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

Tenforde, Mark W; Mokomane, Margaret; Leeme, Tshepo; Patel, Raju Kk; Lekwape, Nametso; Ramodimoosi, Chandapiwa; Dube, Bonno; Williams, Elizabeth A.; Mokobela, Kelebeletse O.; Tawanana, Ephraim; Pilatwe, Tlhagiso; Hurt, William J; Mitchell, Howard E.; Banda, Doreen L; Stone, Hunter H.; Molefi, Mooketsi; Mokgacha, Kabelo; Phillips, Heston; Mullan, Paul C.; Steenhoff, Andrew P.; Mashalla, Yohana; Mine, Madisa; Jarvis, Joseph N

doi:10.1093/cid/cix430

Cited by 60 publications

(54 citation statements)

References 22 publications

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“…We implemented laboratory-reflex CrAg testing instead of relying on the clinical evaluation, [4,14,35]. Our findings therefore support the notion that approaches centered exclusively on HIV treatment are inadequate in reducing AIDS-related mortality and the undisputed need for available first-line antifungals for cryptococcal treatment [18,36].…”

Section: A C C E P T E Dsupporting

confidence: 55%

“…However, even with the early roll-out of ART and implementation of the WHO guidelines, prospective data still report high mortality among CrAg-positive individuals [3,4,17,18]. There are several potential reasons for this, including the increasing lack of available antifungal therapy, the implementation of these guidelines mostly among PLHIV presenting at outpatient HIV clinics, and the low uptake of diagnostic lumbar punctures (LP) for asymptomatic CrAgpositive individuals.…”

Section: A C C E P T E Dmentioning

confidence: 99%

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Laboratory-Reflex Cryptococcal Antigen Screening Is Associated With a Survival Benefit in Tanzania

Faini

Kalinjuma

Katende

et al. 2019

JAIDS Journal of Acquired Immune Deficiency Syndromes

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26This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. ABSTRACTBackground: Cryptococcal antigen (CrAg) screening in persons with advanced HIV/AIDS is recommended to prevent death. Implementing CrAg screening only in outpatients may underestimate the true CrAg prevalence and decrease its potential impact. Our previous 12month survival/retention in CrAg-positive persons not treated with fluconazole was 0%.Methods: HIV testing was offered to all ART-naive outpatients and hospitalized patients in Ifakara, Tanzania, followed by laboratory-reflex CrAg screening for CD4<150 cells/µL. CrAgpositive individuals were offered lumbar punctures, and antifungals were tailored to the presence/absence of meningitis. We assessed the impact on survival and retention-in-care using multivariate Cox regression models. Results:We screened 560 individuals for CrAg. The median CD4 count was 61 cells/µL (IQR 26-103). CrAg prevalence was 6.1% (34/560) among individuals with CD4 ≤150 and 7.5% among ≤100 cells/µL. CrAg prevalence was 2.3-fold higher among hospitalized participants than in outpatients (12% vs. 5.3%, p=0.02). We performed lumbar punctures in 94% (32/34), and 31% (10/34) had cryptococcal meningitis. Mortality did not differ significantly between treated CrAg-positive without meningitis and CrAg-negative individuals (7.3 vs 5.4 deaths per 100persons-year, respectively, p=0.25). Independent predictors of 6-month death/lost to follow-up A C C E P T E D 27 were low CD4, cryptococcal meningitis (adjusted hazard ratio (aHR) 2.76, 95% CI 1.31-5.82)), and no ART initiation (aHR 3.12, 95%CI 2.16-4.50). Conclusions:Implementing laboratory-reflex CrAg screening among outpatients and hospitalized-individuals resulted in a rapid detection of cryptococcosis and a survival benefit.These results provide a model of a feasible, effective and scalable CrAg screening and treatment strategy integrated into routine care in sub-Saharan Africa.

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Section: A C C E P T E Dsupporting

confidence: 55%

Section: A C C E P T E Dmentioning

confidence: 99%

Laboratory-Reflex Cryptococcal Antigen Screening Is Associated With a Survival Benefit in Tanzania

Faini

Kalinjuma

Katende

et al. 2019

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…26,27 Widespread availability of generic flucytosine is urgently needed as an essential part of global programs to reduce HIV-related mortality, as is continued investigation into new drug therapies. Efforts by international agencies to make flucytosine available are gaining momentum.…”

Section: Discussionmentioning

confidence: 99%

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

et al. 2018

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BACKGROUNDCryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODSWe randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTSA total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.

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“…A cross-sectional study was performed using data from the Botswana National Meningitis Survey (BNMS), as described previously but extended through 2015. 11 BNMS included records from laboratory facilities that perform cerebrospinal fluid (CSF) testing for meningitis evaluation. Data sources included paper-based records collected during in-person laboratory visits and records from electronic medical records (EMRs) used during the study period.…”

Section: Study Design and Data Collectionmentioning

confidence: 99%

“…We previously showed ongoing high incidence of HIV-associated cryptococcal meningitis in Botswana despite excellent ART coverage. 11 Incidence and temporal trends for other HIV-associated meningitides have not been described, including potential changes in pneumococcal meningitis following the 2012 introduction of childhood 13-valent pneumococcal conjugate vaccine (PCV13). 12 In a nationwide meningitis study, we collected laboratory records at all facilities that performed microbiological testing of cerebrospinal fluid (CSF).…”

Section: Introductionmentioning

confidence: 99%

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

Tenforde

Mokomane

Leeme

et al. 2019

Journal of Infection

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s u m m a r yObjectives: 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) 20 0 0-2015 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 142.6/10 0,0 0 0 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/10 0,0 0 0 (95%CI:23.2-26.9), and incidence of PM was 2.7/10 0,0 0 0 (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.

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

Cited by 60 publications

References 22 publications

Laboratory-Reflex Cryptococcal Antigen Screening Is Associated With a Survival Benefit in Tanzania

Laboratory-Reflex Cryptococcal Antigen Screening Is Associated With a Survival Benefit in Tanzania

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

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

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