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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!