Cryptococcal Antigen Screening Research Articles

1497. Cryptococcal Antigen Screening and Pre-emptive Fluconazole Therapy in HIV-infected Patients: A Multicenter, Retrospective Study in China

Abstract Background The implementation and effectivention of CrAg screening programs and pre-emptive treatment remains unclear in China. Methods We performed a multicenter, retrospective study at eight hospitals from 1st Jan 2019 to 31st Dec 2020, to evaluate whether CrAg screening programs and preemptive treatment are beneficial for saving lives in China. Results A total of 12768 PLWH were screened for serum CrAg. The prevalence of serum CrAg positivity was 5.3% (678/12768). Lumbar puncture (LP) records were completed and available in 580 patients. Among them, 36.4% (369/580) were diagnosed with CM, and 63.6% (211/580) were diagnosed with isolated cryptococcal antigenemia (ICA). 123 HIV/ICA patients have available clinical data. Of these patients, a median CD4+ T-cell counts were 41cells/µL (IQR, 19-83). Upon Cox proportional-hazards regression analysis, patients with no preemptive fluconazole treatment had a threefold higher risk of CM and/or death [19.0% (8/42) vs 8.6% (7/81), p=0.037] compared to the preemptive fluconazole treatment participants. However, there was no statistically significant difference for the development of CM and/or death in different dosage (therapy as per WHO recommendations vs oral fluconazole 400mg daily therapy) of fluconazole therapy (p=0.836). Also, we found no statistically significant difference in the proportion of CrAg negativity [60.0% (12/20) vs 54.5% (18/33), p=0.779] and the median time from positivity to negativity of serum CrAg [14 (IOR:9.25, 14) vs 14 (10.5, 15), p=1.000] within one year follow up. In our study, Patients who with virological suppression had a lower incidence of CM and/or death than patients who with virological non-suppression [5.6% (1/18) vs (17.2% (5/29), p=0.384], however, there was no statistically significant difference in Cox proportional-hazards regression analysis. Conclusion Rapid ART initiation, appropriate CrAg screening are essential for advanced PLWH. Lp is a necessary intervention in advanced HIV-infected patients for CrAg positive individual to prevent potential missed diagnosis and mistreatment of CM. Targeted improvements to pre-emptive antifungal therapy for cryptococcal antigenemia are required to further improve patient outcomes in CrAg-positive severely immunocompromised people with HIV/AIDS. Disclosures All Authors: No reported disclosures

Rapid antiretroviral therapy initiation in patients with advanced HIV disease: 6-month outcomes of an observational cohort evaluation in Lesotho.

For adults and adolescents, the World Health Organization defines advanced HIV disease (AHD) as a CD4 (cluster of differentiation 4) count of <200 cells/mm3 or a clinical stage 3 or 4 event. We describe clinical outcomes in a cohort of AHD patients at two regional hospitals in Lesotho. From November 2018-June 2019, we prospectively enrolled eligible patients (≥15 years) not on antiretroviral therapy (ART) presenting with WHO-defined AHD into a differentiated model of care for AHD (including rapid ART initiation) and followed them for six months. All patients received Tuberculosis (TB) symptom screening with further diagnostic testing; serum cryptococcal antigen (CrAg) screening was done for CD4 <100 cells/mm3 or WHO clinical stage 3 or 4. Medical record data were abstracted using visit checklist forms. Categorical and continuous variables were summarized using frequencies, percentages, and means, respectively. Kaplan-Meier was used to estimate survival. Of 537 HIV-positive patients screened, 150 (27.9%) had AHD of which 109 were enrolled. Mean age was 38 years and 62 (56.9%) were men. At initial clinic visit, 8 (7.3%) were already on treatment and 33% (36/109) had presumptive TB per symptom screening. Among 39/109 (40.2%) patients screened for CrAg at initial visit, five (12.8%) were CrAg-positive. Among 109 enrolled, 77 (70.6%) initiated ART at their initial clinic visit, while 32 delayed ART initiation (median delay: 14 days). Of the 109 participants enrolled, 76 (69.7%) completed the 6-month follow-up, 17 (15.6%) were lost to follow-up, 5 (4.6%) transferred to other health facilities and 11 (10.1%) died. The 6-month survival was 87.4%; among 74 patients with a viral load result, 6-month viral suppression (<1,000 copies/ml) was 85.1%. Our study found that even after the implementation of Test and Treat of ART in 2016 in Lesotho, over 25% of patients screened had AHD. Patients with AHD had a high prevalence of TB and CrAg positivity, underscoring the need to assess for AHD and rapidly initiate ART within a package of AHD care for optimal patient outcomes.

Cryptococcal antigenemia in a Nigerian child with advanced HIV disease: a case report

Cryptococcal infection in Nigeria’s advanced HIV disease (AHD) population is not uncommon but is sparsely reported in children. The dearth of data on cryptococcal disease in our paediatric population suggests it is an uncommon clinical entity and may cause delayed diagnosis and preventable deaths. It is pertinent that cognizance be done of this clinical entity in our paediatric population. We report a 16-month-old HIV-positive child with complaints of weight loss of 3 months, cough of 1 month, fever, passage of watery stool, fast and difficulty in breathing for 1 week. She was initially managed as a case of paediatric AIDS with septicaemia and was receiving ceftriaxone and cotrimoxazole. The diagnosis was subsequently reviewed to paediatric AIDS with cryptococcal disease as the cryptococcal antigen screening test was positive and oral fluconazole commenced. However, the patient deteriorated and eventually died. This case report suggests a significant knowledge gap in the occurrence of cryptococcosis in our paediatric population and as a matter of urgency the need to conduct studies targeted at ascertaining the burden of cryptococcosis in children living with AHD in Nigeria.

Impact of prior cryptococcal antigen screening on in-hospital mortality in cryptococcal meningitis or fungaemia among HIV-seropositive individuals in South Africa: a cross-sectional observational study

ObjectivesWe investigated whether patients with cryptococcal meningitis (CM) or fungaemia detected through South Africa's laboratory cryptococcal antigen (CrAg) screening programme had better outcomes than those presenting directly to the hospital. MethodsWe compared 14-day in-hospital case-fatality ratios of HIV-seropositive individuals with CD4 counts below 100 cells/μL and laboratory-confirmed CM/fungaemia from 2017–2021, with or without evidence of a positive blood CrAg test within 14 days prior to diagnosis. We evaluated whether the impact of prior CrAg screening on mortality varied according to the study period (pre–COVID-19: before March 2020 vs. COVID-19: after March 2020). ResultsOverall, 24.5% (830/3390) of patients had a prior positive CrAg test within 14 days of diagnosis. CrAg-screened patients were less likely to have an altered mental status at baseline than non-CrAg-screened patients (38.1% [296/776] vs. 42.6% [1010/2372], p = 0.03), and had a lower crude 14-day case-fatality ratio (24.7% [205/830] vs. 28.3% [724/2560]; OR, 0.83 [95% CI, 0.69–0.99]; p = 0.045). Previous CrAg screening was associated with a greater reduction in the crude 14-day mortality during the COVID-19 period (OR, 0.64 [0.47–0.87]; p = 0.005) compared with before (OR, 0.95 [0.76–1.19]; p = 0.68). After adjustment, previous CrAg screening within 14 days was associated with increased survival only during the COVID-19 period (adjusted OR, 0.70 [0.51–0.96]; p = 0.03). DiscussionPrevious CrAg screening was associated with a survival benefit in patients hospitalized with CM/fungaemia during the COVID-19 period, with fewer patients having an altered mental status at baseline, suggesting that these patients may have been diagnosed with cryptococcosis earlier.

A multicenter survey of asymptomatic cryptococcal antigenemia among patients with advanced HIV disease in Nigeria.

As of 2018, cryptococcal antigen (CrAg) screening in patients with advanced human immunodeficiency virus (HIV) disease (AHD) was not routinely implemented in Nigeria despite being recommended in the national HIV treatment guidelines. Our aim was to determine the prevalence and risk factors for asymptomatic cryptococcal antigenemia in adult people living with HIV (PLHIV) in Nigeria to advocate for the implementation of routine CrAg screening. A descriptive cross-sectional study and CrAg screening of consecutive adult PLHIV with CD4 counts ≤200 cells/μL was conducted from April 2018 to April 2019 at HIV clinics in eleven tertiary hospitals spread across Nigeria's six geopolitical regions. Prevalence of asymptomatic cryptococcal antigenemia was estimated by facility and geopolitical zone. Logistic regression was conducted to identify risk factors for cryptococcal antigenemia. In total, 1,114 patients with AHD were screened. The overall prevalence of asymptomatic cryptococcal antigenemia was 3.9% with wide variation across facilities (range: 0/75 [0%]- 15/122 [12.3%]) and geopolitical zones (range: 0/75 [0%]-19/279 [6.8%]). Prevalence of antigenemia was highest in the South-West (19/279 [6.8%]) and lowest in the North-East (0/75 [0%]). Prevalence was 5.2% (26/512) and 3.2% (18/561) in patients with CD4<100 and CD4 of 101-200, respectively. Of all patients with antigenemia, 50% were on antiretroviral therapy (ART) at the time of having a positive CrAg test. In adjusted analysis, cryptococcal antigenemia was significantly less in patients on ART and patients who had completed any formal education. The survey showed a high overall burden of cryptococcal antigenemia in Nigeria, with variable prevalence across geopolitical regions. We provided valuable evidence for implementing routine CrAg screening of AHD patients in Nigeria which has commenced in selected centres.

Cryptococcal antigen prevalence in HIV patients from a tertiary care centre in South India.

Cryptococcosis is an opportunistic mycosis, caused by Cryptococcus neoformans. Cryptococcal meningitis is one of the most fatal opportunistic infections associated with human immunodeficiency virus (HIV) infection. The aim of this study was to find the prevalence of cryptococcal antigenemia in people living with HIV (PLHA) and also to find the prevalence of opportunistic infections among these patients. A total of 204 non duplicate samples were collected from people with HIV aged above 18 years. Samples with CD4 count less than 300 were included in the study. Cryptococcal antigen detection was done by CrAg Lateral flow assay. None of the patients in our study were positive for cryptococcal antigen. Opportunistic infections were observed in 82 (40.2%) HIV positive patients. Candidiasis, tuberculosis and Pneumocystis jiroveci pneumonia were the most common opportunistic infections. This is the first study from the southern state of Kerala on the prevalence of Cryptococcal antigenemia among HIV positive individuals. The study showed that routine screening for cryptococcal antigen will not be cost effective in our population. Similar to other studies, eventhough candidiasis, tuberculosis and PCP were more commonly seen among people with CD4 count < 200 cells/mm3, there was no statistically significant association.

P461 Cryptococcosis screening and isolates characterization in asymptomatic people living with HIV in Kinshasa, DRC

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PMObjectivesCryptococcal meningitis (CM) is a life-threatening invasive mycosis affecting people living with HIV (PLHIV) and has a high prevalence and case fatality rate in sub-Saharan Africa. While most PLHIV presenting CM are symptomatic, the asymptomatic ones are diagnosed following routine screening tests indicated for all advanced PLHIV (CD4 <200/μl). We, therefore, hypothesized that asymptomatic CM patients would be infected with different Cryptococcus spp. strains than those in symptomatic CM patients (referring to the parallel study conducted in the same clinics). This study describes the prevalence of serum and meningeal cryptococcosis in asymptomatic PLHIV presenting a CD4 count of <200 cells/μl in the screening context. We then characterized and determined the antifungal susceptibility of Cryptococcus spp. strains isolated from these patients.MethodsWe performed cross-sectional screening for serum cryptococcal antigen (CrAg) in ambulant PLHIV with <200 CD4/μL in three clinics in Kinshasa (DRC). Lumbar puncture was indicated in positive patients to exclude a meningeal location for therapeutic purposes. The resulting cerebrospinal fluid (CSF) was then analyzed for CrAg and Cryptococcus spp. was isolated and characterized by MALDI TOF MS, serotyping PCR, ITS sequencing, and multilocus sequence typing (MLST). In addition, the EUCAST E.Def.7.3.2 microdilution procedure was followed to determine the susceptibility of strains to antifungal agents.ResultsA total of 47 PLHIV out of 262 included were tested positive for serum CrAg (19%, 95% CI: 14.2–24.3) from which 46.8% (22/47) had a high antigenic titer (≥1/160). The prevalence of asymptomatic CM was then estimated at 50% in CrAg serum-positive patients who consented to lumbar puncture (19/38). Although the female proportion included in the study was higher than that of men, serum CrAg was more positive in men (21.4%, 18/84 men included) than in women (18.0%, 29/161 women included). While the mean CD4 count of CrAg serum-positive patients were significantly lower than that of negative patients (P <.05), the median viral load between the two patient groups was approximately similar (P >.05). Only four CSF samples were positive in culture for Cryptococcus spp. and were all characterized as Cryptococcus neoformans/serotype A.At this stage, two isolates have been analyzed using the ISHAM MLST scheme and two different sequence type (ST) profiles were identified, namely: ST93 and ST63. While ST93 is the main Cryptococcus neoformans profile described in Congolese (DRC) PLHIV with CM, ST63 has not yet been identified in the DRC before. Of note, epidemiological and clinical specificities of ST63 have so far been poorly characterized in the literature. Susceptibility testing against the major antifungals and the MLST typing of the two remaining strains are still ongoing.Conclusions: The prevalence of cryptococcosis should not be neglected among asymptomatic PLHIV in the DRC, to meaning that screening and preventive treatment measures should be integrated into the national policy for HIV management and related diseases. For the rest of the analyses still in progress, conclusions can only be drawn once they have been fully finalized.

Cryptococcal Antigen Screening and Missed Opportunities for Earlier Diagnosis Among People With HIV and Poor Virologic Control in the Bronx, NY.

Background:There is no established cryptococcal antigen (CrAg) screening guideline for people with HIV who are antiretroviral therapy experienced but have poor virologic control. We assessed factors associated with CrAg screening and describe missed opportunities for earlier testing.Setting:Ambulatory clinics affiliated with Montefiore Medical Center, Bronx, NY.Methods:This was a retrospective chart review of CrAg screening among asymptomatic people with HIV with absolute CD4 counts200 cells/mm3 and HIV viral loads (VLs) > 200 copies/mL receiving HIV care from 2015 to 2020. We used Cox proportional hazards regression to identify predictors of screening, including longitudinal CD4 count and HIV VL as time-varying covariables. Among cases of diagnosed cryptococcosis, we assessed for opportunities for earlier diagnosis.Results:Screening CrAg was performed in 2.9% of 2201 individuals meeting the inclusion criteria. Compared with those not screened, those who were screened had a shorter duration of HIV infection (0.09 vs. 5.1 years; P = 0.001) and lower absolute CD4 counts (12 vs. 24 cells/mm3; P < 0.0001). In a multivariable model stratified by median HIV duration, CD4 < 100 [hazard ratio (HR), 7.07; 95% confidence interval (CI): 2.43 to 20.6], VL > 10,000 (HR, 15.0; 95% CI: 4.16 to 54.0), and a shorter duration of HIV infection (HR, 0.60; 95% CI: 0.42 to 0.86) were associated with screening for those with HIV < 5 years. Among those diagnosed with cryptococcosis (n = 14), 6 individuals had an ambulatory visit in the preceding 6 months but did not undergo screening.Conclusion:CrAg screening was infrequently performed in this at-risk population. Those with a longer duration of HIV infection were less likely to undergo CrAg screening, highlighting potential missed opportunities for earlier diagnosis.

Evaluation of the effectiveness of a South African laboratory cryptococcal antigen screening programme using a retrospective cohort and a cluster-randomised trial design

IntroductionCryptococcal meningitis is a common fungal opportunistic infection and a leading cause of death among people with advanced HIV disease in sub-Saharan Africa. The WHO recommends cryptococcal antigen (CrAg) screening...

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

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. 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. 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. 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.

Epidemiology and Mortality of Cryptococcal Disease in Guatemala: Two-Year Results of a Cryptococcal Antigen Screening Program.

Cryptococcal disease is an important opportunistic infection among people living with HIV. The cryptococcal antigen (CrAg) can be detected before the clinical onset of meningitis and its screening is recommended. Here, we evaluated CrAg frequency, and describe the epidemiological characteristics and mortality at 180 days in a cohort of HIV patients from Guatemala. A total of 3457 patients were screened with a CrAg lateral flow assay in serum between January 2017 and December 2018. CrAg positivity was 11.5% in patients with ≤100 CD4/mm3, 8.7% in patients with <200 CD4/mm3, and 6.3% in patients with <350 CD4/mm3. In Latin America, we estimated 9.2% CrAg positivity (IC95% 7.9–10.7%) in patients with ≤100 CD4/mm3. Among patients newly diagnosed with HIV, we estimated 4416 incident cases per year in Latin America in those with <200 CD4/mm3 and 5289 in those with <350 CD4/mm3. In addition, we calculated the burden in people not on ARV or without viral suppression and found 28,672 cases. CrAg screening should be considered in patients who have a CD4 cell count < 350 cells/mm3. Cryptococcal meningitis was associated with 30.8% mortality in Guatemala. Global access to diagnosis as well as to liposomal amphotericin B and flucytosine is a priority.

Retrospective Assessment of a National Reflex Cryptococcal Antigen Screening Program in South Africa Through Interlaboratory Comparison of Lateral Flow Assay Results.

Reflex cryptococcal antigen (CrAg) screening of blood specimens with a CD4 count of <100 cells/µL was performed at 45 South African CD4 laboratories using a lateral flow assay (LFA). Our objective was to evaluate the reliability of routine LFA results through comparative interlaboratory testing. All CrAg-positive and a selected number of CrAg-negative samples from the CD4 laboratories were retested at paired microbiology laboratories using the same LFA. Samples with discordant results were tested at a reference laboratory, using the LFA (with CrAg titers). During interlaboratory testing, 12,502 samples were retested, with 93 (0.7%) discordant results and a between-laboratory agreement of 99.3% (Cohen's kappa, 0.98). The proportion of retested samples with discordant results ranged from 0.17% to 5.31% per laboratory pair (median 0.28%), with 3 reporting >3% of results as discordant. Routine CrAg screening results were reliable, with <1% of samples having discordant results, mainly due to interpretation and transcription errors.

Cryptococcal and Histoplasma Antigen Screening Among People With Human Immunodeficiency Virus in Ghana and Comparative Analysis of OIDx Histoplasma Lateral Flow Assay and IMMY Histoplasma Enzyme Immunoassay.

BackgroundCryptococcal meningitis (CM) and disseminated histoplasmosis (DH) are common in people with human immunodeficiency virus (PWH) and diagnosed by detecting cryptococcal antigen (CrAg) and Histoplasma antigen (HistoAg), respectively. In Ghana, CM and DH are rarely suspected by clinicians due to limited epidemiological data.MethodsThis study was conducted among PWH in Ghana who are unwell. Sociodemographic and clinical data were collected by questionnaire. Serum and/or urine were screened for CrAg and HistoAg, using IMMY CrAg lateral flow assay (LFA) and IMMY Histoplasma enzyme immunoassay (EIA) kits, respectively, regardless of symptoms. Samples run with IMMY Histoplasma EIA were simultaneously run with Optimum Imaging Diagnostics (OIDx) Histoplasma LFA. Laboratory investigations were conducted by the research team, and diagnosis incorporating clinical assessment, screening, and confirmatory testing results and treatment decisions were made by the clinical team. Treatment and outcome information on CM and DH patients were evaluated.ResultsOverall, 150 participants were recruited. There were 73% (n = 109) females, and the age range was 18–62 years. The prevalence rates of CrAg and HistoAg were 2.7% (4 of 150) and 4.7% (5 of 107), respectively. The OIDx Histoplasma LFA showed a high concordance (98.4%) with the IMMY Histoplasma EIA. All antigen-positive cases by standard tests were diagnosed with CM and DH. Antifungal treatment was given in 5 patients and follow-up revealed 2 deaths and 3 recoveries.ConclusionsHistoplasmosis among PWH may be more common than previously anticipated and may be more frequent than cryptococcosis in Ghana. The performance of the OIDx Histoplasma LFA should be further explored.

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

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.

Evaluation of the initial 12\u2009months of a routine cryptococcal antigen screening program in reduction of HIV-associated cryptococcal meningitis in Uganda

BackgroundAsymptomatic Cryptococcal Antigenemia (CrAg) patients develop meningitis within a month of testing positive. Pre-emptive antifungal therapy can prevent progression to Cryptococcal meningitis (CM). In April 2016, a national CrAg screening program was initiated in 206 high-volume health facilities that provide antiretroviral therapy in Uganda. We report the evaluation of the CrAg screening cascade focusing on linkage to care, fluconazole therapy for 10 weeks and 6 months follow up, and ART initiation in a subset of facilities.MethodsWe conducted a retrospective, cross-sectional survey of patients with CD4 < 100 at seven urban and seven rural facilities after 1 year of program implementation. We quantified the number of patients who transitioned through the steps of the CrAg screening cascade over six-months follow-up. We defined cascade completion as a pre-emptive fluconazole prescription for the first 10 weeks. We conducted semi-structured interviews with lab personnel and clinic staff to assess functionality of the CrAg screening program. Data was collected using REDCap.ResultsWe evaluated 359 patient records between April 2016 to March 2017; the majority (358/359, 99.7%) were from government owned health facilities and just over half (193/359, 53.8%) had a median baseline CD4 cell count of < 50 cell/μL. Overall, CrAg screening had been performed in 255/359 (71.0, 95% CI, 66.0–75.7) of patients’ records reviewed, with a higher proportion among urban facilities (170/209 (81.3, 95% CI, 75.4–86.4)) than rural facilities (85/150 (56.7, 95% CI, 48.3–64.7)). Among those who were CrAg screened, 56/255 (22.0, 95% CI, 17.0–27.5%) had cryptococcal antigenemia, of whom 47/56 (83.9, 95% CI, 71.7–92.4%) were initiated on pre-emptive therapy with fluconazole and 8/47 (17.0, 95% CI, 7.6–30.8%) of these were still receiving antifungal therapy at 6 months follow up. At least one CNS symptom was present in 70% (39/56) of those with antigenemia. In patients who had started ART, almost 40% initiated ART prior to CrAg screening. Inadequacy of equipment/supplies was reported by 15/26 (58%) of personnel as a program barrier, while 13/26 (50%) reported a need for training about CM and CrAg screening.ConclusionThere was a critical gap in the follow-up of patients after initiation on fluconazole therapy. ART had been initiated in almost 40% of patients prior to CrAg screening.. Higher antigenemia patients presenting with CNS symptoms could be related to late presentation. There is need to address these gaps after a more thorough evaluation.

Rapid urine-based screening tests increase the yield of same-day tuberculosis diagnoses among patients living with advanced HIV disease.

Investigation of the diagnostic yield of urine-based tuberculosis (TB) screening in patients with advanced HIV disease. A cross-sectional screening study. HIV outpatient clinics and wards at two hospitals in Johannesburg, South Africa, between June 2015 and October 2017. Two hundred and one patients living with advanced HIV disease (CD4+ T-lymphocytes <100 cells/μl) attending healthcare facilities following cryptococcal antigen (CrAg) screening. Screening for TB using sputum for microscopy, culture, and Xpert MTB/Rif and urine for lipoarabinomannan (LAM) and Xpert Ultra. Proportion of positive results using each testing modality, sensitivity, and specificity of urine-based testing compared with culture, and survival outcomes during 6 months follow up. Urine was obtained from 177 of 181 (98%) participants and sputum from 91 (50%). Urine-based screening increased same-day diagnostic yield from 7 (4%) to 31 (17%). A positive urine test with either LAM or Xpert Ultra had 100% sensitivity (95% confidence interval, 59-100%) for detecting culture-positive TB at any site. Patients with newly diagnosed TB on urine-based screening were initiated on treatment and did not have excess mortality compared with the remainder of the cohort. Urine is an easily obtainable sample with utility for detecting TB in patients with advanced HIV disease. Combining urine and sputum-based screening in this population facilitates additional same-day TB diagnoses and early treatment initiation, potentially reducing the risk of TB-related mortality. Urine-based as well as sputum-based screening for TB should be integrated with CrAg screening in patients living with advanced HIV disease.

High Burden of Cryptococcal Meningitis Among Antiretroviral Therapy-Experienced Human Immunodeficiency Virus-Infected Patients in Northern Uganda in the Era of "Test and Treat": Implications for Cryptococcal Screening Programs.

BackgroundThe impact of the “test and treat” program for human immunodeficiency virus (HIV) treatment in rural areas of Uganda on cryptococcal antigen (CrAg) screening or cryptococcal meningitis (CM) is poorly understood.MethodsWe retrospectively evaluated clinical factors in 212 HIV-infected patients diagnosed with CM from February of 2017 to November of 2019 at Lira Regional Referral Hospital in northern Uganda.ResultsAmong 212 patients diagnosed with CM, 58.5% were male. Median age was 35 years; CD4 count and HIV viral load (VL) were 86 cells/μL and 9463 copies/mL, respectively. Only 10% of patients had a previous history of CM. We found that 190 of 209 (90.9%) patients were ART experienced and 19 (9.1%) were ART naive. Overall, 90 of 212 (42.5%) patients died while hospitalized (median time to death, 14 days). Increased risk of death was associated with altered mental status (hazard ratio [HR], 6.6 [95% confidence interval {CI}, 2.411–18.219]; P ≤ .0001) and seizures (HR, 5.23 [95% CI, 1.245–21.991]; P = .024).ConclusionsCurrent guidelines recommend CrAg screening based on low CD4 counts for ART-naive patients and VL or clinical failure for ART-experienced patients. Using current guidelines for CrAg screening, some ART-experienced patients miss CrAg screening in resource-limited settings, when CD4 or VL tests are unavailable. We found that the majority of HIV-infected patients with CM were ART experienced (90.9%) at presentation. The high burden of CM in ART-experienced patients supports a need for improved CrAg screening of ART-exposed patients.

Sero-prevalance of Cryptococcal Antigenemia in HIV Positive Individual having CD4 Counts &lt;100 Cells/mm3

Cryptococcus neoformans is one of the foremost common opportunistic infectious agents in people living with Acquired Immuno Deficiency Syndrome (AIDS). It has been reported to cause about 1 million cases of cryptococcal meningitis per year among HIV/AIDS and 600,000 deaths annually. This study was done to find the prevalence of Cryptococcal antigenemia among HIV positive individuals having CD4counts &lt;100 cells/mm3. A cross-sectional study was conducted in the HIV Reference unit, National public health laboratory from July to December 2015. The study comprised of 99 HIV positive individuals having CD4counts &lt;100 cells/mm3. CD4 T cell count was performed by flow cytometry (BD Biosciences, San Jose, CA, USA) and Cryptococcal antigen test by Latex agglutination assay. The overall prevalence of cryptococcal antigenemia was found to be 18.2%. Of the total ninety-nine subjects enrolled in the study, 72 (72.8%) were males and 27 (27.2%) were females. The mean age of the patients was 38 years ranging from 13 to 69 years. Higher percentage of female (22.2%) showed Cryptococcal infection in our study as compared to male (16.7%). The study concludes higher prevalence of Cryptococcal antigenemia among HIV infected individuals and recommends Cryptococcal antigen screening to be made mandatory in HIV positive patients having CD4 T cells count below 100/μl.

Cost-effectiveness of cryptococcal antigen screening at CD4 counts of 101-200 cells/µL in Botswana.

Background: Cryptococcal antigen (CrAg) screening in individuals with advanced HIV reduces cryptococcal meningitis (CM) cases and deaths. The World Health Organization recently recommended increasing screening thresholds from CD4 ≤100 cells/µL to ≤200 cells/µL. CrAg screening at CD4 ≤100 cells/µL is cost-effective; however, the cost-effectiveness of screening patients with CD4 101-200 cells/µL requires evaluation. Methods: Using a decision analytic model with Botswana-specific cost and clinical estimates, we evaluated CrAg screening and treatment among individuals with CD4 counts of 101-200 cells/µL. We estimated the number of CM cases and deaths nationally and treatment costs without screening. For screening we modeled the number of CrAg tests performed, number of CrAg-positive patients identified, proportion started on pre-emptive fluconazole, CM cases and deaths. Screening and treatment costs were estimated and cost per death averted or disability-adjusted life year (DALY) saved compared with no screening. Results: Without screening, we estimated 142 CM cases and 85 deaths annually among individuals with CD4 101-200 cells/µL, with treatment costs of $368,982. With CrAg screening, an estimated 33,036 CrAg tests are performed, and 48 deaths avoided (1,017 DALYs saved). While CrAg screening costs an additional $155,601, overall treatment costs fall by $39,600 (preemptive and hospital-based CM treatment), yielding a net increase of $116,001. Compared to no screening, high coverage of CrAg screening and pre-emptive treatment for CrAg-positive individuals in this population avoids one death for $2440 and $114 per DALY saved. In sensitivity analyses assuming a higher proportion of antiretroviral therapy (ART)-naïve patients (75% versus 15%), cost per death averted was $1472; $69 per DALY saved. Conclusions: CrAg screening for individuals with CD4 101-200 cells/µL was estimated to have a modest impact, involve additional costs, and be less cost-effective than screening populations with CD4 counts ≤100 cells/µL. Additional CrAg screening costs must be considered against other health system priorities.

Laboratory Reflex and Clinic-Based Point-of-Care Cryptococcal Antigen Screening for Preventing Meningitis and Mortality Among People Living With HIV.

Cryptococcosis remains a leading cause of meningitis and mortality among people living with HIV (PLHIV) worldwide. We sought to evaluate laboratory-based cryptococcal antigen (CrAg) reflex testing and a clinic-based point-of-care (POC) CrAg screening intervention for preventing meningitis and mortality among PLHIV in South Africa. We conducted a prospective pre-post intervention study of adults presenting for HIV testing in Umlazi township, South Africa, over a 6-year period (2013-2019). Participants were enrolled during 3 phases of CrAg testing: CrAg testing ordered by a clinician (clinician-directed testing, 2013-2015); routine laboratory-based CrAg reflex testing for blood samples with CD4 ≤100 cells/mm3 (laboratory reflex testing, 2015-2017); and a clinic-based intervention with POC CD4 testing and POC CrAg testing for PLHIV with CD4 ≤200 cells/mm3 with continued standard-of-care routine laboratory reflex testing among those with CD4 ≤100 cells/mm3 (clinic-based testing, 2017-2019). The laboratory and clinical teams performed serum CrAg by enzyme immunoassay and lateral flow assay (Immy Diagnostics, Norman, OK). We followed up participants for up to 14 months to compare associations between baseline CrAg positivity, antiretroviral therapy and fluconazole treatment initiation, and outcomes of cryptococcal meningitis, hospitalization, and mortality. Three thousand one hundred five (39.4%) of 7877 people screened were HIV-positive, of whom 908 had CD4 ≤200 cells/mm3 and were included in the analyses. Laboratory reflex and clinic-based testing increased CrAg screening (P < 0.001) and diagnosis of CrAg-positive PLHIV (P = 0.011). When compared with clinician-directed testing, clinic-based CrAg testing showed an increase in the number of PLHIV diagnosed with cryptococcal meningitis (4.5% vs. 1.5%; P = 0.059), initiation of fluconazole preemptive therapy (7.2% vs. 2.5%; P = 0.010), and initiation of antiretroviral therapy (96.8% vs. 91.3%; P = 0.012). Comparing clinic-based testing with laboratory reflex testing, there was no significant difference in the cumulative incidence of cryptococcal meningitis (4.5% vs. 4.1%; P = 0.836) or mortality (8.1% vs. 9.9%; P = 0.557). Laboratory reflex and clinic-based CrAg testing facilitated the diagnosis of HIV-associated cryptococcosis and fluconazole initiation but did not reduce cryptococcal meningitis or mortality. In this nonrandomized cohort, clinical outcomes were similar between laboratory reflex testing and clinic-based POC CrAg testing.