Supplemental Table 1. Results of Major Studies on Antiretroviral Interventions to Prevent Perinatal HIV Transmission

Body
Study Name;
Location(s);
Mode of Infant Feeding
Antiretroviral Drugs Antepartum and Intrapartum Interventions Postpartum Interventions Perinatal Transmission Rate and Efficacy
PACTG 076;
United States, France;1
Formula feeding
ZDV vs. placebo Long (from 14 weeks)

IV IP
Long (6 weeks); infant only Perinatal transmission at 18 months was 8.3% in ZDV arm vs. 25.5% in placebo arm (68% efficacy).
CDC Short-Course ZDV Trial;
Thailand;12
Formula feeding
ZDV vs. placebo Short (from 36 weeks)

Oral IP
None Perinatal transmission at 6 months was 9.4% in ZDV arm vs. 18.9% in placebo arm (50% efficacy).
DITRAME (ANRS 049a) Trial;
Ivory Coast, Burkina Faso;11,39 
Breastfeeding
ZDV vs. placebo Short (from 36 weeks)

Oral IP
Short (1 week); mother only Perinatal transmission at 6 months was 18.0% in ZDV arm vs. 27.5% in placebo arm (38% efficacy).

Perinatal transmission at 15 months was 21.5% in ZDV arm vs. 30.6% in placebo arm (30% efficacy).

Perinatal transmission was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% efficacy).
CDC Short-Course ZDV Trial;
Ivory Coast;10,11
Breastfeeding
ZDV vs. placebo Short (from 36 weeks)

Oral IP
None Perinatal transmission at 3 months was 16.5% in ZDV arm vs. 26.1% in placebo arm (37% efficacy).

Perinatal transmission was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% efficacy).
PETRA Trial;
South Africa, Tanzania, Uganda;5
Breastfeeding and formula feeding
AP/IP/PP ZDV plus 3TC

vs.

IP/PP ZDV plus 3TC

vs.

IP-only ZDV plus 3TC

vs.

Placebo
Short (from 36 weeks)

Oral IP
Short (1 week); mother and infant Perinatal transmission at 6 weeks was 5.7% for AP/IP/PP ZDV plus 3TC, 8.9% for IP/PP ZDV plus 3TC, 14.2% for IP-only ZDV plus 3TC, and 15.3% for placebo (efficacy compared with placebo: 63%, 42%, and 0%, respectively).

Perinatal transmission at 18 months was 14.9% for AP/IP/PP ZDV plus 3TC, 18.1% for IP/PP ZDV plus 3TC, 20.0% for IP-only ZDV plus 3TC, and 22.2% for placebo (efficacy compared with placebo: 34%, 18%, and 0%, respectively).
HIVNET 012 Trial;
Uganda;4
Breastfeeding
SD NVP vs. ZDV No AP ARV drugs

Oral IP:
  • SD NVP vs. oral ZDV
SD NVP within 72 hours of birth; infant only

vs.

ZDV for 1 week; infant only
Perinatal transmission at 6–8 weeks was 11.8% in NVP arm vs. 20.0% in ZDV arm (42% efficacy) and 15.7% in NVP arm vs. 25.8% in ZDV arm at 18 months (41% efficacy).
 
SAINT Trial;
South Africa;6
Breastfeeding and formula feeding
SD NVP vs. ZDV plus 3TC No AP ARV drugs

Oral IP:
  • SD NVP vs. ZDV plus 3TC
SD NVP within 48 hours of birth; mother and infant

vs.

ZDV plus 3TC for 1 week; mother and infant
Perinatal transmission at 8 weeks was 12.3% in SD NVP arm vs. 9.3% in ZDV plus 3TC arm (difference not statistically significant, P = 0.11).
PHPT-1;
Thailand;13
Formula feeding
4 ZDV regimens with different durations of AP and infant PP administration; no placebo Long (from 28 weeks) or short (from 36 weeks)

Oral IP
 
Long (6 weeks) or short (3 days); infant only Perinatal transmission rate was 10.5% in the short-short arm. This arm was stopped at interim analysis.

Perinatal transmission at 6 months was 6.5% in long-long arm vs. 4.7% in long-short arm and 8.6% in short-long arm (no statistical difference). In utero transmission was significantly higher with short vs. long maternal therapy regimens (5.1% vs. 1.6%).
PACTG 316 Trial;
Bahamas, Belgium, Brazil, France, Germany, Italy, Spain, Sweden, Switzerland, United Kingdom, United States;21
Formula feeding
SD NVP vs. placebo among women already receiving ZDV alone (23%) or ZDV plus other ARV drugs (77% combination therapy) Nonstudy ARV regimen

Oral IP:
  • Placebo vs. SD NVP plus IV ZDV
     
Placebo vs. SD NVP within 72 hours of birth plus nonstudy ARV drugs (ZDV); infant only 77% of women received dual- or triple-combination ARV regimens during pregnancy.

Trial stopped early because of very low perinatal transmission in both arms: 1.4% in SD NVP arm vs. 1.6% in placebo arm (53% of perinatal transmission was in utero).
PHPT-2;
Thailand;40
Formula feeding
ZDV alone

vs.

ZDV plus maternal and infant SD NVP

vs.

ZDV plus maternal SD NVP
ZDV from 28 weeks

Oral IP:
  • ZDV alone, or
  • ZDV plus SD NVP
ZDV for 1 week with or without SD NVP; infant only ZDV-alone arm was stopped because the rate of perinatal transmission was higher in this arm than in the ZDV/NVP arm (6.3% vs. 1.1%, respectively). In arms in which the mother received SD NVP, the perinatal transmission rate did not differ significantly whether the infant received SD NVP or not (2.0% vs. 2.8%, respectively).
DITRAME Plus (ANRS 1201.0) Trial;
Ivory Coast;15
Breastfeeding and formula feeding
Open label, ZDV plus SD NVP ZDV from 36 weeks

Oral IP:
  • ZDV plus SD NVP
SD NVP plus ZDV for 1 week; infant only Perinatal transmission at 6 weeks was 6.5% (95% CI, 3.9% to 9.1%); perinatal transmission for historical control group receiving short ZDV (98% of whom were breastfed) was 12.8%. 
DITRAME Plus (ANRS 1201.1) Trial;
Ivory Coast;15
Breastfeeding and formula feeding
Open label, ZDV plus 3TC plus SD NVP ZDV plus 3TC from 32 weeks (stopped at 3 days PP)

Oral IP:
  • ZDV plus 3TC plus SD NVP
SD NVP plus ZDV for 1 week; infant only Perinatal transmission at 6 weeks was 4.7% (95% CI, 2.4% to 7.0%); perinatal transmission for historical control group receiving short ZDV (98% of whom were breastfed) was 12.8%.
NVAZ Trial;
Malawi;7
Breastfeeding
Neonatal SD NVP

vs.

SD NVP plus ZDV
 
No AP or IP ARV drugs SD NVP with or without ZDV for 1 week; infant only Perinatal transmission at 6–8 weeks was 15.3% in SD NVP plus ZDV arm vs. 20.9% in SD NVP-only arm. 

Perinatal transmission rates at 6–8 weeks among infants without HIV at birth were 7.7% and 12.1%, respectively (36% efficacy).
Postnatal NVP plus ZDV Trial;
Malawi;8
Breastfeeding
Neonatal SD NVP

vs.

SD NVP plus ZDV
No AP ARV drugs

Oral IP:
  • SD NVP
SD NVP with or without ZDV for 1 week; infant only
 
Perinatal transmission at 6–8 weeks was 16.3% in NVP plus ZDV arm vs. 14.1% in SD NVP-only arm (difference not statistically significant). 

Perinatal transmission rates at 6–8 weeks among infants without HIV at birth were 6.5% and 16.9%, respectively.
Post-Exposure Infant Prophylaxis;
South Africa;9
Breastfeeding and formula feeding
Neonatal SD NVP

vs.

ZDV for 6 weeks
No AP or IP ARV drugs SD NVP vs. ZDV for 6 weeks For formula-fed infants only, perinatal transmission at 6 weeks was 14.3% in SD NVP arm vs. 14.1% in ZDV arm (not significant, P = 0.30). For breastfed infants only, perinatal transmission was 12.2% in SD NVP arm vs. 19.6% in ZDV arm (P = 0.03).
Mashi;
Botswana;41,42
Breastfeeding and formula feeding
Initial:
  • Short-course ZDV with/without maternal and infant SD NVP and with/without breastfeeding
Revised:
  • Short-course ZDV plus infant SD NVP with/without maternal SD NVP and with/without breastfeeding; women with CD4 counts <200 cells/mmreceived combination therapy.
First Randomization:
  • ZDV from 34 weeks
Oral IP:
  • ZDV plus either SD NVP or placebo
Second Randomization:
  • Breastfeeding plus ZDV (infant) 6 months plus SD NVP; infant only, vs.
  • Formula feeding plus ZDV (infant) 4 weeks plus SD NVP; infant only
     
Initial Design:
  • In formula-feeding arm, perinatal transmission at 1 month was 2.4% in maternal and infant SD NVP arm vs. 8.3% in placebo arm (P = 0.05). 
  • In breastfeeding plus infant ZDV arm, perinatal transmission at 1 month was 8.4% in SD NVP arm vs. 4.1% in placebo arm (difference not statistically significant).
     
Revised Design:
  • Perinatal transmission at 1 month was 4.3% in maternal plus infant SD NVP arm vs. 3.7% in maternal placebo plus infant SD NVP arm (no significant difference; no interaction with mode of infant feeding).
Perinatal transmission at 7 months was 9.1% in breastfeeding plus ZDV arm vs. 5.6% in formula-feeding arm; mortality at 7 months was 4.9% in breastfeeding plus ZDV arm vs. 9.3% in formula-feeding arm; HIV-free survival at 18 months was 15.6% in the breastfeeding plus ZDV arm vs. 14.2% in the formula-feeding arm.
SWEN;
Uganda, Ethiopia, India;24
Breastfeeding
SD NVP

vs.

NVP for 6 weeks

 
No AP ARV drugs

Oral IP:
  • SD NVP
Infant SD NVP vs. NVP for 6 weeks Postnatal Infection in Infants Without HIV at Birth:
  • Perinatal transmission at 6 weeks was 5.3% in SD NVP arm vs. 2.5% in extended NVP arm (risk ratio 0.54, P = 0.009).
  • Perinatal transmission at 6 months was 9.0% in SD NVP arm vs. 6.9% in extended NVP arm (risk ratio 0.80, P = 0.16).
     
HIV-free survival was significantly lower in extended NVP arm at both 6 weeks and 6 months of age.
PEPI-Malawi Trial;
Malawi;23
Breastfeeding
SD NVP plus ZDV for 1 week (control)

vs.

2 extended infant regimens (NVP or NVP/ZDV) for 14 weeks
No AP ARV drugs

Oral IP:
  • SD NVP (if mother presents in time)
Infant SD NVP plus ZDV for 1 week (control)

vs.

Control plus NVP for 14 weeks

vs.

Control plus NVP/ZDV for 14 weeks
Postnatal Infection in Infants Without HIV at Birth:
  • Perinatal transmission at 6 weeks was 5.1% in control arm vs. 1.7% in extended NVP arm (67% efficacy) and 1.6% in extended NVP/ZDV arm (69% efficacy).
  • Perinatal transmission at 9 months was 10.6% in control arm vs. 5.2% in extended NVP arm (51% efficacy) and 6.4% in extended NVP/ZDV arm (40% efficacy).
No significant difference in perinatal transmission between the extended prophylaxis arms; however, more hematologic toxicity with NVP/ZDV.
MITRA;
Tanzania;26 
Breastfeeding
Infant 3TC for 6 months (observational) ZDV/3TC from 36 weeks through labor Maternal ZDV/3TC for 1 week; infant 3TC for 6 months Perinatal transmission at 6 months was 4.9% (postnatal perinatal transmission between 6 weeks and 6 months was 1.2%).
Kisumu Breastfeeding Study;
Kenya;29
Breastfeeding
Maternal triple-drug prophylaxis (observational) ZDV/3TC/NVP (NFV if CD4 count >250 cells/mm3) from 34 weeks through labor Maternal ZDV/3TC/NVP (NFV if CD4 count >250 cells/mm3) for 6 months, infant SD NVP Perinatal transmission at 6 months was 5.0% (postnatal perinatal transmission between 7 days and 6 months was 2.6%).
MITRA-PLUS;
Tanzania;25
Breastfeeding
Maternal triple-drug prophylaxis (observational) ZDV/3TC/NVP (NFV if CD4 count >200 cells/mm3) from 34 weeks through labor Maternal ZDV/3TC/NVP (NFV if CD4 count >200 cells/mm3) for 6 months, infant ZDV/3TC for 1 week Perinatal transmission at 6 months was 5.0% (postnatal perinatal transmission between 6 weeks and 6 months was 0.9%), not significantly different from 6-month infant prophylaxis in MITRA.
Kesho Bora;
Multi-African;28
Breastfeeding primarily
AP ZDV/SD NVP with no postnatal prophylaxis

vs.

Maternal triple-drug prophylaxis in women with CD4 counts 200–500 cells/mm3
Arm 1:
  • ZDV/3TC/LPV/r
Arm 2:
  • ZDV plus SD NVP
From 28 weeks through labor
 
Arm 1:
  • Maternal ZDV/3TC/LPV/r for 6 months, infant SD NVP plus ZDV for 1 week
Arm 2:
  • Maternal ZDV/3TC for 1 week (no further postnatal prophylaxis), infant SD NVP plus ZDV for 1 week (no further postnatal prophylaxis)
Perinatal transmission at birth was 1.8% with maternal triple-drug prophylaxis (Arm 1) vs. 2.5% with ZDV/SD NVP (Arm 2), not significantly different. In women with CD4 counts 350–500 cells/mm3, perinatal transmission at birth was 1.7% in both arms.

Perinatal transmission at 12 months was 5.4% with maternal triple-drug prophylaxis (Arm 1) vs. 9.5% with ZDV/SD NVP (with no further postnatal prophylaxis after 1 week) (Arm 2) (P = 0.029).
 
Mma Bana;
Botswana;2
Breastfeeding
Compared 2 maternal triple-drug prophylaxis regimens in women with CD4 counts >200 cells/mm3 Arm 1:
  • ZDV/3TC/ABC
Arm 2:
  • ZDV/3TC/LPV/r
From 26 weeks through labor

 

Arm 1:
  • Maternal ZDV/3TC/ABC for 6 months, infant SD NVP plus ZDV for 4 weeks
Arm 2:
  • Maternal ZDV/3TC/LPV/r for 6 months, infant SD NVP plus ZDV for 4 weeks
Perinatal transmission at 6 months overall was 1.3%: 2.1% in ZDV/3TC/ABC Arm 1 vs. 0.4% in ZDV/3TC/LPV/r Arm 2 (P = 0.53).
BAN;
Malawi;27,43
Breastfeeding
Postpartum maternal triple-drug prophylaxis vs. infant NVP in women with CD4 counts ≥250 cells/mm3  No AP drugs

IP Regimens
Arm 1 (Control):
  • ZDV/3TC plus SD NVP
Arm 2:
  • ZDV/3TC plus SD NVP
Arm 3:
  • ZDV/3TC plus SD NVP
Arm 1 (Control):
  • Maternal ZDV/3TC for 1 week; infant SD NVP plus ZDV/3TC for 1 week
Arm 2:
  • Control as above, then maternal ZDV/3TC/LPV/r for 6 months
Arm 3:
  • Control as above, then infant NVP for 6 months
Postnatal Infection in Infants Without HIV at 2 Weeks:
  • Perinatal transmission at 28 weeks was 5.7% in control Arm 1, 2.9% in maternal triple-drug prophylaxis Arm 2 (P = 0.009 vs. control), and 1.7% in infant NVP Arm 3 (P < 0.001 vs. control).
  • Perinatal transmission at 48 weeks was 7.0% in control Arm 1, 4.0% in maternal triple-drug prophylaxis Arm 2 (P = 0.0273 vs. control), and 4% in infant NVP Arm 3 (P = 0.0027 vs. control).
     
No significant difference between maternal triple-drug prophylaxis (Arm 2) and infant NVP (Arm 3) (P = 0.12 at 28 weeks and P = 0.426 at 48 weeks).
HPTN 046;
South Africa, Tanzania, Uganda, Zimbabwe;38,44
Breastfeeding
Postpartum prophylaxis to prevent breast milk transmission of HIV with 6 weeks of infant NVP vs. 6 months of infant NVP AP drugs allowed if required for maternal health All infants received daily NVP from birth through age 6 weeks.

Arm 1:
  • Daily infant NVP from 6 weeks through 6 months
Arm 2:
  • Daily infant placebo from 6 weeks through 6 months
In infants without HIV at age 6 weeks, the 6-month infant HIV infection rate was 1.1% (0.3% to 1.8%) in the extended NVP arm vs. 2.4% (1.3% to 3.6%) in the placebo arm (P = 0.048). 

18-month postnatal infection rates were 2.2% (1.1% to 3.3%) in the extended NVP arm vs. 3.1% (1.9% to 4.4%) in the placebo arm (P = 0.28). HIV infection and mortality rates did not differ between arms at any age through 18 months.

At infant randomization at age 6 weeks, 29% of mothers in each arm were receiving a triple-drug ARV regimen for the treatment of HIV.

For mothers receiving triple-drug ARV regimens at the time of randomization, in infants without HIV at age 6 weeks, the 6-month infant HIV infection rate was 0.2% and not statistically different from the rates seen in the extended NVP arm (0.5%) and placebo arm (0%). 

For mothers with CD4 counts >350 cells/mm3 who were not receiving triple-drug ARV regimens, in infants without HIV at age 6 weeks, the 6-month infant HIV infection rate was 0.7% (0% to 1.5%) in the extended NVP arm vs. 2.8% (1.3% to 4.4%) in the placebo arm (P = 0.014).
 
NICHD-HPTN 040/PACTG 1043 Trial;
Brazil, Argentina, South Africa, United States;45
Formula feeding
Infant prophylaxis with 6 weeks of ZDV

vs.

6 weeks of infant ZDV plus 3 doses of NVP in first week of life

vs.

6 weeks of infant ZDV plus 2 weeks 3TC/NFV
No AP drugs

If mother presented early enough, IV ZDV during labor through delivery
Arm 1 (Control):
  • Infant ZDV for 6 weeks
Arm 2:
  • Control as above plus NVP, with first dose within 48 hours of birth, second dose 48 hours later, and third dose 96 hours after second dose
Arm 3:
  • Control as above, plus 3TC and NFV from birth through age 2 weeks
IP HIV transmission among infants with negative HIV test at birth: 4.8% (3.2% to 7.1%) with ZDV (Arm 1) vs. 2.2% (1.2% to 3.9%) with ZDV plus NVP (Arm 2) (P = 0.046 compared with Arm 1) vs. 2.4% (1.4% to 4.3%) with ZDV plus 3TC/NFV (Arm 3) (P = 0.046 compared with Arm 1).

Overall HIV transmission rates, including in utero infection: 11.0% (8.7% to 14.0%) with ZDV (Arm 1) vs. 7.1% (5.2% to 9.6%) with ZDV plus NVP (Arm 2) (P = 0.035 compared with Arm 1) vs. 7.4% (5.4% to 9.9%) with ZDV plus 3TC/NFV (Arm 3) (P = 0.035 compared with Arm 1).

Grade 3 or 4 neutropenia more frequent in ZDV/3TC/NFV Arm 3 (70 infants) than in ZDV-alone Arm 1 (33 infants) or ZDV/NVP Arm 2 (32 infants) (P < 0.001).
ANRS 12174 Trial;
Burkina Faso, South Africa, Uganda, Zambia;30,31
Breastfeeding
Compared 2 infant ARV prophylaxis regimens during breastfeeding; infants tested PCR-negative at birth and were born to mothers with CD4 counts >350 cells/mm As per standard of care Arm 1:
  • Daily infant LPV/r from 1 week through 50 weeks of age
Arm 2:
  • Daily infant 3TC from 1 week through 50 weeks of age
Postnatal Infection in Infants Without HIV at Birth:
  • Postnatal transmission at age 50 weeks was 1.4% (0.70–2.76) in Arm 1 vs.1.5% (0.80–2.91) in Arm 2 (P = 0.83).
  • HIV-free survival was 96.5% (84.6–97.7) in Arm 1 vs. 96.3% (94.4–97.5) in Arm 2 (P = 0.85). 
     
PROMOTE;
Uganda;46
Breastfeeding
Compared 2 triple-ARV regimens; no CD4 restriction Arm 1:
  • ZDV/3TC/LPV/r
Arm 2:
  • ZDV/3TC/EFV 
  • ARVs started at 12–28 weeks’ gestation and continued through labor
     
Randomized regimen continued postpartum through 1 year of breastfeeding HIV-free survival was 92.9% in the LPV/r arm vs. 97.2% in the EFV arm (P = 0.10). Only 2 of 374 liveborn infants acquired infection, both in the LPV/r arm.
 
 
PROMISE;
India, Malawi, South Africa, Tanzania, Uganda, Zambia, Zimbabwe;18
Breastfeeding and formula feeding (antepartum component)
Compared ZDV prophylaxis and 2 ART regimens during pregnancy among women at >14 weeks' gestation and with CD4 counts ≥350 cells/mm3  Arm 1:
  • ZDV during pregnancy plus SD NVP plus TDF plus FTC at delivery
Arm 2:
  • ZDV plus 3TC plus LPV/r
Arm 3:
  • TDF plus FTC plus LPV/r
Arm 1:
  • TDF/FTC tail continued for 6–14 days postpartum
Arms 2 and 3:
  • ART regimen continued for 6–14 days postpartum
Infants received once-daily NVP for 6 weeks.
Infant HIV Infection Rates by Age 14 Days
Arm 1:
  • 1.8% (25/1,386)
Arm 2:
  • 0.5% (7/1,385)
Arm 3:
  • 0.6% (2/325)
Combined ART arms vs. ZDV arm difference in perinatal transmission risk:
-1.3% (95% CI, -2.1% to -0.4%)
PROMISE;
India, Malawi, South Africa, Tanzania, Uganda, Zambia, Zimbabwe;18
Breastfeeding (postpartum component)
Compared infant NVP and maternal ART during breastfeeding among infants born to women with CD4 counts ≥350 cells/mm3 This was a postpartum study. intervention only. Eligible women included women enrolled in PROMISE antepartum (see above) and women who received no ARV drugs during pregnancy. Arm 1:
  • Mothers received TDF plus FTC plus LPV/r
Arm 2:
  • Once-daily infant NVP
Regimens were continued until 42 days after last breastmilk exposure or age 18 months, whichever came first.
Infant Infection Rates
Arm 1:
  • 0.57% (7/1,219)
Arm 2:
  • 0.58% (7/1,211)
Rates of Infant HIV-1–Free Survival at 24 Months
Arm 1:
  • 97.1%
Arm 2:
  • 97.7%
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; AP = antepartum; ARV = antiretroviral; ART = antiretroviral therapy; CD4 = CD4 T lymphocyte; CDC = Centers for Disease Control and Prevention; CI = confidence interval; EFV = efavirenz; FTC = emtricitabine; IP = intrapartum; IV = intravenous; LPV/r = lopinavir/ritonavir; NFV = nelfinavir; NVP = nevirapine; PCR = polymerase chain reaction; PP = postpartum; SD = single-dose; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine