Effect of Coronavirus Disease 2019 Lockdowns on Identification of Advanced Human Immunodeficiency Virus Disease in Outpatient Clinics in Uganda.

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).

Outpatient Cryptococcal Antigen Screening Is Associated With Favorable Baseline Characteristics and Improved Survival in Persons With Cryptococcal Meningitis in Uganda.

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.

Advanced HIV disease: A review of diagnostic and prophylactic strategies.

BACKGROUND: Despite expanded access to antiretroviral therapy (ART) and the rollout of the World Health Organization's (WHO) 'test-and-treat' strategy, the proportion of people with HIV (PWH) presenting with advanced HIV disease (AHD) remains unchanged at approximately 30%. Fifty percent of persons with AHD report prior engagement to care. ART failure and insufficient retention in HIV care are major causes of AHD. People living with AHD are at high risk for opportunistic infections and death. In 2017, the WHO published guidelines for the management of AHD that included a comprehensive package of care for screening and prophylaxis of major opportunistic infections (OIs). In the interim, ART regimens have evolved: integrase inhibitors are first-line therapy globally, and the diagnostic landscape is evolving. The objective of this review is to highlight novel point-of-care (POC) diagnostics and treatment strategies that can facilitate OI screening and prophylaxis for persons with AHD. METHODS: We reviewed the WHO guidelines for recommendations for persons with AHD. We summarized the scientific literature on current and emerging diagnostics, along with emerging treatment strategies for persons with AHD. We also highlight the key research and implementation gaps together with potential solutions. RESULTS: While POC CD4 testing is being rolled out in order to identify persons with AHD, this alone is insufficient; implementation of the Visitect CD4 platform has been challenging given operational and test interpretation issues. Numerous non-sputum POC TB diagnostics are being evaluated, many with limited sensitivity. Though imperfect, these tests are designed to provide rapid results (within hours) and are relatively affordable for resource-poor settings. While novel POC diagnostics are being developed for cryptococcal infection, histoplasmosis and talaromycosis, implementation science studies are urgently needed to understand the clinical benefit of these tests in the routine care. CONCLUSIONS: Despite progress with HIV treatment and prevention, a persistent 20%-30% of PWH present to care with AHD. Unfortunately, these persons with AHD continue to carry the burden of HIV-related morbidity and mortality. Investment in the development of additional POC or near-bedside CD4 platforms is urgently needed. Implementation of POC diagnostics theoretically could improve HIV retention in care and thereby reduce mortality by overcoming delays in laboratory testing and providing patients and healthcare workers with timely same-day results. However, in real-world scenarios, people with AHD have multiple comorbidities and imperfect follow-up. Pragmatic clinical trials are needed to understand whether these POC diagnostics can facilitate timely diagnosis and treatment, thereby improving clinical outcomes such as HIV retention in care.

Differences in Reasons for Late Presentation to HIV Care in Uganda Among Men and Women.

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.

Cost-effectiveness of single-dose AmBisome pre-emptive treatment for the prevention of cryptococcal meningitis in African low and middle-income countries.

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 < 100 cells/µL. Costs were estimated for screening, pre-emptive therapy, and hospitalization for an example low-income country (Uganda) and middle-income country (South Africa). We used a discounted price range of AmBisome® at ${\$}$16.25 to ${\$}$40 per 50 mg vial for both Uganda and South Africa. We estimated AmBisome efficacy from 75 to 95%. Parameter assumptions were based on prospective CrAg screening studies and clinical trials in Africa. Disability adjusted life years (DALYs) were calculated using the age-specific life expectancy in Uganda, per WHO Global Health Observatory data. We modeled the theoretical efficacy of adjunctive AmBisome to determine cost per DALY averted.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.

Determinants of cryptococcal antigen (CrAg) screening uptake in Kampala, Uganda: An assessment of health center characteristics.

Cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy for people with CD4 cell counts <100 cells/µl are recommended by the World Health Organization and several national HIV guidelines. We sought to evaluate CrAg screening program implementation across Uganda, in relation to health center level and distance from the capital. We conducted a cross-sectional study of 22 health centers across southern Uganda from April to June 2019. We reviewed laboratory records regarding number of CD4 cell count tests performed, proportion of outpatients with CD4 counts <200 cells/µl, and number of CrAg screening tests performed. We administered surveys to health center staff to understand barriers to advanced HIV care. We observed no significant difference in health center level and performance of CrAg screening; with each subsequent health center level, there was 1.17-fold (95% CI: 0.92-1.41) higher odds of CrAg screening performed per level. CrAg screening uptake was not associated with distance from the capital city (odds ratio = 0.96, 95% CI: 0.89-1.04). Qualitative data from surveys indicated that limitations to uptake of CrAg screening were secondary to dysfunctional CD4 machines, lack of provider awareness of CrAg screening guidelines, and inadequate/intermittent supply of CrAg tests. There were no significant associations between CrAg screening uptake and level of health center or distance of health center from the capital city. We identified systemic barriers to CrAg screening related to inadequate CD4 testing, insufficient knowledge regarding national screening guidelines, and irregular laboratory testing supplies. 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.

Impact of an intensive facility-community case management intervention on 6-month HIV outcomes among select key and priority populations in Uganda.

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 (< 1,000 copies/mL) was approximately 87% in both phases. 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.

Evaluation of the Diagnostic Performance of a Semiquantitative Cryptococcal Antigen Point-of-Care Assay among HIV-Infected Persons with Cryptococcal Meningitis.

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:<10, 1:60, 1:7,680, 1:81,920, and 1:1,474,000, respectively. CSF CrAgSQ grades 3+ or higher were always CSF culture positive. Mortality at 14 days for those with low CrAgSQ grade (1+ to 3+) was 5% (1/22) versus 21% (8/38) with high CrAgSQ grades (4+ to 5+) (P = 0.084). The CrAgSQ demonstrates excellent diagnostic performance, maintaining both the sensitivity and specificity of the CrAg LFA, and counters false-negative prozone effects. The CrAgSQ assay reading is more complex but does provide useful clinical information about disease burden and probability of culture positivity in a single rapid diagnostic test.

Evaluation of Serum Cryptococcal Antigen Testing Using Two Novel Semiquantitative Lateral Flow Assays in Persons with Cryptococcal Antigenemia.

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 <1:5, while the sample with a false-positive result (n = 1) yielded a 1+ result. By CryptoPS, 52 samples were read as positive, with 88% sensitivity (50/57; 95% CI, 0.76 to 0.95) and 95% specificity (40/42; 95% CI, 0.84 to 0.99) (McNemar's, P = 0.18). The CryptoPS false-negative results included samples with titers of <1:5 (n = 1), 1:5 (n = 5), and 1:20 (n = 1), while samples with false-positive results by CryptoPS (n = 2) yielded Positive results. The CryptoPS assay missed 35% (7/20) of samples with CrAg LFA titers of ≤1:20. The new semiquantitative CrAg LFAs allow rapid estimation of titer levels in easy-to-perform platforms. The CrAgSQ demonstrated better qualitative sensitivity and specificity than the CryptoPS compared to the reference standard. The exact grading of the CrAgSQ results has some subjectivity, with interreader variability; however, qualitative reads were generally concordant for both assays.

Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial.

Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4 < 100 cells/µl can reduce meningitis and death, yet preemptive fluconazole therapy fails in ∼25%. Sertraline has in vitro and in vivo activity against Cryptococcus and is synergistic with fluconazole in mice. We evaluated the efficacy and safety of sertraline in asymptomatic cryptococcal antigenemia. We conducted a randomized trial of asymptomatic CrAg-positive Ugandans from November 2017 to February 2018. All subjects received WHO standard therapy of fluconazole 800 mg for 2 weeks, then 400 mg for 10 weeks, then 200 mg through 24 weeks. Participants were randomized to receive adjunctive sertraline or placebo, given in once-weekly escalating 100 mg/day doses up to 400 mg/day, which was then given for 8 weeks, then tapered. The primary endpoint was meningitis-free 6-month survival. The data and safety monitoring board halted the trial after 21 subjects were enrolled due to safety concerns. Meningitis-free 6-month survival occurred in 9 of 11 of placebo participants and 10 of 10 of sertraline participants. However, seven serious adverse events (SAEs) occurred (n = 4 sertraline group; n = 3 placebo group). Three SAEs in the sertraline group presented with psychosis and aggressive behavioral changes with one meeting Hunter's criteria for serotonin syndrome while receiving 200 mg/day sertraline. Two transient psychoses were associated with antecedent fluconazole and sertraline interruption. The serotonin syndrome resolved within 1 day, but psychosis persisted for 4 months after sertraline discontinuation. Sertraline was associated with excess SAEs of psychosis. Due to early stopping, we were unable to determine any efficacy for cryptococcal antigenemia.

Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management.

Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7-1.0 mg/kg). Five were exposed to 200-800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.

Neurocognitive function in HIV-infected persons with asymptomatic cryptococcal antigenemia: a comparison of three prospective cohorts.

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 < 0.001). CONCLUSION: Significant deficits in neurocognitive function were identified in asymptomatic CrAg + persons with advanced HIV/AIDS even without signs or sequelae of meningitis. Neurocognitive function in this group improves over time after initiation of pre-emptive fluconazole treatment and ART, but short term adherence support may be necessary.

Integration of antenatal syphilis screening in an urban HIV clinic: a feasibility study.

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.

Prevalence of Histoplasma Antigenuria among Outpatient Cohort with Advanced HIV in Kampala, Uganda.

In sub-Saharan Africa, an estimated 25% of people with HIV present with advanced HIV and are at high risk of opportunistic infections. Whereas histoplasmosis has occasionally been seen in Uganda, the understanding of the local risk of acute infection is limited. We sought to determine the prevalence of Histoplasma antigenuria using an enzyme immunoassay (EIA, clarus Histoplasma GM EIA, IMMY; Norman, OK, USA) in a cohort of outpatients with advanced HIV disease in Kampala, Uganda. Among the persons with positive urine Histoplasma antigen tests, we assessed their clinical presentation and outcomes. The EIA was run on stored urine samples as per the manufacturer's instructions. Specimens ≥1 EIA units were considered positive. Among the 388 tested urine samples, 4 (1.2%) were positive for Histoplasma antigen. The histoplasmosis prevalence among participants with a CD4 < 100 cells/mcL was 2.5% (4/158). Three of the four participants with a positive Histoplasma antigen test reported systemic symptoms consistent with histoplasmosis. All four participants had a positive urine lipoarabinomannan test and were treated for tuberculosis. By the four-week follow-up visit, all participants were clinically improved, alive, and in care without antifungal therapy. In advanced HIV, the clinical presentations of tuberculosis and histoplasmosis overlap. The value of histoplasmosis screening and pre-emptive treatment is an area of future research.

Hyponatremia as a Predictor of Cryptococcal Meningitis and Death Among Asymptomatic Persons With HIV and Cryptococcal Antigenemia.

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.

Adherence of health workers to guidelines for screening and management of cryptococcal meningitis in Uganda.

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.

Impact of community engagement and social support on the outcomes of HIV-related meningitis clinical trials in a resource-limited setting.

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.

Reflexive Laboratory-Based Cryptococcal Antigen Screening and Preemptive Fluconazole Therapy for Cryptococcal Antigenemia in HIV-Infected Individuals With CD4 <100 Cells/µL: A Stepped-Wedge, Cluster-Randomized Trial.

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 <100 CD4 cells/µL, in a stepped-wedge, cluster-randomized trial from July 2012 to December 2014 at 17 Ugandan clinics. Clinics participated in a prospective observational phase, followed by an interventional phase with laboratory-based, reflexive CrAg screening of residual CD4 count plasma. Asymptomatic CrAg+ participants received preemptive fluconazole therapy. We assessed 6-month survival using Cox-regression, adjusting for nadir CD4, calendar time, and stepped-wedge steps. RESULTS: We included 1280 observational and 2108 interventional participants, of whom 9.3% (195/2108) were CrAg+. CD4-, time-, and stepped-wedge-adjusted analyses demonstrated no difference in survival in the observational vs the interventional arms (hazard ratio = 1.34; 95% confidence interval: 0.86 to 2.10; P = 0.20). Fewer participants initiated ART in the interventional (73%) versus the observational phase (82%, P < 0.001). When ART initiation was modeled as a time-dependent covariate or confounder, survival did not differ. However, 6-month mortality of participants with CrAg titers <1:160 and CrAg-negative patients did not differ. Patients with CrAg titers ≥1:160 had 2.6-fold higher 6-month mortality than patients with titers <1:160. CONCLUSIONS: We observed no overall survival benefit of the CrAg screen-and-treat intervention. However, preemptive antifungal therapy for asymptomatic cryptococcosis seemed to be effective in patients with CrAg titer <1:160. A more aggressive approach is required for persons with CrAg titer ≥1:160.

A qualitative evaluation of an implementation study for cryptococcal antigen screening and treatment in Uganda.

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.