Prevalence and Sequelae of Cryptococcal Antigenemia in Antiretroviral Therapy-Experienced Populations: An Evaluation of Reflex Cryptococcal Antigen Screening in Botswana.

BACKGROUND: Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among ART-experienced populations is lacking. We performed a study evaluating the utility of reflex CrAg screening in Gaborone, Botswana. METHODS: CD4 count data were collected from the HIV reference laboratory from 2014-2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency of repeat CrAg testing described. Analyses ascertained the impact of ART status on CrAg prevalence and outcomes, and whether CrAg titers could be used for risk stratification. RESULTS: Overall, 5.6% (3335/59 300) of individuals tested had CD4 ≤100 cells/µL; 2108 samples with CD4 ≤100 cells/µL from 1645 unique patients were CrAg tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART and 12.1% (255) defaulters; 22% (463) of CrAg tests were on repeat samples. CrAg prevalence was 4.8% (72/1494; 95% CI, 3.8-6.0%) among outpatients and 21.9% (32/151; 95% CI, 15.3-28.5%) among inpatients. CrAg prevalence rates did not differ by ART status, but 6-month mortality was significantly lower in CrAg-positive individuals on ART at screening. Ten CrAg positives were identified through repeat testing. A CrAg titer cutoff ≥1:80 provided the best discrimination for 6-month survival. CONCLUSIONS: CrAg-positivity rates in an ART-experienced population were comparable to those seen in ART-naive populations. Repeat screening identified individuals who seroconverted to CrAg positivity and were at risk of cryptococcal disease. CrAg titers ≥1:80 can help identify the individuals at highest risk of death for more intensive management.

Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey.

OBJECTIVES: Data on meningitis epidemiology in high HIV-prevalence African settings following antiretroviral therapy scale-up are lacking. We described epidemiology of adult meningitis in Botswana over a 16-year period. METHODS: Laboratory records for adults undergoing lumbar puncture (LP) 2000-2015 were collected, with complete national data 2013-2014. Cerebrospinal fluid (CSF) findings and linked HIV-data were described, and national incidence figures estimated for 2013-2014. Temporal trends in meningitis were evaluated. RESULTS: Of 21,560 adults evaluated, 41% (8759/21,560) had abnormal CSF findings with positive microbiological testing and/or pleocytosis; 43% (3755/8759) of these had no confirmed microbiological diagnosis. Of the 5004 microbiologically-confirmed meningitis cases, 89% (4432/5004) were cryptococcal (CM) and 8% (382/5004) pneumococcal (PM). Seventy-three percent (9525/13,033) of individuals undergoing LP with identifiers for HIV registry linkage had documented HIV-infection. Incidence of LP for meningitis evaluation in Botswana 2013-2014 was 142.6/100,000 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/100,000 (95%CI:23.2-26.9), and incidence of PM was 2.7/100,000 (95%CI:2.4-3.1). In contrast to previously reported declines in CM incidence with ART roll-out, no significant temporal decline in pneumococcal or culture-negative meningitis was observed. CONCLUSIONS: CM remained the predominant identified aetiology of meningitis despite ART scale-up. A high proportion of cases had abnormal CSF with negative microbiological evaluation.

Causes of Pediatric Meningitis in Botswana: Results From a 16-Year National Meningitis Audit.

BACKGROUND: Central nervous system infections are an important cause of childhood morbidity and mortality in high HIV-prevalence settings of Africa. We evaluated the epidemiology of pediatric meningitis in Botswana during the rollout of antiretroviral therapy, pneumococcal conjugate vaccine and Haemophilus influenzae type B (HiB) vaccine. METHODS: We performed a cross-sectional study of children (<15 years old) evaluated for meningitis by cerebrospinal fluid (CSF) examination from 2000 to 2015, with complete national records for 2013-2014. Clinical and laboratory characteristics of microbiologically confirmed and culture-negative meningitis were described and incidence of Streptococcus pneumoniae, H. influenzae and cryptococcal meningitis was estimated for 2013-2014. RESULTS: A total of 6796 unique cases were identified. Median age was 1 year [interquartile range 0-3]; 10.4% (435/4186) of children with available HIV-related records were known HIV-infected. Overall, 30.4% (2067/6796) had abnormal CSF findings (positive microbiologic testing or CSF pleocytosis). Ten percent (651/6796) had a confirmed microbiologic diagnosis; including 26.9% (175/651) Cryptococcus, 18.9% (123/651) S. pneumoniae, 20.3% (132/651) H. influenzae and 1.1% (7/651) Mycobacterium tuberculosis. During 2013-2014, national cryptococcal meningitis incidence was 1.3 cases per 100,000 person-years (95% confidence interval, 0.8-2.1) and pneumococcal meningitis incidence 0.7 per 100,000 person-years (95% confidence interval, 0.3-1.3), with no HiB meningitis diagnosed. CONCLUSIONS: Following HiB vaccination, a marked decline in microbiologically confirmed cases of H. influenzae meningitis occurred. Cryptococcal meningitis remains the most common confirmed etiology, demonstrating gaps in prevention-of-mother-to-child transmission and early HIV diagnosis. The high proportion of abnormal CSF samples with no microbiologic diagnosis highlights limitation in available diagnostics.

Advanced Human Immunodeficiency Virus Disease in Botswana Following Successful Antiretroviral Therapy Rollout: Incidence of and Temporal Trends in Cryptococcal Meningitis.

Background: Botswana has a well-developed antiretroviral therapy (ART) program that serves as a regional model. With wide ART availability, the burden of advanced human immunodeficiency virus (HIV) and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis (CM), and describe characteristics of cases during 2000-2014 and temporal trends at 2 national referral hospitals. Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected from the period 2000-2014 to identify cases of CM. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers in the period 2004-2014. Results: A total of 5296 episodes of CM were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 (95% confidence interval [CI], 16.6-19.2) cases per 100000 person-years. In the HIV-infected population, incidence was 96.8 (95% CI, 90.0-104.0) cases per 100000 person-years; male predominance was seen across CD4 strata. At national referral hospitals, cases decreased during 2007-2009 but stabilized during 2010-2014. Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of CM comparable to pre-ART era rates in South Africa. Our findings suggest that a key population of individuals, often men, is developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.