Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Genetic diversity and microevolution in clinical Cryptococcus isolates from Cameroon.

Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and the genetic diversity of these infecting isolates can also be geographically linked. Here, we employ whole genome sequences for 372 clinical Cryptococcus isolates from 341 patients with HIV-associated cryptococcal meningitis obtained via a large clinical trial, across both Malawi and Cameroon, to enable population genetic comparisons of isolates between countries. We see that isolates from Cameroon are highly clonal, when compared to those from Malawi, with differential rates of disruptive variants in genes with roles in DNA binding and energy use. For a subset of patients (22) from Cameroon, we leverage longitudinal sampling, with samples taken at days 7 and 14 post-enrollment, to interrogate the genetic changes that arise over the course of infection, and the genetic diversity of isolates within patients. We see disruptive variants arising over the course of infection in several genes, including the phagocytosis-regulating transcription factor GAT204. In addition, in 13% of patients sampled longitudinally, we see evidence for mixed infections. This approach identifies geographically linked genetic variation, signatures of microevolution, and evidence for mixed infections across a clinical cohort of patients affected by cryptococcal meningitis in Central Africa.

Cryptococcal meningitis, caused by Cryptococcus, results in approximately half a million deaths per year globally. We compare clinical Cryptococcus samples from Cameroon and Malawi to explore the genetic diversity of these isolates. We find instances of mixed-strain infections and identify genetic variants arising in Cryptococcus over disease.

Continental concerted efforts to control the seventh outbreak of Ebola Virus disease in Uganda: The first 90 days of the response.

On 20th September 2022, Uganda declared the 7th outbreak of Ebola virus disease (EVD) caused by the Sudan Ebola strain following the confirmation of a case admitted at Mubende Regional Referral Hospital. Upon confirmation, the Government of Uganda immediately activated the national incident management system to initiate response activities. Additionally, a multi-country emergency stakeholder meeting was held in Kampala; convening Ministers of Health from neighbouring Member States to undertake cross-border preparedness and response actions. The outbreak spanned 69 days and recorded 164 cases (142 confirmed, 22 probable), 87 recoveries and 77 deaths (case fatality ratio of 47%). Nine out of 136 districts were affected with transmission taking place in 5 districts but spilling over in 4 districts without secondary transmission. As part of the response, the Government galvanised robust community mobilisation and initiated assessment of medical counter measures including therapeutics, new diagnostics and vaccines. This paper highlights the response actions that contributed to the containment of this outbreak in addition to the challenges faced with a special focus on key recommendations for better control of future outbreaks.

Closing the gap in our understanding of infectious diseases.

Systematic reviews (SR) and meta-analyses (MA) have become important in addressing specific questions of clinical importance and presenting evidence from an in-depth analysis of literature and aiding clinical decision-making. The "Systematic Reviews on infectious diseases" collection will address several important questions by summarizing large bodies of evidence in a reproducible and concise approach to advance our knowledge and understanding of infectious diseases.

Viral suppression and HIV-1 drug resistance 1 year after pragmatic transitioning to dolutegravir first-line therapy in Malawi: a prospective cohort study.

BACKGROUND: Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing. METHODS: In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15). FINDINGS: Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1-98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0-94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5-99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5-93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3-87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3-215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline. INTERPRETATION: High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen. FUNDING: Médecins Sans Frontières. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

Short-term Mortality Outcomes of HIV-Associated Cryptococcal Meningitis in Antiretroviral Therapy-Naïve and -Experienced Patients in Sub-Saharan Africa.

BACKGROUND: An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) before presentation. There is some evidence suggesting an increased 2-week mortality in those receiving ART for <14 days compared with those on ART for >14 days. However, presentation and outcomes for cryptococcal meningitis patients who have recently initiated ART, and those with virologic failure and/or nonadherence, are not well described. METHODS: Six hundred seventy-eight adults with a first episode of cryptococcal meningitis recruited into a randomized, noninferiority, multicenter phase 3 trial in 4 Sub-Saharan countries were analyzed to compare clinical presentation and 2- and 10-week mortality outcomes between ART-naïve and -experienced patients and between patients receiving ART for varying durations before presentation. RESULTS: Over half (56%; 381/678) the study participants diagnosed with a first episode of cryptococcal meningitis were ART-experienced. All-cause mortality was similar at 2 weeks (17% vs 20%; hazard ratio [HR], 0.85; 95% CI, 0.6-1.2; P = .35) and 10 weeks (38% vs 36%; HR, 1.03; 95% CI, 0.8-1.32; P = .82) for ART-experienced and ART-naïve patients. Among ART-experienced patients, using different cutoff points for ART duration, there were no significant differences in 2- and 10-week mortality based on duration of ART. CONCLUSIONS: In this study, there were no significant differences in mortality at 2 and 10 weeks between ART-naïve and -experienced patients and between ART-experienced patients according to duration on ART.

Global guideline for the diagnosis and management of rare yeast infections: an initiative of the ECMM in cooperation with ISHAM and ASM.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.

Fungal Burden and Raised Intracranial Pressure Are Independently Associated With Visual Loss in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis.

Among 472 patients with human immunodeficiency virus-associated cryptococcal meningitis, 16% had severe visual loss at presentation, and 46% of these were 4-week survivors and remained severely impaired. Baseline cerebrospinal fluid opening pressure ≥40 cmH2O (adjusted odds ratio [aOR], 2.56; 95% confidence interval [CI], 1.36-4.83; P = .02) and fungal burden >6.0 log10 colonies/mL (aOR, 3.01; 95% CI, 1.58-5.7; P = .003) were independently associated with severe visual loss.

Cryptococcal Antigen in Serum and Cerebrospinal Fluid for Detecting Cryptococcal Meningitis in Adults Living With Human Immunodeficiency Virus: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies.

Cryptococcal antigen (CrAg) detection could direct the timely initiation of antifungal therapy. We searched MEDLINE and Embase for studies where CrAg detection in serum/cerebrospinal fluid (CSF) and CSF fungal culture were done on adults living with human immunodeficiency virus (HIV) who had suspected cryptococcal meningitis (CM). With Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), we evaluated the risk of bias in 11 included studies with 3600 participants, and used a random-effects meta-analysis to obtain summary sensitivity and specificity of serum and CSF CrAg, as well as agreement between CSF CrAg and CSF culture. Summary sensitivity and specificity of serum CrAg were 99.7% (97.4-100) and 94.1% (88.3-98.1), respectively, and summary sensitivity and specificity of CSF CrAg were 98.8% (96.2-99.6) and 99.3% (96.7-99.9), respectively. Agreement between CSF CrAg and CSF culture was 98% (97-99). In adults living with HIV who have CM symptoms, serum CrAg negativity may rule out CM, while positivity should prompt induction antifungal therapy if lumbar puncture is not feasible. In a first episode of CM, CSF CrAg positivity is diagnostic.

Burden of hepatitis E virus infection in pregnancy and maternofoetal outcomes: a systematic review and meta-analysis.

BACKGROUND: There is still a dearth of knowledge on the burden of HEV infection in the global population of pregnant women. Therefore, we conducted a systematic review and meta-analysis to estimate the global burden of HEV infection in pregnancy. METHODS: We searched PubMed, Embase, Web of Knowledge, and Global Index Medicus to identify articles published until January 26, 2020. We considered cross-sectional, case-control, and cohort studies reporting the immunoglobulins M HEV seroprevalence in asymptomatic and symptomatic (jaundice or elevated transaminases) pregnant women or investigating the association between HEV infection and maternofoetal outcomes. We used a random-effects model to pool studies. This review was registered with PROSPERO, CRD42018093820. RESULTS: For HEV prevalence estimates, we included 52 studies (11,663 pregnant women). The seroprevalence was 3.5% (95% confidence interval: 1.4-6.4) in asymptomatic women (most of whom from high endemic areas). The prevalence in symptomatic women was 49.6% (42.6-56.7) with data only from HEV high endemic countries. In the multivariable meta-regression model, the prevalence was higher in symptomatic women compared to asymptomatic (adjusted prevalence odds ratio [aPOR]: 1.76; 95%CI: 1.61-1.91) and decreased with increasing year of publication (by 10-year) (aPOR: 0.90; 95%CI: 0.84-0.96). The proportion of HEV vertical transmission was 36.9% (13.3-64.2). Risk of bias was low, moderate and high respectively in 12 (23%), 37 (70%), and 4 studies (7%) addressing HEV prevalence estimation. HEV infection was associated with maternal deaths (pooled OR 7.17; 3.32-15.47), low birth weight (OR: 3.23; 1.71-6.10), small for gestational age (OR: 3.63; 1.25-10.49), preterm < 32 weeks (OR: 4.18; 1.23-14.20), and preterm < 37 weeks (OR: 3.45; 2.32-5.13), stillbirth (OR: 2.61; 1.64-4.14), intrauterine deaths (OR: 3.07; 2.13-4.43), and not with miscarriage (OR: 1.74; 0.77-3.90). All studies which assessed the association between HEV infection and maternofoetal outcomes had a moderate risk of bias. CONCLUSIONS: Findings from this study are suggestive of a high burden of HEV infection in pregnancy in high endemic countries, its association with poor maternofoetal outcomes, and a high rate of vertical transmission. This study supports the need for specific strategies to prevent exposure of pregnant women to HEV infection, especially in high endemic areas.

Infertility and associated factors in three hospitals in Douala, Cameroon: a cross-sectional study.

AIM: We determined the prevalence and factors associated with couple infertility in three hospitals in Douala, Cameroon. METHODS: We conducted a cross-sectional study from December 18th 2015 to March 18th 2016 in three public hospitals in Douala. Three hundred and sixty participants were studied prospectively for associated factors using a multivariate logistic regression model and 4732 files were studied retrospectively for the prevalence of infertility. Statistical significance was set at p < 0.05. RESULTS: The prevalence of couple infertility was 19.2%. In logistic models, the factors which independently increased the risk of couple infertility were a history of reproductive tract infection/STI, a history of uterine fibroids, a history of dysmenorrhea and abortion for the females while for males it was a history of mumps, erectile dysfunction and exposure to chemicals/toxic substances/pesticides. CONCLUSION: One in every five couples in this study was infertile. Several factors affect the risks associated with couple infertility. The identification of these factors could help detect subgroups of couples at high risk of infertility. Reproductive health education, screening programmes for STI's that may lead to infertility should be offered to couples.

Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis.

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. METHODS: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. CONCLUSIONS: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa.

New Insights Into Cryptococcus Spp. Biology and Cryptococcal Meningitis.

PURPOSE OF REVIEW: Defective cell-mediated immunity is a major risk factor for cryptococcosis, a fatal disease if untreated. Cryptococcal meningitis (CM), the main presentation of disseminated disease, occurs through hematogenous spread to the brain from primary pulmonary foci, facilitated by yeast virulence factors. We revisit remarkable recent improvements in the prevention, diagnosis and management of CM. RECENT FINDINGS: Cryptococcal antigen (CrAg), main capsular polysaccharide of Cryptococcus spp. is detectable in blood and cerebrospinal fluid of infected patients with point of care lateral flow assays. Recent World Health Organization guidelines recommend 7-day amphotericin B plus flucytosine, then 7-day high dose (1200 mg/day) fluconazole for induction treatment of HIV-associated CM. Management of raised intracranial pressure, a consequence of CM, should rely mainly on daily therapeutic lumbar punctures until normalisation. In HIV-associated CM, following introduction of antifungal therapy, (re)initiation of antiretroviral therapy should be delayed by 4-6 weeks to prevent immune reconstitution inflammatory syndrome, common in CM. CM is a fatal disease whose diagnosis has recently been simplified. Treatment should always include antifungal combination therapy and management of raised intracranial pressure. Screening for immune deficiency should be mandatory in all patients with cryptococcosis.

Dengue virus infection in people residing in Africa: a systematic review and meta-analysis of prevalence studies.

Better knowledge of the face of the current dengue virus (DENV) epidemiology in Africa can help to implement efficient strategies to curb the burden of dengue fever. We conducted this systematic review and meta-analysis to determine the prevalence of DENV infection in Africa. We searched PubMed, EMBASE, African Journals Online, and Africa Index Medicus from January 1st, 2000 to June 10th, 2019 without any language restriction. We used a random-effects model to pool studies. A total of 76 studies (80,977 participants; 24 countries) were included. No study had high risk of bias. Twenty-two (29%) had moderate and 54 (71%) had low risk of bias. In apparently healthy individuals, the pooled prevalence of DENV was 15.6% (95% confidence interval 9.9-22.2), 3.5% (0.8-7.8), and 0.0% (0.0-0.5) respectively for immunoglobulins (Ig) G, IgM, and for ribonucleic acid (RNA) in apparently healthy populations. In populations presenting with fever, the prevalence was 24.8% (13.8-37.8), 10.8% (3.8-20.6k) and 8.4% (3.7-14.4) for IgG, IgM, and for RNA respectively. There was heterogeneity in the distribution between different regions of Africa. The prevalence of DENV infection is high in the African continent. Dengue fever therefore deserves more attention from healthcare workers, researchers, and health policy makers.

Case fatality rate and viral aetiologies of acute respiratory tract infections in HIV positive and negative people in Africa: The VARIAFRICA-HIV systematic review and meta-analysis.

BACKGROUND: To set priorities for efficient control of acute respiratory tract infection (ARTI) in Africa, it is necessary to have accurate estimate of its burden, especially among HIV-infected populations. OBJECTIVES: To compare case fatality rate (CFR) and viral aetiologies of ARTI between HIV-positive and HIV-negative populations in Africa. STUDY DESIGN: We searched PubMed, EMBASE, Web of Knowledge, Africa Journal Online, and Global Index Medicus to identify studies published from January 2000 to April 2018. Random-effect meta-analysis method was used to assess association (pooled weighted odds ratios (OR) with 95% confidence interval (CI)). RESULTS: A total of 36 studies (126,526 participants) were included. CFR was significantly higher in patients with HIV than in HIV-negative controls (OR 4.10, 95%CI: 2.63-6.27, I²: 93.7%). The risk was significantly higher among children ≤5 years (OR 5.51, 95%CI 2.83-10.74) compared to people aged >5 years (OR 1.48, 95%CI 1.17-1.89); p = 0.0002. There was no difference between children (15 years) and adults and between regions of Africa. There was no difference for viral respiratory aetiologies (Enterovirus, Adenovirus, Bocavirus, Coronavirus, Metapneumovirus, Parainfluenza, Influenza, and Respiratory Syncytial Virus) of ARTI between HIV-positive and HIV-negative people, except for Rhinovirus where being HIV-negative was associated with Rhinovirus (OR 0.70; 95%CI 0.51-0.97, I²: 63.4%). CONCLUSIONS: This study shows an increased risk of deaths among HIV-infected individuals with ARTI, however with no difference in viral aetiologies compared to HIV-negative individuals in Africa. ARTI deserves more attention from HIV health-care providers for efficient control. Specific strategies are needed for HIV-positive children under 5.

Recent advances in managing HIV-associated cryptococcal meningitis.

The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis.

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa.

BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CLINICAL TRIALS REGISTRATION: ISRCTN45035509. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.