What's new in the cryptococcal meningitis field in 2021? - Nelesh Govender - HIV ...
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What’s new in the
cryptococcal meningitis
field in 2021?
Nelesh Govender
@neleshg
Overview 1. Game-changing simpler, better and faster induction treatment regimens 2. Advances in cryptococcal antigen screening 3. An aspirational goal to end global cryptococcal meningitis deaths by 2030
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
ACTA trial
Molloy SF, et al. N Engl J Med 2018;378:1004-17.
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
Induction Consolidation Maintenance
•1 week: AmB + 5-FC •8 weeks: fluconazole •Minimum 12 months:
fluconazole
•2 weeks: fluconazole + 5-FC
•2 weeks: AmB + fluconazole
World Health Organization, March 2018
http://apps.who.int/
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
Induction Consolidation Maintenance
• 2 weeks: AmB + • 8 weeks: fluconazole • Minimum 12
fluconazole months:
fluconazole
Why this induction regimen in SA?
1. 5-FC not registered by South African
Health Products Regulatory Authority
2. High 5-FC costs
3. Few manufacturers of generic 5-FC
National Department of Health, 2019
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
A national 5-FC
access programme
◦ 5-FC obtained through Section 21
(Medicines Act) application for
unregistered medicines
◦ Phase 0: Set up in 2018 by MSF, SAHCS
with approval from DOH
◦ Phases 1-2: Expanded by the National
AHD Task Team in partnership with
CHAI
MSF: Médecins Sans Frontières, SAHCS: Southern African HIV Clinicians Society; DOH:
Department of Health; AHD: advanced HIV disease; CHAI: Clinton Health Access Initiative
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme Surveillance to monitor outcomes ◦ Case definition: Adults aged ≥18 years with CSF India ink+, CSF CrAg+ or culture+ from any specimen ◦ Nested within active national surveillance - 19 enhanced surveillance sites - July 2018 – March 2020 ◦ Demographic/clinical data collected by nurse surveillance officers from medical records/interviews during hospital admission
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
Laboratory-confirmed
cryptococcosis, 2018-2020 Excluded:
N=10,668 • Non-sentinel site cases, N=8192
• Sentinel sites with no 5-FC access, N=162
• HIV-seronegative, N=49
Cases from facilities with 5-FC • HIV status unknown, N=83
access • Recurrent cases, N=99
N=2,083 (20%)
Case report form (CRF) not completed, N=237
Cases with completed CRFs
N=1,776 (85%)
Patients who did not receive antifungal treatment:
• Died, N=135
• Alive but no treatment, N=83
• Unknown outcome status, N=19
Received antifungal therapy
N=1,539 (87%)
5-FC-based regimens Other regimens
N=596 (39%) N=943 (61%)
AmBd L-AmB Flucon AmBd + flucon L-AmB + flucon AmB or flucon alone
565 (95%) 26 (4%) 5 (1%) 811 (86%) 16 (2%) 116 (12)
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
No. of cases of cryptococcosis by hospital and induction regimen, N=1539
250
5-FC regimens Other regimens
200
150
100
50
0
Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
Characteristics of patients on 5-FC vs. other regimens, N=1539
Characteristics N 5FC-regimens, Other regimens, p-value
n=596* n=943*
n (%) n (%)
Median age in years (IQR) 1537 37 (32-43) 36 (31-43) 0.08a
Age category in years 1537
≥18-29 280 97 (16) 183 (19) 0.11
30-39 679 269 (45) 410 (44)
40-49 394 167 (28) 227 (24)
>49 184 63 (11) 121 (13)
Sex, male 1539 341 (57) 565 (60) 0.29
Province (sentinel site hospital) 1539
Gauteng 525 255 (43) 270 (29)Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
Treatment and outcome of patients on 5-FC versus other regimens, N=1539
Characteristics 5-FC regimens Other regimens p-value
n=596 n=943
Median length of treatment in days (IQR) 8 (7-10) 13 (6-14) 0.001a
Crude in-hospital case fatality ratio, n (%) 143 (24) 351 (37)Nelesh Govender Cryptococcal meningitis in-hospital outcomes in a South African 5-FC access programme
Effect of a 5-FC regimen vs. any other regimen on in-hospital mortality, N=1527*
Variable Alive Died Unadjusted OR for p-value Adjusted OR for mortality p-value
N=1033* N=494* mortality (95% CI) (95% CI)
n (%) n (%)
Treatment regimen
Other regimen 586 (63) 351 (37) ref
5-FC-containing regimen 447 (76) 143 (24) 0.53 (0.42-0.67) 49 103 (56) 80 (44) 1.76 (1.20-2.60) 0.004 2.01 (1.00-4.03) 0.05
Sex
Male 606 (67) 295 (33) ref
Female 427 (68) 199 (32) 0.96 (0.77-1.19) 0.7 1.26 (0.87-1.85) 0.23
CD4 count (cells/µl)The Phase 3 Ambition-cm trial
Single high-dose liposomal amphotericin based
treatment for HIV-associated cryptococcal meningitis
David Lawrence
London School of Hygiene and Tropical Medicine
Botswana Harvard AIDS Institute PartnershipBackground
◦ HIV-associated cryptococcal meningitis remains the second leading cause of
AIDS-related mortality1
◦ Conventional treatment with amphotericin B (AmB) is associated with
significant drug-related toxicities2
◦ ACTA trial demonstrated shorter, 7 day courses of AmB can be given with
flucytosine (5FC)3
◦ Liposomal amphotericin (AmBisome, LAmB) is less toxic, has a long half-life
and effectively penetrates the central nervous system4
◦ Phase 2 study demonstrated that a single, high dose of LAmB (10mg/kg) was
non-inferior to 14 daily doses (3 mg/kg) at clearing Cryptococcus from the
cerebrospinal fluid and was well tolerated5
1Rajasingham R, Lancet Infect Dis, 2017. 2Bicanic T, Antimicrob Agents Chemother, 2015. 3Molloy S, N Eng J Med, 2018.
4Groll AH, Clin Infect Dis, 2019. 5Jarvis J, Clin Infect Dis, 2018AmBisome Control
10mg/kg LAmB single dose 1mg/kg AmB for 7 days
AND AND
5FC 100mg/kg/day for 14 days 5FC 100mg/kg/day for 7 days
AND THEN
FLU 1200mg/day for 14 days FLU 1200mg/day for 7 days
Primary outcome
◦ All-cause mortality at 10 weeks (non-inferiority)
Secondary outcomes
◦ All-cause mortality at 2, 4 and 16 weeks (non-inferiority)
◦ All-cause mortality at 10 weeks (superiority)
◦ Early fungicidal activity
◦ Safety
◦ Relapse and IRIS
◦ Cost-effectiveness
◦ PK/PDInclusion criteria ◦ Aged > 18 years ◦ First episode CM (CSF India Ink or cryptococcal antigen) ◦ HIV positive Exclusion criteria ◦ Received >2 doses of AmB or treatment dose fluconazole (>800mg) ◦ Pregnancy or breastfeeding ◦ Previous serious reaction to study drug ◦ Contraindicated medication ◦ HIV negative Late Exclusion criteria ◦ Platelets
CONSORT 1193 assessed for eligibility
349 excluded
844 randomised
421 AmBisome 423 Control
14 excluded:
15 excluded:
• 12 met late exclusion
• 12 met late exclusion
• 1 did not have CM
• 4 did not have CM
• 1 HIV negative
407 in intention-to- 407 in intention-to-
treat treat
19 excluded 11 excluded
388 in per protocol 396 in per protocolBaseline characteristics
AmBisome Control
Characteristic
(N=407) (N=407)
Sex – % male 60% 60%
Median age – years 37 37
(IQR) (32-44) (32-43)
Prior ART use 63% 65%
Median weight – kg 53 53
(IQR) (47-60) (48-60)
Glasgow Coma Scale score 25cm 41% 40%
Median CSF white-cell count – cells/mm3 6 5
(IQR) (4-75) (3-52)
Median CD4+ count – cells/mm3 26 28
(IQR) (9-56) (11-59)Baseline characteristics
AmBisome Control
Characteristic
(N=407) (N=407)
Sex – % male 60% 60%
Median age – years 37 37
(IQR) (32-44) (32-43)
Prior ART use 63% 65%
Median weight – kg 53 53
(IQR) (47-60) (48-60)
Glasgow Coma Scale score 25cm 41% 40%
Median CSF white-cell count – cells/mm3 6 5
(IQR) (4-75) (3-52)
Median CD4+ count – cells/mm3 26 28
(IQR) (9-56) (11-59)Prespecified Non-inferiority Margin
IT T population
Unadjusted
Adjusted
PP population
Unadjusted
Adjusted
-15 -10 -5 0 5 10 15
Better than control Worse than controlConclusions from Ambition-CM trial ◦ Single, high-dose AmBisome given with flucytosine and fluconazole was non- inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis. ◦ The AmBisome regimen was associated with a significant reduction in adverse events including significantly lower rates of anaemia, a reduced need for blood transfusions and a significantly smaller increase in creatinine. ◦ This regimen offers a practical, easier-to-administer and better tolerated treatment for HIV-associated cryptococcal meningitis in Africa. ◦ There is an urgent need to broaden access to AmBisome and flucytosine.
Overview 1. Game-changing simpler, better and faster induction treatment regimens 2. Advances in cryptococcal antigen screening 3. An aspirational goal to end global cryptococcal meningitis deaths by 2030
SQ assays not quite ready for prime time
Control line should always be present
T2 line disappears with a “stronger” reaction
T1 line appears with a “stronger” reaction, then disappears at 5+
C T1 T2
Negative + - +
1+ + +/- +
2+ + + +
3+ + + +/-
4+ + + -
5+ + - -Effect trial
Efficacy of Flucytosine and Fluconazole as Early Cryptococcosis
Treatment
• South Africa and Tanzania, pragmatic open-label trial, within routine
CrAg screening programmes
• 600 asymptomatic CrAg-positive participants randomised to either
fluconazole alone versus fluconazole plus flucytosine (first 2
weeks)
• In analysis, explore cut-off titre (if any) at which combination is
needed. This cut off could then be targeted by semi-quantitative
lateral flow assaysSingle dose liposomal amphotericin for
asymptomatic cryptococcal antigenaemia (ACACIA)
Uganda, enrolling 2019 - 2023
Asymptomatic
CrAg+
Single dose 10 vs Standard of care
mg/kg L-AmB +
fluconazole 800
fluconazole 800
mg
mg
Jarvis et al. Short-course high dose L-AmB for HIV-associated CM: A phase II randomised- Primary: 24 week CM-free survival
controlled trial. CID 2019; 68(3): 398
Secondary: Tolerability/ safety
24-week survival
Cost-effectiveness
Subgroup analysis: blood CrAg titer =160; ART vs
David Meya and naïve; rifampin; symptomatic CrAgaemia
Radha RajasinghamOverview 1. Game-changing simpler, better and faster induction treatment regimens 2. Advances in cryptococcal antigen screening 3. An aspirational goal to end global cryptococcal meningitis deaths by 2030
Thank you to all participating patients &
laboratory, clinical and administrative staff for
submitting case reports and isolates
NICD Centre staff:
CED: Bolele Disenyeng, Dimakatso Dzingayi,
Emily Dloboyi, Elias Khomane, Jack Kekana,
Jaime McDonald, Masindi Ramudzulu, Mzikazi
Dickmolo, Nomsa Tau, Phuti Sekwadi, Portia
Mogale, Rembulwani Netshikweta, Shannon
Smouse, Sandrama Nadan, Tersia Kruger
CHARM: Agnes Sesoko, Amanda Shilubane,
Boitumelo Kgoale, Boniwe Makwakwa, Daniel
Desanto, Denver Jainarain, Ernest Tsotetsi,
Gloria Molaba, Greg Greene, Ivy Rukasha,
Juliet Paxton, Leandi Steynfaardt, Lerato
Qoza, Mabatho Mhlanga, Manqoba Rodney
Shandu, Mbali Dube, Michelle Lowe, Mpho
Thanjekwayo, Naseema Bulbulia, Nikiwe
Valashiya, Nozuko Blasich, Ntombi Dube,
Patrick Pitjeng, Phelly Matlapeng, Rosah
Mabokachaba, Rotondwa Mudau, Rubeina
Badat, Ruth Mogokotleng, Sabelle Jallow,
Serisha Naicker, Siphiwe Kutta, Sydney
Mogokotleng, Tsidiso Maphanga, Wilhelmina
Strasheim
CRDM: Betty Tsosane, Dineo Mogale, Fahima
Moosa, Happy Skosana, Judith Tshabalala, NICD GERMS-SA Meeting, 16-17 July 2019
Kedibone Ndlangisa, Maimuna Carrim, Malefu
Moleleki, Nicole Wolter, Noluthando Duma,
Rivionia Nero, Sibusisiwe Zulu, Thabo Mohale,
Thembi Mthembu GERMS-SA: John Black, Vanessa Pearce (EC); Masego Moncho, Motlatji Maloba (FS); Anwar Hoosen, Charl Verwey, Charles,
CTB: Ali Sicwetsha, Cecilia de Abreu, Danny
Feldman, Colin Menezes, David Moore, Dina Pombo, Gary Reubenson, Grace Ntlemo, Jeannette Wadula, Jeremy Nel,
Lathane, Dumisani Ngcamu, Elizabeth
Kachingwe, George Ngconjana, Halima Said, Maphoshane Nchabeleng, Merika Tsitsi, Moamokgethi Moshe, Mohammed Said, Nicolette du Plessis, Rispah Chomba, Sarah
Lavania Joseph, Lwazi Danisa, Minty van der Stacey, Theunis Avenant, Trusha Nana, Vindana Chibabhai (GA); Adhil Maharj, Douglas Wilson, Fathima Naby, Halima Dawood,
Meulen, Nana Okozi, Ria de Villiers, Shaheed Khine Swe Swe Han, Lisha Sookan, Nomonde Dlamini, Praksha Ramjathan, Prasha Mahabeer, Prathna Bhola, Romola Naidoo,
Vally Omar, Sikelela Nkosi, Thabisile Gwala, Sumayya Haffejee, Surendra Sirkar, Yeishna Ramkillawan (KZN); Ken Hamese, Ngoaka Sibiya, Phetho Mangena, Ruth Lekalakala
Vancy Letsoalo, Yasmin Gardee, Zaheda Bhyat (LP); Greta Hoyland, Sindi Ntuli (MP); Pieter Jooste (NC); Ebrahim Variava, Ignatius Khantsi, Omphile Mekgoe (NW); Adrian
CEZPD: Chantel le Roux, Herman Geyer, Brink, Elizabeth Prentice, Kessendri Reddy, Andrew Whitelaw (WC); Ebrahim Hoosien, Inge Zietsman, Terry Marshall, Xoliswa
Janusz Paweska, Kovashnee Naidoo, Malodi
Poswa (AMPATH); Chetna Govind, Juanita Smit, Keshree Pillay, Sharona Seetharam, Victoria Howell (LANCET); Catherine
Sethedi, Naazneen Moolla, Petrus Jansen van
Vuuren, Sindy Virasamy Samuel, Marthinus Senekal (PathCare); Andries Dreyer, Louis Marcus, Warren Lowman (Vermaak and Vennote); Anne von
DPHSR: Emily Sikanyika, Irma Latsky, Gottberg, Anthony Smith, Azwifarwi Mathunjwa, Cecilia d’Abreu, Cecilia Miller, Cheryl Cohen, Farzana Ismail, Harry Moultrie,
Tsakane Nkuna, Yoliswa Qulu Husna Ismail, Jacqueline Weyer, Jackie Kleynhans, Jenny Rossouw, John Frean, Joy Ebonwu, Judith Mwansa-Kambafwile, Juno
Thomas, Kate Bishop, Kerrigan McCarthy, Liliwe Shuping, Linda de Gouveia, Linda Erasmus, Lynn Morris, Lucille Blumberg,
Marshagne Smith, Martha Makgoba, Michelle Groome, Mignon du Plessis, Mimmy Ngomane, Mokupi Manaka, Myra Moremi, Nazir
Ismail, Nelesh Govender, Neo Legare, Nicola Page, Nombulelo Hoho, Olga Perovic, Phuti Sekwadi, Rindidzani Magobo, Rudzani
Mashau, Ruth Mpembe, Sibongile Walaza, Siyanda Dlamini, Sunnieboy Njikho, Susan Meiring, Tiisetso Lebaka, Vanessa Quan,
Wendy Ngubane (NICD).
Provincial surveillance teams: Badikazi Matiwana, Sandisiwe Joyi (EC); Khasiane Mawasha, Thandeka Kosana (FS); Akhona Mzoneli,
Chulumanco Nkosi, Dikeledi Leshaba, Fiona Timber, Hazel Mzolo, John Mothlasi, Molly Morapeli, Nthabiseng Motati, Ophtia Kaoho, Patience Ngube,
Phindile Ngema, Phumelelo Mthimude, Rachel Nare, Venesa Kok, Vusi Ndlovu, Zodwa Kgaphola (GA); Indran Naidoo, Michelle Tanya Moodley,
Nelisiwe Buthelezi, Nhlakanipho Malinga, Nkoshinathi Mbhele, , Nokuthula Mkhize, Nondumiso Amahle Khoza, Nothando Mthembu, Thobeka
Simelane Shandu (KZN); Tebogo Modiba (LP); Leomile Elizabeth Motaung, Lesley Ingle, Ndugiselo Muravha, Thandeka Ndlovu, Tumelo Leomile
Elizabeth Motaung, Ndugiselo Muravha, Thandeka Ndlovu, Tumelo Thlomelang, Zanele Siwele Gift Mnisi, Jacob Mabunda and Milliah Hlathi are HST
staff (MP); Bernard Motsestse, Busisiwe Zungu, Kholiwe Mgidlana, Koketso Manaka, Paelsa Seutloali, Seiphati Matshogo, Tuelo Matotong,
Tshwanelo Mahloko (NW); Charlene Isaacs, Cheryl Mentor, Lerato Qoza, Lucia Madolo, Nazila Shalabi, Nomvuyiso Yako, Nosisa Simanga, Phathiswa
Rangyana, Priscilla Mouton, Yonela Zokufa, Zama Mfundisi, Zukiswa Kibi (WC).ACKNOWLEDGEMENTS Botswana Harvard AIDS UNC Project Lilongwe University of Cape Town IDI Kampala
Institute Partnership Mina Hosseinipour Graeme Meinjtes David Meya
ALL PARTICIPANTS AND Mosepele Mosepele Cecilia Kanyama Charlotte Schutz David Boulware
CAREGIVERS Tshepo Leeme Chimwemwe Chawinga Kyla Comins Darlisha Williams
Keatlaretse Siamisang Timothy Kachitosi Achita Singh Joshua Rhein
ALL ROUTINE CARE STAFF Nametso Tlhako Emily Kumwenda Lee-Ann Davids Edward Mpoza
Katlego Tsholo Laureen Kafantenganji Siphokazi Hlungulu Lillian Tugume
LSHTM Kwana Lechiile Chimwemwe Maya Mkhanyiseli Mpalali Enock Kagimu
Joe Jarvis Charles Muthoga Janet Zambezi Ida Oliphant Morris Rutakingirwa
Nabila Youssouf Tawe Leabaneng Wilberforce Mhango Tania Morar John Kasibante
Philippa Griffin Norah Mawoko Abineli Mbewe Masina Nomawethu Kenneth Ssebambulidde
Sophia Hafeez Tshepiso Mbangiwa Tapiwa Munthali Rene Goliath Laura Nsangi
Ponego Ponatshego Lusungu Msumba Tom Crede Jane Ndyetukira
SGUL Ikanyeng Rulaganyang Mussah Kazembe Jonathon Naude Abdu Musubire
Tom Harrison Kaelo Seatla Towera Banda Deborah Maughan Jane Gakuru
Angela Loyse Jack Goodall Simon Nicholas Trevor Mnguni Alisat Sadiq
Sile Molloy James Milburn Tarsizio Chikaonda Linda Boloko Cynthia Ahimbisibwe
Refilwe Mmipi Gladys Chitulo Hloni Bookholane Carol Olivie Namuju
LSTM Nelecy Chome Loraine Swanepoel Jane Francis Ndyetukira
Shabbar Jaffar MLW Blantyre Anthomy Stambuli Sonya Koekemoer Florence Kugonza
David Lalloo Henry Mwandumba Beauty Kamanga Regina Hoffmann Eva Laker
Duolao Wang Melanie Alufandika-Moyo Chimwemwe Mphande Samantha April Rhona Muyise
Tao Chen Henry Mzinganjira Lusayo Simwinga Henriette Kyepa Andrew Luswata Lule
Louis Niessen Eltas Dziwani Mary Gwin Sumaiyya Moosa John Kisembo
Tinevimbo Shiri Ebbie Gondwe Masia Ian Kumwenda Sumaya Sayed Daniel Kiiza
Erik van Widenfelt Wezzie Chimang’anga Doris Ngoma Muki Shey Richard Kwizera
Christopher Kukacha Gerald Tegha Abulele Bekiswa Andrew Akampurira
University of Liverpool Ajisa Ahmadu Tonny Luggya
William Hope Steve Kateta IDI Mbarara University of Zimbabwe Tadeo Kiiza
Kat Stott Reya Shah Conrad Muzoora Chiratidzo Ndhlovu Asmus Tukundane
Madalitso Chasweka Edwin Nuwagira Admire Hlupeni Michael Okirwoth
Institut Pasteur Evelyn Kossam Samuel Jjunu Constantin Mutata Fiona Cresswell
Olivier Lortholary Auvrey Kadzilimbile Michael Ssemusu Prosper Kufa
Francoise Dromer John Ndaferankhande Joan Rukundo Tawanda Zinyandu DSMB
Timothee Boyer-Chammard Bright Lipenga Irene Rwomushana Taddy Mwarumba Andrew Nunn
Alexandre Alanio Agnes Zambasa Leo Atwine Edward Mahaka Sayoki Mfinanga
Aude Sturny-Leclere Maureen Ndalama Davis Muganzi Shepherd Mudzingwa Rob Peck
Andrea Singini Peter Buzaare Kathryn Boyd Bill Powderly
James Mwesigye Takudzwa Mtisi
Ninsiima Emily Columbus Moyo Trial Steering Committee
Ankunda Rodgers Secrecy Gondo John Perfect
Samson Kariisa Andrew Kambugu
Christine Inyakuwa Saidi Kapigi
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