Trizivir Vs. Kaletra and Combivir for the Prevention of Mother-to-Child Transmission of HIV

• Virologic suppression [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Infant's HIV status [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

• HIV-1 RNA levels in plasma and breast milk [ Time Frame: At study entry and Months 1, 3, and 5 ] [ Designated as safety issue: No ]
• HIV-1 DNA levels in breast milk [ Time Frame: At Months 1, 3, and 5 ] [ Designated as safety issue: No ]
• Time from randomization to the first adverse event requiring discontinuation of any of the drugs that formed the initial regimen by treatment arm and compared to Mashi study [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Time from randomization to the first Grade 3 or higher adverse event by treatment arm and compared to Mashi study [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Occurrence of Grade 3 or higher adverse events by type, grade, body system, and association with study treatment compared to Mashi study [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Premature birth and very premature birth, defined as 37 and 32 weeks gestation or less, respectively [ Time Frame: At study entry ] [ Designated as safety issue: No ]
• Low birth weight and very low birth weight, defined as less than 2,500 g and less than 1,500 g, respectively [ Time Frame: At study entry ] [ Designated as safety issue: No ]
• Growth and developmental delay, defined as standard norms and neurodevelopmental screening [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Maternal mortality [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Maternal morbidity, defined as occurrence of Grade 3 or 4 adverse events, hospitalizations, and AIDS-defining or AIDS-associated diagnoses [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Change in maternal CD4 count from baseline over time [ Time Frame: Through Month 24 ] [ Designated as safety issue: No ]
• Infant mortality [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Comparison of neurodevelopment at 2 years of age in the Mashi study and this study [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Adherence, as measured by questionnaire and pill count [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Occurrence of HIV-1 RNA genetic mutations associated with viral resistance in maternal plasma and breast milk and infant plasma among transmitting mother-infant pairs at the nearest time to transmission [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Antiretroviral therapy (ARV) toxicities and viral load differences by maternal HLA type, for subset of up to 500 women with HLA-type available [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• ARV concentrations in breast milk and serum and in their infants' serum for all transmitting mother-infant pairs and a matched group of nontransmitting pairs [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

• Virologic suppression to less that 400 copies/ml at both delivery and during the entire breastfeeding period, regardless of whether or not randomized treatment is being taken at the time of each measurement
• virologic suppression to less than 50 copies/ml or 1,000 copies/ml at delivery, during the breastfeeding period, and both at delivery and during the breastfeeding period
• HIV-1 RNA levels in plasma and in breast milk at delivery and at 1, 3, and 5 months postpartum
• time from randomization to the first adverse event requiring discontinuation of any of the drugs that formed the initial regimen
• time from randomization to the first Grade 3 or higher adverse event
• occurrence of Grade 3 or higher adverse events by type, grade, body system, and association with study treatment
• premature birth and very premature birth, defined as 37 and 32 weeks gestation or less, respectively
• low birth weight and very low birth weight, defined as less than 2500 g and less than 1500 g, respectively
• growth and developmental delay, defined as standard norms and neurodevelopmental screening
• maternal mortality
• maternal morbidity, defined as occurrence of Grade 3 or 4 adverse events, hospitalizations, and AIDS-defining or AIDS-associated diagnoses
• change in maternal CD4 count from baseline over time to 12 months postpartum
• infant mortality
• adherence, as measured by questionnaire and pill count
• occurrence of HIV-1 RNA genetic mutations associated with viral resistance in maternal plasma and breast milk and infant plasma among transmitting mother-infant pairs at the nearest time to transmission
• LPV/RTV concentrations in the serum of 10 pregnant women, after 1 month of LPV/RTV and 3TC/ZDV
• antiretroviral concentrations in breast milk and serum and in their infants's serum for all transmitting mother-infant pairs and a matched group of non-transmitting pairs

Anti-HIV drug regimens have dramatically improved the rates of prevention of mother-to-child transmission (MTCT) of HIV in developed countries. However, little is known of the effectiveness of such regimens in developing countries, such as Botswana. This study will determine whether Trizivir (TZV), a single pill containing abacavir sulfate, lamivudine, and zidovudine (ABC/3TC/ZDV), or lopinavir/ritonavir (LPV/r) and lamivudine/zidovudine (3TC/ZDV) is more effective in reducing HIV-1 viral load and preventing MTCT among HIV infected pregnant women in Botswana.

While perinatal HIV infection has become rare in developed countries through the use of highly active antiretroviral therapy (HAART), it remains a serious problem in developing countries. Botswana has a population of approximately 1.7 million; the prevalence of HIV in Botswana is about 37.4%. In the developed world, HAART has revolutionized the prevention of MTCT among nonbreastfed infants. This trial will compare the effectiveness of a protease inhibitor (PI)-based regimen versus a triple nucleoside reverse transcriptase inhibitor (NRTI)-based regimen in preventing MTCT of HIV.

This study will last up to 24 months for mothers and their children. Participants will be stratified based on their CD4 count at screening. Women with CD4 counts of 200 cells/mm3 or more will be in one of two treatment groups and will be randomly assigned to receive either TZV twice daily or LPV/RTV and 3TC/ZDV twice daily. Once in labor, treatment group participants will continue to take their assigned HAART regimen and will also be given additional ZDV. Women with CD4 counts less than 200 cells/mm3 will receive nevirapine (NVP) once daily for the first 14 days, then twice daily, and 3TC/ZDV twice daily; these women will be in the observational group.

Shortly after birth, infants will receive single-dose NVP. A 1-month supply of ZDV will be provided to the mother to administer daily to her child. Mothers will stop HAART at 6 months postpartum or when they stop breastfeeding, whichever occurs earlier. A clinical evaluation, blood collection, and HIV prevention counseling will occur at all maternal visits. An obstetrical exam and physical exam will occur at selected visits. Women will provide at least four samples of breast milk during the first 5 months postpartum. For infants, a clinical evaluation will occur at every visit, and a physical exam and blood collection will occur at selected visits.

• Drug: Trizivir
  300 mg abacavir sulfate/150 mg lamivudine/300 mg zidovudine tablet taken orally twice daily
  Other Name: TZV
• Drug: Lamivudine/Zidovudine
  150 mg lamivudine/300 mg zidovudine tablet taken orally twice daily
  Other Names:

  • 3TC/ZDV
  • Combivir
• Drug: Lopinavir/Ritonavir
  400 mg lopinavir/100 mg ritonavir tablet taken orally twice daily
  Other Name: LPV/RTV
• Drug: Nevirapine
  200 mg tablet taken orally daily for the first 14 days before receiving 200 mg tablet taken orally twice daily
  Other Name: NVP

• Experimental: 1A
  Participants in Arm 1A will have CD4 counts of 200 cells/mm3 or more and will receive TZV twice daily. Once in labor, these participants will continue to take TZV twice daily and will also be given additional ZDV.
  Intervention: Drug: Trizivir
• Experimental: 1B
  Participants in Arm 1B will have CD4 counts of 200 cells/mm3 or more and will receive LPV/RTV and 3TC/ZDV twice daily. Once in labor, these participants will continue to take TZV twice daily and will also be given additional ZDV.
  Interventions:

  • Drug: Lamivudine/Zidovudine
  • Drug: Lopinavir/Ritonavir
• Experimental: 2
  Participants in Arm 2 will have CD4 counts less than 200 cells/mm3 and will receive NVP once daily for the first 14 days, then twice daily, and 3TC/ZDV twice daily; these women will be in the observational group.
  Intervention: Drug: Nevirapine

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Inclusion Criteria for Mothers:

• HIV-infected
• At least at 26th week of pregnancy (treatment group) or 18th week of pregnancy (observational group) but not beyond the 34th week of pregnancy
• Able to complete study visits until at least 6 months postpartum
• Citizen of Botswana

Exclusion Criteria for Mothers:

• Taken ARVs for more than 1 week, other than ZDV, during current or prior pregnancy. Women who have received single-dose NVP in a prior pregnancy are not excluded.
• Certain abnormal laboratory values
• Plan to formula feed
• Known fetal abnormalities that suggest the fetus will not survive to 6 months of gestational age
• Known allergy or medical contraindication to any of the study drugs
• Require certain medications
• Previous participation in the "Prevention of Milk-Borne Transmission of HIV-1C in Botswana" (Mashi) study
• Currently incarcerated