Joint Clinical Research Centre, Kampala, Uganda, 2 University Teaching Hospital, Lusaka,Zambia; 3

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1 CHAPAS 3: A randomised trial comparing stavudine vs zidovudine vs abacavir as NRTI backbone in NNRTI-based first-line ART in 478 HIV-infected children in Uganda and Zambia Victor Musiime 1, Veronica Mulenga 2, Adeodata Kekitiinwa 3, Adrian Cook 4, George Abongomera 5, Margaret J.Thomason 4, Grace Mirembe 1, Violet Korutaro 3, Chisala Chabala 2, Julia Kenny 4, Alice R. Asiimwe 3, James Abach 5, Chifumbe Chintu 2, Cissy Kityo 1, A. Sarah Walker 4, Diana M.Gibb 4, on behalf of the CHAPAS-3 trial team 1 Joint Clinical Research Centre, Kampala, Uganda, 2 University Teaching Hospital, Lusaka,Zambia; 3 Baylor-Uganda, Paediatric Infectious Diseases Clinic, Mulago Hospital, Kampala, Uganda; 4 Medical Research Council Clinical Trials Unit at UCL, London, UK; 5 Joint Clinical Research Centre, Gulu, Uganda

2 Which Nucleoside Reverse Transcriptase Inhibitor (NRTI) in dispersible Fixed Dose Combination (FDC) baby pills? Lipodystrophy is well-documented in adults & adolescents on stavudine (d4t) few data in younger children receiving lower WHOrecommended doses in FDC dispersible pills Alternative NRTIs include: Abacavir (ABC), but its efficacy has been questioned in cohort studies Zidovudine (ZDV) which may cause anaemia, particularly in malnourished children in endemic malaria areas No randomised trials comparing d4t, ZDV, ABC 44

3 FDC baby pills with NNRTI and NRTIs 44

4 44 CHAPAS 3 Trial Design POPULATION Age 1 month to 13 years Naïve no previous ART and ready to start OR Experienced - 2yrs+ d4t with VL<50 copies/ml RANDOMISED 1:1:1 d4t + 3TC/NNRTI ZDV + 3TC/NNRTI ABC + 3TC/NNRTI minimum 96 weeks follow-up PRIMARY ENDPOINT PK substudies Secondary Endpoints Clinical grade 2/3/4 adverse event OR Laboratory adverse event, confirmed grade 3 or any grade 4 Intensive PK of EFV, and of ABC, ZDV, 3TC in FDCs. Sparse sampling for population PK of all drugs Viral load, CD4, lipodystrophy (body circumference, skinfold thickness), anaemia, neutropenia, cardiovascular function, Adherence and acceptability

5 44 Enrolment, Centres & Randomisation 478 children randomised: 365 naïve; 113 experienced Centre UTH, Lusaka 141 JCRC, Kampala 141 Baylor, Kampala 141 JCRC, Gulu 55 Mumbai Randomisation d4t 156 (33%) ZDV 158 (33%) ABC 164 (34%) Cape Town

6 Baseline Characteristics Well-matched between randomised groups ART Naive Experienced* n=365 n=113 Sex, % male 51% 52% Age in years, median (IQR) < 3years, n (%) 2.6 (1.6, 4.0) 207 (57%) 6.2 (5.5, 7.2) 0 Weight-for-age Z, mean (sd) -2.1 (1.6) -1.1 (1.0) Viral load, median (IQR) >100,000c/ml, n (%) CD4%, median (IQR) CD4 count, median 53,768 (23, ,132) 120 (33%) 20 (13,25) 893 All <50c/ml 35 (30,39) 1191 WHO 3/4 pre-art, % 185 (50%) 64 (57%) *On stavudine for median 3.5 years 44

7 Baseline Characteristics Well-matched between randomised groups ART Naive Experienced* n=365 n=113 Sex, % male 51% 52% Age in years, median (IQR) < 3years, n (%) 2.6 (1.6, 4.0) 207 (57%) 6.2 (5.5, 7.2) 0 Weight-for-age Z, mean (sd) -2.1 (1.6) -1.1 (1.0) Viral load, median (IQR) >100,000c/ml, n (%) CD4%, median (IQR) CD4 count, median 53,768 (23, ,132) 120 (33%) 20 (13,25) 893 All <50c/ml 35 (30,39) 1191 WHO 3/4 pre-art, % 185 (50%) 64 (57%) *On stavudine for median 3.5 years 44

8 44 ART Received and Follow-up 353 (74%) received nevirapine, 125 (26%) efavirenz all <3 years and 57% >3 years received nevirapine within each randomised group, ~75% received nevirapine Median follow-up: 2.3 years (range ) 91% in follow-up at trial end 17 lost-to-follow-up; 8 withdrew; 19 died (all naïve, 9 within 12 weeks) similar across randomised arms 9143 follow-up visits completed (98% of scheduled) 30 (6%) substituted first line ART 8 on ZDV for haematological toxicity; 2 on d4t for lipodystrophy; zero on ABC 9 due to TB treatment 5 (1%) switched to second-line ART

9 44 Primary Endpoint Clinical Grade 2/3/4; Laboratory Grade 3/4 Adverse Events 312 children (65%) had total 917 endpoints No difference between arms, p=0.63 Proportion without endpoint Hazard ratios: ZDV v. d4t = 0.99 (0.75, 1.29) ABC v. d4t = 0.88 (0.67, 1.15) Months from randomisation 83 grade 4 EVENTS 200 grade grade 2 36 lab/clinical low haemoglobin or neutrophils 57 pneumonia, 34 malaria, 23 sepsis 40 pneumonia, 119 chest infections, 160 upper respiratory tract infections Arm = d4t Arm = ZDV Arm = ABC Difference between arms excluding grade 2 events, p=0.48

10 44 Secondary Endpoints Numbers of children d4t ZDV ABC p * ART modifying event Serious adverse event Lipodystrophy ** Anaemia (grade 3/4) Neutropenia (grade 3/4) Hypersensitivity / rash Clinical disease progression * time to event ** both cases of lipodystrophy/lipoatrophy were in experienced children (aged 6 & 8 years, on d4t for 2.5 and 5 years)

11 Lipodystrophy Change in Waist-Hip Ratios and Skinfold Thickness 44 Change in waist:hip ratio Z-score Change in sum-of-four skinfolds Z-score Mean change from randomisation (95% CI) Weeks from randomisation Mean change from randomisation (95% CI) Weeks from randomisation d4t naive zdv naive abc naive d4t exper zdv exper abc exper d4t naive zdv naive abc naive d4t exper zdv exper abc exper No difference between D4T, ZDV, ABC Randomised arms p=0.49 No difference between D4T, ZDV, ABC Randomised arms p=0.33 Z-scores from Dutch reference data in normal children

12 44 Viral Load Viral load <100 copies/ml Viral load <400 copies/ml % suppressed % suppressed Weeks from randomisation d4t naive zdv naive abc naive d4t exper zdv exper abc exper Weeks from randomisation d4t naive zdv naive abc naive d4t exper zdv exper abc exper Week 96, % suppressed <100 copies/ml d4t ZDV ABC Naïve 76% 76% 84% Experienced 97% 100% 97% Difference between arms Naïve, p=0.32 Experienced, p=0.51 Week 96, % suppressed <400 copies/ml d4t ZDV ABC Naïve 87% 77% 88% Experienced 100% 100% 97% Difference between arms Naïve, p=0.07 Experienced, p=0.59

13 44 Disease Progression and CD4% p=0.55 Time to progression Number at risk Arm = d4t Arm = ZDV Arm = ABC Weeks from randomisation Arm = d4t Arm = ZDV Arm = ABC Mean change from randomisation (95% CI) p=0.15 Mean change in CD4% Weeks from randomisation d4t naive zdv naive abc naive d4t exper zdv exper abc exper 12 New WHO stage 3 2 New WHO stage 4 19 Deaths: all naïve, 9 in 1st 12wks on ART Naïve Experienced Baseline 20% 35% Week 96 36% 37% No significant differences between randomised groups in new WHO stage 3/4 or death No significant differences between randomised groups in CD4%

14 44 Conclusions Young naïve children did very well on d4t, ZDV or ABC based triple ART given as WHO-recommended FDCs Low toxicity including anaemia, which appears mainly HIV-related Including any signs of lipodystrophy High VL suppression; including with ABC Experienced children previously on d4t did well on all arms: Lipodystrophy was rare suppressed viral load was maintained Priority should be to identify children early and start ART, whichever NRTI is available d4t could be used in younger children

15 Acknowledgements Members of the CHAPAS 3 trial team: University Teaching Hospital, Lusaka, Zambia: Veronica Mulenga, Chifumbe Chintu, Chishala Chabala, Desire Kabamba, Musaku Mwenechanya, Monica Kapasa, Carol Chijoka, Joyce Lungu, Semy Zulu, Terence Chipoya, Elias Chambela Joint Clinical research Centre, Kampala, Uganda: Cissy Kityo, Victor Musiime, Grace Mirembe, Elizabeth Kaudha, Amos Drasiku, Bernard Bainomuhwezi, Priscilla Wavamunno, Florence Odongo, Winnie Namala, Daniel Sseremba, Alison Balaba, Alice Kwaga, Joshua Kayiwa, Matthew Odera, Paul Oronon, Edith Bagurukira, Phyllis Mwesigwa, Philip Apugulu Joint Clinical Research Centre, Gulu, Uganda: George Abongomera, James Abach, Willy Odong, Beatrice Arach Baylor-Uganda, PIDC, Mulago Hospital, Uganda: Adeodata Kekitiinwa, Alice Asiimwe, Vincent Tukei, Violet Korutaro, Justine Komunyena, Carol Nansubuga, Muzamil Kisekka, Justine Mpanga Medical Research Council, Clinical Trials Unit, London, UK: Diana Gibb, Sarah Walker, Margaret Thomason, Adrian Cook, Julia Kenny, Ellen Owen-Powell, Charlotte Male, Adam Glabay Institute of Child Health, University College London, UK: Nigel Klein, Julia Kenny Radboud University, Nijmegen, Netherlands: David Burger, Quirine Fillekes University of Cape Town, Republic of South Africa: Helen McIlleron Trial Steering Committee: Elwyn Chomba, Zainab Akol, Jose Tomas Ramos, Harriet Nakimuli Kyakuha, Cissy Kityo, Adeodata Kekitiinwa, Diana Gibb, Veronica Mulenga Data Monitoring committee: Tim Peto, James Tumwine, Margaret Siwale Endpoint Review Committee: Hermione Lyall, Diana Gibb, Julia Kenny, Anna Turkova Funder: EDCTP Sponsor: Medical Research Council First-line drugs provided by: Cipla Ltd, India Special thanks to all the children and their families participating in the CHAPAS 3 trial in Zambia and Uganda

16 The CHAPAS 3 study team