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

Loyse, Angela; Burry, Jessica; Cohn, Jennifer; Ford, Nathan; Chiller, Tom; Ribeiro, Isabela; Koulla‐Shiro, Sinata; Mghamba, Janneth; Ramadhani, Angela; Nyirenda, Rose; Aliyu, Sani H; Wilson, Douglas P.; Le, Thuy; Oladele, Rita O.; Lesikari, Sokoine; Muzoora, Conrad; Kalata, Newton; Temfack, Elvis; Mapoure, Yacouba Njankouo; Sini, Victor; Chanda, Duncan; Shimwela, Meshack; Lakhi, Shabir; Ngoma, Jonathon; Gondwe-Chunda, Lilian; Perfect, Chase; Shroufi, Amir; Andrieux-Meyer, Isabelle; Chan, Adrienne K.; Schutz, Charlotte; Hosseinipour, Mina C.; Horst, Charles van der; Klausner, Jeffrey D.; Boulware, David R.; Heyderman, Robert S.; Lalloo, David G.; Day, Jeremy; Jarvis, Joseph N; Rodrigues, Márcio L.; Jaffar, Shabbar; Denning, David W.; Migone, Chantal; Doherty, Megan; Lortholary, Olivier; Dromer, Françoise; Stack, Muirgen; Molloy, Síle F.; Bicanic, Tihana; Oosterhout, Joep van; Mwaba, Peter; Kanyama, Cecilia; Kouanfack, Charles; Mfinanga, Sayoki; Govender, Nelesh P.; Harrison, Thomas S.

doi:10.1016/s1473-3099(18)30493-6

Cited by 77 publications

(88 citation statements)

References 19 publications

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“…The most common opportunistic FIs are cryptococcal meningitis (CM), Pneumocystis jirovecii pneumonia (PCP), invasive candidiasis and disseminated aspergillosis [4]. Diagnosis and management of these opportunistic mycosis in RLSs is challenging as standard diagnostic methods and essential antifungal medicines are often absent [5].…”

Section: Introductionmentioning

confidence: 99%

The Burden of Fungal Infections in Ethiopia

Tufa¹,

Denning

2019

JoF

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The burden of severe fungal infections (FIs) is not well addressed in Ethiopia. We have estimated the burden of FIs from multiple demographic sources and by searching articles from PubMed. Opportunistic FIs were estimated using modelling and 2017 national HIV data. The burdens of chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA) were estimated by using the prevalence of asthma, chronic obstructive pulmonary disease, and annual the incidence of tuberculosis. Of the 105,000,000 estimated Ethiopian population, 610,000 are thought to have HIV infection. Our estimation of HIV-related FIs were: 9900 cryptococcal meningitis (CM), 12,700 Pneumocystis jirovecii pneumonia (PCP), 76,300 oral and 56,000 oesophageal candidiasis cases. A remarkable 7,051,700 4–14-year-olds probably have tinea capitis and 1,469,000 women probably have recurrent Candida vaginitis. There were 15,200 estimated CPA cases (prevalence) and 11,500 invasive aspergillosis (IA) cases (incidence). Data are scant, but we estimated 5300 candidaemia and 800 Candida peritonitis cases. In conclusion, approximately 8% of Ethiopians suffer from FIs annually, mostly schoolchildren with tinea capitis. IA, CM and PCP are the major causes of fungal deaths. The absence of CD4 count is challenging the identification of HIV patients at risk of opportunistic FIs. There is a pressing need to improve FI diagnosis, probably including national surveillance.

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Section: Introductionmentioning

confidence: 99%

The Burden of Fungal Infections in Ethiopia

Tufa¹,

Denning

2019

JoF

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“…The introduction of flucytosine as the mainstay of induction therapy for the treatment of cryptococcal meningitis has been hampered by issues of affordability and sustainable access, particularly in LMICs in Africa (24). This study, using outcomes data from the ACTA trial, has shown that it is cost-effective in the pre-flucytosine cohort, however this was not significant (25).…”

Section: Discussionmentioning

confidence: 97%

“…Generally, cryptococcal meningitis in HIV-infected patients in South Africa is treated initially with intravenous amphotericin B either alone or in combination with oral fluconazole (3). Fluconazole and amphotericin B have been the mainstay of treatment for many years, however recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity (4). The World Health Organization (WHO) has updated its guideline to recommend a combination induction phase of one week of intravenous amphotericin B and oral 5-flucytosine or, as an alternative, two weeks of oral flucytosine and fluconazole (5).…”

Section: Introductionmentioning

confidence: 99%

“…Lack of availability and access to 5-flucytosine is a common problem, especially in low-middle income countries. Also, the current international price renders it unaffordable in such countries (4) (6). In South Africa, flucytosine is not currently registered by the South African Health Products Regulatory Authority (SAPHRA) and therefore is only available on a named-patient basis under Sect.…”

Section: Introductionmentioning

confidence: 99%

“…This model did not specifically include relapses or recurrences; however, these were included in the total count of cases of CM per year and assumed to have similar costs to first infections. Although paradoxical cryptococcal immune reconstitution inflammatory syndrome does occur with an estimated frequency of 10-50%(24) in patients initiating ART in all the treatment regimens and this condition is associated with a high mortality, it is assumed that this is already included in the overall mortality rate attributed to CM as per the outcomes based on the clinical trial data.It was assumed that patients had one diagnostic LP and one therapeutic LP regardless of which regimen they were treated with. In the ACTA trial patients received on average 3 LPs, at baseline and on days 7 and 14, however this was conducted under clinical trial conditions and the WHO guidelines do not recommend routine follow up LPs in resource limited countries (4) A sensitivity analysis was conducted to assess the impact of increasing the number of LPs.Generally, there is no vial sharing for Amphotericin B for patients, so it was assumed that 2 vials per dose were used.…”

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confidence: 99%

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Cost-effectiveness and budget impact of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

Miot

Leong

Takuva

et al. 2020

Preprint

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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 budget 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 four treatment arms: (a) standard of care; 2-week course of amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course of amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) and (d) oral course; 2-week oral fluconazole/flucytosine (oral). A sensitivity analysis was conducted on key variables. Results The highest total treatment costs were in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, then the 1-week AmBd/5FC with the lowest cost in the standard of care arm. Compared to standard of care the 1-week flucytosine course is most cost-effective at USD31/QALY, followed by the oral 2-week course at USD155/QALY and the 2-week flucytosine course at USD568/QALY. The budget impact analysis shows that the 1-week course has the lowest incremental cost, followed by the oral course and then the 2-week flucytosine course compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to the price of flucytosine and hospital costs, particularly 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 regardless of whether it is used as a 1-week, 2-week or oral regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

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