High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B–Based Therapy Under Routine Care Conditions in Africa

Patel, Raju Kk; Leeme, Tshepo; Azzo, Caitlin; Tlhako, Nametso; Tsholo, Katlego; Tawanana, Ephraim; Molefi, Mooketsi; Mosepele, Mosepele; Lawrence, David; Mokomane, Margaret; Tenforde, Mark W; Jarvis, Joseph N

doi:10.1093/ofid/ofy267

Cited by 30 publications

(53 citation statements)

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“…Our findings also suggest that improved availability of more fungicidal – but more toxic – amphotericin B therapy alone may not have a large impact in reducing mortality. Under routine care settings, short‐term mortality for amphotericin‐based and fluconazole‐based regimens was similar at around 40% and long‐term mortality was reported at 65% even with amphotericin B and high‐dose fluconazole in Botswana . Recent evidence from a large RCT suggests that, combined with flucytosine (5FC), a shortened one‐week course of amphotericin B is the most effective antifungal regimen to reduce mortality from HIV‐associated cryptococcal meningitis , with similar rates of early fungal clearance compared to longer two‐week courses and less drug toxicity .…”

Section: Discussionmentioning

confidence: 99%

“…In 10% (4/41) of included studies, the period of observation began prior to 2000. Seventeen countries were represented, with greatest representation from South Africa (14 studies) [34,[37][38][39][40][41][42][43][44][45][46][47][48][49], Ethiopia (three studies) [50][51][52] and Uganda (three studies) [53][54][55]; other countries had two or fewer studies [11,35,36,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Amphotericin B-based induction therapy (with or without fluconazole) was the predominant induction regimen in 16 studies, fluconazole in 13 studies, and a mix of treatments (45% fluconazole and 43% amphotericin B) in one study [44], with antifungal regimens not specified in 11 studies.…”

Section: Overall Search Findingsmentioning

confidence: 99%

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Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

et al. 2020

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Introduction HIV‐associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub‐Saharan Africa (SSA). We performed a systematic review and meta‐analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. Methods We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized‐controlled trials (RCTs) or investigator‐managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short‐term (in‐hospital or two weeks), medium‐term (up to 10 weeks) and long‐term (up to six months). Results and discussion Seventy‐nine studies met inclusion criteria. In routine care settings, pooled short‐term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole‐based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short‐term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short‐term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized‐controlled trials. Few studies evaluated long‐term outcomes. Conclusions Mortality rates from HIV‐associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV‐associated meningitis in the region.

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Section: Discussionmentioning

confidence: 99%

Section: Overall Search Findingsmentioning

confidence: 99%

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

et al. 2020

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“…[ 13 , 14 ] Furthermore, there are no data regarding discordant DRMs in the context of HIV-associated CM, which may be of clinical and public health relevance given the increasing proportion of CM patients who are now ART-experienced. [ 15 , 16 ]…”

Section: Introductionmentioning

confidence: 99%

Differences in human immunodeficiency virus-1C viral load and drug resistance mutation between plasma and cerebrospinal fluid in patients with human immunodeficiency virus-associated cryptococcal meningitis in Botswana

et al. 2020

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To determine effects of cryptococcal meningitis (CM) on human immunodeficiency virus (HIV)-1C cerebrospinal fluid (CSF) viral escape, CSF/plasma viral discordance, and drug resistance mutation (DRM) discordance between CSF and plasma compartments, we compared CSF and plasma viral load (VL) and DRMs in individuals with HIV-associated CM in Botswana. This cross-sectional study utilized 45 paired CSF/plasma samples from participants in a CM treatment trial (2014–2016). HIV-1 VL was determined and HIV-1 protease and reverse transcriptase genotyping performed. DRMs were determined using the Stanford HIV database. CSF viral escape was defined as HIV-1 ribonucleic acid ≥0.5 log 10 higher in CSF than plasma and VL discordance as CSF VL > plasma VL. HIV-1 VL was successfully measured in 39/45 pairs, with insufficient sample volume in 6; 34/39 (87.2%) participants had detectable HIV-1 in plasma and CSF, median 5.1 (interquartile range: 4.7–5.7) and 4.6 (interquartile range:3.7–4.9) log 10 copies/mL, respectively ( P ≤.001). CSF viral escape was present in 1/34 (2.9%) and VL discordance in 6/34 (17.6%). Discordance was not associated with CD4 count, antiretroviral status, fungal burden, CSF lymphocyte percentage nor mental status. Twenty-six of 45 (57.8%) CSF/plasma pairs were successfully sequenced. HIV-1 DRM discordance was found in 3/26 (11.5%); 1 had I84IT and another had M46MI in CSF only. The third had K101E in plasma and V106 M in CSF. Our findings suggest that HIV-1 escape and DRM discordance may occur at lower rates in participants with advanced HIV-disease and CM compared to those with HIV associated neurocognitive impairment.

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“…[3][4][5] Outcomes from cryptococcal meningitis have been relatively well described in clinical trials and observational studies. [6][7][8][9] However, data regarding long-term outcomes from tuberculous or pneumococcal meningitis in routine-care settings are limited. 5,10,11 Furthermore, most patients with suspected meningitis evaluated by lumbar puncture and cerebrospinal fluid (CSF) analysis in resource-limited settings have no pathogen identified through diagnostic studies.…”

Section: Introductionmentioning

confidence: 99%

Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study

Tenforde

Mokomane

Leeme

et al. 2019

The Lancet Infectious Diseases

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Background CNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults. Methods In this prevalent cohort study, patient records from 2004-15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per µL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per µL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality. Findings We included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with cultureconfirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per µL and 1209 with CSF WCC above 20 cells per µL). Median age was 37 years (IQR 31-46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per µL (IQR 63-271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0-20 cells per µL vs >20 cells per µL) was not predictive of mortality (average hazard ratio 0•93, 95% CI 0•80-1•09). Interpretation Mortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms.

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High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B–Based Therapy Under Routine Care Conditions in Africa

Cited by 30 publications

References 32 publications

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

Differences in human immunodeficiency virus-1C viral load and drug resistance mutation between plasma and cerebrospinal fluid in patients with human immunodeficiency virus-associated cryptococcal meningitis in Botswana

Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study

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