Cost-effectiveness analysis of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa.

BACKGROUND: Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135,000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. METHODS: A decision analytic cost-effectiveness and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables. RESULTS: The highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to the lowest cost option the 1-week flucytosine course is most cost-effective at USD119/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to life expectancy and hospital costs, particularly infusion costs and length of stay. CONCLUSIONS: The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

Time to embrace access programmes for medicines: lessons from the South African flucytosine access programme.

BACKGROUND: Cryptococcal meningitis (CM) is estimated to cause 181 000 deaths annually, with the majority occurring in Sub-Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure, quality-assured flucytosine remains unregistered and largely inaccessible throughout Africa. METHODS: The recently established South African flucytosine clinical access programme is an attempt to address the market failure that led to a lack of public sector access to flucytosine for CM, by making the medicine freely available to tertiary hospitals in South Africa. RESULTS: Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale-up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observations from this experience that may have wider relevance. CONCLUSIONS: The South African flucytosine access programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.

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.

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.

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

Cryptococcal Meningitis Treatment Strategies Affected by the Explosive Cost of Flucytosine in the United States: A Cost-effectiveness Analysis.

BACKGROUND: In the United States, cryptococcal meningitis causes approximately 3400 hospitalizations and approximately 330 deaths annually. The US guidelines recommend treatment with amphotericin B plus flucytosine for at least 2 weeks, followed by fluconazole for a minimum of 8 weeks. Due to generic drug manufacturer monopolization, flucytosine currently costs approximately $2000 per day in the United States, with a 2-week flucytosine treatment course costing approximately $28 000. The daily flucytosine treatment cost in the United Kingdom is approximately $22. Cost-effectiveness analysis was performed to determine the value of flucytosine relative to alternative regimens. METHODS: We estimated the incremental cost-effectiveness ratio (ICER) of 3 cryptococcal induction regimens: (1) amphotericin B deoxycholate for 4 weeks; (2) amphotericin and flucytosine (100 mg/kg/day) for 2 weeks; and (3) amphotericin and fluconazole (800 mg/day) for 2 weeks. Costs of care were calculated using 2015 US prices and the medication costs. Survival estimates were derived from a randomized trial and scaled relative to published US survival data. RESULTS: Cost estimates were $83 227 for amphotericin monotherapy, $75 121 for amphotericin plus flucytosine, and $44 605 for amphotericin plus fluconazole. The ICER of amphotericin plus flucytosine was $23 842 per quality-adjusted life-year. CONCLUSIONS: Flucytosine is currently cost-effective in the United States despite a dramatic increase in price in recent years. Combination therapy with amphotericin and flucytosine is the most attractive treatment strategy for cryptococcal meningitis, though the rising price may be creating access issues that will exacerbate if the trend of profiteering continues.

Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis.

BACKGROUND: Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations. METHODS AND FINDINGS: We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800-1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens. CONCLUSIONS: Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is "very cost effective" per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease. Please see later in the article for the Editors' Summary.

Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma.

Despite impressive improvements in neurosurgical techniques, radiation and chemotherapy during the past few years, little progress has been made in the treatment of malignant gliomas. Recently, the efficacy of suicide gene therapy based on replication-competent retroviral (RCR) vectors as delivery vehicles for the therapeutic gene has been described in the treatment of experimental cancer, including gliomas. In this study, we have thus critically evaluated a panel of human and rodent glioma/glioblastoma cell lines (U-87MG, U-118MG, LN-18, LN-229, 8-MG-BA, 42-MG-BA, A-172, T-98G, UVW, C6, 9L, G-26, GL-261, Tu-2449, Tu-9648) with respect to RCR virus vector spread, sensitivity towards the cytosine deaminase (CD)/5-flurocytosine (5-FC)/5-flurouracil (5-FU) suicide system, and orthotopic growth characteristics in mice to identify suitable preclinical animal models for the development of a glioblastoma gene therapy. Rapid virus spread was observed in eight out of nine human cell lines tested in vitro. As expected, only CD-expressing cells became sensitive to 5-FC, due to their ability to convert the prodrug in its toxic form, 5-FU. All LD(50) values were within the range of concentrations obtained in human body fluids after conventional antifungal 5-FC administration. In addition, a significant bystander effect was observed in all human glioma cell lines tested. Injection of the RCR vector into pre-established orthotopic mouse tumor xenografts revealed substantial infection and virus spread of tumor tissue from most cell types.

Five-year retrospective review of guideline-based management of fungal endophthalmitis.

PURPOSE: Guidelines were introduced in 2000 at the Bristol Eye Hospital (BEH) for the management of fungal endophthalmitis. A 5-year retrospective audit re-evaluated the guidelines and monitored the management of this rare condition. Clinical effectiveness and management costs were considered in light of visual outcome. METHODS: Cases were identified through a 5-year retrospective review of theatre logbooks, Patient Administration System coded admissions with primary diagnosis of purulent endophthalmitis and pharmacy logbooks of patients receiving antifungal therapy. Data correlation and review of patient management were carried out in light of the findings. RESULTS: Twenty-three cases were included, based on clinical disease and/or positive smears or cultures. Age range was 13-74 years, with a male : female ratio of 16 : 7 and right eye : left eye ratio of 14 : 9. Risk factors for fungal endophthalmitis included septicaemia caused by intravenous drug use (78%), presence of indwelling lines (9%), postocular surgery (9%) and post-trauma (4%). Guidelines were rigidly followed in 56% of cases, with improved visual acuity in 9/13 patients compared to 4/10 where management deviated from guidelines. Deviation from guidelines occurred with incomplete use of the recommended drug regimen for the disease severity or use of drugs that were alternative to the suggested guidelines. Treatment was initiated on clinical judgement in 91% of cases and laboratory diagnosis in 9%. CONCLUSION: The BEH guidelines provided a useful reference when managing this uncommon condition. Voriconazole, a newer broad-spectrum agent with good ocular penetration (used in 9%), has been added to the revised guidelines. Monitoring rare conditions over prolonged time frames supports evidence-based medicine

Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing.

Amphotericin B and flucytosine (5FC) have an additive effect when used for disseminated candidiasis. Here, we bridge the results of an experimental pharmacodynamic study to humans and demonstrate that a 5FC dosage of 25 mg/kg of body weight/day in four divided doses in combination with amphotericin B produces near-maximal effect.

Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model.

AIM: To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model. METHODS: To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine (5-FC), we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase (YCD) and the yeast uracil phosphoribosyltransferase (YUPRT) gene. RESULTS: In vitro stably transduced Morris rat hepatoma cells (MH) expressing the bifunctional SuperCD suicide gene (MH SuperCD) showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with MH cells stably expressing YCD solely (MH YCD) or the cytosine deaminase gene of bacterial origin (MH BCD), respectively. In vivo, MH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions (P<0.01) under both high dose as well as low dose systemic 5-FC application, whereas MH tumors without transgene expression (MH naive) showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness (SuperCD>> YCD>>BCD>>>negative control) was defined as a result of a direct in vivo comparison of all three suicide genes. CONCLUSION: Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine.

Antifungal therapy for keratomycoses.

Keratomycoses have recently emerged as an important cause of ocular morbidity, especially in third-world countries. Available antifungal agents are limited in their efficacy, due to limited penetration into the cornea, the fungistatic nature and the development of drug resistance. Effective usage of the available drugs is hampered by the inefficiency of currently available antibiotic sensitivity tests for fungal organisms. There is also limited knowledge regarding the ideal combination(s) of antifungal agents, including issues of synergism and antagonism. Despite these problems, recent publications indicate encouraging outcomes in the treatment of a large series of fungal keratitis. Advances include better drug formulations, new agents and novel methods of drug delivery into the eye. As our ability to deal with advanced fungal keratitis remains limited, the importance of early diagnosis has been stressed and molecular biological techniques may play an important role in the future. This article summarises the important new advances in these areas in the past 2 years and provides guidelines for the management of these serious corneal infections.

Cost implications of alternative treatments for AIDS patients with cryptococcal meningitis. Comparison of fluconazole and amphotericin B-based therapies.

The extra demands placed upon health care resources by management of AIDS patients have increased the focus on cost implications of therapeutic alternatives. Cryptococcal meningitis is a common life-threatening infection in AIDS patients, usually treated with amphotericin B, often in combination with flucytosine. Administered intravenously, this therapy is associated with frequent and often severe side effects. Fluconazole is a new alternative which can be given orally once daily and has fewer such side effects. The purpose of this study was to examine the cost implications of these different therapies for both primary and maintenance treatment of cryptococcal meningitis. Comparison of these two therapies in recent clinical trials has indicated that fluconazole is at least as effective as amphotericin B, and therefore cost-minimisation analysis is an appropriate method to study the economic consequences of the alternative treatments. Patient management and resource-use information for both treatments was obtained using a modified Delphi technique with a panel of European physicians experienced in the treatment of this disease, and three models were developed to reflect the variability of practice evident among the panel members. U.K. health care costs were used to value these resources. The results indicated that, despite the higher cost of the drug itself, the costs associated with fluconazole were likely to be markedly less than those for amphotericin B for primary treatment, and similar or slightly cheaper for maintenance treatment. Over 1 year of treatment, the saving from the use of fluconazole would be in the range of 4000-14,000 pounds.

Assessment of antifungal therapy in an 800-gram infant with candidal arthritis and osteomyelitis.

A 720-g premature newborn developed disseminated candidiasis during treatment with systemic antibiotics and total parenteral nutrition through an umbilical arterial catheter. Clinical features were typical for candidal skeletal infection at this age and included warmth and fusiform swelling of the lower extremities together with radiographic evidence of osteolysis and cortical bone erosion. Candida albicans was cultured from blood, urine, joint fluid, and a bone aspirate. The infection was cured with a 44-day course of amphotericin B and flucytosine (5-fluorocytosine). Antifungal therapy was monitored closely with serum drug levels and laboratory tests for bone marrow toxicity and renal dysfunction. Serum levels of both drugs were comparable to those achieved in older patients treated with similar doses. Significant concentrations of amphotericin B were detected in serum four and 17 days after completion of therapy, indicating a slow rate of elimination similar to that which occurs in adults. There was no evidence of drug-induced toxicity other than transient elevation in the fractional urinary excretion of sodium. This suggests that antifungal therapy may be effectively and safely administered to infants in dose schedules similar to those used for older patients.

[Results of cellular immune reaction assessment under 5-fluorocytosine therapy]. / Ergebnisse der Beurteilung zellulärer Immunreaktionen unter der Behandlung mit 5-Fluorozytosin.

In the judgment of cellular immune reactions with the help of LTT, taking into consideration age-specific variations in generalised mycoses negative and decreased results, respectively, are found after testing with PHA, PPD, in the mixed culture and with candidine. After overcoming of the generalisation of fungi the finding normalised. While using metabolites in other clinical pictures always a decrease of the cellular immune reaction is found, under treatment with 5-fluorocytosin in generalised mycoses no decrease of the transformation of lymphocytes is to be observed. Here after successful therapy even an adequate increase is shown. The examinations confirm the opinion that 5-fluorocytosin does not condition an influence on the function of the T-lymphocytes.