of HCWs had never been trained on moments of hand hygiene, only 44.4% recognized the presence of an IPC program in the hospital and 49% were not aware of problems associated with poor IPC practices. Conclusion: this study demonstrated that hands of HCWs at Naguru Regional Referral Hospital were colonized with pathogenic bacteria with varying prevalence, some with multidrug-resistant strains including MRSA and ESBL.

What is the appropriate antimicrobial use surveillance tool at the health facility level for Uganda and other low- and middle-income countries?

BACKGROUND: An appropriate antimicrobial use (AMU) surveillance system provides critical data and evidence on which antimicrobial stewardship interventions are based. However, Uganda and most other low- and middle-income countries (LMICs) lack efficient systems for monitoring AMU due to unique health system challenges. METHODS: We reviewed the key tools available for AMU surveillance in health facilities. Based on our implementation experience, we present arguments on the need for country authorities to adapt a customized and standardized tool for national uses. RESULTS: Despite ongoing efforts to set up AMU surveillance programs in Uganda, AMU data remain sparse, with most of the available data collected through antimicrobial stewardship related continuous quality improvement efforts implemented by global AMR control programs. There is variability in the interpretation of available AMU surveillance tools and a need to identify the most appropriate AMU surveillance methodologies and tools for Uganda and other LMICs. Data fields for sex and gender are incorrectly categorized and there is no tool that records pregnancy variable. Based on the past four years of practical implementation experience since the launch of the World Health Organization's Point Prevalence Survey methodology in 2018 for inpatient settings, we believe that the tool should be modified in cognizance of existing capacity and priorities in resource-constrained settings. CONCLUSIONS: The World Health Organization, regional experts, ministry of health authorities, and other stakeholders should urgently review available tools with a view to adopting a customized and standardized facility AMU surveillance methodology suitable for national-level rollout in LMICs.

Development and evaluation of a continuous quality improvement programme for antimicrobial stewardship in six hospitals in Uganda.

BACKGROUND: Appropriate antimicrobial use is essential for antimicrobial stewardship (AMS). Ugandan hospitals are making efforts to improve antibiotic use, but improvements have not been sufficiently documented and evaluated. METHODS: Six Ugandan hospitals implemented AMS interventions between June 2019 and July 2022. We used the WHO AMS toolkit to set-up hospital AMS programmes and implemented interventions using continuous quality improvement (CQI) techniques and targeting conditions commonly associated with antibiotic misuse, that is, urinary tract infections (UTIs), upper respiratory tract infections (URTIs) and surgical antibiotic prophylaxis (SAP). The interventions included training, mentorship and provision of clinical guidelines to support clinical decision-making. Quarterly antibiotic use surveys were conducted. RESULTS: Data were collected for 7037 patients diagnosed with UTIs. There was an increase in the proportion of patients receiving one antibiotic for the treatment of UTI from 48% during the pre-intervention to 73.2%, p<0.01. There was a 19.2% reduction in the number of antimicrobials per patient treated for UTI p<0.01. There was an increase in use of nitrofurantoin, the first-line drug for the management of UTI. There was an increase in the use of Access antibiotics for managing UTIs from 50.4% to 53.8%. The proportion of patients receiving no antimicrobials for URTI increased from 26.3% at pre-intervention compared with 53.4% at intervention phase, p<0.01. There was a 20.7% reduction in the mean number of antimicrobials per patient for URTI from the pre-intervention to the intervention phase, from 0.8 to 0.6, respectively, p<0.001 and reduction in the number of treatment days, p=0.0163. Among patients undergoing surgery, 49.5% (2212) received SAP during the pre-intervention versus 50.5% (2169) during the intervention. CONCLUSIONS: Using CQI approaches to focus on specific causes of inappropriate antibiotic use led to desirable overall reductions in antibiotic use for URTI and UTI.

Antimicrobial susceptibility surveillance and antimicrobial resistance in Neisseria gonorrhoeae in Africa from 2001 to 2020: A mini-review.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae (NG), compromising gonorrhea treatment, is a global public health concern. Improved, quality-assured NG AMR monitoring at the global level is essential. This mini-review examined NG AMR susceptibility surveillance and AMR data from the African continent from 2001 to 2020. Eligible peer-reviewed publications (n = 30) containing NG AMR data for antimicrobials currently recommended for gonorrhea treatment were included. Overall, very limited NG surveillance and AMR data was available. Furthermore, the NG AMR surveillance studies varied greatly regarding surveillance protocols (e.g., populations and samples tested, sample size, antimicrobials examined), methodologies (e.g., antimicrobial susceptibility testing method [agar dilution, minimum inhibitory concentration (MIC) gradient strip test, disc diffusion test] and interpretative criteria), and quality assurance (internal quality controls, external quality assessments [EQA], and verification of AMR detected). Moreover, most studies examined a suboptimal number of NG isolates, i.e., less than the WHO Global Gonococcal Antimicrobial Surveillance Program (GASP) and WHO Enhanced GASP (EGASP) recommendations of ≥100 isolates per setting and year. The notable inter-study variability and frequently small sample sizes make appropriate inter-study and inter-country comparisons of AMR data difficult. In conclusion, it is imperative to establish an enhanced, standardized and quality-assured NG AMR surveillance, ideally including patient metadata and genome sequencing as in WHO EGASP, in Africa, the region with the highest gonorrhea incidence globally. This will enable the monitoring of AMR trends, detection of emerging AMR, and timely refinements of national and international gonorrhea treatment guidelines. To achieve this aim, national and international leadership, political and financial commitments are imperative.

Moving from assessments to implementation: promising practices for strengthening multisectoral antimicrobial resistance containment capacity.

BACKGROUND: Antimicrobial resistance (AMR) poses a global threat to human, animal, and environmental health. AMR is a technical area in the Global Health Security Agenda initiative which uses the Joint External Evaluation tool to evaluate national AMR containment capacity. This paper describes four promising practices for strengthening national antimicrobial resistance containment capacity based on the experiences of the US Agency for International Development's Medicines, Technologies, and Pharmaceutical Services Program work with 13 countries to implement their national action plans on AMR in the areas of multisectoral coordination, infection prevention and control, and antimicrobial stewardship. METHODS: We use the World Health Organization (WHO) Benchmarks on International Health Regulations Capacities (2019) to guide national, subnational, and facility actions that advance Joint External Evaluation capacity levels from 1 (no capacity) to 5 (sustainable capacity). Our technical approach is based on scoping visits, baseline Joint External Evaluation scores, benchmarks tool guidance, and country resources and priorities. RESULTS: We gleaned four promising practices to achieve AMR containment objectives: (1) implement appropriate actions using the WHO benchmarks tool, which prioritizes actions, making it easier for countries to incrementally increase their Joint External Evaluation capacity from level 1 to 5; (2) integrate AMR into national and global agendas. Ongoing agendas and programs at international, regional, and national levels provide opportunities to mainstream and interlink AMR containment efforts; (3) improve governance through multisectoral coordination on AMR. Strengthening multisectoral bodies' and their technical working groups' governance improved functioning, which led to better engagement with animal/agricultural sectors and a more coordinated COVID-19 pandemic response; and (4) mobilize and diversify funding for AMR containment. Long-term funding from diversified funding streams is vital for advancing and sustaining countries' Joint External Evaluation capacities. CONCLUSIONS: The Global Health Security Agenda work has provided practical support to countries to frame and conduct AMR containment actions in terms of pandemic preparedness and health security. The WHO benchmarks tool that Global Health Security Agenda uses serves as a standardized organizing framework to prioritize capacity-appropriate AMR containment actions and transfer skills to help operationalize national action plans on AMR.

Identifying and addressing challenges to antimicrobial use surveillance in the human health sector in low- and middle-income countries: experiences and lessons learned from Tanzania and Uganda.

BACKGROUND: Antimicrobial resistance (AMR) is a global health security threat and is associated with increased morbidity and mortality. One of the key drivers of AMR is the inappropriate use of antibiotics. A key component of improving antibiotic use is conducting antimicrobial use (AMU) surveillance. METHODS: USAID Medicines Technologies and Pharmaceutical Services Program has supported the implementation of antimicrobial stewardship activities, including setting up systems for AMU surveillance in Tanzania and Uganda. Results from both countries have been previously published. However, additional implementation experience and lessons learned from addressing challenges to AMU surveillance have not been previously published and are the subject of this narrative article. RESULTS: The team identified challenges including poor quality data, low digitalization of tools, and inadequate resources including both financial and human resources. To address these gaps, the Program has supported the use of continuous quality improvement approaches addressing gaps in skills, providing tools, and developing guidelines to fill policy gaps in AMU surveillance. Recommendations to fill these gaps, based on the Potter and Brough systematic capacity building model have been proposed. CONCLUSIONS: Strengthening AMU surveillance through using a capacity-building approach will fill gaps and strengthen efforts for AMR control in both countries.

Point Prevalence Survey of Antibiotic Use across 13 Hospitals in Uganda.

Standardized monitoring of antibiotic use underpins the effective implementation of antimicrobial stewardship interventions in combatting antimicrobial resistance (AMR). To date, few studies have assessed antibiotic use in hospitals in Uganda to identify gaps that require intervention. This study applied the World Health Organization's standardized point prevalence survey methodology to assess antibiotic use in 13 public and private not-for-profit hospitals across the country. Data for 1077 patients and 1387 prescriptions were collected between December 2020 and April 2021 and analyzed to understand the characteristics of antibiotic use and the prevalence of the types of antibiotics to assess compliance with Uganda Clinical Guidelines; and classify antibiotics according to the WHO Access, Watch, and Reserve classification. This study found that 74% of patients were on one or more antibiotics. Compliance with Uganda Clinical Guidelines was low (30%); Watch-classified antibiotics were used to a high degree (44% of prescriptions), mainly driven by the wide use of ceftriaxone, which was the most frequently used antibiotic (37% of prescriptions). The results of this study identify key areas for the improvement of antimicrobial stewardship in Uganda and are important benchmarks for future evaluations.

Implementation of the World Health Organization Global Antimicrobial Resistance Surveillance System in Uganda, 2015-2020: Mixed-Methods Study Using National Surveillance Data.

BACKGROUND: Antimicrobial resistance (AMR) is an emerging public health crisis in Uganda. The World Health Organization (WHO) Global Action Plan recommends that countries should develop and implement National Action Plans for AMR. We describe the establishment of the national AMR program in Uganda and present the early microbial sensitivity results from the program. OBJECTIVE: The aim of this study is to describe a national surveillance program that was developed to perform the systematic and continuous collection, analysis, and interpretation of AMR data. METHODS: A systematic qualitative description of the process and progress made in the establishment of the national AMR program is provided, detailing the progress made from 2015 to 2020. This is followed by a report of the findings of the isolates that were collected from AMR surveillance sites. Identification and antimicrobial susceptibility testing (AST) of the bacterial isolates were performed using standard methods at both the surveillance sites and the reference laboratory. RESULTS: Remarkable progress has been achieved in the establishment of the national AMR program, which is guided by the WHO Global Laboratory AMR Surveillance System (GLASS) in Uganda. A functional national coordinating center for AMR has been established with a supporting designated reference laboratory. WHONET software for AMR data management has been installed in the surveillance sites and laboratory staff trained on data quality assurance. Uganda has progressively submitted data to the WHO GLASS reporting system. Of the 19,216 isolates from WHO GLASS priority specimens collected from October 2015 to June 2020, 22.95% (n=4411) had community-acquired infections, 9.46% (n=1818) had hospital-acquired infections, and 68.57% (n=12,987) had infections of unknown origin. The highest proportion of the specimens was blood (12,398/19,216, 64.52%), followed by urine (5278/19,216, 27.47%) and stool (1266/19,216, 6.59%), whereas the lowest proportion was urogenital swabs (274/19,216, 1.4%). The mean age was 19.1 (SD 19.8 years), whereas the median age was 13 years (IQR 28). Approximately 49.13% (9440/19,216) of the participants were female and 50.51% (9706/19,216) were male. Participants with community-acquired infections were older (mean age 28, SD 18.6 years; median age 26, IQR 20.5 years) than those with hospital-acquired infections (mean age 17.3, SD 20.9 years; median age 8, IQR 26 years). All gram-negative (Escherichia coli, Klebsiella pneumoniae, and Neisseria gonorrhoeae) and gram-positive (Staphylococcus aureus and Enterococcus sp) bacteria with AST showed resistance to each of the tested antibiotics. CONCLUSIONS: Uganda is the first African country to implement a structured national AMR surveillance program in alignment with the WHO GLASS. The reported AST data indicate very high resistance to the recommended and prescribed antibiotics for treatment of infections. More effort is required regarding quality assurance of laboratory testing methodologies to ensure optimal adherence to WHO GLASS-recommended pathogen-antimicrobial combinations. The current AMR data will inform the development of treatment algorithms and clinical guidelines.

Strengthening multisectoral coordination on antimicrobial resistance: a landscape analysis of efforts in 11 countries.

BACKGROUND: Increasingly, there has been recognition that siloed approaches focusing mainly on human health are ineffective for global antimicrobial resistance (AMR) containment efforts. The inherent complexities of AMR containment warrant a coordinated multisectoral approach. However, how to institutionalize a country's multisectoral coordination across sectors and between departments used to working in silos is an ongoing challenge. This paper describes the technical approach used by a donor-funded program to strengthen multisectoral coordination on AMR in 11 countries as part of their efforts to advance the objectives of the Global Health Security Agenda and discusses some of the challenges and lessons learned. METHODS: The program conducted a rapid situational analysis of the Global Health Security Agenda and AMR landscape in each country and worked with the governments to identify the gaps, priorities, and potential activities in multisectoral coordination on AMR. Using the World Health Organization (WHO) Joint External Evaluation tool and the WHO Benchmarks for International Health Regulations (2005) Capacities as principal guidance, we worked with countries to achieve key milestones in enhancing effective multisectoral coordination on AMR. RESULTS: The program's interventions led to the achievement of key benchmarks recommended actions, including the finalization of national action plans on AMR and tools to guide their implementation; strengthening the leadership, governance, and oversight capabilities of multisectoral governance structures; establishing and improving the functions of technical working groups on infection prevention and control and antimicrobial stewardship; and coordinating AMR activities within and across sectors. CONCLUSION: A lot of learning still needs to be done to identify best practices for building mutual trust and adequately balancing the priorities of individual ministries with cross-cutting issues. Nevertheless, this paper provides some practical ideas for countries and implementing partners seeking to improve multisectoral coordination on AMR. It also demonstrates that the WHO benchmark actions, although not intended as an exhaustive list of recommendations, provide adequate guidance for increasing countries' capacity for effective multisectoral coordination on AMR in a standardized manner.

Implementation of a standardised and quality-assured enhanced gonococcal antimicrobial surveillance programme in accordance with WHO protocols in Kampala, Uganda.

OBJECTIVES: The emergence of multidrug-resistant Neisseria gonorrhoeae (NG) is a major global health threat necessitating response and control measures. NG antimicrobial resistance (AMR) surveillance data from sub-Saharan countries is exceedingly limited. This paper aims to describe the establishment, design and implementation of a standardised and quality-assured gonococcal surveillance programme and to describe the susceptibility patterns of the cultured gonococcal isolates in Kampala, Uganda. METHODS: From March 2018 to September 2019, using the WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) protocol, consecutive males with urethral discharge syndrome were recruited from 10 surveillance sites in Kampala City, Uganda, in collaboration with the Ministry of Health. Males completed a questionnaire and provided a urethral swab specimen. Culture, identification and antimicrobial susceptibility testing (Etest) were performed. RESULTS: Of the 1013 males recruited, 73.1% (740/1013) had a positive Gram stain and 51.1% (n=518) were culture-positive for NG. Using Etest (458 isolates), the resistance to ciprofloxacin was 99.6%. Most isolates were susceptible to azithromycin, cefoxitin and gentamicin, that is, 99.8%, 98.5% and 92.4%, respectively, and all isolates were susceptible to ceftriaxone and cefixime. CONCLUSIONS: We established a standardised, quality-assured WHO EGASP. Using Etest, 458 isolates were characterised, with associated epidemiological surveillance data, in 1.5 years, which by far exceed the minimum 100 isolates per year and country requested in the WHO Global GASP, to detect AMR levels with confidence. These isolates with the epidemiological data can be used to develop population level interventions.

Evaluation of Infection Prevention and Control Readiness at Frontline Health Care Facilities in High-Risk Districts Bordering Ebola Virus Disease-Affected Areas in the Democratic Republic of the Congo - Uganda, 2018.

Infection prevention and control (IPC) in health care facilities is essential to protecting patients, visitors, and health care personnel from the spread of infectious diseases, including Ebola virus disease (Ebola). Patients with suspected Ebola are typically referred to specialized Ebola treatment units (ETUs), which have strict isolation and IPC protocols, for testing and treatment (1,2). However, in settings where contact tracing is inadequate, Ebola patients might first seek care at general health care facilities, which often have insufficient IPC capacity (3-6). Before 2014-2016, most Ebola outbreaks occurred in rural or nonurban communities, and the role of health care facilities as amplification points, while recognized, was limited (7,8). In contrast to these earlier outbreaks, the 2014-2016 West Africa Ebola outbreak occurred in densely populated urban areas where access to health care facilities was better, but contact tracing was generally inadequate (8). Patients with unrecognized Ebola who sought care at health care facilities with inadequate IPC initiated multiple chains of transmission, which amplified the epidemic to an extent not seen in previous Ebola outbreaks (3-5,7). Implementation of robust IPC practices in general health care facilities was critical to ending health care-associated transmission (8). In August 2018, when an Ebola outbreak was recognized in the Democratic Republic of the Congo (DRC), neighboring countries began preparing for possible introduction of Ebola, with a focus on IPC. Baseline IPC assessments conducted in frontline health care facilities in high-risk districts in Uganda found IPC gaps in screening, isolation, and notification. Based on findings, additional funds were provided for IPC, a training curriculum was developed, and other corrective actions were taken. Ebola preparedness efforts should include activities to ensure that frontline health care facilities have the IPC capacity to rapidly identify suspected Ebola cases and refer such patients for treatment to protect patients, staff members, and visitors.

Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial.

BACKGROUND: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. METHODS: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7-14 days of intravenous amphotericin B (0·7-1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. FINDINGS: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93-1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 -log10 CFU/mL per day [95% CI 0·37-0·50] in the sertraline group vs 0·47 -log10 CFU/mL per day [0·40-0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. INTERPRETATION: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. FUNDING: National Institutes of Health and Medical Research Council, Wellcome Trust.

Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis.

BACKGROUND: Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. METHODS: We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. RESULTS: We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/µL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). CONCLUSIONS: Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. CLINICAL TRIALS REGISTRATION: NCT01802385.

HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts.

BACKGROUND: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts. METHODS: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/µL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival. RESULTS: Among first episode of cryptococcosis, 9% presented with CD4 ≥100 cells/µL. Participants with CD4 ≥100 cells/µL presented more often with altered mental status (52% vs 39%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/µL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47% with CD4 <50, 35% with CD4 50-99, and 40% with CD4 ≥100 cells/µL (P = .04). CONCLUSION: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/µL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework. CLINICAL TRIAL REGISTRATION: NCT01075152 and NCT01802385.

Detrimental Outcomes of Unmasking Cryptococcal Meningitis With Recent ART Initiation.

BACKGROUND: Increased antiretroviral therapy (ART) availability has been associated with more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis in those already receiving ART are limited. We compared clinical presentations and outcomes among ART-naïve and ART-experienced Ugandans. METHODS: We prospectively enrolled 605 HIV-infected persons with first-episode cryptococcal meningitis from August 2013 to May 2017 who received amphotericin-based combination therapy. We classified participants by ART status and ART duration and compared groups for 2-week survival. RESULTS: Overall, 46% (281/605) of participants were receiving ART at presentation. Compared with those not receiving ART, those receiving ART had higher CD4 counts (P < .001) and lower cerebrospinal fluid fungal burdens (P < .001). Of those receiving ART, 56% (156/281) initiated ART within 6 months, and 18% (51/281) initiated ART within 14 days. Two-week mortality did not differ by ART status (27% in both ART-naïve and ART-experienced%; P > .99). However, 47% (24/51) of those receiving ART for ≤14 days died within 2 weeks, compared with 19% (20/105) of those receiving ART for 15-182 days and 26% (32/125) of those receiving ART for >6 months (P < .001). Among persons receiving ART for >6 months, 87% had HIV viral loads >1000 copies/mL. CONCLUSIONS: Cryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of central nervous system infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent cryptococcal meningitis after ART initiation.

Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis.

AIM: Tuberculosis meningitis (TBM) diagnosis is difficult, new biomarkers are needed. We evaluated the diagnostic utility of delta-like 1 protein (DLL1), vitamin D binding protein (VDBP) and fetuin. METHODS: Biomarker concentrations were measured by ELISA in cryopreserved cerebrospinal fluid from 139 HIV-infected Ugandans with suspected meningitis. TBM was diagnosed by GeneXpert MTB/Rif or culture. Cohort diagnoses included TBM (n = 22), cryptococcal (n = 71), or aseptic meningitis (n = 16) and no meningitis (n = 30). RESULTS: DLL1 (cut-off value 1150 pg/ml) provided 32% sensitivity and 98% specificity. Adding fetuin, cryptococcal antigen and IFN-γ resulted in sensitivities of 36, 63 and 76% with specificities of 98, 90 and 92%, respectively. VDBP (cut-off value 2.0 µg/ml) provided 81% sensitivity and 68% specificity while fetuin (cut-off value 2 µg/ml) provided a sensitivity of 86% and specificity of 68%. CONCLUSION: CSF DLL1, VDBP and fetuin exhibited fair diagnostic performance for TBM diagnosis.

Evaluation of a point-of-care immunoassay test kit 'StrongStep' for cryptococcal antigen detection.

BACKGROUND: HIV-associated cryptococcal meningitis is the leading cause of adult meningitis in Sub-Saharan Africa, accounting for 15%-20% of AIDS-attributable mortality. The development of point-of-care assays has greatly improved the screening and diagnosis of cryptococcal disease. We evaluated a point-of-care immunoassay, StrongStep (Liming Bio, Nanjing, Jiangsu, China) lateral flow assay (LFA), for cryptococcal antigen (CrAg) detection in cerebrospinal fluid (CSF) and plasma. METHODS: We retrospectively tested 143 CSF and 77 plasma samples collected from HIV-seropositive individuals with suspected meningitis from 2012-2016 in Uganda. We prospectively tested 90 plasma samples collected from HIV-seropositive individuals with CD4 cell count <100 cells/µL from 2016-2017 as part of a cryptococcal antigenemia screening program. The StrongStep CrAg was tested against a composite reference standard of positive Immy CrAg LFA (Immy, Norman, OK, USA) or CSF culture with statistical comparison by McNemar's test. RESULTS: StrongStep CrAg had a 98% (54/55) sensitivity and 90% (101/112) specificity in plasma (P = 0.009, versus reference standard). In CSF, the StrongStep CrAg had 100% (101/101) sensitivity and 98% (41/42) specificity (P = 0.99). Adjusting for the cryptococcal antigenemia prevalence of 9% in Uganda and average cryptococcal meningitis prevalence of 37% in Sub-Saharan Africa, the positive predictive value of the StrongStep CrAg was 50% in plasma and 96% in CSF. CONCLUSIONS: We found the StrongStep CrAg LFA to be a sensitive assay, which unfortunately lacked specificity in plasma. In lower prevalence settings, a majority of positive results from blood would be expected to be false positives.