1. Abraham Siika1, Leanne McCabe2, Mutsa Bwakura-Dangarembizi3, Cissy Kityo4, Jane Mallewa5, Kath Maitland6, Anna Griffiths2, Keith Baleeta7,
Shepherd Mudzingwa3, James Abach8, Kusum Nathoo3, Andrew J. Prendergast9, A Sarah Walker2, Diana M Gibb2 and the REALITY Trial Team
1Moi University School of Medicine, Eldoret, Kenya; 2MRC Clinical Trials Unit at UCL, London, UK; 3University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; 4Joint Clinical Research Centre, Kampala, Uganda; 5Department/College of Medicine and Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; 6KEMRI Wellcome Trust Research Programme, Kilifi, Kenya; 7Joint Clinical Research Centre, Mbale, Uganda; 8Joint Clinical Research Centre, Gulu, Uganda; 9Queen Mary University of London, London, UK
LATE PRESENTATION WITH HIV IN AFRICA: PHENOTYPES, RISK AND RISK STRATIFICATION
Poster XXX
Contact details
Professor Diana Gibb, MRC Clinical Trials Unit at UCL 90 High Holborn, Second floor London WC1V 6LJ
ISRCTN
ABSTRACT (updated)
RESULTS
Background: In sub-Saharan Africa, severely immunocompromized individuals are at high risk of mortality during the first few months after starting ART. We aimed to determine predictors of this early mortality and whether such “late presenters” could be grouped into phenotypes with different mortality risks.
Methods: ART-naïve adults/children ≥5y with CD4<100 cells/ul initiating ART in Uganda, Zimbabwe, Malawi and Kenya were included in the REALITY trial (ISRCTN ). Baseline predictors of mortality through 48 weeks on ART were identified using Cox regression with backwards elimination (exit p>0.1). Late presenter phenotypes were identified using hierarchical clustering.
Results: Final multivariable models included 1711 participants (26<13y) of whom 203(12%) died. Mortality was independently higher in those who were older (p=0.002), with lower CD4s (p<0.001), lower albumin (p=0.001), lower haemoglobin (p=0.01) and weaker grip strength (p=0.03); those in whom physicians reported WHO stage 3/4 weight loss (p=0.04); and in those patients reporting fever (p=0.001), vomiting (p=0.02), some problems with mobility (p=0.005) and inability to wash or dress themselves (p=0.003) at baseline. Five “late presenter” groups were identified (figure), with mortality ranging from 4-25%. Group-1 had the highest mortality (25%) and median CD4 28 cells/ul; they had a high burden of symptoms/signs other than rash, weight loss, and problems with mobility and self-care; they also had lower albumin and haemoglobin. Group-2 (11% mortality; median CD4 43 cells/ul) had higher white blood cells, platelets and neutrophils, despite only 31% reporting infections at baseline. Group-3 (10% mortality) were mainly younger women; they had similarly low CD4s (median 27 cells/ul), haemoglobin and BMI to Group-1, but low symptom burden and maintained fat mass. The remaining two groups had lower (4-6%) mortality, higher CD4 (median 42 and 48 cells/ul) and had predominantly maintained their weight within normal ranges. Of note, the effect of the randomized enhanced prophylaxis bundle on mortality was similar across all groups (interaction p=0.32).
Conclusions: Clinical and laboratory characteristics identified groups at highest risk of mortality following ART initiation. A screening tool appropriate to the level of facility could therefore help identify which patients with low CD4 counts should be prioritized, e.g. for same-day ART initiation, more intensive follow-up, and enhanced prophylaxis.
Table 1: Independent predictors of mortality in the first 48 weeks on ART initiated with CD4 <100 cells/mm3
225 (12%) of 1805 participants starting ART with CD4<100 cells/mm3 died before 48w
median 8 weeks (IQR 3-18) on ART
Mortality was independently higher in those who were older, with lower CD4s, lower albumin, lower haemoglobin and weaker grip strength; those in whom physicians reported WHO stage 3/4 weight loss; and in those patients reporting fever, vomiting, some problems with mobility and inability to wash or dress themselves at baseline (Table 1)
Receiving enhanced-prophylaxis independently reduced mortality (p=0.02) as in the trial overall (Hakim et al NEJM PMID ), but receiving raltegravir (p=0.60) and receiving ready-to-use-supplementary food (p=0.37) did not
The area under the receiver operating curve was 80% (95% CI 76-83%) supporting good model discrimination
VL was not an independent predictor once problems with mobility were included as a prognostic factor, suggesting mobility may be a broad physical marker for the detrimental impact of ongoing viral replication
There was a marginal association between WBC and mortality in our final model, supporting infection and/or inflammation playing a role in early increased mortality risk
We were able to identify a more detailed and slightly different set of clinical predictors to a recent analysis of a smaller trial with lower mortality (7%) (Bisson et al, AIDS 2017, PMID )
High HIV VL and WBC, but not neutrophil percent, were independent predictors of mortality in REALITY participants when fitting the prognostic model from this previous study (Table 1)
However, other clinical factors were more predictive than these laboratory parameters in REALITY participants
We then considered whether risk factors clustered in specific groups of patients, that is, whether late presenters could be phenotyped
We identified 5 groups of patients (all with CD4<100 cells/mm3) whose mortality ranged from 25% (Group-1) to 4% (Group-5) (Figure 1)
Group-1 (25% mortality; median CD4 28 cells/mm3) had high burden of problems reported on the EQ-5D, particularly for mobility, self-care and usual activities (Figure 2). Excluding rash, they also had the highest burden of symptoms and illness, especially weight loss, difficulty walking and poor appetite
Group-2 (11% mortality; median CD4 43 cells/mm3) had high levels of WBC, platelets and neutrophils, despite lower levels of reported fever (12%) than Group-1 (28%).
Only 122 (31%) had an infection reported at enrolment, suggesting they may have had underlying infections/inflammation
This group also had substantial weight loss and low fat mass, and low BMI, albumin and haemoglobin, similar to Group-1. However, median CD4 was higher in Group-2 vs Group-1 as was grip strength (median 24.5 vs 20.0kg)
Group-3 (10% mortality; median CD4 27 cells/mm3) were mainly (non-pregnant non-breastfeeding) females (76%) and younger (median 30 vs 36 years overall). They had low CD4 counts, WBC, neutrophils, haemoglobin, BMI, MUAC and grip strength, but despite this had low burden of symptoms/ illnesses and maintained a reasonable fat mass and higher albumin.
Group-4 (6% mortality; median CD4 48 cells/mm3) was also mostly female (97%), but older than Group-3 and much higher fat mass BMI and MUAC
Group-5 (4% mortality; median CD4 42 cells/mm3) was predominately male (86%) and older (median 39 years) with higher fat mass, fat free mass and grip strength
Figure 1: Mortality by late presenter “phenotype”
Mortality
25% 11% 10% 6% 4%
Factor (effect in Cox models)
Median (IQR) or n (%)
Univariable effects of factors selected for multivariable model
Final multivariable model in REALITY trial participants (n=1711)
Multivariable model from Bisson et al fitted to REALITY trial participants HR
95% CI P
(95% CI
Age (per 5 years older)
36 (29,42)
1.09
(1.03, 1.16)
0.005
1.12
(1.04, 1.20)
0.002
1.13
(1.06, 1.21)
<0.001
CD4 (per 10 cells/mm3 higher)
37 (16,63)
0.89
(0.85, 0.94)
0.90
(0.85, 0.95)
0.87
(0.82, 0.92)
Haemoglobin (per g/dl higher)
11.2 (9.6,12.7)
0.77
(0.72, 0.82)
(0.83, 0.99)
0.01
(0.80, 0.94)
Albumin (per g/l higher)
35 (30,40)
0.92
(0.90, 0.93)
0.96
(0.94, 0.98)
0.001
0.94
(0.92, 0.97)
White blood cells (per 109/L higher)
3.5 (2.7,4.7)
1.17
(1.08, 1.26)
1.08
(1.00, 1.17)
0.054
1.16
(1.06, 1.25)
Grip strength (per kg higher)
24.5 (19.3,31.0)
0.93
(0.91, 0.95)
0.98
(0.96,1.00)
0.03 -
Previous healthcare contact †
163 (9%)
(0.75, 1.79)
0.50
0.63
(0.39, 1.03)
0.067
WHO 3/4 weight loss
327 (18%)
1.90
(1.42, 2.53)
1.43
(1.01, 2.03)
0.04
Patient-reported fever
240 (13%)
3.37
(2.54, 4.47)
1.67
(1.19,2.35)
0.003
Patient-reported vomiting
114 (6%)
3.72
(2.64, 5.26)
1.55
(1.00, 2.39)
0.048
EQ5D Mobility:
Some problems (vs none)
364 (20%)
4.42
(3.36, 5.81)
1.88
(1.21, 2.93)
Confined to bed (vs none)
28 (2%)
11.87
(7.00, 20.1)
2.47
(1.00, 6.08)
0.050
EQ5D Self-care: Some problems (vs none)
286 (16%)
3.73
(2.78, 5.02)
1.32
(0.82, 2.13)
0.26
Unable to wash/dress (vs none)
77 (4%)
8.59
(5.91, 12.5)
2.78
(1.42, 5.43)
Enhanced prophylaxis
906 (50%)
0.75
(0.57, 0.97)
0.72
(0.54, 0.96)
0.02
Sex (female vs male)
961 (53%)
1.23
(0.95, 1.60)
0.12
1.19
(0.89, 1.60)
0.23
BMI: <18.5 (vs >25)
731 (41%)
2.41
(1.30, 4.48)
(0.52, 1.55)
0.70
(vs >25)
909 (51%)
1.38
(0.74, 2.58)
0.32
(0.41, 1.19)
0.19
HIV VL (per log10 higher)
5.4 (5.0,5.8)
1.52
(1.22, 1.89)
1.37
(1.09, 1.74)
0.008
Neutrophil % (per 5% higher)
50% (40,62)
1.07
(1.02, 1.12)
0.99
(0.95, 1.04)
0.64
Figure 2: Characterisation of late presenter “phenotypes” by baseline factors
† chronic health conditions or prescribed medications more than 14 days prior to screening visit. Note: final multivariable model in REALITY participants also adjusted for centre.
BACKGROUND
METHODS
CONCLUSIONS
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/µL
Patients initiated standard WHO-recommended 2NRTI+NNRTI with cotrimoxazole prophylaxis, and were randomized using a factorial design to three different additional 12 week interventions that might reduce early mortality (enhanced antimicrobial prophylaxis, raltegravir, ready-to-use supplementary food)
Baseline demographics, laboratory results (including VL assayed retrospectively on stored samples), physical
measurements (including height, weight, MUAC, body composition, blood pressure), physician reported diagnoses (WHO stage 3/4 events), participant-reported symptoms, EQ-5D scores and randomized groups were all considered as predictors of mortality during the first 48 weeks on ART (using Cox models), after which participants exited the trial.
Factors were selected using backwards elimination (exit p>0.1 for an explanatory model). Clinical centre (reflecting management and access to diagnostic facilities) was included in all models which were restricted to complete cases.
Different patterns of “late presenters” were identified using hierarchical cluster analysis.
Clinical and laboratory characteristics identified groups of patients (all with CD4<100 cells/mm3) at highest risk of mortality following ART initiation
A screening tool appropriate to the level of facility could therefore help identify which patients with low CD4 counts should be prioritized, e.g. for same-day ART initiation, more intensive follow-up, and enhanced prophylaxis
~20-25% of people starting ART in Africa have CD4 <100 cells/µL
~10% die within three months of starting treatment
Studies in “late presenters” are important to identify their key characteristics, particularly if baseline CD4 count testing is not always available, in order to identify them earlier at healthcare facilities and prioritize them for additional interventions
In adults and older children enrolled in the REALITY trial, we investigate in detail:
Predictors of mortality in the first 48 weeks on ART
Different patterns of “late presentation”
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).