CrAg Prevalence Research Articles

CD4 Cell Count Threshold for Cryptococcal Antigen Screening of HIV-Infected Individuals: A Systematic Review and Meta-analysis.

BackgroundCurrent guidelines recommend screening all people living with human immunodeficiency virus (PLHIV) who have a CD4 count ≤100 cells/µL for cryptococcal antigen (CrAg) to identify those patients who could benefit from preemptive fluconazole treatment prior to the onset of meningitis. We conducted a systematic review to assess the prevalence of CrAg positivity at different CD4 cell counts.MethodsWe searched 4 databases and abstracts from 3 conferences up to 1 September 2017 for studies reporting prevalence of CrAg positivity according to CD4 cell count strata. Prevalence estimates were pooled using random effects models.ResultsSixty studies met our inclusion criteria. The pooled prevalence of cryptococcal antigenemia was 6.5% (95% confidence interval [CI], 5.7%–7.3%; 54 studies) among patients with CD4 count ≤100 cells/µL and 2.0% (95% CI, 1.2%–2.7%; 21 studies) among patients with CD4 count 101–200 cells/µL. Twenty-one studies provided sufficient information to compare CrAg prevalence per strata; overall, 18.6% (95% CI, 15.4%–22.2%) of the CrAg-positive cases identified at ≤200 cells/µL (n = 11823) were identified among individuals with a CD4 count 101–200 cells/µL. CrAg prevalence was higher among inpatients (9.8% [95% CI, 4.0%–15.5%]) compared with outpatients (6.3% [95% CI, 5.3%–7.4%]).ConclusionsThe findings of this review support current recommendations to screen all PLHIV who have a CD4 count ≤100 cells/µL for CrAg and suggest that screening may be considered at CD4 cell count ≤200 cells/µL.

Prevalence of cryptococcal infection among advanced HIV patients in Argentina using lateral flow immunoassay.

BackgroundGlobally, Latin America ranks third among regions with most cases of AIDS related cryptococcal meningitis. In 2009, a lateral flow immunoassay (LFA) for the detection of cryptococcal antigen (CrAg) was developed as a potential point-of-care test for diagnosis of cryptococcal infection. In 2011 World Health Organizations recommended on CrAg screening for HIV positive persons with CD4 below 100 cells/μL, followed by preemptive fluconazole treatment. However, in Argentina no formal recommendations for CrAg screening have been issued.MethodsHIV positive patients > = 18 years with advanced immunosuppression (CD4 counts ≤100 cells/μL within 3 months or WHO stage III/IV), who visited the hospital between April 1, 2014 and January 31, 2015, were included. The LFA was performed according to the manufacturer’s instructions on all serum samples. When CrAg detection was positive, a lumbar puncture was performed to rule out cryptococcal meningitis. Patients without evidence of meningeal involvement were treated with preemptive oral fluconazole in ambulatory care.ResultsWe included 123 patients. Prevalence of CrAg-positivity was 8.1%. Among the 10 CrAg-positive patients, 6 had meningeal involvement detected through the CSF analysis (CSF India-ink testing, CSF CrAg and culture). The remaining 4 patients with positive CrAg received targeted preemptive treatment with oral fluconazole and were free of cryptococcal disease during the follow-up period. None of the 113 patients with a negative CrAg test result developed cryptococcal disease.ConclusionsThis is the first study in Argentina, to our knowledge, describing the prevalence of cryptococcosis and usefulness of CrAg screening. LFA provided early diagnosis to determine a high prevalence of CrAg in our hospital, and that screening for subclinical infection with preemptive antifungal treatment, prevented a substantial proportion of meningeal disease.

Estimated Prevalence of Cryptococcus Antigenemia (CrAg) among HIV-Infected Adults with Advanced Immunosuppression in Namibia Justifies Routine Screening and Preemptive Treatment

BackgroundCryptococcal meningitis is common and associated with high mortality among HIV infected persons. The World Health Organization recommends that routine Cryptococcal antigen (CrAg) screening in ART-naïve adults with a CD4+ count <100 cells/μL followed by pre-emptive antifungal therapy for CrAg-positive patients be considered where CrAg prevalence is ≥3%. The prevalence of CrAg among HIV adults in Namibia is unknown. We estimated CrAg prevalence among HIV-infected adults receiving care in Namibia for the purpose of informing routine screening strategies.MethodsThe study design was cross-sectional. De-identified plasma specimens collected for routine CD4+ testing from HIV-infected adults enrolled in HIV care at 181 public health facilities from November 2013 to January 2014 were identified at the national reference laboratory. Remnant plasma from specimens with CD4+ counts <200 cells/μL were sampled and tested for CrAg using the IMMY® Lateral Flow Assay. CrAg prevalence was estimated and assessed for associations with age, sex, and CD4+ count.ResultsA total of 825 specimens were tested for CrAg. The median (IQR) age of patients from whom specimens were collected was 38 (32–46) years, 45.9% were female and 62.9% of the specimens had CD4 <100 cells/μL. CrAg prevalence was 3.3% overall and 3.9% and 2.3% among samples with CD4+ counts of CD4+<100 cells/μL and 100–200 cells/μL, respectively. CrAg positivity was significantly higher among patients with CD4+ cells/μL < 50 (7.2%, P = 0.001) relative to those with CD4 cells/μL 50–200 (2.2%).ConclusionThis is the first study to estimate CrAg prevalence among HIV-infected patients in Namibia. CrAg prevalence of ≥3.0% among patients with CD4+<100 cells/μL justifies routine CrAg screening and preemptive treatment among HIV-infected in Namibia in line with WHO recommendations. Patients with CD4+<100 cells/μL have a significantly greater risk for CrAg positivity. Revised guidelines for ART in Namibia now recommend routine screening for CrAg.

Brief Report: Geographical Variation in Prevalence of Cryptococcal Antigenemia Among HIV-Infected, Treatment-Naive Patients in Nigeria: A Multicenter Cross-Sectional Study.

Worldwide, HIV-associated cryptococcal meningitis affects approximately 1 million persons and causes 600,000 deaths each year mostly in sub-Saharan Africa. Limited data exist on cryptococcal meningitis and antigenemia in Nigeria, and most studies are geographically restricted. We determined the prevalence of cryptococcal antigenemia (CrAg) among HIV-infected, treatment-naive individuals in Nigeria. This was a retrospective, cross-sectional study across 4 geographic regions in Nigeria. We performed CrAg testing using a lateral flow immunoassay on archived whole-blood samples collected from HIV-infected participants at US President's Emergency Plan for AIDS Relief (PEPFAR)-supported sites selected to represent the major geographical and ethnic diversity in Nigeria. Eligible samples were collected from consenting patients (>15 years) naive to antiretroviral therapy with CD4 count less than 200 cells per cubic millimeter and were stored in an -80°C freezer. A total of 2752 stored blood samples were retrospectively screened for CrAg. Most of the samples were from participants aged 30-44 years (57.6%), and 1570 (57.1%) were from women. The prevalence of CrAg positivity in specimens with CD4 <200 cells per cubic millimeter was 2.3% (95% confidence interval: 1.8% to 3.0%) and varied significantly across the 4 regions (P < 0.001). At 4.4% (3.2% to 5.9%), the South East contained the highest prevalence. The significant regional variation in CrAg prevalence found in Nigeria should be taken into consideration as plans are made to integrate routine screening into clinical care for HIV-infected patients.

Screening HIV-Infected Patients with Low CD4 Counts for Cryptococcal Antigenemia prior to Initiation of Antiretroviral Therapy: Cost Effectiveness of Alternative Screening Strategies in South Africa.

BackgroundIn 2015 South Africa established a national cryptococcal antigenemia (CrAg) screening policy targeted at HIV-infected patients with CD4+ T-lymphocyte (CD4) counts <100 cells/ μl who are not yet on antiretroviral treatment (ART). Two screening strategies are included in national guidelines: reflex screening, where a CrAg test is performed on remnant blood samples from CD4 testing; and provider-initiated screening, where providers order a CrAg test after a patient returns for CD4 test results. The objective of this study was to compare costs and effectiveness of these two screening strategies.MethodsWe developed a decision analytic model to compare reflex and provider-initiated screening in terms of programmatic and health outcomes (number screened, number identified for preemptive treatment, lives saved, and discounted years of life saved) and screening and treatment costs (2015 USD). We estimated a base case with prevalence and other parameters based on data collected during CrAg screening pilot projects integrated into routine HIV care in Gauteng, Free State, and Western Cape Provinces. We conducted sensitivity analyses to explore how results change with underlying parameter assumptions.ResultsIn the base case, for each 100,000 CD4 tests, the reflex strategy compared to the provider-initiated strategy has higher screening costs ($37,536 higher) but lower treatment costs ($55,165 lower), so overall costs of screening and treatment are $17,629 less with the reflex strategy. The reflex strategy saves more lives (30 lives, 647 additional years of life saved). Sensitivity analyses suggest that reflex screening dominates provider-initiated screening (lower total costs and more lives saved) or saves additional lives for small additional costs (< $125 per life year) across a wide range of conditions (CrAg prevalence, patient and provider behavior, patient survival without treatment, and effectiveness of preemptive fluconazole treatment).ConclusionsIn countries with substantial numbers of people with untreated, advanced HIV disease such as South Africa, CrAg screening before initiation of ART has the potential to reduce cryptococcal meningitis and save lives. Reflex screening compared to provider-initiated screening saves more lives and is likely to be cost saving or have low additional costs per additional year of life saved.

Implementation and Operational Research: Evaluation of a Public-Sector, Provider-Initiated Cryptococcal Antigen Screening and Treatment Program, Western Cape, South Africa.

Screening for serum cryptococcal antigen (CrAg) may identify those at risk for disseminated cryptococcal disease (DCD), and preemptive fluconazole treatment may prevent progression to DCD. In August 2012, the Western Cape Province (WC), South Africa, adopted provider-initiated CrAg screening. We evaluated the implementation and effectiveness of this large-scale public-sector program during its first year, September 1, 2012-August 31, 2013. We used data from the South African National Health Laboratory Service, WC provincial HIV program, and nationwide surveillance data for DCD. We assessed the proportion of eligible patients screened for CrAg (CrAg test done within 30 days of CD4 date) and the prevalence of CrAg positivity. Incidence of DCD among those screened was compared with those not screened. Of 4395 eligible patients, 26.6% (n = 1170) were screened. The proportion of patients screened increased from 15.9% in September 2012 to 36.6% in August 2013. The prevalence of positive serum CrAg was 2.1%. Treatment data were available for 13 of 24 CrAg-positive patients; 9 of 13 were treated with fluconazole. Nine (0.8%) incident cases of DCD occurred among the 1170 patients who were screened for CrAg vs. 49 (1.5%) incident cases among the 3225 patients not screened (P = 0.07). Relatively few eligible patients were screened under the WC provider-initiated CrAg screening program. Unscreened patients were nearly twice as likely to develop DCD. CrAg screening can reduce the burden of DCD, but needs to be implemented well. To improve screening rates, countries should consider laboratory-based reflexive screening when possible.

Low Prevalence of Cryptococcal Antigenemia among Patients Infected with HIV/AIDS in Haiti

Cryptococcal meningitis is a common opportunistic infection among persons with advanced HIV-associated immunosuppression and is associated with high mortality. The prevalence of asymptomatic cryptococcal antigenemia (CrAg) can inform the potential utility of screening and pre-emptive treatment prevention strategies. We assessed CrAg prevalence in a cohort of patients infected with HIV at 28 health facilities from February to September 2014 in order to inform Haitian national clinical guidelines. Of 13,000 patients that underwent CD4 cell count, 1,025 (7.9%) had a count ≤200 cells/mm3. Of these, 11 (1.1%) were CrAg positive. The CrAg positivity rate among patients with CD4 cell counts <100 cell/mm3 was 1.8%. Patients with CD4 cell counts <50 cells/mm3 had the highest CrAg rate (2.3%). CrAg prevalence was low but still warranted a CrAg screening and pre-emptive therapy approach for people infected with HIV with CD4 cell counts <100 cell/mm3 in Haiti.

Cryptococcal Antigen Screening and Treatment: The Current State of Global Screening Programs to Prevent Death from Cryptococcal Infection

Cryptococcal meningitis (CM) is the leading cause of death among people with AIDS. The World Health Organization issued a conditional recommendation in 2011 for countries to consider serum cryptococcal antigen (CrAg) screening in patients with CD4 count <100 cells/μL in order to identify those at risk for CM and to treat them preemptively with fluconazole to prevent progression to CM. This paper outlines the evidence behind CrAg screening, the prevalence of CrAg in various settings, and our current understanding of the state of CrAg screening programs. A growing number of countries are incorporating CrAg screening into their national HIV treatment guidelines and are beginning to implement national screening programs, while others are piloting in select regions to assess the feasibility of such programs. Strategies used to conduct CrAg screening, including reflexive laboratory-based screening, provider-initiated screening, and point-of-care screening, are also discussed. Countries considering large-scale rollout of CrAg screening should assess what combination of screening methods works best in their specific contexts.

Feasibility and Acceptability of Cryptococcal Antigen Screening and Prevalence of Cryptocococcemia in Patients Attending a Resource-Limited HIV/AIDS Clinic in Malawi.

The World Health Organization (WHO) recommends screening patients living with AIDS to detect and treat early cryptococcal infection. The authors evaluated a cryptococcal antigen (CrAg) screening and treatment program at an HIV/AIDS clinic in Malawi. Eligible patients were of age >18 years, had a CD4 count <100 cells/µL or WHO clinical HIV/AIDS stage III or IV. Of 552 patients who presented for care, 113 were eligible, and all (100%) agreed to CrAg screening. Of them, 2 (1.8%; 95% confidence interval [CI]: 0-4.2%) patients were CrAg positive. Among those with CD4 count <100 cells/µL or WHO stage IV, the CrAg prevalence was 3.5% (95% CI: 0-8.4%) and 5.0% (95% CI: 0-15%), respectively. A CrAg screening program was acceptable to new patients in a Malawian HIV/AIDS clinic. The CrAg prevalence for patients with CD4 count < 100 cells/µL and WHO stage IV was consistent with cost-effectiveness estimates. CrAg screening and treatment programs for patients living with AIDS should be expanded.

Comparison of Cryptococcal Antigenemia between Antiretroviral Naïve and Antiretroviral Experienced HIV Positive Patients at Two Hospitals in Ethiopia

BackgroundCryptococcal meningitis is a major cause of HIV/AIDS-related deaths in Africa. Cryptococcosis is a neglected killer. However, meningitis can be prevented by early cryptococcal antigen (CrAg) screening and preemptive antifungal treatment during a prolonged period of detectable, subclinical infection. We determined the prevalence of cryptococcal antigenemia in comparison to CD4 count and clinical symptoms.MethodsWe surveyed 254 consenting HIV-infected participants to obtain demographic information and clinical history. Serum CrAg was measured by latex agglutination at two sites in the Oromia region of Ethiopia among all persons receiving a CD4 count.ResultsOf the 254 participants, 127(50.0%) were ART-naïve, 121(47.6%) were ART-experienced, and 6(2.4%) were ART-defaulters. The prevalence of cryptococcal antigenemia was 10.2% overall being 14.2% among ART-naive, 4.1% among ART-experienced, and 50% (3/6) among ART-defaulters, irrespective of CD4 count. Cryptococcal antigenemia was more frequently detected from ART-naïve patients (p = 0.012) and ART-defaulters (p = 0.001) compared with ART-experienced. Serum CrAg positivity was 20.9% in persons with CD4≤150 cells/µL, 12.2% in 151–200 cells/µL, 5.8% among 201–350 CD4/µL, and none above 350 cells/µL. Potential meningitis symptoms were common in the outpatient cohort irrespective of CrAg-status, with only fever and altered mental status statistically more common in CrAg-positive compared to CrAg-negative persons (P<0.05), yet no symptom had a positive predictive value >33%.ConclusionWe report a 20.9% cryptococcal antigenemia prevalence among those with CD4+ T cells count ≤150 cells/µL, irrespective of ART status, with even higher CrAg prevalence in ART-naïves and ART-defaulters. These groups are target populations for CrAg screening at entry into HIV care.

Prevalence of Cryptococcal Antigenemia and Cost-Effectiveness of a Cryptococcal Antigen Screening Program – Vietnam

BackgroundAn estimated 120,000 HIV-associated cryptococcal meningitis (CM) cases occur each year in South and Southeast Asia; early treatment may improve outcomes. The World Health Organization (WHO) recently recommended screening HIV-infected adults with CD4<100 cells/mm3 for serum cryptococcal antigen (CrAg), a marker of early cryptococcal infection, in areas of high CrAg prevalence. We evaluated CrAg prevalence and cost-effectiveness of this screening strategy in HIV-infected adults in northern and southern Vietnam.MethodsSerum samples were collected and stored during 2009–2012 in Hanoi and Ho Chi Minh City, Vietnam, from HIV-infected, ART-naïve patients presenting to care in 12 clinics. All specimens from patients with CD4<100 cells/mm3 were tested using the CrAg lateral flow assay. We obtained cost estimates from laboratory staff, clinicians and hospital administrators in Vietnam, and evaluated cost-effectiveness using WHO guidelines.ResultsSera from 226 patients [104 (46%) from North Vietnam and 122 (54%) from the South] with CD4<100 cells/mm3 were available for CrAg testing. Median CD4 count was 40 (range 0–99) cells/mm3. Nine (4%; 95% CI 2–7%) specimens were CrAg-positive. CrAg prevalence was higher in South Vietnam (6%; 95% CI 3–11%) than in North Vietnam (2%; 95% CI 0–6%) (p = 0.18). Cost per life-year gained under a screening scenario was $190, $137, and $119 at CrAg prevalences of 2%, 4% and 6%, respectively.ConclusionCrAg prevalence was higher in southern compared with northern Vietnam; however, CrAg screening would be considered cost-effective by WHO criteria in both regions. Public health officials in Vietnam should consider adding cryptococcal screening to existing national guidelines for HIV/AIDS care.

Reconsidering Cryptococcal Antigen Screening in the U.S. Among Persons With CD4 &lt;100 cells/mcL

To the Editor—The 2012 International AIDS Conference was themed around the need for an “AIDS free generation.” The concept is that the HIV virus is not yet curable, but with medications, we can prevent those who are HIV-infected from developing complications of AIDS and opportunistic infections. Cryptococcal meningitis is one such opportunistic infection that causes 20%–25% of AIDS-related mortality in Africa [1]. Cryptococcal antigen (CrAg) can be detected in a subclinical phase, weeks prior to onset of symptomatic infection, and can be screened and preemptively treated with fluconazole to prevent overt cryptococcal meningitis. The new Food and Drug Administration–approved point-of-care CrAg lateral flow assay (LFA; Immy, Inc., Norman, OK) has fundamentally changed the cost-effectiveness of CrAg screening to prevent cryptococcal meningitis from occurring in those with subclinical infection. The CrAg LFA assay cost is $2.00 in resource limited regions and $5.00 in high-income countries, which translates to a probable real world cost of approximately $2.50–$5.00 in resource limited settings and $10 in high-income countries when including labor, shipping, and overhead costs. This screen and preemptive treatment strategy has the potential to vastly diminish and eliminate cryptococcal meningitis from occurring after antiretroviral therapy (ART) initiation and reduce the 20%–25% of early ART mortality caused by cryptococcosis [2–4]. Previously Meya et al showed the value of CrAg screening in a prospective cohort, using the CrAg latex agglutination at a cost of $16.75 in Uganda [3]. Now with a real world cost of the CrAg LFA at $2.50, the cost per life saved with CrAg screening and pre-emptive fluconazole therapy is $39.73 in Uganda among persons with CD4<100 cells/μL, and $2.21 per quality adjusted life year saved [5]. In contrast to the cost of cryptococcal meningitis hospitalization, CrAg screening and targeted preemptive treatment of those CrAg+ is cost saving to healthcare systems at ≥1% CrAg+ prevalence (Figure 1). But is this program only relevant to Africa? While early HIV testing is key, the US reality is that 38% of newly HIV diagnosed Americans received an AIDS diagnosis concurrently or within 1 year of their HIV diagnosis between 1996–2005 [6]. In North America, our opinion is CrAg screening should also be considered among those who do present with advanced AIDS and CD4<100. The US cost of cryptococcal meningitis hospitalization is extraordinarily high, in contrast to CrAg screening (approximately $10) followed by pre-emptive treatment with 10 weeks of fluconazole per World Health Organization guidelines ($30.24) at 800 mg daily for 2 weeks followed by 8 weeks of 400 mg daily [7]. The approximate cost of hospitalization for cryptococcosis from one Boston hospital including room and board ($700/day), liposomal amphotericin (approximately $350/day), and flucytosine (approximately $500/day) for 14 days is on average $50 000. For this cost, assuming that the LFA would cost $10 in high-income settings, one could screen approximately 5000 persons for asymptomatic antigenemia. Thus while the prevalence of cryptococcal antigenemia among those with CD4 0.1%. Thus, US CrAg prevalence data are needed. Given the improved cost considerations, the US Department of Health and Human Services Opportunistic Infection guidelines should reexamine the benefit of routine pre-ART CrAg screening for those with CD4 < 100 or among persons hospitalized shortly after ART initiation [8]. While ideally in the future this population of late HIV presenters will be eliminated, among those who do present late, CrAg screening in the U.S. may not only be cost saving, but life saving.​saving.Figure 1.Cost Figure 1. Cost of serum cryptococcal antigen screening using the latex agglutination versus the lateral flow assay based on asymptomatic prevalence. The figure displays the relative cost-effectiveness of cryptococcal antigen (CrAg) screening and preemptive fluconazole ...

Screening for Cryptococcal Antigenemia in Anti-Retroviral Naïve AIDS Patients in Benin City, Nigeria

Cryptococcus neoformans is the most incriminated fungal pathogen causing meningitis in acquired immune deficiency syndrome (AIDS) patients, and is known to constitute a major cause of deaths in AIDS patients. This study thus aimed to determine the baseline sero-prevalence of Cryptococcus neoformans infection in anti-retroviral naïve (ART-naïve) AIDS patients using the serum Cryptococcal antigen (crag) detection method. Baseline effect of variation in CD4 counts, as well as sex and age with sero-positivity for crag were also determined. This descriptive cross-sectional study included 150 (61 males and 89 females) ART-naïve AIDS patients attending the Human Immunodeficiency Virus clinic (HIV) at the University of Benin Teaching hospital, Benin City, Nigeria, within the period from February 2011- July 2011. Forty (18 males and 22 females) HIV positive outpatients with CD4 counts >200 cells/µl who were ART-naive were recruited and used as controls. The sero-prevalence of crag in the patients and the control group was measured using the cryptococcal antigen latex agglutination system (CALAS) (Meridian Bioscience, Europe) and CD4 counts were measured using flow cytometry (Partec flow cytometer, Germany). Of the 150 ART-naïve AIDS patients with CD4 counts ≤200 cells/µL; 19 (12.7%) were positive for serum Cryptococcal antigen. ART-naïve AIDS patients with CD4 count ≤50 cells/µl had the highest prevalence of serum crag. Lower CD4 counts were significantly associated with positivity for serum crag (p<0.001). Age and sex had no significant effect on the sero-positivity for serum crag. One (2.5%) of the controls was sero-positive for crag. Thus, serum crag was significantly associated with AIDS but not with HIV (p<0.001). This study uncovers a high prevalence of crag in ART- naïve AIDS patients in Benin City. The prevalence of crag was higher in ART-naïve AIDS patients with lower CD4 counts. There is an urgent need to introduce routine screening for crag in ART- naïve AIDS patients in our locality to reduce the rapid mortality from Cryptococcal meningitis which accounts for a majority of the morbidity factor if undiagnosed during ART therapy.