The Mma Bana StudyA Randomized Trial Comparing Highly Active Antiretroviral Therapy Regimens for Virologic

Efficacy and the Prevention of Mother-to-Child HIV Transmission among Breastfeeding

Women in Botswana

R. Shapiro, M. Hughes, A. Ogwu, D. Kitch, S. Lockman, C. Moffat, J. Makhema, S. Moyo, I. Thior, K. McIntosh, E. van Widenfelt, J. Leidner, K.

Powis, A. Asmelash, E. Tumbare, S. Zwerski, U. Sharma, E. Handelsman, K. Mburu, O. Jayeoba, E. Moko, S. Souda, E. Lubega, M. Akhtar, C. Wester,

W. Snowden, M. Martinez-Tristani, L. Mazhani, M. Essex, and The Mma Bana Study Team

HAART for PMTCT• No randomized clinical trial has previously

compared HAART regimens during pregnancy or breastfeeding

• Little is known about the safety and efficacy of using maternal HAART to prevent MTCT during breastfeeding

Study Background• At 4 clinical sites in southern

Botswana, HIV-infected pregnant women were referred from government antenatal clinics, and 730 eligible women were enrolled in the study

• Eligible women were stratified by CD4 count:• Women with CD4 counts > 200 cells/mm3 were

randomized to either Trizivir or Kaletra/Combivir• Women with CD4 counts < 200 cells/mm3 were

enrolled observationally, and received Nevirapine/Combivir according to Botswana government guidelines

560 women with CD4 > 200 cells/mm3 randomized to:

170 women with CD4 < 200 cells/mm3 or AIDS enrolled observationally:

Infants received single-dose NVP at birth and AZT x 1 month

Study Design

Arm A vs. Arm B

Intrapartum (supplemental AZT)

Trizivir (Abacavir/AZT/3TC)

Antepartum (26-34 wks)

Kaletra / Combivir(Lopinavair/ritonavir/AZT/3TC)

Nevirapine / Combivir(Nevirapine/AZT/3TC)

Breastfeeding (6 months)(Rapid weaning before 6 mo visit)

Obs Arm

HAART continuedfor treatment

Follow-up(2 years)

Intrapartum (supplemental AZT)

Antepartum (18-34 wks) Breastfeeding (6 months)(Rapid weaning before 6 mo visit)

Follow-up(2 years)

Primary Objectives1) Maternal HIV-1 RNA suppression to < 400

copies/mL among randomized arms at: (a) Delivery (b) Throughout breastfeeding at 1, 3,

and 6 months (or by weaning)

2) MTCT rate in overall study population

Follow-up and Study Completeness

• Loss to follow-up was low:• 95% of women and 97% of infants were followed to 6 months

or death

• Endpoint completeness was high:• Virologic:

• 98% of women had a delivery HIV-1 RNA, 99.7% of breastfeeding women had >1 HIV-1 RNA during breastfeeding

• MTCT:• 99.6% of infants had known birth PCR status (3 died

before testing)• 95% of infants had known PCR status at 6 months or

within 1 day of death

Maternal Baseline Characteristics

Baseline Characteristics at Enrollment

Arm A(TZV)

N=285

Arm B(KAL/CBV)

N=275

Obs Arm(NVP/CBV)

N=170

Median age (years) 26 25 29

Median gestational age (weeks)(10th, 90th percentile)

27(26, 33)

27(26, 33)

26(19, 31)

Median baseline CD4+ count (cells/mm3) 398 403 147

Median baseline HIV-1RNA (copies/mL) >100,000 copies/mL (%)

13,30015%

9,10013%

51,70037%

HLA-B*5701 (N=377 tested) 0 0 0

No differences by arm in education, income, electricity in home, baseline hemoglobin, or hepatitis B status.

Median HAART duration prior to delivery = 11 weeks (randomized), 13 weeks (obs)

• Breastfeeding:• 97% of women initiated breastfeeding (all on HAART)

• 93% exclusively breastfed through the time of weaning• 71% breastfed for > 5 months • < 1% breastfed beyond the 6 month visit

• HAART Adherence (similar by HAART regimen):• 6% missed 3 or more total days of HAART

Duration of Breastfeeding and HAART Adherence

Primary Virologic Endpoints: HIV-1 RNA Suppression to < 400 copies/mL at Delivery

and During BreastfeedingArm A(TZV)

Arm B(KAL/CBV)

Obs Arm(NVP/CBV)

Delivery (N=709) 96% 93% 94%

Breastfeeding (N=669)* 92% 93% 95%

* Suppression during breastfeeding defined as at least one available viral load while breastfeeding, and no result > 400 copies/mL

95% CI for difference between Arm A vs. B at delivery = (-2%, 10%)95% CI for difference between Arm A vs. B during breastfeeding = (-8%, 6%)

Maternal HIV RNA Suppression to < 400 copies/mL

Arm A (TZV) Arm B (Kal/CBV) Obs Arm (NVP/CBV)

Delivery 1 Months 3 Months 6 Months During breastfeedingN: 709 661 633 501 669

%

Primary MTCT EndpointInfections among live-born infants, by maternal arm

Arm A(TZV)N=283

Arm B(KAL/CBV)

N=270

Obs Arm(NVP/CBV)

N=156

In utero 3 (1.1%)* 1 (0.4%) 1 (0.6%)

Intrapartum 0 0 0

Breastfeeding 2 (0.7%) 0 0

Total at 6 months 5 (1.8%)* 1 (0.4%) 1 (0.6%)

1% overall transmission through 6 months•95% CI for overall MTCT rate = (0.5%, 2.0%)

P-value for difference in proportions for Arm A vs. B = 0.53*Results exclude one unconfirmed + birth PCR followed by death in Arm A

•Including this infant as a + PCR: P-value for difference in proportions for Arm A vs. B = 0.42

Characteristics of Transmitting Women

Arm Weeksgestation

at delivery

Wks on HAART before

delivery

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 39 7 237 80,300 <50 n/a No

A 39 12 322 128,000 51 n/a Yes

A 38 11 524 204,000 <50 n/a Yes

A* 30 3 317 >750,000 ? ** n/a Yes

B 41 7 213 176,000 542 n/a Yes

Obs 28 2 193 124,000 917 n/a No

Arm Weeksgestation

at delivery

Wks on HAARTbefore +PCR

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 32 17 331 171,000 257 <50, <50 No

A 40 27 448 28,500 <50 <50, <50 Yes

In utero transmissions

Breastfeeding transmissions

* Unconfirmed infection: positive PCR followed by infant death ** maternal death at delivery

Characteristics of Transmitting Women

Arm Weeksgestation

at delivery

Wks on HAART before

delivery

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 39 7 237 80,300 <50 n/a No

A 39 12 322 128,000 51 n/a Yes

A 38 11 524 204,000 <50 n/a Yes

A* 30 3 317 >750,000 ? ** n/a Yes

B 41 7 213 176,000 542 n/a Yes

Obs 28 2 193 124,000 917 n/a No

Arm Weeksgestation

at delivery

Wks on HAARTbefore +PCR

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 32 17 331 171,000 257 <50, <50 No

A 40 27 448 28,500 <50 <50, <50 Yes

* Unconfirmed infection: positive PCR followed by infant death ** maternal death at delivery

In utero transmissions

Breastfeeding transmissions

Characteristics of Transmitting Women

Arm Weeksgestation

at delivery

Wks on HAART before

delivery

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 39 7 237 80,300 <50 n/a No

A 39 12 322 128,000 51 n/a Yes

A 38 11 524 204,000 <50 n/a Yes

A* 30 3 317 >750,000 ? ** n/a Yes

B 41 7 213 176,000 542 n/a Yes

Obs 28 2 193 124,000 917 n/a No

Arm Weeksgestation

at delivery

Wks on HAARTbefore +PCR

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 32 17 331 171,000 257 <50, <50 No

A 40 27 448 28,500 <50 <50, <50 Yes

* Unconfirmed infection: positive PCR followed by infant death ** maternal death at delivery

In utero transmissions

Breastfeeding transmissions

Characteristics of Transmitting Women

Arm Weeksgestation

at delivery

Wks on HAART before

delivery

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 39 7 237 80,300 <50 n/a No

A 39 12 322 128,000 51 n/a Yes

A 38 11 524 204,000 <50 n/a Yes

A* 30 3 317 >750,000 ? ** n/a Yes

B 41 7 213 176,000 542 n/a Yes

Obs 28 2 193 124,000 917 n/a No

Arm Weeksgestation

at delivery

Wks on HAARTbefore +PCR

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 32 17 331 171,000 257 <50, <50 No

A 40 27 448 28,500 <50 <50, <50 Yes

* Unconfirmed infection: positive PCR followed by infant death ** maternal death at delivery

In utero transmissions

Breastfeeding transmissions

Characteristics of Transmitting Women

Arm Weeksgestation

at delivery

Wks on HAART before

delivery

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 39 7 237 80,300 <50 n/a No

A 39 12 322 128,000 51 n/a Yes

A 38 11 524 204,000 <50 n/a Yes

A* 30 3 317 >750,000 ? ** n/a Yes

B 41 7 213 176,000 542 n/a Yes

Obs 28 2 193 124,000 917 n/a No

Arm Weeksgestation

at delivery

Wks on HAARTbefore +PCR

Baseline CD4+ count

Baseline HIV-1 RNA

Plasma HIV-1

RNA at delivery

Plasma and breast milk

HIV-1 RNA at 1 and 3 months

HAART adherence

issues identified?

A 32 17 331 171,000 257 <50, <50 No

A 40 27 448 28,500 <50 <50, <50 Yes

* Unconfirmed infection: positive PCR followed by infant death ** maternal death at delivery

In utero transmissions

Breastfeeding transmissions

Stillbirths, Prematurity, Low Birth Weight, and Congenital Abnormalities

Arm A(TZV)

Arm B(KAL/CBV)

Obs Arm(NVP/CBV)

Stillbirths (% of deliveries) 8 (3%) 5 (2%) 11 (7%)(p=0.07 for randomized vs. observational arms)

Live births (including twins) 283 270 156

Prematurity (< 37 weeks*)

42 (15%) 61 (23%)(p=0.04 for

Arm A vs. Arm B)

16 (10%)

Low Birth Weight (< 2.5 kg)

37 (13%) 45 (17%) 23 (15%)

Congenital Abnormality 5 (2%) 5 (2%) 5 (3%)

* Gestational age determined by last menstrual period and/or ultrasound

Maternal Deaths and Adverse Events Arm A(TZV)

N=285

Arm B(KAL/CBV)

N=275

Obs Arm(NVP/CBV)

N=170

Deaths 1 (<1%) 0 3 (2%)

Number of women with > 1 grade 3 or 4 diagnosis

17 (6%) 16 (6%) 25 (15%)

Number of women with any grade 3 or 4 laboratory event: Number of women with common grade 3 or 4 laboratory events: Anemia Neutropenia Hepatic Pancreatic

42 (15%)

15 (5%)18 (6%)

8 (3%)6 (2%)

32 (12%)

12 (4%)5 (2%)5 (2%)8 (3%)

48 (28%)

19 (11%)19 (11%)

1 (1%)12 (7%)

Treatment-modifying adverse events 7 (2%) 6 (2%) 18 (11%)

More grade 3 and 4 adverse events in the observational arm (CD4 < 200)

Infant Deaths and Adverse Events

Arm A(TZV)

N=283

Arm B(KAL/CBV)

N=270

Obs Arm(NVP/CBV)

N=156

Deaths 7 (2%) 7 (3%) 7 (4%)

Number of infants with > 1 grade 3 or 4 diagnoses 28 (10%) 17 (6%) 13 (8%)

Number of infants with any grade 3 or 4 laboratory event: Number of infants with common grade 3 or 4 laboratory events: Anemia Neutropenia Bilirubin

116 (41%)

36 (13%)43 (15%)34 (12%)

125 (47%)

43 (16%)49 (7%)

43 (16%)

64 (41%)

31 (18%)34 (22%)

5 (3%)

Grade 3 and 4 adverse events similar for all infants, including those born to women with more advanced HIV in the observational arm

Mortality > 6 months NOT included in these results

Summary• HIV-1 RNA suppression to < 400 copies/mL was

similar at delivery and throughout breastfeeding by randomized arm, and for the observational arm• 95% suppressed at delivery, 93% throughout breastfeeding

• Among 709 live births, HIV transmission was only 1% overall, and only 2 transmissions occurred during breastfeeding (0.3%)• Lowest MTCT rate reported in a breastfeeding population

• HAART regimens were safe and well-tolerated for women and for their breastfeeding infants

Conclusion• Maternal HAART from early in the

third trimester of pregnancy through 6 months of breastfeeding is a safe and very effective strategy for preventing MTCT while allowing for the benefits of breastfeeding

Acknowledgements

The Mma Bana Study ParticipantsBHP and HSPH Staff: Lillian Makori, Gloria Mayondi, Agnes Modise, Venice Modikwa, Ria Madison, Tlhongbotho Masoloko, Daisy Ramalekane, Molly Pretorius Holme, Heather Carey, Sara Mazzola, Carrie Kachoria, Raabya Rossenkahn, Vlad Novitsky, Chris Rowley, Michael Roy, Lendsey Melton, Chikezie Nwankwo, Scott Dryden Peterson, Onalenna Nthase, Norah Mawoko, Elias Woldegabriel, Kasonde Micheal, Chandan Harikrishnan, Jane Magetse, Joyce Lubinda, Tebogo Kakhu, Thena Tumediso, Modiegi Diseko, Mosetsanagape Galekhutle, Keamogetse Rebatenne, Mavis Moeng, Kebaibphe Ntalabgwe, Ditlamelo Mareme, Victoria Kgwadi, Kaone Kgati, Keitumetse Sakana, Best Mafoko, Lazarus Moremi, Jimmy Nkgau, Ilori Adewale, Banno Janet Moorad, Dipotso Arbi, Thena Tumediso, Kesego Dudu Kooreng, Selebaleng Vinoliah Simon, Maggie Mosetsanagape Nkgau, Collen Rananna, Rejoice Molefe, Nametso Dimpho Lekwape, Tebogo Ncube, Eldah Kakanyo Tshotlego, Segomotso Mapote, Radinku Tshegofatso, Emmanuel Keikotlhae, William Keboutlwe, Hanqiwe Olebeng, Seleetso Ndicky Modibedi, Tshepo Silwane, Tshepiso Patricia Morupisis, Ntsholeng Kekgethile, Sydney Kgwefane, Julius Kgangetsile, Nnahurumnanya Iwe, Modiegi Diseko, Tseo Khudube, Malebogo Ntshimane, Hanqiwe Olebeng, Maureen Gower, Nthabiseng Kgaodi, Kate Selathwe, Lorraine Phiri, Rosemary Musonda, Phillimon Segopodi , Dorcas Moses, Bonolo Khumotaka , Phibeon Munyanadzi Mangwendeza, Gertrude Ditshotlo, Alex Ntau, Poko Molwan

Botswana Ministry of Health: Dr. Khumo Sepoine, Mrs. Shenaaz El Halabi, Mr Pilate Khulumani, Mrs Mary Kasule, Dr. Howard Moffat, Dr. Haruna Baba Jubril, Dr Balosang, PMTCT unit

Princess Marina Hospital, Gaborone

Staff of Maternity, Post natal & Children’s ward 

Scottish Livingstone Hospital, Molepolole

Staff of Maternity, Post natal & Children’s ward

Deborah Retief Memorial Hospital, Mochudi

Staff of Maternity, Post natal & Children’s ward

Athlone Hospital Lobatse

Staff of Maternity, Post natal & Children’s ward

District Health Teams (Molepolole & Mochudi).

City Council Clinics team (Lobatse & Gaborone)

GSK: Edde Loeliger

Baylor: Prof Gabriel Anabwani, Dr Elizabeth Lowenthal

Brigham and Women’s Hospital: Ruth Tuomola

Beth Israel Deaconess Medical Ctr: Linda Shipton

Harvard Medical School: Jennifer Chen

Oxford University: Philip Goulder, Philippa Mathews

NIH: Lynne Mofenson

DSMB Members

Support for this study was provided by NIAID (U01-AI066454)Medications provided by: the Botswana Government, Glaxo Smith Kline, and Abbott

We also want to thank:

Thank you!