Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Personal View
Cryptococcal meningitis: improving access to essential
antifungal medicines in resource-poor countries

Angela Loyse*, *Harry Thangaraj*, Philippa Easterbrook, Nathan Ford, Monika Roy, Tom Chiller, Nelesh Govender, Thomas S Harrison, Tihana Bicanic Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of Published Online
AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for cryptococcal
June 2, 2013
meningitis relies on three old, off -patent antifungal drugs: amphotericin B deoxycholate, fl ucytosine, and fl uconazole.
Widely accepted treatment guidelines recommend amphotericin B and fl ucytosine as fi rst-line induction treatment for *AL and HT contributed equally
cryptococcal meningitis. However, fl ucytosine is unavailable in Africa and most of Asia, and safe amphotericin B to this personal view
administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side- Cryptococcal Meningitis Group,
eff ects. Therefore, fl uconazole monotherapy is widely used in low-income and middle-income countries for induction Research Centre for Infection
therapy, but treatment is associated with signifi cantly increased rates of mortality. We review the antifungal drugs used and Immunity, Division of
to treat cryptococcal meningitis with respect to clinical eff ectiveness and access issues specifi c to low-income and Clinical Sciences, St George’s

University of London, UK
middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic eff ects, and (A Loyse MRes,
ciently coordinated distribution; fl ucytosine through cost and scarcity of registration; and fl uconazole through Prof T S Harrison FRCP,
challenges in maintenance of local stocks—eg, sustainability of donations or insuffi
cient generic supplies. We advocate T Bicanic BM BCh); Access to
ten steps that need to be taken to improve access to safe and eff ective antifungal therapy for cryptococcal meningitis.
Pharmaceuticals Project,
Research Centre for Infection
and Immunity, Division of

highlight the main obstacles to access of essential Clinical Sciences, St George’s
The right to health is fi rmly established in international antifungal drugs for the treatment of cryptococcal University of London, UK
human rights law, and encompasses the right to ad-
meningitis in patients with HIV in low-income and (H Thangaraj MBBS); HIV
Department, World Health
equate access to health care and essential medicines.1–4 middle-income countries. We review the three main Organisation, Geneva,
Unfortunately, people in low-income and middle-income antifungal drugs for cryptococcal meningitis—ampho- Switzerland
countries continue to face large barriers to the access of tericin B, fl ucytosine, and fl uconazole—with re spect to (Prof P Easterbrook MD);
essential medicines, often with devastating consequences
clinical eff ectiveness and access considerations specifi c to Médecins Sans Frontières and
Centre for Infectious Disease
to individuals and public health. Essential medicines are low-income and middle-income countries, and suggest Epidemiology and Research,
the second largest family expenditure after food for the steps to improve access to safe and eff ective antifungal University of Cape Town, South
90% of the population in the developing world who have
treatment for cryptococcal meningitis.
Africa (N Ford PhD); Centre for
to purchase medicines privately.5 Barriers to access Infectious Disease
Epidemiology and Research,

include drug expense, paucity of research and develop- Treatment of HIV-associated cryptococcal
University of Cape Town, South
ment on diseases predominantly aff ecting low-income meningitis
Africa (N Ford); Mycotic
cient competition Both the 2010 Infectious Diseases Society of America Diseases Branch, Centers for
from generic manufacturers, inadequate drug procure- (IDSA) and 2011 WHO rapid advice guidelines Disease Control and
Prevention, Atlanta, GA, USA
ment and supply chains, and increasingly constrained recommend amphotericin B and fl ucytosine as fi rst-line (M Roy MD, T Chiller MD);
global health funding.6–12
induction treatment for patients with cryptococcal National Institute for
As a common opportunistic infection in patients meningitis, with alternative regimens tailored to Communicable Diseases, a
Division of the National Health
with advanced HIV infection, cryptococcal meningitis is individual clinical settings (table 1).16,17 For settings in Laboratory Service (NHLS)
the leading cause of meningitis in adults living in which fl ucytosine is unavailable, second-line induction (N Govender MBBCh); and
sub-Saharan Africa, and contributes to up to 20% of AIDS-
treatment consists of amphotericin B and high-dose Faculty of Health Sciences,
related deaths every year in low-income and middle-income (800–1200 mg per day) fl uconazole.16,17 Where University of the
Witwatersrand, Johannesburg,
ough increased access to antiretroviral amphotericin B is unavailable or cannot be safely given South Africa (N Govender)
therapy has resulted in a substantial reduction in and moni tored, high-dose fl uconazole and fl ucytosine is Correspondence to: incidence of cryptococcal meningitis in high-income recom mended.16,17 The initial 2 week induction treatment Angela Loyse, Cryptococcal countries,14 the infection is likely to remain a major cause is followed by consolidation and maintenance phases of Meningitis Group, Research of HIV-related mortality in the foreseeable future in low- income and middle-income countries, where antiretroviral Immunity, Division of Clinical Sciences, St George’s Hospital cient and initiated at an Amphotericin B
advanced stage of HIV. In addition to delays in the Amphotericin B was introduced in the 1950s to treat London SW17 ORE, UK
diagnosis and treatment of cryptococcal meningitis, poor systemic mycoses.19 The drug has a broad antifungal [email protected]
access to essential antifungal medicines is a major range and only few reports of resistance have been
contributor to this unacceptably high mortality. Although documented.20 Additionally, amphotericin B is used to
fl uconazole monotherapy is associated with increased treat visceral leishmaniasis.21 Substantial and common
rates of mortality, inadequate access to alternative side-eff ects of conventional amphotericin B formulations
treatments means it is widely used in the treatment of are anaemia, hypokalaemia, hypomag
cryptococcal meningitis.15 In this Personal View, we nephrotoxicity.22,23 These eff ects are reversible upon Published online June 2, 2013
Personal View
Amphotericin B accessible,
Amphotericin B accessible;
Amphotericin B accessible,
Amphotericin B not
Amphotericin B not
facilities for management of toxic
fl ucytosine not accessible
facilities for management of
accessible; fl ucytosine
accessible, facilities for
eff ects* available; fl ucytosine
toxic eff ects* restricted;
management of toxic
fl ucytosine not accessible
eff ects* not available;
fl ucytosine not accessible

Diseases Society of day) and fl ucytosine (100 mg/kg per per day) or liposomal day favoured) and fl ucytosine day) for 10–12 weeks or 2007 South African Not applicable: fl ucytosine available; if not possible, fl uconazole (800 mg/day) for 4 weeks All induction cryptococcal meningitis courses are for 2 weeks, unless stated. *Minimum package of prehydration, electrolyte replacement, and monitoring and management of toxic eff ects are available in these s ettings.16 Table 1: Guidelines for the induction treatment of cryptococcal meningitis depending on accessibility to amphotericin B and fl ucytosine
treatment termination,23 but are con cerning in settings The cost of amphotericin B continues to be a barrier to where availability of blood transfusion and renal access.35 Prices range from US$3·51 to $12·20 per 50 mg replacement treatment is scarce. The need for vial (table 2), which is equivalent to the cost of a daily intravenous administration, monitoring of blood count dose for cryptococcal meningitis treatment for a 50 kg and renal function, and perception of unmanageable adult, dosed at 1 mg/kg per day. Implementation of toxic eff ects frequently prevent the use of amphotericin B amphotericin B is connected with further attendant costs in poorly resourced and understaff ed hospital settings. of hospitalisation, intravenous administration, and Fluid and sodium loading and pre-emptive potassium monitoring of toxic eff ects. Insuffi replacement can reduce the risk of nephrotoxicity, and amphotericin B is a challenge in some African countries make administration of amphotericin B in low-income (table 3).37and middle-income countries more feasible.24 WHO In 2005, Bristol-Myers Squibb was lobbied for a reduction guidelines for the management of cryptococcal in the price of amphotericin B in South Africa by the AIDS meningitis provide clear guidance on how to safely Law Project on behalf of the Treatment Action Campaign. administer amphotericin B deoxycholate.16 The Southern African HIV Clinicians Society attained a Amphotericin B is the most rapidly acting fungicidal price reduction from ZAR 146 to ZAR 26 ($18–$3) per agent against Cryptococcus neoformans. On the basis 50 mg vial.35 This reduction made possible the expanded of evidence from clinical trials,23,25–31 treatment guide- use of amphotericin B and a switch away from initial lines for crypto coccal meningitis recommend 2 weeks fl uconazole monotherapy for cryptococcal meningitis of amphotericin B-based treatment as fi rst-line treatment in South Africa. In a survey of 25 sentinel treatment, where possible.16–18 A strategy of short-course hospitals in South Africa, the use of amphotericin B for (5–7 days) ampho tericin B was associated with rapid cryptococcal meningitis induction treatment increased cryptococcal clearance in two African studies,28,31 substantially, from 34% in 2005 to 83% in 2010.38 enabling substantial reductions in both cost and toxic Access to amphotericin B might be further restricted by eff ects of induction treatment. Although prohibitively uncoordinated funding, procurement, and distribution of expensive for patients in low-income and middle- the drug. In low-income and middle-income countries, income countries, liposomal formulations of amphotericin B is funded, procured, and distributed by amphotericin B allow the delivery of high doses of diff erent organisations, both governmental (President’s amphotericin B and seem to be at least as eff ective and Emergency Plan for AIDS Relief, the Global Fund, less nephrotoxic than conventional amphotericin B.32,33 UNITAID) and non-governmental (International Drug Bristol-Myers Squibb (USA) is the main manufacturer Purchase Facility, Doctors without Borders, and Clinton of amphotericin B as Fungizone. At least one US Food Health Access Initiative [CHAI]); therefore, coordination and Drug Administration (FDA)-approved therapeutic is not neces sarily at country or regional levels. For equivalent of amphotericin B is marketed in the USA example, a 2006 collaborative CHAI–UNITAID paediatric by X-Gen Pharmaceuticals (USA).34 HIV/AIDS programme donated essential paediatric Published online June 2, 2013
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Buyer prices per
Information on supplier
Supplier prices per
50 mg vial (US$)
50 mg vial (US$)
Mission for Essential Not-for-profi t Christian organisation. Coverage: Kenya, Tanzania, Ethiopia, Sudan, and Democratic Republic of Congo. Headquarters in Nairobi.
Supplies generic medicines, medical devices and (MISSION), Denmark equipment, and medical kits. Coverage: Africa, India, and China. Headquarters in Denmark.
Leading not-for-profi t supplier of pharmaceutical products. Supplies 3000 diff erent medicines and medical supplies to more than 100 countries worldwide. Headquarters in Netherlands.
Modifi ed from Management Sciences for Health and World Health Organization,36 by permission of Management Sciences for Health. Table 2: Price of amphotericin B for buyers in African and Caribbean countries
medi cines, including amphotericin B, to national HIV Flucytosine (250 mg or
Amphotericin B (50 mg/vial injection)
ment programmes in more than 40 countries in 500 mg capsules)
Africa, Asia, and the Caribbean. Uptake of amphotericin Registered Availability (at Price per vial B was low compared with other drugs, in part attributable to clinician unawareness of the need for, and inexperience in clinical use of amphotericin B in children (S Essajee, Perceived unmanageable toxic eff ects as a result of cient local education and inadequate facilities for safe administration and monitoring are an important disincentive to clinician uptake of amphotericin B for adults with cryptococcal meningitis, even when use is recommended by guidelines. This situation causes a fall in demand, which might contribute to intermittent failures of supply chains (in both high-income and low- income countries35). At least three diff erent lipid-based Data collected November–December 2011. *Through Section 21 of the Medicines Act, which allows for an unregistered formulations are marketed (table 4). The most widely used medicine to be used on a named-patient basis (price=$US 1·4 per 500 mg capsule). †Prices represent supplier prices. liposomal intravenous formulation is AmBisome (Gilead Modifi ed from Milani and Ford,37 by permission of South African Medical Journal.
Sciences, CA, USA), the patent of which has recently Table 3: Registration, availability, and price of fl ucytosine and amphotericin B in ten African countries
expired in several countries. Dosed at 3 mg/kg per day, it is substantially less nephrotoxic than amphotericin B, but is prohibitively expensive for low-income and middle- for the local market (table 4). Therefore, cost remains an income countries (2011 British National Formulary list important barrier to a switch from con ventional to less For British National Formulary
price per 50 mg vial: $150 in the UK; CIMS list price toxic liposomal formulations of amphotericin B in low- list prices see http://www.bnf.
$225 in India). A substantial reduction in price to $18 per income and middle-income countries. Cheap in-house org/bnf/index.htm
50 mg vial was negotiated by WHO for their visceral pre
parations of amphotericin B lipid emulsions, with For CIMS Directory Online list
price data for India see http://
leishmaniasis programme.39 An equivalent price was rates of nephrotoxicity com parable to liposomal formu- ered by Gilead Sciences to the South African lations, warrant further effi Government for treatment of patients with cryptococcal middle-income countries.42meningitis (N Geff en, Treatment Action Campaign, So far, only intravenous formulations of amphotericin B personal communication), but was not accepted. Gilead have been licensed. New oral formulations of
recently donated 445 000 vials of AmBisome for use over amphotericin B are in early stages of development as part
5 years for the WHO visceral leishmaniasis programme.40
of the drive to improve access to treatment for visceral Fungisome (Lifecare Innovations Ltd, India) a liposomal leishmaniasis,43,44 and are being developed by a Canadian formulation of amphotericin B developed and trialled in fi rm iCoTherapeutics. Under the terms of a socially India,41 has a maximum retail price of $122 per 50 mg vial responsible licensing agreement from the University of Published online June 2, 2013
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Generic version suppliers (approved by Route of
Trial data Patent status, representative
US Food and Drug Administration)
patents, or patent applications
Amphotericin B
Lipid formulations of amphotericin B
treaty application WO2011045809. Indian patent offi Flucytosine
Roxane (USA) Aurobindo Pharmaceuticals (India) Data from US Food and Drug Administration.34 Table 4: Formulations of antifungal drugs for cryptococcal meningitis
British Columbia who devised the initial formulation,45–49 The use of fl ucytosine was originally restricted because iCoTherapeutics are committed to ensuring access to of the drug’s toxic eff ects at high doses (150 mg/kg per day); these formulations for treatment of visceral leishmaniasis however, since the 1980s, clinical trials of cryptococcal in some low-income and middle-income countries, while meningitis with progressively shorter courses of fl u- allowing the company to pursue more lucrative high- cytosine at lower doses (100 mg/kg per day) have shown income markets for treatment of fungal infections.43,44,50 that fl ucytosine can be used safely and eff ectively in com-bination with amphotericin B (0·7–1 mg/kg per day).25,26,29 Flucytosine
A trial in Vietnam showed an association between Flucytosine was created in 1957 as a potential antitumour decreased mortality rates and treatment with fl ucytosine agent, and fi rst used to treat human candidiasis and and amphotericin B compared with treatment with cryptococcosis in 1968.51,52 Flucytosine exerts its antifungal amphotericin B alone.29 Therefore, 2 weeks of ampho- activity through rapid conversion into 5-fl uorouracil,51,53 tericin B plus fl ucytosine remains the gold standard for and is available in intravenous and oral formulations, induction treatment of cryptococcal meningitis. In low-marketed as Ancotil 2·5 g/250 ml solution for infusion income and middle-income countries, where ampho-and Ancobon (Meda Pharmaceuticals, France) 500 mg tericin B treatment is not available or feasible, fl ucytosine capsules. Flucytosine is always used in combination with can be safely and eff ectively paired with high-dose other antifungals because resistance emerges rapidly to fl uconazole (1200 mg/day),57–60 as recommended by IDSA monotherapy. Side-eff ects are mediated by 5-fl uorouracil, and WHO guidelines.16,17 Despite these guideline and include gastrointestinal and bone marrow toxic recommendations, fl ucytosine is not yet available in eff ects.53–56 Studies in low-income and middle-income most of Asia and Africa (table 3). The main barriers to countries have shown that oral fl ucytosine can be used access to fl ucytosine include absence of drug registration safely and eff ectively without monitoring drug levels in and generic drug manufacturing in low-income and settings in which complete blood count and renal function middle-income countries. Flucytosine is not registered in are monitored and dosing intervals are extended if renal any African country.35,37 Flucytosine was previously impairment occurs.23,26,28,30 Flucytosine can be given marketed by Roche in South Africa, but registration of nasogastrically in unconscious patients.25 Published online June 2, 2013
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The local National Health Service trust tender price for Fluconazole is off patent, generally widely available and oral fl ucytosine is 85p ($1·33) per 500 mg tablet for cheap, and numerous generic versions have FDA approval
Ancobon (L Whitney, St George’s Hospital Pharmacy, (table 4, price range with WHO Global Price Reporting For WHO Global Price Reporting
Mechanism see http://apps.who.
personal com muni cation), or $182 for a 50 kg adult with Mechanism: $0·08–$1·36 per day when dosed at 800 int/hiv/amds/price/hdd/t
cryptococcal meningitis receiving 14 days of induction mg36). Although cost has greatly restricted access to treatment. Conversely, generic oral fl ucytosine, fl uconazole in the past,72 availability has gradually manufactured by Sigmapharm, and approved by the FDA improved through increased production by generic in 2011, retails in the USA at $34 per 500 mg fl ucytosine manufacturers. Since 2000, Pfi zer’s (NY, USA) Difl ucan For the Difl ucan Partnership
tablet (A Sheppard, IMS Health, personal communication)
Partnership programme has provided free Difl ucan to programme see http://www.
or $4760 per 14-day course. Although fl ucytosine is a 63 low-income and middle-income countries for the difl ucanpartnership.comnucleotide analogue of simple chemical structure that has treatment of patients with cryptococcal meningitis and been off -patent for many years, there seems to be market oesopha geal candidiasis (not for the pre-emptive treatment failure because of insuffi cient demand and supply. A of cryptococcal antigenaemia) and is set to continue sustained eff ort is needed to make this key component of indefi nitely (Difl ucan Partnership programme, Pfi zer, cryptococcal meningitis treatment more widely available personal communication). However, imple mentation of in low-income and middle-income countries.
the programme varies: at teaching hospital pharmacies at investigators’ collaborating trial sites in South Africa (Cape Fluconazole
Town, Pietermaritzburg, and Durban) and Uganda Fluconazole has excellent bioavailability and cerebro- (Mbarara and Kampala), donated Difl ucan is readily spinal fl uid (CSF) penetration and few adverse eff ects.61,62 available, whereas in Malawi (Blantyre and Lilongwe), The drug is available in intravenous formulation and is Zambia (Lusaka), Cameroon (Douala and Yaoundé), and commonly given orally to treat cryptococcal meningitis. Tan zania (Arusha), purchased generic fl uconazole rather Clinical and mycological outcomes in trials of low-dose than donated Difl ucan is in stock, attributable to the fl uconazole monotherapy (200–400 mg/day) as induction challenges of sustaining timely and streamlined ordering treatment have been disappointing, with high mortality through the donation programme. Although free fl u-and prolonged time to CSF sterilisation.15,63,64 This slow conazole has been crucial for the treatment of cryptococcal fungal clearance can predispose to development of meningitis in Africa, increased availability of fl uconazole secondary drug resistance and cryptococcal immune by comparison with amphotericin B might have led to reconstitution syndrome.65–67 Phase 2 studies30,68 with high- dose fl uconazole in com bination with amphotericin B B-based induction treatment.73,74yielded good mycological and clinical outcomes and, in a larger trial, no diff erence in 2 week and 10 week mortality Recommendations for improvement of access
was evident between amphotericin B plus fl uconazole to antifungals
800 mg/day and amphotericin B plus fl ucytosine.29
We propose ten measures to improve access to crypto- Therefore, WHO and IDSA guidelines recommend the coccal meningitis treatment (panel). Improved estimates use of amphotericin B with high-dose fl uconazole as of disease burden, building upon studies by the CDC,13 second-line induction antifungal regimens.16,17 either via national cryptococcal surveillance systems (eg, Higher doses of fl uconazole (800–1200 mg/day) as South African National Institute for Communicable For the South African National
induction treatment are well tolerated and have faster Diseases)75 or through localised epidemiological studies, Institute for Communicable
rates of fungal clearance than a dose of 400 mg daily.69
would help with drug forecasting, streamline ordering, Diseases see
Clearance rates are further improved when fl uconazole and maximise the use of donations. Such data would is combined with fl ucytosine.57,58 WHO guidelines allow estimates of market size for manufacturers to be include high-dose fl uconazole monotherapy as an made and allow competitive price negotiation.
induction treatment option (table 1), but only when The 2011 WHO rapid advice guidelines16,76 provide amphotericin B and fl ucytosine are unavailable.16 recommendations on antifungal regimens tailored to Fluconazole is also a cornerstone of consolidation and clinical settings (table 1), and off ers guidance on how to maintenance treatment of cryptococcal meningitis16–18 minimise toxic eff ects and monitor amphotericin B,16–18 with published guidelines recommending step-down to so that increased access does not produce more harm fl uconazole after the initial 2 week induction to prevent than good. These recommendations need to be trans-recurrence of disease.16–18 Since 2012, fl uconazole has also lated into country-specifi c or region-specifi c treatment been used to treat early cryptococcal disease detected guidelines,18 and implemented alongside capacity through cryptococcal antigen screening.70 Pre-emptive building measures to improve facilities for rapid treatment of patients with a CD4 count less than or equal diagnosis, monitoring of toxic eff ects, and fast-track to 100 cells per μL and asymptomatic cryptococcal referral into antiretroviral therapy programmes.
For the WHO Model List of
antigenaemia with fl uconazole is being piloted in South In the WHO Model List of Essential Medicines,the core Essential Medicines see http://
Africa as a public health strategy to reduce death and (the most effi cacious, safe and cost-eff ective medicines morbidity caused by cryptococcal meningitis.67,71 for priority conditions for use in a basic health-care medicines/en/ Published online June 2, 2013
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Medicines Control Council inspection (C Chuma, Panel: Ten measures to improve access to antifungal
Lighthouse Healthcare, personal communication). drugs for the treatment of cryptococcal meningitis
• Improve estimates of cryptococcal meningitis disease eff ective coordination of regional governments, global health organisations and funders, and pharma ceutical • Ensure wider dissemination of best clinical practice companies and distributors.78 Drug funding and • Include all cryptococcal meningitis drugs on WHO core distribution could be integrated with existing anti- retroviral therapy programmes to provide antifungals • Register antifungals in low-income and middle-income alongside antiretrovirals, antituberculous drugs, and The optimisation of antifungal regimens in mortality- • Increase competition through generation of generics endpoint trials in low-income and middle-income • Ensure preferential pricing for low-income and countries is a driver for policy change. A multicentre middle-income countries by pharmaceutical companies African phase 3 trial (ISRCTN 45035509) is comparing • Ensure socially responsible licensing of intellectual standard with short-course amphotericin B-based regi- property for new antifungals or formulations developed mens and a purely oral combination (ie, fl uconazole plus fl ucytosine). Additionally, socially responsible licensing • Optimise existing antifungal strategies in clinical trials in of intellectual property79 should apply to new antifungals or formulations made through research funded by the • Stimulate research and development of novel public or by foundations. To our knowledge, only one antifungals by designation of cryptococcal meningitis as new long-acting azole-like compound is in development in a joint project between Viamet pharmaceuticals and the NIH Therapeutics for Rare and Neglected Diseases system) list includes only fl uconazole, while amphotericin programme.80 The scarcity of drug development for B and fl ucytosine, despite their greater eff ectiveness in cryptococcal meningitis is in stark contrast to the range treatment of cryptococcal meningitis, are on the of new drugs emerging from product-development complementary list. Amphotericin B and fl ucytosine partnerships for the treatment of malaria and tuber-should be included in the core list and national essential culosis,81 diseases that are associated with a comparable medicine lists and exempted from import duties and mortality burden to cryptococcal meningitis in sub-taxes.5–11 Antifungal drugs should be registered in low- income and middle-income countries, and a requirement The research and advisory group Policy Cures lists equivalence, quality standards (ie, good three criteria essential to classify a disease as neglected:81 manufacturing practice), and eff ectiveness of new generic the disease must predominantly aff ect people in low- formulations should be included. In many low-income income countries; needs new, improved, or additional and middle-income countries, medicines regulatory products; and suff ers from market failure because of an authorities are hampered by insuffi cient commercial market, resulting in insuffi human capacity. Successful registration of antifungal research and development by industry. Cryptococcal drugs might need support from experienced authorities meningitis fulfi such as the Medicines Control Council of South Africa, classifi cation of cryptococcal meningitis as a neglected the FDA, or European Medicines Agency,77 or even the disease would help attract funding for drug development.
introduction of a pan-African reciprocal drug-approval process. In South Africa, eff orts are underway for fast- Conclusions
track registration of fl ucytosine with the Medicines Although continued global scale-up of antiretroviral Control Council (C Chuma, Lighthouse Healthcare, therapy and initiation before the CD4 count falls below personal communication).
350 cells per μL remains the most important long-term Drug companies should include antifungals in strategy to reduce the incidence of cryptococcal meningitis, corporate responsibility policies on HIV, and consider the infection will remain a major cause of HIV-related preferential pricing for low-income and middle-income morbidity and mortality, particularly in sub-Saharan Africa countries. Increased competition through generation of in the foreseeable future. Treatment for cryptococcal generics is needed. Generic pharmaceutical manufac- meningitis relies on three old, off -patent antifungal drugs, turers should be given incentives and manufacturing which each pose specifi c access challenges for low-income support to produce generic versions of fl ucytosine for and middle-income countries: amphotericin B through the low-income and middle-income country markets. cost, toxic eff South Africa is exploring the manufacture of cheaper distribution; fl ucytosine through cost and insuffi generic fl ucytosine at facilities contracted by GSK and registration; and fl Pfi zer in Bangladesh; a lengthy process that needs a full maintenance of local stocks, be it through sustainability of Published online June 2, 2013
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cient generic supplies. If patients with 4 United Nations. General Comment No. 14 (2000). The right to the coccal meningitis survive the acute disease and highest attainable standard of health (article 12 of the International Covenant on Economic, Social and Cultural Rights). http://www.
become established on antiretroviral therapy, long-term prog nosis is excellent.15 It is unacceptable that up to one be?Opendocument (accessed April 26, 2013). half of patients with cryptococcal meningitis in low-income World Health Organization. Equitable access to essential medicines: a framework for collective action. WHO Policy Perspectives on and middle-income countries do not survive to 10 weeks, medicines. March 2004. and do not benefi t from expansion of antiretroviral therapy EDM_2004.4.pdf (accessed April 26, 2013). programmes, partly because even the basic range of 6 Hoen E, Berger J, Calmy A, Moon S. Driving a decade of change: HIV/AIDS, patents and access to medicines for all. J Int AIDS Soc antifungal drugs is not available to them.
2011; 14: 15.
Access to the most eff ective antifungal drugs for 7 Moon S, Jambert E, Childs M, von Schoen-Angerer T. A win-win treatment of cryptococcal meningitis in developing solution? A critical analysis of tiered pricing to improve access to
medicines in developing countries. Global Health 2011; 7: 39.
countries needs to be urgently improved as part of the 8 World Health Organization. Access to medicines. Intellectual global response to the HIV pandemic. A concerted property protection: impact on public health. WHO Drug Information move away from the widely-practised fl uconazole 2005; 19: 236–41.
monotherapy, towards more eff ective combination 9 Smith RD, Correa C, Oh C. Trade, TRIPS, and pharmaceuticals.
Lancet 2009; 373: 684–91.
induction treatment regimens including amphotericin 10 Cameron C, Ewen M, Ross-Degnen D, Ball D, Laing R. Medicine B or fl ucytosine or both, is needed. A coordinated prices, availability, and aff ordability in 36 developing and international eff ort should involve relevant public and middle-income countries: a secondary analysis. Lancet 2009;
373: 240–49.
private organisations and we must learn from models 11 Médecins Sans Frontières. Campaign for Access to Essential with proven success in the implementation of access to Medicines. Untangling the web of price reductions: a pricing guide medicines for other important global infectious for the purchase of ARVs for developing countries. 13th Edition July 2010. Geneva: Médecins Sans Frontières, 2006.
diseases. Facilitated by WHO, a meeting of key 12 The Global Fund. Options for modifi cation of the application, stakeholders took place in March 2013 and has given renewal and approval processes for new and existing investments. rise to a concerted advocacy eff ort to improve access to 25th board meeting; Accra, Ghana, Nov 21–22, 2011. http://www. fth/documents/ essential antifungals for cryptococcal meningitis.
13 Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the The concept and structure of the manuscript was devised by HT, AL, TB, global burden of cryptococcal meningitis among persons living with TSH. AL, HT, MR, PE, NG, TB collated data, including drug costings. HIV/AIDS. AIDS 2009, 23: 525–30.
AL, HT, and TB wrote the fi rst draft of the manuscript. All authors 14 Mirza SA, Phelan M, Rimland D. The changing epidemiology of contributed to writing and editing the fi nal manuscript.
cryptococcosis: an update from population-based active surveillance in
2 large metropolitan areas, 1992–2000. Clin Infect Dis 2003; 36: 789–94.
Confl icts of interest
15 Bicanic T, Jarvis J, Loyse A, et al. Determinants of acute outcome and HT is funded by a European Union grant (FP7 Health 241839). TB is long-term survival in HIV-associated cryptococcal meningitis: results funded by a Wellcome Trust Intermediate Fellowship (WT 089966). The of a combined cohort of 523 patients. 18th conference on retroviruses fi ndings and conclusions of this personal view are those of the authors and opportunistic infections; Boston, USA; Feb 27–Mar 2, 2011. 892.
and do not necessarily represent the offi 16 World Health Organization. Rapid advice: diagnosis, prevention and Disease Control and Prevention. The use of product names in this management of cryptococcal disease in HIV-infected adults, manuscript does not imply their endorsement by the US Department of adolescents and childrenGeneva: WHO, Dec 2011. http://www.who.
int/hiv/pub/cryptococcal_disease2011/en/index.html. (accessed Aug 6, 2012).
17 Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice The following people kindly provided or collated information on local guidelines for the management of cryptococcal disease: 2010 update or international antifungal drug prices or both: Iman Wanis and by the infectious diseases society of America. Clin Infect Dis 2010; Boniface Dongmo Nguimfack (WHO, Switzerland), Alan Sheppard 50: 291–322.
(IMS Health, USA), and Laura Whitney (St George’s Hospital 18 South African HIV Clinicians Society. Guidelines for the prevention, Pharmacy, London, UK). Chomba Chuma of Lighthouse Healthcare diagnosis and management of cryptococcal meningitis and (Johannesburg, South Africa) is exploring registration and disseminated cryptococcosis in HIV- infected patients. Cape Town; manufacture of generic fl ucytosine for South Africa, and provided Health and Medical Publishing Group, 2007. http://www.sahivsoc.
relevant information on this process. Shaffi org/practise-guidelines/sa-hiv-clinicians-society-guidelines (accessed provided unpublished information regarding the uptake of amphotericin B through the CHAI UNITAID donation. We thank 19 Brajtburg J, Powderly WG, Kobayashi GS, Medoff G. Amphotericin Richard Mahoney of the International Vaccine Institute (Seoul, South B: current understanding of mechanisms of action.
Antimicrob Agents Chemother 1990; 34: 183–88.
Korea) for critical reading of the manuscript, and Nathan Geff en of the Treatment Action Campaign (Cape Town, South Africa) for 20 Ellis D. Amphotericin B: spectrum and resistance. J Antimicrob Chemother 2002; 49 (suppl 1): 7–10.
information regarding price negotiations for liposomal amphotericin B. We thank David Boulware (University of Minnesota, USA) and 21 Sundar S, Sinha PK, Rai M, et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis Mark Jacobson (Selian Hospital, Arusha, Tanzania) for providing in India: an open-label, non-inferiority, randomised controlled trial. information regarding Difl ucan availability in Arusha, Tanzania.
Lancet 2011; 377: 477–86.
22 Thakur CP, Kumar A, Mitra DK, Roy A, Sinha AK, Ranjan A. World Health Organization. Constitution of the World Health Improving outcome of treatment of Kala-Azar by supplementation of amphotericin B with physiologic saline and potassium chloride. United Nations General Assembly. Universal Declaration of Human Am J Trop Med Hyg 2010; 83: 1040–43.
Rights. Paris; United Nations, 1948.
23 Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with United Nations General Assembly. International covenant on fl ucytosine for the treatment of cryptococcal meningitis in HIV- economic, social and cultural rights (ICESCR). New York; United infected patients: A randomised trial. Clin Infect Dis 2008; 47: 123–30. Published online June 2, 2013
Personal View
24 Bahr N, Rolfes MAR, Musubire B, et al. The impact of routine 44 The Alliance for Case Studies for Global Health. Case studies for electrolyte supplementation during amphotericin induction therapy in global health. Building relationships. Sharing knowledge. http:// resource-limited settings. 8th International Conference on Cryptococcus and Cryptococcosis; Charleston, USA; May 1–5, 2011. 183. 25 Van der Horst CM, Saag MS, Cloud GA, et al. Treatment of 45 Sachs-Barrable K, Lee SD, Wasan EK, Thornton SJ, Wasan KM. cryptococcal meningitis associated with the acquired Enhanced drug absorption using lipids: A case study presenting the immuno-defi ciency syndrome. N Engl J Med 1997; 337: 15–21.
development and pharmacological evaluation of a novel lipid-based 26 Brouwer A, Rajanuwong A, Chierakul W, et al. Combination oral Amphotericin B formulation for the treatment of systemic antifungal therapies for HIV-associated Cryptococcal Meningitis: fungal infections. Adv Drug Deliv Rev 2008; 60: 692–701.
a randomised trial. Lancet 2004; 364: 1764–67.
46 Thornton SJ, Wasan KM, Piecuch A, Lynd LL, Wasan EK. Barriers 27 Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early to treatment for visceral leishmaniasis in hyperendemic areas: fungicidal activity, and outcome in cryptococcal meningitis in India, Bangladesh, Nepal, Brazil and Sudan. Drug Dev Ind Pharm antiretroviral-naive or antiretroviral-experienced patients treated 2010; 36: 1312–19.
with amphotericin B or fl uconazole. Clin Infect Dis 2007; 45: 76–80.
47 Wasan EK, Gershkovich P, Zhao J, et al. A novel tropically stable oral 28 Jackson AT, Nussbaum JC, Phulusa J, et al. A phase II amphotericin B formulation (iCo-010) exhibits effi randomized controlled trial adding oral fl ucytosine to high-dose Leishmaniasis in a murine model. PLoS Negl Trop Dis 2010; 4: e913.
fl uconazole, with short-course amphotericin B, for cryptococcal 48 iCo Therapeutics. Oral amphotericin B delivery system. http://www.
meningitis AIDS 2012; 26: 1363–70. (accessed June 12, 2012).
29 Day JN, Chau TTH, Wolbers M, et al. Combination antifungal 49 Gershkovich P, Sivak O, Wasan EK, et al. Biodistribution and tissue therapy for HIV-associated cryptococcal meningitis. N Engl J Med toxicity of amphotericin B in mice following multiple dose 2013; 368: 1291–302.
administration of a novel oral lipid-based formulation (iCo-009). 30 Loyse A, Wilson D, Meintjes G, et al. Comparison of the early J Antimicrob Chemother 2010; 65: 2610–13.
fungicidal activity of high-dose fl uconazole, voriconazole, and 50 Busang R, Boisjoly-Letourneau K, Bernard Fourie, Mulder M, fl ucytosine as second-line drugs given in combination with Thangaraj H. Socially responsible licensing of health technologies; amphotericin B for the treatment of HIV-associated cryptococcal policy and practice in South Africa. LES J 2011; 2: 69–77.
meningitis. Clin Infect Dis 2012; 54: 121–28.
51 Duchinsky R, Pleven E, Heidelberger C. The synthesis of 31 Muzoora CK, Kabanda T, Ortu G, et al. Short course AmB with 5-fl uoropyrimidines. J Am Chem Soc 1957; 79: 4559–60.
high-dose fl uconazole for HIV-associated cryptococcal meningitis. 52 Tassel D, Madoff MA. Treatment of candida sepsis and J Infect 2012; 64: 76–81.
cryptococcus meningitis with 5-fl uorocytosine. A new antifungal 32 Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B agent. JAMA 1968; 206: 803–32.
(AmBisome) compared with amphotericin B both followed by oral 53 Bennett J. E Flucytosine. Ann Intern Med 1977; 86: 319–21.
fl uconazole in the treatment of AIDS-associated cryptococcal 54 Block ER, Bennett JE. Pharmacological studies with meningitis. AIDS 1997; 11: 1463–71.
5-fl uorocytosine. Antimicrob Agents Chemother 1972; 1: 476–82.
33 Hamill RJ, Sobel RD, El-Sadr W, et al. Comparison of 2 doses of 55 Vermes A, Guchelaar H-J, Dankert J. Flucytosine: a review of its liposomal amphotericin B and conventional amphotericin B pharmacology,clinical indications, pharmacokinetics, toxicity and deoxycholate for treatment of AIDS-associated acute cryptococcal drug interactions. J Antimicrob Chemother 2000; 46: 171–79.
meningitis: a randomised, double-blind clinical trial of effi 56 Brouwer AE, van Kan HJ, Johnson E, et al. Oral versus intravenous safety. Clin Infect Dis 2010; 51: 225–32.
fl ucytosine in patients with human immunodefi ciency 34 US Food and Drug Administration. FDA orange book: approved virus-associated cryptococcal meningitis. drug product with therapeutic equivalence evaluations. Rockville; Antimicrob Agents Chemother 2007; 51: 1038–42.
57 Nussbaum JC, Jackson A, Namarika D, et al. A randomised-controlled 35 Bicanic T, Wood R, Bekker L-G, Darder M, Meintjes G, Harrison TS. trial of addition of fl ucytosine to high-dose fl uconazole for treatment Antiretroviral roll-out, antifungal roll-back: Access to treatment for of HIV-associated cryptococcal meningitis in Malawi 2009. cryptococcal meningitis. Lancet Infect Dis 2005; 5: 530–31.
Clin Infect Dis 2010; 50: 338–44.
36 Management Sciences for Health and World Health Organization. 58 Larsen RA, Bozette SA, Jones BE, et al. Fluconazole combined with 2012. International Drug Price Indicator Guide 2011. Frye JE, ed. fl ucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994; 19: 741–45.
59 Mayanja-Kizza H, Oishi K, Mitarai S, et al. Combination therapy 37 Milani B, Ford N. Responding to the evidence for improved with fl uconazole and fl ucytosine for cryptococcal meningitis in treatment for cryptococcal meningitis in resource-limited settings. Ugandan patients with AIDS. Clin Infect Dis 1998; 26: 1362–66.
S Afr Med J 2012; 102: 196–97.
60 Milfechik E, Leal MA, Haubrich R, et al. Fluconazole alone or 38 Govender N. Cryptococcosis in developing countries: where are we combined with fl ucytosine for the treatment of AIDS-associated after a decade of population-based surveillance in South Africa. cryptococcal meningitis. Med Mycol 2008; 46: 393–95.
8th international conference on climate change; Charleston, USA; 61 Palou de Fernandez E, Patino MM, Graybill JR, Tarbit MH. Treatment of cryptococcal meningitis in mice with fl uconazole. 39 World Health Organization. Report of a WHO informal Antimicrob Agents Chemother 1986; 18: 261–70.
consultation on liposomal amphotericin B in the treatment of 62 Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new visceral leishmaniasis. Rome; World Health Organization, triazoles. Antimicrob Agents Chemother 1988; 32: 1–8.
63 Mwaba P, Mwansa J, Chintu C, et al. Clinical presentation, natural 40 Gilead Sciences and WHO establish new fi ve year initiative to history, and cumulative death rates of 230 adults with primary prevent deaths from visceral leishmaniasis. National AIDS cryptococcal meningitis in Zambian AIDS patients treated under Treatment Advocacy Project. local conditions. Postgrad Med J 2001; 77: 769–73.
newsUpdates/121211_04.htm (accessed April 26, 2013). 64 Schaars CF, Meintjes GA, Morroni C, Post FA, Maartens G. 41 Jadhav MP, Bamba A, Shinde VM, et al. Liposomal amphotericin B Outcome of AIDS-associated cryptococcal meningitis initially (FungisomeTM) for the treatment of cryptococcal meningitis in HIV/ treated with 200mg/day or 400mg/day of fl uconazole. AIDS patients in India: a multicentric, randomized controlled trial. BMC Infect Dis 2006; 6: 118.
J Postgrad Med 2010; 56: 71–75.
65 Bicanic T, Harrison T, Niepieklo A, Dyakopu N, Meintjes G. 42 Mistro S, Maciel Ide M, de Menenzes RG, et al. Does lipid emulsion Symptomatic relapse of HIV-associated cryptococcal meningitis reduce amphotericin B nephrotoxicity? A systematic review and after initial fl uconazole monotherapy: the role of fl uconazole meta-analysis. Clin Infect Dis 2012; 54: 1774–77.
resistance and immune reconstitution. Clin Infect Dis 2006; 43 Wasan KM, Thornton SJ, Bell I, et al. The global access initiative at 43: 1069–73.
the University of British Columbia (UBC): Availability of UBC 66 Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Cryptococcocal discoveries and technologies to the developing world. J Pharm Sci immune reconstitution disease: a major cause of early mortality in 2009; 98: 791–94.
a South African antiretroviral programme. AIDS 2005; 19: 2050–52. Published online June 2, 2013
Personal View
67 Jarvis JN, Lawn SD, Vogt M, et al. Screening for cryptococcal 76 Doctors without Borders. First ever treatment guidelines released for antigenaemia in patients accessing an antiretroviral treatment major cause of death of people living with HIV. Addis Ababa; Dec 7, program in South Africa. Clin Infect Dis 2009; 48: 856–62.
68 Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II cfm?id=5654 (accessed June 12, 2012).
randomized trial of Amphotericin B alone or combined with 77 Moran M, Guzman J, McDonald A, Wu L, Omune B. Registering fl uconazole in the treatment of HIV-associated cryptococcal new drugs; the African context. New tools for new times. Jan, 2010. meningitis. Clin Infect Dis 2009; 48: 1784–86. 69 Longley N, Muzoora C, Taseera K, et al. Dose response eff ect of Drugs-The_African_Context_20100108.pdf (accessed April 26, 2013). high-dose fl uconazole for HIV-associated cryptococcal meningitis in 78 Waning B, Kaplan W, King AC, Lawrence DA, Leufkens HG, Southwestern Uganda. Clin Infect Dis 2008; 47: 1556–61.
Fox MP. Global strategies to reduce the price of antiretroviral 70 South African Department of Health. National strategic plan on medicines: evidence from transactional databases. http://www.who.
HIV, STIs, and TB 2012–16. Feb 15, 2012. Cape Town. http://www.
int/bulletin/volumes/87/7/08-058925/en/ (accessed May 16, 2012). (accessed April 29, 79 Thangaraj H, Reljic R. Social leverage of intellectual property: road to the development of better therapy for tuberculosis. 71 Jarvis J, Harrison TS, Govender N, et al. Routine cryptococcal Recent Pat Antiinfect Drug Discov 2009; 4: 114–22.
antigen screening for HIV-infected patients with low CD4+ 80 Najvar LK, Wiederhold NP, Fothergill AW, et al. The novel fungal T-lymphocyte counts—time to implement in South Africa? Cyp51 inhibitor VT-1129 demonstrates potent in vitro and in vivo S Afr Med J 2011; 101: 232–34.
against Cryptococcus species. 8th International conference on 72 Perez-Casas C, Chirac P, Berman D, Ford N. Access to fl uconazole cryptococcus and cryptococcosis. Charleston, USA; May 1–5, 2011.
in less-developed countries. Lancet 2000; 356: 2102.
81 Drake P, Thangaraj H. Molecular farming, patents and access to 73 Hamill RJ. Free fl uconazole for cryptococcal meningitis: too little of medicines. Expert Rev Vaccines 2010; 9: 811–19.
a good thing? Clin Infect Dis 2006; 43: 1074–76.
82 Moran M, Guzman J, Abela-Oversteegen L, et al. Neglected disease 74 Collett GG, Parrish AA. Fluconazole donation and outcomes research and development: Is innovation under threat? Policy Cures assessment in cryptococcal meningitis. S Afr Med J 2007; 97: 175–76.
G-Finder Report. Dec, 2011.
75 Meiring ST, Quan VC, Cohen C, et al. A comparison of paediatric- and adult-onset cryptococcosis detected through population-based
surveillance in South Africa, 2005–2007. AIDS 2012; 26: 2307–14. Published online June 2, 2013


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