World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

Kesho Bora Study

Isabelle de Vincenzi (devincenzii@who.int)

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

• Efficacy of MTCT prevention interventions in developing countries needs to be improved

• Health of HIV-infected mothers needs more attention

• Alternatives to replacement feeding for children born to HIV-infected mothers need to be identified

HAART duringpregnancy and breastfeedingmay achieve all 3 purposes

Rationale

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

Goal

• To optimize the use of ARV drugs during the antepartum, intrapartum and postpartum periods to prevent MTCT of HIV and preserve the health of the mother in settings where the majority of HIV-positive women breastfeed

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

General Outline - Mothers• Intervention according to disease status in late

pregnancy – CD4 count < 200 or HIV Stage 4 (prospective cohort)

• ZDV+3TC+NVP during pregnancy, delivery and continued as long as required, potentially lifelong

– CD4 count > 500 (prospective cohort)• ZDV from 34-36 wks until onset of labour

and one dose NVP in labour

– CD4 count 200 – 500 (randomised study)• Triple-ARV MTCT prophylaxis:

ZDV+3TC+LPV/r from 28 wks until 6 mths post-partum

• Short-course MTCT prophylaxis (see above) from 28 wks + ZDV+3TC (mother)

Not enrolled anymore

Not enrolled anymore

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

Infants• All infants receive single-dose NVP + ZDV 1 wk

• Standard WHO/UNICEF infant feeding counselling

• Study implemented in sites where majority of women choose to breastfeed

• Free formula offered to mother/children opting for replacement feeding

• All women choosing to breastfeed counselled to breastfeed exclusively for 5½ months, followed by weaning over a 2-week period

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

Main study endpoints• HIV-free infant survival at 6 weeks and 12 months,

irrespective of mode of infant feeding• HIV-free infant survival at 12 months among infants who

received any breastmilk• AIDS-free survival among mothers by 18 months

postpartum• Incidence of serious adverse events in mothers and children

Sample sizeN = 850 randomized

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

5 study sites

• Bobo-Dioulaso, Burkina-Faso:

Centre Muraz, Nicolas Meda

• Mombasa, Kenya:

ICRH – Stanley Luchters

• Nairobi, Kenya:

KNH - Ruth Nduati

• Durban, South Africa:

U. KwaZulu Natal - Nigel Rollins

• Mtubatuba, South Africa:

Africa Centre – Marie-Louise Newell

Bobo Dioulasso

Durban

MombasaNairobi

Mtubatuba

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

Protocol changes

Version6

(Jan05)

Version7

(Mar05)

Version8

(Mar06)

Version9

(Sep06)

Version10

(Sep07)

Extension follow-up

(Jan08)

CD4<200 ARTZDV+3TC+NVP

ARTZDV+3TC+NVP

ARTZDV+3TC+NVP

- - - - - - - - -

CD4≥500 ShortZDV+sd NVP

ShortZDV+sd NVP

- - - - - - - - - - - -

200<CD4<500(randomised)

ShortZDV+sd NVP

Triple ARV(6 mths after del)

ZDV+3TC+NVP*

ShortZDV+sd NVP

Triple ARV(6 mths after del)

ZDV+3TC+LPVr

ShortZDV+sd NVP

Triple ARV(6 mths after del)

ZDV+3TC+LPVr

ShortZDV+sd NVP

Triple ARV(6 mths after del)

ZDV+3TC+LPVr

ShortZDV+sd NVP

Triple ARV(6 mths after del)

ZDV+3TC+LPVr

ShortZDV+sd NVP

Triple ARV(6 mths after del)

ZDV+3TC+LPVr

Tail (after delivery if short)

- - - - - - - - - - - -

Mother

ZDV+3TC 1 wk

Child

ZDV 1 wk

Mother

ZDV+3TC 1 wk

Child

ZDV 1 wk

Start intervention (wks pregnancy)

34-36 wks** 34-36 wks** 34-36 wks** 34-36 wks** From 28 wks From 28 wks

Follow-up (mths after delivery)

24 months 24 months 24 months 12 months 12 months 18 months

* Never implemented – mother and children received short regimen** From 18 weeks if ART needed

World Health Organization - Department of Reproductive Health and Research Kes

ho B

ora

upda

te –

12F

eb08

Status

2005 2006 2007 2008 2009 2010

Bobo

Nairobi

Mombasa

Durban

Africa Centre

First interm analyis (25% 12 months follow-up)

6-weeks results

6-months results

12-months results

Final results

Recruitment

Follow-up

Kesho Bora Study12 months follow-up for women not

randomized:CD4+ < 200/mm3 or > 500/mm3

Women enrolled 131119

114 127

Lost to follow-up before delivery -Death before delivery 1Did not initiate ARVs 1Stillbirths 2

Lost to follow-up before delivery 1Death before delivery -Did not initiate ARVs - Stillbirths 4

Women with live births (incl 3 multiple pregs)

114 127Live singletons or first born

HIV Status unknown(4 early deaths)

HIV Status unknown(1 early death, 1 lost to follow-up)

Live singletons or first born with known HIV status

110 125

CD4 > 500 /mm3CD4 < 200 /mm3

Study Population

CD4+ < 200/mm3

(n=119)CD4+ > 500/mm3

(n=131)

Age [mean] (years) 28.9 26.7

Parity (% primigravida) 7.6% 21.4%

CD4+ [median and IQR] (cells/mm3)- At enrolment- At delivery - At 12 months

134 [ 91 - 170 ]184 [ 129 - 277 ]305 [ 228 - 419 ]

621 [ 559 - 731 ]740 [ 603 - 906 ]676 [ 540 - 870 ]

Time on ARV before delivery Median duration on ARV [IQR] (wks)- % on ARV for at least 4 weeks- % on ARV for 2 - 4 weeks- % on ARV for less than 2 weeks

6.9 [ 8.9 - 5.0 ]85.7%10.9% 2.5%

5.1 [ 7.0 - 4.0 ]77.1%18.3% 3.8%

Adherence to ARVs (% who took > 95% ARVs before del.)

88.9 % 85.0 %

Characteristics of enrolled women

Characteristics of live born infants

CD4+ < 200/mm3

(n=114)

CD4+ > 500/mm3 (n=127)

P

Birth weight ≤ 2500g 19.4% 12.0% 0.14

Ever breastfed (BF)

Duration of breastfeeding in weeks (if ever BF)Median [IQR]

57.0%

20.9 [13.1 - 26.1]

77.2%

17.8 [9.0 - 24.9]

<0.001

0.26

Grade 3 or 4 anaemia- At birth: Hb<12g/l - At 3 month: Hb<7g/l

17.4%2.2%

9.4%0%

0.130.21

Kesho Bora StudyCumulative Risk of HIV Infection at 12 months

7.6%

5.8%

CD4+ <200

CD4+ >500

(n=110)

(n=125)

Kesho Bora Study- Infant Mortality

12.3%

8.9%

CD4+ <200

CD4+ >500

(n=114)

(n=127)

12-Months Transmission and Survival

Mother Status Transmission Deaths Tx or Death

CD4+ < 200/mm3 8/1107.6% [ 2.5 to 12.6 ]

14/11412.3% [6.3 to 18.3]

20/11417.6% [10.6 to 24.6]

CD4+ > 500/mm3 7/1255.8% [1.6 to 9.9]

11/1278.9% [3.9 to 14.0]

15/12612.2% [6.4 to 18.0]

Comparative data

Study CD4 range

Regimen Timing Tx Rate

Mitra+ All Triple (NVP) 6 mths 5.0%

KiBS

< 250/mm3 Triple (Nelfinavir) 12 mths 5.9%

> 250/mm3 Triple (Nelfinavir) 12 mths 5.2%

Kesho Bora

< 200/mm3 Triple (LPV/r) 12 mths 7.6%

> 500/mm3 ZDV + sd-NVP 12 mths 5.8%

Comparative data

Study CD4 range

Regimen Timing Tx Rate

AMATAAll Triple (EFV) 9 mths 1.5%

Abidjan < 200/mm3 Triple (NVP) 12 mths 1%

Dream

Preliminary commentsHigh CD4 counts :

•Similar Tx rates with "long triple" (KiBS) and "short" (KB);

• Costs of triple prophylaxis (resistance in particular) not well assessed yet: prevalence and impact of resistance? Maternal HIV progression after stopping triple prophylaxis?

•Only 1 case of post-partum Tx (KB) despite only short-ARV: consider triple-proph. in ante-partum, but unclear when to stop (! viral rebound during breastfeeding)

Low CD4 counts :

• Relatively high transmission rate in KB, KiBS,MITRA (~ 6%): problems of adherence when ART started during pregnancy and immediately after HIV diagnosis? Importance of starting early? Feasibility of rapid clinical/CD4 evaluation?

•Much lower rates in Abidjan, AMATA, DREAM….

Remaining results to be coming out

• Results from randomized trials (KB, BAN, Botswana, PROMISE 2)

• Trials related to infant prophylaxis (PEPI, SWEN, PROMISE 1, BAN)

• How to make replacement feeding safe

• Vaccines