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

Thank you very much for your attention

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