scholarly journals HIV-associated Cryptococcal Meningitis: a Review of Novel Short-Course and Oral Therapies

2020 ◽  
Vol 12 (4) ◽  
pp. 422-437
Author(s):  
Letumile R. Moeng ◽  
James Milburn ◽  
Joseph N. Jarvis ◽  
David S. Lawrence
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Liposomal Amphotericin ◽  
Phase Iii ◽  
Induction Treatment ◽  
High Dose ◽  
Ongoing Research ◽  
Short Course ◽  
Incidence And Mortality ◽  
The Impact

Abstract Purpose of review HIV-associated cryptococcal meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for cryptococcal meningitis. Recent findings Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. Summary The incidence and mortality associated with cryptococcal meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for cryptococcal meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease.

scholarly journals AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study

BMJ Open ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. e026288 ◽  
Author(s):  
Ponego Lloyd Ponatshego ◽  
David Stephen Lawrence ◽  
Nabila Youssouf ◽  
Sile F Molloy ◽  
Melanie Alufandika ◽  
...  
Keyword(s):  
Economic Evaluation ◽  
Economic Analysis ◽  
Cryptococcal Meningitis ◽  
Liposomal Amphotericin ◽  
Standard Treatment ◽  
Sub Saharan Africa ◽  
Phase Iii ◽  
High Dose ◽  
Historical Cohort ◽  
Single High Dose

IntroductionCryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation.Methods and analysisCountry-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial.Ethics and disseminationThe AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings.Trial registrationISRCTN72509687; Pre-results.

scholarly journals Short-Course Induction Treatment with Intrathecal Amphotericin B Lipid Emulsion for HIV Infected Patients with Cryptococcal Meningitis

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Gerardo Alvarez-Uria ◽  
Manoranjan Midde ◽  
Raghavakalyan Pakam ◽  
Pradeep Sukumar Yalla ◽  
Praveen Kumar Naik ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Risk Reduction ◽  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Lipid Emulsion ◽  
Absolute Risk ◽  
White Blood Cells ◽  
Sub Saharan Africa ◽  
Induction Treatment ◽  
Short Course

Cryptococcal meningitis (CM) is a common cause of death among HIV infected patients in developing countries, especially in sub-Saharan Africa. In this observational HIV cohort study in a resource-limited setting in India, we compared the standard two-week intravenous amphotericin B deoxycholate (AmBd) (Regimen I) with one week of intravenous AmBd along with daily therapeutic lumbar punctures and intrathecal AmB lipid emulsion (Regimen II) during the intensive phase of CM treatment. 78 patients received Regimen I and 45 patients received Regimen II. After adjustment for baseline characteristics (gender, age, altered mental status or seizures at presentation, CD4 cell count, white blood cells, cerebrospinal fluid white cells, and haemoglobin), the use of Regimen II was associated with a significant relative risk reduction in mortality (adjusted hazard ratio 0.4, 95% confidence interval, 0.22–0.76) and 26.7% absolute risk reduction (95% confidence interval, 9.9–43.5) at 12 weeks. The use of Regimen II resulted in lower costs of drugs and hospital admission days. Since the study is observational in nature, we should be cautious about our results. However, the good tolerability of intrathecal administration of AmB lipid emulsion and the clinically important mortality reduction observed with the short-course induction treatment warrant further research, ideally through a randomized clinical trial.

Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis

2012 ◽  
Vol 64 (1) ◽  
pp. 76-81 ◽  
Author(s):  
Conrad K. Muzoora ◽  
Taseera Kabanda ◽  
Giuseppina Ortu ◽  
John Ssentamu ◽  
Pasco Hearn ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
High Dose ◽  
Short Course

scholarly journals A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis

AIDS ◽  
2012 ◽  
Vol 26 (11) ◽  
pp. 1363-1370 ◽  
Author(s):  
Arthur T. Jackson ◽  
Jesse C. Nussbaum ◽  
Jacob Phulusa ◽  
Dan Namarika ◽  
Maria Chikasema ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Amphotericin B ◽  
Phase Ii ◽  
Cryptococcal Meningitis ◽  
Controlled Trial ◽  
High Dose ◽  
Randomized Controlled ◽  
Short Course

scholarly journals Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

2015 ◽  
Vol 59 (12) ◽  
pp. 7224-7231 ◽  
Author(s):  
Tihana Bicanic ◽  
Christian Bottomley ◽  
Angela Loyse ◽  
Annemarie E. Brouwer ◽  
Conrad Muzoora ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Induction Treatment ◽  
Standardized Protocol ◽  
Short Course ◽  
Amphotericin B Deoxycholate ◽  
Intravenous Saline ◽  
Electrolyte Replacement ◽  
Grade Iii ◽  
Electrolyte Abnormalities

ABSTRACTAmphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3;P= 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11;P= 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

High-dose Weekly Liposomal Amphotericin B Antifungal Prophylaxis in Patients Undergoing Liver Transplantation

2015 ◽  
Vol 99 (4) ◽  
pp. 848-854 ◽  
Author(s):  
Maddalena Giannella ◽  
Giorgio Ercolani ◽  
Francesco Cristini ◽  
Mariacristina Morelli ◽  
Michele Bartoletti ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Antifungal Prophylaxis ◽  
Liposomal Amphotericin B ◽  
High Dose

Triple therapy in uncontrolled asthma: a network meta-analysis of Phase III studies

2021 ◽  
pp. 2004233
Author(s):  
Paola Rogliani ◽  
Beatrice Ludovica Ritondo ◽  
Luigino Calzetta
Keyword(s):  
Meta Analysis ◽  
Phase Iii ◽  
Fixed Dose ◽  
High Dose ◽  
Severe Exacerbation ◽  
Triple Combination ◽  
Combination Therapies ◽  
Uncontrolled Asthma ◽  
Long Acting ◽  
The Impact

Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS), long-acting β2-adrenoceptor agonist (LABA), and long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC). Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of Phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma. Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk [RR] from 0.61 to 0.80) and increasing trough forced expiratory volume in the 1st second (mL from +33 to +114). Triple combination therapies including HD ICS were superior (p<0.05) than MD ICS/LABA/LAMA FDC in preventing severe exacerbation (RR from 0.46 to 0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns. This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

scholarly journals Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial

2018 ◽  
Vol 36 (25) ◽  
pp. 2578-2584 ◽  
Author(s):  
Jonathan Strosberg ◽  
Edward Wolin ◽  
Beth Chasen ◽  
Matthew Kulke ◽  
David Bushnell ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Health Status ◽  
Global Health ◽  
Phase Iii ◽  
High Dose ◽  
Health Related Qol ◽  
Health Related ◽  
Phase Iii Study ◽  
The Impact

Purpose Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of 177Lu-Dotatate treatment on time to deterioration in health-related QoL. Methods The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with 177Lu-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration ≥ 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date. Results TTD was significantly longer in the 177Lu-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning. Conclusion This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, 177Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.

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