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Home > Topics > Perinatal Interventions > Overview of PI Trials
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Overview of Perinatal Intervention Trials

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Antiretroviral Studies: Phase II/III ARV Clinical Trials [PDF, 344K]
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Infant ARV Prophylaxis of Breast Milk Transmission [PDF, 152K]
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Maternal ARV Prophylaxis Of Breast Milk Transmission [PDF, 158K]
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ARV Clinical Trials: Single-dose Nevirapine Resistance Issues -- Prevention of Resistance [PDF, 135K]
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ARV Clinical Trials: Single-dose Nevirapine Resistance Issues -- Response to ARV Therapy, Second Pregnancy [PDF, 128K]
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Phase I/II ARV Clinical Trials [PDF, 214K]
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Nutrient Supplementation [PDF, 147K]
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Immunization: Passive Immunization (Immune Globulin) [PDF, 154K]
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Immunization: Active Immunization (Vaccines) [PDF, 154K]
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Mode of Delivery [PDF, 86K]
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Vaginal Cleansing [PDF, 109K]
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Other Interventions [PDF, 181K]
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Breast-Feeding [PDF, 140K]
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Key to Abbreviations
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Antiretroviral Studies: Phase II/III ARV Clinical Trials [PDF, 344K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
US/FRANCE (NIH, ANRS) (PACTG 076)
  • ZDV only
  • 2 arm, randomized, placebo-control (enrolled 1991-93)
  • Formula feeding
  • N=477

Starting at 14-34 wks

Arm 1: ZDV 100 mg 5x/d

Arm 2: Placebo

Arm 1: ZDV intravenous infusion

Arm 2: Placebo

No ARV

Arm 1: ZDV 2 mg/kg qid x 6 wk

Arm 2: Placebo

  • At 18 mo, tx 8.3% ZDV vs 25.5% placebo, 68% efficacy
  • ZDV resistance delivery, mother: no high-level, 3% low-level at delivery; at 6 wks, infant: none

Connor et al. NEJM 1994; 331:1173-80;

Eastman et al. J Infect Dis 1998; 177:557-64;

McSherry et al. J Pediatr 1999;134:717-24

THAILAND (CDC)
  • ZDV only
  • 2 arm, randomized, placebo-control (enrolled 1996-97)
  • Formula feeding
  • N=392

Starting at 36 wks

Arm 1: ZDV 300 mg bid

Arm 2: Placebo

Arm 1: ZDV 300 mg q 3 hr

Arm 2: Placebo

No ARV

No ARV

  • At 6 mos, tx 9.4% ZDV vs 18.9% placebo, 50% efficacy

Shaffer et al. Lancet 1999; 353:773-80

IVORY COAST (CDC)
  • ZDV only
  • 2 arm, randomized, placebo-control (enrolled 1996-98)
  • Breastfeeding
  • N=280

Starting at 36 wks

Arm 1: ZDV 300 mg bid

Arm 2: Placebo (stopped 2/98)

Arm 1: ZDV 300 mg q 3 hr

Arm 2: Placebo (stopped 2/98)

No ARV

No ARV

  • At 3 mos, tx 16.5% ZDV vs 26.1% placebo, 37% efficacy
  • Pooled analysis from CDC and ANRS 049a trials:
    • At 24 mos, tx 22.5% ZDV vs 30.2% placebo, 26% efficacy; risk of PP tx similar ZDV/placebo.

Wiktor et al. Lancet 1999; 353:781-85;

Leroy et al. AIDS 2002;16:631-41

Leroy et al. AIDS 2003 Jul 4;17(10):1493-501.

IVORY COAST/BURKINA FASO (ANRS)
  • ZDV only (DITRAME; ANRS 049a)
  • 2 arm, randomized, placebo-control (enrolled 1995-98)
  • After trial completion, continued to enroll into an open-label ZDV regimen cohort
  • Breastfeeding
  • N=400

Starting at 36-38 wks

Arm 1: ZDV 300 mg bid

Arm 2: Placebo (stopped 2/98)

Arm 1: ZDV 600 mg x1

Arm 2: Placebo (stopped 2/98)

Arm 1: ZDV 300 mg bid x 1 wk

Arm 2: Placebo (stopped 2/28)

No ARV

  • At 6 mos, tx 18.0% ZDV vs 27.5% placebo, 38% efficacy
  • At 15 mos, tx 21.5% ZDV vs 30.6% placebo, 30% efficacy
  • At 24 mos (pooled analysis with CDC), tx 22.5% ZDV vs 30.2% placebo, 26% efficacy
  • 18 mo mortality: 17.6% ZDV vs 22.1% placebo
  • Open-label ZDV cohort (N=209), 15 mo tx with ZDV regimen, 19.6%

Dabis et al. Lancet 1999; 353:786-92;

DITRAME ANRS 049 Study Grp. Lancet 1999; 354:2050-1;

Dabis et al. AIDS 2001;15: 771-9;

Leroy et al. AIDS 2002;16:631-41;

Meda. AIDS 2002; 16: 2323-8

THAILAND/PHPT (Harvard [NIH])
  • ZDV only
  • 4 arm randomized, comparative, factorial (enrolled 1997-99)
  • No placebo (076-like control)
  • Formula feeding
  • N=1,437

ZDV 300 mg bid

Arm 1: (Long-Long, LL): 28 wks

Arm 2: (Long-Short, LS): 28 wks

Arm 3: (Short-Long, SL): 36 wks

Arm 4: (Short-short, SS): 36 wks

ZDV 300 mg q 3 hr

Arm 1: Oral

Arm 2: Oral

Arm 3: Oral

Arm 4: Oral

No ARV

ZDV 2 mg/kg qid

Arm 1: 6 wks

Arm 2: 3 d

Arm 3: 6 wks

Arm 4: 3 d

  • Interim analysis 3/99 (N=449 enrolled), stopped SS arm due to sign. higher tx than LL,
    • At 6 mos, tx 10.5% SS vs 4.1% LL
  • Final analysis 7/00, no sign. differences;
    • At 6 mos, tx 6.5% LL vs 4.7% LS vs 8.6% SL
  • In utero tx sign. different:
    • 1.6% [LL+LS] vs 5.1% [SL+SS]

Lallemant et al. NEJM 2000; 343:982-91

SOUTH AFRICA, UGANDA, TANZANIA (PETRA) (UNAIDS)
  • ZDV/3TC
  • 4 arm, randomized, placebo-control (enrolled 1996-2000)
  • Breastfeeding
  • N=1,797

Starting at 36 wks

Arm 1: ZDV 300 mg bid plus 3TC 150 mg bid

Arm 2: Placebo

Arm 3: Placebo

Arm 4: Placebo (stopped 2/98)

Arm 1: ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hr

Arm 2: ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hr

Arm 3: ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hr

Arm 4: Placebo (stopped 2/98)

Arm 1: ZDV 300 mg bid plus 3TC 150 mg bid x 7 d

Arm 2: ZDV 300 mg bid plus 3TC 150 mg bid x 7 d

Arm 3: Placebo

Arm 4: Placebo (stopped 2/98)

Arm 1: ZDV 4 mg/kg bid plus 3TC 2 mg/kg bid x 7 d

Arm 2: ZDV 4 mg/kg bid plus 3TC 2 mg/kg bid x 7 d

Arm 3: Placebo

Arm 4: Placebo(stopped 2/98)

  • At 6 wks, tx:
    • 5.7% AP/IP/PP (63% efficacy)
    • 8.9% IP/PP (42% efficacy)
    • 14.2% IP
    • 15.3% placebo
  • At 18 mos, tx:
    • 14.9% AP/IP/PP
    • 18.1% IP/PP
    • 20.0% IP
    • 22.2% placebo
  • 3TC resistance, mother 1 wk PP (N=100), 12% arm 1, 0% arm 2

The Petra Study Team. Lancet 2002; 359:1178-86.

Giuliano et al. AIDS 2003 ;17 :1570-3.

FRANCE (ANRS)
  • ZDV/3TC (ANRS 075)
  • Non-randomized, open-label (enrolled 1997-98)
  • Formula feeding
  • N=445

Standard ZDV after 14 wks

3TC 150 mg bid added at 32 wks

Standard intravenous ZDV

Non-study ARV

Standard ZDV x 6 wks

3TC 2 mg/kg bid x 6 wks

  • Tx 1.6% ZDV/3TC vs 6.8% 1994-97 historical, ZDV-alone control
  • M184V mutation in 39% women (only if ≥4 wks 3TC)

Mandelbrot et al. JAMA 2001; 285:2083-93

THAILAND (Ministry of University Affairs, Bangkok)
  • ZDV/3TC
  • Non-randomized, open-label (enrolled 1999-2000)
  • Formula feeding
  • N=106

Starting at 34 wks

ZDV 300 mg bid plus 3TC 150 mg bid

ZDV 300 mg q 3 hr plus 3TC 150 mg q 3 hr

No ARV

ZDV 2 mg/kg qid x 4 wks

  • At 18 mos, tx 2.8% vs 11.7% historical, ZDV-alone control (N=60: 36 wk start, oral IP, 4 wk infant)

Chaisilwattana et al. CID 2002; 35:1405-13

UGANDA (HIVNET 012) (NIH)
  • NVP vs ZDV
  • 2 arm, randomized; originally had 3rd placebo arm, stopped 2/98 (enrolled 1997-99)
  • Breastfeeding
  • N=626

Arm 1: No ARV

Arm 2: No ARV

Arm 3: No ARV

Arm 1: NVP 200 mg x1

Arm 2: ZDV 300 mg q 3 hr

Arm 3: Placebo (stopped 2/98)

No ARV

Arm 1: NVP 2 mg/kg x 1 at 48-72 hr

Arm 2: ZDV 4 mg/kg bid x 7 d

Arm 3: Placebo (stopped 2/98)

  • At 6-8 wks, tx 11.8% NVP vs 20.0% ZDV, 47% efficacy
  • At 18 mos, tx 15.7% NVP vs 25.8% ZDV, 41% efficacy
  • At 18 mos, HIV or death, 20.7% NVP vs 30.7% ZDV, 37% efficacy
  • At 18 mos, no diff. mortality in uninfected or infected by arm:
    • Uninfected, 7.5% NVP vs 7.8% ZDV
    • HIV-infected, 40.1% NVP vs 40.7% ZDV
  • Multivariate analysis: effect of NVP independent of CD4, RNA
  • NVP resistance PP:
    • mother (N=279), 25% 6 wk PP (not detected at 12-15 mos in tested pt)
    • resistance as early as 1 wk PP; differing pattern 1 vs 6 wk PP (Y181C at wk 1, K103N at wk 6, some complex pattern)
    • infant, 46%
    • subtype D>A

Guay et al. Lancet 1999; 354:795-802;

Eshleman et al. J Infect Dis 2001; 184:914-7;

Eshleman et al. JAIDS 2002; 31:327-30;

Jackson et al. Lancet 2003 Sep 13;362(9387):859-68.

Eshleman et al. JAIDS 2004 Feb 1;35(2):126-30.

Eshleman et al. AIDS Res Hum Retroviruses. 2004 Jun;20(6):595-9.

Eshleman et al. J Infect Dis. 2005 Jul 1;192(1):30-6.

Eshleman et al. J Acquir Immune Defic Syndr. 2005 Aug 15;39(5):593-7

Eshleman et al. J Acquir Immune Defic Syndr. 2005 Sep 1;40(1):24-9

US/EUROPE/BRAZIL/BAHAMAS (PACTG 316) (NIH, ANRS, ECS)
  • NVP vs placebo
  • 2 arm, randomized, [NVP] placebo-control (enrolled 1997-2000)
  • Women and infants received non-study standard ARV
  • Formula feeding
  • N=1,248

Non-study ARV (23% ZDV alone, 36% combo without PI, 41% combo with PI)

Standard intravenous ZDV

Arm 1: NVP 200 mg x 1

Arm 2: Placebo

Non-study ARV

Standard ZDV (with or without other ARV) x 6 wks

Arm 1: NVP 2 mg/kg x 1 at 48-72 hr

Arm 2: Placebo

  • Stopped early due to low 1.5% overall tx (53% in utero)
  • At 6 mos, tx 1.4% NVP vs 1.6% placebo
  • NVP resistance 6 wk PP:
    • mother, 15%
  • Sx/lab abnl <5% women regardless non-study ART; only gest diabetes varied by type ART (higher with combo PI from early pregnancy)

Dorenbaum et al. JAMA 2002; 288:189-98;

Cunningham et al. J Infect Dis 2002; 186:181-8

Watts et al. Am J Ob Gyn 2004;190:506-16

SOUTH AFRICA (SAINT)
  • NVP vs ZDV/3TC
  • 2 arm, randomized, comparative (enrolled 1999-2000)
  • Breastfeeding (42%) and formula feeding
  • N=1,331

Arm 1: No ARV

Arm 2: No ARV

Arm 1: NVP 200 mg x1

Arm 2: ZDV 600 mg then 300 mg q 3 hr plus 3TC 150 mg q 12 hr

Arm 1: NVP 200 mg x 1 at 24-48 hr

Arm 2: ZDV 300 mg bid plus 3TC 150 mg bid x 7 d

Arm 1: NVP 6 mg x 1 at 24-48 hr (>2kg)

Arm 2: ZDV 12 mg bid plus 3TC 6 mg bid x 7 d (>2 kg)

  • At 8 wks, tx 12.3% NVP vs 9.3% ZDV/3TC (p=0.11)
  • NVP resistance 6 wk PP:
    • mother, 67% (received 2 NVP doses; 20% persist at 12 mos)
    • infant, 53%

Moodley et al., J Infect Dis 2003; 187:725-35;

Sullivan et al. XIV AIDS Conf Barcelona, Spain, 2002 (abs. LBPeB9024)

THAILAND (CDC)
  • ZDV + NVP
  • Non-randomized, open-label (enrolled 2/01-1/03)
  • Formula feeding
  • N=220

Starting at 34-36 wks

ZDV 300 mg bid

ZDV 300 mg q3 hrs plus NVP 200 mg x1

No ARV

ZDV 2 mg/kg qid x 4 wks plus NVP 2 mg/kg x 1 at 48-72 hr

  • Tx, 4.6% (95% CI 2.5-8.5%)
  • Resistance analyses:
    • mother (N=190), NVP: 18% (34/190) at 4 wks, persisted 13% (2/15) at 4 mos; ZDV: 2%
    • assoc with RNA, CD4
    • infant (N=10), NVP: 20% at 2 mos; ZDV: 0%

Chalermchokcharoenkit et al., 11th Retrovirus Conf 2004 (abs. 96)

IVORY COAST (ANRS)
  • ZDV + NVP (DITRAME PLUS; ANRS 1201 cohort 1.0)
  • Non-randomized, open-label
  • Modified 8/02 to add 3TC (see below)
  • Breastfeeding (54%) and formula feeding (historical ZDV alone control breastfeeding 97.6%)
  • N=420 ZDV/NVP

Starting at 36-38 wks

ZDV 300 mg bid

ZDV 600 mg x 1 plus NVP 200 mg x1

No ARV

ZDV 2 mg/kg qid x

7 d plus NVP 2 mg/kg x 1 at 48-72 hrs

  • At 4-6 wks, tx 6.5% (95% CI, 3.9-9.1%) ZDV/NVP vs 12.8% historical, ZDV-alone (1995-2000, ANRS 049 + open label) control
  • NVP resistance at 4 wk PP:
    • mother. 33%
    • infant, 23%
    • No diff. tx NVP resistance vs no resistance
  • Comparing 2 yr outcome in formula and breastfed with early weaning in both ZDV/SD NVP and ZDV/3TC/SD NVP ANRS 1201 studies, no signif difference in rate of adverse health outcome or death

Dabis et al. 10th Retrovirus Conf 2003 (abs. 854)

Chaix et al. 11th Retrovirus Conf 2004 (abs.657)

DITRAME PLUS Study Grp. AIDS. 2005 Feb 18;19(3):309-318.

Chaix et al. Antiviral Ther 2004;9:S176

Becquet et al. XVI AIDS Conference, Toronto, 2006 (abs. TUPE0350)

THAILAND/PHPT-2 (Harvard [NIH])
  • ZDV with/without NVP
  • 3 arm, randomized, comparative
  • All women/infant get short-course ZDV
  • Formula feeding
  • Interim analysis 6/02 stopped ZDV only Arm A early due to significantly lower efficacy than NVP arms
  • N=1,844

Starting at 28 wks

Arm 1: ZDV 300 mg bid

Arm 2: ZDV 300 mg bid

Arm 3: ZDV 300 mg bid

Arm 1: ZDV 300 mg q 3 hr

Arm 2: ZDV 300 mg q 3 hr plus NVP 200 mg x

Arm 3: ZDV 300 mg q 3 hr plus NVP 200 mg x 1

No ARV

Arm 1: ZDV 2 mg/kg qid x 7 d

Arm 2: ZDV 2 mg/kg qid x 7 d

Arm 3: ZDV 2 mg/kg qid x 7 d plus NVP 6 mg x 1 at 48-72 hr

  • Does SD NVP provide added efficacy to ZDV (Arm 1 vs 2 & 3)?:
    • Arm 1 ZDV-only d/c 6/02, sign. higher tx than combo ZDV/NVP arms
    • tx 6.3% Arm 1 vs 2.1% Arm 2 and 1.1% Arm 3
  • Does infant NVP provided added efficacy (Arm 2 vs 3)?:
    • tx 2.8% (Arm 2, mat NVP) vs 2.0% (Arm 3, mat + infant NVP)
  • NVP resistance
    • women, 10d PP: 66/209 32% (vary by AP RNA)
    • infant at 6wk-4 mo?: 4/50, 8%
  • After 6 mos NVP-based HAART?:
    • RNA <400, no sign. diff. by SD NVP exp
    • RNA <50, resp lower if SD NVP + resist: 68%, 27/40, with no SD NVP?; 52%, 92/188, with SD NVP, no resist?; 38%, 23/ 61 with SD NVP + resist
    • Clinical (weight gain) and CD4 increase did not differ by NVP exposure.
  • F/U to 18 mos on HAART:
    • no further accumulation failure in SD NVP grp;
    • if <50 at 6 mos, RNA <50 at 18 mos in 67% SD NVP vs 71% no NVP

Lallemant et al. NEJM 2004;351:217-28;

Jourdain et al. NEJM 2004;351:229-40;

Jourdain et al., 11th Retrovirus Conf 2004 (abs 41LB)

Ngo-Giang-Huong et al., 12th Retrovirus Conf 2005 (abs 802)

Lallemant et al. 3rd IAS Conference, Brazil 2005 (abs TuFo0205)

IVORY COAST (ANRS)
  • ZDV+ 3TC + NVP (DITRAME-PLUS; ANRS 1201 1.1)
  • Non-randomized, open-label
  • Breastfeeding (66%) and formula feeding (historical ZDValone control breastfeeding 97.6%)
  • N=373

Starting at 32 wks

ZDV 300 mg bid plus

3TC 150 mg bid

ZDV 600 mg x1 plus

3TC 150 mg x1 plus

NVP 200 mg x1

ZDV 300 mg bid plus 3TC 150 mg bid x 3 days

ZDV 2 mg/kg qid x

7 d plus NVP 2 mg/kg x 1 at 48-72 hrs

  • At 4-6 wks, tx 4.7% (95% CI, 2.4-7.0%) (not signif differ than 6.5% with ZDV+SD NVP, p=0.34) vs 12.8% historical, ZDV-alone (1995-2000) control
  • At 4 wks, maternal NVP resistance 1.1% (95% CI 0.03-6.2%); 3TC resistance 8.3% (95% CI 3.7-15.8%); infants 25% (1 NVP, 4 3TC)
  • Comparing 2 yr outcome in formula and breastfed with early weaning in both ZDV/SD NVP and ZDV/3TC/SD NVP ANRS 1201 studies, no signif difference in rate of adverse health outcome or death

Dabis et al., 2nd IAS Conference, Paris, France, July 2003 (abs 219)

Dabis et al., 12th Retrovirus Conf 2005 (abs 72LB)

DITRAME PLUS Study Grp. AIDS. 2005 Feb 18;19(3):309-318

Becquet et al. XVI International AIDS Conf, 2006 (Abs. TUPE0350)

MALAWI (NVAZ) (Fogarty)
  • Infant post-exposure prophylaxis, NVP vs NVP + ZDV ('NVAZ')
  • 2 arm, randomized, comparative
  • Designed for infants of women 1st identified as HIV+ in labor/PP
  • Breastfeeding
  • N=1,780 (enrolling now only IP NVP strata)

No ARV

If identified early enough in labor

NVP 200 mg x 1 (all women; stratification factor)

No ARV

Arm 1: NVP 2 mg/kg x 1 at 48-72 hr

Arm 2: NVP 2 mg/kg x 1 at 48-72 hr plus ZDV 4 mg/kg bid x 7 d

  • When mothers did get IP NVP:
    • 6-8 wk tx 14.1% NVP vs 16.3% NVP/ZDV
    • 6-8 wk tx if uninfected at birth: 6.5% NVP vs 6.9% NVP/ZDV
  • When mother didn't get IP NVP:
    • 6-8 wk tx overall: 20.9% NVP vs 15.3% NVP/ZDV
    • 6-8 wk tx if uninfected at birth: 12.1% NVP vs 7.7% NVP/ZDV (36% efficacy)
    • Mortality did not differ
  • Infant SD NVP/ZDV, NVP resistance lower with no maternal NVP:
    • Infant SD NVP/ZDV, resistance 27%, tx 16.7%
    • Infant SD NVP/ZDV + maternal SD NVP, resistance 74%, tx 16.9%.
  • Comparing BF patterns and mortality:
    • BF not associated with maternal mortality
    • BF pattern was associated with infant mortality; adjusted hazard:
      • 0.44 overall BF
      • 0.45 mixed BF
      • 0.40 excl. BF

Taha et al. Lancet 2003;362:1171-7

Taha et al. JAMA 2004;292:202-9

Eshleman et al. JID 2006;193(4):479-81

Taha et al. Bull WHO 2006;84:546-54

ZIMBABWE
  • Intrapartum/infant post-exposure prophylaxis, NVP vs NVP + ZDV
  • 2 arm, randomized, placebo-controlled
  • Breastfeeding
  • N=1,172 (data available on infection status for 577 infants as of 12/05)

No ARV

Arm 1: NVP 200 mg x 1

Arm 2: NVP 200 mg x 1 plus AZT 600 mg, then 300 mg q 3 hr

No ARV

Arm 1: NVP 2 mg/kg x 1 at < 72 hr

Arm 2: NVP 2 mg/kg x 1 at <72 hr plus ZDV 2 mg/kg qid x 3 d

  • Stopped for futility as superiority could not be found with MTCT rates.
  • Cumulative tx at 6 wks:
    • SD NVP: 50/281 (17.8%)
    • SD NVP plus IP/PP 3d AZT: 46/296 (15.5%)

Thistle P et al. 45th ICAAC, 12/05 (abs H-416)

Thistle P et al. CID 2007;44:1110

SOUTH AFRICA (PEP) (Secure the Future)
  • Infant post-exposure prophylaxis, NVP vs ZDV
  • 2 arm, randomized, comparative
  • Designed for infants of women 1st identified as HIV+ in labor/PP
  • Formula feeding (84%) and breastfeeding (16%)
  • N=1,051 (wk 12 infection status available N=718)

No ARV

No ARV

No ARV

Arm 1: NVP 2 mg/kg x 1 at birth

Arm 2: ZDV 4 mg/kg bid x 6 wks

  • 29% loss F/U (24 death, 216 loss, 58 no PCR)
  • Cumulative tx
    • at 6 wks: 11.9% NVP vs 13.6% ZDV (p=0.6)
    • at 12 wks: 14.3% NVP vs 18.1% ZDV (p=0.4)
  • Peripartum tx (birth not infected): 7.9% NVP vs 13.1% ZDV
    • Breastfed: 9.9% NVP vs 20.6% ZDV
    • Formula: 7.3% NVP vs 11.1% ZDV
  • NVP effective breast or formula (p=0.3); ZDV less effective if breastfed (p=0.004)

Gray et al. XIV AIDS Conf 2002 (abs LbOr13)

Gray et al. AIDS 2005;19(12):1289-97.

BRAZIL/US/ARGENTINA/S AFRICA (NICHD HTPN 040, PACTG 1043) (NIH)
  • Infant post-exposure prophylaxis, ZDV vs ZDV/NVP vs ZDV/3TC/ Nelfinavir
  • 3 arm, randomized, open-label, comparative
  • Designed for infants of women 1st identified as HIV+ in labor/PP
  • Formula feeding
  • N=1,731 (enrolling)

No ARV

If identified early enough in labor

Standard intravenous ZDV (all women)

Non-study ARV if required

Arm 1: ZDV 12 mg bid x 6 wks

Arm 2: ZDV 12 mg bid x 6 wks plus NVP 12 mg at birth, 48 hrs, and 144 hrs

Arm 3: ZDV 12 mg bid x 6 wks plus 3TC 6 mg bid x 2 wks plus NFV 200 mg bid x 2 wks

  • Standard dosing adjusted by weight category:
    • ZDV, 8 mg if ≤2 kg;
    • NVP, 8 mg if ≤2 kg;
    • 3TC, 4 mg if <2 kg;
    • NFV, 150 mg if 2-3 kg or 100 mg if ≤2 kg)
  • NVP PK showed 3 dose regimen maintain levels >70 ng/mL to day 9-12
  • NFV PK (med dose 58 mg/kg BID) gave median AUC and Cmin levels above target; large inter-individual variability, 44% failed target - increasing dose would = toxic levels in some & low in some so did not change; rec TDM if using for rx in infants.

Mirochnick et al 15th CROI 2008 (abs 571)

Mirochnick et al. JAIDS 2008;47:334-7;

Mirochnick et al. HIV Clin Tr 2008;9:115-25

THAILAND (CDC)
  • Maternal prophylaxis with HAART
  • Non-breastfeeding
  • 3 arm, randomized for CD4 >200, open-label, safety and resistance phase II study
  • N=360 (in planning)

Starting at 32 wks

Arm 1: D4T 40 mg plus 3TC 150 mg bid plus NVP 200 mg bid (generic GPOvir)

Arm 2: ZDV 300 mg/3TC 150 mg (Combivir) bid plus NVP 200 mg bid

Arm 3: ZDV 300 mg bid

Arm 1: D4T 40 mg q 12 hr plus 3TC 150 mg q 12 hr plus NVP 200 mg q 12 hr

Arm 2: ZSV 300 mg q 3 hr plus 3TC 150 mg q 12 hr plus NVP 200 mg q 12 hr

Arm 3: ZDV 300 mg q 3 hr plus NVP 200 mg x 1

Arm 1: D4T 40mg plus 3TC 150 mg bid x 2 wks

Arm 2: ZDV 300 mg/3TC 150 mg (Combivir) bid x 2 wks

Arm 3: No ARV

Arm 1: ZDV 2 mg/kg qid x 4 wks plus NVP 2 mg/kg x 1 at <72 hr

Arm 2: ZDV 2 mg/kg qid x 4 wks plus NVP 2 mg/kg x 1 at <72 hr

Arm 3: ZDV 2 mg/kg qid x 4 wks plus NVP 2 mg/kg x 1 at <72 hr

BOTSWANA (Harvard [NIH])
  • Short-course ZDV with/without maternal NVP and with/without breastfeeding (MASHI)
  • 4 arm randomized, comparative, factorial
  • Original protocol maternal/infant [at 72 hrs] N/N vs maternal/infant P/P; modified revised study 8/02 after PHPT2, so all infants got NVP at birth (maternal/infant N/N vs maternal/infant P/N)
  • 10/02 revised study modified so women with CD4 <200 get HAART (AP HAART, 71 [6%] women - 40 NN, 31 NP; PP HAART, 82 [7%] women)
  • Second study is evaluating NVP resistance and response to NNRTI-HAART in mothers who require therapy PP (see Mashi-Plus)
  • N=1,200

Starting at 34 wks

Arm 1: ZDV 300 mg bid

Arm 2: ZDV 300 mg bid

1st randomization:

Arm 1: ZDV 300 mg q 3 hr

Arm 2: ZDV 300 mg q 3 hr plus NVP 200 mg x1

No ARV

2nd randomization:

Arm 1: Breastfeed: NVP 6 mg x 1 at birth plus ZDV 4 mg/kg bid x4 wks; 4 mg/kg q8hr 4 wk-2 mos; 6 mg/kg q8 hr 2-6 mos

Arm 2: Formula feed: NVP 6 mg x 1 at birth plus ZDV 4 mg/kg bid x 1 mo

  • Original study: Maternal/ infant N/N added efficacy if formula-fed but not BF+AZT: formula-at 1 mo, tx 2.4%N/N vs 8.3% P/P; BF+AZT-at 1 mo, tx 8.4% N/N vs 4.1% P/P
  • Revised study: Maternal N did not provide added efficacy when infant N given at birth regardless feeding: at 1 mo, 4.3% N/N vs 3.7% P/N.
  • BF+AZT higher tx than formula at 7 mos, 9.1% vs 5.6%, however, higher 7 mo mortality in formula-fed, 9.3% vs 4.9% BF+AZT.
  • Incremental BF+AZT late tx btn 1-7 mos, 4.5% (BHITS, where no ARV, 1-6 mo, late tx 4.2%)
  • 18 mo HIV-free survival similar by infant feeding: 13.9% formula-fed [33 infected, 62 deaths] vs 15.1% BF+AZT [53 infected, 48 deaths].
  • ≥ Grade 3 heme toxicity higher in BF+AZT; ≥ Grade 3 sign/sx and hospitalizations higher in formula-fed.
  • NVP resistance 69/155 N women (45%) at 4 wk PP

Shapiro et al., AIDS. 2006 Jun 12;20(9):1281-8

Thior et al., JAMA. 2006 Aug 16;296(7):794-805

Infant ARV Prophylaxis of Breast Milk Transmission [PDF, 152K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
TANZANIA (MITRA) (SWEDEN)
  • Short-course ZDV/3TC mother; infant prophylaxis postnatal tx, 3TC
  • Non-randomized, open label
  • Breastfeeding
  • N=412

ZDV 300 mg bid plus

3TC 150 mg bid

(all women)

Starting at 36 wks

ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hr

(all women)

ZDV 300 mg bid plus 3TC150 mg bid x 1 wk

ZDV 4 mg/kg bid plus/3TC 2 mg/kg bid x 1 week, then 3TC 2 mg/kg bid x 6 mos

  • Median duration of BF, 20 wks (at 26 wks, only 23% still BF)
  • At 6 wks: 3.8%
  • At 26 wks: 4.9%
  • Incremental postnatal tx risk btn 6 to 26 wks 1.1%

Kilewo et al. 4th IAS Sydney Australia 2007 Abs. TuAX101

Kilewo et al. JAIDS 2008;Mar 13 epub

UGANDA/RWANDA (SIMBA) (IAS)
  • Short-course ZDV/ddI mother; infant prophylaxis postnatal tx, NVP vs 3TC
  • 2 arm, randomized, comparative
  • Breastfeeding (**median duration only 3.3-3.5 mo; upper IQR 4.9-5.3 mos; thus, <6 mo total**)
  • N=397

ZDV 300 mg bid plus ddI 200 mg bid

(all women)

Starting at 36 wks

ZDV 300 mg q 3 hr plus ddI 200 mg q 12 hr

(all women)

ZDV 300 mg bid plus ddI 200 mg bid x 1 wk

(all women)

Arm 1: NVP 2 mg/kg q d x 2 wks, then 2 mg/kg bid x 22 wks

Arm 2: 3TC 2 mg/kg bid x 4 wks, then 4 mg/kg bid for 20 wk

  • No sign. diff. NVP vs 3TC
  • Overall:
    • Birth to 3 d, tx 5.3% (21/397)
    • 4 d to 28 d, tx 1.6% (6/375)
    • 4 wk to 6 mo, 0.8% (3/362) (note: median BF only 3 months)
    • PP to 6 mo, 2.4% (9/375)
  • Median RNA delivery only 2.74 log

Vyankandondera et. al. 2nd IAS Conference, France, 2003 (LB) (modified as per 12/09/03 memo to HTPN 046 team with corrections)

ETHIOPIA (Hopkins)
  • Infant prophylaxis postnatal tx, NVP x 1 vs NVP x 6 wk
  • 2 arm, randomized, comparative
  • Breastfeeding
  • Collaboration with India, Uganda
  • N=970

No ARV

Arm 1: NVP 200 mg x 1

Arm 2: NVP 200 mg x 1

No ARV

Arm 1: NVP 2 mg/kg x 1 at 48-72 hr

Arm 2: NVP 2 mg/kg q d x 6 wks

  • Combined results Ethiopia/India/ Uganda show effective in decreasing MTCT at 6 wks but not 6 mos, but increased survival at 6 mos.
  • MTCT
    • 6 wks: MTCT 2.5% Ext NVP vs 5.3% SD NVP (p=.009)
    • 6 mos: 6.9% Ext NVP vs 9.0% SD NVP (p=.16)
  • Death:
    • 6 wks: 0.9% Ext NVP vs 1.6% SD NVP (p=.3)
    • 6 mos: 1.1% Ext NVP vs 3.6% SD NVP (p=0.016)
  • HIV or Death:
    • 6 wks: 3.7% Ext NVP vs 6.8% SD NVP (p=.008)
    • 6 mos: 8.1% Ext NVP vs 11.6% SD NVP (p=0.028)

Substudy on resistance:

  • India :
    • Overall 6 wks: 81% Ext NVP vs 50% SD NVP had resistance.
    • If infected at <6 wks: 92% Ext NVP vs 38% SD NVP had resistance
    • If infected at >6 wks: 15% Ext NVP vs 18% SD NVP had resistance
    • lower risk of resistance if infected later (>6 wks) when off prophylaxis
  • Uganda: :
    • Overall 6 wks: 84% Ext NVP vs 50% SD NVP resistant
    • Resistance more likely to persist at 6 mos if Ext NVP group.

Sastry J et al 15th CROI 2008 (abs 43)

Moorthy A. 15th CROI 2008 (abs44)

Six Week Extended Nevirapine (SWEN) Study Team. Lancet. 2008;372:300-13

Church JD et al. JID 2008;198:1075-82.

INDIA (Hopkins [NIH])
  • Infant prophylaxis postnatal tx, NVP x 1 vs NVP x 6 wk
  • 2 arm, randomized, comparative
  • Breastfeeding
  • Collaboration with Ethiopia, Uganda
  • N=970

No ARV

Arm 1: NVP 200 mg x 1

Arm 2: NVP 200 mg x 1

No ARV

Arm 1: NVP 2 mg/kg x 1 at 48-72 hr

Arm 2: NVP 2 mg/kg q d x 6 wks

UGANDA (Hopkins [NIH])
  • Infant prophylaxis of postnatal tx, HIVIGLOB vs NVP x1 vs extended NVP
  • 3 arm, randomized
  • Breastfeeding
  • N=570

At 37-38 wks

Arm 1: HIVIGLOB 400 mg/kg IVx 1

Arm 2: No drug

Arm 3: No drug

NVP 200 mg x1 (all women)

No ARV

Arm 1: HIVIGLOB 400 mg/kg IV x 1 plus NVP 2 mg/kg x 1 at 48 hr

Arm 2: NVP 2 mg/kg x 1 at 48 hr

Arm 3: NVP 2 mg/kg q d x 6 wks

MALAWI (CDC/NICHD)
  • Infant post-exposure prophylaxis postnatal tx, ZDV vs NVP
  • 3 arm, randomized, comparative
  • For infants of women 1st identified as HIV+ PP
  • Breastfeeding
  • N=3,500 (enrolling)

No ARV

No ARV

No ARV

(referral for ARV treatment if CD4 <200)

Arm 1: ZDV 4 mg/kg bid x 7 d plus NVP 2 mg/kg x 1 (NVAZ)

Arm 2: ZDV 4 mg/kg bid x 7 d plus NVP 2 mg/kg x 14 wks

Arm 3: ZDV 4 mg/kg bid plus NVP 2 mg/kg both given x 14 wks

  • Effective in decreasing MTCT at 9 mos, but no sign. diff. death; no sign. diff. Ext NVP vs Ext NVP/AZT
  • MTCT at 9 mos: 5.2% Ext NVP (51% decrease) vs 6.4% Ext NVP/AZT (40% decrease) vs 10.0% NVAZ
  • Survival at 9 mos: 6.8% Ext NVP vs 6.3% vs 8.9% NVAZ
  • HIV or death at 9 mos: 10.6% Ext NVP vs 11.2% Ext NVP/AZT vs 16.8% NVAZ
  • Ext NVP/AZT had more low ANC possibly assoc.

Taha T et al. 15th CROI 2008 (abs 42LB)

Kumwenda et al. NEJM 2008;June 4 epub

SOUTH AFRICA/ TANZANIA/UGANDA/ZIMBABWE (HPTN 046) (NIH)
  • Infant prophylaxis postnatal tx, NVP x 1 vs NVP x 6 mos
  • 2 arm, randomized, [NVP] placebo-controlled
  • Breastfeeding
  • N=1,576 (enrolling)

Outside study

Outside study

No ARV

Open label sdNVP followed by daily NVP from 5 days to 42 days of age, then randomize:

Arm 1: NVP standardized dose adjusted as age

Arm 2: NVP placebo x 6 mos

BURKINA FASO, S AFRICA, UGANDA, ZAMBIA (ANRS - PEP )
  • Infant prophylaxis postnatal tx, no infant prophylaxis during BF vs 3TC x 9 mos
  • 2 arm, randomized, placebo controlled
  • Breastfeeding
  • N=1,500 (in planning)

?

?

No ARV

Open label sdNVP at birth

Arm 1: start at d 7: 3TC standardized dose adjusted as age x 9 mos

Arm 2: start at day 7 3TC placebo x 9 mos

THAILAND (PHPT-5) Thailand
  • Antepartum/intrapartum/postpartum intervention evaluating whether maternal NVP is needed for efficacy of sdNVP, and comparing short course AZT/sdNVP to short course AZT/protease inhibitor
  • Formula feeding
  • N=1,992 (enrolling)

CD4 >250 cells/µL Starting at 28 weeks:

Arm 1: AZT

Arm 2: AZT

Arm 3: AZT/LPV-rtv

Arm 1: sdNVP + AZT/3TC

Arm 2: Placebo + AZT

Arm 3: AZT/LPV-rtv

Arm 1: AZT/3TC x 7 days

Arm 2: Placebo x 7 days

Arm 3: No drugs

Arm 1: sdNVP birth and 48 hours + AZT x 1 week

Arm 2: sdNVP birth and 48 hours + AZT x 1 week

Arm 3: AZT x 1 week

  • Started spring 2009
Maternal ARV Prophylaxis Of Breast Milk Transmission [PDF, 158K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
KENYA (Kisumu Breast-feeding Study, KiBS) (CDC)
  • Maternal prophylaxis of postnatal tx, HAART (ZDV/3TC/LPV/rtv)
  • Non-randomized, open-label
  • Breastfeeding
  • N=500

ZDV 300 mg/3TC 150 mg (Combivir) bid plus NVP 200 mg q d x 2 wks, then 200 mg bid

Starting at 34-36 wks

ZDV 300 mg/3TC 150 mg q 12 hr plus NVP 200 mg q 12 hrs

If CD4 >200:

ZDV/3TC bid plus NVP 200 mg bid x 6 mos

NVP 2 mg/kg x 1 at <72 hrs (all infants)

  • Mid-2005, regimen modification:
    • Women with CD4<250 get ZDV/3TC/NVP
    • Women with CD4>250 get ZDV/3TC/NFV
  • Overall MTCT at 6 mos 5.0% and 12 mos 5.9%.
  • Postnatal PMTCT at 6 mos 2.6% and 12 mos 3.5%
  • No sign. diff. CD4 <or >250 or NVP vs NFV
  • Resistance overall in 67% infected infants (43% if mom NVP, 100% if mom NFV)
    • 16% on first test but increasing to 67% by wk 14-24
    • suggests emergence of resistance with infected infant exposure to ARV in milk

Thomas T. 15th CROI 2008 (abs 45aLB)

Zeh C. 15th CROI 2008 (abs 84LB)

Mid- 2005 mod:

If CD4 >250:

ZDV 300 mg/3TC 150 mg (Combivir) plus NFV, all bid

Mid- 2005 mod:

If CD4 >250:

ZDV 300 mg/3TC 150 mg plus NFV, all bid

CD4 <200: Continue indefinite

Mid- 2005 mod:

If CD4 >250:

ZDV/3TCplus NFV all bid

AFRICA MULTISITE (WHO/CDC/NICHD)
  • Maternal prophylaxis postnatal tx, HAART (ZDV/3TC/LPV/rtv) vs short-course ZDV + NVP (Kesho Bora Project)
  • 2 arm, randomized for CD4 200-500, open-label, comparative; observational for CD4 <200 or >500
  • Breastfeeding (~ 50%) and formula feeding
  • N=2,400 (enrolling)
Observational:
  • Randomized trial modified from ZDV/3TC/NVP to ZDV/3TC/LPV/rtv for women with CD4 200-500 due to NVP toxicity concerns
  • MTCT at birth :
    • Maternal HAART: 1.8% (0.8-3.7%)
    • Short course AZT: 2.2% (1.2-4.3%)
  • MTCT between birth-6 months (postpartum HAART vs no prophylaxis)
    • Maternal HAART: 3.1%
    • Short course AZT: 6.3%
  • Overall MTCT at 12 months
    • Maternal HAART: 5.5% (3.6-8.4%)
    • Short course AZT: 9.5% (6.9-13.0%)
  • Observational CD4 <200 , MTCT at 12 months: 7.6%
  • Observational CD4 >500 , MTCT at 12 months: 5.8%

de Vincenzi I. 15th CROI 2008 (Ab. 638)

de Vincenzi I. 5th IAS 2009 (Abs. LB PEC01)

Starting at 18-36 wks
CD4 < 200
:

ZDV 300 mg/3TC 150 mg bid (Combivir) plus NVP 200 mg q d x 2 wks, then 200 mg bid

ZDV 300 mg/3TC 150 mg q 12 hr plus NVP 200 mg q 12 hrs

ZDV 300 mg/3TC 150 mg bid plus NVP 200 mg q d

ZDV 4 mg/kg bid x 1 wk plus NVP 2 mg/kg x 1 at <72 hrs

Starting at 34-36 wks:
CD4 > 500
:

ZDV 300 mg bid

ZDV 300 mg q 3 hr plus NVP 200 mg x 1

No ARV

ZDV 4 mg/kg bid x 1 wk plus NVP 2 mg/kg x 1 at <72 hrs

Randomized trial:

Starting at 28-36 wks
CD4 200-500
:

Arm 1: ZDV 300 mg/ 3TC 150 mg bid plus LPV/rtv bid

Arm 2: ZDV 300 mg bid

Arm 1: ZDV 300 mg/ 3TC 150 mg q 12 hr plus LPV/rtv bid

Arm 2: ZDV 300 mg q 3 hr plus NVP 200 mg x 1

Arm 1: ZDV 300 mg/3TC 150 mg bid plus LPV/rtv bid x 6 mos

Arm 2: No ARV

Arm 1: ZDV 4 mg/ kg bid x 1 wk plus NVP 2 mg/kg x 1 at <72 hrs

Arm 2: ZDV 4 mg/ kg bid x 1 wk plus NVP 2 mg/kg x 1 at <72 hrs

BOTSWANA (Mma Bana Study) (Harvard [NIH])
  • Maternal prophylaxis postnatal tx, safety and efficacy of HAART (ZDV/3TC/ABC vs ZDV/3TC/LPV/rtv)
  • 2-arm, randomized for CD4 >200 open-label, comparative; observational for CD4 <200
  • Breastfeeding
  • N=560 randomized (N=170 observational)
Observational
  • MTCT at birth:
    • AZT/3TC/ABC: 1.1%
    • AZT/3TC/LPV-r: 0.4%
    • Observational
  • MTCT at 6 months (cumulative):
    • AZT/3TC/ABC: 1.8%
    • AZT/3TC/LPV-r: 0.4%
  • No significant difference 6 months MTCT between regimens (p-=0.53)
  • Observational CD4 <200, MTCT 0.6% at 6 months

Shapiro R. 5th IAS 2009 (Abs. We LBB101)

Starting at 18-34 weeks:

CD4 <200:
ZDV 300 mg/3TC 150 mg bid (Combivir) plus NVP 200 mg q d x 2 wks, then 200 mg bid

Supplemental ZDV for q 3 hr dosing; other drugs continue bid

Continue for life

Basic regimen all:

NVP 6 mg x 1 at birth plus ZDV (4 mg/kg bid)x 4 wks

Randomized trial:

Starting at 26-34 wks:

Arm 1: ZDV/3TC/ABV

Arm 2: ZDV/3TC/LPV/rtv

Supplemental ZDV for q 3 hr dosing; other drugs continue bid

Arm 1: ZDV/3TC/ABV

Arm 2: ZDV/3TC/LPV/rtv

Through 6 mos PP

Arm 1: ZDV/3TC/ABV

Arm 2: ZDV/3TC/LPV/rtv

Basic regimen all:

NVP 6 mg x 1 at birth plus ZDV (4 mg/kg bid)x 4 wks

TANZANIA (MITRA-Plus)
  • Maternal prophylaxis postnatal tx, safety and efficacy of HAART (ZDV/3TC/NVP)
  • Observational
  • Breastfeeding
  • N=560 randomized (N=140 observational) (enrolling)

Starting at 34 weeks (earlier if needed for own health):

ZDV/3TC/NVP

ZDV/3TC/NVP

Through 6 mos PP (stop if don't need for treatment):

ZDV/3TC/NVP

ZDV/3TC x 1 week

  • Healthy group of women: 94% women WHO Stage 1 (asymptomatic); median CD4 415 (17.5% <200); median RNA 14,621
  • Median duration BF 24 wks
  • Tx 4.1% (2.2-6.0%) at 6 wks and 5.0% (3.6-8.0%) at 6 mos (comparable to MITRA with infant prophylaxis); at 12 mos, 5.8%, and 18 mos, 6.0%.
  • Incremental postnatal tx risk btn 6 to 24 wks 1.0% (0.02-2.0%) and between 6 wks to 18 mos 2.1% (0.7-3.5%).

Kilewo et al. 4th IAS Sydney Australia 2007 Abs. TuAX101

Kilewo et al. JAIDS 2009 Aug 27; Epub

MALAWI (BAN) (CDC/UNC)
  • Maternal prophylaxis postnatal tx, HAART (ZDV/3TC/LPV/rtv) with or without PP nutritional supplement
  • 3 arm, randomized only if CD4 ≥200 and Hb ≥7g/dL (CD4 <200 referred for HAART), open-label, factorial, comparative
  • Breastfeeding
  • All receive maize supplements pp
  • N=2,637

Arm 1: No ARV

Arm 2: No ARV

Arm 3: No ARV

Basic regimen all:

ZDV 300 mg/3TC150 mg q 12 hr plus NVP 200 mg x1

1st randomization: Randomized to nutritional supplement (high calorie and micronutrient fortified) or not for mother postpartum x 6 mos

Basic regimen all:

ZDV 300 mg/3TC 150 mg bid x 1 wk

Arm 1: Basic regimen

Arm 2: ZDV 300 mg/3TC 150 mg bid plus NVP 200 mg bid (changed to LPV/rtv 3/05) start at 7 d x 6 mos

Arm 3: Basic regimen

Basic regimen all:

ZDV/3TC x 1 wk plus NVP 2 mg/kg x 1 at <72 hrs

Arm 1: Basic regimen

Arm 2: Basic Regimen (no further infant drug)

Arm 3: NVP 2 mg/kg q d (4 mg/kg >2 wk/o), start at 7 d x 6 mos

  • April 2005 regimen modification: Maternal HAART during BF, changed from NVP-based HAART to LPV/rtv-based HAART due to concerns re: FDA label change for women with CD4 >250.
  • March 2008: DSMB recommended control Arm 1 close
  • 7 month MTCT (in infants uninfected at birth):
    • Control: 6.4%
    • Maternal HAART: 3.0%
    • Infant NVP: 1.8%
  • Maternal HAART vs control, p=0.0032
  • Infant NVP vs control, p<0.0001
  • Maternal HAART vs infant NVP, p=0.12

Chasela C. 54th IAS 2009 (Abs. WE LBC103)

COTE D'IVOIRE, OTHERS? (ANRS 12200)
  • Maternal prophylaxis postnatal tx, safety and efficacy of 2 HAART regimens (TDF/FTC/EFV vs ZDV/3TC/LPV-r)
  • Randomized trial (non-inferiority design)
  • Breastfeeding
  • N=? randomized (in planning)

Starting at 20 weeks

Arm 1: TDF/FTC/EFV

Arm 2: ZDV/3TC/LPV/r

Arm 1: TDF/FTC/EFV

Arm 2: ZDV/3TC/LPV/r

Through 6 mos PP (stop if don't need for treatment based on CD4 at baseline/ clinical stage at BF cessation):

Arm 1: TDF/FTC/EFV

Arm 2: ZDV/3TC/LPV/r

AZT x 1 week?

MULTIPLE (IMPAACT 1077: PROMISE)
  • Resource-limited countries: Women with CD4 >350, undergo 2-4 sequential randomizations
    • AP(28 wk): Short course vs HAART
    • PP (if BF mom-baby): infant ART vs maternal ART
    • Infant health (if BF baby): If infant is uninfected + <12 mos at weaning, continue CTX vs CTX placebo
    • Maternal health: Mom on HAART and CD4 >350: Stop HAART vs continue HAART (if FF, randomize after delivery; if BF, randomize post weaning)
  • Randomized
  • Formula-feeding; breastfeeding
  • AP: N=4,560 (FF: 1,040; BF: 3,520)
  • PP: N=4650 (3,100 AP, 1,500 late present)
  • IH: N=2,286 (all PP)
  • MH: N=5,950 (FF, BF)
  • In US/Brazil (where AP HAART and FF standard, P1077B):
    • Maternal health: Mom on HAART and CD4 >400 at delivery: Stop HAART vs continue HAART
  • N=2,000

CD4 >350, starting at 28 weeks:
ANTEPARTUM RANDOMIZATION
Arm 1: AZT

Arm 2: ZDV/3TC/LPV-RTV

Arm 1: sd NVP + TFV/FTC

Arm 2: ZDV/3TC/LPV-RTV

Arm 1: sd NVP + TFV/FTC x 7 d

Arm 2: ZDV/3TC/ LPV-RTV x 7 d

FF Mom: MAT HEALTH RANDOMIZATION (day 7-12, CD4 >350)
New Arm 1: Stop HAART

New Arm 2: Continue HAART

BF Pts: POSTPARTUM RANDOMIZATION (day 7-12, CD4 >350)
New Arm 1: TFV/ FTC/LPV-RTV duration of BF

New Arm 2: No maternal ART after day 7

BF Mom: MAT HEALTH RANDOMIZATION (on HAART, at weaning, CD4 >350)
Arm 1: Stop HAART

Arm 2: Continue HAART

Arm 1: sd NVP + AZT x 7 d

Arm 2: sd NVP + AZT x 7 d

FF Baby:
MATERNAL HEALTH RANDOMIZATION
(day 7-12)
New Arm 1: No infant ART after 7 d

New Arm 2: No infant ART after 7 d

BF Pts:
POSTPARTUM RANDOMIZATION
(day 7-12)
New Arm 1: No infant ART after 7 d

New Arm2: Infant NVP duration of BF

BF Baby:
INFANT HEALTH RANDOMIZATION
(if <12 mos and uninfected)
New Arm 1: CTX to 18 mos

New Arm 2: CTX placebo to 18 mos

  • To enroll women who do not require ART for own health (CD4 >350) to address
    • what is optimal AP regimen for PMTCT?
    • what is optimal PP regimen for PMTCT BF tx?
    • what is optimal way to maintain health uninfected babies after weaning?
    • is it safe for mothers to stop HAART after receiving only for PMTCT?
ARV Clinical Trials: Single-dose Nevirapine Resistance Issues -- Prevention of Resistance [PDF, 135K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
SOUTH AFRICA (BI 1413; TOPS)
  • Reduce development NVP resistance
  • 3 arm, randomized, open-label
  • Breastfeeding and formula feeding
  • N=228

No ARV

Arm 1: NVP 200 mg x 1

Arm 2: NVP 200 mg x 1 plus ZDV 300 mg/3TC 150 mg (Combivir) q 12 hr

Arm 3: NVP 200 mg x 1 plus ZDV 300 mg/3TC 150 mg (Combivir) q 12 hr

Arm 1: No ARV

Arm 2: ZDV 300 mg/3TC 150 mg (Combivir) bid x 4 days

Arm 3: ZDV 300 mg/3TC 150 mg (Combivir) bid x 7 days

Arm 1: NVP 2 mg/kg x 1 at 72 hrs

Arm 2: NVP 2 mg/kg x 1 at 72 hr plus ZDV 4 mg/kg bid plus 3TC 2 mg/kg bid x 4 days

Arm 3: NVP 2 mg/kg x 1 at 72 hr plus ZDV 4 mg/kg bid plus 3TC 2 mg/kg bid x 7 days

  • Preliminary unplanned interim analysis led to early stopping Arm 1
  • Overall tx, 24/228 (10.5%) (21/24 IU tx)
  • Resistance data on 203; rate of NVP resist at either 2 or 6 wk PP:
    • Mother: 41/68 (60%) Arm 1: vs 8/67 (12%) Arm 2: vs 7/68 (10%) Arm 3.
    • Infected infant: 5/9 (56%) Arm 1: vs 1/8 (13%) Arm 2: vs 1/7 (14%) Arm 3.

McIntyre J et al. XV AIDS Conference, Bangkok, Thailand 2004 (Abs LbOrB09)

McIntyre J et al. 3rd IAS Conference, Brazil 2005 (Abs TuFo0204)

HAITI, AFRICA - (AACTG 5207, MOMS) (NIH)
  • Reduce development NVP resistance
  • 4-arm, randomized, open label
  • Sized to detect decrease cum NVP resistance at 6 wk PP from 60% to ≥30%
  • N=420 (enrolling)

No ARV

or

ZDV alone starting at 28 weeks

Arm 1: NVP 200 mg x1 plus ZDV 300 mg/ 3TC150 mg

Arm 2: NVP 200 mg x1 plus TDF 300 mg/ FTC200 mg

Arm 3: NVP 200 mg x1 plus LPV 400 mg/r100 mg

2nd randomization by 7 vs 21 days

ZDV/3TC x 7 or 21 d

ZDV/3TC/TDF x 7 or 21 d

LPV/r x 7 or 21 d

NVP 2 mg/kg x1

NVP 2 mg/kg x1

NVP 2 mg/kg x1

THAILAND (P1032S) (NIH)
  • Reduce development NVP resistance
  • 3-arm, randomized, open label
  • Sized to detect decrease cum NVP resistance at 12 wk PP from 75% to ≥25%
  • Formula feeding
  • N=150 (enrolling)

All women receive ZDV starting at 28 wks gestation

Arm 1: NVP 200 mg x1 plus ZDV 300 mg q 3 hr plus ddI EC125 (<60 kg) or 200 mg (>60 kg) plus LPV/rtv 400/ 100 mg q 12hr

Arm 2: NVP 200 mg x1 plus ZDV 300 mg q 3 hr plus ddI EC 125 (<60 kg) or 200 mg (>60 kg) q 12

Arm 3: NVP 200 mg x1 plus ZDV 300 mg q 3 hr plus ddI 125 (<60 kg) or 200 mg (>60 kg) plus LPV/rtv 400/ 100mg q 12hr

ZDV/ddI EC/ LPV/rtv BID x 7 d

ZDV/ddI EC BID x 30 d

ZDV/ddI EC/LPV/rtv BID x 30 d

All infants receive NVP 2 mg/kg x1 plus ZDV x 7 d

  • NVP resistance at 2-6 weeks:
    • ZDV+ddI+LPV/rtv x 7 days: 0% standard genotype, 3.6% sensitive assay
    • ZDV+ddI x 30 days: 0% standard genotype, 7.1% sensitive assay
    • ZDV+ddI+LPV/rtv x 30 days: 0% standard genotype, 5.3% sensitive assay

Van Dyke R et al. 16th CROI 2009, Montreal (abs. 95aLB)

ZAMBIA (TD2 Study) (U. AL)
  • Addition of SD maternal TFV/FTC to SD NVP to reduce resistance with PMTCT
  • Open-label, randomized (at labor), controlled
  • Breastfeeding
  • N=329

Women receive ZDV starting at 28-38 wks

Arm 1: NVP 200 mg x 1

Arm 2: NVP 200 mg x 1 plus 1 tablet Truvada (300 mg TFV/200 mg FTC) x 1

All infants:
NVP 2 mg/kg x 1 at 48-72 hrs

  • Primary evaluation is safety and development of NVP resistance at 6 + 12 wks PP and TFV/FTC resistance at 2 + 6 wks
  • At 2/6 wks, NVP resistance; 30% SD NVP vs 13% TFV/FTC
  • No difference in IP/early PP tx; at 6 wks tx in uninfected at birth was 1.6% TFV/FTC vs 2.8% SD NVP, p=0.67

Chi B et al. Lancet 2007;370:1698-705

Chi B et al. JAIDS 2008;48:220-3

COTE D'IVOIRE, S AFRICA, VIETNAM (TEmAAM, ANRS 12109)
  • Reduce development NVP resistance
  • 1 arm open label
  • Breast & formula feeding
  • N=38

All women receive ZDV starting at 28 wks gestation

NVP 200 mg x1 plus 2 tablets Truvada (600 mg TFV/400 mg FTC) x1

Truvada 1 tabletl (300 mg TFV/200 mg FTC) QD x 7 d

All infants receive NVP 2 mg/kg x1 plus ZDV x 7 d

  • At 4 weeks: no resistance to ZDV, NVP, TFV or FTC

Arrive E et al. 4th Dormont Conf, Paris 2007 (abs 20)

TEmAA ANRS 12109 Study Group, Arrive E et al. AIDS 2009;27:825-33

TANZANIA (U. Copenhagan)
  • Addition of SD maternal TFV/FTC vs AZT/3TC x7 d to SD NVP to reduce resistance with PMTCT
  • Open-label, randomized (at labor), controlled
  • Breastfeeding
  • Endpoint : NVP resistance in two regimens; MTCT secondary endpoint
  • N=300 (enrolling)

No ARV

All women:
SD NVP 200 mg x1

Plus

Arm 1: Combivir (AZT 300 mg/3TC 150 mg) x1

Arm 2: Truvada (TFV 300 mg/FTC 200 mg) x1

All women:
SD NVP 200 mg x1

Plus

Arm 1: Combivir twice daily x 7d

Arm 2: no further drugs

All infants
NVP 2 mg/kg x 1 at 48-72 hrs

ARV Clinical Trials: Single-dose Nevirapine Resistance Issues -- Response to ARV Therapy, Second Pregnancy [PDF, 128K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
BOTSWANA (MASHI-PLUS) (Harvard [NIH])
  • Viral and CD4 response ARV post SD NVP woman and small number infected infants
  • Observational: Mashi study women with/ without SD NVP exposure who require NVP-based ART
  • Women started on ART: N=106 women with no SD NVP exposure, N=112 women with prior SD NVP exposure
  • Infected infants started on ART with data: N=12 infants with no SD NVP exposure; N=13 infants with SD NVP exposure

All women received ZDV starting at 34 weeks gestation

All women received ZDV intrapartum

Prior NVP 200 mg x1
or
No prior NVP exposure

When CD4 <200, received NVP-based HAART

Prior NVP 200 mg x1
or
No prior NVP exposure

If diagnosed at <12 months, had symptoms or CD4 <25%, received NVP-based HAART

  • Viral response (RNA <400) differed by when started ART post SD NVP.
  • 60 women started ART <6 mos post SD NVP: viral failure after 6 mos on ART was 0/36 placebo vs 10/24 SD NVP (p<0.001).
  • 158 women started ART >6 mos post SD NVP: viral failure after 6 mos on ART was 5/70 (8%) placebo 10/88 (12%) SD NVP (p=0.39) (of 87 women tested with ultrasensitive, 77% each group had RNA <50).
  • CD4 response after 24 mos ART same regardless of when start ART post SD NVP
  • Of 25 infected infants (median age start ART, 8 mos), viral failure after 6 mos on ART was 1/12 (9%) placebo vs 10/13 (77%) SD NVP (p<0.001)

Lockman S et al. 43rd IDSA, San Francisco 2005 (abs. LBS)

Lockman S et al. NEJM 2007;356:135-47

S. AFRICA (NEVEREST) (Columbia U [NIH])
  • Response ARV post SD NVP woman
  • Observational: Viral response to NVP-HAART in women without prior SD NVP vs prior SD NVP exposure ≥18 months prior to starting ART
  • N=150 (90 SD NVP exposed, 60 no SD NVP) (enrolling)

No ARV

Prior NVP 200 mg x1 >18 months prior to start ART
or
No prior NVP exposure

When CD4 <200, received NNRTI-based HAART

  • Interim analysis: N=59 prior SD NVP, started ART median 25 mo (range 16-36 mos) post SD NVP exposure; N=34 no SD NVP, started ART median 19 mos (12-36 mos) PP
  • Viral response <50 copies/mL to ART after 6 mos no different with/ without SD NVP exposure:
    • SD NVP: 100%
    • no SD N VP: 74%
  • CD4 response after 6 mos ART same regardless of SD NVP exposure

Coovadia A et al. 13th CROI, Denver 2006 (abs 641)

AFRICA (AACTG 5208) (OCTANE) (NIH)
  • Response ARV post NVP woman
  • 2-arm, randomized, open label
  • NVP exp: superiority PI vs NNRTI regimen
  • No NVP exp: equivalence PI vs NNRTI regimen
  • Formula feeding?
  • N-640 (240 with prior SD NVP exposure, 420 without SD NVP exposure) (enrolling)

No ARV

Prior NVP 200 mg x1 (N=240)
or
No prior NVP exposure (N=420)

When CD4 <200, randomize in each exposure group (stratify by CD4 <>50):

Arm 1: TFV 300 mg plus FTC 200 mg qd plus NVP 200 mg bid

Arm 2: TFV 300 mg plus FTC 200 mg qd plus LPV 400 mg/rtv 100 mg bid

  • Pts who fail NVP or LPV/rtv arm in step 1 will change to other drug + 2 NRTIs in step 2.
S. AFRICA, TANZANIA, UGANDA, ZIMBABWE, ZAMBIA (PACTG 1060)
  • Response ARV post NVP infant 6 mos- 3 yrs old
  • 2-arm, randomized, open label
  • NVP exp: superiority PI vs NNRTI regimen
  • No NVP exp: equivalence PI vs NNRTI regimen
  • Formula feeding
  • N-480 (enrolling)

Prior NVP 200 mg x1
or
No prior NVP exposure

When CD4 <25% if <11 mo/o or <20% if >12-25 mo/o, or clinical AIDS, randomize in each exp grp

Arm 1: AZT/3TC/NVP

Arm 2: AZT/3TC/LPV/rtv

  • Primary endpoint (viral failure, off drug or death) at 24 wks: 40% with NVP vs 22% with LPV/rtv (P=0.027)
  • Viral failure endpoint at 24 wks: 24% with NVP vs 7% with LPV/rtv (p=0.009)
  • Baseline NNRTI resistance and age <12 mos associated with failure.

Palumbo P et al. 5th IAS 2009 (Abs. LB PEB12)

SOUTH AFRICA/COTE d'IVORIE
  • Effectiveness of single-dose NVP in 2nd pregnancy
  • Compared MTCT in 1st pregnancy to MTCT rates in 2nd pregnancy; got SD NVP both pregnancies
  • Formula fed
  • N=121

No ARV

NVP 200 mg x1 (all women)

No ARV

NVP 2 mg/kg x 1 at 48-72 hrs (all infants)

  • Effectiveness SD NVP not reduced by prior exposure:
    • S. Africa: MTCT 10.5% both pregnancies
    • Cote d'Ivorie: MTCT 8.6% both pregnacies
  • MTCT 1st pregnancy didn't predict in 2nd

Martinson N et al. 13th CROI, Denver 2006 (abs 722)

Martinson N et al. JAIDs 2007;45:206-9

UGANDA
  • Effectiveness of single-dose NVP in 2nd pregnancy
  • Observational
  • Breastfeeding
  • N=100 retrospective (59 without, 41 with prior SD NVP)
  • N=101 prospective (63 without, 38 with prior SD NVP)

No ARV

Prior NVP 200 mg x1
or
No prior NVP exposure

No ARV

NVP 2 mg/kg x 1 at 48-72 hrs (all infants)

  • SD NVP stays effective:
  • Retrospective: MTCT 2nd pregnancy 11.8% if prior SD NVP, 17.1% if no prior SD NVP
  • Prospective: MTCT 2nd pregnancy 18.4% if prior SD NVP, 17.5% if no prior SD NVP

Eure C et al. 13th CROI, Denver 2006 (abs 125)

McConnell MS et al. JAIDS 2007;46:291-6

Phase I/II ARV Clinical Trials [PDF, 214K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
US (PACTG 249)
  • ZDV/ddI
  • Phase I, safety and PK, pregnant women/infant
  • Formula feeding
  • N=9

Starting at 26-36 wks

Standard ZDV plus ddI 1.6 mg/kg intravenous infusion d 1; then 200 mg (125 mg if <60 kg) single dose d 2-7; then 200 mg bid >d 7

Standard intravenous ZDV plus ddI intravenously 1 mg/kg over 30 min, then 0.25 mg/kg/hr

Standard ZDV plus ddI 200 mg bid x 6 wk

Standard ZDV plus single dose ddI 60 mg/m at d 1 and wk 6

  • Pregnancy: AP and PP PK similar, dose same as non-pregnant
  • Infant (N=4): PK highly variable

Wang et al. J Infect Dis 1999;180: 1536-41

UGANDA (HIVNET 006)
  • NVP single dose
  • Phase I, safety and PK, pregnant women/infant
  • Breastfeeding
  • N=21

No ARV

NVP 200 mg x1

No ARV

NVP 2 mg/kg x 1 at 48-72 hrs

  • Same PK as PACTG 250
  • Colostrum/maternal NVP ratio 0.61; median milk NVP, 103 ng/mL 1st wk

Musoke et al AIDS 1999; 13: 479-86

US (PACTG 324)
  • ZDV oral IP dosing
  • Phase I, safety and PK
  • Formula feeding
  • N=20

Non-study ARV

Oral ZDV 300 mg q 3 hr

Non-study ARV

Non-study ARV

  • Recommend: ZDV 600 mg, then 300 mg q 3 hr

Dorenbaum et al. 7th CROI, San Francisco 2000 (abs 660)

Mirochnick M et al. HIV Med 2007;8:451-6

US (PACTG 250)
  • NVP
  • Phase I, safety and PK, pregnant women/infant
  • Part 1, single dose NVP; Part 2, multiple dose NVP
  • Formula feeding
  • N=17 (Part 1) and N=15 (Part 2)

Starting at 38 wks

Part 1: Non-study ARV

Part 2: NVP 200 mg q d (multiple dose cohort)

Part 1: Standard intravenous ZDV plus NVP 200 mg x1 (single dose cohort)

Part 2: Standard intravenous ZDV plus NVP 200 mg x1

Non-study ARV

Part 1: Standard ZDV plus NVP 2 mg/kg x 1 at 48 hr

Part 2: Standard ZDV plus NVP 2 mg/kg x 1 at 48 hr

  • With single dose:
    • T1/2 increased, peak decreased in women
    • Infant NVP maintained >100 ng/mL x 7 d
  • With multiple dose:
    • PK in pregnant similar non-pregnant.
    • Infant elimination increased; only 50% NVP <100 ng/mL at 7 d

Mirochnick et al. J Infect Dis 1998; 178:368-74 and PIDJ 2001; 20:803-805

US (PACTG 331)
  • ZDV in preterm infants <35 wks
  • Phase I, safety and PK, preterm infant
  • N=38

Non-study ARV

Non-study ARV

Non-study ARV

ZDV 1.5 mg/kg intravenous or oral q 12 hr x 2 wks, then 2m/kg q 8 hr through 6 wks

  • Clearance lower than full term infant
  • Recommendation: ZDV 1.5 mg/kg intravenous or 2.0 mg/kg oral q 12 hrs, then increase to q 8 hrs at 2 wk (if ≥30 wks at birth) or 4 wk (<30 wks at birth)

Capparelli et al. J Pediatr 2003; 142:47-52

US (PACTG 332)
  • d4T/3TC
  • Phase I, safety and PK, pregnant woman/infant
  • Formula feeding
  • N=14

Starting at 14-32 wks

d4T 40 mg bid (30 mg if <60kg) plus 3TC 150 mg bid (with or without ZDV other ARV)

Intravenous d4T 0.05 mg/kg continuous infusion (part 1) or oral d4T 40 mg q 12 hr (part 2) plus 3TC 150 mg q 12 hr

Non-study ARV

ZDV 2 mg/kg qid x 6 wks plus d4T 1 mg/kg single dose at 6 d and 42 d

  • Pregnancy: PK and dose similar to non-pregnant
  • Cord/maternal ratio 1.3
  • Infant: prolonged T1/2 at 6 d compared to 42 d

Wade et al. 10th Retrovirus Conf 2003 (abs 886)

Wade et al. JID 2004;190: 2167-74

US (PACTG 353)
  • Nelfinavir plus ZDV/3TC
  • Phase I, safety and PK, pregnant woman/infant
  • Formula feeding
  • N=33

Starting at 28-34 wks

ZDV 200 mg tid plus 3TC150 mg bid plus NFV 1250 mg bid

Standard intravenous ZDV plus 3TC 150 mg q 12 hr plus NFV 1250 mg q 12 hr

ZDV 200 mg tid plus 3TC150 mg bid plus NFV 1250 mg bid

ZDV 2.6 mg/kg tid plus 3TC 2 mg/kg bid plus NFV 40 mg/kg bid x 6 wks

  • Pregnancy: Inadequate levels at 750 mg tid dosing; adequate at 1250 mg bid
  • Infant: NFV inadequate levels at 10 mg/kg tid and 40 mg/kg bid

Mirochnick et al. JAIDS. 2005 Jun 1;39(2):189-94

Bryson et al. HIV Clin Tr 2008;9:115-25

US (PACTG 354)
  • Ritonavir plus ZDV/3TC
  • Phase I, safety and PK, pregnant woman/infant
  • Formula feeding
  • N=7

Starting at 28-34 wks

ZDV 200 mg tid plus 3TC150 mg bid plus RTV 500 or 600 mg bid

Standard intravenous ZDV plus 3TC 150 mg q 12 hr plus RTV 500-600 mg q 12 hr

ZDV 200 mg tid plus 3TC150 mg bid plus RTV 500 or 600 mg bid

ZDV 2.6 mg/kg tid plus 3TC 2 mg/kg bid x 6 wks plus RTV 350 mg/kg single dose at day 8 and 12

  • Pregnancy: RTV levels higher PP than AP
  • Infant: RTV levels low, higher dose needed

Scott et al. 9th Retrovirus Conf 2002 (abs 794-W)

US (PACTG 358)
  • Indinavir plus ZDV/3TC
  • Phase I, safety and PK, pregnant woman/infant
  • Formula feeding
  • N=16

Starting at 14-32 wks

ZDV 200 mg tid plus 3TC150 mg bid plus IDV 800 mg tid

Standard intravenous ZDV plus 3TC 150 mg q 12 hr

ZDV 200 mg tid plus 3TC150 mg bid plus IDV 800 mg tid

ZDV 2.6 mg/kg tid plus 3TC 2 mg/kg bid x 6 wks

  • Pregnancy: IDV levels were approximately 2x as high PP than AP; mean AP level low vs non-pregnant adult
  • May need to give with low dose RTV boost in pregnancy

Wara et al. 2nd Global Strategies Conf 1999 (abs 447)

Unadkat et al. AAC 2007;51:783-6

SOUTH AFRICA
  • ZDV/3TC
  • Phase I, safety and PK, pregnant women/infant
  • Breastfeeding
  • N=20

Starting at 38 wks

3TC 300 mg bid
or
ZDV 300 mg bid plus 3TC 150 mg bid

3TC 300 mg q 12
or
ZDV 300 mg q 12 hr plus 3TC 150 mg q 12 hr

3TC 300 mg bid x 1 wk
or
ZDV 300 mg bid plus 3TC 150 mg bid x 1 wk

Starting at 12 hrs

3TC 4 mg/kg bid
or
ZDV 2 mg/kg qid plus 3TC 4 mg/kg bid x 1 wk

  • Pregnancy: 3TC PK similar to non-pregnant, no change with ZDV
  • 3TC/ZDV levels similar mother, cord, and infant
  • Infants: 3TC clearance ~1/2 of older children

Moodley et al. J Infect Dis 1998; 178:1327-33

SOUTH AFRICA (Triangle)
  • Emivirine (new NNRTI) plus ZDV or ZDV/3TC
  • Phase I, safety and PK, pregnant woman
  • Breastfeeding
  • N=14

Starting at 36- 37 wks

ZDV alone if RNA >20,000; ZDV/3TC if >20,000

plus

Arm 1: Emivirine 750 mg bid d 15-21

Arm 2: Emivirine 750 mg bid d 8-21

?

?

?

  • Pregnancy: Clearance reduced by 50% in pregnant vs non-pregnant
  • Cord blood/maternal ratio 0.77
  • Infant: T½, 11 hr with 1 wk, and 8 hr with 2 wk maternal dosing

Gray et al. XIII AIDS Conf 2000 (abs TuPeB3255)

US (PACTG 386)
  • Saquinavir plus ZDV/3TC
  • Phase I, safety and PK, pregnant woman/infant
  • Formula feeding
  • N=18

Start at 14-32 wks

ZDV 200 mg tid plus 3TC150 mg bid plus SQV 800 mg/RTV100 mg bid

Standard intravenous ZDV plus 3TC 150 mg q 12 hr plus SQV 800 mg/RTV100 mg q 12 hrs

ZDV 200 mg tid plus 3TC 150 mg bid plus SQV 800 mg/RTV100 mg bid

ZDV 2.6 mg/kg tid
plus 3TC 2 mg/kg bid x 6 wks

  • Pregnancy: Inadequate levels with SQV 1200 mg tid alone
  • Adequate levels with low dose RTV boost

Acosta et al. HIV Clin Trials. 2001 Nov-Dec;2(6):460-5;

Acosta et al. Antimicrob Agents Chemother. 2004 Feb;48(2):430-6.

SOUTH AFRICA (C Baragwanath Hosp/ Bristol-Myers-Squibb 049)
  • ddI vs d4T vs ddI/d4T vs ZDV
  • 4 arm, randomized, phase II pilot (non-comparative)
  • Formula feeding
  • N=362

Starting at 34-36 wks

Arm 1: ddI 200 mg bid

Arm 2: d4T 40 mg bid

Arm 3: ddI 200 mg bid plus d4T 40 mg bid

Arm 4: ZDV 300 mg bid

Arm 1: ddI 200 mg q 12 hr

Arm 2: d4T 40 mg q 12 hr

Arm 3: ddI 200 mg q 12 hr plus d4T 40 mg q 12 hr

Arm 4: ZDV 300 mg q 12 hr

No ARV

Arm 1: ddI 120 mg/m bid x 6 wk

Arm 2: d4T 1 mg/kg bid x 6 wk

Arm 3: ddI 120 mg/m bid plus d4T 1 mg/kg bid x 6 wks

Arm 4: ZDV 2 mg/kg qid x 6 wks

  • RNA decrease at 4 wks: -1.12 log with d4T; -1.33 log with ddI; -1.91 log with d4T/ddI; -0.76 with ZDV
  • Tx at 6 mos (final data): 10.6% ddI, 12.1% d4T, 4.6% ddI/d4T, 5.6% ZDV
  • Infected babies, no resistance to ddI/d4T/ ZDV at 6-12 wks

Gray et al. XIII AIDS Conf 2000 (abs TuOrB355);

Pillay et al. XIV AIDS Conf 2002 (abs TuPeB4583)

Gray et al. JAIDS 2006 Jun; 42(2):169-76.

SOUTH AFRICA, ZIMBABWE (HIVNET 023)
  • Infant post-exposure prophylaxis of postnatal tx, NVP
  • Phase I, safety and PK, infant
  • Breastfeeding
  • N=75

No ARV

NVP 200 mg x1 (all women)

No ARV

For 6 mos:

Arm 1: NVP 2 mg/kg (4 mg/kg, 3 wks) q d

Arm 2: NVP 4 mg/kg (8 mg/kg, 3 wks) 2x/wk

Arm 3: NVP 4 mg/kg (8 mg/kg, 3 wks) q wk

  • Dose increase at 3 wks
  • Daily best for keeping NVP >100 ng/mL
  • Phase III trial (HPTN 046) will use daily NVP
  • NVP resistance 8 wk PP in mother (N=20): 50% plasma, 65% breast milk (diff. mutations pattern)

Shetty et al. JAIDS 2003 Dec 15;34(5):482-90.

Katzenstein et al. 10th Retrovirus Conf (abs 96)

Lee et al. JID 2005;192:1260-4

US (PACTG 394)
  • Tenofovir
  • Phase I, safety and PK, pregnant woman/infant
  • Part 1, mom only; part 2, mom and infant
  • Formula feeding
  • N=10 (cohort 1)
  • N=15 (cohort 2)

Non-study ARV

Non-study ARV

Cohort 1: Tenofovir 600 mg x1

Cohort 2 (N=7): Tenofovir 900 mg x1

Modified to (N=8): Tenofovir 900 mg plus FTC 600 mg x1

Non-study ARV

Non-study ARV (standard 6 wks ZDV minimum ARV)

Cohort 2: Tenofovir 2 mg/kg x 1 at <6 hrs

Modified to: Tenofovir 2 mg/kg plus FTC 3 mg/kg x 1 at <6 hrs

  • 1st cohort (N=10):
    • median time TDF dose to delivery 5.7 hrs
    • Maternal/cord blood ratio 0.66; median cord TDF 64 ng/mL
    • TDF levels <50 ng/mL in all infants >age 12 hrs
    • Increased maternal TDF to 900 mg x1 as infant cord blood levels low and highly variable
  • 2nd cohort (N=15)
    • Median time TDF dose to delivery 7 hrs
    • Maternal peak levels increased by 83% but AUC not different from 600 mg dose
    • Maternal/cord blood ratio 0.67; median cord TDF 68.2 ng/mL (not different than 600 mg mom dose)
    • TDF cord blood levels <50 ng/mL in 33%
    • At time infant dose, median TDF level 44 ng/mL; by 24 hours post infant dose mean TDF levels 50 ng/mL
    • None of 8 women tested to 12 wks PP had K65R mutation

Rodman et al. 13th CROI, Denver 2006 (abs 708)

Flynn et al. 16th CROI 2009 (abs939)

AFRICA/BRAZIL (HPTN 057)
  • Tenofovir
  • Phase I, safety, PK, pregnant woman/infant
  • Part 1, mom only; part 2, infant only; part 3, mom and infant
  • Breastfeeding
  • N= 75 (enrolling)

Non-study ARV

Non-study ARV

Tenofovir 600 mg x1

Non-study ARV

Non-study ARV

Tenofovir 2 mg/kg at birth and once q d at days 1, 3 and 5

  • Maternal TDF exposure after 600 mg dose similar to non-pregnant
  • TDF accumulates in amniotic fluid (median amniotic fluid/maternal level 3.01)
  • Median maternal/cord blood ratio 0.60; median cord TDF 76 ng/mL; cord blood below target 50 ng/mL in 34%
  • Increased maternal TDF to 900 mg x1 under study
  • TDF in breast milk low levels (6.3-17.8 ng/mL) day 1-6
  • Infant dosing 4 mg/kg on day 1, 3 and 5 did not keep infant level >50 ng/mL entire first week.

Mirochnick M et al. 16th CROI 2009 (abs 940)

COTE D'IVOIRE/S AFRICA/CAMBODIA (TEmAA/ANRS 12109)
  • Tenofovir/FTC
  • Phase I, safety and PK, pregnant woman/infant
  • Part 1, mom only; part 2 mom and infant
  • Breastfeeding
  • N= 60 (enrolling)

All women received ZDV 300 mg BID starting at 28-36 wks

Part 1: NVP 200 mg x 1 plus 2 tablets Truvada (600 mg TFV/400 mg FTC) x 1

Part 2: NVP 200 mg x 1 plus 2 tablets Truvada (600 mg TFV/400 mg FTC) x 1

1 tablet Truvada (300 mg TFV/200 mg FTC) once daily x 7 d

1 tablet Truvada (300 mg TFV/200 mg FTC) once daily x 7 d

NVP 2 mg/kg x 1 at 48-72 hrs plus ZDV BID x 7 d

NVP 2 mg/kg x 1 at 48-72 hrs plus TFV and FTC syrup x 1 plus ZDV BID x 7 d

  • PK, safety and resistance evaluations (see resistance section for those results)
  • Maternal concentration post IP dose ~ non-pregnant on TFV/FTC 300/200
  • Cord levels vs maternal?: TFV 76%; FTC 74%

Hirt E et al. 15th CROI 2008 ( abs 47LB & 626 )

Nutrient Supplementation [PDF, 147K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
TANZANIA (Harvard)
  • Vitamin A, multi-vitamins (MV) (B1, B2, B6, niacin, B12, C, E, folic acid)
  • 4 arm, randomized, placebo-control, factorial (enrolled 1995-97)
  • Breastfeeding
  • All moms get AP iron and folate; infants get vit A at 6, 12, 18 mos
  • N=1,083

No ARV

Starting at 12-28 wks

Arm 1: Vit A 5,000 IU + 30 mg carotene q d

Arm 2: MV q d

Arm 3: Vit A5,000 IU + 30 mg carotene plus MV q d

Arm 4: Placebo

No ARV

Arm 1: Vit A 200,000 IU x 1

Arm 2: Placebo

Arm 3: Vit A 200,000 IU x 1

Arm 4: Placebo

No ARV

For period lactation

Arm 1: Vit A 5,000 IU + 30 mg carotene q d

Arm 2: MV q d

Arm 3: Vit A 5,000 IU + 30 mg carotene plus MV q d

Arm 4: Placebo

No ARV

Vit A 100,000 IU at 6 mos, then 200,000 IU q 6 mos (all infants)

  • At 24 mos, overall tx:
    • 31% MV vs 29% no MV (RR1.04)
    • 34% vit A vs 25% no vit A (RR 1.38)
  • MV no sign. effect on tx or 24 mo infant death
    • MV reduced PP tx and infant death in subgroup low maternal CD4 or Hb, high ESR, or LBW infant
    • MV grp infants had lower diarrhea and higher CD4 (HIV- and +)
  • MV reduced develop AIDS in women PP
  • Vit A no effect AP/IP tx or infant mortality, but increased PP tx
    • Vit A grp infants had lower rate pneumonia
  • Maternal MV reduced infant developmental delay on Baylor motor scale and increased psychomotor development index score by mean 2.6 pts, but not mental development.

Fawzi et al. JAIDS 2000; 23:246-54

Fawzi et al. JAIDS 2002; 31:331-8

Fawzi et al. AIDS 2002;16:1935-44;

Fawzi et al. Clin Infect Dis. 2003 Apr 15;36(8):1053-62

Fawzi et al. NEJM 2004;351:23-32

McGrath et al. Pediatrics. 2006;117(2):216-25.

MALAWI (Hopkins)
  • Vitamin A
  • 2 arm, randomized, placebo-control (enrolled 1995-96)
  • Breastfeeding
  • All moms get AP iron and folate
  • N=700

No ARV

Starting 18-34 wks

Arm 1: Vit A 10,000 IU q d

Arm 2: Placebo

No ARV

Arm 1: Vit A 200,000 IU x 1

Arm 2: Placebo

No ARV

No ARV

  • No effect vit A on overall tx:
    • At 6 wks, 26.6% vit A vs 27.8% placebo
    • At 12 mos, 27.3% vit A vs 32.0% placebo
    • At 24 mos, 27.7% vit A vs 32.8% placebo
  • Vit A did not increase PP tx:
    • If uninfected at 6 wks but + at 24 mos, tx 2.8% vit A vs 7.7% placebo (p=0.04)
  • Vit A improved pregnancy outcome and reduced LBW
  • Vit A less infant anemia and better growth at age 6 wks
  • Mastitis and breast milk RNA associated with tx

Semba et al. J Infect Dis 1999; 180:93-8

Kumwenda et al. Clin Infect Dis. 2002 Sep 1;35(5):618-24.

ZIMBABWE (Denmark)
  • 13 micronutrients (MN) including vit A 10,000 IU
  • 2 arm, randomized, placebo control
  • Breastfeeding
  • N=1,800 (600 HIV+)

No ARV

Starting 2nd trimester

Arm 1: MN q d

Arm 2: Placebo

No ARV

Arm 1: MN x 1

Arm 2: Placebo

No ARV

Arm 1: MN q d x 3 mos

Arm 2: Placebo

No ARV

  • Insufficient follow-up, no data available on tx
  • MN did not effect prevalence subclinical mastitis in HIV- women, borderline decrease in HIV+ women (p=0.07)

Gomo et al. Trans R Soc Trop Med Hyg. 2003 Mar-Apr;97(2):212-6.

SOUTH AFRICA (U. Natal)
  • Vitamin A
  • 2 arm, randomized, placebo-control (enrolled 1995-98)
  • Breastfeeding
  • All moms get AP iron and folate
  • N=728

No ARV

Starting at 28-32 wks

Arm 1: Vit A 5,000 IU + 30 mg carotene q d

Arm 2: Placebo

No ARV

Arm 1: Vit A 200,000 IU x 1

Arm 2: Placebo

No ARV

No ARV

  • 3 mos, tx 20.3% vit A vs 22.3% placebo (not sign.)
  • Non-sign. trend for lower tx with vit A in preterm subgroup (N=80):
    • At 3 mo, tx 17.9% vit A vs 33.8% placebo
  • Vit A sign. lowered preterm delivery, 11.4% vit A vs 17.4% placebo
  • Vit A did not reduce infant death: at 12 mos, mortality 9.3% vit A vs 10.0% placebo
  • Infant morbidity, never breastfed vs breastfed:
    • Overall morbidity 1.9x more likely 1st 2 mo life; 4x more likely in HIV+

Coutsoudis et al. AIDS 1999;13:1517-24

Coutsoudis et al. Acta Paed 2003;92:890-5

ZIMBABWE (Hopkins/ USAID/Canada) (ZVITAMBO)
  • Vitamin A
  • 4 arm factorial, randomized, placebo-control
  • Rapid HIV testing women during labor/PP; enroll PP
  • N=14,110 (in analysis; expect 30% HIV+, for N=4,200)

No ARV

If identified early enough in labor: NVP 200 mg x 1 (all women)

No ARV

Arm 1: Vit A 400,000 IU x 1

Arm 2: Vit A 400,000 IU x 1

Arm 3: Placebo

Arm 4: Placebo

NVP 2 mg/kg x1 at 48 hrs (all infants)

Arm 1: Vit A 50,000 IU x 1

Arm 2: Placebo

Arm 3: Vit A 50,000 IU x 1

Arm 4: Placebo

  • Vit A supplementation did not reduce tx (p>0.7) or infant mortality
  • Overall late postnatal tx (btn 6wk-18mo) 12.1%; 68% of postnatal (PN) tx occurred age >6 mos
  • Mixed feeding assoc higher risk PN tx: 6.9% excl BF; 8.5% predom BF; 14.1% mixed BF

Iliff PJ et al. AIDS 2005;19:699-708

Malaba L et al. Am J Clin Nutr 2005;81:454-60

TANZANIA (Harvard)
  • Selenium
  • 2 arm, randomized, placebo-control, phase II
  • All women receive multivitamins
  • N=300 (to open)

Starting at 12-28 wks

Arm 1: Selenium 200 ug q d

Arm 2: Placebo

NVP 200 mg x 1 (all women)

For 6 mos PP

Arm 1: Selenium 200 ug q d

Arm 2: Placebo

NVP 2 mg/kg x 1 at 48-72 hrs (all infants)

  • Primary endpoints maternal (CD4 count, RNA, genital HIV shedding, mastitis)
Immunization: Passive Immunization (Immune Globulin) [PDF, 154K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
US (PACTG 185)
  • HIVIG vs IVIG
  • 2 arm, randomized, blinded, enrolled women with CD4 ≤500 (enrolled 1993-97)
  • Formula feeding
  • N=454

Non-study ARV

Starting at 20-30 wks

Arm 1: HIVIG 200 mg/kg IV q mo

Arm 2: IVIG 200 mg IV q mo

Standard intravenous ZDV (all women)

Non-study ARV

ZDV 2 mg/kg qid x 6 wks (all infants)

Arm 1: HIVIG 200 mg/kg IV x 1 at birth

Arm 2: IVIG 200 mg/kg IV x 1 at birth

  • PK study: maternal HIVIG T1/2 15 d after 1st, 32 d after 3rd infusion; infant HIVIG T1/2 30 d
  • No change viral or immune parameters with HIVIG infusion
  • Enrollment stopped early due to unexpected low tx rate in both arms (overall 5.0%):
    • HIVIG 4.1%
    • IVIG 6.0%
  • Maternal delivery HIV RNA most sign. risk factor for tx

Lambert et al. J Infect Dis. 1997 Feb;175(2):283-91

Stiehm et al. J Infect Dis 1999;179: 567-75

Mofenson et al. NEJM 1999;341:385-93

UGANDA (Hopkins)
  • HIVIGLOB
  • Phase I, dose-escalating (50, 200, 400 mg/kg) safety and PK, pregnant woman/infant (enrolled 1996-97)
  • Breastfeeding
  • N=31 (29 infants)

At 37-38 wks

HIVIGLOB 50, 200 or 400 mg/kg IV x 1

No ARV

No ARV

No ARV

HIVIGLOB 50, 200 or 400 mg/kg IV x 1 at <16 hrs

  • Well-tolerated
  • No change viral or immune parameters with infusions
  • Median T½, 28 d women, 30 d infant
  • Chose 400 mg/kg for phase III trial

Guay et al. AIDS 2002;16: 1391-1404

UGANDA (Hopkins)
  • Infant prophylaxis of postnatal tx, HIVIGLOB vs NVP x1 vs extended NVP
  • 3 arm, randomized
  • Breastfeeding
  • N=570 (in analysis)

At 37-38 wks

Arm 1: HIVIGLOB 400 mg/kg IVx 1

Arm 2: No drug

Arm 3: No drug

NVP 200 mg x1 (all women)

No ARV

Arm 1: HIVIGLOB 400 mg/kg IV x 1 plus NVP 2 mg/kg x 1 at 48 hr

Arm 2: NVP 2 mg/kg x 1 at 48 hr

Arm 3: NVP 2 mg/kg q d x 6 wks

Immunization: Active Immunization (Vaccines) [PDF, 154K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
US (PACTG 235)
  • rgp 120 vaccine in pregnant women
  • Phase I, randomized, alum placebo-control (enrolled 1993-95)
  • Formula feeding
  • N=26

Non-study ARV

Starting at 16-24 wks

Arm 1: 300 ug rgp120 vaccine q mo

Arm 2: Alum placebo

Non-study ARV

Non-study ARV

Non-study ARV

  • No change CD4, HIV RNA, neutralizing antibody, or binding antibody with vaccine

Wright et al. J Infect Dis 1999;180:1080-8

US (PACTG 230)
  • rgp120 vaccine (2 vaccines Genetech and Chiron)
  • Phase I/II, randomized, dose-finding, blinded adjuvant placebo-control (enrolled 1993-96)
  • Formula feeding
  • N=183

Non-study ARV

Non-study ARV

Non-study ARV

Non-study ARV

Vaccine schedule

Part 1: At birth, 1, 3 5 mos

Part 2: At birth, 2 wk, 2 mos and 5 mos

Arm 1: Genetech (30, 100 or 300 ug) or Chiron rgp120 (5, 15, or 50 ug)

Arm 2: Adjuvant placebo (alum or MF-59, respectively)

  • No serious events
  • Immunogenic (antibody, LPA response) in >50%, persist at 104 wks
  • Need 2 immunizations to get response
  • Accelerated schedule with 5 ug Chiron vaccine had 100% response by age 4 wks
  • Genetech less response regardless dose/schedule

Borkowsky et al. J Infect Dis 2000; 181:890-6

McFarland et al. J Infect Dis 2001; 184:1331-5

Cunningham et al. CID 2001; 32:801-7

US (PACTG 326)
  • ALVAC vCP 1452 (canarypSox vaccine) with and without AIDSVAX rgp120 B/B boost in newborns
  • Phase I/II, randomized, blinded adjuvant placebo control
  • N=48

Non-study ARV

Non-study ARV

Non-study ARV

Non-study ARV

Vaccine schedule:

ALAVC/placebo at birth, 4, 8, 12 wks; AIDSVAX/placebo at 8, 12 wks

Arm 1: ALVAC 1 mL

Arm 2: Saline placebo

Arm 3: ALVAC1 mL plus AIDSVAX 0.33 mL

Arm 4: Saline plus alum placebo

  • Originally studied ALVAC vCP205, modified to study newer generation ALVAC vCP1452
  • ALVAC vCP205 results:
    • LPA response ≥2 time 44-56% vaccinees, 0% placebo
    • CTL response ≥1 time 44-63%vaccinees and only 1 placebo pt
    • Mucosal IgA response rare (11-33%); no Ab
  • Modified study interim:
    • Safety: 3 infants with grade 3 reactions, resolved
    • Immunogenicity: LPA response best with combination; CTL less frequent

McFarland et al. 10th Retrovirus Conf 2003 (abs 404)

Johnson et al. 10th Retrovirus Conf 2003 (abs 99)

Johnson et al. JID 2005;192:2129-33

UGANDA (HIVNET 027)
  • ALVAC vCP 1521 (canarypox)
  • Phase I/II, randomized, blinded saline placebo-control
  • Breastfeeding
  • N=50 (enrolling)

No ARV

Non-study NVP 200 mg x 1 (all women)

No ARV

NVP 2 mg/kg x1 at 48 hr (all infants)

Vaccine schedule:

At birth, 4, 8, 12 wks

Arm 1: ALVAC

Arm 2: Saline placebo

Mode of Delivery [PDF, 86K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
EUROPE (ECS)
  • Cesarean vs vaginal
  • 2 arm, randomized (enrolled 1993-98)
  • Formula feeding
  • N=436

Non-study ARV (most ZDV)

Non-study ZDV

Arm 1: Vaginal

Arm 2: Cesarean

Non-study ARV

Non-study ARV (most ZDV)

  • At 18 mo, tx 1.8% C/S vs 10.5% vaginal, 80% efficacy

European Mode of Delivery Collaboration. Lancet 1999; 353:1035-9

US/EUROPE (NICHD)
  • Meta-analysis of individual patient data on mode delivery from 15 studies
  • Formula feeding
  • N=8,533

Non-study ZDV

Non-study ZDV

Elective cesarean vs all other mode of delivery

Non-study ARV if required

Non-study ZDV

  • Tx 8.2% elective CS vs 16.7% other mode, 57% efficacy
  • With 3-part ZDV, tx 2.0% C/S vs 7.3% other mode, 87% efficacy

International Perinatal HIV Group. NEJM 1999;340: 977-87

Vaginal Cleansing [PDF, 109K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
MALAWI (NIH)
  • Chlorhexidine (CH) swabbing
  • 2 arm, randomized, "no wash" control (enrolled in 1994)
  • Breastfeeding
  • N=2,094

No ARV

No ARV

Arm 1: CH 0.25% vaginal swabbing q 4 hr

Arm 2: No swabbing

No ARV

No ARV

Arm 1: CH baby bath at birth

Arm 2: No bath

  • At 12 wks, tx 27% CH vs 28% no intervention
  • Subgroup analysis, ROM >4 hrs, tx 25% CH vs 39% no intervention
  • Reduced sepsis and hospitalizations for mom/baby with CH

Biggar et al. Lancet 1996; 347:1647-50;

Taha et al. BMJ 1997; 315:216-9

KENYA (U. Ghent, Belgium)
  • Chlorhexidine (CH) lavage
  • 2 arm, randomized, "no lavage" control (enrolled 1996-99)
  • Breastfeeding
  • N=606

No ARV

No ARV

Arm 1: CH 0.2% (increased to 0.4% last 11mo of 38 mo recruitment period) vaginal lavage q 3 hr

Arm 2: No lavage

No ARV

No ARV

  • At 6-14 wks, tx 20.5% lavage vs 21.7% no lavage
  • IP tx 17.2% lavage vs 15.9% non-lavage
  • Subgroup with 0.4% CH lavage before ROM had lower tx (adjusted OR 0.1, 95% CI 0.0-0.9)

Gaillard et al. AIDS 2001;15:389-96

IVORY COAST (ANRS)
  • Benzalkonium chloride (BC) suppository
  • 2 arm, randomized, placebo-controlled, phase II (enrolled 1996-97)
  • N=107

No ARV

Starting at 36 wks

Arm 1: BC suppository q d

Arm 2: Placebo

No ARV

Arm 1: BC suppository x 1 at onset labor

Arm 2: Placebo

No ARV

No ARV

Arm 1: 1% BC solution within 30 min birth

Arm 2: Placebo

  • BC well-tolerated
  • At 15 mos, tx 23.5% BC vs 24.8% placebo

Mandelbrot et al. Sex Transm Infect 2002; 78:267-70

SOUTH AFRICA (HIVNET 025)
  • Chlorhexidine (CH) lavage
  • Phase II, safety, escalating dose-finding (0.25%, 1%, and 2%)
  • N=225

No ARV

No ARV

CH vaginal wash with each examination

No ARV

No ARV

CH baby wash

  • Tolerance:
    • 0.25% CH [N=29], no complaints
    • 1% CH [N=79], 13% complaints, 6% d/c
    • 2% CH [N=75], 31% complaints, 16% d/c
  • 1% was maximum tolerated concentration

Wilson et al. JAIDS 2004 Feb 1;35(2):138-43

Other Interventions [PDF, 181K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
UGANDA (RAKAI STUDY) (Hopkins)
  • Presumptive rx STDs
  • 2 arm, community-based randomization (enrolled 1994-98)
  • N=3,643 (N=351 HIV+)

No ARV

Arm 1: Azithromycin, cefixime, metronidazole x 1 (varying gestational ages)

Arm 2: No STD rx

No ARV

No ARV

No ARV

  • At 6 wks, no effect on tx:
    • 18.4%, STD rx vs
    • 20.8% no rx
  • Lowering maternal STDs associated with improved pregnancy outcome (newborn mortality, prematurity, low birth weight)

Gray et al. Am J Ob Gyn 2001;185:1209-17

MALAWI/ZAMBIA/ TANZANIA (HPTN 024)
  • Antibiotic prophylaxis of chorioamnionitis
  • 2 arm, randomized, placebo control
  • Breastfeeding
  • Single-dose NVP to all
  • N=3,120 (will also enroll 600 HIV-) (closed 2/03 by DSMB, data from 1,160 women)

No ARV

At 20-24 wks

Arm 1: Metranidazole (MET) 250 tid plus erythromycin 250 tid x 7 d

Arm 2: Placebo

NVP 200 mg x1 (all women)

Arm 1: MET 250 mg plus ampicillin 500 mg q 4 hr

Arm 2: Placebo

No ARV

Arm 1: MET 250 mg plus ampicillin 500 mg tid to complete 7 d

Arm 2: Placebo

NVP 2 mg/kg x1 at 48 hr (all infants)

  • No sign. difference in tx, chorio or preterm birth between antibiotic and placebo grps
  • Final analysis 1,444 women, tx 4-6 wks:
    • tx 16.0% antibiotic group vs 15.7% placebo group (OR 1.02).

Kafulafula et al. February 2004 HPTN meeting, Washington DC

Goldenberg et al. Am J Ob Gyn 2006;194:650-61

Taha et al. AIDS 2006;20(9):1313-21

ZAMBIA (EGPAF)
  • Targeted vs universal NVP
  • 2 arm, clinic- random-ized, cross-over
  • Adherence measured by NVP in cord blood and/or direct observation NVP
  • Breastfeeding
  • N=1,025; 246 HIV+

No ARV

Arm 1: Targeted (NVP offered to women tested and found to be HIV+)

Arm 2: Universal (NVP offered to all women without HIV testing)

No ARV

NVP 6 mg x 1 at 48-72 hrs (for infants whose mothers receive NVP)

  • Participation, 64% targeted vs 71% universal (p<0.01)
  • Uptake correlated with universal strategy, clinic, prior fetal infant death
  • NVP adherence, 74% targeted vs 61% universal (p=0.04)

Stringer et al. JAIDS 2003; 32; 506-13

SOUTH AFRICA (P1031S)
  • Rapid HIV testing for late presenters: intrapartum vs postpartum
  • 2-arm cluster- randomized (by calendar week)
  • Evaluate rapid tests
  • Compare feasibility, acceptability, and early infant tx btn rapid testing intrapartum vs immediately postpartum
  • Breast or formula feeding
  • N=12,000 (to identify 3,300 infected women) (open)

Standard of care in country (eg, SD NVP)

Arm 1: Rapid testing intrapartum

No ARV

Arm 2: Rapid testing immediately postpartum

Standard of care in country (eg, SD NVP)

Breast-Feeding [PDF, 140K]
SITE/SPONSOR ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT RESULTS REFERENCES
KENYA (Seattle/NIH)
  • Breast vs formula feeding
  • 2 arm, randomized (enrolled 1992-97)
  • N=435

No ARV

No ARV

No ARV

No ARV

Arm 1: Breastfeed

Arm 2: Formula feed

  • At 24 mos, tx 36.7% breastfeeding vs 20.5% formula feeding, 44% efficacy
  • Infant mortality similar: at 24 mos, 24.4% breastfeeding vs 20.0% formula feeding
  • Maternal mortality at 24 mos, 10.5% breastfeeding vs 3.8% formula feeding

Nduati et al. JAMA 2000; 283:1167-74

Nduati et al. Lancet 2001; 357:1651-5;

Mbori-Ngacha et al. JAMA 2001; 286:2413-20

ZAMBIA (ZEBS) (Harvard/NIH)
  • Exclusive breastfeeding with abrupt vs routine weaning
  • 2 arm, randomized
  • Counseled to exclusive BF through 4 mos both arms; Arm 1: abruptly weans while Arm 2: continued breastfeeding for duration of maternal choice
  • N=1,200 (in analysis)

No ARV

NVP 200 mg x1 (all women)

No ARV

NVP 2 mg/kg x 1 at 48 hrs (all infants)

Arm 1: Exclusive breastfeed, abrupt wean

Arm 2: Exclusive breastfeed, continued breastfeeding with wean per woman's choice

  • Substudy NVP resistance risk in 23 women with rpt SD NVP exposure vs 24 without; NVP resistance %:
    • No prior SD NVP exposure, 33%
    • Rpt SD NVP same pregnancy, 25%
    • Prior pregnancy SD NVP, 27%
    • OR for resistance with repeat exposure, 1.06, p=0.86
  • Detection/quantity of HIV RNA in milk higher with abrupt weaning vs continuing BF (68% vs 42% detectable, p=0.03; 448 vs <50 copies/mL, p=0.005)
  • Median duration BF in abrupt wean group 4 mo vs continued BF 16 mo
  • MTCT at 4 mos 4.0% if exclusive BF vs 10.1% if mixed fed
  • For infants uninfected at 4 mo, no difference HIV-free survival at 24 mos: 17% abrupt wean vs 19% continued BF (p=0.21)
  • For infants who were HIV-infected by 4 mo, benefit to continue BF (mortality at 12 mos 57% if wean vs 29% if continue BF, p=0.01).
  • Uninfected infants at 4 mo: mother CD4 >350, continue BF better survival at 24 mo (p=0.03); mother CD4 <350, no difference

Kuhn et al. JAIDS 2006 Jun;42(2):260-2.

Thea D et al. AIDS. 2006 Jul; 13;20(11):1539-47.

Sinkala M et al. 14th Retrovirus Conf 2007 (abs 74LB)

SOUTH AFRICA (U. Natal-Wellcome Trust)
  • Exclusive breastfeeding promotion
  • Non-randomized, observational cohort study
  • N=2,722 (1372 HIV-infected)

No ARV

NVP 200 mg x 1 (all women)

No ARV

NVP 2 mg/kg x 1 at 48 hrs (all infants)

Exclusive breastfeeding

  • 83% exclusively breastfed at least 6 wk, median duration 159 d.
  • Overall MTCT 14.1% at 6 wks; 18.1% at 4 mo; 18.6% at 5 mo; 19.5% at 6 mo
  • MTCT associated with maternal CD4 <200 and BW <2500 g
  • Postnatal MTCT if not infected at 6 wk: 1.1% after 1 mo, 2.2%, 2 mo; 2.7%, 3 mo; 3.3%, 4 mo; 4.0%, 5 mo (~age 6 mo)
  • MTCT per 100-child days if uninfected at 6 wks: 0.029 exclusive BF vs 0.044 for mixed feed
  • Mixed feed with solids 10.9-fold increased risk MTCT compared to exclusive BF; mixed feed with formula 1.8-fold increased risk
  • Cumulative mortality: 6.1% at 3 exclusive BF vs 15.1% at 3 mo replacement feeding; HR 2.06 for formula feed

Coovadia H et al. Lancet 2007;369:1107-16

IVORY COAST (ANRS)
  • ZDV+3TC+NVP (DITRAME PLUS, ANRS 1202)
  • Non-randomized, open-label antiretroviral prophylaxis
  • Infant feeding, mother choice: exclusive breastfeeding, wean at 3-5 mos, vs formula
  • N=1,000 (enrolling)

Starting at 32 wks

ZDV 300 mg bid plus
3TC 150 mg bid

ZDV 600 mg x1 plus
3TC 150 mg x1 plus
NVP 200 mg x1

No ARV

ZDV 2 mg/kg qid x 7 d plus NVP 2 mg/kg x 1 at 48-72 hrs

Infant feeding:

Exclusive breast-feeding, wean at 3-5 mos

Formula feeding

  • 622 infants in DITRAME PLUS 1201 and 1202: 52% formula fed from birth, 48% BF from birth (median duration 124 d); by age 3 mos, 22% had been mixed fed
  • Breastfeeding longer than 6 mos (OR 7.5, p=.001) and mixed feeding in 1st mo life (OR 6.3, p.04) associated with increased postnatal (PN) tx; mixed feeding in mo 2 and 3 not associated with risk
  • Comparing 2 yr outcome in formula and breastfed with early weaning in both ZDV/SD NVP and ZDV/3TC/SD NVP ANRS 1201 studies, no sign. difference in rate of adverse health outcome or death

Leroy V et al. XV International AIDS Conf, 2004 (Abs. MoPpB2007)

Becquet et al. XVI International AIDS Conf, 2006 (Abs. TUPE0350)

Bequet et al. PLosMed 2007;4 :e17

Bequet et al. Prev Med 2007 Dec 4 epub

RWANDA (CHARGE) (IATEC)
  • Chloroquine
  • 2 arm, randomized, placebo-control, pilot study
  • Breastfeeding
  • N=30 (in analysis)

No ARV

Standard NVP 200 mg x 1

No ARV

Arm 1: Chloroquine 200 mg q d x 16 wks

Arm 2: Placebo x 16 wks

Standard NVP 2 mg/kg x1 at 48-72 hr

  • Pilot study to assess feasibility and effect of chloroquine on cell-free virus in breast milk
BHITS (NICHD/Ghent)
  • Meta-analysis of individual patient data on mode infant feeding from 9 African perinatal clinical trials
  • Breastfeeding
  • N=4,085 (analysis ongoing)

Country standard care

Country standard care

Country standard care

Country standard care

Breastfeeding

  • Overall tx, 23%
  • Timing of tx:
    • 58% infections, birth to 4 wks (IU, IP, early PP);
    • 42% infection, late postnatal tx (HIV negative at 4 wks, but positive after)
  • Cum probability of late postnatal tx at 18 mos, 15.6%
  • Overall maternal mortality 28.7/1000 pt-yr at 12 mos and 32.2/1000 pt-yr at 18 mos
  • Infant feeding modality not associated with maternal mortality (p=0.11); maternal CD4 count was associated with mortality risk

Read et al. XIV AIDS Conf 2002 (abs TuOrB1177)

Read et al. 10th Retrovirus Conf 2003 (abs 97)

Newell et al. 2nd IAS Conf, Paris, France, July 2003 (abs. 221)

BHITS. JID 2004;189:2154-66

Key to Abbreviations
3TC: lamivudine mg: milligrams
AP: antepartum mL: milliliter
ANRS: Agence nationale de recherches sur le sida MN: micronutrient
ARV: antiretroviral Mo(s): month(s)
BC: benzalkonium chloride MV: multivitamin
BF: breast-feed NFV: nelfinavir
BID: twice per day Ng: nanogram
CDC: Centers for Disease Control and Prevention NNRTI: nonnucleoside reverse transcriptase inhibitor
CH: chlorhexidine NRTIs: nucleoside reverse transcriptase inhibitor
CI: Confidence Interval NVP: nevirapine
C/S: cesarean section OR: odds ratio
CTL: cytotoxic T lymphocyte PI: protease inhibitor
d: day(s) PK: pharmacokinetic
D4T: stavudine PP: postpartum
d/c: discontinuation Q: every
ddI: didanosine Q12H: every 12 hours
ECS: European Collaborative Study Q3H: every 3 hours
ESR: erythrocyte sedimentation rate QD: each day
F/U: follow-up QID: four times per day
FTC: emtricitabine rgp120: recombinant HIV envelope glycoprotein (gp 120)
g: grams RNA: ribonucleic acid
GPOvir: fixed-dose combination of stavudine, lamivudine, and nevirapine RR: relative risk
HAART: highly active antiretroviral therapy RTV: ritonavir
Hb: hemoglobin Rx: prescription
HIVIG: HIV immunoglobulin SD: single dose
Hr: hour SQ: subcutaneous
IDV: indinavir SQV: saquinavir
IP: Intrapartum STD(s): sexually transmitted disease(s)
IQR: interquartile range T 1/2: pharmacokinetic half-life
IU: international unit TDF: Tenofovir
IU: intrauterine TID: three times per day
IVIG: intravenous immunoglobulin Tx: transmission
kg: kilograms Wks: weeks
LBW: low birth weight ZDV: zidovudine (AZT)
LPA: lymphocyte proliferation assay
LPV/r: Lopinavir/ritonavir
mcg: microgram
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