Trial Outcomes & Findings for Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women (NCT NCT01494038)

Last Updated: 2021-11-05

Results Overview

Incidence rate, calculated by Mantel-Haenszel (MH), weighted by gestational age strata 1) gestational age at entry less than 24 weeks or 2) gestational age at entry greater than or equal to 24 weeks. AE's include laboratory results, signs/symptoms, or diagnoses; graded as per Division of AIDS (DAIDS) or by protocol-defined hepatotoxicity measures. Related to treatment indicates possibly, probably, or definitely related to INH or Placebo for INH as judged by Independent Endpoint Review Committee. Discontinuation refers to permanent discontinuation of study treatment.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

956 participants

Primary outcome timeframe

Measured from study entry through Week 48 after birth

Results posted on

2021-11-05

Participant Flow

HIV-infected pregnant women and their infants, gestational age greater than 14 but less than 34 weeks, who reside in a high TB prevalence area. Recruited at participating medical clinics in those areas, a total of 13 sites in Haiti, India, Thailand, and in 5 countries in central and southern Africa. Recruitment from August 2014 to April 2016.

Participant milestones

Participant milestones
Measure	Arm A (Immediate INH Treatment) Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Arm B (Deferred INH Treatment) Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit
Overall Study STARTED	477	479
Overall Study COMPLETED	389	396
Overall Study NOT COMPLETED	88	83

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A (Immediate INH Treatment) Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Arm B (Deferred INH Treatment) Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit
Overall Study Protocol Violation	1	1
Overall Study Lost to Follow-up	18	20
Overall Study Withdrawal by Subject	44	34
Overall Study Not able to get to clinic	21	15
Overall Study Not willing to adhere to reqs	2	9
Overall Study Death	2	4

Baseline Characteristics

N=4 participants did not have baseline CD4 result available.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum (Arm B) Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit (Arm B)	Total n=956 Participants Total of all reporting groups
Age, Continuous	29 years n=477 Participants	29 years n=479 Participants	29 years n=956 Participants
Sex: Female, Male Female	477 Participants n=477 Participants	479 Participants n=479 Participants	956 Participants n=956 Participants
Sex: Female, Male Male	0 Participants n=477 Participants	0 Participants n=479 Participants	0 Participants n=956 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=477 Participants	0 Participants n=479 Participants	0 Participants n=956 Participants
Race (NIH/OMB) Asian	32 Participants n=477 Participants	35 Participants n=479 Participants	67 Participants n=956 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=477 Participants	0 Participants n=479 Participants	0 Participants n=956 Participants
Race (NIH/OMB) Black or African American	445 Participants n=477 Participants	444 Participants n=479 Participants	889 Participants n=956 Participants
Race (NIH/OMB) White	0 Participants n=477 Participants	0 Participants n=479 Participants	0 Participants n=956 Participants
Race (NIH/OMB) More than one race	0 Participants n=477 Participants	0 Participants n=479 Participants	0 Participants n=956 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=477 Participants	0 Participants n=479 Participants	0 Participants n=956 Participants
Region of Enrollment Haiti	8 participants n=477 Participants	15 participants n=479 Participants	23 participants n=956 Participants
Region of Enrollment Botswana	60 participants n=477 Participants	60 participants n=479 Participants	120 participants n=956 Participants
Region of Enrollment Tanzania	41 participants n=477 Participants	39 participants n=479 Participants	80 participants n=956 Participants
Region of Enrollment South Africa	91 participants n=477 Participants	91 participants n=479 Participants	182 participants n=956 Participants
Region of Enrollment Uganda	83 participants n=477 Participants	83 participants n=479 Participants	166 participants n=956 Participants
Region of Enrollment Zimbabwe	162 participants n=477 Participants	157 participants n=479 Participants	319 participants n=956 Participants
Region of Enrollment Thailand	15 participants n=477 Participants	18 participants n=479 Participants	33 participants n=956 Participants
Region of Enrollment India	17 participants n=477 Participants	16 participants n=479 Participants	33 participants n=956 Participants
Gestational age at entry 14 - <24 weeks	161 Participants n=477 Participants	160 Participants n=479 Participants	321 Participants n=956 Participants
Gestational age at entry 24 - 34 weeks	316 Participants n=477 Participants	319 Participants n=479 Participants	635 Participants n=956 Participants
CD4 Count < 350 cells/mm^3	118 Participants n=475 Participants • N=4 participants did not have baseline CD4 result available.	114 Participants n=477 Participants • N=4 participants did not have baseline CD4 result available.	232 Participants n=952 Participants • N=4 participants did not have baseline CD4 result available.
CD4 Count 350 - <500 cells/mm^3	129 Participants n=475 Participants • N=4 participants did not have baseline CD4 result available.	128 Participants n=477 Participants • N=4 participants did not have baseline CD4 result available.	257 Participants n=952 Participants • N=4 participants did not have baseline CD4 result available.
CD4 Count 500 - <650 cells/mm^3	95 Participants n=475 Participants • N=4 participants did not have baseline CD4 result available.	105 Participants n=477 Participants • N=4 participants did not have baseline CD4 result available.	200 Participants n=952 Participants • N=4 participants did not have baseline CD4 result available.
CD4 Count >= 650 cells/mm^3	133 Participants n=475 Participants • N=4 participants did not have baseline CD4 result available.	130 Participants n=477 Participants • N=4 participants did not have baseline CD4 result available.	263 Participants n=952 Participants • N=4 participants did not have baseline CD4 result available.
Efavirenz-containing anti-retroviral (ARV) regimen No	72 Participants n=477 Participants	70 Participants n=479 Participants	142 Participants n=956 Participants
Efavirenz-containing anti-retroviral (ARV) regimen Yes	405 Participants n=477 Participants	409 Participants n=479 Participants	814 Participants n=956 Participants
Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) Positive	139 Participants n=470 Participants • All enrolled participants with IGRA results available	144 Participants n=472 Participants • All enrolled participants with IGRA results available	283 Participants n=942 Participants • All enrolled participants with IGRA results available
Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) Negative	301 Participants n=470 Participants • All enrolled participants with IGRA results available	297 Participants n=472 Participants • All enrolled participants with IGRA results available	598 Participants n=942 Participants • All enrolled participants with IGRA results available
Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) Indeterminate	30 Participants n=470 Participants • All enrolled participants with IGRA results available	31 Participants n=472 Participants • All enrolled participants with IGRA results available	61 Participants n=942 Participants • All enrolled participants with IGRA results available

PRIMARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: All women enrolled.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment	14.93 events per 100 person-years	15.03 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through end of pregnancy

Population: Mothers who had at least one live birth, stillbirth, or spontaneous abortion. One participant with outcome of induced abortion not included

Fetal deaths include both stillbirths and spontaneous abortions; in case of a multiple birth, mothers who had at least one fetal death

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=466 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=459 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Mothers With a Fetal Death	9 Participants	17 Participants	—

SECONDARY outcome

Timeframe: Measured at delivery

Population: Measurement of small-for-gestational-age was deemed to be unreliable. Analysis not performed.

Small for gestational age was determined by physician at site

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Measured at delivery

Population: Mothers who had at least one live birth

Premature birth is defined as gestational age of \< 37 weeks at delivery.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=458 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=442 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Mothers With an Infant Born Prematurely	40 Participants	48 Participants	—

SECONDARY outcome

Timeframe: Measured on day of birth

Population: Mothers who had at least one live birth available to be weighed at time of delivery

Low birth weight is defined as weight \< 2500 mg

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=446 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=430 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Mothers With a Low Birth-weight Infant No	400 Participants	368 Participants	—
Number of Mothers With a Low Birth-weight Infant Yes	46 Participants	62 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Mothers who had at least one live birth able to be assessed between birth and 48 weeks after birth

Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=458 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=440 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Mothers With an Infant With a Congenital Anomaly Yes	6 Participants	10 Participants	—
Number of Mothers With an Infant With a Congenital Anomaly No	452 Participants	430 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Mothers who had at least one live birth, stillbirth, or spontaneous abortion; participant with induced abortion is omitted, and whose babies were available for examination after birth (if born alive)

In case of a multiple birth, mothers who had at least one adverse pregnancy outcome. Spontaneous abortion is intra-uterine fetal death prior to 20 weeks of gestational age; stillbirth, the same, \>= 20 weeks; preterm delivery, \< 37 weeks of gestational age; low birth weight, \< 2,500 grams, and congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=460 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=449 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly Yes	78 Participants	106 Participants	—
Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly No	382 Participants	343 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Infants born alive

Laboratory, sign/symptom, or diagnoses graded as 3 or higher by DAIDS criteria.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Infants With Grade 3 or Higher Clinical or Laboratory AE	196 Participants	193 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Infants born alive

As before, but AE is judged to be possibly, probably, or definitely related to INH or Placebo for INH, by clinic medical staff

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment	6 Participants	5 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through study Week 44

Population: Infants born alive

HIV infection determined during follow-up period. Infection at birth or during breastfeeding

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Infants Which Are HIV-infected Yes	7 Participants	3 Participants	—
Number of Infants Which Are HIV-infected No	451 Participants	436 Participants	—
Number of Infants Which Are HIV-infected Unknown	6 Participants	6 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Infants born alive

Hospitalization due to reasons other than birth

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Infants Hospitalized	75 Participants	73 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry to Week 48 after birth

Population: All participants enrolled without active TB at entry

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB infection, as judged by Secondary Endpoint Review Committee

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=478 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of TB Infection Among Mothers	0.59 events per 100 person-years	0.60 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Live-born infants of enrolled women

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB, or congenital TB as defined using the Cantwell criteria (see reference), judged by the Secondary Endpoint Review Committee. Includes an infant death due to unknown cause.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Tuberculosis (TB) Among Infants	0.52 events per 100 person-years	0.54 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Live-born infants of enrolled women

Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Infant Death	4.42 events per 100 person-years	2.99 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 postpartum

Population: All participants enrolled without active TB at entry

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=478 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Maternal Deaths	0.78 events per 100 person-years	0.40 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: All participants enrolled without active TB at entry.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=478 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death	1.38 events per 100 person-years	1.00 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Live-born infants of enrolled women

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=464 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=445 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Combined Endpoints: Infant TB or Infant Death	4.68 events per 100 person-years	2.99 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: Number of mother-infant pairs with at least one infant live birth and in which mother did not have active TB at entry.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=458 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=442 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death	4.72 events per 100 person-years	3.42 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through end of pregnancy

Population: All women enrolled.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE	13.79 events per 100 person-years	15.93 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through 12 weeks after birth

Population: All women enrolled.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate of Combined Endpoint, up to 12 Weeks Postpartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE	10.09 events per 100 person-years	16.98 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through end of pregnancy

Population: All women enrolled.

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, Antepartum, of Grade 3 or Higher AE	50.88 events per 100 person-years	56.36 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through 12 weeks postpartum

Population: All women enrolled.

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE	40.59 events per 100 person-years	56.48 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through delivery

Population: All women enrolled.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. Protocol-specific definition of hepatotoxicity: Any one of the following: 1) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN), where ULN is specified by the clinic physician; 2) Total bilirubin \> 3 X ULN; 3) ALT greater than 3 X ULN and total bilirubin greater than 2 X ULN; or 4) ALT \> 3 X ULN and persistent symptomatic clinical hepatitis

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment	2.59 events per 100 person-years	1.77 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through 12 weeks postpartum

Population: All women enrolled.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment	4.52 events per 100 person-years	7.91 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through delivery

Population: All women enrolled.

Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause	2.59 events per 100 person-years	1.77 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through 12 weeks postpartum

Population: All women enrolled

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause	4.98 events per 100 person-years	8.37 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through delivery

Population: All women.

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Hepatotoxicity definition as defined by DAIDS AE grading criteria 1.0.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment	2.59 events per 100 person-years	1.77 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study start through 12 weeks postpartum

Population: All women

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment	4.52 events per 100 person-years	7.91 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through delivery

Population: All women

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause	2.59 events per 100 person-years	1.77 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study start through 12 weeks postpartum

Population: All women.

Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause	4.98 events per 100 person-years	8.37 events per 100 person-years	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 postpartum

Population: Mothers with culture-confirmed TB

Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of mothers who develop culture-confirmed TB

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=2 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=2 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Mothers With Tuberculosis Resistant to INH	0 Participants	1 Participants	—

SECONDARY outcome

Timeframe: Measured from study entry through Week 48 after birth

Population: No infants had culture-confirmed TB

Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of infants who develop culture-confirmed TB

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Measured at antepartum (third trimester and >= 2 weeks after starting study drug) and week 16 postpartum (+/-) 4 weeks) while on active INH; blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hours post-dosing.

Population: Participants with intensive pharmacokinetic results while on active INH, who were established on INH.

Pharmacokinetic parameter was estimated from population PK modeling fitted to the intensive PK data. AUC0-24h was predicted using population pharmacokinetic model using the NONMEM software program. A 2-compartment model with first-order absorption with transit compartment and first-order elimination with well-stirred liver model to capture hepatic clearance and first-pass extraction with 1 parameter (hepatic intrinsic clearance) was used,

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=15 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=5 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers n=12 Participants Those women having a genotype of slow INH metabolism.
Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH Third trimester of pregnancy	6.55 hour*mg/L Interval 5.31 to 7.88	3.63 hour*mg/L Interval 2.88 to 4.88	21.6 hour*mg/L Interval 18.5 to 26.0
Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH Week 16 postpartum	7.67 hour*mg/L Interval 6.49 to 9.18	4.25 hour*mg/L Interval 3.29 to 5.54	25.3 hour*mg/L Interval 22.2 to 26.0

SECONDARY outcome

Population: Participants with intensive pharmacokinetic results while on active EFV and who were stabled on EFV-based ART.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=10 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=3 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers n=8 Participants Those women having a genotype of slow INH metabolism.
Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV Third trimester of pregnancy	62.5 hour*mg/L Interval 51.4 to 94.9	38.5 hour*mg/L Interval 33.4 to 47.6	153.02 hour*mg/L Interval 140.21 to 167.0
Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV Week 16 postpartum	76.2 hour*mg/L Interval 61.1 to 111.0	46.9 hour*mg/L Interval 42.1 to 59.7	186 hour*mg/L Interval 166.0 to 210.0

SECONDARY outcome

Timeframe: Measured at delivery

Population: Women tested for tuberculosis infection at delivery

IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=517 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=208 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery Positive tuberculin skin test	27 Participants	87 Participants	—
Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery Negative tuberculin skin test	490 Participants	121 Participants	—

SECONDARY outcome

Timeframe: Measured at week 44 after birth

Population: Infants with tuberculin tests performed at week 44 postpartum

The TST result was positive if greater than or equal to 10 mm in HIV-negative infants, or greater than or equal to 5 mm in HIV-positive infants.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=642 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=42 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Agreement Between IGRA and TST TB Test Results, Infant Positive tuberculin skin test	45 Participants	8 Participants	—
Agreement Between IGRA and TST TB Test Results, Infant Negative tuberculin skin test	597 Participants	34 Participants	—

SECONDARY outcome

Timeframe: Measured at Week 44 postpartum

Population: Women who were tested for tuberculosis infection at 44 weeks postpartum

IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=227 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum Positive tuberculin skin test	20 Participants	100 Participants	—
Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum Negative tuberculin skin test	459 Participants	127 Participants	—

SECONDARY outcome

Timeframe: Adherence reported every 4 weeks during active treatment; study entry through week 28 for Arm A, week 12 postpartum through week 40 postpartum for Arm B

Population: All women enrolled.

Adherence is the percentage of expected doses taken during the 28 week active treatment period, categorized as poor (\<60%), reasonable (\>= 60%, \<80%), good (\>=80%, \<90%), or excellent (\>= 90%). Measured by participant's self-report of doses taken within the last 3 days.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report Excellent adherence	363 Participants	400 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report Good adherence	35 Participants	47 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report Reasonable adherence	8 Participants	15 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report Poor adherence	7 Participants	4 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report Unknown	66 Participants	11 Participants	—

SECONDARY outcome

Timeframe: Adherence reported every 4 weeks during active treatment; study entry through week 28 for Arm A, week 12 postpartum through week 40 postpartum for Arm B

Population: All enrolled women

Adherence is the percentage of expected doses taken during the 28 week active treatment period. Pill count: participants returned their prescription pill containers, and the remaining (unused) pills were counted.

Outcome measures

Outcome measures
Measure	Arm B (Deferred INH Treatment) n=479 Participants Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum. Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit.	Arm A (Immediate INH Treatment) n=477 Participants Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum	Slow Metabolizers Those women having a genotype of slow INH metabolism.
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count Poor adherence	3 Participants	5 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count Excellent adherence	376 Participants	408 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count Good adherence	28 Participants	42 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count Reasonable adherence	6 Participants	8 Participants	—
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count Unknown	66 Participants	14 Participants	—

Adverse Events

Mother/Immediate INH

Serious events: 71 serious events

Other events: 438 other events

Deaths: 2 deaths

Mother/Deferred INH

Serious events: 69 serious events

Other events: 449 other events

Deaths: 4 deaths

Infant/Immediate INH

Serious events: 86 serious events

Other events: 417 other events

Deaths: 11 deaths

Infant/Deferred INH

Serious events: 91 serious events

Other events: 430 other events

Deaths: 17 deaths

Serious adverse events

Other adverse events

Additional Information

Melissa Allen, Director, IMPAACT Operations Center

Family Health International (FHI 360)

Phone: (919) 405-1429

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place