1. Diana M Gibb on behalf of the REALITY trial team
Impact of Raltegravir Intensification of first-line ART on IRIS in the REALITY trial
Diana M Gibb on behalf of the REALITY trial team

2. Background
The Reality trial, in adults/children with CD4<100 cells/µl initiating ART in sub-Saharan Africa, showed:
RAL-intensified therapy faster VL declines, but
no reduction in mortality or WHO 3/4 events1
Integrase inhibitors (INSTIs) replacing NNRTIs in 1st-line
Concern that rapid VL declines may increase rates of immune reconstitution inflammatory syndrome (IRIS) in individuals starting ART with very low CD4
Two observational studies found higher rates of IRIS in those initiating INSTI combinations2, 3
Dutertre M, et al. Initiation of Antiretroviral Therapy Containing Integrase Inhibitors Increases the Risk of IRIS Requiring Hospitalization. J Acquir Immune Defic Syndr Sep 1;76(1):e23-e26.
1) Kityo et al. IAC ) Wijting et al. CROI ) Dutertre et al. JAIDS 2017

3. Initiate ART with 2NRTI+NNRTI+12 weeks additional raltegravir
Design
1805 ART-naïve HIV-infected adults, adolescents & children
≥5 years with CD4<100 cells/µl
Follow-up to week 48
Safety bloods at screening, weeks 4 and 48; FBC & CD4 at weeks 0, 12, 24, 36, 48; Viral loads retrospectively at weeks 0, 4, 12, 24, 48
Primary endpoint: 24-week mortality
Two other factorial randomisations investigated
12 weeks enhanced prophylaxis (Hakim et al., NEJM 2017)
12 weeks supplementary food (Mallewa et al., CROI 2017)
ISRCTN
1:1 randomisation
Initiate ART with 2NRTI+NNRTI+12 weeks additional raltegravir
Initiate ART with 2NRTI+NNRTI alone (standard of care)

4. REALITY Trial Sites (ISRCTN43622374)
Uganda
Fort Portal
Gulu
Mbale
Mbarara
Kenya
Kilifi
Eldoret
Zimbabwe
Malawi
Opened sites between June 2013 and Nov 2013

5. Methods A ‘blinded’ Endpoint Review Committee (ERC) adjudicated:
Serious adverse and grade 3/4 events & WHO stage 3 & 4 events
causes of death, and compatibility with IRIS
IRIS-compatible = atypical/exaggerated presentation of opportunistic infection/tumour soon after ART initiation
VL not available in real time (retrospective, on stored plasma)
First CD4 count (and VL) at week 4
Diagnostic testing limited; so published IRIS definitions1, 2 modified
ERC relied heavily on description of clinical presentation
timing of presentation; evolution in relation to ART initiation
radiology/microbiology/histology where available
ERC also adjudicated type of IRIS (e.g. TB, cryptococcal)
Predictors of time to first fatal/non-fatal IRIS-compatible event
Used backwards elimination (exit p=0.05), treating death from other causes as a competing risk
1) French et al. AIDS ) Meintjes et al. LID 2008

6. Baseline characteristics n (%) or median (IQR) [range]
RAL-intensified (N=902)
Standard (N=903)
Male
479 (53%)
482 (53%)
Age (years)
36 (30-42) [6-72]
36 (29-42) [5-78]
5-17 years
39 (4%)
33 (4%)
WHO stage 1 or 2
419 (46%)
435 (48%)
CD4 (cells/µl)
38 (16-64)
36 (16-61)
0-24 cells/µl
321 (36%)
335 (37%)
VL (c/ml)
246,700 (N=902)
250,000 (N=902)
≥100,000 c/ml
677 (74%)
667 (74%)
EFV-based ART
803 (89%)
816 (90%)
TDF/FTC NRTI backbone
703 (78%)
719 (80%)

7. Baseline characteristics n (%) or median (IQR) [range]
RAL-intensified (N=902)
Standard (N=903)
Male
479 (53%)
482 (53%)
Age (years)
36 (30-42) [6-72]
36 (29-42) [5-78]
5-17 years
39 (4%)
33 (4%)
WHO stage 1 or 2
419 (46%)
435 (48%)
CD4 (cells/µl)
38 (16-64)
36 (16-61)
0-24 cells/µl
321 (36%)
335 (37%)
VL (c/ml)
246,700 (N=902)
250,000 (N=902)
≥100,000 c/ml
677 (74%)
667 (74%)
EFV-based ART
803 (89%)
816 (90%)
TDF/FTC NRTI backbone
703 (78%)
719 (80%)

8. Baseline characteristics n (%) or median (IQR) [range]
RAL-intensified (N=902)
Standard (N=903)
Male
479 (53%)
482 (53%)
Age (years)
36 (30-42) [6-72]
36 (29-42) [5-78]
5-17 years
39 (4%)
33 (4%)
WHO stage 1 or 2
419 (46%)
435 (48%)
CD4 (cells/µl)
38 (16-64)
36 (16-61)
0-24 cells/µl
321 (36%)
335 (37%)
VL (c/ml)
246,700 (N=902)
250,000 (N=902)
≥100,000 c/ml
677 (74%)
667 (74%)
EFV-based ART
803 (89%)
816 (90%)
TDF/FTC NRTI backbone
703 (78%)
719 (80%)

9. VL<50 copies/ml Raltegravir-intensified Standard
Overall p<0.0001
13.4%
51.7%
74.7%
79.2%
41.0%
71.9%
76.7%
80.7% 20 40 60 80
100
Percentage with VL<50 copies/ml (95% CI) 4 12 24 48
Week since randomisation (ART initiation)

10. Geometric mean VL at baseline and week 450
100
1 000
10 000
Geometric mean [95% CI] 4
Week since randomisation (ART initiation)
Standard
Raltegravir-intensified
226,430
217,710
480 80
Mean change in log10 VL at week 4 was –3.4(SE 0.03) in raltegravir-intensified vs -2.7(0.03) in standard (p<0.001)

11. All cause mortality
Mortality at 24 weeks: 10.9% RAL vs 10.2% standard-of-care
0.20
w24: HR=1.10 (95% CI ) p=0.53
w48: HR=0.98 (95% CI ) p=0.91
Additional RAL
0.15
12.4%
10.9%
Died
13.0%
0.10
10.2%
Standard-of-care
0.05
0.00 8 16 24 32 40 48
Week since randomisation (ART initiation)
Number at risk (deaths)
Standard-of-care
903
(57)
830
(23)
801
(10)
789
(7)
776
(10)
760
(8)
669
Additional RAL
902
(65)
825
(20)
801
(11)
786
(6)
775
(3)
766
(5)
657
56 (3.1%) lost to follow-up at 48 weeks
No interactions with other randomisations (p>0.7)

12. Incidence of fatal IRIS-compatible events1 2 3 4 5 D e a t h r / P Y ( z d ) 8 16 24 32 40 48
Week since randomisation (ART initiation)
Standard
Raltegravir-intensified
36 (4.0%) RAL vs 31 (3.4%) standard experienced fatal IRIS (p=0.54),
occurring a median 4.4 (IQR ) weeks after ART initiation

13. Fatal IRIS-compatible events
Additional RAL
Standard-of-care p
All
36 (4.0%)
31 (3.4%)
0.54
TB-IRIS
20 (2.2%)
21 (2.3%)
1.00
Cryptococcal-IRIS
8 (0.9%)
5 (0.6%)
0.42
Other of known aetiology
4 (0.4%)
0.75
Kaposi’s sarcoma 1 2
Viral hepatitis
CNS (unknown pathogen)
CMV
Lung (unknown pathogen)
Other
Unknown aetiology
3 (0.3%)
1 (0.1%)

14. Incidence of fatal and non-fatal IRIS-compatible events5 1 E v e n t r a / P Y ( h z d ) 8 16 24 32 40 48
Week since randomisation (ART initiation)
Standard
Raltegravir-intensified
Fatal/non-fatal IRIS-compatible events occurred in 89 (9.9%) raltegravir-intensified vs 86 (9.5%) standard (p=0.79)

15. Fatal/non-fatal IRIS-compatible events
Additional RAL
Standard-of-care p
All
89 (9.9%)
86 (9.5%)
0.79
TB-IRIS
53 (5.9%)
54 (6.0%)
1.00
Cryptococcal-IRIS
15 (1.7%)
16 (1.8%)
Other of known aetiology
17 (1.9%)
14 (1.6%)
0.59
Kaposi’s sarcoma 8 4
Viral hepatitis 1 3
CNS (unknown pathogen)
CMV 2
Toxoplasmosis
PCP
Lung (unknown pathogen)
Other
Unknown aetiology
4 (0.4%)
2 (0.2%)

16. Independent predictors of fatal/non-fatal IRIS events
Subhazard ratio (sHR) [95% CI] p
Raltegravir-intensified vs standard ART
1.08 [ ]
0.63
Enhanced-prophylaxis vs standard-prophylaxis
0.60 [ ]
0.001
CD4 count (per 10 cells/µl higher)
0.87 [ ]
<0.001
Age at last birthday (per year older)
≤29 years
≥30 years
1.07 [ ]
0.99 [ ]
0.03
0.008
0.44
Current TB disease at ART initiation
1.62 [ ]
0.01

17. Independent predictors of fatal/non-fatal IRIS events
Subhazard ratio (sHR) [95% CI] p
Raltegravir-intensified vs standard ART
1.08 [ ]
0.63
Enhanced-prophylaxis vs standard-prophylaxis
0.60 [ ]
0.001
CD4 count (per 10 cells/µl higher)
0.87 [ ]
<0.001
Age at last birthday (per year older)
≤29 years
≥30 years
1.07 [ ]
0.99 [ ]
0.03
0.008
0.44
Current TB disease at ART initiation
1.62 [ ]
0.01
No additional effect of:
log10 VL (p=0.40)
current cryptococcus at ART initiation (p=0.22),
current steroid treatment at ART initiation (p=0.41)
gender (p=0.24)

18. Incidence of fatal/non-fatal IRIS by prophylaxis randomisation
Standard-prophylaxis
Cotrimoxazole
Enhanced-prophylaxis
Cotrimoxazole +
12 weeks isoniazid/B6
12 weeks fluconazole
5 days azithromycin
single-dose albendazole
Fatal/non-fatal IRIS-compatible events occurred in 67 (7.4%) enhanced-prophylaxis vs 108 (12.0%) standard
(p=0.001)

19. Incidence of fatal/non-fatal IRIS by prophylaxis randomisation
Poster
490
Standard-prophylaxis
Cotrimoxazole
Enhanced-prophylaxis
Cotrimoxazole +
12 weeks isoniazid/B6
12 weeks fluconazole
5 days azithromycin
single-dose albendazole
*CTX/INH/B6 scored FDC
Fatal/non-fatal IRIS-compatible events occurred in 67 (7.4%) enhanced-prophylaxis vs 108 (12.0%) standard (p=0.001)

20. Conclusions
Our randomised trial, in severely immunocompromised patients, found no evidence supporting higher rates of IRIS associated with faster VL decline in ART with raltegravir
Rates of IRIS were lower than some studies1
Some IRIS potentially misclassified due to limited information and grade 1/2 events not reviewed
Likely included most clinically important events & ERC blind
Close EARLY contact with patients (even if asymptomatic), ensuring they seek urgent medical care if new symptoms
Current move to first-line integrase inhibitor (INSTI)-based ART across many lower/middle-income countries
Similar rapid VL reductions with all INSTIs2
Results can likely be extrapolated to INSTIs other than raltegravir, including dolutegravir
1) Müller et al. LID ) Raffi et al. Lancet 2013

21. Acknowledgments
We thank all the patients and staff from all the centres participating in the REALITY trial. Participating Centres: Joint Clinical Research Centre (JCRC), Kampala, Uganda (coordinating centre for 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 and 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 Clinical Research Centre, 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. Trial Coordination and Oversight: 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. Data Management Systems: M Rauchenberger, N Van Looy, E Little, K Fairbrother. 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 Monitoring Committee: T Peto (Chair), P Musoke, J Matenga, S Phiri. Endpoint Review Committee (independent members): H Lyall (Co-Chair), V Johnston (Co-Chair), F Fitzgerald, F Post, F Ssali, A Prendergast, A Turkova, A Bamford, A Arenas-Pinto. Social Science Group: F Cowan, J Seeley, S Bernays, R Kawuma, Z Mupambireyi. Independent REALITY Trial Monitors: F Kyomuhendo, S Nakalanzi, J Peshu, S Ndaa, J Chabuka, N Mkandawire, L Matandika, C Kapuya

22. Acknowledgments
We thank all the patients and staff from all the centres participating in the REALITY trial. Participating Centres: Joint Clinical Research Centre (JCRC), Kampala, Uganda (coordinating centre for 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 and 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 Clinical Research Centre, 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. Trial Coordination and Oversight: 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. Data Management Systems: M Rauchenberger, N Van Looy, E Little, K Fairbrother. 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 Monitoring Committee: T Peto (Chair), P Musoke, J Matenga, S Phiri. Endpoint Review Committee (independent members): H Lyall (Co-Chair), V Johnston (Co-Chair), F Fitzgerald, F Post, F Ssali, A Prendergast, A Turkova, A Bamford, A Arenas-Pinto. Social Science Group: F Cowan, J Seeley, S Bernays, R Kawuma, Z Mupambireyi. Independent REALITY Trial Monitors: F Kyomuhendo, S Nakalanzi, J Peshu, S Ndaa, J Chabuka, N Mkandawire, L Matandika, C Kapuya Funders: REALITY was funded by Joint Global Health Trials Scheme of the UK Department for International Development (DFID), the Wellcome Trust and Medical Research Council (MRC). Additional funding support is provided by the PENTA foundation. Merck Sharp & Dohme, Gilead Sciences, Cipla Ltd, ViiV Healthcare/GlaxoSmithKline donated drugs for REALITY and Valid International supplied Ready-to-Use-Supplementary-Food (RUSF).