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Among persons with human immunodeficiency virus–associated cryptococcal meningitis serum hyponatremia is a risk factor for mortality; however, the role of hyponatremia in persons with asymptomatic cryptococcal antigenemia is unknown. We found that serum hyponatremia ≤130 mmol/L is an independent risk factor for progression to meningitis and death in asymptomatic persons with cryptococcal antigenemia.

Using data from 67 Ugandan human immunodeficiency virus (HIV) clinics (July 2019–January 2022), we report a 40% (1005/1662) reduction in the number of people with HIV presenting to care after August 2021 compared to prepandemic levels, with a greater proportion presenting with advanced HIV disease (20% vs 16% in the pre–coronavirus disease 2019 period).

Background Despite HIV test and treat initiatives, the World Health Organization (WHO) estimates that 25% to 40% of persons living with HIV (PLWH) have advanced HIV disease (CD4< 200 cells/mcL). The objective of this study is to understand how the Covid-19 pandemic affected identification of persons with advanced HIV disease in Ugandan HIV clinics. Methods We retrospectively reviewed data from 67 HIV clinics surrounding Kampala, Uganda. As part of routine data collection for PEPFAR reporting, number of persons entering care by clinic and number of persons presenting with CD4< 200 cells/mcL were summarized by month between July 2019 and January 2022. We used the Johns Hopkins Coronavirus Resource Center website to summarize Ugandan Covid-19 cases by month. Covid-19 lockdown dates were taken from the Ugandan government’s COVID-19 information website. Specifically, between March and May 2020, there was a period of strict lockdown where public transportation was halted. Between May and July 2020 there was a less stringent lockdown (public transportation was available, but schools and many businesses remained closed). Again between June and July 2021 a strict lockdown occurred. Results Prior to the Covid-19 pandemic, between July 2019 and February 2020, an average of 16% (265/1675) of PLWH presented monthly with advanced HIV disease. During Covid-19 lockdowns from March 2020 to July 2020, only 9% (102/1124) of PLWH presented with advanced HIV disease. During the period of lockdown, there was a 33% reduction in the monthly average number of PLWH presenting to HIV clinics, and a 62% reduction in the monthly average number of PLWH presenting with advanced HIV disease. From February 2021 to January 2022, 18% (185/987) of PLWH presented with advanced HIV disease. During this period, there was a 42% reduction in the number of persons presenting to HIV care; of those who presented, a larger portion presented with advanced HIV disease. Conclusion The Covid-19 lockdowns negatively affected presentation of PLWH to care, most significantly among persons with advanced HIV disease. This reduction in presentation to care has persisted and not recovered to pre-Covid levels. In the past year, 18% of PLWH presented with advanced HIV disease. Disclosures All Authors: No reported disclosures.

Background It is unknown whether persons with symptomatic cryptococcal meningitis detected during routine blood cryptococcal antigen (CrAg) screening have better survival than persons presenting with overt meningitis. Methods We prospectively enrolled Ugandans with HIV and cryptocococcal meningitis from December 2018 to December 2021. Participants were treated with amphotericin-based combination therapy. We compared outcomes between persons who were CrAg screened then referred to hospital with those presenting directly to the hospital with symptomatic meningitis. Results Among 489 participants with cryptococcal meningitis, 40% (194/489) received blood CrAg screening and were referred to hospital (median time to referral 2 days; interquartile range [IQR], 1–6). CrAg-screened persons referred to hospital had lower 14-day mortality than non–CrAg-screened persons who presented directly to hospital with symptomatic meningitis (12% vs 21%; hazard ratio, .51; 95% confidence interval, .32–.83; P = .006). Fewer CrAg-screened participants had altered mental status versus non–CrAg-screened participants (29% vs 41%; P = .03). CrAg-screened persons had lower quantitative cerebrospinal fluid (CSF) culture burden (median [IQR], 4570 [11–100 000] vs 26 900 [182–324 000] CFU/mL; P = .01) and lower CSF opening pressures (median [IQR], 190 [120–270] vs 225 [140–340] mmH2O; P = .004) compared with non–CrAg-screened persons. Conclusions Survival from cryptococcal meningitis was higher in persons with prior CrAg screening than those without CrAg screening. Altered mental status was the most potent predictor for mortality in a multivariate model. We suggest that CrAg screening detects cryptococcal meningitis at an earlier stage, as evidenced by a favorable baseline risk profile and notably fewer persons with altered mental status.

Introduction Health workers’ failure to adhere to guidelines for screening, diagnosis and management of HIV-associated cryptococcal meningitis (CM) remains a significant public health concern. We aimed to assess adherence to the standards of care and management of HIV patients at risk of CM per the MoH guidelines and assess stock management of CM supplies in the period of January to June 2021 at selected public health facilities (HFs) in Uganda. Methods The study employed an observational cross-sectional design to assess the level of adherence of health workers to standards of clinical care and management of HIV positive patients at risk of CM as per the clinical guidelines for Uganda, and stock management of CM supplies in the period of January to June 2021in selected public health facilities. The study team used a survey guide designed by MoH to assess and score the screening, diagnosis and management practices of Health Facilities towards CM. Scoring was categorized as red (< 80%), light green (80%-95%), and dark green (˃95%) in the order from worst to best adherence. The data was transcribed into a spread sheet and analysed using STATA–v15. Results The study team visited a total of 15 public health facilities including 5 general hospitals, 9 regional referral hospitals (RRHs) and 1 National Referral hospital (NRH). The mean score for adherence to screening and management of CM for all the combined facilities was 15 (64.7%) classified as red. 10 (66.7%) HFs had not performed a baseline CD4 test for eligible patients within 2 weeks of ART initiation. With regards to treatment, 9 (60%) of the HFs were scored as light green on knowledge of the procedure for reconstituting intravenous Liposomal Amphotericin B. None of the HFs visited had potassium chloride tablets in stock. Conclusion Major MoH guidelines are generally not being adhered to by health workers while managing cryptococcal meningitis. It is vital that government and implementing partners regularly support HFs with training, mentorship, and support supervision on CM management to improve adherence to CM screening and treatment guidelines.

Late presentation to HIV care, i.e., presenting with 200 CD4 cells/mL, is associated with higher mortality and worse outcomes. Despite that, a quarter of people living with HIV in Uganda still present late to care. We surveyed Ugandans living with HIV who enrolled in clinic ≤ 90 days prior. We compared groups who presented 'late' with CD4 200 and 'early' with CD4 350, stratifying by sex. We found men who presented late had higher externalized stigma than early presenters. Thirty-six percent of the entire cohort were depressed. Social support was stronger in late presenters versus early, although weak overall. Social support was inversely correlated with depression, with social support dropping as depression increased. Interventions to improve clinic privacy, reduce stigma, improve social support, and help women disclose their HIV status to male partners are needed to reduce late presentation to HIV care.

Introduction Key and priority populations (with risk behaviours and health inequities) are disproportionately affected by HIV in Uganda. We evaluated the impact of an intensive case management intervention on HIV treatment outcomes in Kalangala District, predominantly inhabited by fisher folk and female sex workers. Methods This quasi-experimental pre-post intervention evaluation included antiretroviral therapy naïve adults aged ≥ 18 years from six health facilities in the pre-intervention (Jan 1, 2017–December 31, 2017) and intervention phase (June 13, 2018–June 30, 2019). The primary outcomes were 6-month retention and viral suppression (VS) before and after implementation of the intervention involving facility and community case managers who supported participants through at least the first three months of ART. We used descriptive statistics to compared the characteristics, overall outcomes (i.e., retention, lost to follow up, died), and VS of participants by phase, and used mixed-effects logistic regression models to determine factors associated with 6-month retention in care. Marginal (averaging over facilities) probabilities of retention were computed from the final multivariable model. Results We enrolled 606 and 405 participants in the pre-intervention and intervention phases respectively. Approximately 75% of participants were aged 25–44 years, with similar age and gender distributions among phases. Approximately 46% of participants in the intervention were fisher folk and 9% were female sex workers. The adjusted probability of 6-month retention was higher in the intervention phase, 0.83 (95% CI: 0.77–0.90) versus pre-intervention phase, 0.73 (95% CI: 0.69–0.77, p = 0.03). The retention probability increased from 0.59 (0.49–0.68) to 0.73 (0.59–0.86), p = 0.03 among participants aged 18–24 years, and from 0.75 (0.71–0.78) to 0.85 (0.78–0.91), p = 0.03 among participants aged ≥ 25 years. VS ( Conclusions After implementation of the case management intervention, we observed significant improvement in 6-month retention in all age groups of a highly mobile population of predominantly fisher folk.

Cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy for people with CD4 cell counts Lay summary The objective of this study was to evaluate cryptococcal antigen (CrAg) screening program implementation in Uganda, by type of healthcare center and by distance from the capital city. CrAg screening uptake was not associated with distance from the capital city, or the type of healthcare center.

Cryptococcal antigen (CrAg) screening is recommended for patients with advanced HIV to reduce AIDS-related mortality. For asymptomatic CrAg-positive persons, fluconazole pre-emptive therapy is standard, despite a ∼25% failure rate. Single-dose liposomal amphotericin B (AmBisome) is non-inferior to standard treatment for cryptococcal meningitis. We evaluate the threshold of efficacy necessary for AmBisome + fluconazole to be cost-effective as pre-emptive therapy for CrAg-positive persons. We created a decision analytic model to evaluate CrAg screening and treatment in HIV-infected persons with CD4 In South Africa, at ${\$}$16.25 per vial cost and a minimum efficacy of 85%, adjunctive AmBisome is cost-saving compared to fluconazole monotherapy. Compared to fluconazole pre-emptive therapy in Uganda, AmBisome + fluconazole would cost ${\$}$475, ${\$}$220, or ${\$}$136 per DALY averted if meningitis-free survival efficacy was 80, 85, or 90% at ${\$}$24 per vial cost. Investing in AmBisome may be cost-effective in low-income settings compared to using fluconazole pre-emptive therapy alone, if efficacy is 85% or greater. AmBisome pre-emptive therapy appears more cost-efficient in middle-income settings where hospitalization costs for meningitis, and GDP per capita are higher. Lay Summary We evaluate the efficacy necessary for AmBisome + fluconazole to be cost-effective to prevent cryptococcal meningitis. We found that if AmBisome pre-emptive therapy has an efficacy of 85% or greater, it is likely to be cost-effective in low-income settings.

A newly developed cryptococcal antigen (CrAg) semiquantitative (SQ) lateral flow assay (LFA) provides a semiquantitative result in a rapid one-step test instead of performing serial dilutions to determine CrAg titer. We prospectively compared the diagnostic performance of the CrAgSQ assay (IMMY) with the CrAg LFA (IMMY) on cerebrospinal fluid (CSF) samples collected from persons with HIV-associated meningitis. The CrAgSQ grades (1+ to 5+) were compared with CrAg LFA titers and quantitative CSF fungal cultures. Among 87 participants screened for HIV-associated meningitis, 60 had cryptococcal meningitis (59 CrAg positive [CrAg(+)] by LFA and 1 false negative due to prozone with CrAg LFA titer of 1:1,310,000 and culture positivity), and 27 had no cryptococcal meningitis by CrAg LFA or culture. The CrAgSQ on CSF had 100% (60/60) sensitivity and 100% specificity (27/27). CSF CrAg titers ranged from 1:5 to 1:42 million. CrAgSQ grades of 1+, 2+, 3+, 4+, and 5+ corresponded to median CrAg LFA titers of 1

Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4

Background Clinical trials remain the cornerstone of improving outcomes for HIV-infected individuals with cryptococcal meningitis. Community engagement aims at involving participants and their advocates as partners in research rather than merely trial subjects. Community engagement can help to build trust in communities where these trials are conducted and ensure lasting mutually beneficial relationships between researchers and the community. Similarly, different studies have reported the positive effects of social support on patient’s outcomes. We aimed to describe our approach to community engagement in Uganda while highlighting the benefits of community engagement and social support in clinical trials managing patients co-infected with HIV and cryptococcal meningitis. Methods We carried out community engagement using home visits, health talks, posters, music and drama. In addition, social support was given through study staff individually contributing to provide funds for participants’ food, wheel chairs, imaging studies, adult diapers, and other extra investigations or drugs that were not covered by the study budget or protocol. The benefits of this community engagement and social support were assessed during two multi-site, randomized cryptococcal meningitis clinical trials in Uganda. Results We screened 1739 HIV-infected adults and enrolled 934 with cryptococcal meningitis into the COAT and ASTRO-CM trials during the period October 2010 to July 2017. Lumbar puncture refusal rates decreased from 31% in 2010 to less than 1% in 2017. In our opinion, community engagement and social support played an important role in improving: drug adherence, acceptance of lumbar punctures, data completeness, rate of screening/referrals, reduction of missed visits, and loss to follow-up. Conclusions Community engagement and social support are important aspects of clinical research and should be incorporated into clinical trial design and conduct. Trial registration ClinicalTrials.gov number, NCT01075152 and NCT01802385.

Early cryptococcal disease can be detected via circulating antigen in blood before fulminant meningitis develops, when early antifungal therapy improves survival. Two semiquantitative cryptococcal antigen (CrAg) lateral flow assays (LFAs) have been developed, but their diagnostic performance has not been defined. Cryopreserved serum samples from HIV-infected Ugandans obtained as part of a prospective CrAg-screening cohort were tested in duplicate for CrAg by the CrAgSQ (IMMY) and CryptoPS (Biosynex) lateral flow assays. Case-controlled diagnostic performance was measured using the FDA-approved CrAg LFA (IMMY) as a reference standard via McNemar’s test. Of 99 serum samples tested, 57 were CrAg positive (CrAg(+)) by the CrAg LFA reference standard. By CrAgSQ, 57 were read as positive, with 98% sensitivity (56/57; 95% confidence interval [CI], 0.91 to 0.99) and 98% specificity (41/42; 95% CI, 0.88 to 0.99) (McNemar’s, P = 0.99). The sample with a false-negative result by CrAgSQ (n = 1) had a titer of

Supplemental Digital Content is Available in the Text., Background: HIV-infected persons with cryptococcal antigenemia (CrAg) are at high risk for meningitis or death. We evaluated the effect of CrAg screening and preemptive fluconazole therapy, adjunctive to antiretroviral therapy (ART), on 6-month survival among persons with advanced HIV/AIDS. Methods: We enrolled HIV-infected, ART-naive participants with

BACKGROUND Cryptococcus is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) is detectable in blood before meningitis onset and predicts death. CrAg screening among those with advanced HIV, and treatment of those CrAg+ with fluconazole, has demonstrated survival benefit. However, implementation and widespread uptake have been slow outside clinical trials. METHODS We designed a CrAg screening program for routine care that incorporated intensive education and training of clinic staff. We evaluated programmatic implementation, including time to initiation of fluconazole, time to initiation of antiretroviral therapy, and 6-month clinical outcomes. RESULTS Between December 2015 and January 2017, 1440 persons were screened at 11 HIV clinics in Kampala, and CRAG+ prevalence was 6.5% (n = 94/1440) among adults with a CD4

Background HIV-infected persons with detectable cryptococcal antigen (CrAg) in blood have increased morbidity and mortality compared with HIV-infected persons who are CrAg-negative. This study examined neurocognitive function among persons with asymptomatic cryptococcal antigenemia. Methods Participants from three prospective HIV cohorts underwent neurocognitive testing at the time of antiretroviral therapy (ART) initiation. Cohorts included persons with cryptococcal meningitis (N = 90), asymptomatic CrAg + (N = 87), and HIV-infected persons without central nervous system infection (N = 125). Z-scores for each neurocognitive test were calculated relative to an HIV-negative Ugandan population with a composite quantitative neurocognitive performance Z-score (QNPZ-8) created from eight tested domains. Neurocognitive function was measured pre-ART for all three cohorts and additionally after 4 weeks of ART (and 6 weeks of pre-emptive fluconazole) treatment among asymptomatic CrAg + participants. Results Cryptococcal meningitis and asymptomatic CrAg + participants had lower median CD4 counts (17 and 26 cells/μL, respectively) than the HIV-infected control cohort (233 cells/μL) as well as lower Karnofsky performance status (60 and 70 vs. 90, respectively). The composite QNPZ-8 for asymptomatic CrAg + (−1.80 Z-score) fell between the cryptococcal meningitis cohort (−2.22 Z-score, P = 0.02) and HIV-infected controls (−1.36, P = 0.003). After four weeks of ART and six weeks of fluconazole, the asymptomatic CrAg + cohort neurocognitive performance improved (−1.0 Z-score, P

Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and microscopy, which have low sensitivity and longer turn-around-times are not widely available, leading to delays in timely antifungal therapy and detrimental patient outcomes. The evolution of cryptococcal antigen (CrAg) testing to develop inexpensive and more sensitive methods to detect cryptococcal antigen is significant. These newer tests employ immunoassays as part of point-of-care platforms, which do not require complex laboratory infrastructure and they have the potential to detect early disease and reduce time to diagnosis of cryptococcal infection. Advocacy for widely available and efficacious life-saving antifungal treatment should be the only remaining challenge.

INTRODUCTION Improving HIV outcomes among severely immunocompromised HIV-infected persons who have increased morbidity and mortality remains an important issue in sub-Saharan Africa. We sought to evaluate the impact of targeted clinic-based nurse care on antiretroviral therapy (ART) initiation and retention among severely immunocompromised HIV-infected persons. METHODS The study included ART-naive patients with CD4 counts

Cryptococcal meningiti s causes 15% of AIDS-related deaths globally. Screening and preemptive treatment for cryptococcal antigen (CrAg) in the blood of persons with advanced HIV/AIDS reduces mortality. National and international HIV guidelines recommend CrAg screening; however, implementation studies and evaluations of how to integrate CrAg screening programs into existing HIV care infrastructure are lacking. During a CrAg screening program in Kampala, Uganda, we interviewed 15 health care workers (2 coordinating research nurses and 13 clinic personnel) from 6 HIV clinics between March and April 2017, to identify barriers to implementation as well as facilitating factors for program success. The interviews were coded and themes compiled. We found key factors for successful implementation of a CrAg screening program were: adequate supplies of fluconazole and CrAg lateral flow assay (LFA) point-of-care tests, timely patient follow-up, and quick turnaround time of laboratory results. Although both CrAg LFA kits and fluconazole are on the national formulary, stockouts are common, affecting patient care. The CrAg screening recommendation by national HIV guidelines remains integral to the success of the program, as overburdened clinics are otherwise reluctant to adopt additional screening. Collaboration with Ministries of Health for support with enforcing national guidelines, and procuring supplies is paramount to a successful CrAg screening program. Development of a CrAg screening and treatment program within the HIV clinic infrastructure has a number of barriers. Education and training of clinic staff, along with partnership with the Ministry of Health to ensure adequate supplies, facilitated the program.

BackgroundHIV-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.MethodsWe 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 ResultsStrongStep 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.ConclusionsWe 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.

Cryptococcosis remains a significant cause of morbidity and mortality among HIV-infected patients, especially in sub-Saharan Africa where it causes up to 20 % of AIDS-related deaths in HIV programs. A new, highly sensitive, and affordable point of care diagnostic test for cryptococcal infection, the lateral flow assay, can detect early sub-clinical cryptococcosis especially in areas with limited laboratory infrastructure. With a prevalence of detectable sub-clinical cryptococcal infection averaging 7.2 % (95 % CI 6.8–7.6 %) among 36 cohorts with CD4

BACKGROUND: Syphilis infection during pregnancy leads to avoidable morbidity and mortality and remains a significant problem in sub-Saharan Africa. Despite global initiatives to increase the proportion of pregnant women screened, implementation has been slow. We sought to investigate the feasibility of adding syphilis screening within an integrated antenatal HIV clinic. METHODS: Pregnant women attending the HIV antenatal clinic were sequentially enrolled and consenting participants answered a questionnaire on sexual behavior and previous pregnancies, provided sociodemographic data, and were tested using rapid plasmin reagin (RPR). If positive, participants were treated with benzathine penicillin. All were given a partner notification slip and were followed up after delivery to determine birth outcomes. RESULTS: 584 of 606 (95.7%) women approached and consented to test for syphilis. 570 women were enrolled (median age 29 (IQR 25-32) with a median (IQR) CD4 of 372 (257-569) cells/μL). Of the 5.1% (29/570) with a positive RPR, all were asymptomatic, were successfully contacted, and treated with benzathine penicillin without adverse reactions. Overall, 61 (12.1%) of the participants had an adverse birth outcome. In the bivariate analysis, only age was significantly different between those with and without a positive RPR (RR = 1.15, 95% CI 1.065-1.248; p < 0.001). Partners of only 10 (34.5%) participants returned for treatment. CONCLUSIONS: Structural interventions such as opt-out testing for syphilis within integrated HIV-antenatal care clinics are feasible and capitalize on the excellent care programs that have already been established for HIV care. Novel approaches are required for partner notification.