Lallemant M. и др. «Antiretroviral intensification to prevent intrapartum HIV transmission in late comers» 8th IAS Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, 2015. MOAC0204.

1. Antiretroviral Intensification
to Prevent Intrapartum HIV
Transmission in Late Comers
Lallemant M, Amzal B, Urien S, Sripan P, Cressey TR, Ngo-
Giang-Huong N, Rawangban B, Sabsanong P,
Siriwachirachai T, Jarupanich T, Kanjanavikai P, Wanasiri P,
Koetsawang S, Jourdain G, Le Cœur S
for the PHPT-5 team
Funding
NICHD/NIH [grant number R01 HD052461 and R01 HD056953]

2. Background (1)
• The original PHPT-5 trial (NCT00409591, R01 HD052461/R01
HD056953) comparing 3 PMTCT regimens was terminated
prematurely due to changes in national/international guidelines
Mother Infant
Reference ArmZDVNVP-NVP
Plac.-NVP
LPV/r
ZDV
ZDVZDV-LPV/r
• Transmission rates across treatment arms were similar, but more
than 80% of the observed transmissions occurred in mothers
who had received a short treatment duration during pregnancy
Arms

3. Objective
To assess the efficacy of
Maternal sd-NVP during labor
+ infant ZDV+3TC+NVP prophylaxis
in addition to universal maternal LPV/r based HAART
for the prevention of intrapartum transmission of
HIV-1 in women presenting late in pregnancy
(received <8 weeks of ARV prophylaxis)
ARV intensification schemes for high risk infants are
recommended in various guidelines but these
recommendations are based on few studies

4. How to design a study to answer this question?
Issues
• Ethics of placebo control in high risk infants
• Low HIV transmission rates (women come early)
• Difficult/slow recruitment (prevalence is low)
but
• Solid prior knowledge of the efficacy of such
interventions
• Quality historical data (PHPT1, 2, 5)
Study Design (PHPT-5-Second Phase)
• Multicenter, phase 3, adaptive single arm trial
– With 3 interim analysis allowing for early
discontinuation for futility/efficacy

5. MATERNAL TREATMENT
INFANT TREATMENT
ZDV+3TC+LPV/r
Delivery
4 weeks
ZDV
Standard of Care
2nd/3rd Trimester
Perinatal Antiretroviral Intensification

6. MATERNAL TREATMENT
INFANT TREATMENT
ZDV+3TC+LPV/r
Delivery
4 weeks
ZDV
Standard of Care
< 8 weeks
Perinatal Antiretroviral Intensification

7. MATERNAL TREATMENT
INFANT TREATMENT
Standard of Care
Perinatal Antiretroviral
Intensification
4 weeks
ZDV+3TC+LPV/r
sd-NVP
4 weeks
ZDV+3TC+NVP ZDV+3TC
2 weeksBirth
AZT syrup: 4 mg/kg, bid; 3TC syrup: 2 mg/kg, bid;
NVP syrup: 2 mg/kg every 24 hours for 7 days, then 4 mg/kg every 24 hours for 7 days
4 weeks
ZDV
Delivery
< 8 weeks
ZDV+3TC+LPV/r
Perinatal Antiretroviral Intensification

8. Principles of Bayesian Inference
Prior
0 0.2 0.4 0.6 0.8 1
What we now today
Characteristics, VL time
course, transmissions for
3,737 mother-infant
pairs enrolled in PHPT
trials 1, 2, 51st
PRIOR
What we now today
Characteristics, VL time
course, transmissions for
3,737 mother-infant
pairs enrolled in PHPT
trials 1, 2, 51st
Likelihood
0 0.2 0.4 0.6 0.8 1
+ What the new data could
tell us
Developped scenarios for
the intervention group to
be enrolled: sample sizes,
numbers of observed
intrapartum transmissions
DATA
Posterior
0 0.2 0.4 0.6 0.8 1
What we would know
then
Updated probabilities,
Power calculations,
Stopping rules
=
POSTERIOR
Computationally intensive methods which derive probability distributions, not P values
• Meta-analyse previous PMTCT studies conducted in Thailand
• Model the VL time course during pregnancy according to ART regimens
• Model intrapartum transmission based on known risk factors
• Predict intrapartum HIV transmission rates +/- ARV intensification
• Simulate bayesian posterior distributions and power curves to design
interim analyses and stopping rules

9. Adaptative Design: Interim Analyses
Interim
analysis
Sample
size
Number of intrapartum transmissions to be observed
N=0 N=1 N=2 N=3 N=4 N>4
1 58 GO GO Stop for
futility
Stop for
futility
Stop for
futility
Stop for futility
2 118 Stop for
efficacy
GO GO Stop for
futility
Stop for
futility
Stop for futility
3 275 - Stop for
efficacy
GO GO Stop for
futility
Stop for futility
Final 410 - - Final
success
Final
success
Final
success
Unconclusive
or futility
In green: RR<0.5 with more than 95% posterior probability
In orange: RR<0.77 with more than 95% posterior probability
In red: proof of futility or lack of efficacy
• Sample size to reach 80% probability to show a two-fold reduction
as compared to standard of care
At first interim analysis, no transmission was observe but
enrollment was very slow
At second interim, before reaching 118, DSMB advised to
stop enrollment and report the results

10. Inclusion/Exclusion criteria
Inclusion Criteria
• Confirmed HIV-infection
• >=18 years old
• Consent to participate and be followed for the study duration
• Agreement not to breastfeed (as per national guidelines)
Exclusion Criteria
• Evidence of pre-existing
fetal anomalies
incompatible with life
Screened (1054)
Enrolled (379)
Delivered (336)
Observation
(248)
Intervention
(88)
31 Loss to FU
10 Withdraw consent
2 No antenatal care

11. Women’s Characteristics
Maternal Characteristic at
enrollment
Observation
(N=248)
Intervention
(N=88)
Median Age (yrs)
IQR
27.7
22.8-32.2
26.3
22.3-33.0
Median GA at enrollment (wks)
IQR
22.3
17.6-26.9
34.6
32.7-36.5
Median GA at start HAART (wks)
IQR
19.1
15.0-23.9
34.0
32.4-36.3
Median Hemoglobin level (g/dl)
IQR
10.9
10.0-11.6
11.2
10.4-12.0
Median CD4 count (cells/mm3)
IQR
359
250-498
379
256-502

12. Delivery Characteristics
Observation
(N=248)
Intervention
(N=88)
Median GA at delivery (wk)
IQR
38.6
37.6-39.6
38.6
38.0-39.3
Median Duration of HAART
IQR
19.5
14.1-23.3
4.3
2.6-6.3
Median time from onset of labor
to sdNVP (hr)
IQR
-
-
4.0
2.0-6.7
Median Time from sdNVP to
delivery (hr)
IQR
-
-
3.4
1.3-6.4
Cesarean delivery 41.5 36.4

13. Characteristics of live-born infants
Observation
(N=249)
Intervention
(N=88)
Median Birth weight (kg)
IQR
2.8
2.5-3.1
2.9
2.7-3.1
Median time from birth to
intensification (hr)
IQR
-
-
0.7
0.5-1.5

14. PHPT-5 Final Efficacy Analysis
1. Updated the meta-analysis with PHPT-52nd observational
Total: 3,965 mother-infant pairs
2. Updated Modeling of VL time course during pregnancy
according to ART regimens (ZDV/3TC/LPV/r)
3. Re-calibrated the Model of intrapartum transmission
4. Predicted prior intrapartum transmission probabilities
with/without post-natal ARV intensification (88 mothers
with individual characteristics)
5. Updated posterior distributions of the risk of intrapartum
transmission based on observed transmissions in the
intensification group

15. Meta-analysis prior distributions
Probability of superior efficacy of
intensification over standard of care (RR< 1)
Prior probabilities of intrapartum transmission in women
with < 8 weeks ZDV+3TC+LPV/r with/without intensification
0.00 0.02 0.04 0.06 0.08 0.10
Risk of intrapartum transmission
Posteriorprobabilitydensity
Mean posterior risk of transmission
under ARV intensification=0.0062
Mean posterior risk of transmission
under standard care =0.020
Standard of care
Intensification

16. Posterior distribution of the risk of intrapartum transmisson
after observation of 88 mother-child pairs
with no intrapartum transmission
Posterior distribution of intrapartum
risk of transmission
Probability of superior efficacy of
intensification over standard of care
Probability of superiority of intensification over standard of care: 94.1%
Probability of at least a 2-fold reduction of risk (RR< 0.5): 82.9%
0.00 0.02 0.04 0.06 0.08 0.10
Risk of intrapartum transmission
Posteriorprobabilitydensity
Mean posterior risk of transmission
under ARV intensification=0.0039
Mean posterior risk of transmission
under standard care =0.020
Standard of care
Intensification

17. No safety concerns
Women Observation
(N=248)
Intervention
(N=88)
At least 1 Serious Adverse Event 21 (8.5%) 4 (4.5%)
Death 0 (0%) 0 (0%)
Children (N=249) (N=88)
At least 1 Serious Adverse Event 54 (21.7%) 12 (13.6%)
Deaths (not neonatal) 2a 1b
a -Down Syndrome with cardiac malformation, died of sepsis at 2 months. Neg PCR
- Fever & Seizures at 5 months. Uninfected
b. -Sudden death at 1 month. Negative PCR

18. Conclusion
• ARV intensification is effective and safe in
preventing intrapartum HIV transmission in
pregnant women receiving a short course (< 8
weeks) antepartum ARVs before delivery.

19. Acknowledgments
Women and children who participated in the study
Coinvestigators: Kanokwan Jittayanun, Suraphan Sangsawang, Wanmanee Matanasarawut,
Pornpun Wannarit, Jittapol Hemvuttiphan, Pornchai Techakunakorn, Jullapong Achalapong,
Kanchana Preedisripipat, Chaiwat Putiyanun, Vanichaya Wanchaitanawong, Sookchai
Theansavettrakul, Premjit Charoenweerakul, Jariyarat Nitipipatkosol, Surachai Piyaworawong,
Sudanee Buranabanjasatean, Prapap Yuthavisuthi, Chaiwat Ngampiyaskul, Siriluk
Phanomcheong, Prateep Kanjanavikai, Suchat Hongsiriwon, Nantasak Chotivanich, Weerapong
Suwankornsakul, Warit Karnchanamayul, Annop Kanjanasing, Ratchanee Kwanchaipanich, Aram
Limtrakul, Suparat Kanjanavanit, Boonsong Rawangban, Sadhit Santadusit, Prapaisri Layangool,
Sinart Prommas, Somsak Wachirachaikan, Surat Sirinontakan, Surachai Pipatnakulchai, Sinchai
Wanwaisart, Kanchapan Sukonpan, Narong Lertpienthum, Thitiporn Borkird, Tapnarong
Jarupanich, Thitiporn Siriwachirachai, Pornpimon Rojanakarin, Ruaengkitti Sirikanchanakul,
Sansanee Hanpinitsak, Sunida Panna, Sathit Potchalongsin, Sawitree Krikajornkitti, Supang
Varadisai, Phaiboon Wanasiri, Sakulrat Srirojana, Rucha Kongpanichkul, Suthunya Bunjongpak,
Prapan Sabsanong, Wantana Likhitwisetkul, Worapong Worachet, Sakchai Tonmat, Sathaporn
Na-Rajsima, Prateung Liampongsabuddhi, Kultida Pongdetudom, Pichit Puernngooluerm,
Anucha Saereejittima, Prayoon Khamja, Noppadon Akarathum, Sompong Wannun, Weerasak
Lawtongkum, Wannee Limpitikul, Supha-arth Phon-in, Jantana Jungpipun, Apichai Phiyarom,
Arunsri Iamthongin, Sukit Mahattanan, Somsri Kotchawet, Manoch Chakorngowit, Wisith
Pholsawat, Ittipol Chaitha, Toranong Pilalai.
DSMB: Wiput Phoolcharoen , Suwachai Intaraprasert , Ridiwilai Samakoses

20. Thank you very much for your
attention

21. Adverse Pregnancy Outcomes
Observation
(N=248)
Intervention
(N=88)
Premature Delivery
(<37 weeks) 25 (10.1%) 8 (9.1%)
Low birth weight
(<2500g) 62 (25.0%) 8 (9.1%)
Fetal deaths 0 (0%) 0 (0%)
Neonatal death 1* (0.4%) 0 (0%)
* Severe prematurity (GA: 21 weeks). Died after 5 min

22. Background (2)
• Even in the context of HAART PMTCT, infants born to HIV-
infected pregnant women presenting late during pregnancy
are at high risk of intrapartum infection
• Recommended infant ARV intensification schemes for high
risk infants (formula feeding) are based on few studies
Recommendations Infant Regimens Duration
United States AZT
+ 3 NVP doses
6 weeks
Birth-48 hrs, 48 and 96 hrs after 1st dose
United Kingdom AZT+3TC+NVP 4 weeks
France
Thailand
AZT+3TC
+NVP
4 weeks
2 weeks
South Africa AZT+NVP • 4 weeks (if maternal prophylaxis > 8 weeks)
• 6 weeks (if maternal prophylaxis <8 weeks)
WHO NVP 6 to 12 weeks