Breastfeeding, Antiretroviral, and Nutrition Study

• Postpartum weight loss between delivery and 28 weeks [ Time Frame: between delivery and 28 weeks ] [ Designated as safety issue: Yes ]
• Infant HIV status at 28 weeks. (Infants found to have HIV at birth or 2 weeks after delivery will have been disenrolled.) [ Time Frame: birth to 28 weeks ] [ Designated as safety issue: No ]
• Exclusive breastfeeding and breastfeeding cessation by 28 weeks [ Time Frame: birth to 28 weeks ] [ Designated as safety issue: No ]

• 1. Postpartum weight loss between delivery and 28 weeks.
• 2. Infant HIV status at 28 weeks. (Infants found to have HIV at birth or 2 weeks after delivery will have been disenrolled.)
• 3. Exclusive breastfeeding and breastfeeding cessation by 28 weeks.

• Duration of exclusive breastfeeding [ Time Frame: birth to 28 weeks ] [ Designated as safety issue: No ]
• Infant HIV status through 48 weeks [ Time Frame: birth to 48 weeks ] [ Designated as safety issue: No ]
• Maternal adherence to ARV, maternal CD4 count, and clinical assessment of opportunistic infection status through 48 weeks [ Time Frame: delivery to 48 weeks ] [ Designated as safety issue: No ]

• 1. Duration of exclusive breastfeeding;
• 2. Infant HIV status through 48 weeks;
• 3. Maternal adherence to ARV, maternal CD4 count, and clinical assessment of opportunistic infection status through 48 weeks.

This is a comparative clinical trial among HIV-infected women and their infants to determine:

1. the benefit of nutritional supplementation given to women during breastfeeding
2. the benefit and safety of antiretroviral (ARV) medications given either to infants or to their mothers to prevent HIV transmission during breastfeeding
3. the feasibility of exclusive breastfeeding followed by early, rapid breastfeeding cessation

This study addresses the complex issues of HIV related maternal morbidity, mortality, and postnatal HIV transmission during breastfeeding and weaning in resource-poor countries. Objectives include assessment of mortality and morbidity among HIV-infected women; evaluation of interventions to reduce HIV transmission to infants exposed by breast milk; and assessment of early weaning as a risk-reduction strategy for infants of HIV-infected mothers.

The study will evaluate the following:

1. The efficacy of a high-density caloric/micronutrient nutritional supplement given to HIV-infected women who breastfeed in preventing maternal depletion (weight loss and micronutrient status).
2. The safety and efficacy of maternal or infant antiretroviral regimens, taken for up to 6 months during breastfeeding, in reducing infant HIV infection rates at 48 weeks.
3. The feasibility of exclusive breastfeeding for 6 months followed by rapid weaning.

Additional study objectives are to evaluate the feasibility of delivering these interventions in resource poor settings and to identify maternal, infant, and virologic factors associated with HIV transmission during breastfeeding.

• Drug: Maternal zidovudine/lamivudine/lopinavir-ritonavir
  Total daily dose: zidovudine 600mg, lamivudine 300mg, (taken as Combivir 1 tab twice a day with food). Lopinavir/ritonavir 400/100mg (taken as 2 tabs twice a day). Commencing after delivery and through to 28 weeks.
  Other Names:

  • Combivir tabs (zidovudine 300mg and lamivudine 150mg)
  • Aluvia tabs (lopinavir 200mg /ritonavir 50mg)
• Drug: Infant nevirapine

  Nevirapine suspension once daily dose. 0-14days: 10mg; 3-18weeks: 20mg; 19-28weeks: 30mg.

  To 28 weeks while breastfeeding.

  Other Name: Viramune (Nevirapine) suspension 50mg/5ml
• Dietary Supplement: Maternal protein and calorie supplement
  High energy, nutrient-dense, micronutrient fortified nutritional supplement. Daily: Energy 700kcal, Protein 20g, 100% of recommended dietary allowance for all micronutrients during the 6 months of lactation. Vitamin A is excluded.
  Other Name: Produced by Nutriset. Daily dose: 2 sachets.

• Active Comparator: Maternal ARVs & Nutrition Supplement
  Extended maternal ARVs for prophylaxis (for the infant) & daily nutritional supplement given to the mother
  Interventions:

  • Drug: Maternal zidovudine/lamivudine/lopinavir-ritonavir
  • Dietary Supplement: Maternal protein and calorie supplement
• Active Comparator: Infant NVP & Nutrition Supplement
  Extended infant nevirapine for prophylaxis & daily nutritional supplment given to the mother
  Interventions:

  • Drug: Infant nevirapine
  • Dietary Supplement: Maternal protein and calorie supplement
• Active Comparator: Maternal ARVs & No Nutrition Supplement
  Extended maternal ARVs for prophylaxis (for the infant) & no nutritional supplement given to the mother
  Intervention: Drug: Maternal zidovudine/lamivudine/lopinavir-ritonavir
• Active Comparator: Infant NVP & No Nutrition Supplement
  Extended infant nevirapine for prophylaxis & no nutritional supplment given to the mother
  Intervention: Drug: Infant nevirapine
• Active Comparator: No Drugs & Nutrition Supplement

  No extended maternal ARV prophylaxis nor infant nevirapine prophylaxis & daily nutritional supplement given to the mother.

  Note: As of March 2008, the third arm of the antiretroviral intervention, in which neither mother nor infant received drugs beyond enhanced standard of care, was stopped based on recommendations of a Data and Safety Monitoring Board review of interim efficacy results and safety data after 77% participants had received treatment assignment.

  Intervention: Dietary Supplement: Maternal protein and calorie supplement
• No Intervention: No Drugs & No Nutrition Supplement

  No extended maternal ARV prophylaxis nor infant nevirapine prophylaxis & no nutritional supplement given to the mother.

  Note: As of March 2008, the third arm of the antiretroviral intervention, in which neither mother nor infant received drugs beyond enhanced standard of care, was stopped based on recommendations of a Data and Safety Monitoring Board review of interim efficacy results and safety data after 77% participants had received treatment assignment.

• Flax VL, Bentley ME, Chasela CS, Kayira D, Hudgens MG, Kacheche KZ, Chavula C, Kourtis AP, Jamieson DJ, van der Horst CM, Adair LS. Lipid-based nutrient supplements are feasible as a breastmilk replacement for HIV-exposed infants from 24 to 48 weeks of age. J Nutr. 2013 May;143(5):701-7. doi: 10.3945/jn.112.168245. Epub 2013 Mar 6.
• Flax VL, Bentley ME, Chasela CS, Kayira D, Hudgens MG, Knight RJ, Soko A, Jamieson DJ, van der Horst CM, Adair LS. Use of lipid-based nutrient supplements by HIV-infected Malawian women during lactation has no effect on infant growth from 0 to 24 weeks. J Nutr. 2012 Jul;142(7):1350-6. Epub 2012 May 30.
• Jamieson DJ, Chasela CS, Hudgens MG, King CC, Kourtis AP, Kayira D, Hosseinipour MC, Kamwendo DD, Ellington SR, Wiener JB, Fiscus SA, Tegha G, Mofolo IA, Sichali DS, Adair LS, Knight RJ, Martinson F, Kacheche Z, Soko A, Hoffman I, van der Horst C; BAN study team. Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial. Lancet. 2012 Jun 30;379(9835):2449-58. Epub 2012 Apr 26.
• Chasela CS, Hudgens MG, Jamieson DJ, Kayira D, Hosseinipour MC, Kourtis AP, Martinson F, Tegha G, Knight RJ, Ahmed YI, Kamwendo DD, Hoffman IF, Ellington SR, Kacheche Z, Soko A, Wiener JB, Fiscus SA, Kazembe P, Mofolo IA, Chigwenembe M, Sichali DS, van der Horst CM; BAN Study Group. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010 Jun 17;362(24):2271-81.

Inclusion Criteria:

Recruitment and primary eligibility criteria:

• Age > 14 years.
• Ability to give informed assent or consent.
• Evidence of HIV infection, as documented by 2 positive ELISA antibody tests; or 1 positive ELISA, and 1 Western Blot; or 2 separate concurrent rapid tests.
• Currently pregnant (with a single or multiple fetuses).
• Gestation < 30 weeks at referral from 'Call to Action' Program
• No serious current complications of pregnancy.
• Intention to breastfeed.
• Intention to deliver at the institution at which the study is based.
• Not previously enrolled in this study for an earlier pregnancy.
• Other than HIV, no active serious infection, such as tuberculosis or other potentially serious illnesses.
• No previous use of antiretrovirals including the HIVNET 012 regimen.
• Mother's CD4 count > 250 cells/uL determined in the antenatal clinic.
• Mother's ALT < 2.5 x ULN (upper limit of normal) determined in the antenatal clinic

Secondary eligibility criteria and treatment assignment:

• Mother who delivers outside of the institution at which the study is based must present with her infant to the study site within 36 hours of delivery.
• Mother accepts nevirapine and zidovudine+lamivudine 7-day regimen for herself and her infant.
• Infant birth weight > 2000 g.
• No severe congenital malformations or other condition(s) not compatible with life.
• Based on clinical assessment, no maternal condition which would preclude the start of the study intervention.

• University of North Carolina, Chapel Hill
• Kamuzu Central Hospital, Lilongwe, Malawi