Early mortality following ART initiation in HIV-infected ...€¦ · Early mortality following ART initiation in HIV-infected adults and children in Uganda and Zimbabwe A Sarah Walker,

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

2

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

3

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

4

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

5

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

6

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

7



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)

8



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)

9

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

10

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

11

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


12

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+


13

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


14

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

15

• 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

16

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

17



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)


1816



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

19

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


20

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

21

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.

Documents

Early mortality following ART initiation in HIV-infected ...€¦ · Early mortality following ART initiation in HIV-infected adults and children in Uganda and Zimbabwe A Sarah Walker,