Preventing MothertoChild HIV Transmission and Antiretroviral Drug Resistance

1
Preventing Mother-to-Child HIV Transmission and
Antiretroviral Drug Resistance

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

2
Overview

• Current status of ARV prophylaxis for prevention
  MTCT
• US
• Resource-limited countries
• Development of ARV resistance in women/infants
  receiving MTCT prophylaxis
• General issues
• AZT
• 3TC
• Single-dose nevirapine
• Research issues

3
Current Status of Antiretroviral Prophylaxis of
Mother-to-Child HIV TransmissionUnited States
4
PACTG 076 AZT Regimen Targeted Multiple
Potential Time Points of Transmission
5
AZT Mechanism of Action is Multi-factorial

• Lowering viral load Important mechanism in women
  with high RNA. However, in 076, baseline RNA
  levels low (median 5,700), median decrease RNA
  only 0.28 log, and change RNA accounted for only
  17 observed efficacy (Sperling et al. NEJM
  19963351621-9).
• Two other important mechanisms through which AZT
  reduces transmission
• Pre-exposure prophylaxis of infant (through
  transplacental AZT passage).
• Post-exposure prophylaxis of infant (through
  continued AZT administration to the infant after
  birth).

6
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.
7
Current Status of Antiretroviral Prophylaxis of
Mother-to-Child HIV TransmissionResource-Limite
d Settings
8
International Perinatal HIV Trials

• Following PACTG 076
• Need to develop shorter, less expensive regimens
  more applicable to resource-limited settings.
• Studies first focused on modifications of
  AZT-alone prophylactic regimens.
• Studies also explored whether short-course
  combination regimens might have improved
  efficacy.
• Studies asked if similar efficacy to combination
  could be achieved with alternative drugs that
  were less expensive and could be used in simple
  regimens.
• Current studies looking at enhancing short-course
  regimens, breast milk transmission.

9
Clinical Trial Regimens Shown to Prevent MTCT
IP
AP
PP (baby, mother or both)
3d to 1 wk
36 wks
14 wks
6 wks
28 wks
076
Thai (Harvard)
Thai (Harvard)
Thai (Harvard)
IvC (ANRS), PETRA, Thai (Harvard)
Thai (CDC), IvC (CDC)
PETRA, 012, SAINT

NVAZ
Regimens AZT AZT3TC single dose (SD) NVP
AZT SD NVP
10
Perinatal HIV Clinical Trial Early Efficacy
Results (6 Wks-4 Mos)

• 1994 U.S. AZT Trial ACTG 076 (no BF) 67
  reduction in transmission
• 1998 Thai Bangkok short AP/IP AZT (no BF) 50
  reduction in transmission
• 1998 Ivory Coast short AP/IP AZT (BF) 37
  reduction in transmission
• 1999 PETRA AZT/3TC trial (BF) 63 reduction
  with longest (AP/IP/PP) arm
• 42 reduction with the IP/PP arm
• 1999 Uganda 2-dose IP/PP nevirapine (BF) 42
  reduction in transmission
• 2003 Malawi NVAZ infant NVP vs NVP/AZT (BF)
• 32 reduction in IP/PP transmission

11
Importance of Breastfeeding Postnatal
TransmissionTiming of Mother-to-Child HIV
Transmission with Breastfeeding and No
Antiretroviral Prophylaxis
Late Postpartum (6-24 months)
Early Postpartum (0-6 months)
Early Antenatal (lt36 wks)
Labor and Delivery
Late Antenatal (36 wks to labor)
0
20
40
60
80
100
Proportion of infections
12
Effect of Breastfeeding on PMTCT Prophylaxis
37 No ARV, BF
22.5 AZT AP-IP
20
18.1 AZT/3TC IP-PP
16.5
15.7 NVP IP-PP
14.9 AZT/3TC AP-IP-PP
11.8
8.9
8.6 076 AZT-no BF
5.7
1.6 316 comb-no BF
Infant Age
13
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?
14
Randomized Maternal HAART Prophylaxis Trial Design
AP
IP
PP
6 mos
34-36 wks
1 wk
Malawi (CDC/ UNC)
ZDV/3TC NVP x1
ZDV/3TC NVP x1
ZDV/3TC NVP x1
ZDV/3TC NVP x1
ZDV/3TC/NVP Mother
ZDV/3TC NVP x1
ZDV/3TC NVP x1
NVP Infant
Multisite Africa (WHO)
ZDV
ZDV NVP x1
ZDV NVP x1
ZDV/3TC/NVP
ZDV/3TC/NVP
ZDV/3TC/NVP Mother ZDV x 1 wk NVP x1 Infant
In randomized studies, CD4 lt200 all get HAART,
CD4 gt200 are randomized and stop ARV at 6 months
15
Antiretroviral Prophylaxis of Mother-to-Child
HIV TransmissionDevelopment of Drug Resistance
16
Factors Associated with Acquisition of ARV
Resistance with MTCT Antiretroviral Prophylaxis

• Type of ARV received
• Number mutations (single vs multiple) required
  for resistance
• PK (half-life of drug)
• Single vs combination ARV
• Does combination ARV reduce incidence?
• Presence of other viral mutations
• Can modify whether mutation develops or type of
  mutation that develops
• Duration ARV exposure
• Level of viral replication during exposure

17
Drug-Specific Factors Associated with ARV
Resistance Post MTCT Antiretroviral Prophylaxis

• AZT requires a stepwise accumulation of multiple
  mutations to result in drug resistance.
• Generally takes gt6-12 months of daily AZT therapy
  to develop AZT resistance.
• Nevirapine and 3TC resistance are associated with
  a single mutation.
• Resistance observed rapidly (within days) with
  non-suppressive NVP or 3TC therapy.
• Thus, anticipate development of resistance
  following PMTCT ARV would be less frequent for
  AZT and more common for NVP or 3TC.

18
Antiretroviral Prophylaxis of Mother-to-Child
HIV Transmission and Acquisition of Drug
ResistanceAZT and 3TC
19
AZT Genotypic Drug Resistance in Women and
Infected Infants Rare in PACTG 076
(1989-1991)Eastman PS, et al. J Infect Dis
1998177557-64McSherry G et al. J Pediatr
1999134717-24

• PACTG 076 HIV pregnant women with CD4 gt200,
  not needing therapy and no/minimal prior ARV.
• No high level (codon 215) resistance
  entry/delivery
• Low level (codon 70) resistance (at entry) 2.6
• Incidence low level (codon 70) (delivery) 2.6
• Codon 70 not associated with transmission
  (p0.35).
• No resistance in infected infants in AZT arm.

20
AZT Genotypic Drug Resistance More Common in
Sicker Women in PACTG 185 (1993-1997)Mofenson L
et al. XIII AIDS Conf, Durban S. Africa, 2000
(Abs. 1229)

• PACTG 185 HIV pregnant women with CD4 lt500 who
  require therapy and are receiving AZT before
  entry (14 dual NRTIs)
• Randomized to monthly HIVIG or IVIG starting 20
  weeks gestation with single infusion at birth to
  infant tx 6 vs 4, NS.
• Case-control study 24 transmitting mothers
  matched by baseline RNA to 75 non-transmitting
  mothers genotypic resistance assessed at entry
  and delivery.

21
Incidence AZT Resistance Mutations in Women/
Infants Higher in PACTG 185 than PACTG 076
Mofenson L et al. XIII AIDS Conf, Durban S.
Africa, 2000 (Abs. 1229)
Incidence High-Level Resistance 4
Incidence Low-Level Resistance 11
Maternal Virus at Entry and Delivery Infected
Infant
22
ANRS 075 Open-Label Addition of 3TC to PACTG 076
AZT Prophylaxis and ARV Drug Resistance
Mandelbrot et al. JAMA 20012852083-93
Tx 1.6
IP
AP
PP (baby)
14 wks
6 wks
32 wks
France ANRS 075 (75 ARV naïve)
076 Backbone
AZT
AZT plus 3TC

PACTG 076 AZT backbone 3TC added to maternal
regimen at 32 weeks gestation Infants received
AZT/3TC for 6 weeks



23
ANRS 075 Open-Label AZT/3TC Prophylaxisand ARV
Drug Resistance in 132 Women Mandelbrot et al.
JAMA 20012852083-93

• AZT Resistance at 6 weeks PP
• Women 7 high and 11 low level AZT resistance
• 2/5 infected infants (40) AZT resistant
• 3TC Resistance (M184V) at 6 weeks PP
• Women 39 3TC resistance
• 2/5 infected infants (40) 3TC resistant
• Risk factors for 3TC resistance
• Lower CD4
• Higher HIV RNA
• Longer duration 3TC
• 0 (0/12) if lt1 month 3TC
• 20 (14/70) if 1-2 months 3TC
• 50 (37/74) if gt2 months 3TC

24
AZT Resistance in CDC Côte dIvorie Short-Course
AZT Prophylaxis Study in Breastfed
Infants Wiktor et al. Lancet 1999353781-5 Leroy
V et al. AIDS 200216631-41
Côte dIvorie N 280
Efficacy at 6 Mos at 24 Mos
37 26

INTRA- PARTUM q 3 hr
PRENATAL 36 wks
AZT vs Placebo
Combined Analysis with ANRS 049a DITRAME Short
AZT Study
25
No AZT Resistance Observed with Short-Course AZT
in CDC Côte dIvoire StudyEkpini R-A et al.
AIDS 200216625-30.

• As part of intensive virologic sub-study, 20
  women in AZT group with available samples at
  delivery assessed for AZT resistance mutations in
  DNA.
• No AZT resistance mutations in any specimens
  observed (upper bound 95 CI, 15).

26
PETRA AZT/3TC Short-Course Prophylaxis Study and
AZT and 3TC Resistance 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
Arm A Arm B Arm C
INTRA
POST
INTRA
PLACEBO
27
AZT or 3TC Antiretroviral Resistance,
PETRAGiuliano M et al. AIDS 2003171570-3

• Evaluated AZT and 3TC resistance in sample of
  women from the 2 effective prophylaxis arms.
• At 1 week PP
• Arm A (ante-, intra-, postpartum) AZT/3TC
• New 3TC (M184V) mutation in 12 (6/50).
• AZT (M41L) mutation in 1/50 before drug.
• Arm B (intra-, postpartum) AZT/3TC
• None of 50 women had new 3TC or AZT resistance
  mutations.

28
Antiretroviral Prophylaxis of Mother-to-Child
HIV Transmission and Acquisition of Drug
Resistance Nevirapine
29
Alternative Antiretrovirals Single-Dose
Nevirapine vs Ultra-Short AZT - HIVNET 012 Guay L
et al. Lancet 1999354795-802 Jackson B et al.
Lancet 2003362859-68.
Transmission 14-16 Wks 18 Mos
13.5 15.7 22.1 25.8
Efficacy 42 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
30
Prolonged Exposure with Single-Dose Intrapartum
NVP Increases Risk Resistance

• In phase I studies PACTG 250 and HIVNET 006, NVP
  elimination was prolonged after intrapartum dose
  median T½ 62-66 hours, and median NVP level
  gt100 ng/mL at 8 days.
• In recent Thai trial (PHPT-2), NVP concentrations
  gt50 ng/mL were detectable up to 19 days after
  intrapartum dosing.
• Modeling indicates NVP levels would be gt10 ng/mL
  (IC5010 ng/mL) to 28 days in some women - thus,
  selection of NVP resistant variants is possible
  for prolonged period.

31
NVP Resistance at 6-8 Weeks after Single-Dose NVP
for PMTCT in Women/Infants NVP HIVNET 012

• Eshleman S et al. JAIDS (2004) 35126-30
• In final analysis of women in NVP arm (279/306,
  91 evaluable), NVP resistance mutations detected
  in 25 (70/279) of women at 6 weeks postpartum.
• K103N Y181C most common (53 24).
• Eshleman AIDS (2000) 151951-7
• As part of a substudy of HIVNET 012 including
  evaluation of infected infants, NVP resistance
  detected in 46 (11/24) of infected infants.
• Mutations differed between mothers/infants (Y181C
  gt K103N) most infected in utero.
• Mutations faded from detection by about 12 months
  in all evaluable women and infants.

32
10 Infants Infected with NVP Resistant Virus
Infant and Maternal Genotypes are Different
Eshleman S et al. AIDS 2001151951-7
33
Shift in Specific NNRTI-related Drug Resistance
Mutations in 65 Ugandan Women in HIVNET
012Eshleman et al. 2004 in press
Mutation at codon
HIV Subtypes A D
with NNRTI Mutations 14/65 (22)
18/65 (28)
34
Shift in Specific NNRTI-related Drug Resistance
Mutations in 33 Zimbabwean Women in HIVNET
023Katzenstein D (2003 Cabo resistance meeting)
Mutation at codon
HIV Subtype C
with NNRTI Mutations 21/28 (75)
11/32 (34) 1/8 (13)
35
NVP Resistance in the South African Intrapartum
Nevirapine Trial (SAINT) Moodley D et al. JID
2003187725-35
Tx at 8 Weeks 12
Nevirapine (variant of HIVNET 012)
INTRA
POST
Note 2 maternal doses
Mom 200 mg x1 Baby 2 mg/kg x1
200 mg x1
versus
AZT/3TC (PETRA Arm B)
INTRA
POST
9 p0.11
Mom baby x1 wk
Q 3 hr
36
Selection of NVP (and AZT or 3TC) Resistance
Mutations in SAINTSullivan J. XVI AIDS Conf,
July 2002 (abs. LbPeB9024)

• NVP resistance
• At 4-6 weeks PP, 67 (44/111) women had
  detectable mutations - 62 K103N, 45 Y181C.
• At 12 months, 78 wild type, 20 persistent NVP
  resistance most persistent mutations were K103N.
• 53 (21/40) infected infants had NVP resistance
  mutations in 1st available sample.
• Majority of mutations in infants were Y181C.
• AZT or 3TC resistance
• At 4-6 weeks PP, none of 37 women had resistance.

37
Does NVP Resistance Occur if NVP is Given with
Additional ARV? - Thailand Perinatal HIV
Prevention Trial - PACTG 316
38
Thailand Perinatal HIV Prevention Trial-2
Single-Dose NVP Improves Efficacy of Short-Course
AZT Lallemant M et al. 2nd IAS Conf, Paris,
France, 2003 Abs 62
N1,792
28 wk
1 wk
oral
AZT Backbone
Plus
Arm 1 -
NVP
NVP
Is infant NVP dose needed?
Arm 2 -
PL
NVP
Arm 3 -
D/Cd 04/02
PL
PL
DSMB stopped AZT alone PL/PL arm (N629) due to
significantly higher transmission than AZT/NVP
arms 6.3 AZT alone vs 1.1 AZT/NVP, plt0.0004

39
Preliminary Data on NNRTI-Related Drug Resistance
Mutations in PHPT-2

• Random sample of 90 women receiving AZT plus
  single-dose NVP evaluated.
• A 10 day sample was assessed for detectable
  resistance mutations (using standard resistance
  assays).
• Estimated incidence of detectable NNRTI mutations
  was 18.
• Most frequent mutations were
• K103N
• G190A and
• Y181C.

40
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 (NNRTI
naïve)
Continue ARV
6 Wks 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
41
Maternal Antenatal ARV Treatment at Entry into
PACTG 316 (N1,270)
77 received combo ARV
42
NVP Resistance in Women Receiving ARV Therapy and
with Detectable Delivery RNA in PACTG
316Cunningham C et al. J Infect Dis
2002186181-8

• Sub-study of 217 of 1,270 women enrolled in PACTG
  316 from US or France (70 receiving combination
  antepartum ARV).
• At 6 weeks postpartum, new NVP resistance
  mutations observed in 15 (14/95) in NVP arm (and
  2 - 2/122 in placebo arm).
• K103N most common (alone in 7 and in combination
  in 3 women).
• All women with K103N mutation had mixture of
  mutant and wild-type virus.

43
Pre-Pregnancy ARV Type of Antenatal ARV Was Not
Associated with Acquisition of NVP Resistance
Cunningham C et al. J Infect Dis 2002186181-8
71
72
No ARV Before Pregnancy
50 48
44
What are Factors Associated with the Development
of NVP Resistance with Single-Dose NVP
Prophylaxis?
45
Factors Associated with Development of NVP
Resistance

• Increased NVP exposure
• HIVNET 006 women who developed resistance had
  longer NVP T½
• High baseline (pre-NVP) HIV RNA
• OR 3.1 (95 CI 1.8-5.1) per log increase
• Low baseline CD4 count
• OR 1.3 (95 CI 1.1-1.5) per 100 cell decrease
• Viral subtype (DgtA)
• OR 2.5 (95 CI 1.3-4.9) for subtype D vs A
• Compartment (eg, breast milk vs plasma)
• HIVNET 023 data

46
HIVNET 023 NVP Resistance in Plasma and Breast
Milk of Women Receiving Single-Dose NVPLee E et
al. 10th Retro Conf, February 2003 (abs. 96)

• HPTN 023 studied 3 different doses of NVP given
  for infant prophylaxis for 6 months all mothers
  received single-dose NVP.
• Virus from plasma and breast milk from 20 women
  at Zimbabwe site was genotyped.
• NVP resistance mutations at 8 weeks PP detected
  in
• 8/20 (40) plasma samples
• 13/20 (65) breast milk samples
• One infant had late HIV infection (negative at
  week 24, positive at week 32) but mother had
  wild-type maternal virus in milk and plasma.

47
K103N is Most Common NNRTI Mutation Detected in
Both Breast Milk and Plasma Lee E et al. 10th
Retro Conf, February 2003 (abs. 96)

Breast-milk (13/20)65 Plasma (8/20) 40

48
Differential Selection of NVP Resistance
Mutations in Breast Milk and Plasma SamplesLee
E et al. 10th Retro Conf, February 2003 (abs. 96)

• 9 pairs had the same mutation patterns in milk
  and plasma
• 6 had wild type
• 3 had K103N in both
• 11 pairs had different patterns in milk and
  plasma
• 5 K103N in milk but not plasma
• 6 divergent patterns

49
Important Factors to Consider When Comparing
Nevirapine Resistance in Different Studies

• Timing of sampling
• Higher rates may be seen with early (1-2 wks)
  than later (6-8 wks) samples also affects type
  mutation (Y181C vs K103N)
• Viral subtype (geographic locale)
• Higher rate with subtype D or C than A
• What was sampled
• Plasma vs breast milk vs genital fluids (?)
• Resistance assay used (and algorithm for sequence
  interpretation)
• Sensitivity to detect minor quasispecies
• Prior exposure to NVP or number of NVP doses?
• HIVNET 012 vs SAINT

50
Summary Acquisition of Antiretroviral Resistance
in Mothers Following Antiretroviral Prophylaxis
AZT
gt1 ARV
NVP
3TC
AZT
51
Summary ARV Resistance at Age 6 Weeks in Infants
Infected Despite ARV Prophylaxis
AZT

ANRS 075 data on only 5 infants
52
Research Issues Related to PMTCT and ARV Drug
Resistance Primary Focus has been NVP
Resistance because WHO Recommends NNRTI-Based
Regimens as First-Line Therapy
53
Research Issues Related to Use of ARVs for PMTCT
and Resistance in Resource-Limited Settings

• NVP and 3TC resistance following short-course
  prophylaxis of MTCT of most concern.
• Clinical relevance of NVP resistance post
  single-dose exposure is unclear.
• In absence of continued drug pressure, mutations
  fade thus, transmission of NVP resistant virus
  less likely and efficacy with next pregnancy may
  be maintained.
• However, effect on future treatment options
  unknown.

54
Research Issues Related to Use of ARVs for PMTCT
and Resistance in Resource-Limited Settings

• NVP resistance after single-dose NVP prophylaxis
  most common in women who are sickest low CD4,
  high RNA and who should be considered for HAART
  treatment for own health.
• Risk of NVP resistance in healthier women
  higher CD4 and low RNA is less.
• In antenatal programs, those women at most risk
  for development of NVP resistance should be
  receiving HAART for own health, and single-dose
  NVP might be reserved for healthier women at
  lower risk of resistance.

55
Critical Research Questions in Resource-Limited
Settings

• How long does mutant virus persist after single
  dose (SD) NVP exposure for PMTCT in women,
  children in different compartments?
• Will SD NVP used for PMTCT negatively impact on
  use of NVP for PMTCT in repeat pregnancies?
• Will SD NVP negatively impact on later treatment
  options for HIV-infected women or their infected
  infants?
• If yes, what strategies could reduce this risk?
• Is there a relationship between time since
  exposure and treatment response?
• Proportion of resistant virus and response?

56
Does Prior SD NVP Effect Efficacy of SD NVP in
Subsequent Pregnancy? What are the Kinetics of
NVP Resistance?
Prospective Group N100 (33 NVP-exposed cases,
66 controls)
Retrospective Group N80 HIVNET 012 (NVP vs AZT)
Assess HIV Transmission Rates in NVP Exposed and
Unexposed Women
Assess Background Levels of NVP Genotypic
Resistance
Assess Waning Patterns of Resistant Virus and RT
PCR
Assess Frequency and Type of Resistance Mutations
Uganda CDC JHU-Makerere U. NVP Resistance Study
57
Can Maternal Viral Resistance post Single-Dose
NVP be Reduced With Short-Term Maternal PP
ARV? PACTG 1032S (Thailand) AZT/SD NVP background
IP PP
AP (28-38 wk)
Arm 1 Arm 2 Arm 3
Mom NVP x1
Mom AZT
Baby NVP x1
Mom NVP x1
AZT ddI x 30 days
Mom AZT
Baby NVP x1
AZT ddI LPV/r x 30 days
Mom NVP x1
Mom AZT
Baby NVP x1
58
Can Maternal Viral Resistance post Single-Dose
NVP be Reduced With Short-Term Maternal PP
ARV? AACTG 5027 (Haiti, others?)
IP PP
Mom NVP x1
Arm 1 Arm 2 Arm 3 Arm 4
Baby NVP x1
Mom NVP x1
AZT 3TC x 28 days
Baby NVP x1
AZT 3TC TDF x 28 days
Mom NVP x1
Baby NVP x1
Mom NVP x1
AZT LPV/r x 28 days
Baby NVP x1
59
Response to NNRTI-Based HAART after SD NVP Mashi
Perinatal Clinical TrialBotswana-Harvard AIDS
Institute Collaboration

• Randomized study of 2 PMTCT strategies in 1200
  mother-infant pairs all mothers get AZT starting
  at 34 weeks gestation and IP
• Women randomized to
• Single-dose NVP or placebo
• Infants receive
• If breastfeed Single-dose NVP AZT x 6 months
• If formula fed Single-dose NVP AZT x 1 month
• New study compares women who later get NVP-based
  HAART (AZT/3TC/NVP) (150 NVP exposed, 150
  unexposed gt15 difference)
• Will compare viral failure after 6 months among
  women randomized NVP or placebo.

60
Will Prior Single-Dose NVP Exposure Effect
Subsequent Response to NNRTI-Based Therapy?A5208

• Compares viral response to NNRTI vs PI-based
  therapy in women with CD4 lt200
• Women with prior SD NVP (N240)
• Superiority of PI vs NNRTI therapy
• Women with no prior NVP exposure (N320)
• Equivalence of PI vs NNRTI therapy
• Maternal regimens
• A TDF/FTC/NVP
• B TDF/FTC/LPV/rtv