Antiretroviral intensification to prevent intrapartum HIV transmission in late comers
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Transcript of Antiretroviral intensification to prevent intrapartum HIV transmission in late comers
Antiretroviral Intensificationto 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
FundingNICHD/NIH [grant number R01 HD052461 and R01 HD056953]
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
ObjectiveTo 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
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
MATERNAL TREATMENT
INFANT TREATMENT
ZDV+3TC+LPV/r
Delivery
4 weeks
ZDV
Standard of Care
2nd/3rd Trimester
Perinatal Antiretroviral Intensification
MATERNAL TREATMENT
INFANT TREATMENT
ZDV+3TC+LPV/r
Delivery
4 weeks
ZDV
Standard of Care
< 8 weeks
Perinatal Antiretroviral Intensification
MATERNAL TREATMENT
INFANT TREATMENT
Standard of CarePerinatal Antiretroviral
Intensification
4 weeks
ZDV+3TC+LPV/rsd-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
Principles of Bayesian InferencePrior
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
DATAPosterior
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
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
Unconclusiveor futility
In green: RR<0.5 with more than 95% posterior probabilityIn orange: RR<0.77 with more than 95% posterior probabilityIn 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 slowAt second interim, before reaching 118, DSMB advised to stop enrollment and report the results
Inclusion/Exclusion criteriaInclusion 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 FU10 Withdraw consent2 No antenatal care
Women’s CharacteristicsMaternal Characteristic at
enrollmentObservation
(N=248)Intervention
(N=88)Median Age (yrs)
IQR27.7
22.8-32.226.3
22.3-33.0Median GA at enrollment (wks)
IQR22.3
17.6-26.934.6
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
10.910.0-11.6
11.210.4-12.0
Median CD4 count (cells/mm3)IQR
359250-498
379256-502
Delivery CharacteristicsObservation
(N=248)Intervention
(N=88)Median GA at delivery (wk)
IQR38.6
37.6-39.638.6
38.0-39.3Median Duration of HAART IQR
19.514.1-23.3
4.32.6-6.3
Median time from onset of labor to sdNVP (hr)
IQR--
4.02.0-6.7
Median Time from sdNVP to delivery (hr)
IQR--
3.41.3-6.4
Cesarean delivery 41.5 36.4
Characteristics of live-born infants
Observation (N=249)
Intervention (N=88)
Median Birth weight (kg)IQR
2.82.5-3.1
2.92.7-3.1
Median time from birth to intensification (hr)
IQR--
0.70.5-1.5
PHPT-5 Final Efficacy Analysis1. 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
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
Pos
terio
r pr
obab
ility
den
sity
Mean posterior risk of transmission under ARV intensification=0.0062
Mean posterior risk of transmission under standard care =0.020
Standard of careIntensification
Posterior distribution of the risk of intrapartum transmisson after observation of 88 mother-child pairs
with no intrapartum transmissionPosterior 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
Pos
terio
r pr
obab
ility
den
sity Mean posterior risk of transmission
under ARV intensification=0.0039
Mean posterior risk of transmission under standard care =0.020
Standard of careIntensification
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. Uninfectedb. -Sudden death at 1 month. Negative PCR
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.
AcknowledgmentsWomen 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
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
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 weeksBirth-48 hrs, 48 and 96 hrs after 1st dose
United Kingdom AZT+3TC+NVP 4 weeks
FranceThailand
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