Drake et. al.28 |
Kenya |
To quantify the effect of HSV-2 suppression on reducing plasma, cervical, and breast milk HIV-1 RNA levels among pregnant and postpartum Kenyan women coinfected with HIV-1 and HSV-2. |
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Inclusion criteria: ≥ 18 years of age, HIV-1 and HSV-2 seropositive, 28–32 weeks of gestation, CD4 count > 0.250 cells/mm3.
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Exclusion criteria: hypersensitivity to acyclovir or valacyclovir, clinical indication for HAART (WHO stage 3 or 4).
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148 subjects enrolled 74 randomized to each arm 146 women were included in analyzes |
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Mothers: n (%/weeks):
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Gestational age (weeks) Valacyclovir = 39 (38–40), Placebo = 39 (38–41)
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Infants: Median (IQR) or n (%): B
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irth weight (kg) Valacyclovir = 3.2 (2.9–3.5), Placebo = 3.0 (2.9–3.5)
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Female Valacyclovir = 38 (53), Placebo = 47 (66)
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A) valacyclovir group (n = 74) valacyclovir (500 mg twice a day) 51 included in pregnancy analyzes 72 included in postpartum analyzes |
B) Placebo group (n = 74) 49 included in pregnancy analyzes 73 included in postpartum analyzes |
Most infants were breastfed |
Median: 6.0 months in the valacyclovir arm 5.3 months in the placebo arm (IQR, 3.4–6.5, both arms). |
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Antenatal visits: at 34 and 38 weeks of gestation
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Postpartum follow-up visits: at 2, 6, 10, and 14 weeks and 6, 9, and 12 months postpartum.
|
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HIV-1 transmission rate:
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10 infants (6 valacyclovir, 4 placebo) acquired HIV-1 by 12 months for a transmission rate of 7.0%.
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There was no difference in transmission between arms (hazard ratio [HR], 1.45; 95% CI, 0.41–5.12).
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HIV-1–free survival: similar between study arms (HR, 0.86; 95% CI, 0.33–2.22).
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Nagot et. al.7 |
Burkina Faso, South Africa, Uganda, and Zambia |
To compare the effect of lopinavir–ritonavir and lamivudine on the rate of HIV-1 transmission and adverse events in infants exposed to HIV-1 in Africa. |
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Inclusion criteria: Infants:
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7 days of age; singleton; breastfed by their mothers at the 7th day of life; negative HIV-1 DNA PCR at the 7th day of life; received PMTCT;
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Mothers: ≥ 18 years of age, intending to continue breastfeeding, infected with HIV-1, not eligible for ART nor taking ART, received perinatal antiretroviral prophylaxis during pregnancy or delivery.
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Exclusion criteria: Infants: clinical signs or biological abnormalities of grade 2 ≤ on DAIDS adverse events grading tables, haemoglobin < 120 g/L, neutrophils < 1200 cells per μL, serious congenital malformations or birthweight ≤ 2.0 kg.
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1,273 infants exposed to HIV-1 enrolled
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1,236 infants included in the modified intention-to-treat analysis
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Mothers:
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Median age: 27·1 years (IQR 23·3–31·1).
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Infants: Boys Lopinavir–ritonavir group = 322 (51%) Lamivudine group = 335 (53%)
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Girls Lopinavir–ritonavir group = 309 (49%) Lamivudine group = 301 (47%)
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Birthweight (g) Lopinavir–ritonavir group = 3000 (2740–3350) Lamivudine group = 3000 (2800–3325)
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A) lopinavir–ritonavir (n = 615)
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Mothers: zidovudine from 28 weeks of pregnancy until birth, intrapartum single-dose nevirapine, zidovudine–lamivudine for 7 days after birth.
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Infants:
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7 days of nevirapine from birth.
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40 mg of lopinavir and 10 mg of ritonavir twice a day if weighing 2–4 kg, and 80 mg and 20 mg, twice a day if weighing > 4 kg
|
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B) lamivudine (n = 621)
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Mothers: zidovudine from 28 weeks of pregnancy until birth, intrapartum single-dose nevirapine, zidovudine–lamivudine for 7 days after birth.
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Infants:
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7 days of nevirapine from birth.
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Lamivudine: 75 mg twice a day if weighing 2–4 kg, 25 mg twice a day if weighing 4–8 kg, and 50 mg twice a day if weighing > 8 kg
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Breastfeeding only
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Median: Lopinavir–ritonavir group = 41.1 weeks (IQR 34.4–45.6), Lamivudine group = 41.4 weeks (35.9–46.7). |
2 weeks after enrolment, then every 4 weeks until week 50. |
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Infant HIV-1 acquisition: 17 HIV-1 infections were confirmed in infants:
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lopinavir–ritonavir = 8, 1.4% (95% CI 0.4–2.5) lamivudine = 9, 1.5% (0.7–2.5) cumulative postnatal transmission rate (p = 0.83).
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Hazard ratio [HR] of lopinavir–ritonavir versus lamivudine of 0.90, 95% CI 0.35–2.34; p = 0.83.
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Pooling the two groups, the cumulative transmission rate was 0.7% (n = 9; 95% CI 0.2–1.2) at 26 weeks and 1.5% (n = 17; 0.8–2.2) at 50 weeks.
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Coovadia et. al.8
|
South Africa, Tanzani a, Uganda, Zimbabwe |
To assess the incremental safety and efficacy of extension of prophylaxis after 6 months. |
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Eligible women and infants were enrolled within 7 days of delivery. Inclusion criteria: Mothers: ≥ 18 years of age. Infants: negative HIV-1 DNA PCR, birthweight 2000 g ≤. negative HIV-1 DNA PCR based on a specimen obtained within 21 days before randomization, breastfed. Exclusion criteria: serious medical disorders that could interfere with study participation, development of HIV-1 infection.
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|
|
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All enrolled infants received open-label nevirapine (10 mg/mL oral suspension) once a day during the first 6 weeks of life. After this treatment (at 6–8 weeks of age): A) Extended nevirapine group (n = 759) The nevirapine dose increased with age, ranging from 20 mg once a day at 6–8 weeks of age to 28 mg once a day at 5–6 months of age.
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All enrolled infants received open-label nevirapine (10 mg/mL oral suspension) once a day during the first 6 weeks of life. After this treatment (at 6–8 weeks of age): B) Placebo group (n = 763)
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Breastfeeding only
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Infant study visits took place within 7 days postpartum, at 2, 5, 6, and 8 weeks, and at 3, 6, 9, 12, and 18 months. |
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Extended nevirapine group: 1.1% (95% CI 0.3–1.8) from 6 weeks to 6 months of age. Placebo group: 2.4% (1.3–3.6) (1·3% difference, 95% CI 0–2.6; p = 0.049). equating to a 54% reduction in HIV-1 transmission. Study interventions stopped at 6 months of age. Differences between study groups were no longer significant at 9 and 12 months of age.
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Fowler et. al.29
|
South Africa, Tanzania, Uganda, and Zimbabwe. |
To compare the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to receive NVP or placebo for postnatal infection prevention. |
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Inclusion criteria:
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Mothers: women infected with HIV, ≥ 18 years of age, no other serious illnesses
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Infants: not infected with HIV based on a specimen obtained within 7 days of birth, birth weight of ≥ 2000 g, no life-threatening conditions, breastfed.
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Exclusion criteria:
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Women and their infants (n = 1,522)
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|
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A) Extended daily NVP (n = 759) All enrolled infants received open-label NVP (10 mg/mL oral suspension) once a day during the first 6 weeks of life.
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NVP administered once a day until 6 months of age or until cessation of breastfeeding (whichever came first).
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B) Placebo (n = 763)
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Breastfeeding only
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Median: 184 days in both study arms; by 12 months, cessation of breastfeeding was reported for 95% of infants. |
Infant follow-up study visits were scheduled at 2, 5, 6, and 8 weeks and at 3, 6, 9, 12, and 18 months. |
39 postnatal HIV infections from 6 weeks to 18 months. HIV infection rates at 6 weeks and 6 months of age were significantly different between study arms: 1.1% (95% CI 0.3–1.8) in the NVP arm versus 2.4% (95% CI: 1.3% to 3.6%) in the placebo arm, p = 0.049. By 18 months, there were 16 infections in the NVP arm and 23 infections in the placebo arm, with a cumulative postnatal infection rate of 2.2% (95% CI: 1.1–3.3) versus 3.1% (95% CI: 1.9–4.4, p = 0.28), translating into HIV-free rates of 97.8% in the NVP arm versus 96.9% in the placebo arm. |
Humphrey et. al.11
|
Zimbabwe |
To investigate the effect of single-high-dose maternal/neonatal vitamin A supplementation on MTCT, HIV-free survival, and mortality in infants exposed to HIV. |
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14,110 mother-infant pairs 4,495 infants
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Maternal age, mean ± SD, years:
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Aa = 25.6 ± 5.0
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Ap = 25.6 ± 4.9
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Pa = 25.5 ± 5.0
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Pp = 25.6 ± 5.0
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Infant birth weight, mean ± SD, kg:
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Aa = 2.88 ± 0.45
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Ap = 2.92 ± 0.47
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Pa = 2.91 ± 0.48
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Pp = 2.94 ± 0.47
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Male sex:
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Aa = 534 (48.4)
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Ap = 593 (52.7)
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Pa = 570 (49.8)
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Pp = 585 (52.2)
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Gestational age, mean ± SD, weeks:
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Aa = 39.1 ± 1.5
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Ap = 39.2 ± 1.5
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Pa = 39.1 ± 1.6
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Pp = 39.1 ± 1.4
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Aa Group (n = 3,529)
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HIV+ Mothers (n = 1,103)
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HIV- Infants (n = 1,012)
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Ap Group (n = 3,529)
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HIV+ Mothers (n = 1,126)
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HIV- Infants (n = 1,006)
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Pa Group (n = 3,530)
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HIV+ Mothers (n = 1,144)
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HIV- Infants (n = 1,026)
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A) maternal vitamin
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A supplementation (400,000 IU), a) infant vitamin A supplementation (50,000 IU), P) maternal placebo, p) infant placebo.
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Pp Group (n = 3522)
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HIV+ Mothers (n = 1122)
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HIV- Infants (n = 1020)
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Breastfeeding only
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All but 4 mothers infected with HIV initiated breastfeeding, and 97%, 92%, 66%, and 19% were still breastfeeding at 6, 12, 18, and 24 months postpartum, respectively.
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These proportions did not differ between treatment groups (for all x2 tests [3 df], P > 0.7).
|
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Visits took place at 6 weeks, 3 months, and then every 3 months for 12–24 months.
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24%, 48%, and 100% of the pairs were reassigned to 24-month, ≥ 18-month, and ≥ 12-month follow-up, respectively.
|
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Aa Group: Infection events at 12 and 24 months: 278 (29.6%: CI: 26.6-32.5) and 297 (35.9%, CI: 31.9 – 40.3), respectively
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Ap Group: Infection events at 12 and 24 months: 333 (35.2%%: CI: 32.4 – 38.6) and 346 (42.8%, CI: 36.7 – 51.8), respectively
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Pa Group: Infection events at 12 and 24 months: 332 (35.2%%: CI: 32.1 – 38.2) and 347 (40.5%, CI: 36.3 – 46.0), respectively
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Pp Group: Infection events at 12 and 24 months: 293 (31.9%: CI: 28.6 – 34.6) and 310 (35.3%, CI: 31.8 – 39.2), respectively
|
Jamieson et. al.30 |
Ivory Coast |
To examine the maternal risk factors for HIV-1 transmission to children aged 1 and 24 months in a population of lactating women infected with HIV in Ivory Coast. |
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Inclusion criteria: pregnant women seropositive for HIV-1
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Exclusion criteria: women seropositive for HIV-2, previous treatment with ZDV
|
|
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Mothers: Age (years)
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≤ 25: 106 (42.4)
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> 25: 144 (57.6)
|
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A) Oral ZDV prophylaxis (300 mg orally twice a day) (n = 126) treatment from 36 weeks of gestational age until delivery. Upon onset of labor, a single additional dose of ZDV was administered (300 mg every 3 h until delivery).
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After delivery, antiretroviral medication was not given to either the baby or the mother.
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B) Placebo (n = 124)
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Breastfeeding only
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All but 2 children were breastfed from birth, and only 2.4% (6/249) were weaned at the 3-month visit. |
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Before delivery, women were enrolled at 34 weeks and followed up every 2 weeks until delivery.
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After delivery, women and infants were followed up at 1 and 3 months and then every 3 months until 24 months after delivery.
|
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Of the 250 infants, 42 were detected as infected by the age of 1 month and an additional 20 were detected as infected from 1 to 24 months of age.
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Two of the weaned children tested positive at the age of 1 month.
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Cumulative transmission: the overall risk of transmission in the ZDV group was 11.9% and 22.1% by 1 and 24 months, respectively. In the placebo group, the cumulative transmission risk was 21.9% and 29.2% by 1 and 24 months, respectively.
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Petra Study Team12
|
South Africa, Uganda, and Tanzania. |
To assess the efficacy of short-course regimens with zidovudine and lamivudine in a predominantly breastfeeding population. |
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1,457 women
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366 in regimen A (380 infants; 14 twins)
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371 in regimen B (382 infants; 11 twins)
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368 in regimen C (377 infants; 9 twins)
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352 in the placebo regimen (362 infants; 10 twins)
|
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Mothers: Age (years, median [IQR])
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Regimen A: 26 (23–29)
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Regimen B: 26 (23–30)
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Regimen C: 26 (23–30)
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Placebo: 26 (22–30)
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Infants: Male
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Regimen A: 199 (53%)
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Regimen B: 205 (54%)
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Regimen C: 185 (50%) Placebo: 181 (50%)
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Female
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Regimen A: 178 (47%)
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Regimen B: 175 (46%)
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Regimen C: 187 (50%)
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Placebo: 177 (50%)
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Birthweight (kg, median [range])
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Regimen A: 3.1 (2.8–3.4)
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Regimen B: 3.1 (2.8–3.4)
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Regimen C: 3.1 (2.8–3·4)
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Placebo: 3.1 (2.8–3.4)
|
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* Longest drug regimen (Regimen A): (n = 366 infants) From week 36 of pregnancy until the onset of labor: zidovudine (zi) 300 mg plus lamivudine (la) 150 mg twice a day
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During labor: zi 300 mg every 3 h and la 150 mg every 12 h until delivery.
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First 7 days postpartum: women: zi 300 mg plus la 150 mg twice a day newborns: zi 4 mg/kg plus la 2 mg/kg twice a day.
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*Intermediate regimen (Regimen B): (n = 371 infants) Started at the onset of labor: zi 600 mg and la 150 mg followed by zi 300 mg every 3 h and la 150 mg every 12 h until delivery.
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First 7 days postpartum: women: zi 300 mg plus la 150 mg twice a day newborns: zi 4 mg/kg plus la 2 mg/kg twice a day.
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* Shortest regimen (Regimen C): (n = 368 infants) women: zi 600 mg and la 150 mg at the onset of labor, then zi 300 mg every 3 h and la 150 mg every 12 h until delivery.
|
Placebo: (n = 352 infants)
|
Breastfeeding only
|
|
Follow-up visits at weeks 1, 3, and 6, and months 3, 6, 9, 12, 15, and 18. |
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At week 6, HIV-1 transmission rates were 5.7% for regimen A, 8.9% for regimen B, 14.2% for regimen C, and 15.3% for the placebo group (p = 0.0002).
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After 18 months, these proportions were 14.9% (95% CI 9.4–22.8), 18.1% (12.1–26.2), 20.0% (12.9–30.1), and 22·2% (15.9–30.2), respectively.
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Following week 6, continued HIV-1 transmission was rarely seen among non-breastfed children and predominantly occurred in breastfed infants.
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Due to weaning and HIV transmission, the proportion of breastfed children who were not infected with HIV-1 (the children at risk) declined over time, from 65% after 3 months of follow-up to 53% after 6 months, 31% after 1 year and 20% after 18 months.
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