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 Musiime1, Veronica Mulenga2, Adeodata Kekitiinwa3, Adrian Cook4, George Abongomera5, Margaret J.Thomason4, Grace Mirembe1, Violet Korutaro3, Chisala

Chabala2, Julia Kenny4, Alice R. Asiimwe3, James Abach5, Chifumbe Chintu2, Cissy Kityo1, A. Sarah Walker4, Diana M.Gibb4, on behalf of the CHAPAS-3 trial team

1Joint Clinical Research Centre, Kampala, Uganda, 2University Teaching Hospital, Lusaka,Zambia; 3Baylor-Uganda, Paediatric Infectious Diseases Clinic, Mulago Hospital, Kampala, Uganda;

4Medical Research Council Clinical Trials Unit at UCL, London, UK; 5Joint Clinical Research Centre, Gulu, Uganda

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 WHO-

recommended 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

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FDC baby pills with NNRTI and NRTIs

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CHAPAS 3 Trial Design 44

Age 1 month to 13 years Naïve – no previous ART and ready to start OR Experienced - 2yrs+ d4T with VL<50 copies/ml

d4T + 3TC/NNRTI ZDV + 3TC/NNRTI ABC + 3TC/NNRTI

minimum 96 weeks follow-up

Clinical grade 2/3/4 adverse event OR Laboratory adverse event, confirmed grade 3 or any grade 4

POPULATION

RANDOMISED 1:1:1

PRIMARY ENDPOINT

Viral load, CD4, lipodystrophy (body circumference, skinfold thickness), anaemia, neutropenia, cardiovascular function, Adherence and acceptability

PK substudies Intensive PK of EFV, and of ABC, ZDV, 3TC in FDCs. Sparse sampling for population PK of all drugs

Secondary Endpoints

478 children randomised: 365 naïve; 113 experienced

Enrolment, Centres & Randomisation

44

Mumbai

Cape Town

UTH, Lusaka 141 JCRC, Kampala 141 Baylor, Kampala 141 JCRC, Gulu 55

Centre

d4T 156 (33%) ZDV 158 (33%) ABC 164 (34%)

Randomisation

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 (%)

53,768 (23,060-146,132) 120 (33%)

All <50c/ml

CD4%, median (IQR) CD4 count, median

20 (13,25) 893

35 (30,39) 1191

WHO 3/4 pre-ART, % 185 (50%) 64 (57%)

*On stavudine for median 3.5 years

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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 (%)

53,768 (23,060-146,132) 120 (33%)

All <50c/ml

CD4%, median (IQR) CD4 count, median

20 (13,25) 893

35 (30,39) 1191

WHO 3/4 pre-ART, % 185 (50%) 64 (57%)

*On stavudine for median 3.5 years

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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 1.8-3.1) – 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

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312 children (65%) had total 917 endpoints

Primary Endpoint Clinical Grade 2/3/4; Laboratory Grade 3/4 Adverse Events

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0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36

Arm = d4T Arm = ZDV Arm = ABC

Pro

porti

on w

ithou

t end

poin

t

Months from randomisation

Hazard ratios: ZDV v. d4T = 0.99 (0.75, 1.29) ABC v. d4T = 0.88 (0.67, 1.15)

No difference between arms, p=0.63

83 grade 4

200 grade 3

634 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

EVENTS

Difference between arms excluding grade 2 events, p=0.48

Secondary Endpoints 44

d4T ZDV ABC p*

ART modifying event 6 12 5 0.01

Serious adverse event 46 44 42 0.46

Lipodystrophy** 2 0 0 0.11

Anaemia (grade 3/4) 5 9 6 0.42

Neutropenia (grade 3/4) 4 12 5 0.04

Hypersensitivity / rash 2 1 0 0.22

Clinical disease progression 10 7 16 0.55

Numbers of children

* time to event ** both cases of lipodystrophy/lipoatrophy were in experienced children (aged 6 & 8 years, on d4T for 2.5 and 5 years)

Lipodystrophy Change in Waist-Hip Ratios and Skinfold Thickness

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

44 -1

-.50

.51

0 12 24 48 72 96Weeks from randomisation

d4t naive zdv naive abc naived4t exper zdv exper abc exper

(95%

CI)

Mea

n ch

ange

from

rand

omis

atio

n

Change in waist:hip ratio Z-score

-1.5

-1-.5

0.5

0 12 24 48 72 96Weeks from randomisation

d4t naive zdv naive abc naived4t exper zdv exper abc exper

(95%

CI)

Mea

n ch

ange

from

rand

omis

atio

n

Change in sum-of-four skinfolds Z-score

Viral Load 44

d4T ZDV ABC

Naïve 87% 77% 88%

Experienced 100% 100% 97%

d4T ZDV ABC

Naïve 76% 76% 84%

Experienced 97% 100% 97%

Week 96, % suppressed <100 copies/ml Week 96, % suppressed <400 copies/ml

020

4060

8010

0

0 48 96Weeks from randomisation

d4t naive zdv naive abc naived4t exper zdv exper abc exper

% s

uppr

esse

d

Viral load <100 copies/ml

Difference between arms Naïve, p=0.32 Experienced, p=0.51

020

4060

8010

0

0 48 96Weeks from randomisation

d4t naive zdv naive abc naived4t exper zdv exper abc exper

% s

uppr

esse

d

Viral load <400 copies/ml

Difference between arms Naïve, p=0.07 Experienced, p=0.59

Disease Progression and CD4% 0.

000.

250.

500.

751.

00

164 158 152 148 146 145 85 21 0Arm = ABC158 151 147 146 146 146 86 29 0Arm = ZDV156 148 145 143 140 138 77 20 1Arm = d4t

Number at risk

0 20 40 60 80 100 120 140 160

Arm = d4t Arm = ZDV Arm = ABC

Weeks from randomisation

Time to progression

p=0.55

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%

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-50

510

1520

0 6 12 24 48 72 96Weeks from randomisation

d4t naive zdv naive abc naived4t exper zdv exper abc exper

(95%

CI)

Mea

n ch

ange

from

rand

omis

atio

n

Mean change in CD4%

p=0.15

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

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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

Special thanks to all the children and their families participating in the CHAPAS 3 trial in Zambia and Uganda

Acknowledgements

Funder: EDCTP Sponsor: Medical Research Council First-line drugs provided by: Cipla Ltd, India

The CHAPAS 3 study team