Optimising the Prevention and management of HIV associated cryptococcal meningitis
Submitting InstitutionSt George's, University of London
Unit of AssessmentClinical Medicine
Summary Impact TypePolitical
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Medical Microbiology
Summary of the impact
Researchers from St Georges have evaluated and optimised anti-fungal
therapy for cryptococcal
meningitis, the commonest cause of adult meningitis in sub-Saharan Africa.
They have developed
a "screen-and-treat" strategy to prevent the development of clinical
disease in HIV-positive
patients, and with collaborators developed and tested a novel
point-of-care diagnostic test. These
advances have led to changes in and development of a series of
international guidelines and
application of these new strategies in parts of Africa. A case for reduced
costs of amphotericin was
advanced by the group who were instrumental in reducing these costs in
South Africa, allowing
wider drug provision.
Cryptococcal meningitis is the commonest cause of meningitis in most of
Africa, and a major cause
of death in HIV-infected individuals globally. It accounts for up to 0.5
million deaths per year.
Harrison, Bicanic and colleagues at St George's conducted a series of
phase II studies in Asia and Africa [1-4], to optimise antifungal dosages
and combinations for the
treatment of cryptococcal meningitis. Specifically, to obtain evidence of
improved efficacy the
group looked for increased rates of clearance of the infection, a metric
of efficacy that they
developed for this purpose. They studied:
- Amphotericin B compared to fluconazole 
- Higher doses of amphotericin B
- Amphotericin B plus flucytosine compared to amphotericin B alone ,
- Increased doses of fluconazole up to 1200 mg/d , and
- Addition of flucytosine to high dose fluconazole .
Fluconazole, which unlike flucytosine is widely and often freely
available in the developing world,
was shown to be as rapidly effective as flucytosine as a second drug to
prescribe in combination
with amphotercin B. Furthermore, a one week course of amphotericin B was
shown to be much
better tolerated than the standard 2 week course, with no decrease in the
rate of clearance of
infection. This work underpinned the analysis of drug costs for this
Prevention and early diagnosis:
Cryptococcal meningitis is a major cause of mortality in HIV-positive
patients in Africa. The team
provided the rationale for a pre-emptive treatment strategy that has the
potential to prevent over
half of all cases presenting after a diagnosis of HIV has been made .
5-10% of HIV-infected
patients with a low CD4 cell count (<100 cells/mm3) were
found to test positive for cryptococcal
antigen in plasma (indicative of early sub-clinical infection) prior to
initiation of antiretroviral therapy
(ART). One third of antigen positive patients developed clinical
cryptococcal disease in the first
year of antiretroviral therapy, while none of over 660 patients testing
antigen negative developed
clinical cryptococcosis. This would give a 100% negative predictive value
for the test if it were
used to screen patients prior to ART .
The team, with collaborators from University of Nevada and
Immuno-Mycologics, developed and
tested a novel point-of-care diagnostic test for early infection that
would make "screen-and-treat"
feasible, and enable earlier, primary care-based diagnosis of cases
presenting with symptomatic
disease . The novel test was shown to have excellent sensitivity in
both blood and urine, making
routine screening for antigen practicable in resource-limited settings
References to the research
1. A.E. Brouwer, A. Rajanuwong, W. Chierakul, G.E. Griffin, R.A. Larsen,
N.J. White, T.S.
Harrison. Combination antifungal therapies for HIV-associated cryptococcal
randomized trial. The Lancet 2004; 363:1764-67. No DOI available.
2. N. Longley, C. Muzoora, K. Taseera, J Mwesigye, J. Rwebembera, A.
Chakera, E. Wall, I.
Andia, S. Jaffar, T.S Harrison. Dose-Response Effect of high dose
fluconazole for HIV-associated
cryptococcal meningitis in Southwest Uganda. Clinical Infectious
Diseases 2008; 47:1556-61. doi:
3. Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba C,
Jarvis JN, Jaffar S,
Hosseinipour MC, Kamwendo D, van der Horst CM, Harrison TS. Combination
flucytosine and high
dose fluconazole is superior to fluconazole monotherapy for cryptococcal
meningitis: a randomized
trial in Malawi. Clinical Infectious Diseases 2010; 50:338-44
(plus accompanying Editorial). doi:
4. T. Bicanic, C. Muzoora, A.E. Brouwer, G. Meintjes, N. Longley, K.
Taseera, K. Rebe, A. Loyse,
J. Jarvis, L. G.Bekker, R. Wood, D. Limmathurotsakul, W. Chierakul, K.
Stepniewska, N.J. White,
S. Jaffar, and T.S. Harrison. Independent Association between Rate of
Clearance of Infection and
Clinical Outcome of HIV- Associated Cryptococcal Meningitis: Analysis of a
Combined Cohort of
262 Patients. Clinical Infectious Diseases 2009; 49:702-9. doi:
5. Bicanic T, Wood R, Bekker LG, Darder M, Meintjes G, Harrison TS.
antifungal roll-back: access to treatment for cryptococcal meningitis. Lancet
Infect Dis 2005;
5:530-1. No DOI available.
6. Jarvis JN , Lawn SD , Vogt M, Bangani N , Wood R , Harrison TS.
Screening for cryptococcal
antigenemia in patients accessing an antiretroviral treatment program in
South Africa. Clinical
Infectious Diseases 2009; 48:856-62. doi: 10.1086/597262.
7. Jarvis JN, Percival A, Bauman S, Pelfrey J, Meintjes G, Williams GN,
Longley N, Harrison TS,
Kozel TR. Evaluation of a Novel Point of Care Cryptococcal Antigen (CRAG)
Test on Serum,
Plasma and Urine from Patients with HIV-associated Cryptococcal
Meningitis. Clin Infect Dis 2011;
53:1019-23. doi: 10.1093/cid/cir613.
Details of the impact
The major impacts of the work can be summarised:
International guidelines for the management of cryptococcal
The results of the research outlined above have been central to the
development of the Infectious
Disease Society of America (IDSA) guidelines for management of
Cryptococcal meningitis (2010)
[A], the "WHO Rapid Advice: Diagnosis, prevention, and management of
cryptococcal disease in
HIV-infected adults, adolescents, and children" published in 2011
[B], and the Southern African
guidelines published in 2007 [C] and updated in 2013 [D]. Specifically,
these guidelines endorse
findings from the underpinning research outlined above, and advise:
- Superiority of amphotericin B over fluconazole — and preference for
use of amphotericin B
wherever it is possible to use it safely.
- Addition of flucytosine (when available) to amphotericin B supported
by demonstration of the
added fungicidal activity resulting from the combination.
- High dose amphotericin B based on superior sterilizing activity.
- At least 1200 mg/d as the preferred initial fluconazole dose, and high
dose fluconazole plus
flucytosine as preferred oral treatment option.
- Adoption of a short, one week, course of amphotericin B where
resources do not allow safe,
sustainable use of standard 2 weeks courses.
The impact of adopting these recommendations in resource-limited
settings, which previously used
ineffective fluconazole monotherapy, is a reduction in the the 10-week
mortality from over 50% to
25-35% when amphoteracin B based treatments are used (see Research
References 1 & 4
above). This is achieved through wider use of standard amphotericin B
induction, and of effective
but also affordable and sustainable alternatives (short course
amphotericin B, and combination oral
therapy with high dose fluconazole).
The cost comparisons, lobbying and advocacy initiated by the study team
[E,F] caused the
pharmaceutical company Bristol Myers Squibb to reduce the price of
amphotericin B in South
Africa by 80% (146 to 26 ZAR/50mg vial). This has resulted in the use of
amphotericin B (as
opposed to fluconazole) for induction therapy being increased from an
estimated 34% of patients in
2005 to 83% in 2010 [F,G]. Based on the work of the group, and in line
with the international
guidelines, an increasing number of Sub-Saharan Africa countries have
adopted 1200 mg/d as the
standard fluconazole dose, with the effect that this dose is now routinely
used in initial therapy
throughout those countries [H].
Adoption of the screen and pre-emptive treatment strategy after HIV
Following the evidence produced by the St George's group The Department
of Health in South
Africa has agreed to a phased implementation of the introduction of a
screen and pre-emptive
treatment strategy for cryptococcal meningitis in newly diagnosed HIV
patients. In many African
centres this now represents over half of all cases. This was incorporated
into the 2012 Department
of Health strategic plan [I] following meetings in Pretoria in February
2011 with CDC, PEPFAR
representatives and Harrison. Of note is that a cost-effectiveness
analysis demonstrated that
screening has become the optimal standard of care — i.e. it both saves
lives and saves money
(through a reduction in costs associated with caring for patients) [J].
Screening is now in routine
use in South Africa's Western Cape and Gauteng provinces; further projects
based on this strategy
are being implemented in Uganda, Kenya, Zambia, and Tanzania. Screening,
using the new point-of-care
diagnostic test, was endorsed by the 2011 WHO guidelines for areas of high
and recommended in the updated 2013 Southern African Clinicians Society
Effective screening with subsequent treatment substantially reduces the
number of cases of
cryptococcal meningitis presenting after a diagnosis of HIV has been made
therapy started, demonstrating the extensive reach and significance of
Sources to corroborate the impact
A. Clinical Practice Guidelines for the Management of Cryptococcal
Disease: 2010 Update by the
Infectious Disease Society of America. Perfect JR, Dismukes WE, Dromer F,
Goldman DL, Graybill
JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH,
Pappas PG, Powderly WG,
Singh N, Sobel JD, Sorrell TC. Clinical Infectious Diseases 2010;
B. "WHO Rapid Advice: Diagnosis, prevention, and management of
cryptococcal disease in HIV-infected
adults, adolescents, and children", December 2011. Harrison TS
expert panel member; T
Bicanic, J Jarvis Peer Review Panel
C. Southern African HIV Clinicians' Society Guidelines for the
prevention, diagnosis and
management of cryptococcal meningitis and disseminated cryptococcosis in
Conveners McCarthy K, Meintjes G. Writing committee: Arthington-Skaggs B,
Bicanic T, Cotton M,
Chiller T, Govender N, Harrison T, Karstaedt A, Maartens G,
Varavia E, Venter F, Vismer H.
Southern African J HIV Med Sept 2007; 25-35. No DOI available.
D. Southern African HIV Clinicians' Society Guidelines for the
Prevention, Diagnosis and
Management of Cryptococcal Meningitis among HIV-infected Persons. Update —
Govender N, Meintjes G. Expert Panel members: Bicanic T, Dawood H,
Harrison T, Jarvis J,
Karstaedt A, Maartens G, McCarthy K, Rabie H, Varavia E, Venter F. Southern
African J HIV Med
2013 in press. No DOI available.
E. Bicanic T, Wood R, Bekker L-G, Darder M, Meintjes G, Harrison
TS. Antiretroviral roll-out,
antifungal roll-back: access to amphotericin B and flucytosine for the
treatment of cryptococcal
meningitis. Lancet Infectious Diseases 2005; 5:530-1. DOI: http://dx.doi.org/10.1016/S1473-3099(05)70197-3.
F. Loyse A, Thangaraj H, Easterbrook P, Ford N, Roy M, Chiller T,
Govender N, Harrison TS,
Bicanic T. Cryptococcal meningitis: improving access to essential
antifungal medicines in resource
poor countries. Lancet Infectious Diseases 2013; May 31st
G. Personal communication: Nelesh Govender, Head Mycology Laboratory
Health Laboratory Service, South Africa
H. Ministry of Health 2011. Clinical Management of HIV in children and
adults. Malawi Integrated
guidelines. First Edition, Malawi Ministry of Health.
I. South African DoH — have adopted the screen-and treat prevention
strategy in the National
Strategic Plan on HIV, STIs, and TB 2012-16; dated 15th Feb
2012, accessed at
see intervention 3.19 page 49; and reference to cost effectiveness
analysis in South Africa: ref 34
J. Jarvis JN, Harrison TS, Lawn SD, Meintjes G, Wood R, Cleary S.
Cryptococcal Antigen Screening as a Strategy to Prevent HIV-associated
in South Africa. PLoS One 2013; 8(7): e69288. DOI: