1. Sarah L. Pett1, Lewis Haddow2, Ruth Nhema3, Moira Spyer1, Laura Benjamin2, Grace Najjuka4, Ibrahim Daud5, Jay Berkley6, Juliet Kitabalwa4, James Hakim3, Robert Heyderman7,8, A. Sarah Walker1, Diana M Gibb1 and the REALITY Trial Team
1MRC Clinical Trials Unit at UCL, London, UK; 2Institute for Global Health, UCL, London, UK; 3University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; 4Joint Clinical Research Centre, Kampala, Uganda; 5 Moi University School of Medicine, Eldoret, Kenya; 6KEMRI Wellcome Trust Research Programme, Kilifi, Kenya; 7Division of Infection and Immunity, UCL, London, UK; 8Department/College of Medicine and Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi;
CRAG STATUS AND EFFECT ON BENEFITS FROM ENHANCED PROPHYLAXIS IN THE REALITY TRIAL
Poster 784
Contact details
Dr Sarah L Pett MRC Clinical Trials Unit at UCL 90 High Holborn, Second floor London WC1V 6LJ
ISRCTN
ABSTRACT (updated)
RESULTS
Background: In HIV-infected adults/children with CD4<100 cells/mm3 starting ART in sub- Saharan Africa, the REALITY trial (ISRCTN ) showed that an enhanced prophylaxis (Px+) package (minimum cost $5.6) including 12 weeks’ fluconazole 100mg OD at ART initiation significantly reduced all-cause mortality, mortality from unknown causes and cryptococcus, and incidence of new cryptococcal disease vs cotrimoxazole alone (CTX). We assessed the impact of enrolment cryptococcal antigen (CRAG) status on these outcomes.
Methods: Stored enrolment plasma was tested using the IMMY CrAg lateral flow assay. Logistic regression with backwards elimination (p>0.1) identified independent predictors of baseline CRAG status, and proportional hazards models estimated the impact of Px+ vs CTX on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks by baseline CRAG.
Results: Excluding 23(1.5%) participants with active cryptococcal disease at enrolment, one with prior disease and 7 without test results, 133(7.5%) of 1774 participants were CRAG+, 69/884 (7.8%) in CTX vs 64/890 (7.2%) in Px+. Median baseline CD4 in these participants was 37 cells/ul (IQR 16-63) and VL 5.4 log10 c/ml (IQR ). CRAG+ patients had lower CD4 (OR=0.89 per 10 cells/mm3 higher (95% CI ) p=0.001) and were older (OR per 10 years older=1.18 ( p=0.06). Over 24 weeks on ART, there were 105 CTX vs 78 Px+ deaths. 7 of 9 CTX deaths and 2 of 3 Px+ deaths due to cryptococcal disease were CRAG+, whereas there was only 1 CRAG+ among 46 deaths from unknown causes in CTX vs 1 among 28 on Px+. Over 24 weeks, there were 17 CTX vs 6 Px+ new cryptococcal meningitis cases; 14 vs 5 respectively were baseline CRAG+. Px+ reduced new cryptococcal disease equally in CRAG+ (HR=0.33) and CRAG- (HR=0.36) (interaction p=0.95) (figure 2); similarly for all deaths (interaction p=0.39). Of 46 patients treated for cryptococcal disease post- enrolment, only 16 (35%) were CRAG+ at enrolment.
Conclusions: 7.5% patients without overt cryptococcal disease were CRAG+ pre-ART. CRAG+ was rare among unknown deaths suggesting these were unlikely due to cryptococcus. The relative benefits of fluconazole-containing Px+ were similar among CRAG+ and CRAG- patients. These data support the use of this affordable fluconazole-containing enhanced Px+ bundle in this severely immunocompromized group, particularly where costs of tests are similar to costs of fluconazole ($2.6) or where availability of tests is limited.
Baseline CRAG results were available for (99.6%) of the 1805 REALITY participants
10 results were from screening samples taken 4 days to 3 weeks prior to ART initiation (enrolment samples unavailable)
We excluded 23 (1.3%) participants with physician identified active cryptocococcal disease at baseline (22 CRAG+ with titres , 1 CRAG-) and one participant with previous cryptococcal disease (CRAG+ at enrolment, titre 2560, on 400mg FLU), leaving 1774 participants in analyses
133 (7.5%) participants were CRAG+
69/884 (7.8%) in CTX vs 64/890 (7.2%) in Px+
Median titre 40 (IQR )
Median CD4 30 vs 38 cells/mm3 in CRAG+ vs CRAG- (p=0.003)
Median log10 VL 5.5 vs 5.4 in CRAG+ vs CRAG- (p=0.79)
172 (9.7%) participants had received FLU in the 14 days prior to randomisation (mostly (80%) 200mg daily), but this did not affect CRAG+ rates (p=0.74)
The only independent predictors of CRAG+ vs CRAG- status were lower CD4 (OR=0.89 per 10 cells/mm3 higher (95% CI ) p=0.001) and older age (OR per 10 years older=1.18 ( ) p=0.06).
Figure 1: Incidence through week 24
Figure 2: Impact of Px+ by baseline CRAG status
46 patients without current or previous cryptococcal disease were subsequently treated for presumptive (e.g. due to severe headaches) or definitive cryptococcal disease post-enrolment: only 16 (35%) were CRAG+ at enrolment
19 were reportedly treated for cryptococcal disease: 14 (74%) were CRAG+ at enrolment
Similar percentages of those with new cryptococcal disease died in CTX (9/17,53%) and Px+ (3/6,50%), but numbers were small
All-cause mortality
Baseline CRAG -
Baseline CRAG +
Cryptococcal deaths
Deaths of unknown cause
New cryptococcal disease (fatal and non-fatal)
To 24 weeks
94/815 (11.5%)
11/69 (15.9%)
2/815 (0.2%)
7/69 (10.1%)
45/815 (5.5%)
1/69 (1.4%)
3/815 (0.4%)
14/69 (20.3%)
CTX
73/826 (8.8%)
5/64 (7.8%)
1/826 (0.1%)
2/64 (3.1%)
27/826 (3.3%)
1/64 (1.6%)
Px+
0.75 [0.56, 1.02]
0.47 [0.16, 1.34]
0.49 [0.04, 5.41]
0.29 [0.06, 1.40]
0.58 [0.36, 0.94]
1.07 [0.07, 17.47]
0.33 [0.03, 3.14]
0.36 [0.13, 0.98]
HR [95% CI]
Px+:CTX
0.39
0.73
0.67
0.95
P(het)
Px+ better
CTX better 1
.12
.25 .5 2 4 8
.05 .1 .2 .5 1 2 5 10 20 50
100
Incidence per 100PY
in first 24 weeks on ART
All-cause mortality
Cryptococcal deaths
Deaths of unknown cause
New cryptococcal disease
Std CTX: CRAG-
Std CTX: CRAG+
Px+: CRAG-
Px+: CRAG+
CONCLUSIONS
7% patients initiating ART with CD4<100 cells/mm3 were CRAG+, without overt cryptococcal disease
Most deaths with unknown cause occurred in CRAG- participants suggesting these were unlikely due to cryptococcus
This indirectly supports the efficacy of azithromycin in preventing deaths from unknown cause; since only cryptococcal and unknown deaths were reduced by Px+ (Poster XXX)
The relative clinical benefits of fluconazole- containing Px+ were similar among CRAG+ and CRAG- patients; as expected, absolute benefits were greater amongst the CRAG+ patients who were at much higher absolute risk
This could be due to imperfect test sensitivity, unmasking post ART initiation or new acquisition
Limitations include the fact that isolates were not stored so resistance cannot be assessed
These data support the use of this affordable (minimum total cost $5.6 over 12 weeks) fluconazole- containing enhanced Px+ bundle in this severely immunocompromized group, particularly where costs of tests are similar to costs of fluconazole ($2.6) or where availability of tests is limited 5 10 15 20 25
Number of participants 1 40 80
160
320
640
1280
2560
Baseline titre
Over 24 weeks on ART, there were 105 CTX vs 78 Px+ deaths
7 of 9 CTX deaths and 2 of 3 Px+ deaths due to cryptococcal disease were CRAG+ at baseline, whereas there was only 1 CRAG+ among 46 deaths from unknown causes in CTX vs 1 among 28 on Px+
Over 24 weeks on ART, there were 17 CTX vs 6 Px+ new cryptococcal meningitis cases; 14 vs 5 respectively were baseline CRAG+
Although the absolute incidence of cryptococcal deaths and disease was significantly greater in CRAG+ (p<0.001) (Figure 1), the relative benefits from Px+ did not vary by baseline CRAG status (Figure 2)
Px+ reduced new cryptococcal disease equally in CRAG+ (HR=0.33) and CRAG- (HR=0.36) (interaction p=0.95) (Figure 2)
There was also no evidence that the relative benefit from Px+ differed between CRAG+ and CRAG- for all deaths (interaction p=0.39), cryptococcal deaths (interaction p=0.73) or deaths of unknown cause (interaction p=0.67) (Figure 2)
101/884 (11.4%) CTX vs 37/890 (4.2%) were prescribed FLU at randomisation (predominantly 200mg daily for oral/oesophageal candida)
There was no evidence that the relative benefit from Px+ differed according to receipt of FLU outside the randomisation for death (interaction p=0.13), cryptococcal death (interaction p=0.44), death from unknown causes (interaction p=0.19) or new cryptococcal disease (interaction p=0.77)
BACKGROUND
In HIV-infected adults/children with CD4<100 cells/mm3 starting ART in sub-Saharan Africa, the REALITY trial showed that an enhanced prophylaxis (Px+) package (minimum cost $5.6) including 12 weeks’ fluconazole (FLU) 100mg OD at ART initiation significantly reduced all-cause mortality; mortality from unknown causes and cryptococcus; and incidence of new cryptococcal disease vs cotrimoxazole alone (CTX)
We assessed the impact of enrolment cryptococcal antigen (CRAG) status, assayed retrospectively on stored samples, on these outcomes
METHODS
REALITY (ISRCTN ) recruited 1805 HIV-infected ART-naïve adults and children ≥5 years (98% aged ≥13 years) from Zimbabwe, Uganda, Malawi and Kenya with CD4<100 cells/mm3
All patients initiated standard WHO-recommended 2NRTI+NNRTI, and were randomized to enhanced (Px+) vs standard CTX prophylaxis
Px+ comprised 12 weeks fluconazole (FLU), 12 weeks fixed-dose- combination (FDC) of co-trimoxazole/isoniazid/pyridoxine, 5 days azithromycin and single-dose albendazole
Stored enrolment plasma was tested retrospectively using the IMMY CrAg lateral flow assay
Independent predictors of baseline CRAG status were identified using logistic regression with backwards elimination (p>0.1), adjusting for centre
The impact of Px+ vs CTX on all, cryptococcal and unknown deaths; and new cryptococcal disease; through 24 weeks (when the majority of events occurred) was estimated using proportional hazards models according to baseline CRAG status.
We thank all the patients and staff from all the centres participating in the REALITY trial. Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, C Kityo, V Musiime, P Wavamunno, E Nambi, P Ocitti, M Ndigendawani; JCRC, Fort Portal, Uganda: S Kabahenda, M Kemigisa, J Acen, D Olebo, G Mpamize, A Amone, D Okweny, A Mbonye, F Nambaziira, A Rweyora, M Kangah, V Kabaswahili; JCRC. Gulu, Uganda: J Abach, G Abongomera, J Omongin, I Aciro, A Philliam, B Arach, E Ocung, G Amone, P Miles, C Adong, C Tumsuiime, P Kidega, B Otto, F Apio; JCRC. Mbale, Uganda: K Baleeta, A Mukuye, M Abwola, F Ssennono, D Baliruno, S Tuhirwe, R Namisi, F Kigongo, D Kikyonkyo, F Mushahara, D Okweny, J Tusiime, A Musiime, A Nankya, D Atwongyeire, S Sirikye, S Mula, N Noowe; JCRC. Mbarara, Uganda: A Lugemwa, M Kasozi, S Mwebe, L Atwine, T Senkindu, T Natuhurira, C Katemba, E Ninsiima, M Acaku, J Kyomuhangi, R Ankunda, D Tukwasibwe, L Ayesiga; University of Zimbabwe, Harare, Zimbabwe: J Hakim, K Nathoo, M Bwakura-Dangarembizi, A Reid, E Chidziva, T Mhute, GC Tinago, J Bhiri, S Mudzingwa, M Phiri, J Steamer, R Nhema, C Warambwa, G Musoro, S Mutsai, B Nemasango, C Moyo, S Chitongo, K Rashirai, S Vhembo, B Mlambo, S Nkomani, B Ndemera, M Willard, C Berejena, Y Musodza, P Matiza, B Mudenge, V Guti; KEMRI Wellcome Trust Research Programme, Kilifi, Kenya: A Etyang, C Agutu, J Berkley, K Maitland, P Njuguna, S Mwaringa, T Etyang, K Awuondo, S Wale, J Shangala, J Kithunga, S Mwarumba, S Said Maitha, R Mutai, M Lozi Lewa, G Mwambingu, A Mwanzu, C Kalama, H Latham, J Shikuku, A Fondo, A Njogu, C Khadenge, B Mwakisha; Moi University Clinical Research Centre, Eldoret, Kenya: A Siika, K Wools-Kaloustian, W Nyandiko, P Cheruiyot, A Sudoi, S Wachira, B Meli, M Karoney, A Nzioka, M Tanui, M Mokaya, W Ekiru, C Mboya, D Mwimali, C Mengich, J Choge, W Injera, K Njenga, S Cherutich, M Anyango Orido, G Omondi Lwande, P Rutto, A Mudogo, I Kutto, A Shali, L Jaika, H Jerotich, M Pierre; Department of Medicine and MLW Clinical Research Programme, College of Medicine, Blantyre, Malawi: J Mallewa, S Kaunda, J Van Oosterhout, B O'Hare, R Heydermann, C Gonzalez, N Dzabala, C Kelly, B Denis, G Selemani, L Nyondo Mipando, E Chirwa, P Banda, L Mvula, H Msuku, M Ziwoya, Y Manda, S Nicholas, C Masesa, T Mwalukomo, L Makhaza, I Sheha, J Bwanali, M Limbuni; MRC Clinical Trials Unit at UCL, London, UK:D Gibb, M Thomason, AS Walker, S Pett, A Szubert, A Griffiths, H Wilkes, C Rajapakse, M Spyer, A Prendergast, N Klein. Independent REALITY Trial Monitors: F Kyomuhendo, S Nakalanzi, J Peshu, S Ndaa, J Chabuka, N Mkandawire, L Matandika, C Kapuya. Trial Steering Committee:I Weller (Chair), E Malianga, C Mwansambo, F Miiro, P Elyanu, E Bukusi, E Katabira, O Mugurungi, D Gibb, J Hakim, A Etyang, P Mugyenyi, J Mallewa. Data and Safety Monitoring Committee: T Peto (Chair), P Musoke, J Matenga, S Phiri. Endpoint Review Committee: H Lyall (Co-Chair), V Johnston (Co-Chair), F Fitzgerald, F Post, F Ssali, A Prendergast, A Turkova, A Bamford, A Arenas-Pinto. Funding: REALITY was funded by the UK Department for International Development (DFID), the Wellcome Trust and the Medical Research Council (MRC). Additional funding support was provided by the PENTA foundation. Merck Sharp & Dhome, Gilead Sciences, Cipla Ltd, ViiV Healthcare/GlaxoSmithKline donated drugs for REALITY and Valid International supplied Ready-to-Use-Supplementary-Food (RUSF).