Overview of Clinical Trials on Prevention of Mother-to-Child HIV Transmission

1
Overview of Clinical Trials on Prevention of
Mother-to-Child HIV Transmission

• Lynne M. Mofenson, M.D.
• Pediatric, Adolescent and Maternal AIDS Branch
• National Institute of Child Health and Human
  Development
• National Institutes of Health
• Department of Health and Human Services

2
Overview

• Briefly touch on trends in mother-to-child
  transmission in the U.S.
• Mother-to-child transmission in resource-limited
  countries
• Results of short-course antiretroviral trials and
  lessons learned.
• Review ongoing and planned studies and research
  questions.

3
Perinatal Transmission in the U.S.
4
Mother to Child Transmission in the U.S. Over
Time
Decline due to - Enhanced prenatal HIV testing
- Increase in use of
HAART by HIVwomen
- Increase in elective C/S by HIV women.
5
More Potent Antiretroviral Regimens Are
Associated with Lower Perinatal Transmission
Women Infants Transmission Study,
1990-1999Cooper E et al. JAIDS 200229484-94
6
Increasing Rates of Cesarean Delivery Among
HIV-infected Women 1994-2000, U.S. Pediatric
Spectrum of Disease, CDC
N6,467
7
International Perinatal HIV TrialsNeed for
Development of Shorter, Less Expensive
Prophylaxis Regimens That Are More Applicable to
Implementation in Resource-Limited Settings
8
Completed Trials Focused on Prevention AP/IP
Transmission
IP
AP
PP (baby, mother or both)
3d to 1 wk
36 wks
14 wks
6 wks
28 wks
076
NonBF
NonBF
Thai (Harvard)
NonBF
Thai (Harvard)
NonBF
Thai (Harvard), BMS
IvC (ANRS), PETRA, Thai (Harvard)
BF/NonBF
Thai (CDC), IvC (CDC)
NonBF/BF
PETRA, 012, SAINT
BF
PETRA
BF

PP Minimal duration? Is it needed?
AP Minimum duration? Is it needed?
IP Work alone?
9
Short-Course AZT RegimensFollowing PACTG 076,
Studies Focused on Modifications of AZT Alone
Prophylactic Regimens
10
Short-Course AZT Prophylaxis, Formula-Fed
Infants Duration of AP/PP Therapy Lallemant M et
al. N Engl J Med 2000343982-91
AP
IP
PP Infant
28 wk
36 wk
6 wk
3 d
Most Effective (Tx 4 vs SS)
Long- Long
Intermediate (Tx 5)
Long- Short
Intermediate (Tx 9)
Short- Long
Least Effective (Tx 11)
Short- Short
11
Long Better than Short Maternal Antepartum
Therapy for Preventing In Utero Transmission
Lallemant M et al. N Engl J Med 2000343982-91
5.1
Plt0.001
1.6
AP 28 wks
AP 36 wks
12
Short-Course AZT Prophylaxis Efficacy In
Breast-Fed vs Formula-Fed Infants
Efficacy at 6 Mos 50 37 37
Thailand Non-Breast Feeding
PRENATAL 36 wks
INTRA
Ivory Coast Breast Feeding
INTRA
PRENATAL 36 wk
26 at 24 mos (combined)
Ivory Coast/Burkina Faso Breast Feeding
POST MOM 1 wk
INTRA
PRENATAL 36 wks
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Conclusions Short-Course AZT Studies

• Short-course AZT prophylaxis is effective.
• Longer (28 weeks) antepartum treatment is more
  effective than shorter (36 weeks) antepartum
  therapy so significant proportion of in utero
  infection occurs between 28 and 36 weeks.
• Efficacy of prophylaxis is diminished by
  breastfeeding, but still persists at 24 months
  with short-course AZT.

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Short-Course Combination RegimensAfter
Short-Course AZT Prophylaxis Found Effective
Questioned Whether Short-Course Combination
Regimens Might Have Improved Efficacy
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Open-Label AZT/3TC Perinatal Prophylaxis Studies
in Formula-Fed Populations
IP
AP
PP (baby)
Tx
14 wks
6 wks
32 wks
France ANRS 075 Mandelbrot JAMA 2001
1.6
vs AZT only 1994-1996 hx control, 6.8
076 Backbone
34 wks
4 wks
Thailand Chaisilwattana CID 2002

2.8

Short AZT Backbone
vs AZT only 1994-1996 hx control, 11.7


AZT
AZT plus 3TC
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AZT/3TC Prophylaxis in Breast-Fed Infants Petra
Study Team. Lancet 20023591178-86
Efficacy 6 Wk 18 Mo 63 32 42 18 0 0
1 wk mom baby
36 wks
PRENATAL
INTRA
POST
INTRA
POST
INTRA
PLACEBO
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ConclusionsShort-Course Combination Regimens

• AZT/3TC prophylaxis appears more effective than
  AZT alone.
• 3-part AP/IP/PP drug prophylaxis is more
  effective than IP/PP alone.
• IP-only not effective, showing importance of
  post-exposure prophylaxis component.
• Efficacy diminished by breastfeeding and did not
  persist at 18 mos for the IP/PP AZT/3TC regimen.

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Alternative Antiretroviral Short-Course
RegimensCan Similar Efficacy to Combination be
Achieved with Less Expensive and Simpler
Single-Drug Regimens

• Nevirapine
• More potent than NRTIs
• Long half-life
• Rapid oral absorption
• Rapid transplacental passage

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Alternative Antiretrovirals Single-Dose
Nevirapine vs Ultra-Short AZT - HIVNET 012 Guay L
et al. Lancet 1999354795-802
Transmission 14-16 Wks 18 Mos
13.1 15.7 25.1 25.8
Efficacy 47 41
Breastfed Infants
INTRA
POST
Nevirapine
2 mg/kg x1
200 mg x1
versus
Ultra-Short AZT
INTRA
POST
4 mg/kg bid x1 wk
300 mg q 3 hr
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Comparison of IP/PP Regimens Single-Dose
Nevirapine vs PETRA AZT/3TC - SAINT Moodley D et
al. JID 2003 (in press)
Transmission Birth Btn Birth-8 Wks
7.0 5.7 (2.0-5.3) Overall, 8 wks
12.3 5.9 3.6 (3.7-7.8) Overall, 8
wks 9.3 (Overall p0.11)
Nevirapine (variant of HIVNET 012)
INTRA
POST
Mom 200 mg x1 Baby 2 mg/kg x1
200 mg x1
versus
AZT/3TC (PETRA)
INTRA
POST
Mom baby x1 wk
Q 3 hr
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Higher Transmission with Breast (N623) than
Formula (N694) Feeding, Regardless of Treatment
SAINT Moodley D. JID 2003 (in press)
AZT/ 3TC
Formula
Breast
Formula
Breast
NVP
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Efficacy of AZT/3TC and NVP Prophylaxis Similar
Regardless of Mode of Infant Feeding SAINT
Moodley D. JID 2003 (in press)
Formula Fed
Breast Fed
AZT/3TC
NVP
AZT/3TC
NVP
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Does the Addition of Single Dose NVP to
Short-Course AZT Improve Efficacy?
Lallemant M et al. 2002 AIDS Conf, Barcelona Abs
LBOr22
AZT
28 wk
1 wk
oral
DSMB stopped AZT alone (arm 3) _at_ interim
analysis due to significantly higher transmission
Arm 1 -
Plus
NVP
NVP
Arm 2 -
PL
NVP
Arm 3 -
PL
PL
Formula fed
F Dabis F et al. 2002 AIDS Conf, Barcelona Abs
ThOrD1428
AZT
Transmission 7 compared to 13 historical
control AZT alone (95 breastfed)
oral
1 wk
36 wk
NVP
NVP
50 breastfed
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Single-Dose NVP Does Not Improve Efficacy of
Longer or More Complex ARV RegimensDorenbaum A
et al. JAMA 2002288189-98
Pregnancy Labor Newborn
Transmission Rates
Women receiving ARV during pregnancy
Continue ARV
AZT Perinatal Prophylaxis
1.4 (95 CI, 1-3) 1.6 (95 CI, 1-3)
200 mg dose of NVP vs NVP Placebo
2 mg/kg dose of NVP _at_ 48-72 hr vs NVP Placebo
Randomize, stratified by 1) AP ARV (no, mono,
combo) 2) Entry CD4
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No Additional Benefit of Single-Dose NVP
Regardless of Maternal AP Antiretroviral
PACTG 316
Include long AP ARV, intravenous AZT IP, 6 wk
infant
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ConclusionsAlternative Prophylaxis Regimens

• When only IP/PP prophylaxis is given, single-dose
  NVP is superior to IP/PP AZT alone, and similar
  to IP/PP AZT/3TC.
• Efficacy diminished by breastfeeding however,
  while 2-part PETRA AZT/3TC was not effective at
  18 months, NVP retained efficacy.
• Addition of single-dose NVP to short-course AZT
  appears to improve efficacy.
• However, addition of NVP to standard ARV regimens
  used in U.S. did not offer additional benefit.

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Short-Course Antiretroviral Prophylaxis and Drug
Resistance
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Antiretroviral Resistance in Mothers Occurs Even
with Concomitant Antiretroviral Use
6 Weeks Postpartum
Delivery
Eshelman JID 2001 NVP x1
Sullivan XIV AIDS Conf NVP x2
Vanprapar PACTG 2002 AZT NVP x1
Cunningham JID 2001 ARV NVP x1
Mandelbrot JAMA 2001 AZT 3TC _at_ 32 wks
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Nevirapine Resistance in Infected Infants at 6
Weeks Postpartum
Vanprapar PACTG 2002 AZT NVP x1

Eshelman JID 2001 NVP x1
Besser PACTG 2002 NVP x2
Mutations in infant differ from those in mothers
likely develop following receipt of NVP in
infants infected at birth
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ConclusionsAntiretroviral Resistance After
Prophylaxis

• Detection of NVP resistance mutations at 6 weeks
  postpartum occurs in 15-19 of women who receive
  single-dose NVP (but may no longer be detectable
  at 12 months PP).
• Risk of resistance appears greatly increased with
  receipt of second dose (SAINT).
• Resistance incidence not decreased by concomitant
  ARV therapy if viral replication.
• Infants may develop NVP resistance, but most
  cases occur de novo and are not from mother.
• 3TC resistance seen in almost 40 of women
  receiving 4 or more weeks of AP 3TC.
• Effect on future treatment options unknown.

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Infant Prophylaxis for Infants Born to Women with
Late HIV Diagnosis
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Infant Post-Exposure Prophylaxis Needs to Start
Soon After Birth to Be Effective Wade N et al.
N Engl J Med 19993391409
AZT Component (s) Received
33
Preliminary Data Infant Post-Exposure
Prophylaxis Trials (South Africa, Malawi ongoing)
Gray G. 2002 AIDS Conf, Barcelona Abs LBOr13
7 11
NB NVP
AZT 6 wk
Problem 25 loss to follow-up between birth-6
wks
Taha T. 2002 AIDS Conf, Barcelona Abs ThOrD1427
ThPpD2146
22 14
NB NVP
Stratify Late vs
Early Presenter
NB NVP
AZT 1 wk
14 18
NB NVP
IP NVP

NB NVP
AZT 1 wk
IP NVP
Problem Why opposite results with/without IP
NVP?
34
Is Combination Better than Standard 6 Wk AZT
Post-Exposure Prophylaxis in Formula-Fed Infants?
Post-Exposure Infant Prophylaxis
(PEPI) NICHD/HPTN 040 Trial (Brazil, U.S.)
Infant
AZT x 6 wks
IV AZT
NVP birth, 72, 168 hr
AZT x 6 wks
IV AZT
3TC/NFV x 2 wks
AZT x 6 wks
IV AZT
If mom diagnosed in time for IP prophylaxis
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ConclusionsInfant Prophylaxis

• Epidemiologic data suggest AZT given to the
  infant for 6 weeks after birth reduces
  transmission.
• Infant prophylaxis must begin within 24-48 hours
  after birth to be effective when the mother has
  not received AP/IP drug.
• Preliminary data (needs confirmation) suggest
• Single dose NVP given to the infant at birth may
  have efficacy similar to AZT.
• Single dose NVP plus AZT may have better efficacy
  than NVP alone if mother hasnt received single
  dose IP NVP.

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Current/Planned Perinatal TrialsInfant or
Maternal Antiretroviral Prophylaxis to Reduce
Postnatal Breast Milk HIV Transmission
37
Design of Ongoing/Planned Infant Prophylaxis
Trials
IP
AP
PP -- Infant


36 wks
6 wks
34 wks
1 wk
6 mo
28 wks
14 wks
Botswana
SIMBA/MITRA
HPTN 046
Ethiopia/India
Malawi (CDC/NICHD)
S. Africa/Brazil

Thai (Harvard)
DITRAME1
Malawi (ongoing)
Zambia (Harvard)/SA/ HIVNET 024/Uganda
PP Optimal duration? Will it work alone?
What drug? Is combo better?
Exclusive BF, type weaning?
AP Optimal duration? Is it needed?
38
Infant Prophylaxis Trials A Variety of
Regimens/Durations Under Study
Antepartum (28, 34, 36 wks) Intrapartum (oral) Infant Postpartum (1, 6, 14 wks,6 mos)
None AZT alone AZT
AZT NVP x1 NVP
AZT/3TC AZT NVP x1 3TC
AZT/ddI AZT/3TC NVP x1 AZT NVP
AZT/ddI NVP x1 AZT/3TC/NFV
Exclusive BF type weaning
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Maternal Antiretroviral Prophylaxis
StudiesRationale/Goals

• Improve maternal health and survival.
• Prevent resistance from developing with use of
  ARV for PMTCT (3TC, nevirapine are special
  concerns), which could potentially limit future
  maternal treatment options.
• Lower maternal antenatal viral load and decrease
  perinatal transmission.
• Potential for prevention of breast milk
  transmission.

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Design of Maternal HAART Prophylaxis Trials
PP maternal regimen
IP
AP
PP Mother

6 mos
34-36 wks

Kenya (CDC) open label
AZT/3TC/NVP
Botswana (Harvard/EGPAF) open label
AZT/3TC/NVP?

AZT/3TC/NFV vs Baby NVP x 6 mos vs NVP x1 -
multivits
Malawi (CDC/UNC)



AZT/3TC/NVP vs AP/IP AZT/NVP x1 Baby AZT x1 wk
NVP x1
Multisite Africa (WHO)

In randomized studies, CD4 lt200 all get HAART,
CD4 gt200 or 200-500 are randomized
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Unresolved Issues About Maternal Antiretroviral
Treatment

• What is optimal ARV regimen for pregnant women
  (issues drug PK/dose, resistance, safety mother
  and fetus/child)?
• Should HAART be used solely to prevent
  transmission if not needed for treatment?
• Treat mother antenatally, postpartum, both?
• If antepartum, when to start?
• If postpartum, when to stop? Adherence issues
  particularly postpartum.
• Effect on development of resistant HIV in milk
  (subtherapeutic levels).
• Infant toxicity (ARV in milk).