Application for WHO Model List of Essential Medicines: Amphotericin B
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1. Summary statement of the proposal for inclusion, change or deletion
This is a proposal for inclusion of ‘amphotericin B deoxycholate’ as a WHO Essential Medication, effectively moving amphotericin B deoxycholate from the complimentary list to the essential list. Cryptococcal meningitis is the most common cause of meningitis in adults in sub-Saharan Africa and accounts for 20-25% of AIDS-related mortality [1]
The principal reasons for requesting the inclusion of Amphotericin B in the WHO essential list are as follows:
 Current cryptococcal meningitis mortality rates with fluconazole monotherapy are unacceptably high (≥60% 10-week mortality). Amphotericin B therapy, when compared to fluconazole monotherapy, provides a 25-30% improved 10-week survival [2].
 All current cryptococcal meningitis guidelines, including the 2011 WHO rapid advice for the diagnosis, prevention, and management of cryptococcal disease, recommend AmB-based antifungal regimens as first line therapy [3].
2. Name of the focal point in WHO submitting or supporting the application
Philippa Easterbrook
HIV Department
WHO Headquarters
Geneva, Switzerland
E-mail: easterbrookp@who.int
3. Name of the organizations consulted and/or supporting the application
Centers for Disease Control and Prevention, USA
St. George’s University of London, UK
Médecins Sans Frontières
Clinton Health Access Initiative (CHAI)
University of Minnesota, USA
Management Sciences for Health, USA
National Institute for Communicable Diseases, South Africa
4. International Nonproprietary Name (INN, generic name) of the medicine
Amphotericin B deoxycholate
5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)
Intravenous
6. International availability - sources, if possible manufacturers and trade names:
Amphotericin B deoxycholate (Fungizone™) was originally manufactured by Bristol-Meyers Squibb; however, multiple generic manufacturers exist in every region. (Table 1) X-Gen Pharmaceuticals (US) manufacturers the only FDA approved generic formulation of amphotericin B, as listed in the 2012 version of the Orange Book (www.accessdata.fda.gov).
Application for WHO Model List of Essential Medicines: Amphotericin B
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Table 1. Amphotericin B manufacturers and trade names
No.
Trade Name(s)
Manufacturer, Country
1.
Fungizone
Bristol-Meyers Squibb
2.
Amfotex
Alkem Laboratories Ltd (Cytomed), India
3.
Amphotret
Bharat Serum & Vaccines Ltd, India; Xeno Pharmaceuticals, Philippines
4.
Phoricin
Chandra Bhagat Pharma Pvt Ltd, India
5.
Amfocare, Amphocil
Criticare Laboratories Pvt. Ltd. , India
6.
Amfocan
Dabur Pharmaceuticals Ltd., India
7.
Fungitericin
Lifecare Innovations Pvt. Ltd., India
8.
Fungizone Intravenous
Nicholas Piramal India Ltd. , India
9.
Mycol
V.H. Bhagat Pharmaceuticals Pvt. Ltd., India
10.
Amphotericin B
Taj Pharmaceuticals Ltd., India
11.
Anfotericina B
BestPharma, Peru
12.
Anfotericina B
Biosano, Chile
13.
Anfotericina B
Northia, Argentina
14.
Anfotericina
Fada, Argentina
15.
Anfotericina
Richet, Argentina
16.
Anfotericina B
Richet (Dominican Republic, Guatemala, Honduras, Panama, Venezuela)
17.
Fengkesong
Asia Pioneer, China;
Shanghai Pharma Group, China
18.
Ampholin
Mediorals, Thailand
19.
Amphotericin B Biolab
Biolab, Thailand
20.
Amphotericin B Asence
Asence, Thailand
21.
Halizon
Fuji Yakuhin, Japan
22.
Amphotericin B
Dumex, Ethiopia
23.
Amphotericin B
Sintez, Russia
24.
Amphotericin B
Abbott Laboratories, APP Pharmaceuticals, Pharma Tek, Sicor Pharmaceuticals, X-Gen, USA
7. Whether listing is requested as an individual medicine or as a therapeutic group
Individual medicine under EML section 6.3 Antifungal medicines.
8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population):
Cryptococcal meningitis is the most common cause of meningitis in sub-Saharan
Africa [4-6], accounting for 20-25% of AIDS-related mortality in Africa and causing an estimated 500,000 deaths annually [1]. In meningitis surveillance studies from South Africa, Malawi, and Uganda, cryptococcal meningitis is more common in adults than all causes of
Application for WHO Model List of Essential Medicines: Amphotericin B
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bacterial meningitis combined [4-6]. Cryptococcosis primarily occurs among HIV-infected persons living with AIDS, predominantly when CD4 T cell counts are < 100 cells/mcL.
9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills):
Amphotericin B deoxycholate dosed at 0.7-1.0 mg/kg/day for 1-2 weeks is the standard induction therapy as recommended by the WHO [3], South African HIV Clinicians Society [7], Infectious Disease Society of America [8], and U.S. Department of Health and Human Services [9]. (Table 2) (Figures 1 & 2) WHO recommendations for children are the same as for adults but with weight based dosing regimens.
Table 2. WHO, IDSA & South African HIV Clinician Society Guidelines for the induction treatment of CM depending on the clinical setting
Clinical setting for treatment of cryptococcal meningitis
WHO 2011 Rapid Guidelines [3]
IDSA 2010 Guidelines [8]
South African HIV Clinician Society 2007 guidelines [7] Amphotericin B deoxycholate (AmBd) 5FC
Accessible
Facilities for toxicity management* available
Accessible
AmBd (0.7-1 mg/kg/day)
+
5-FC (100 mg/kg/day)
AmBd (0.7–1.0 mg/kg/day) + 5-FC (100 mg/kg/day)
or
Liposomal AmB (3–4 mg/kg/day)
or
ABLC (5 mg/kg/day)
+ 5-FC (100 mg/kg/day)
Not applicable-5-FC currently unavailable in SA
Accessible
Facilities for toxicity management* available
Not accessible
AmBd (0.7-1 mg/kg/day)
+
Fluconazole (800 mg/day)
AmBd (0.7–1.0 mg/kg/day)
or
liposomal AmB (3–4 mg/kg/day)
or
ABLC (5 mg/kg/day)
or
AmBd plus fluconazole
AmBd (1 mg/kg/day) IV
For 2 weeks (minimum 1 week)
Accessible
Facilities for toxicity management* limited
Not accessible
AmBd (0.7-1 mg/kg/day) For 5-7 days +Fluconazole (800 mg/day)
For 2 weeks
Scenario not addressed
AmBd (1mg/kg/day)
Minimum 1 week
Not accessible
Accessible
Fluconazole (1200 mg/day)
+
5-FC (100 mg/kg/day)
For > 2 weeks
Fluconazole (800 – 1200(favoured) mg/day)+
5-FC (100 mg/kg/day orally)
For 6 weeks
Not applicable-5-FC currently unavailable in SA
Not accessible
Facilities for toxicity management* not available
Not accessible
Fluconazole (1200 mg/day)
For >2 weeks
Fluconazole (800–2000 mg/day)
For 10–12 weeks
(Fluconazole 1200 mg/day favoured)
Transfer patient to centre where AmBd available.
If not possible, Fluconazole (800mg/day) For 4 weeks
All induction CM courses are for 2 weeks’ duration, unless stated
*Minimum package of pre-hydration, electrolyte replacement and toxicity monitoring/management available
Application for WHO Model List of Essential Medicines: Amphotericin B
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Figure 1. WHO Rapid Advice: Diagnosis, prevention and management of cryptococcal
disease in HIV-infected adults, adolescents and children (Dec 2011): Text description
[3] (http://www.who.int/hiv/pub/cryptococcal_disease2011/en/)
Figure 2. WHO Rapid Advice: Diagnosis, prevention and management of cryptococcal
disease in HIV-infected adults, adolescents & children (Dec 2011): Table summary [3]
Application for WHO Model List of Essential Medicines: Amphotericin B
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10. Summary of comparative effectiveness in a variety of clinical settings
• Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)
In 2012, a systematic review assessed the cost-effectiveness of cryptococcal treatment outcomes in resource-limited settings [2]. In brief, Rajasingham et al [2] performed a MESH search of “Cryptococcal Meningitis” AND “Therapy”, and limited their findings to Humans, Adults, and English language results, to identify 10-week mortality data from trials and cohort studies evaluating treatment outcomes of cryptococcal meningitis induction regimens from 1996 onwards in the antiretroviral therapy (ART) era. This search yielded 33 publications. After manually reviewing abstracts and references, 18 studies were included that presented mortality data for HIV-infected adults from resource-limited settings. Rajasingham et al excluded studies that did not report 10-week mortality, and U.S.-based, and European-based CM studies. The systematic review was limited to resource-constrained settings, as a cost-effectiveness analysis would be most pertinent and generalizable to these settings. From these studies, pooled 10-week mortality estimates were calculated for each of the treatment regimens.
Differences in 10-week survival correspond with the known anti-fungal activities of the various induction treatment regimens as quantified by the clearance of Cryptococcus neoformans yeast colony forming units (CFU) per mL of cerebrospinal fluid (CSF) per day (Δlog10 CFU/mL CSF/day) – termed the early fungicidal activity (EFA) [10]. Rhein et al [11] summarizes recent clinical trials that have compared the EFA of various induction treatment regimens.
• Summary of available data* (appraisal of quality, outcome measures, summary of results)
See Table 3 for summary of 10-week mortality outcome measures.
See Table 4 for summary of EFA outcome measures.
Table 3. Cost-effectiveness of cryptococcal treatment outcomes in RLS [2].
Induction Regimen
Induction Duration
10-week Mortality
95% CI
Ref Fluconazole 800-1200mg 14 days 54.9% (73/133) 46.0-63.5% [12-15]
Flucytosine + fluconazole 1200mg
14 days
43.5% (20/46)
28.9-58.9%
[15, 16] Amphotericin + fluconazole 1200mg 5-7 days 26.0% (33/127) 18.6-34.5% [17-20]
Amphotericin
14 days
34.4% (128/372)
29.6-39.5%
[20-26] Amphotericin + fluconazole 800mg 14 days 30.0% (61/203) 23.8-36.9% [25-28]
Amphotericin + flucytosine (5FC)
14 days
26.8% (62/231)
21.2-33.0%
[26-30]
95% CI = 95% confidence interval for the 10-week mortality
Application for WHO Model List of Essential Medicines: Amphotericin B
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Table 4. Trials comparing early fungicidal activity of induction treatment regimens [11]
Cryptococcal Induction Regimen
EFA
+ SD
n
Ref AmB + 5FC -0.41 0.22 21 [27] AmB + fluc (800 mg daily) -0.38 0.18 22 AmB + fluc (1200 mg daily) -0.41 0.35 23 AmB + voriconazole -0.44 0.20 13
AmB (short course 5 days) + 5FC
-0.30
0.11
30
[18] AmB + 5FC -0.49 NA 30 [30] AmB + 5FC + INF-γ -0.64 NA 60
5FC + fluconazole (1200 mg daily)
-0.28
0.17
21
[15]
Fluconazole (1200 mg daily)
-0.11
0.09
20 AmB (0.7 mg/kg/day) + 5FC -0.45 0.16 28 [29] AmB (1 mg/kg/day) + 5FC -0.56 0.24 29
Fluconazole (1200 mg daily)
-0.18
0.11
30
[12]
Fluconazole (800 mg daily)
-0.07
0.17
30 AmB (1 mg/kg/day) -0.48 0.28 49 [17] Fluconazole (400 mg daily) -0.02 0.05 5
AmB (0.7 mg/kg/day)
-0.31
0.18
14
[26]
AmB (0.7 mg/kg/day) + 5FC
-0.54
0.19
12
AmB + fluconazole (400 mg daily)
-0.39
0.15
11
AmB + 5FC + fluc (400 mg daily)
-0.38
0.13
15
EFA = early fungicidal activity (log CFU/mL CSF/day)
AmB = amphotericin B deoxycholate (0.7 or 1 mg/kg/day or as indicated)
5FC = flucytosine (100mg/kg/day divided 4 times daily)
Fluc = fluconazole (doses indicated)
Voriconazole (300 mg twice daily; 400 mg twice on day 1)
INF-γ = interferon-gamma (100 μg subcutanously, 2 or 6 doses over induction period)
• Summary of available estimates of comparative effectiveness
Amphotericin-based regimens have 25-30% better 10-week survival than fluconazole monotherapy regimens [2]. (Table 3)
Amphotericin-based regimens have superior microbiologic activity with EFA that ranged from -0.38 to -0.49 log CFU/ml CSF/day compared to -0.07 to -0.28 log CFU/ml CSF/day in non-amphotericin based regimens. [11] (Figure 3) For reference, based on a pooled series of Phase II clinical trials, the mean rate of clearance of infection for those who survived at 2 weeks was -0.40 log CFU/ml CSF/day compared to -0.17 log CFU/ml CSF/day in those who died at 2 weeks [10]. At 10 weeks, mean EFA was -0.41 log CFU/ml CSF/day in those who survived compared to -0.27 log CFU/ml CSF/day in those who died [10].
Application for WHO Model List of Essential Medicines: Amphotericin B
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Figure 3. Comparative Early Fungicidal Activity (EFA) of Cryptococcal Induction Treatment Regimens [11]
11. Summary of comparative evidence on safety
• Estimate of total patient exposure to date
Amphotericin B has been used extensively since the 1950s for the treatment of invasive fungal infections including cryptococcosis, aspergillosis, zygomycosis, blastomycosis, coccidiodomycosis, histoplasmosis, and systemic candidiasis.
• Description of adverse effects/reactions
The adverse reactions most commonly observed are (FDA Package Insert):
 General (body as a whole): fever (sometimes accompanied by shaking chills usually occurring within 15 to 20 minutes after initiation of treatment); malaise; weight loss.
 Cardiopulmonary: hypotension; tachypnea.
 Gastrointestinal: anorexia; nausea; vomiting; diarrhea; dyspepsia; cramping epigastric pain.
 Hematologic: normochromic, normocytic anemia.
 Local: pain at the injection site with or without phlebitis or thrombophlebitis.
 Musculoskeletal: generalized pain, including muscle and joint pains.
 Neurologic: headache.
 Renal: decreased renal function and renal function abnormalities including: azotemia, hypokalemia, hyposthenuria, renal tubular acidosis; and nephrocalcinosis. These usually improve with interruption of therapy. However, some permanent impairment often occurs, especially in those patients receiving large amounts (over 5 g) of
Application for WHO Model List of Essential Medicines: Amphotericin B
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amphotericin B or receiving other nephrotoxic agents. In some patients hydration and sodium repletion prior to amphotericin B administration may reduce the risk of developing nephrotoxicity. Supplemental alkali medication may decrease renal tubular acidosis.
The following adverse reactions have also been reported:
 General (body as a whole): flushing
 Allergic: anaphylactoid and other allergic reactions; bronchospasm; wheezing.
 Cardiopulmonary: cardiac arrest; shock; cardiac failure; pulmonary edema; hypersensitivity pneumonitis; arrhythmias, including ventricular fibrillation; dyspnea; hypertension.
 Dermatologic: rash, in particular maculopapular; pruritus.
 Gastrointestinal: acute liver failure; hepatitis; jaundice; hemorrghagic gastroenteritis; melena.
 Hematologic: agranulocytosis; coagulation defects; thrombocytopenia; leukopenia; eosinophilia; leukocytosis.
 Neurologic: convulsions; hearing loss; tinnitus; transient vertigo; visual impairment; diplopia; peripheral neuropathy; encephalopathy; other neurologic symptoms.
 Renal: acute renal failure; anuria; oliguria.
Frequency of side effects
In a meta-analysis conducted by Girois et al, infusion related reactions occurred with conventional amphotericin B with the following frequency when data from 48 studies were combined: fever (34%), nausea (19%), rash (3%), and bronchospasm (7%) [31]. Nephrotoxicity occurred in 33% of patients receiving conventional amphotericin B compared to 15% in patients receiving liposomal amphotericin B [31].
Altered Laboratory Findings
 Serum Electrolytes: Hypomagnesemia; hypo- and hyperkalemia; hypocalcemia.
 Liver Function Tests: Elevations of AST, ALT, GGT, bilirubin, and alkaline phosphatase.
 Renal Function Tests: Elevations of BUN and serum creatinine.
• Identification of variation in safety due to health systems and patient factors
Pregnancy
Reproduction studies in animals have revealed no evidence of harm to the fetus due to amphotericin B for injection. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B for injection without obvious effects to the fetus, but the number of cases reported has been small [32]. Because animal reproduction studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, this drug should be used during pregnancy only if clearly indicated. For cryptococcal meningitis, amphotericin is the drug of choice in pregnant women [8].
• Summary of comparative safety against comparators
Although, Amphotericin B has more frequent serious side effects than fluconazole [31], it is more effective in treating cryptococcal meningitis than other anti-fungal drugs (as described above). The most common adverse reactions (injection
Application for WHO Model List of Essential Medicines: Amphotericin B
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reactions, anemia, hypokalemia, hypomagnesaemia, and renal insufficiency) are often reversible and harm can be mitigated with careful monitoring and treatment. Lipid formulations of amphotericin B have also been shown to be less nephrotoxic.
The 2011 WHO Rapid Advice recommends a core safety package of: intravenous hydration coupled with electrolyte management and monitoring when administering amphotericin. Where monitoring is not possible, WHO recommends 1-week induction therapy. In prior clinical trials severe kidney and electrolyte toxicities did not occur with 1-week of amphotericin [17-19], as the majority of toxicity occurs in the second week of amphotericin.
12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group
• Range of costs of the proposed medicine
Range of costs for amphotericin B (per 50 mg vial) are summarized in Table 5.
Table 5. Wholesale International Drug Pricing for Amphotericin B (50 mg vial), 2010
International Supplier
Information on supplier
Supplier Prices
Buyer (Country Level)
Buyer Prices
MEDS
(Mission for Essential Drugs & Supplies)
Not-for-profit Christian organization. (Coverage: Kenya, Tanzania, Ethiopia, Sudan DRC. HQ Nairobi.)
$ 3.51 South Africa (Department of Health) $ 4.23
MISSION (Missionpharma)
Supplies generic medicines, medical devices & equipment and medical kits.
(Coverage: Africa, India, China.
HQ Denmark.)
$ 6.35
Rwanda
(Centrale d'achat des Médicaments Essentiels, Consommables et Equipements Médicaux du Rwanda -CAMERWA)
$ 4.65 Uganda (Uganda National Medical Store -UGANDANMS) $ 5.00
IDA Foundation
Leading not-for-profit supplier of pharmaceutical products. Supplies 3000 different medicines and medical supplies to over 100 countries worldwide
HQ Holland.
$ 7.86
Namibia
(Namibia Ministry of Health and Social Services)
$ 6.97 Barbados Drug Service (BDS) $ 5.27
Guatemalan Office of Contracting and Acquisitions
$ 9.75 Costa Rica Social Security $ 12.20
Management Sciences for Health International Reference Prices. 2010 data. http://erc.msh.org/dmpguide/resultsdetail.cfm
• Comparative cost-effectiveness presented as range of costs per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality adjusted life year gained).
The cost of cryptococcal care as per WHO guidelines is summarized in Table 6 [2] and is based on the range of 2010 international reference medication costs for
Application for WHO Model List of Essential Medicines: Amphotericin B
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amphotericin (50 mg vial) (median of US$5.27 (range: US$4.23–US$6.97 in Africa),
and fluconazole (200-mg tablet), median of US$0.16 (range: US$0.14–US$0.19 in
Africa)) [33].
The cost-effectiveness of cryptococcal treatment, comparing the cost of various
induction cryptococcal meningitis treatments with expected mean quality adjusted life
years (QALY) saved, is summarized in Figure 4.[2]
Table 6. Cost of cryptococcal care (utilizing WHO guidelines) [2]
Induction Regimen
Duration of
Induction
Costs
Total Cost
Medication of Care
3 LPs with
Manometers
Hospital
Supplies
Lab
Costs
Personnel
(Uganda)
Fluconazole 800–1,200 mg 14 d
$8.23 –
$12.34
$53.85 $32.63 $36.95 $18.40a
$150.06–
$154.17
5FC + fluconazole 1,200 mg 14 d $85.98 $53.85 $32.63 $49.35 $20.74a $242.55
Amphotericin + fluconazole 1,200 mg 7 d $53.85 $53.85 $54.53 $36.95 $18.40a $217.58
Amphotericin 14 d $83.02 $53.85 $108.21 $107.35 $41.41 $393.84
Amphotericin + fluconazole 800 mg 14 d $91.25 $53.85 $108.21 $107.35 $41.41 $402.07
Amphotericin + 5FC 14 d $156.66 $53.85 $108.21 $107.35 $41.41 $467.48
Figure 4. Cost-effectiveness of comparative cryptococcal meningitis treatment
regimens[2]
Figure 4 displays the cost of induction therapy for cryptococcal meningitis in
resource-limited regions (in US$) versus the effectiveness as measured by QALYs
saved per regimen. The radius of the circles represents the standard deviation of the
cost estimate. Based on the existing outcome data, the short-course amphotericin (1
Application for WHO Model List of Essential Medicines: Amphotericin B
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mg/day) + fluconazole (1,200 mg/day) regimen has similar effectiveness to but lower costs than traditional 2-week amphotericin-based regimens. This short-course amphotericin + fluconazole regimen has marginally higher cost but significantly greater effectiveness than oral fluconazole-based therapies. Detailed references on model assumptions can be found in Rajasingham et al. [2]
13. Summary of regulatory status of the medicine
Amphotericin is registered in Europe, North and South America, and most Asian countries, including India and China. Registration and availability in Africa is limited.
Table 7. Summary of amphotericin drug registration and availability in Africa
Country
Registered
Available Cameroon No No
Dem. Rep. of Congo
Yes
No Ethiopia Yes No
Guinea
No
No Kenya Yes Yes
South Africa
Yes
Yes Sudan Yes Yes
Swaziland
N/A
Yes Uganda No Special Order
Modified from table at: http://tinyurl.com/857zxdf
14. Availability of pharmacopoeial standards
Current WHO: http://apps.who.int/phint/en/p/docf/
U.S. Full monograph available at:
http://www.drugs.com/monograph/amphotericin-b.html
U.S. brief monograph available at: https://online.epocrates.com/u/10a91/amphotericin+B+deoxycholate
15. Proposed text for the WHO Model Formulary
amphotericin B deoxycholate
Powder for injection: 50 mg in vial.
Application for WHO Model List of Essential Medicines: Amphotericin B
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16. References
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2. Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis. PLoS Med 2012; 9: e1001316.
3. WHO. Rapid advice: Diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva: World Health Organization, 2011.
4. Jarvis JN, Dromer F, Harrison TS, Lortholary O. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis 2008; 21: 596-603.
5. Cohen DB, Zijlstra EE, Mukaka M, et al. Diagnosis of cryptococcal and tuberculous meningitis in a resource-limited African setting. Trop Med Int Health 2010; 15: 910-7.
6. National Institute for Communicable Diseases. Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa. GERMS-SA Annual Report 2010. In: Govender N, Quan V, 2010.
7. McCarthy KM, Meintjes G, Arthington-Skaggs B, et al. Southern African HIV Clinicians Society: Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients. South Afr J HIV Med 2007; 28: 25-35.
8. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50: 291-322.
9. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009; 58: 1-207.
10. Bicanic T, Muzoora C, Brouwer AE, et al. Independent association between rate of clearance of infection and clinical outcome of HIV associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis 2009; 49: 702-9.
11. Rhein J, Boulware DR. The prognosis and management of cryptococcal meningitis in HIV infected patients. Neurobehavioral HIV Med 2012; 4: 45-61.
12. Longley N, Muzoora C, Taseera K, et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis 2008; 47: 1556-61.
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13. Kisenge PR, Hawkins AT, Maro VP, et al. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis 2007; 7: 39.
14. Wajanga BM, Kalluvya S, Downs JA, Johnson WD, Fitzgerald DW, Peck RN. Universal screening of Tanzanian HIV-infected adult inpatients with the serum cryptococcal antigen to improve diagnosis and reduce mortality: an operational study. J Int AIDS Soc 2011; 14: 48.
15. Nussbaum JC, Jackson A, Namarika D, et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis 2010; 50: 338-44.
16. Mayanja-Kizza H, Oishi K, Mitarai S, et al. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 1998; 26: 1362-6.
17. Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis 2007; 45: 76-80.
18. Muzoora CK, Kabanda T, Ortu G, et al. Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis. J Infect 2012; 64: 76-81.
19. Jackson AT, Nussbaum JC, Phulusa J, et al. A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis. AIDS 2012; 26: 1363-70.
20. Tansuphaswadikul S, Maek-a-Nantawat W, Phonrat B, Boonpokbn L, Mctm AG, Pitisuttithum P. Comparison of one week with two week regimens of amphotericin B both followed by fluconazole in the treatment of cryptococcal meningitis among AIDS patients. J Med Assoc Thai 2006; 89: 1677-85.
21. Butler EK, Boulware DR, Bohjanen PR, Meya DB. Long term 5-year survival of persons with cryptococcal meningitis or asymptomatic subclinical antigenemia in Uganda. PLoS One 2012; 7: e51291.
22. Chang CC, Dorasamy AA, Elliott JH, et al. HIV-infected patients with cryptococcal meningitis who attain CSF sterility pre-cART commencement experience improved outcomes in the first 24 weeks. Abstract 955. Conference on Retroviruses and Opportunistic Infections (CROI). Seattle, WA, 2012.
23. Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2010; 7: e1000384.
24. Boulware DR, Bonham SC, Meya DB, et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis 2010; 202: 962-70.
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