Cryptococcal meningitis.

Cryptococcus neoformans and Cryptococcus gattii species complexes cause meningoencephalitis with high fatality rates and considerable morbidity, particularly in persons with deficient T cell-mediated immunity, most commonly affecting people living with HIV. Whereas the global incidence of HIV-associated cryptococcal meningitis (HIV-CM) has decreased over the past decade, cryptococcosis still accounts for one in five AIDS-related deaths globally due to the persistent burden of advanced HIV disease. Moreover, mortality remains high (~50%) in low-resource settings. The armamentarium to decrease cryptococcosis-associated mortality is expanding: cryptococcal antigen screening in the serum and pre-emptive azole therapy for cryptococcal antigenaemia are well established, whereas enhanced pre-emptive combination treatment regimens to improve survival of persons with cryptococcal antigenaemia are in clinical trials. Short courses (≤7 days) of amphotericin-based therapy combined with flucytosine are currently the preferred options for induction therapy of cryptococcal meningitis. Whether short-course induction regimens improve long-term morbidity such as depression, reduced neurocognitive performance and physical disability among survivors is the subject of further study. Here, we discuss underlying immunology, changing epidemiology, and updates on the management of cryptococcal meningitis with emphasis on HIV-associated disease.

Clinical characteristics and morbidity among hospitalized adults with advanced HIV disease in Uganda during 'test and treat' era.

Nearly four decades after the first case of AIDS was described, the global number of AIDS-related deaths has steadily declined but falls short of the elimination targets, especially in sub-Saharan Africa. Despite interventions to promote early HIV diagnosis and treatment, hospitalization and mortality related to advanced HIV disease (AHD) remains a significant public health problem in Uganda. We assessed the HIV treatment history and causes of hospitalization among in-patients with AHD at a tertiary hospital in Uganda. In this cross-sectional study, pre-hospitalization HIV treatment history and clinical characteristics of HIV-positive in-patients with CD4<200 cells/µL or WHO stage 3 or 4 clinical events were assessed. Descriptive data were summarized using percentages and medians. Among hospitalized adults with AHD from November 2021 to June 2022, 74% (260/353) knew their HIV status prior to hospitalization and 62% (219/353) were ART experienced at presentation. The median time since ART initiation was 28 months (IQR; 2-97). Overall, 73% (258/353) had at least two etiological diagnoses and the majority (non-mutually exclusive) were diagnosed with tuberculosis (61.2%), cryptococcal meningitis (20.7%), mucosal candidiasis (16.1%) and bacterial infections (15%). In conclusion, nearly two-thirds of in-patients with advanced HIV disease were ART experienced prior to hospitalization and tuberculosis was the most common cause of hospitalization. Innovative strategies to strengthen HIV diagnosis, linkage, and retention in HIV care and to increase coverage of TB preventive therapy are urgently needed.

Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV.

Background: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. Methods: We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status. Results: We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75). Conclusions: CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.

Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial.

BACKGROUND: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. METHODS: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). RESULTS: We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10  Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). CONCLUSIONS: This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. CLINICAL TRIALS REGISTRATION: NCT04031833.

Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in HIV-Associated Cryptococcal Meningitis.

Background: Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis from being normal to markedly elevated. However, the clinical implications of CSF protein levels in cryptococcal meningitis remain unclear. Methods: We analysed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into ≥100 mg/dL (n=249) and <100 mg/dL (n=641). We described baseline clinical variables and mortality by CSF protein levels. Results: Approximately one-third of individuals had a baseline CSF protein ≥100 mg/dL. Those with CSF protein ≥100 mg/dL were more likely to present with Glasgow coma scale scores <15 (P<0.01), self-reported seizures at baseline (P=0.02), higher CD4 T-cells (p<0.001), and higher CSF white cells (p<0.001). Moreover, those with a baseline CSF protein ≥100 mg/dL also had a lower baseline CSF fungal burden (p<0.001) and a higher percentage of sterile CSF cultures at day 14 (p=0.02). Individuals with CSF protein ≥100 mg/dL demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules pro-inflammatory cytokines, type-1 T-helper cell cytokines, type-3 chemokines, and immune-exhaustion marker (p<0.05). 18-week mortality risk in individuals with a CSF protein <100 mg/dL was 34% higher, (unadjusted Hazard Ratio 1.34; 95% CI, 1.05 to 1.70; p=0.02) than those with ≥100 mg/dL. Conclusion: In cryptococcal meningitis, individuals with CSF protein ≥100 mg/dL more frequently presented with seizures, altered mental status, immune activation, and favourable fungal outcomes. Baseline CSF protein levels may serve as a surrogate marker of immune activation and prognosis.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Distal jejunal obstruction due to Cryptococcus neoformans and rifampicin-resistant Mycobacterium tuberculosis co-infection: A case report.

Jejunal obstruction secondary to Cryptococcus neoformans and rifampicin-resistant Mycobacterium tuberculosis co-infection in HIV is not previously reported. This is a case of a 30-year-old HIV-positive male with severe headaches, a positive cerebrospinal fluid cryptococcal antigen assay, and elevated intracranial pressure requiring serial lumbar punctures and opioids. He developed constipation and abdominal distension, had partial jejunectomy and histopathology revealed Cryptococcus yeasts and caseous granulomas with Mycobacterium tuberculosis (TB). Post-operatively, rifampicin-resistant TB was detected in urine.

Therapeutic Lumbar Punctures in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Should Opening Pressure Direct Management?

Background: Increased intracranial pressure (ICP) frequently complicates cryptococcal meningitis. Therapeutic lumbar punctures (LPs) have acute survival benefits in the first week, and we sought to understand the longer-term survival impact of therapeutic LPs. Methods: We prospectively enrolled human immunodeficiency virus (HIV)-seropositive adults with cryptococcal meningitis from 2013 to 2017 in Uganda. We assessed the association between clinical characteristics, CSF parameters, and 14- and 30-day mortality by baseline ICP. We also assessed 30-day mortality by number of follow-up therapeutic LPs performed within 7 days. Results: Our analysis included 533 participants. Participants with baseline ICP >350 mm H2O were more likely to have Glasgow Coma Scale (GCS) score <15 (P < .001), seizures (P < .01), and higher quantitative cryptococcal cultures (P < .001), whereas participants with ICP <200 mm H2O were more likely to have baseline sterile CSF cultures (P < .001) and CSF white blood cell count ≥5 cells/µL (P = .02). Thirty-day mortality was higher in participants with baseline ICP >350 mm H2O and ICP <200 mm H2O as compared with baseline ICP 200-350 mm H2O (hazard ratio, 1.55 [95% confidence interval, 1.10-2.19]; P = .02). Among survivors at least 7 days, the 30-day relative mortality was 50% higher among participants who did not receive any additional therapeutic LPs compared to those with ≥1 additional follow-up LP (33% vs 22%; P = .04), irrespective of baseline ICP. Conclusions: Management of increased ICP remains crucial in improving clinical outcomes in cryptococcal meningitis. Guidelines should consider an approach to therapeutic LPs that is not dictated by baseline ICP.

Association of Hyponatremia on Mortality in Cryptococcal Meningitis: A Prospective Cohort.

Background: Sodium abnormalities are frequent in central nervous system infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion, or medication adverse events. In cryptococcal meningitis (CM), the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown. Methods: We conducted a secondary analysis of data from 2 randomized trials of human immunodeficiency virus-infected adult Ugandans with CM. We grouped serum sodium into 3 categories: <125, 125-129, and 130-145 mmol/L. We assessed whether baseline sodium abnormalities were associated with clinical characteristics and survival. Results: Of 816 participants with CM, 741 (91%) had a baseline sodium measurement available: 121 (16%) had grade 3-4 hyponatremia (<125 mmol/L), 194 (26%) had grade 2 hyponatremia (125-129 mmol/L), and 426 (57%) had a baseline sodium of 130-145 mmol/L. Hyponatremia (<125 mmol/L) was associated with higher initial cerebrospinal fluid (CSF) quantitative culture burden (P < .001), higher initial CSF opening pressure (P < .01), lower baseline Glasgow Coma Scale score (P < .01), and a higher percentage of baseline seizures (P = .03). Serum sodium <125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses (adjusted hazard ratio, 1.87 [95% confidence interval, 1.26-2.79]; P < .01) compared to those with sodium 130-145 mmol/L. Conclusions: Hyponatremia is common in CM and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in CM needs to be developed and tested.

Cerebrospinal fluid AFB smear in adults with tuberculous meningitis: A systematic review and diagnostic test accuracy meta-analysis.

BACKGROUND: Cerebrospinal fluid (CSF) Ziehl-Neelsen acid-fast bacilli (AFB) smear is a rapid, cheap, widely available test for tuberculous meningitis (TBM). Yet, reported test sensitivity is highly variable. We performed a systematic review and meta-analysis for CSF AFB smear vs. other mycobacterial tests to diagnose TBM. METHODS: We searched MEDLINE and Embase for studies reporting sensitivity and specificity of AFB smear against mycobacterial tests (reference standard) in adults (≥15 years) with suspected TBM. We used the QUADAS-2 tool to assess risk of bias. We estimated pooled sensitivity and specificity of AFB smear versus the reference standard using random-effects bivariate modeling. We used the I2 statistic to assess heterogeneity between studies. RESULTS: Of 981 articles identified, 11 were eligible for inclusion with a total of 1713 participants. Seven studies were from high-TB burden settings and 4 from low-TB burden settings. The pooled sensitivity and specificity of CSF AFB smear were 8% (95%CI 3-21) and 100% (95%CI 90-100), with substantial heterogeneity in diagnostic performance (I2 >95% for both) and reference standards. CONCLUSION: CSF AFB smear has poor sensitivity in most settings. If other more sensitive tests are available, those should be used preferentially rather than CSF AFB smear.

Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis.

OBJECTIVES: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. METHODS: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. RESULTS: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. CONCLUSION: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.

Diagnostic and Prognostic Value of Cerebrospinal Fluid Lactate and Glucose in HIV-Associated Tuberculosis Meningitis.

The role of cerebrospinal fluid (CSF) lactate in tuberculosis meningitis (TBM) diagnosis and prognosis is unclear. The aim of this study was to evaluate the performance of CSF lactate alone and in combination with CSF glucose in predicting a diagnosis of TBM and 14-day survival. HIV-positive Ugandan adults were investigated for suspected meningitis. The baseline CSF tests included smear microscopy; Gram stain; cell count; protein; and point-of-care glucose, lactate, and cryptococcal antigen (CrAg) assays. Where CrAg was negative or there was suspicion of TBM, a CSF Xpert MTB/RIF Ultra (Xpert Ultra) test was performed. We recorded baseline demographic and clinical data and 2-week outcomes. Of 667 patients, 25% (n = 166) had TBM, and of these, 49 had definite, 47 probable, and 70 possible TBM. CSF lactate was higher in patients with definite TBM (8.0 mmol/L; interquartile ratio [IQR], 6.1 to 9.8 mmol/L) than in those with probable TBM (3.4 [IQR, 2.5 to 7.0] mmol/L), possible TBM (2.6 [IQR 2.1 to 3.8] mmol/L), and non-TBM disease (3.5 [IQR 2.5 to 5.0] mmol/L). A 2-fold increase in CSF lactate was associated with 8-fold increased odds of definite TBM (odds ratio, 8.3; 95% confidence interval [CI], 3.6 to 19.1; P < 0.01) and 2-fold increased odds of definite/probable TBM (odds ratio, 2.3; 95% CI, 1.4 to 3.7; P < 0.001). At a cut point of >5.5 mmol/L, CSF lactate could be used to diagnose definite TBM with a sensitivity of 87.7%, specificity of 80.7%, and a negative predictive value of 98.8%. CSF lactate was not predictive of 2-week mortality. IMPORTANCE Tuberculosis meningitis (TBM) is the most severe form of tuberculosis, and its fatality is largely due to delays in diagnosis. The role of CSF lactate has not been evaluated in patients with HIV presenting with signs and symptoms of meningitis. In this study, using a point-of-care handheld lactate machine in patients with HIV-associated meningitis, we showed that high baseline CSF lactate (>5.5 mmol) may be used to rapidly identify patients with TBM and shorten the time to initiate treatment with a similar performance to the Xpert Ultra assay for definite TBM. Elevated CSF lactate levels, however, were not associated with increased 2-week mortality in patients with HIV-associated TBM. Due to moderate specificity, other etiologies of meningitis should be investigated.

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

Sterile Cerebrospinal Fluid Culture at Cryptococcal Meningitis Diagnosis Is Associated with High Mortality.

Cryptococcus is the leading cause of AIDS-related meningitis in sub-Saharan Africa. The clinical implications of a sterile cerebrospinal fluid (CSF) culture among individuals diagnosed with cryptococcal meningitis using CSF cryptococcal antigen (CrAg) are unclear. We prospectively enrolled 765 HIV-positive Ugandans with first-episode cryptococcal meningitis from November 2010 to May 2017. All persons were treated with amphotericin-based induction therapy. We grouped participants by tertile of baseline CSF quantitative Cryptococcus culture burden and compared clinical characteristics, CSF immune profiles, and 18-week mortality. We found 55 (7%) CSF CrAg-positive participants with sterile CSF cultures. Compared to the non-sterile groups, participants with sterile CSF cultures had higher CD4 counts, lower CSF opening pressures, and were more frequently receiving ART. By 18 weeks, 47% [26/55] died in the sterile culture group versus 35% [83/235] in the low culture tertile, 46% [107/234] in the middle tertile, and 56% [135/241] in the high tertile (p < 0.001). The sterile group had higher levels of CSF interferon-gamma (IFN-γ), IFN-α, interleukin (IL)-6, IL-17, G-CSF, GM-CSF, and chemokine CXCL2 compared with non-sterile groups. Despite persons with sterile CSF cultures having higher CD4 counts, lower CSF opening pressures, and CSF cytokine profiles associated with better Cryptococcus control (e.g., IFN-γ predominant), mortality was similar to those with higher fungal burdens. This unexpected finding challenges the traditional paradigm that increasing CSF fungal burdens are associated with increased mortality but is consistent with a damage-response framework model.

Establishing targets for advanced HIV disease: A call to action.

The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. We suggest that setting 95-95-95 targets for CD4 testing, cryptococcal antigen and TB testing, and treatment that are aligned to the WHO AHD package of care would be a step in the right direction to achieving the greater goal of the WHO End TB strategy and the proposed new strategy to end cryptococcal meningitis deaths. However, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for AHD, and health systems strengthening to minimise delays in initiating the WHO-recommended therapies for TB and cryptococcal disease.

Short Communication: A Descriptive Analysis of Dried Blood Spot Adherence Testing Among Ugandans with HIV Presenting with Cryptococcal Meningitis.

Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, and those unmasking cryptococcosis after <2 weeks of ART have higher mortality. However, it is unknown if those presenting as ART experienced are actually adherent to their ART. Unknowingly, restarting ART in persons, who have discontinued ART, may be a fatal iatrogenic error. To evaluate ART adherence in an exploratory analysis, we collected dried blood spots on 44 HIV-infected persons presenting with cryptococcal meningitis. We quantified tenofovir diphosphate (TFV-DP) and lamivudine (3TC) from dried blood spots. We quantified cumulative ART adherence over the preceding 6-8 weeks based on TFV-DP concentrations and adherence over the last few days based on 3TC concentrations. Of 22 ART experienced, 20 (91%) had quantifiable concentrations. Of 18 receiving tenofovir, 15 (83%) had TFV-DP consistent with drug intake of ≥4 doses/week or moderate adherence. With 3TC, 72% (18/22) had detectable levels consistent with adherence over the last 3 days before measurement. Only three ART-experienced subjects were alive and virally suppressed at 4 months (n = 2 on ART for <30 days; n = 1 with undetectable antiretrovirals). Surprisingly, of 22 who reported not receiving ART, 4 (18%) had quantifiable tenofovir. Most ART-experienced subjects were taking their ART with moderate to good adherence with the majority likely having viral resistance given generally at good ART levels, receipt of intensive adherence counseling, and lack of subsequent viral suppression. The World Health Organization (WHO) guidelines recommend adherence counseling with ART continuation and repeat viral loads in 1-3 months before switching to second-line ART. These recommendations are likely inappropriate in those with central nervous system infections given the additional possible harm of central nervous system immune reconstitution syndrome. Further study to evaluate continuation of ART regimens when presenting with cryptococcosis has benefit, with checking blood levels at presentation potentially being a helpful option. ClinicalTrials.gov Identifier: NCT01802385.

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial.

BACKGROUND: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. METHODS: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events. RESULTS: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34). CONCLUSIONS: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC.

Impact of biological sex on cryptococcal meningitis mortality in Uganda and South Africa.

The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00-1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07-1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94-1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P = .02). Of the 373 participants with CSF biomarkers, men had higher median pro- and anti-inflammatory, monocyte/macrophage differentiation, maturation, and migration, immune exhaustion, and cytotoxicity cytokines than women (P < .05). We identified biological sex as proxy for anemia, a potentially modifiable risk factor for cryptococcal meningitis mortality. Immune response may contribute to the multifaceted underlying mechanisms for the discrepancy in mortality based on sex. LAY SUMMARY: We examined the role of biological sex in cryptococcal meningitis mortality in a large cohort. Our findings reveal significant differences in inflammatory markers by biological sex. Women have significantly higher mortality due to cryptococcal meningitis that is attributable to anemia at baseline.

Cerebrospinal Fluid Lactate as a Prognostic Marker of Disease Severity and Mortality in Cryptococcal Meningitis.

BACKGROUND: Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacterial and viral meningitis. We measured CSF lactate in individuals with cryptococcal meningitis to determine its clinical significance. METHODS: We measured point-of-care CSF lactate at the bedside of 319 Ugandan adults living with human immunodeficiency virus at diagnosis of cryptococcal meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. RESULTS: Individuals with high CSF lactate >5 mmol/L at cryptococcal diagnosis more likely presented with altered mental status (P < .0001), seizures (P = .0005), elevated intracranial opening pressure (P = .03), higher CSF white cells (P = .007), and lower CSF glucose (P = .0003) compared with those with mid-range (3.1 to 5 mmol/L) or low (≤3 mmol/L) CSF lactate levels. Two-week mortality was higher among individuals with high baseline CSF lactate >5 mmol/L (35%; 38 of 109) compared with individuals with mid-range (22%; 25 of 112) or low CSF lactate (9%; 9 of 97; P =<.0001). After multivariate adjustment, CSF lactate >5 mmol/L remained independently associated with excess mortality (adjusted hazard ratio = 3.41; 95% confidence interval, 1.55-7.51; P = .002). We found no correlation between baseline CSF lactate levels and blood capillary lactate levels. CONCLUSIONS: Baseline point-of-care CSF lactate levels are a prognostic marker of disease severity and mortality in cryptococcal meningitis. Individuals with an elevated baseline CSF lactate level are more likely to present with altered mental status, seizures, and elevated CSF opening pressure and are at a greater risk of death. Future studies are needed to determine targeted therapeutic management strategies in persons with high CSF lactate.

Baseline Serum C-Reactive Protein Level Predicts Mortality in Cryptococcal Meningitis.

BACKGROUND: C-reactive protein (CRP) is an acute phase protein produced by the liver in response to systemic inflammation. CRP is a helpful surrogate biomarker used for following the progression and resolution of infection. We aimed to determine the association of baseline CRP level and the temporal change in CRP over time with cryptococcal meningitis outcome. METHODS: We reviewed 168 prospectively enrolled HIV-infected Ugandans with confirmed first-episode cryptococcal meningitis. Baseline plasma CRP collected within 5 days of meningitis diagnosis was categorized into quartiles. We compared baseline CRP with 18-week survival using time-to-event analysis. RESULTS: Of 168 participants, the baseline first quartile of serum CRP was <29.0 mg/L, second quartile 29.0-49.5 mg/L, third quartile 49.6-83.6 mg/L, and fourth quartile >83.6 mg/L. Baseline CD4 count, HIV viral load, and cerebrospinal fluid results did not differ by CRP quartile. Participants with CRP >49.5 mg/L more likely presented with Glasgow Coma Scale (GCS) <15 (P = .03). The 18-week mortality rate was 55% (46/84) in the highest 2 quartile CRP groups (>49.5 mg/L), 41% (17/42) in the mid-range CRP group (29.0-49.5 mg/L), and 14% (6/42) in the low-CRP group (<29.0 mg/L; P < .001). After adjustment for possible confounding factors including GCS <15, CRP remained significantly associated with mortality (adjusted hazard ratio, 1.084 per 10 mg/L; 95% CI, 1.031-1.139; P = .0016). CONCLUSIONS: Higher baseline CRP is associated with increased mortality in HIV-infected individuals with first-episode cryptococcal meningitis. CRP could be a surrogate marker for undiagnosed coinfections or may reflect immune dysregulation, leading to worse outcomes in persons with advanced AIDS and concomitant cryptococcal meningitis.