Early mortality following ART initiation in HIV-infected ...€¦ · Early mortality following ART...
Transcript of Early mortality following ART initiation in HIV-infected ...€¦ · Early mortality following ART...
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Early mortality following ART initiation Early mortality following ART initiation
in HIVin HIV--infected adults and children in infected adults and children in
Uganda and ZimbabweUganda and Zimbabwe
A Sarah Walker, Peter Mugyenyi, Paula Munderi, James Hakim, Adeodata Kekitiinwa, Elly Katabira, Charles F Gilks, Cissy Kityo, Patricia Nahirya-
Ntege, Kusum Nathoo, Diana M Gibb
on behalf of the DART and ARROW Trial Teams
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BackgroundBackground
Higher mortality has been observed in the first 2-3 months on ART in adults initiating ART in low/middle-income compared to high income settings, even after adjusting for important co-factors, with more similar mortality risks subsequently
unadjusted (low-income:high-income)
adjusted for age, sex, pre-ART CD4, stage, regimen
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ObjectivesObjectives
• To investigate the specific pattern of how mortality risk changes over time following ART initiation in adults in resource-limited settings
• To investigate whether children initiating ART in the same resource-limited settings have a similarly high risk of early mortality
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MethodsMethods
• Mortality during the first year on ART estimated in
– adults (18+ years) from the DART trial
– children (4 months-15 years) from the ARROW trial
• Flexible parametric survival models (Royston & Parmar Stat Med 2002)
– estimate a smooth, continuously varying, death rate (“hazard”)
• Survival estimated according to pre-ART CD4 in those 4 years or older
– CD4% used for children under 4 years initiating ART
• Additional impact of age, sex, WHO stage and cotrimoxazole investigated in multivariable models including adults & children
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ResultsResults
• DART trial in Uganda and Zimbabwe
– 3316 eligible adults aged 18-73 years
– 43 (1.3%) vital status unknown at 1 year after ART initiation
• ARROW trial in Uganda and Zimbabwe
– 1207 eligible children aged 4 months to 17 years
• 7 16&17 year olds excluded from this analysis
– 9/1200 (0.8%) vital status unknown at 1 year after ART initiation
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Estimated mortality 1 year after ART initiationEstimated mortality
1 year after ART initiation
0%
2%
4%
6%
8%
10%
12%
0-49 50-99 100-150 150-199
DART, 18+ years
CD4 at ART initiation
Est
imate
d m
ort
ality
at 1 y
ear
9.4 4.5 3.2 2.5
Deaths 103 36 23 17
Number 1109 785 759 663
62% in DART were taking cotrimoxazole at ART initiation
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Estimated mortality 1 year after ART initiationEstimated mortality
1 year after ART initiation
0%
2%
4%
6%
8%
10%
12%
0-49 50-99 100-150 150+*
DART, 18+ years ARROW, 4-15 years
CD4 at ART initiation
Estimated m
ort
ality
at 1 y
ear
9.4 10.1 4.5 4.4 3.2 2.0 2.5 1.2
Deaths 103 14 36 2 23 1 17 6
Number 1109 131 785 56 759 52 663 500
* No upper CD4 criteria in ARROW if met WHO guidelinesAll ARROW children received
cotrimoxazole with ART (62% in DART)
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Estimated mortality 1 year after ART initiationEstimated mortality
1 year after ART initiation
0%
2%
4%
6%
8%
10%
12%
0-490-<5%
50-995-<10%
100-15010-<15%
150+*15%+*
DART, 18+ years ARROW, 4-15 years ARROW, 4m-3 years
CD4/CD4% at ART initiation
Estimated m
ort
ality
at 1 y
ear
9.4 10.1 9.1 4.5 4.4 4.5 3.2 2.0 2.0 2.5 1.2 3.2
Deaths 103 14 2 36 2 4 23 1 3 17 6 7
Number 1109 131 27 785 56 87 759 52 128 663 500 219
* No upper CD4 criteria in ARROW if met WHO guidelinesAll ARROW children received
cotrimoxazole with ART (62% in DART)
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Death rate DART 18+ yearsDeath rate
DART 18+ yearsDeath
rate
/100 P
Y (haza
rd)
Months from ART initiation
0-49 50-99
100-149 150-199
Pre-ART CD4
0 3 6 9 12
0
5
10
15
20
25
30peak 30-43d heterogeneity p<0.0001
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Death rate ARROW 4 months-15 years
Death rate ARROW 4 months-15 years
0-49,4+
<5%,<4
50-99,4+ 150+,4+
15%+,<4
Pre-ART CD4/CD4% & age
5-<10%,<4 10-<15%,<4
100-149,4+
Death
rate
/100 P
Y (haza
rd)
0
5
10
15
20
25
30 heterogeneity p=0.00074-15 years: p=0.0001
4 months-3 years: p=0.36
peak 41-51d
Months from ART initiation0 3 6 9 12
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Survival DART 18+ years
Survival DART 18+ years
4.9%
2.1%
1.1%1.4%
9.4%
4.5%
2.5%3.2%
90 daymortality
365 daymortality
.88
.9
.92
.94
.96
.98
1
Pro
port
ion surv
ivin
g
0-49 50-99
100-149 150-199
Pre-ART CD4
Months from ART initiation0 3 6 9 12
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SurvivalARROW 4 months-15 years
SurvivalARROW 4 months-15 years
5.9%
2.3%
0.6% 1.0%
10.1%
4.5%
1.2%1.9%
90 daymortality
365 daymortality
.88
.9
.92
.94
.96
.98
Pro
port
ion surv
ivin
g
0-49,4+
<5%,<4
50-99,4+ 150+,4+
15%+,<4
Pre-ART CD4/CD4% & age
5-<10%,<4 10-<15%,<4
100-149,4+
Months from ART initiation0 3 6 9 12
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SurvivalAll agesSurvivalAll ages
0-49,18+
<5%,<4
50-99,4-15
5-<10%,<4
100-149,4-15
10-<15%,<4
150+,4-15
15%+,<4
Pre-ART CD4/CD4% & age50-99,18+ 150-199,18+100-149,18+
0-49,4-15
0.95
0.98
0.24
heterop (3df)
0.77
.88
.9
.92
.94
.96
.98
1
Pro
port
ion surv
ivin
g
Months from ART initiation0 3 6 9 12
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Results - multivariable modelsResults - multivariable models
Pooling data from adults and children and adjusting for CD4/CD4% group
• There was no evidence of an additional effect of
– age (p=0.63)
– sex (p=0.17)
• There was evidence of an additional effect of
– clinical stage (p<0.0001)
• WHO 3: RR=1.43 (95% CI 1.16-1.77)
• WHO 4: RR=1.89 (95% CI 1.51-2.37)
– cotrimoxazole at ART initiation (DART) (p<0.0001)
• RR=0.77 (95% CI 0.67-0.89)
– no evidence of interactions with pre-ART CD4 group
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• Carry-over effect of high mortality before starting ART at low CD4s
– “ART just can’t work quickly enough”
– investigate by comparing mortality rates with cohorts presenting for care with low CD4 and not receiving ART
• adults: pre-ART era Entebbe cohort, Uganda (n=514, 1996-2000)
• children: 3Cs4kids (n=1594) (censored at ART initiation)
• ART toxicity– not supported as 8/179 (4%) & 1/39 (3%) early deaths in
DART and ARROW adjudicated as drug-related by ERC
• 22 (12%) & 5 (13%) respectively possibly drug-related
• IRIS/inflammation
Possible causes of the early peak in mortality
Possible causes of the early peak in mortality
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Adults: ART (DART) vs no ART (EC)
Adults: ART (DART) vs no ART (EC)
DART: 0-49 50-99 100-149 150-199Pre-enrolment CD4
0
20
40
60
80
100
Death
rate
/100 P
Y (haza
rd)
Months from enrolment/ART initiation0 3 6 9 12
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Adults: ART (DART) vs no ART (EC)
Adults: ART (DART) vs no ART (EC)
DART: 0-49 50-99 100-149 150-199
EC: 0-49 50-99 100-149 150-199
Pre-enrolment CD4
0
20
40
60
80
100
Death
rate
/100 P
Y (haza
rd)
Months from enrolment/ART initiation0 3 6 9 12
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Adults: ART (DART) vs no ART (EC)
Adults: ART (DART) vs no ART (EC)
0 .25 .5 .75 1Years from ART initiation
DART: 0-49 50-99 100-149 150-199
EC: 0-49 50-99 100-149 150-199
Pre-ART CD4
0
20
40
60
80
100
Death
rate
/100 P
Y (haza
rd)
0
5
10
15
20
25
30
0 1 2 3
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Children 4-15 years: ART (ARROW) vs no ART (3Cs4kids)
Children 4-15 years: ART (ARROW) vs no ART (3Cs4kids)
ARROW: 0-49 50-99 100-149 150+
3Cs4kids: 0-49 50-99 100-149 150+
Pre-enrolment CD4
0
20
40
60
80
100
Death
rate
/100 P
Y (haza
rd)
befo
re A
RT
Months from enrolment/ART initiation0 3 6 9 12
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ConclusionsConclusions
• Children do not have significantly poorer initial survivalon ART than adults per se
• Adults and children aged 4 years and over with low CD4 have remarkably similar, and high, risks of mortality in the first 3 months after ART initiation compared to those with higher CD4
– children under 4 years with low CD4% are at similarly high mortality risks
– nevertheless, these risks are still lower than risks without ART
• Interventions focussing on reducing mortality should target both adults and children
– earlier HIV diagnosis and prompt ART initiation remain key goals
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AcknowledgmentsAcknowledgmentsWe thank all the patients and staff from all the centres participating in the DART and
ARROW trials, and the Entebbe Cohort and 3Cs4kids Cohort Collaboration.
DART: Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, C Kityo, F Ssali, D Tumukunde, T Otim, J Kabanda, H Musana, J Akao, H Kyomugisha, A Byamukama, J Sabiiti, J Komugyena, P Wavamunno, S Mukiibi, A Drasiku, R Byaruhanga, O Labeja, P Katundu, S Tugume, P Awio, A Namazzi, GT Bakeinyaga, H Katabira, D Abaine, J Tukamushaba, W Anywar, W Ojiambo, E Angweng, S Murungi , W Haguma, S Atwiine, J Kigozi, L Namale. A Mukose, G Mulindwa, D Atwiine, A Muhwezi, E Nimwesiga, G Barungi, J Takubwa, S Murungi, D Mwebesa, G Kagina, M Mulindwa, F Ahimbisibwe, P Mwesigwa, S Akuma, C Zawedde, D Nyiraguhirwa, C Tumusiime, L Bagaya, W Namara, J Kigozi, J Karungi, R Kankunda, R Enzama. MRC Research Unit on AIDS/Uganda Virus Research Institute, Entebbe, Uganda: H Grosskurth, P Munderi, G Kabuye, D Nsibambi, R Kasirye, E Zalwango, M Nakazibwe, B Kikaire, G Nassuna, R Massa, K Fadhiru, M Namyalo, A Zalwango, L Generous, P Khauka, N Rutikarayo, W Nakahima, A Mugisha, J Todd, J Levin, S Muyingo, A Ruberantwari, P Kaleebu, D Yirrell, N Ndembi, F Lyagoba, P Hughes, M Aber, A Medina Lara, S Foster, J Amurwon, B Nyanzi Wakholi, K Wangati, B Amuron, D Kajungu, J Nakiyingi, W Omony, K Fadhiru, D Nsibambi, P Khauka. University of Zimbabwe, Harare, Zimbabwe: A Latif, J Hakim, V Robertson, A Reid, E Chidziva, R Bulaya-Tembo, G Musoro, F Taziwa, C Chimbetete, L Chakonza, A Mawora, C Muvirimi, G Tinago, P Svovanapasis, M Simango, O Chirema, J Machingura, S Mutsai, M Phiri, T Bafana, M Chirara, L Muchabaiwa, M Muzambi, E Chigwedere, M Pascoe, C Warambwa, E Zengeza, F Mapinge, S Makota, A Jamu, N Ngorima, H Chirairo, S Chitsungo, J Chimanzi, C Maweni, R Warara, M Matongo, S Mudzingwa, M Jangano, K Moyo, L Vere, I Machingura. Infectious Diseases Institute (formerly the Academic Alliance) Makerere University, Mulago, Uganda: E Katabira, A Ronald, A Kambungu, F Lutwama, I Mambule, A Nanfuka, J Walusimbi, E Nabankema, R Nalumenya, T Namuli, R Kulume, I Namata, L Nyachwo, A Florence, A Kusiima, E Lubwama, R Nairuba, F Oketta, E Buluma, R Waita, H Ojiambo, F Sadik, J Wanyama, P Nabongo, J Oyugi, F Sematala, A Muganzi, C Twijukye, H Byakwaga. The AIDS Support Organisation (TASO), Uganda: R Ochai, D Muhweezi, A Coutinho, B Etukoit. Imperial College: C Gilks, K Boocock, C Puddephatt, C Grundy, J Bohannon, D Winogron. MRC Clinical Trials Unit: J Darbyshire, DM Gibb, A Burke, D Bray, A Babiker, AS Walker, H Wilkes, M Rauchenberger, S Sheehan, C Spencer-Drake, K Taylor, M Spyer, A Ferrier, B Naidoo, D Dunn, R Goodall. DART Virology Group: P Kaleebu (Co-Chair), D Pillay (Co-Chair), V Robertson, D Yirrell, S Tugume, M Chirara, P Katundu, N Ndembi, F Lyagoba, D Dunn, R Goodall, A McCormick. DART Health Economics Group: A Medina Lara (Chair), S Foster, J Amurwon, B Nyanzi Wakholi, J Kigozi, L Muchabaiwa, M Muzambi. Independent DART Trial Monitors: R Nanfuka, C Mufuka-Kapuya. Trial Steering Committee:I Weller (Chair), A Babiker (Trial Statistician), S Bahendeka, M Bassett, A Chogo Wapakhabulo, J Darbyshire, B Gazzard, C Gilks, H Grosskurth, J Hakim, A Latif, C Mapuchere, O Mugurungi, P Mugyenyi; Observers C Burke, M Distel, S Kinn, E Loeliger, C Newland, G Pearce, M Roberts, S Rahim, J Rooney, M Smith, W Snowden, J-M Steens. Data and Safety Monitoring Committee: A Breckenridge (Chair), A McLaren (Chair-deceased), C Hill, J Matenga, A Pozniak, D Serwadda. Endpoint Review Committee: T Peto (Chair), A Palfreeman, M Borok. GlaxoSmithKline, Gilead Sciences and Boehringer-Ingelheim donated first-line drugs for DART, and Abbott provided Kaletra/Aluvia as part of the second-line regimen for DART. DART was funded by the UK Medical Research Council, the UK Department for International Development (DFID), and the Rockefeller Foundation.
ARROW: Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, V Musiime, VD Afayo, E Bagurukira, J Bwomezi, J Byaruhanga, P Erimu, C Karungi, H Kizito, M Mutumba, WS Namala, J Namusanje, R Nandugwa, TK Najjuko, E Natukunda, M Ndigendawani, SO Nsiyona, F Odongo, K Robinah, M Ssenyonga, D Sseremba, J Tezikyabbiri, CS Tumusiime; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda: P Munderi, P Nahirya-Ntege, M Aber, FN Kaggwa, P Kaleebu,R Katuramu, JH Kyalimpa, J Lutaakome, L Matama, M Musinguzi, G Nabulime, A Ruberantwari, R Sebukyu, IM Ssekamatte, G Tushabe, D Wangi. Baylor-Uganda, Paediatric Infectious Disease Centre, Mulago Hospital, Uganda: A Kekitiinwa, P Musoke, S Bakeera-Kitaka, R Namuddu, P Kasirye, JK Balungi, A Babirye, J Asello, S Nakalanzi, NC Ssemambo, J Nakafeero, JN Kairu, EK George, G Musoba, J Ssanyu, S Ssenyonjo. University of Zimbabwe, Harare, Zimbabwe: KJ Nathoo, MF Bwakura-Dangarembizi, F Mapinge, T Mhute, T Vhembo, R Mandidewa, D Nyoni, C Katanda, GC Tinago, J Bhiri, D Muchabaiwa, S Mudzingwa, MM Chipiti, M Phiri, J Steamer, CC Marozva, SJ Maturure, L Matanhike, S Tsikirayi, L Munetsi. Medical Research Council Clinical Trials Unit, London, UK: DM Gibb, MJ Thomason, AD Cook, JM Crawley, AA Ferrier, B Naidoo, MJ Spyer, AS Walker, LK Kendall. Independent ARROW Trial Monitors: R Nanfuka, I Machuringa. Trial Steering Committee: I Weller (Chair), E Luyirika, H Lyall, E Malianga, C Mwansambo, M Nyathi, A Wapakhabulo, DM Gibb, A Kekitiinwa, P Mugyenyi, P Munderi, KJ Nathoo: Observers S Kinn, M MacNeil, M Roberts, W Snowden. Data and Safety Monitoring Committee: A Breckenridge (Chair), C Hill, J Matenga, A Pozniak, J Tumwine. Endpoint Review Committee: G Tudor-Williams (Chair), H Barigye, HA Mujuru, G Ndeezi. Funding: ARROW is funded by the UK Medical Research Council and the UK Department for International Development (DfID). Drugs are provided by GlaxoSmithKline.
Entebbe Cohort: MRC Research Unit on AIDS/Uganda Virus Research Institute, Entebbe, Uganda: C Watera, G Miiro, S Zawedde, J Nakiyingi, D Rutebarika, H Grosskurth.3Cs4kids: South Africa: H Zar, B Eley, P Roux, M Cotton, T Meyers, H Moultrie. Zambia: V Mulenga, C Chintu, C Kankasa. Cote d’Ivoire: PMsellati, P Fassinou, N Elenga. Malawi: S Graham, J Ellis, R Weigel. Uganda: C Giaquinto, M Nanyonga, E Morelli, B Atai. Brazil: J Pinto, C Arau´jo, A Carvalho, I Carvalho, A Diniz, F Ferreira, V Lobato, T Sanchez. UK: T Duong, D Dunn, DM Gibb, C Duff. Funding: Research grant from WHO, for meetings from PENTA, GlaxoSmithKline and DFID, UK.