Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis

Rajasingham, Radha; Rolfes, Melissa A.; Birkenkamp, K.; Meya, David B.; Boulware, David R.

doi:10.1371/journal.pmed.1001316

Cited by 85 publications

(82 citation statements)

References 38 publications

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“…Although if further patients were tested, HSV likely would have been detected, the prevalence appears quite low and testing would not be cost-effective compared with other interventions. 29 Overall, meningitis remains a highly prevalent condition among hospitalized HIV-infected adults in our setting, where HIV prevalence is estimated at 64% in hospitalized patients. 30 Other settings that are similar with endemic TB, delayed HIV diagnosis, and challenges with retention-in-care likely also struggle with diagnosis and management of meningitis.…”

Section: Discussionmentioning

confidence: 96%

Epidemiology of Meningitis in an HIV-Infected Ugandan Cohort

Rajasingham¹,

Rhein²,

Klammer³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical.

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Section: Discussionmentioning

confidence: 96%

Epidemiology of Meningitis in an HIV-Infected Ugandan Cohort

Rajasingham¹,

Rhein²,

Klammer³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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“…Definitive evidence to support AmB-fluconazole induction therapy is lacking, but reports from several countries describe rapid EFA when intravenous AmBd (0.7–1 mg/kg/day) is prescribed alongside oral fluconazole (800–1,200 mg/day) 109,113,121,122. A meta-analysis of various induction strategies in resource-poor settings has described AmBd-fluconazole as cost-effective 123. The WHO recommends this approach when flucytosine cannot be obtained 99…”

Section: Treatment and Prognosismentioning

confidence: 99%

Cryptococcal meningitis: epidemiology and therapeutic options

Sloan¹,

Parris²

2014

CLEP

227

183

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Cryptococcal meningitis causes morbidity and mortality worldwide. The burden of disease is greatest in middle- and low-income countries with a high incidence of human immunodeficiency virus (HIV) infection. Patients taking immunosuppressive drugs and some immunocompetent hosts are also at risk. Treatment of cryptococcal meningitis consists of three phases: induction, consolidation, and maintenance. Effective induction therapy requires potent fungicidal drugs (amphotericin B and flucytosine), which are often unavailable in low-resource, high-endemicity settings. As a consequence, mortality is unacceptably high. Wider access to effective treatment is urgently required to improve outcomes. For human immunodeficiency virus-infected patients, judicious management of asymptomatic cryptococcal antigenemia and appropriately timed introduction of antiretroviral therapy are important.

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“…Since the initial standardization, the assay has been adapted successfully for use in C. neoformans (18)(19)(20)28). While this assay was developed for a wide range of antifungal drugs, we examined the MICs of fluconazole and amphotericin B, as they are the primary antifungal medications used in sub-Saharan Africa (11). Additionally, we examined the MIC values for sertraline, which recently had been shown to exhibit antifungal effects on C. neoformans (15).…”

Section: Drug Resistance Determination Using Clsi Assaymentioning

confidence: 99%

“…Different mechanisms of action for these drugs make it difficult for the cells to develop resistance to both drugs during the course of treatment (8)(9)(10). However, flucytosine is prohibitively expensive (Ͼ$500/day) and not licensed in many countries (11). The WHO guidelines then recommend the use of fluconazole in place of flucytosine, as it is much more readily available (4).…”

mentioning

confidence: 99%

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Smith

Achan

Hullsiek

et al. 2015

Antimicrob Agents Chemother

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167

132

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iCryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/l, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC 50 of 4 g/ml and an MIC 90 of 8 g/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC 50 to 8 g/ml and an MIC 90 value of 32 g/ml, with 31% of isolates with a fluconazole MIC of >16 g/ml. We observed an amphotericin B MIC 50 of 0.5 g/ml and an MIC 90 of 1 g/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC 50 of 4 g/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P ‫؍‬ 0.52).

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Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis

Abstract: David Boulware and colleagues assess the cost effectiveness of different treatment strategies in low- and middle-income countries for cryptococcal meningitis, one of the most common opportunistic infections of people with HIV.

Cited by 85 publications

References 38 publications

Epidemiology of Meningitis in an HIV-Infected Ugandan Cohort

Epidemiology of Meningitis in an HIV-Infected Ugandan Cohort

Cryptococcal meningitis: epidemiology and therapeutic options

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

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