Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

Jarvis, Joseph N; Leeme, Tshepo; Molefi, Mooketsi; Chofle, Awilly A; Bidwell, Gabriella; Tsholo, Katlego; Tlhako, Nametso; Mawoko, Norah; Patel, Raju Kk; Tenforde, Mark W; Muthoga, Charles; Bisson, Gregory P.; Jeremiah, Kidola; Changalucha, John; Lawrence, David; Jaffar, Shabbar; Hope, William; Molloy, Síle F.; Harrison, Thomas S.

doi:10.1093/cid/ciy515

Cited by 68 publications

(74 citation statements)

References 30 publications

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“…Most HIV-infected individuals undergoing LP were profoundly immunocompromised (median CD4 < 100 cells/μL) despite almost half having a history of ART use. This mirrors findings from recent studies showing approximately half of patients with cryptococcal meningitis are now ART-experienced, [19][20][21] reflecting a combination of late presentation to care with severe immune-suppression, 9 default from care, and ART failure from resistance. Interpreted alongside recent data showing that approximately half of patients with culture-negative suspected meningitis and two-thirds diagnosed with cryptococcal meningitis die within one year of presentation in Botswana, 13,22 these findings demonstrate that CNS infections remain an important cause of mortality in HIV-infected individuals over a decade into the ART era.…”

Section: Discussionsupporting

confidence: 81%

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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Section: Discussionsupporting

confidence: 81%

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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“…The trial recruited 80 participants across 2 sites: Princess Marina Hospital (Gaborone, Botswana) and Bugando Medical Centre and Seko Toure Hospital (Mwanza, Tanzania) between October 2014 and September 2016. [ 16 ]…”

Section: Methodsmentioning

confidence: 99%

“…[ 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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“…The quality was judged to be good for most studies (details on therapeutic lumbar puncture details in 12/18, timing of ART initiation in 17/18 and description of antifungal regimen in all studies), and most RCTs had been previously evaluated using GRADE criteria [30]. Nine countries were represented (including several multi-country RCTs); greatest representation was from South Africa (six studies) [85][86][87][88][89][90], Uganda (six studies) [22,[91][92][93][94][95] and Malawi (four studies) [7,22,96,97], with other countries represented in two or fewer studies [98][99][100]. Ten of the eighteen studies excluded patients on ART at the time of enrolment.…”

Section: Cryptococcal Meningitis Outcomes For Treatment Provided Unmentioning

confidence: 99%

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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Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

Abstract: Single dose 10mg/kg L-AmB was well tolerated and led to non-inferior EFA compared to 14 days of 3mg/kg/d L-AmB in HIV-associated CM. Induction based on single 10mg/kg L-AmB dose is being taken forward to a phase-III clinical endpoint trial.

Cited by 68 publications

References 30 publications

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

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

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

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