1. email: diana.gibb@ucl.ac.uk
Cissy Kityo1, A. Sarah Walker2, Immaculate Nankya1, Moira Spyer2, Eva Nabulime1, Mutsa Bwakura-Dangarembizi3, Linda Mipando4, Simon Wachira5, Anthony Etyang6,
Godfrey Musoro3, Esther Nambi1, Kusum Nathoo3, Sarah L. Pett2, Diana M Gibb2 and the REALITY Trial Team
1 Joint Clinical Research Centre, Kampala, Uganda; 2MRC Clinical Trials Unit at UCL, London, UK; 3University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; 4Department/College of Medicine and Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; 5 Moi University School of Medicine, Eldoret, Kenya; 6KEMRI Wellcome Trust Research Programme, Kilifi, Kenya;
EFFECT OF 12-WEEK RALTEGRAVIR-INTENSIFICATION OF FIRST-LINE ART ON HIV RESISTANCE
Poster 531
Contact details
Professor Diana Gibb, MRC Clinical Trials Unit at UCL 90 High Holborn, Second floor London WC1V 6LJ
ISRCTN
ABSTRACT (updated)
RESULTS
Background: The REALITY trial (ISRCTN ) showed that 12-week raltegravir (RAL)- intensified ART (Std+RAL) was well tolerated, reduced VL faster through 24 weeks, but did not affect mortality or WHO 3/4 events through 48 weeks compared to standard 2NRTI+NNRTI (Std) ART in ART-naïve HIV-infected adults/children >5y with CD4<100 cells/mm3. The impact of RAL intensification on HIV resistance in those initiating ART with low CD4 and high VL is unknown. 
Methods: Integrase (INT) was sequenced from Std+RAL samples with VL>1000 c/ml at week 12, and reverse transcriptase (RT) sequenced in samples >1000 c/ml from both groups at week 48. INT/RT resistance was predicted using Stanford. 
Results: 1550 eligible patients were from Kenya, Uganda and Zimbabwe (Malawi samples not available) and randomized to Std+RAL (n=775) vs Std (n=775). Median baseline CD4 was 36 cells/ mm3 and VL 275,700 c/ml (76%≥100,000 c/ml). At week 12, VL was <50 c/ml in in 470/667 (69%) Std+RAL vs 334/685 (49%) Std (p<0.001). 45(7%) Std+RAL had VL>1000 c/ml, of whom INT genotypes were obtained in 33(73%) (median c/ml). The primary/major accessory mutations T97A, R263K, L74M, Y143R/C or N155H were found in 7, 5, 1, 1, 1 respectively, translating into 1 with intermediate (T97A+R263K) and 2 with high-level (N155H,Y143R&C+T97A) RAL resistance (9% of sequenced at week 12; 0.6% of randomized) (week-48 VL 22976, and <50 c/ml respectively). No patient had intermediate/high-level dolutegravir resistance. At 48 weeks, VL was <50 c/ml in 527/654 (81%) Std+RAL vs 495/642 (77%) Std (p=0.12) and >1000 c/ml in 76(12%) vs 90(14%) respectively (p=0.20). RT genotypes were obtained in 75(99%) Std+RAL vs 87(97%) Std. K219E/Q (p=0.004), K101E/P (p=0.03) and P225H (p=0.007) were less common in Std+RAL. However, there was no evidence of differences between Std+RAL vs Std in intermediate/high-level resistance to 3TC (overall 73%,p=0.20), ZDV (12%,p=0.90), EFV/NVP (87%,p=0.28), or ETR (39%,p=0.18); whereas there was marginally less intermediate/high-level resistance with Std+RAL to TDF (24% vs 38% Std, p=0.06), ABC (40% vs 54%,p=0.08),  and RPV (39% vs 53%, p=0.07).
Conclusions: 12 week RAL intensification had no clinical benefit and did not substantially protect against developing clinically meaningful NRTI/NNRTI resistance. Major INT mutations potentially compromising RAL, but not dolutegravir, occurred in very small numbers of those receiving 12 week RAL; whether this was transmitted or emergent is uncertain, as baseline INT sequencing was not performed.
Figure 1: INT mutations after 12 weeks’ RAL intensification (N=33 with VL>1000 c/ml)
Figure 2: NRTI and NNRTI mutations in participants with VL >1000 copies/ml at week-48 (N=162)
Figure 3: Predicted phenotypic resistance in participants with VL >1000 c/ml at week 48 (N=162)
K103S
E138G
E138Q
Y188C
Y188H
M230 any 20 40 60 80
100
% of successful sequences
NRTI
NNRTI
NRTI/NNRTI
TAMS
TAMS1
TAMS2
M41L
K65R
D67N
K70 any
K70E
K70R
L74V
Y115F
M184 any
M184I
M184V
L210W
T215 any
T215F
T215Y
K219 any
K219E
K219Q
L100I
K101 any
K101E
K101P
K103 any
K103N
V106 any
V106A
V106M
V108I
E138 any
E138A
E138K
Y181 any
Y181C
Y188 any
Y188L
G190 any
G190A
G190S
H221Y
P225H
F227C
M230L
K219 any: p=0.004; K219E: p=0.01
Std (n=87)
Std+RAL (n=75)
K101 any: p=0.03; K101E: p=0.0509; P225H: p=0.007
All others p>0.1
P (intermediate/high vs susceptible/low/potential low level resistance) 20 40 60 80
100
Percentage
3TC
ABC
ZDV
DDI
D4T
FTC
TDF
NVP
EFV
ETR
RPV
Std
Std+RAL
Susceptible
Potential low
Low
Intermediate
High
Of 677 Std+RAL participants from Kenya, Uganda and Zimbabwe with VL assayed at w12, 45 (6.6%) were >1000 copies/ml
Integrase genotypes were obtained in 33 (73.3%) (median VL 47,724 copies/ml)
The primary/major accessory mutations T97A, R263K, L74M, Y143R/C or N155H were found in 7, 5, 1, 1 and 1 participants respectively (Figure 1)
1 participant (T97A+R263K) had predicted intermediate RAL resistance: w48 was VL 22,976 c/ml (with M184VK103N E138A M230L)
2 (N155H, Y143R&C+T97A) had predicted high-level RAL resistance: w48 was VLs 212,418 (with K65R M184V L100I Y188L G190A) and <50 c/ml respectively
Predicted intermediate/high-level RAL resistance was found in 9% of those sequenced at week 12; 0.6% of those randomized (accounting for missing genotypes using probability weights)
No patient had predicted intermediate or high-level dolutegravir resistance at week 12
Of those from Kenya, Uganda and Zimbabwe with VL assayed at w48, 76/654 (11.6%) Std+RAL vs 90/642 (14.0%) Std were >1000 copies/ml (p=0.20), similarly to the trial as a whole (p=0.73)
RT genotypes were available for 75/76 (98.7%) vs 87/90 (96.7%) respectively with median VL 89,815 copies/ml
The NRTI mutation K219E/Q (p=0.004), and the NNRTI mutations K101E/P (p=0.03) and P225H (p=0.007), were less common in the STd+RAL group (Figure 2)
There was no evidence of difference between Std+RAL vs Std for other mutations (p>0.1)
There was no evidence of differences between Std+RAL vs Std in predicted intermediate/high-level resistance to (Figure 3)
3TC (overall 72.8%, p=0.20)
ZDV (overall 12.3%, p=0.90) demonstrating that this drug should have excellent activity in second- line regimens
EFV or NVP (overall 87.0%, p=0.28)
ETR (overall 38.9%, p=0.18)
There was weak evidence of less predicted intermediate or high-level resistance in Std+RAL to
TDF: 24.0% (18/75) Std+RAL vs 37.9% (33/87) Std (p=0.06)
ABC: 40.0% (30/75) Std+RAL vs 54.0% (47/87) Std (p=0.08)
RPV: 38.7% (29/75) Std+RAL vs 52.9% (46/87) Std (p=0.07)
CONCLUSIONS
12 week RAL intensification had no clinical benefit and did not substantially protect against developing clinically meaningful NRTI/NNRTI resistance in the small number of patients with VL>1000 c/ml at 48 weeks
Specific NRTI and NNRTI mutations were significantly less common with Std+RAL than Std at week 48
These specific mutations may arise early in treatment, and, even if then suppressed, ultimately re-emerge at failure
Major INT mutations potentially compromising RAL, but not dolutegravir, occurred in very small numbers of those receiving 12 week RAL with VL>1000 c/ml at 12 weeks
Whether mutations were transmitted or emergent is uncertain, as baseline sequencing was not performed
The large numbers randomised should give balance between groups in transmitted drug resistance
BACKGROUND
12-week raltegravir (RAL)-intensified ART (Std+RAL) was well tolerated, reduced VL faster through 24 weeks, but did not affect mortality or WHO 3/4 events through 48 weeks compared to standard 2NRTI+NNRTI (Std) ART in ART-naïve HIV-infected adults/children >5 years with CD4<100 cells/mm3 initiating ART in the REALITY trial
We investigated the impact of RAL intensification on HIV genotypic resistance in those initiating ART with low CD4 and high VL, specifically integrase resistance at week 12 and reverse transcriptase at week 48
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
Patients initiated standard WHO-recommended 2NRTI+NNRTI with cotrimoxazole prophylaxis, and were randomized to 12 weeks adjunctive raltegravir or not.
VL was assayed retrospectively on stored samples. No VL results were used for patient management
Integrase (INT) was sequenced from stored Std+RAL samples with VL>1000 c/ml at week 12 , and reverse transcriptase (RT) sequenced in samples >1000 c/ml from both groups at week 48
Sequencing was centralised at the Joint Clinical Research centre, Kampala, Uganda
Ethical approval was not granted to ship samples from Malawi
INT/RT resistance was predicted using Stanford v7.0
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).