HIV in Africa: An Incremental Comprehensive Approach

1
Both maternal HAART and daily infant Nevirapine
(NVP) are effective in reducing HIV-1
transmission during breastfeeding in a randomized
trial in Malawi initial results of the
Breastfeeding, Antiretroviral and Nutrition (BAN)
Study Charles Chasela1, Michael Hudgens2, Denise
Jamieson3, Dumbani Kayira1, Mina Hosseinipour1,
Yusuf Ahmed3, Gerald Tegha1, Rodney Knight,
Athena Kourtis3, Deborah Kamwendo1, Irving
Hoffman2, Sascha Ellington3, Zebrone Kacheche1,
Jeffrey Wiener3, Francis Martinson1, Susan
Fiscus2, Peter Kazembe, Innocent Mofolo1, Dustin
Long2, Alice Soko1, Sarah Beth Smith2 and Charles
van der Horst2 for the BAN Study team. 1UNC
Project, Lilongwe, Malawi 2University of North
Carolina, Chapel Hill, North Carolina, USA,
3Centers for Disease Control and Prevention,
Atlanta, Georgia, USA
2
BAN Study Background

• Current international guidelines recommend
  exclusive breastfeeding by HIV-infected women for
  the first six months of life unless replacement
  feeding is acceptable, feasible, affordable,
  sustainable, and safe for them and their infants
  before that time1
• Formula is not recommended in Malawi since it is
  expensive and if used for the first 6 months
  yields higher infant mortality2
• Urgent need for interventions to make
  breastfeeding safer for infants of HIV-infected
  women
• 1 HIV and infant feeding new evidence and
  programmatic experience. Report of a technical
  consultation.WHO 2007. http//whqlibdoc.who.int/p
  ublications/2007/9789241595971_eng.pdf
• 2 Thior I, et al. Breastfeeding plus infant
  zidovudine prophylaxis for 6 months vs formula
  feeding plus infant zidovudine for 1 month to
  reduce mother-to-child HIV transmission in
  Botswana a randomized trial the Mashi Study.
  Jama. 2006 Aug 16296(7)794-805.

Recommendations
3
BAN Study Description

• 2x3 factorial, randomized, controlled,
  open-label design to evaluate 2 interventions
  given to HIV-infected mothers or their infants
  during 24-weeks of exclusive breastfeeding and 4
  weeks weaning
• Antiretroviral medications given either to
  infants or to their mothers to prevent infant HIV
  transmission compared to an enhanced standard of
  care arm
• Nutritional supplementation given to women to
  prevent maternal depletion compared to enhance
  standard of care

van der Horst CM, et al. Contemporary Clinical
Trials. 20093024-33 www.thebanstudy.org
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ARV intervention
Mother and Infant
Enhanced Control
ZDV/3TC sdNVP x1
ZDV/3TC X 1 wk
ZDV/3TC sdNVP x1
ZDV/3TC x1 wk
Maternal HAART
ZDV/3TC/NVP x 28 wks to mother
Infant NVP
ZDV/3TC x1 wk
ZDV/3TC sdNVP x1
NVP x 28 wks to infant
Exclusive Breastfeeding for 24 weeks with
weaning over 4 weeks. Weaning food plumpy nut
provided until week 48 NVP changed to NFV
February 2005 NFV Changed to LPV/r January 2006
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BAN Study Primary Endpoints

• The primary end point was infant HIV status at 28
  weeks in those uninfected at birth
• Standard survival analysis methods were used to
  estimate time to first positive HIV-1 test and
  time to first positive HIV-1 test or death by
  treatment arm
• Infant testing real time at birth, 2, 12, 28 and
  48 weeks by DNA PCR
• Dried Blood Spots (DBS) obtained at each visit
  and tested to narrow the window of transmission
  to less than 4 weeks
• All positives were confirmed with a second
  specimen

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THE BAN STUDY AS OF April 1, 2009
3572 HIV-infected pregnant women consented to
screening at antenatal visit

• 377 Failed primary eligibility
• 289 CD4lt250
• 22 Previous ARV
• 66 Other
• 405 Did not report at delivery

2790 women delivered

• 404 Failed secondary eligibility
• 185 late presentation
• 91 lt 2kg infants
• 47 still birth
• 81 Other
• 19 Chose not to participate

2367 mother-infant pairs randomized
851 Maternal HAART
848 Infant NVP
668 Enhanced Control
Arms uneven due to DSMB recommended change in
study design March 2008
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BAN Baseline Characteristics
Infant NVP N848 25 (22-30) 0.14 440 (331-
590) 11.8 (10.7-12.8) 3009 (404)
Maternal HAART N851 26 (22-29)
0.71 428 (322- 565) 11.9 (10.7-12.9)
2998 (418)
Maternal Factors Age Median (Interquartile
range) BMI lt 17kg/cm2 () CD4 Median
(Interquartile range) Hemoglobin g/dl Median
(Interquartile range) Infant Factors Birth
weight Mean (STD)
Enhanced Control N668 26 (22-29) 0.36 442 (3
34- 589) 11.8 (10.5-12.8) 3008 (434)
P-value 0.70 0.21 0.16 0.40 0.83
Arms uneven due to DSMB recommended change in
study design March 2008
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BAN Grade 3 and 4 Toxicities (Birth to 28 weeks)
Infant NVP N 848
Maternal HAART N 851
Enhanced Control N 668
Low Hgb () Low Neutrophil Count () Low
Platelets () High ALT () NVP Hypersensitivity
(number) Death (number) Low Hgb () Low ANC
() Low Platelets () High ALT () NVP
Hypersensitivity (number)
0.7 2.9 1.0 0.4 0 0 21.3 0.6 1.3 0.6 16
1.8 2.0 1.2 0.8 0 2 22.8 1.3 1.5 0.8 0
2.1 6.7 1.5 1.6 6 0 19.4 0.4 1.0 0.6 1
Maternal toxicities
Infant toxicities
Neutrophil Count for Maternal HAART vs Control
plt0.0001
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BAN Probability HIV positive by week 28 visit in
infants uninfected at birth
10
BAN Probability HIV positive or death by week 28
visit in infants uninfected at birth
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Conclusions

• Either maternal HAART or infant NVP prophylaxis
  during 28 weeks of breastfeeding are safe and
  effective in reducing postnatal mother-to-child
  transmission of HIV
• Although this study was not powered to compare
  the maternal and infant interventions, there was
  some suggestion that infants had a lower
  probability for HIV-infection or death in the
  infant NVP arm

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Implications

• The BAN results give global and national policy
  makers the choice of which intervention to
  implement based on the appropriateness for their
  particular setting
• The final 28 week visit will occur in August 2009
  
• The final 48 week visit will occur in January 2010

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The BAN Study Team

• BAN Study Team at University of North
  Carolina Chapel Hill, Centers for Disease Control
  and Prevention, Atlanta, and UNC Project team in
  Lilongwe including Linda Adair, Yusuf Ahmed,
  Sandra Albrecht, Shrikant Bangdiwala, Ronald
  Bayer, Margaret Bentley, Brian Bramson, Emily
  Bobrow, Nicola Boyle, Sal Butera, Charles
  Chasela, Charity Chavula, Joseph Chimerangambe,
  Maggie Chigwenembe, Maria Chikasema, Norah
  Chikhungu, David Chilongozi, Grace Chiudzu,
  Lenesi Chome, Anne Cole, Amanda Corbett, Amy
  Corneli, Ann Duerr, Henry Eliya, Sascha
  Ellington, Joseph Eron, Sherry Farr, Yvonne Owens
  Ferguson, Susan Fiscus, Shannon Galvin, Laura
  Guay, Chad Heilig, Irving Hoffman, Elizabeth
  Hooten, Mina Hosseinipour, Michael Hudgens, Stacy
  Hurst, Lisa Hyde, Denise Jamieson, George Joaki
  (deceased), David Jones, Zebrone Kacheche, Esmie
  Kamanga, Gift Kamanga, Coxcilly Kampani, Portia
  Kamthunzi, Deborah Kamwendo, Cecilia Kanyama,
  Angela Kashuba, Damson Kathyola, Dumbani Kayira,
  Peter Kazembe, Rodney Knight, Athena Kourtis,
  Robert Krysiak, Jacob Kumwenda, Misheck Luhanga,
  Victor Madhlopa, Maganizo Majawa, Alice Maida,
  Cheryl Marcus, Francis Martinson, Chrissie Matiki
  (deceased), Isabel Mayuni, Joyce Meme, Ceppie
  Merry, Khama Mita, Chimwemwe Mkomawanthu,
  Gertrude Mndala, Ibrahim Mndala, Agnes Moses,
  Albans Msika, Wezi Msungama, Beatrice Mtimuni,
  Jane Muita, Noel Mumba, Bonface Musis, Charles
  Mwansambo, Gerald Mwapasa, Jacqueline Nkhoma,
  Richard Pendame, Ellen Piwoz, Byron Raines, Zane
  Ramdas,  Mairin Ryan, Ian Sanne, Christopher
  Sellers, Diane Shugars, Dorothy Sichali, Alice
  Soko, Allison Spensley, Gerald Tegha, Martin
  Tembo, Roshan Thomas, Hsiao-Chuan Tien, Beth
  Tohill, Charles van der Horst, Jeffrey Wiener,
  Cathy Wilfert, Patricia Wiyo, Innocent Zgambo,
  Chifundo Zimba. Finally and most especially, all
  the women and infants that have agreed to
  participate in the study.

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Acknowledgements

• Funding/Support This research was funded by the
  Prevention Research Centers Special Interest
  Project SIP 13-01  U48-CCU409660-09 and SIP 26-04
  U48-DP000059-01, Centers for Disease Control and
  Prevention supported by the NIAID P30-AI50410
  UNC Center for AIDS Research DHHS/NIH/FIC 2-D43
  Tw01039-06 AIDS International Training and
  Research Program and Abbott Laboratories,
  GlaxoSmithKline, Boehringer-Ingelheim, Roche
  Pharmaceuticals and Bristol-Myers Squibb.  The
  Call to Action PMTCT program has been supported
  by the Elizabeth Glaser Pediatric AIDS Foundation
  Call to Action Award and International Leadership
  Awards, UNICEF, World Food Programme, Malawi
  Ministry of Health and Population, Johnson and
  Johnson and USAID.

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The BAN Study Team Lilongwe, Malawi July 2009