Opportunistic fungal infections continue to take an unacceptably heavy toll on the most disadvantaged living with HIV-AIDS, and are a major driver for HIV-related deaths. At the second EMBO Workshop on AIDS-Related Mycoses, clinicians and scientists from around the world reported current progress and key priorities for improving outcomes from HIV-related mycoses

Armstrong-James, D

Bicanic, T

Brown, GD

Hoving, JC

Meintjes, G

Nielsen, K

Working Group from the EMBO Workshop on AIDS-Related Mycoses

Armstrong-James, Darius

Bicanic, Tihana

Brown, Gordon D

Hoving, Jennifer C

Meintjes, Graeme

Nielsen, Kirsten

DukeSpace (Duke Univ.)

Trends in Microbiology

AIDS-Related Mycoses: Current Progress in the Field and Future Priorities

Acknowledgement The RItrain project is funded by the European Commission, grant agreement number 654156.Peer reviewe

Working Group from the EMBO-AIDS Related Mycoses Workshop

The Open University

1  AIDS-Related Mycoses: Current progress in the field and future priorities  1  2 Darius Armstrong-James1*, Tihana Bicanic2, Gordon D. Brown3,4, Jennifer C. Hoving3,  3 Graeme Meintjes3, Kirsten Nielsen5, and the Working Group from the EMBO-AIDS Related 4 Mycoses Workshop (Akilmali A, Alupo P, Andrianopoulos A, Armstrong-James D, Barr D, 5 Bauman S, Bicanic T, Botha A, Boulware D, Bradley S, Brand S, Brown G, Burgers W, Chari 6 R, Chiller T, Cohen O, Dambuza I, Day J, Denning D, Edwards J, Fisher M, Frazer J, 7 Garelnabi M, Gomez B, Govender N, Hanise P, Harrison J, Harison T, Heath CH, Hope W, 8 Hoving J, Huppler Hullseik K, Jarvis J, Jenkins M, Kamuyango A, Kannambath S, Katende 9 A, Kauffman C, Klausner J, Kolls J, Kwizera R, Lalloo DG, Le T, Lerm B, Letang E, Levitz S, 10 Limper A, Longley N, Loyse A, Madu L, Maphanga T, Marakalala M, Mashao-Mphaphuli B, 11 May R, Mbwanji G, Meintjes G, Meya D, Mhlanga M, Molloy S, Mthembu N, Mukaremera L, 12 Nacher M, Ndiitwani D, Netea M, Nielsen K, Ogundeji A, Okurut S, Oladele R, Omondi F, 13 Irchard A, Osherov N, Otieno P, Perez Casas C, Perfect J, Rhein J, Romani L, Rukasha I, 14 Samie A, Schutz C, Schwartz I, Scriven J, Sebolai O, Seleteng Kopse L, Shikwambane-15 Ntlemo G, Smulian G, Sobel J, Sriruttan C, Stone N, Trollope K, Tugeme L, Valentine M, 16 Vreulink J, Wake R, Wasserman S, Wilkinson R, Williams D, Williamson P, Wood K, 17 Youngchim S) 18  19 1 Fungal Pathogens Laboratory, National Heart and Lung Institute, Imperial College London, SW7 20 2AY UK 21  22 2 Institute of Infection and Immunity, St. George’s University of London, London SW17 0RS3 23 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 24 7925, Cape Town, South Africa 25  26 4 MRC Centre for Medical Mycology, Aberdeen Fungal Group, University of Aberdeen, Institute of 27 Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK  28  29 5 Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, 30 55455 31  32 *Corresponding Author 33 Email: d.armstrong@imperial.ac.uk 34 Tel: +4477905003385 35  36  37 Abstract 38 Opportunistic fungal infections continue to take an unacceptably heavy toll on the most 39 disadvantaged living with HIV-AIDS, and are a major driver for HIV-related deaths. At the second 40 EMBO AIDS-Mycoses Workshop, clinicians and scientists from around the world reported current 41 progress and key priorities for improving outcomes from HIV-related mycoses.  42  43 Key words 44 HIV; AIDS; fungal infection; mortality; translational research; immunity  45  46 Global burden of HIV-related fungal disease 47 Whilst many fungi cause low grade superficial infections, these microorganisms are a major cause 48 of high-mortality invasive infections in immunocompromised individuals[1]. Advanced HIV infection 49 continues to be a major driver for invasive fungal diseases, despite the global scale-up of 50 antiretroviral therapies (ART)[1]. Defining the global burden of fungal diseases presents a major 51 challenge, as they are often insidious in nature, and there are intrinsic challenges in their 52 diagnosis, as well as a global lack of capacity for fungal diagnostics[1]. Best estimates suggest 53 there are up to a million invasive fungal infections per annum related to HIV-AIDS (primarily 54 cryptococcosis, pneumocystosis, histoplasmosis, and talaromycosis (formerly penicilliosis)), with a 55 consequent mortality of up to 500,000 per annum [2]. This places HIV-related fungal disease at 56 2  nearly the same level of mortality as other major infectious diseases such as malaria and 57 tuberculosis[3, 4]. Current case fatality rates for cryptoccocal meningitis vary between 30% and 58 70% for patients diagnosed and treated in sub-Saharan Africa[5, 6]. Recent data from the Amazon 59 region for HIV-associated histoplasmosis indicates a 50% overall mortality rate at 1 year[7]. 60 Studies in Uganda indicate on overall mortality of around 20% for HIV-related Pneumocystis 61 pneumonia[8], and a mortality rate of 28% for HIV-associated talaromycosis in Viet Nam[9]. In 62 addition, oral candidiasis is very common and associated with a high degree of morbidity if 63 untreated[1].   64  65 The Joint United Nations Programme on HIV/AIDS (UNAIDS) has established an ambitious 66 treatment target known as 90-90-90 to control the AIDS epidemic(ii). But even if these targets are 67 reached, there will still be a substantial burden of fungal disease in patients who present for care 68 late or disengage from or fail ART. Despite this, fungal disease has not had the same level of focus 69 from the global community, although as a result of recent efforts from the medical mycology 70 community, we hope this is now changing. 71  72 At the inaugural meeting of the EMBO AIDS-Mycoses Working Group in Cape Town, South Africa 73 in July 2013, 5 key goals were identified to improve outcomes from these deadly diseases: 74  75 1. Better epidemiological surveillance for HIV-related fungal diseases. 76 2. Better laboratory and point-of-care testing. 77 3. Improved access to existing drugs. 78 4. Expansion of capacity for medical mycology training. 79 5. Increased funding for development of diagnosis, treatment and implementation programmes, 80 especially in resource-poor settings.  81  82 Recent progress in the field 83 As part of ongoing efforts to stem the tide of fungal disease, over 100 researchers spearheading 84 the battle against HIV-related fungal diseases in Africa, Asia, North and South America, Europe 85 and Australasia met at the 2nd EMBO AIDS-Mycoses Workshop for three days in July 2016 in 86 Cape Town, South Africa, to discuss current progress in the field and future priorities. 87  88 The workshop was notable for the geographic breadth of participants, as well as excellent 89 coverage for all the major HIV-related fungal diseases. The major topics discussed were 90 epidemiology and public health, diagnostics, host-pathogen interactions, immunology, drug 91 resistance, treatment strategies, new antifungal drugs, and vaccines. Detailed updates were given 92 on epidemiology and public health aspects of the major AIDS-related mycoses including 93 cryptococcosis, histoplasmosis, talaromycosis and pneumocystosis. In addition, newly recognized 94 HIV-associated invasive fungal infections due to Emmonsia spp. (recently renamed Emergomyces) 95 were highlighted. These infections appear to be unique to Southern Africa, and the clinical 96 presentation mimics disseminated histoplasmosis. A notable observation was that whilst 97 antiretroviral roll out appears to have had some impact on the incidence of cryptococcal meningitis 98 in recent years, half of all cases occur after ART has been established[10]. When taken in the 99 context of the global failure to reduce new HIV infections, emerging HIV drug resistance and 100 challenges in retaining patients in ART care in resource-limited settings, it is clear that the ongoing 101 epidemic of cryptococcal meningitis will be sustained. The high rates of HIV-associated infection 102 and mortality from histoplasmosis in Latin America and talaromycosis in South and South East 103 Asia were also highlighted[9, 11]. Key highlights in fundamental research in AIDS-related mycoses 104 included genomics-based studies of cryptococcal evolution and resistance in the host, a number of 105 studies detailing aspects of metabolic adaptation of Cryptococcus neoformans and Talaromyces 106 marneffei in the host, and descriptions of the latest discoveries in understanding the innate and 107 adaptive immune responses to Pneumocystis spp.  108  109 A number of advances in the development and implementation of point-of-care-based testing 110 (POCT) strategies were highlighted during the meeting. In particular, there has been enormous 111 progress with the implementation of cryptococcal lateral flow device-based screening programmes 112 3  in sub-Saharan Africa. South Africa has recently implemented national reflex laboratory screening 113 with a projected 250 000 persons estimated to screened per annum[12]. The strategy of treating 114 antigen-positive patients reduces the likelihood of future cryptococcal meningitis[13]. Further 115 progress was also reported with the development of rapid tests for Talaromyces marneffei and 116 Histoplasma capsulatum infection.  117  118 Access to currently available antifungal medicines as well as the development of novel antifungal 119 drugs is an urgent priority, due to the limited drug classes and emerging resistance to triazoles. 120 Planned recruitment to the AMBITION study was outlined (intermittent high dose AmBisome 121 [liposomal amphotericin B] on a high dose fluconazole backbone for cryptococcal meningitis 122 induction therapy in sub-Saharan Africa), as well as current Phase 1/2 studies for VT-1129, a new 123 oral agent for cryptococcal disease, progress of the ACTA trial (oral fluconazole plus flucytosine or 124 one week amphotericin B-based therapy versus two weeks amphotericin B-based therapy) and the 125 ASTRO trial (Adjunctive Sertraline for the Treatment of HIV-associated cryptococcal meningitis). 126 There continues to be inadequate access to flucytosine, amphotericin B and itraconazole in 127 countries with major burdens of either cryptococcal meningitis or endemic mycoses. The 128 emergence of triazole resistance in both Cryptococcus neoformans and Aspergillus fumigatus was 129 also discussed[14, 15]. Notable progress has been made in understanding the genetic basis for the 130 emergence of cryptococcal heteroresistance during therapy, and combination antifungal strategies 131 to limit this. 132  133 Advocacy for fungal diseases continues to gather pace, through the Global Action Fund for Fungal 134 Infections(GAFFI) (i), the Cryptococcal Meningitis Advocacy Group(CryptoMAG) (iii), and the 135 planned establishment of new groups focused on pneumocystosis and histoplasmosis. Whilst 136 CryptoMAG successfully proposed the addition of flucytosine and amphotericin B to the essential 137 medicines list, recent attempts to include itraconazole, a crucial drug for histoplasmosis, 138 talaromycosis, and aspergillosis, on the WHO(World Health Organisation)’s essential medicines list 139 have been unsuccessful. Furthermore, none of these AIDS-related mycoses are currently 140 classified as neglected tropical diseases by the WHO.  141  142 Key priorities for the future 143 During the meeting, there was a major focus on discussing the key priorities to move the field 144 forward, and 5 priorities were identified: 145  146 1. Better collaborative working structures for basic scientists and clinical researchers to 147 accelerate translational medicine. The meeting itself acted as an environment in which basic 148 scientists and clinical researchers intensively interacted. Promoting greater interaction in the 149 future will lead to accelerated translation. The 3rd AIDS-related Mycoses Conference is planned 150 in 3 years’ time.  151  152 2. Better diagnostics and improved surveillance. It is particularly apparent that without POCTs 153 for the major AIDS-related mycoses these infections remain difficult to diagnose, and treat, and 154 their true global burden remains very difficult to ascertain.   155  156 3. Access to established medicines, as well as development of new medicines and 157 vaccines. Access in particular to flucytosine, amphotericin B, and itraconazole are particularly 158 patchy, and liposomal amphotericin B (Ambisome) remains very expensive in many countries. 159 Acceleration of vaccination programmes should be a key priority, but will be challenging due to 160 the difficulties in eliciting immune responses in immunocompromised people.  161  162 4. Consolidation and extension of consortia for the delivery of multi-centre clinical trials. 163 Whilst there are major groups working in the area of cryptococcal meningitis, better cohesion 164 and extension to other AIDS-related mycoses will enable more rapid progress in this area. 165   166 4  5. Extension of current advocacy groups and public engagement. New advocacy groups are 167 being established, based on CryptoMAG, covering histoplasmosis and pneumocystis. GAFFI is 168 currently supporting the Kenyan government in an ambitious 5-year development program(ii).  169  170 Concluding remarks 171 Invasive fungal infections continue to be a major cause of mortality in the context of advanced HIV 172 infection globally. The medical mycology community made significant recent progress in delivering 173 novel diagnostic and therapeutic strategies to limit mortality from these infections, and there are 174 some encouraging novel therapies on the horizon. However, engagement of major funding bodies 175 and governmental and non-governmental organizations is urgently needed to enable substantial 176 reductions in the unacceptably high morbidity and mortality from the AIDS-related mycoses.  177  178 Resources 179 i. http://www.unaids.org/en/resources/documents/2014/90-90-90 180 ii. http://www.gaffi.org 181 iii. http://preventcrypto.org/about-us/ 182   183 5  References 184 1. Brown, G.D. et al. (2012) Hidden killers: human fungal infections. Science translational medicine 185 4 (165), 165rv13. 186 2. Armstrong-James, D. et al. (2014) A neglected epidemic: fungal infections in HIV/AIDS. Trends 187 Microbiol 22 (3), 120-7. 188 3. Murray, C.J. et al. (2012) Global malaria mortality between 1980 and 2010: a systematic 189 analysis. Lancet 379 (9814), 413-31. 190 4. Dirlikov, E. et al. (2015) Global Tuberculosis Control: Toward the 2015 Targets and Beyond. Ann 191 Intern Med 163 (1), 52-8. 192 5. Meiring, S. et al. (2016) Prevalence and Hospital Management of Amphotericin B Deoxycholate-193 Related Toxicities during Treatment of HIV-Associated Cryptococcal Meningitis in South Africa. 194 PLoS Negl Trop Dis 10 (7), e0004865. 195 6. Park, B.J. et al. (2011) Long-term follow-up and survival of antiretroviral-naive patients with 196 cryptococcal meningitis in the pre-antiretroviral therapy era, Gauteng Province, South Africa. Int J 197 STD AIDS 22 (4), 199-203. 198 7. Nacher, M. et al. (2014) Histoplasmosis or tuberculosis in HIV-infected patients in the amazon: 199 what should be treated first? PLoS Negl Trop Dis 8 (12), e3290. 200 8. Koss, C.A. et al. (2015) A Clinical Predictor Score for 30-Day Mortality among HIV-Infected 201 Adults Hospitalized with Pneumonia in Uganda. PLoS One 10 (5), e0126591. 202 9. Le, T. et al. (2011) Epidemiology, seasonality, and predictors of outcome of AIDS-associated 203 Penicillium marneffei infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis 52 (7), 945-52. 204 10. Jarvis, J.N. and Harrison, T.S. (2016) Forgotten but not gone: HIV-associated cryptococcal 205 meningitis. Lancet Infect Dis 16 (7), 756-8. 206 11. Adenis, A. et al. (2014) HIV-associated histoplasmosis early mortality and incidence trends: 207 from neglect to priority. PLoS Negl Trop Dis 8 (8), e3100. 208 12. Larson, B.A. et al. (2016) Screening HIV-Infected Patients with Low CD4 Counts for 209 Cryptococcal Antigenemia prior to Initiation of Antiretroviral Therapy: Cost Effectiveness of 210 Alternative Screening Strategies in South Africa. PLoS One 11 (7), e0158986. 211 13. Longley, N. et al. (2016) Cryptococcal Antigen Screening in Patients Initiating ART in South 212 Africa: A Prospective Cohort Study. Clin Infect Dis 62 (5), 581-7. 213 14. Smith, K.D. et al. (2015) Increased Antifungal Drug Resistance in Clinical Isolates of 214 Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother 59 (12), 7197-204. 215 15. Abdolrasouli, A. et al. (2015) Genomic Context of Azole Resistance Mutations in Aspergillus 216 fumigatus Determined Using Whole-Genome Sequencing. MBio 6 (3), e00536. 217  218 

English

AIDS-Related Mycoses : Current Progress in the Field and Future Priorities

The Publisher's final version can be found by following the DOI link.Opportunistic fungal infections continue  to  take  an  unacceptably heavy  toll  on  the  most  disadvantaged   living   with   HIV-AIDS,   and are  a  major  driver  for  HIV-related deaths.    At    the    second    EMBO Workshop on AIDS-Related Mycoses, clinicians and scientists from around the world reported current progress   and   key   priorities   for improving   outcomes   from   HIV-related mycoses

Brown, Gordon D.

Hoving, Jennifer C.

Working group from the, EMBO Workshop on AIDS-Related Mycoses

Kamuyango, Alfred A.

De Montfort University Open Research Archive

Darius Armstrong-James

Tihana Bicanic

Gordon D. Brown

Jennifer C. Hoving

Graeme Meintjes

Kirsten Nielsen

Crossref

St George's Online Research Archive

1  AIDS-Related Mycoses: Current progress in the field and future priorities  1  2 Darius Armstrong-James1*, Tihana Bicanic2, Gordon D. Brown3,4, Jennifer C. Hoving3,  3 Graeme Meintjes3, Kirsten Nielsen5, and the Working Group from the EMBO-AIDS Related 4 Mycoses Workshop (Akilmali A, Alupo P, Andrianopoulos A, Armstrong-James D, Barr D, 5 Bauman S, Bicanic T, Botha A, Boulware D, Bradley S, Brand S, Brown G, Burgers W, Chari 6 R, Chiller T, Cohen O, Dambuza I, Day J, Denning D, Edwards J, Fisher M, Frazer J, 7 Garelnabi M, Gomez B, Govender N, Hanise P, Harrison J, Harison T, Heath CH, Hope W, 8 Hoving J, Huppler Hullseik K, Jarvis J, Jenkins M, Kamuyango A, Kannambath S, Katende 9 A, Kauffman C, Klausner J, Kolls J, Kwizera R, Lalloo DG, Le T, Lerm B, Letang E, Levitz S, 10 Limper A, Longley N, Loyse A, Madu L, Maphanga T, Marakalala M, Mashao-Mphaphuli B, 11 May R, Mbwanji G, Meintjes G, Meya D, Mhlanga M, Molloy S, Mthembu N, Mukaremera L, 12 Nacher M, Ndiitwani D, Netea M, Nielsen K, Ogundeji A, Okurut S, Oladele R, Omondi F, 13 Irchard A, Osherov N, Otieno P, Perez Casas C, Perfect J, Rhein J, Romani L, Rukasha I, 14 Samie A, Schutz C, Schwartz I, Scriven J, Sebolai O, Seleteng Kopse L, Shikwambane-15 Ntlemo G, Smulian G, Sobel J, Sriruttan C, Stone N, Trollope K, Tugeme L, Valentine M, 16 Vreulink J, Wake R, Wasserman S, Wilkinson R, Williams D, Williamson P, Wood K, 17 Youngchim S) 18  19 1 Fungal Pathogens Laboratory, National Heart and Lung Institute, Imperial College London, SW7 20 2AY UK 21  22 2 Institute of Infection and Immunity, St. George’s University of London, London SW17 0RS3 23 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 24 7925, Cape Town, South Africa 25  26 4 MRC Centre for Medical Mycology, Aberdeen Fungal Group, University of Aberdeen, Institute of 27 Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK  28  29 5 Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, 30 55455 31  32 *Corresponding Author 33 Email: d.armstrong@imperial.ac.uk 34 Tel: +4477905003385 35  36  37 Abstract 38 Opportunistic fungal infections continue to take an unacceptably heavy toll on the most 39 disadvantaged living with HIV-AIDS, and are a major driver for HIV-related deaths. At the second 40 EMBO AIDS-Mycoses Workshop, clinicians and scientists from around the world reported current 41 progress and key priorities for improving outcomes from HIV-related mycoses.  42  43 Key words 44 HIV; AIDS; fungal infection; mortality; translational research; immunity  45  46 Global burden of HIV-related fungal disease 47 Whilst many fungi cause low grade superficial infections, these microorganisms are a major cause 48 of high-mortality invasive infections in immunocompromised individuals[1]. Advanced HIV infection 49 continues to be a major driver for invasive fungal diseases, despite the global scale-up of 50 antiretroviral therapies (ART)[1]. Defining the global burden of fungal diseases presents a major 51 challenge, as they are often insidious in nature, and there are intrinsic challenges in their 52 diagnosis, as well as a global lack of capacity for fungal diagnostics[1]. Best estimates suggest 53 there are up to a million invasive fungal infections per annum related to HIV-AIDS (primarily 54 cryptococcosis, pneumocystosis, histoplasmosis, and talaromycosis (formerly penicilliosis)), with a 55 consequent mortality of up to 500,000 per annum [2]. This places HIV-related fungal disease at 56 Manuscript Click here to download Manuscript AIDS Related Mycoses V3Clean.docx2  nearly the same level of mortality as other major infectious diseases such as malaria and 57 tuberculosis[3, 4]. Current case fatality rates for cryptoccocal meningitis vary between 30% and 58 70% for patients diagnosed and treated in sub-Saharan Africa[5, 6]. Recent data from the Amazon 59 region for HIV-associated histoplasmosis indicates a 50% overall mortality rate at 1 year[7]. 60 Studies in Uganda indicate on overall mortality of around 20% for HIV-related Pneumocystis 61 pneumonia[8], and a mortality rate of 28% for HIV-associated talaromycosis in Viet Nam[9]. In 62 addition, oral candidiasis is very common and associated with a high degree of morbidity if 63 untreated[1].   64  65 The Joint United Nations Programme on HIV/AIDS (UNAIDS) has established an ambitious 66 treatment target known as 90-90-90 to control the AIDS epidemic(ii). But even if these targets are 67 reached, there will still be a substantial burden of fungal disease in patients who present for care 68 late or disengage from or fail ART. Despite this, fungal disease has not had the same level of focus 69 from the global community, although as a result of recent efforts from the medical mycology 70 community, we hope this is now changing. 71  72 At the inaugural meeting of the EMBO AIDS-Mycoses Working Group in Cape Town, South Africa 73 in July 2013, 5 key goals were identified to improve outcomes from these deadly diseases: 74  75 1. Better epidemiological surveillance for HIV-related fungal diseases. 76 2. Better laboratory and point-of-care testing. 77 3. Improved access to existing drugs. 78 4. Expansion of capacity for medical mycology training. 79 5. Increased funding for development of diagnosis, treatment and implementation programmes, 80 especially in resource-poor settings.  81  82 Recent progress in the field 83 As part of ongoing efforts to stem the tide of fungal disease, over 100 researchers spearheading 84 the battle against HIV-related fungal diseases in Africa, Asia, North and South America, Europe 85 and Australasia met at the 2nd EMBO AIDS-Mycoses Workshop for three days in July 2016 in 86 Cape Town, South Africa, to discuss current progress in the field and future priorities. 87  88 The workshop was notable for the geographic breadth of participants, as well as excellent 89 coverage for all the major HIV-related fungal diseases. The major topics discussed were 90 epidemiology and public health, diagnostics, host-pathogen interactions, immunology, drug 91 resistance, treatment strategies, new antifungal drugs, and vaccines. Detailed updates were given 92 on epidemiology and public health aspects of the major AIDS-related mycoses including 93 cryptococcosis, histoplasmosis, talaromycosis and pneumocystosis. In addition, newly recognized 94 HIV-associated invasive fungal infections due to Emmonsia spp. (recently renamed Emergomyces) 95 were highlighted. These infections appear to be unique to Southern Africa, and the clinical 96 presentation mimics disseminated histoplasmosis. A notable observation was that whilst 97 antiretroviral roll out appears to have had some impact on the incidence of cryptococcal meningitis 98 in recent years, half of all cases occur after ART has been established[10]. When taken in the 99 context of the global failure to reduce new HIV infections, emerging HIV drug resistance and 100 challenges in retaining patients in ART care in resource-limited settings, it is clear that the ongoing 101 epidemic of cryptococcal meningitis will be sustained. The high rates of HIV-associated infection 102 and mortality from histoplasmosis in Latin America and talaromycosis in South and South East 103 Asia were also highlighted[9, 11]. Key highlights in fundamental research in AIDS-related mycoses 104 included genomics-based studies of cryptococcal evolution and resistance in the host, a number of 105 studies detailing aspects of metabolic adaptation of Cryptococcus neoformans and Talaromyces 106 marneffei in the host, and descriptions of the latest discoveries in understanding the innate and 107 adaptive immune responses to Pneumocystis spp.  108  109 A number of advances in the development and implementation of point-of-care-based testing 110 (POCT) strategies were highlighted during the meeting. In particular, there has been enormous 111 progress with the implementation of cryptococcal lateral flow device-based screening programmes 112 3  in sub-Saharan Africa. South Africa has recently implemented national reflex laboratory screening 113 with a projected 250 000 persons estimated to screened per annum[12]. The strategy of treating 114 antigen-positive patients reduces the likelihood of future cryptococcal meningitis[13]. Further 115 progress was also reported with the development of rapid tests for Talaromyces marneffei and 116 Histoplasma capsulatum infection.  117  118 Access to currently available antifungal medicines as well as the development of novel antifungal 119 drugs is an urgent priority, due to the limited drug classes and emerging resistance to triazoles. 120 Planned recruitment to the AMBITION study was outlined (intermittent high dose AmBisome 121 [liposomal amphotericin B] on a high dose fluconazole backbone for cryptococcal meningitis 122 induction therapy in sub-Saharan Africa), as well as current Phase 1/2 studies for VT-1129, a new 123 oral agent for cryptococcal disease, progress of the ACTA trial (oral fluconazole plus flucytosine or 124 one week amphotericin B-based therapy versus two weeks amphotericin B-based therapy) and the 125 ASTRO trial (Adjunctive Sertraline for the Treatment of HIV-associated cryptococcal meningitis). 126 There continues to be inadequate access to flucytosine, amphotericin B and itraconazole in 127 countries with major burdens of either cryptococcal meningitis or endemic mycoses. The 128 emergence of triazole resistance in both Cryptococcus neoformans and Aspergillus fumigatus was 129 also discussed[14, 15]. Notable progress has been made in understanding the genetic basis for the 130 emergence of cryptococcal heteroresistance during therapy, and combination antifungal strategies 131 to limit this. 132  133 Advocacy for fungal diseases continues to gather pace, through the Global Action Fund for Fungal 134 Infections(GAFFI) (i), the Cryptococcal Meningitis Advocacy Group(CryptoMAG) (iii), and the 135 planned establishment of new groups focused on pneumocystosis and histoplasmosis. Whilst 136 CryptoMAG successfully proposed the addition of flucytosine and amphotericin B to the essential 137 medicines list, recent attempts to include itraconazole, a crucial drug for histoplasmosis, 138 talaromycosis, and aspergillosis, on the WHO(World Health Organisation)’s essential medicines list 139 have been unsuccessful. Furthermore, none of these AIDS-related mycoses are currently 140 classified as neglected tropical diseases by the WHO.  141  142 Key priorities for the future 143 During the meeting, there was a major focus on discussing the key priorities to move the field 144 forward, and 5 priorities were identified: 145  146 1. Better collaborative working structures for basic scientists and clinical researchers to 147 accelerate translational medicine. The meeting itself acted as an environment in which basic 148 scientists and clinical researchers intensively interacted. Promoting greater interaction in the 149 future will lead to accelerated translation. The 3rd AIDS-related Mycoses Conference is planned 150 in 3 years’ time.  151  152 2. Better diagnostics and improved surveillance. It is particularly apparent that without POCTs 153 for the major AIDS-related mycoses these infections remain difficult to diagnose, and treat, and 154 their true global burden remains very difficult to ascertain.   155  156 3. Access to established medicines, as well as development of new medicines and 157 vaccines. Access in particular to flucytosine, amphotericin B, and itraconazole are particularly 158 patchy, and liposomal amphotericin B (Ambisome) remains very expensive in many countries. 159 Acceleration of vaccination programmes should be a key priority, but will be challenging due to 160 the difficulties in eliciting immune responses in immunocompromised people.  161  162 4. Consolidation and extension of consortia for the delivery of multi-centre clinical trials. 163 Whilst there are major groups working in the area of cryptococcal meningitis, better cohesion 164 and extension to other AIDS-related mycoses will enable more rapid progress in this area. 165   166 4  5. Extension of current advocacy groups and public engagement. New advocacy groups are 167 being established, based on CryptoMAG, covering histoplasmosis and pneumocystis. GAFFI is 168 currently supporting the Kenyan government in an ambitious 5-year development program(ii).  169  170 Concluding remarks 171 Invasive fungal infections continue to be a major cause of mortality in the context of advanced HIV 172 infection globally. The medical mycology community made significant recent progress in delivering 173 novel diagnostic and therapeutic strategies to limit mortality from these infections, and there are 174 some encouraging novel therapies on the horizon. However, engagement of major funding bodies 175 and governmental and non-governmental organizations is urgently needed to enable substantial 176 reductions in the unacceptably high morbidity and mortality from the AIDS-related mycoses.  177  178 Resources 179 i. http://www.unaids.org/en/resources/documents/2014/90-90-90 180 ii. http://www.gaffi.org 181 iii. http://preventcrypto.org/about-us/ 182   183 5  References 184 1. Brown, G.D. et al. (2012) Hidden killers: human fungal infections. Science translational medicine 185 4 (165), 165rv13. 186 2. Armstrong-James, D. et al. (2014) A neglected epidemic: fungal infections in HIV/AIDS. Trends 187 Microbiol 22 (3), 120-7. 188 3. Murray, C.J. et al. (2012) Global malaria mortality between 1980 and 2010: a systematic 189 analysis. Lancet 379 (9814), 413-31. 190 4. Dirlikov, E. et al. (2015) Global Tuberculosis Control: Toward the 2015 Targets and Beyond. Ann 191 Intern Med 163 (1), 52-8. 192 5. Meiring, S. et al. (2016) Prevalence and Hospital Management of Amphotericin B Deoxycholate-193 Related Toxicities during Treatment of HIV-Associated Cryptococcal Meningitis in South Africa. 194 PLoS Negl Trop Dis 10 (7), e0004865. 195 6. Park, B.J. et al. (2011) Long-term follow-up and survival of antiretroviral-naive patients with 196 cryptococcal meningitis in the pre-antiretroviral therapy era, Gauteng Province, South Africa. Int J 197 STD AIDS 22 (4), 199-203. 198 7. Nacher, M. et al. (2014) Histoplasmosis or tuberculosis in HIV-infected patients in the amazon: 199 what should be treated first? PLoS Negl Trop Dis 8 (12), e3290. 200 8. Koss, C.A. et al. (2015) A Clinical Predictor Score for 30-Day Mortality among HIV-Infected 201 Adults Hospitalized with Pneumonia in Uganda. PLoS One 10 (5), e0126591. 202 9. Le, T. et al. (2011) Epidemiology, seasonality, and predictors of outcome of AIDS-associated 203 Penicillium marneffei infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis 52 (7), 945-52. 204 10. Jarvis, J.N. and Harrison, T.S. (2016) Forgotten but not gone: HIV-associated cryptococcal 205 meningitis. Lancet Infect Dis 16 (7), 756-8. 206 11. Adenis, A. et al. (2014) HIV-associated histoplasmosis early mortality and incidence trends: 207 from neglect to priority. PLoS Negl Trop Dis 8 (8), e3100. 208 12. Larson, B.A. et al. (2016) Screening HIV-Infected Patients with Low CD4 Counts for 209 Cryptococcal Antigenemia prior to Initiation of Antiretroviral Therapy: Cost Effectiveness of 210 Alternative Screening Strategies in South Africa. PLoS One 11 (7), e0158986. 211 13. Longley, N. et al. (2016) Cryptococcal Antigen Screening in Patients Initiating ART in South 212 Africa: A Prospective Cohort Study. Clin Infect Dis 62 (5), 581-7. 213 14. Smith, K.D. et al. (2015) Increased Antifungal Drug Resistance in Clinical Isolates of 214 Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother 59 (12), 7197-204. 215 15. Abdolrasouli, A. et al. 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AIDS-Related Mycoses: Current Progress in the Field and Future Priorities.

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AIDS-Related Mycoses: Current Progress in the Field and Future Priorities.

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