Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01494038
• Collaborator: (none)
• Enrollment: 956
• Locations: 13
• Arms: 2
• Actual Duration (Months): 36.6
• Patients Per Site: 73.5
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

Tuberculosis (TB) is a leading cause of death among HIV-infected persons in low-income settings and can be a serious complication for HIV-infected pregnant women and their infants. Isoniazid (INH) preventive therapy (IPT) is effective in preventing TB infection in HIV-infected adults, but the safety of IPT in pregnant women is unknown. This study evaluated the safety of IPT among HIV-infected pregnant women.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections; Tuberculosis	Drug: Isoniazid (INH); Drug: Placebo for isoniazid (INH)	Phase 4

Detailed Description

TB disease is the most common HIV-related opportunistic infection and is a leading cause of death among HIV-infected persons in low-income settings. When TB occurs during or soon after pregnancy, it can cause complications for the mother as well as infant TB or death. Infant TB is very difficult to diagnose, and up to half of infant TB cases are caused by maternal TB. It has been shown that treatment for active TB is safe and effective during pregnancy and that IPT is safe and effective in preventing TB infection in HIV-infected adults. However, the safety of IPT in HIV-infected pregnant women is not known, especially in regard to its combination with highly active retroviral therapy (HAART). This study evaluated the safety of immediate (antepartum, or before delivery) versus deferred (postpartum, or after delivery) IPT among HIV-infected pregnant women in high TB incidence settings.

HIV-infected pregnant women were randomly assigned (1:1) to one of two arms: Arm A (immediate/antepartum INH) and Arm B (deferred/postpartum INH group). Women in both arms received oral prenatal multivitamins and pyridoxine (vitamin B6) once daily from study entry through Week 40 postpartum.

Study visits for women occurred at screening, entry, every 4 weeks until labor and delivery, at labor and delivery, and every 4 weeks after delivery until 48 weeks postpartum. Visits consisted of giving a medical history and undergoing a physical exam and blood collection; all visits through the delivery visit also included an obstetrical exam. Presence of HIV infection was documented at screening and a tuberculin skin test (TST) was administered at the delivery visit and at the Week 44 postpartum visit. Study visits for infants occurred at birth and at several time points through Week 48. These visits included a medical history, physical exam, and blood collection. Intensive pharmacokinetic (PK) samples, that is, samples taken at many different time points within a 24-hour test period, were collected from a small subset of women, one test period at antepartum and one at postpartum. Sparse PK samples, that is, samples taken at fewer time points within the test period, were collected on all women, once each at antepartum and postpartum.

Study Design

• Study Type: Interventional
• Actual Enrollment: 956 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Prevention
• Official Title: A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid Preventive Therapy Among HIV-Infected Women in High Tuberculosis (TB) Incidence Settings
• Actual Study Start Date: Aug 19, 2014
• Actual Primary Completion Date: Sep 6, 2017
• Actual Study Completion Date: Sep 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Isoniazid (INH); 300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B); Drug: Placebo for isoniazid (INH); Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)
Experimental: 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.	Drug: Isoniazid (INH); 300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B); Drug: Placebo for isoniazid (INH); Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)

Outcome Measures

Primary Outcome Measures

1. Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment [Measured from study entry through Week 48 after birth]

   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.

Secondary Outcome Measures

1. Number of Mothers With a Fetal Death [Measured from study entry through end of pregnancy]

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

2. Number of Mothers With a Fetus Small for Gestational Age [Measured at delivery]

   Small for gestational age was determined by physician at site

3. Number of Mothers With an Infant Born Prematurely [Measured at delivery]

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

4. Number of Mothers With a Low Birth-weight Infant [Measured on day of birth]

   Low birth weight is defined as weight < 2500 mg

5. Number of Mothers With an Infant With a Congenital Anomaly [Measured from study entry through Week 48 after birth]

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

6. Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly [Measured from study entry through Week 48 after birth]

   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.

7. Number of Infants With Grade 3 or Higher Clinical or Laboratory AE [Measured from study entry through Week 48 after birth]

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

8. Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment [Measured from study entry through Week 48 after birth]

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

9. Number of Infants Which Are HIV-infected [Measured from study entry through study Week 44]

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

10. Number of Infants Hospitalized [Measured from study entry through Week 48 after birth]

    Hospitalization due to reasons other than birth

11. Incidence Rate of TB Infection Among Mothers [Measured from study entry to Week 48 after birth]

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

12. Incidence Rate of Tuberculosis (TB) Among Infants [Measured from study entry through Week 48 after birth]

    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.

13. Incidence Rate of Infant Death [Measured from study entry through Week 48 after birth]

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

14. Incidence Rate of Maternal Deaths [Measured from study entry through Week 48 postpartum]

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

15. Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death [Measured from study entry through Week 48 after birth]

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

16. Incidence Rate of Combined Endpoints: Infant TB or Infant Death [Measured from study entry through Week 48 after birth]

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

17. Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death [Measured from study entry through Week 48 after birth]

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

18. Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE [Measured from study entry through end of pregnancy]

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

19. 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 [Measured from study entry through 12 weeks after birth]

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

20. Incidence Rate, Antepartum, of Grade 3 or Higher AE [Measured from study entry through end of pregnancy]

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

21. Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE [Measured from study entry through 12 weeks postpartum]

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

22. Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment [Measured from study entry through delivery]

    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

23. Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment [Measured from study entry through 12 weeks postpartum]

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

24. Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause [Measured from study entry through delivery]

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

25. Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause [Measured from study entry through 12 weeks postpartum]

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

26. Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment [Measured from study entry through delivery]

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

27. Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment [Measured from study start through 12 weeks postpartum]

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

28. Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause [Measured from study entry through delivery]

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

29. Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause [Measured from study start through 12 weeks postpartum]

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

30. Number of Mothers With Tuberculosis Resistant to INH [Measured from study entry through Week 48 postpartum]

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

31. Number of Infants With Tuberculosis Resistant to INH [Measured from study entry through Week 48 after birth]

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

32. Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH [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.]

    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,

33. Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV [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.]

    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,

34. Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery [Measured at delivery]

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

35. Agreement Between IGRA and TST TB Test Results, Infant [Measured at week 44 after birth]

    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.

36. Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum [Measured at Week 44 postpartum]

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

37. Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report [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]

    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.

38. Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count [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]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented HIV-1 infection, defined as positive results from two samples collected at different time points. All samples tested must be whole blood, serum, or plasma. More information on this criterion can be found in the protocol.

• Documented HIV treatment, according to World Health Organization (WHO) guidelines, for prevention of mother-to-child transmission (PMTCT) and standard of care for HIV infection

• Pregnant females age 18 years or older

• Pregnant females between greater than or equal to 13 and less than 18 who are able and willing to provide signed informed consent under local law or pregnant females unable to consent under local law whose parents/legal guardians provide consent or "minimum age of consent according to locally applicable laws or regulations"

• Pregnancy gestational age confirmed by best available method at site to be greater than or equal to 14 weeks through less than or equal to 34 weeks (34 weeks, 6 days)

• Weight greater than or equal to 35 kg at screening

• The following laboratory values obtained within 30 days prior to study entry:

• Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3

• Hemoglobin greater than or equal to 7.5 g/dL

• Platelet count greater than or equal to 50,000/mm^3

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALT)/serum glutamic pyruvic transaminase (SGPT), and total bilirubin less than or equal to 1.25 times the upper limit of normal (ULN). (Note: If participant is taking atazanavir, direct bilirubin may be used to determine eligibility.)

• Intent to remain in current geographical area of residence for the duration of the study

Exclusion Criteria:

• Any woman with a positive TB symptom screen per WHO guidelines, including any one or more of the following: any cough, fever, self-reported weight loss, or night sweats. Note: If a potential participant is found to be negative for TB upon further testing, the participant may be rescreened for the study.

• Any positive acid-fast bacillus (AFB) smear, Xpert, or any other rapid TB screening test or culture from any site within the past 12 weeks, or chest radiograph (x-ray) with findings suggestive of active TB, or clinician suspects active TB

• Known exposure to AFB smear-positive active TB case within past 12 weeks prior to study entry

• Reported INH exposure (more than 30 days) in the past year prior to study entry

• Receipt of any TB or atypical mycobacteria therapy for more than 30 days in the past year

• Evidence of acute hepatitis, such as jaundice, dark urine (not concentrated urine), and/or acholic stools sustained for more than 3 days within 90 days prior to entry. More information on this criterion can be found in the protocol.

• Grade 1 or higher peripheral neuropathy. More information on this criterion can be found in the protocol.

• History of acute systemic adverse reaction or allergy to INH

• Known current heavy alcohol use (more than 2 drinks per week) or alcohol exposure that, in the investigator's opinion, would compromise participation and the outcome of this study

• Presence of new AIDS-defining opportunistic infection that has been treated less than 30 days prior to study entry

• Receipt of an investigational agent or chemotherapy for active malignancy within 30 days prior to study entry

• Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise participation and the outcome of this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gaborone CRS	Gaborone		Botswana
2	Molepolole CRS	Gaborone		Botswana
3	Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS	Port-au-Prince		Haiti	HT-6110
4	Byramjee Jeejeebhoy Medical College (BJMC) CRS	Pune	Maharashtra	India	411001
5	Soweto IMPAACT CRS	Johannesburg	Gauteng	South Africa	1862
6	Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS	Cape Town	Western Cape Province	South Africa	7505
7	Fam-Cru Crs	Cape Town	Western Cape Province	South Africa	7505
8	Kilimanjaro Christian Medical Centre (KCMC)	Moshi		Tanzania
9	Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS	Chiang Mai		Thailand	50200
10	MU-JHU Research Collaboration (MUJHU CARE LTD) CRS	Kampala		Uganda
11	Seke North CRS	Chitungwiza		Zimbabwe
12	St Mary's CRS	Chitungwiza		Zimbabwe
13	Harare Family Care CRS	Harare		Zimbabwe

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Amita Gupta, MD, MHS, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol - Oct 28, 2015
• Statistical Analysis Plan - Nov 2, 2017

More Information

Additional Information:

• Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS), Version 2.0, January 2010
• Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)
• Metropolitan Atlanta Congenital Defects Program (MACDP)

Publications

• Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000171. doi: 10.1002/14651858.CD000171.pub3. Review.
• Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA. 1994 Aug 17;272(7):535-9.
• Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. Epub 2006 Nov 3.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01494038
• Other Study ID Numbers: P1078; 10732; IMPAACT P1078
• First Posted: Dec 16, 2011
• Last Update Posted: Nov 5, 2021
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Tuberculosis; Isoniazid

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	477	479
COMPLETED	389	396
NOT COMPLETED	88	83

Baseline Characteristics

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)	Total
Arm/Group Description	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	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 of all reporting groups
Overall Participants	477	479	956
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	29	29	29
Sex: Female, Male (Count of Participants)
Female	477 100%	479 100%	956 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	32 6.7%	35 7.3%	67 7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	445 93.3%	444 92.7%	889 93%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Haiti	8 1.7%	15 3.1%	23 2.4%
Botswana	60 12.6%	60 12.5%	120 12.6%
Tanzania	41 8.6%	39 8.1%	80 8.4%
South Africa	91 19.1%	91 19%	182 19%
Uganda	83 17.4%	83 17.3%	166 17.4%
Zimbabwe	162 34%	157 32.8%	319 33.4%
Thailand	15 3.1%	18 3.8%	33 3.5%
India	17 3.6%	16 3.3%	33 3.5%
Gestational age at entry (Count of Participants)
14 - <24 weeks	161 33.8%	160 33.4%	321 33.6%
24 - 34 weeks	316 66.2%	319 66.6%	635 66.4%
CD4 Count (Count of Participants)
< 350 cells/mm^3	118 24.7%	114 23.8%	232 24.3%
350 - <500 cells/mm^3	129 27%	128 26.7%	257 26.9%
500 - <650 cells/mm^3	95 19.9%	105 21.9%	200 20.9%
>= 650 cells/mm^3	133 27.9%	130 27.1%	263 27.5%
Efavirenz-containing anti-retroviral (ARV) regimen (Count of Participants)
No	72 15.1%	70 14.6%	142 14.9%
Yes	405 84.9%	409 85.4%	814 85.1%
Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) (Count of Participants)
Positive	139 29.1%	144 30.1%	283 29.6%
Negative	301 63.1%	297 62%	598 62.6%
Indeterminate	30 6.3%	31 6.5%	61 6.4%

Outcome Measures

1. Primary Outcome

Title	Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment
Description	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.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	15.03	14.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Calculate the difference between the immediate arm incidence rate and the deferred arm incidence rate; if the upper bound of the 95% confidence interval is lower than a 5% difference in incidence rates, non-inferiority will be considered to be proven.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -4.77 to 4.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Mothers With a Fetal Death
Description	Fetal deaths include both stillbirths and spontaneous abortions; in case of a multiple birth, mothers who had at least one fetal death
Time Frame	Measured from study entry through end of pregnancy

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	459	466
Count of Participants [Participants]	17 3.6%	9 1.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.093
	Comments
	Method	Fisher Exact
	Comments	mid-P adjustment

3. Secondary Outcome

Title	Number of Mothers With a Fetus Small for Gestational Age
Description	Small for gestational age was determined by physician at site
Time Frame	Measured at delivery

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	0	0

4. Secondary Outcome

Title	Number of Mothers With an Infant Born Prematurely
Description	Premature birth is defined as gestational age of < 37 weeks at delivery.
Time Frame	Measured at delivery

Outcome Measure Data

Analysis Population Description

Mothers who had at least one live birth

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	442	458
Count of Participants [Participants]	48 10.1%	40 8.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.288
	Comments
	Method	Fisher Exact
	Comments	mid-P adjustment

5. Secondary Outcome

Title	Number of Mothers With a Low Birth-weight Infant
Description	Low birth weight is defined as weight < 2500 mg
Time Frame	Measured on day of birth

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	430	446
Yes	62 13%	46 9.6%
No	368 77.1%	400 83.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Fisher Exact
	Comments	mid-P adjustment

6. Secondary Outcome

Title	Number of Mothers With an Infant With a Congenital Anomaly
Description	Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	440	458
Yes	10 2.1%	6 1.3%
No	430 90.1%	452 94.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments
	Method	Fisher Exact
	Comments	mid-P adjustment

7. Secondary Outcome

Title	Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly
Description	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.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

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)

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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
Measure Participants	449	460
Yes	106 22.2%	78 16.3%
No	343 71.9%	382 79.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Fisher Exact
	Comments	Mid-P adjustment

8. Secondary Outcome

Title	Number of Infants With Grade 3 or Higher Clinical or Laboratory AE
Description	Laboratory, sign/symptom, or diagnoses graded as 3 or higher by DAIDS criteria.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

Infants born alive

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Count of Participants [Participants]	193 40.5%	196 40.9%

9. Secondary Outcome

Title	Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment
Description	As before, but AE is judged to be possibly, probably, or definitely related to INH or Placebo for INH, by clinic medical staff
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

Infants born alive

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Count of Participants [Participants]	5 1%	6 1.3%

10. Secondary Outcome

Title	Number of Infants Which Are HIV-infected
Description	HIV infection determined during follow-up period. Infection at birth or during breastfeeding
Time Frame	Measured from study entry through study Week 44

Outcome Measure Data

Analysis Population Description

Infants born alive

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Yes	3 0.6%	7 1.5%
No	436 91.4%	451 94.2%
Unknown	6 1.3%	6 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.279
	Comments
	Method	Fisher Exact
	Comments	mid-P adjustment

11. Secondary Outcome

Title	Number of Infants Hospitalized
Description	Hospitalization due to reasons other than birth
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

Infants born alive

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Count of Participants [Participants]	73 15.3%	75 15.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.893
	Comments
	Method	Fisher Exact
	Comments	mid-P adjustment

12. Secondary Outcome

Title	Incidence Rate of TB Infection Among Mothers
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB infection, as judged by Secondary Endpoint Review Committee
Time Frame	Measured from study entry to Week 48 after birth

Outcome Measure Data

Analysis Population Description

All participants enrolled without active TB at entry

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	478
Number [events per 100 person-years]	0.60	0.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.94 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Incidence Rate of Tuberculosis (TB) Among Infants
Description	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.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

Live-born infants of enrolled women

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Number [events per 100 person-years]	0.54	0.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -1.02 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Incidence Rate of Infant Death
Description	Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

Live-born infants of enrolled women

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Number [events per 100 person-years]	2.99	4.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-1.43
	Confidence Interval	(2-Sided) 95%; -4.17 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Incidence Rate of Maternal Deaths
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through Week 48 postpartum

Outcome Measure Data

Analysis Population Description

All participants enrolled without active TB at entry

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	478
Number [events per 100 person-years]	0.40	0.78

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -1.33 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

All participants enrolled without active TB at entry.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	478
Number [events per 100 person-years]	1.00	1.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -1.72 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Incidence Rate of Combined Endpoints: Infant TB or Infant Death
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

Live-born infants of enrolled women

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	445	464
Number [events per 100 person-years]	2.99	4.68

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-1.69
	Confidence Interval	(2-Sided) 95%; -4.48 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	442	458
Number [events per 100 person-years]	3.42	4.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-1.30
	Confidence Interval	(2-Sided) 95%; -3.86 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata
Time Frame	Measured from study entry through end of pregnancy

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	15.93	13.79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	2.14
	Confidence Interval	(2-Sided) 95%; -7.86 to 12.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	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
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through 12 weeks after birth

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	16.98	10.09

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	6.89
	Confidence Interval	(2-Sided) 95%; -0.08 to 13.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Incidence Rate, Antepartum, of Grade 3 or Higher AE
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through end of pregnancy

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	56.36	50.88

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	5.49
	Confidence Interval	(2-Sided) 95%; -13.7 to 24.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through 12 weeks postpartum

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	56.48	40.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	15.88
	Confidence Interval	(2-Sided) 95%; 2.11 to 29.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment
Description	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
Time Frame	Measured from study entry through delivery

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	1.77	2.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -4.63 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata
Time Frame	Measured from study entry through 12 weeks postpartum

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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
Measure Participants	477	479
Number [events per 100 person-years]	7.91	4.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	3.38
	Confidence Interval	(2-Sided) 95%; -1.31 to 8.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Description	Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through delivery

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	1.77	2.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -4.63 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through 12 weeks postpartum

Outcome Measure Data

Analysis Population Description

All women enrolled

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	8.37	4.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	3.39
	Confidence Interval	(2-Sided) 95%; -1.46 to 8.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Hepatotoxicity definition as defined by DAIDS AE grading criteria 1.0.
Time Frame	Measured from study entry through delivery

Outcome Measure Data

Analysis Population Description

All women.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	1.77	2.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -4.63 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata
Time Frame	Measured from study start through 12 weeks postpartum

Outcome Measure Data

Analysis Population Description

All women

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	7.91	4.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	3.38
	Confidence Interval	(2-Sided) 95%; -1.31 to 8.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study entry through delivery

Outcome Measure Data

Analysis Population Description

All women

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	1.77	2.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -4.63 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Description	Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time Frame	Measured from study start through 12 weeks postpartum

Outcome Measure Data

Analysis Population Description

All women.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	477	479
Number [events per 100 person-years]	8.37	4.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate difference
	Estimated Value	3.39
	Confidence Interval	(2-Sided) 95%; -1.46 to 8.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

31. Secondary Outcome

Title	Number of Mothers With Tuberculosis Resistant to INH
Description	Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of mothers who develop culture-confirmed TB
Time Frame	Measured from study entry through Week 48 postpartum

Outcome Measure Data

Analysis Population Description

Mothers with culture-confirmed TB

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	2	2
Count of Participants [Participants]	1 0.2%	0 0%

32. Secondary Outcome

Title	Number of Infants With Tuberculosis Resistant to INH
Description	Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of infants who develop culture-confirmed TB
Time Frame	Measured from study entry through Week 48 after birth

Outcome Measure Data

Analysis Population Description

No infants had culture-confirmed TB

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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.
Measure Participants	0	0

33. Secondary Outcome

Title	Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH
Description	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,
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fast Metabolizers	Intermediate Metabolizers	Slow Metabolizers
Arm/Group Description	Those women having a genotype of fast INH metabolism.	Those women having a genotype of intermediate INH metabolism.	Those women having a genotype of slow INH metabolism.
Measure Participants	5	15	12
Third trimester of pregnancy	3.63	6.55	21.6
Week 16 postpartum	4.25	7.67	25.3

34. Secondary Outcome

Title	Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV
Description	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,
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fast Metabolizers	Intermediate Metabolizers	Slow Metabolizers
Arm/Group Description	Those women with a phenotype of fast EFV metabolism.	Those women with a phenotype of intermediate EFV metabolism.	Those women with a phenotype of slow EFV metabolism.
Measure Participants	3	10	8
Third trimester of pregnancy	38.5	62.5	153.02
Week 16 postpartum	46.9	76.2	186

35. Secondary Outcome

Title	Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery
Description	IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm
Time Frame	Measured at delivery

Outcome Measure Data

Analysis Population Description

Women tested for tuberculosis infection at delivery

Arm/Group Title	Positive IGRA TB Test	Negative IGRA TB Test
Arm/Group Description	Women who had positive IGRA TB test at delivery	Women who had negative IGRA TB test at delivery
Measure Participants	208	517
Positive tuberculin skin test	87 18.2%	27 5.6%
Negative tuberculin skin test	121 25.4%	490 102.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Other
	Comments	Measuring agreement between the tests
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Chi-squared
	Comments	McNemars test

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Other
	Comments	Agreement between tests
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kappa coefficient
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

36. Secondary Outcome

Title	Agreement Between IGRA and TST TB Test Results, Infant
Description	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.
Time Frame	Measured at week 44 after birth

Outcome Measure Data

Analysis Population Description

Infants with tuberculin tests performed at week 44 postpartum

Arm/Group Title	Positive IGRA Test	Negative IGRA Tuberculin Test
Arm/Group Description	Infants with positive IGRA test at week 44 postpartum	Infants with a negative IGRA test at 44 weeks postpartum
Measure Participants	42	642
Positive tuberculin skin test	8 1.7%	45 9.4%
Negative tuberculin skin test	34 7.1%	597 124.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Other
	Comments	Agreement between tests
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Chi-squared
	Comments	McNemar's test

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Other
	Comments	Agreement between tests
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kappa coefficient
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.001 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

37. Secondary Outcome

Title	Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum
Description	IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm
Time Frame	Measured at Week 44 postpartum

Outcome Measure Data

Analysis Population Description

Women who were tested for tuberculosis infection at 44 weeks postpartum

Arm/Group Title	Positive IGRA TB Test	Negative IGRA TB Test
Arm/Group Description	Women who had positive IGRA TB test at 44 weeks postpartum	Women who had negative IGRA TB test at 44 weeks postpartum
Measure Participants	227	479
Positive tuberculin skin test	100 21%	20 4.2%
Negative tuberculin skin test	127 26.6%	459 95.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Other
	Comments	Agreement between tests
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Chi-squared
	Comments	McNemar's test

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment)
	Comments
	Type of Statistical Test	Other
	Comments	Agreement between tests
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kappa coefficient
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

38. Secondary Outcome

Title	Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

All women enrolled.

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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
Measure Participants	477	479
Excellent adherence	400 83.9%	363 75.8%
Good adherence	47 9.9%	35 7.3%
Reasonable adherence	15 3.1%	8 1.7%
Poor adherence	4 0.8%	7 1.5%
Unknown	11 2.3%	66 13.8%

39. Secondary Outcome

Title	Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

All enrolled women

Arm/Group Title	Arm A (Immediate INH Treatment)	Arm B (Deferred INH Treatment)
Arm/Group Description	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	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
Measure Participants	477	479
Excellent adherence	408 85.5%	376 78.5%
Good adherence	42 8.8%	28 5.8%
Reasonable adherence	8 1.7%	6 1.3%
Poor adherence	5 1%	3 0.6%
Unknown	14 2.9%	66 13.8%

Adverse Events

Time Frame	From study entry to study completion at week 48 postpartum or premature study discontinuation
Adverse Event Reporting Description	At entry, all diagnoses, signs/symptoms, and laboratory events were collected. Post-entry, all new diagnoses, signs/symptoms, or laboratory events of >= 3 and all signs/symptoms and laboratory events that led to a change in treatment, regardless of grade, were collected. The DAIDS AE Grading Table (V1.0) and EAE Manual (V2.0) were used. All eligible participants who initiated study treatment and their live-born infants are included.
Arm/Group Title	Mother/Immediate INH		Mother/Deferred INH		Infant/Immediate INH		Infant/Deferred INH
Arm/Group Description	Women in Arm A received immediate, or antepartum-initiated, INH treatments. 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.		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 month, 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.		Infants born alive to mothers on arm A (Immediate INH).		Infants born alive to mothers on Arm B (Deferred INH).
All Cause Mortality
	Mother/Immediate INH		Mother/Deferred INH		Infant/Immediate INH		Infant/Deferred INH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/477 (0.4%)		4/479 (0.8%)		11/445 (2.5%)		17/464 (3.7%)
Serious Adverse Events
	Mother/Immediate INH		Mother/Deferred INH		Infant/Immediate INH		Infant/Deferred INH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/477 (14.9%)		69/479 (14.4%)		86/445 (19.3%)		91/464 (19.6%)
Blood and lymphatic system disorders
Anaemia	1/477 (0.2%)		2/479 (0.4%)		1/445 (0.2%)		0/464 (0%)
Anaemia neonatal	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Anaemia of pregnancy	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Haemorrhagic disease of newborn	0/477 (0%)		0/479 (0%)		2/445 (0.4%)		0/464 (0%)
Iron deficiency anaemia	1/477 (0.2%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Microcytic anaemia	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Thrombocytopenia	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Cardiac disorders
Mitral valve prolapse	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Congenital, familial and genetic disorders
Atrial septal defect	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Choledochal cyst	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Congenital cytomegalovirus infection	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Congenital hydrocephalus	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Congenital pneumonia	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Congenital syphilis	0/477 (0%)		0/479 (0%)		2/445 (0.4%)		0/464 (0%)
Dysmorphism	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Exomphalos	0/477 (0%)		0/479 (0%)		0/445 (0%)		2/464 (0.4%)
Patent ductus arteriosus	0/477 (0%)		0/479 (0%)		0/445 (0%)		2/464 (0.4%)
Gastrointestinal disorders
Abdominal pain	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Abdominal pain lower	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Diarrhoea	0/477 (0%)		1/479 (0.2%)		1/445 (0.2%)		1/464 (0.2%)
Haemorrhoidal haemorrhage	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Inguinal hernia	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Vomiting	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
General disorders
Death	0/477 (0%)		0/479 (0%)		2/445 (0.4%)		1/464 (0.2%)
Fever neonatal	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Macrosomia	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Pyrexia	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		3/464 (0.6%)
Sudden infant death syndrome	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		1/464 (0.2%)
Hepatobiliary disorders
Drug-induced liver injury	2/477 (0.4%)		4/479 (0.8%)		1/445 (0.2%)		0/464 (0%)
Hepatitis	0/477 (0%)		3/479 (0.6%)		0/445 (0%)		0/464 (0%)
Hepatitis acute	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Hepatotoxicity	1/477 (0.2%)		2/479 (0.4%)		0/445 (0%)		0/464 (0%)
Immune system disorders
Rhesus incompatibility	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Infections and infestations
Acute sinusitis	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Ascariasis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Breast abscess	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Bronchiolitis	0/477 (0%)		0/479 (0%)		3/445 (0.7%)		5/464 (1.1%)
Bronchitis	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Croup infectious	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Cryptosporidiosis infection	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Diarrhoea infectious	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		1/464 (0.2%)
Diverticulitis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Endometritis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Enterococcal sepsis	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Exanthema subitum	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		1/464 (0.2%)
Gastroenteritis	1/477 (0.2%)		3/479 (0.6%)		3/445 (0.7%)		6/464 (1.3%)
Gastroenteritis viral	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Genitourinary tract infection	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Haemophilus sepsis	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Herpangina	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Impetigo	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Lower respiratory tract infection	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Meningitis	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Oral candidiasis	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Parvovirus B19 infection	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Pharyngitis	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Pneumonia	0/477 (0%)		1/479 (0.2%)		8/445 (1.8%)		10/464 (2.2%)
Pneumonia bacterial	0/477 (0%)		1/479 (0.2%)		2/445 (0.4%)		4/464 (0.9%)
Postoperative wound infection	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Postpartum sepsis	1/477 (0.2%)		2/479 (0.4%)		0/445 (0%)		0/464 (0%)
Pulmonary tuberculosis	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Respiratory syncytial virus bronchitis	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Sepsis	1/477 (0.2%)		0/479 (0%)		2/445 (0.4%)		2/464 (0.4%)
Sepsis neonatal	0/477 (0%)		0/479 (0%)		11/445 (2.5%)		16/464 (3.4%)
Upper respiratory tract infection	1/477 (0.2%)		0/479 (0%)		1/445 (0.2%)		1/464 (0.2%)
Urinary tract infection	7/477 (1.5%)		5/479 (1%)		0/445 (0%)		0/464 (0%)
Vaginal infection	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Viral rash	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Vulvovaginal candidiasis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Injury, poisoning and procedural complications
Adverse event following immunisation	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Anal injury	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Burns second degree	1/477 (0.2%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Femur fracture	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Foreign body in respiratory tract	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Induced abortion failed	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Postoperative wound complication	1/477 (0.2%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Uterine rupture	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Investigations
Haemoglobin decreased	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Malnutrition	0/477 (0%)		0/479 (0%)		2/445 (0.4%)		2/464 (0.4%)
Musculoskeletal and connective tissue disorders
Symphysiolysis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's lymphoma	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Nervous system disorders
Convulsion neonatal	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Headache	2/477 (0.4%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Hypocalcaemic seizure	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Hypoxic-ischaemic encephalopathy	0/477 (0%)		0/479 (0%)		2/445 (0.4%)		1/464 (0.2%)
Intercostal neuralgia	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Paraparesis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	2/477 (0.4%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Eclampsia	1/477 (0.2%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
False labour	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Foetal death	12/477 (2.5%)		9/479 (1.9%)		0/445 (0%)		0/464 (0%)
Foetal distress syndrome	0/477 (0%)		2/479 (0.4%)		0/445 (0%)		0/464 (0%)
Foetal growth restriction	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		1/464 (0.2%)
Foetal hypokinesia	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Gestational hypertension	5/477 (1%)		5/479 (1%)		0/445 (0%)		0/464 (0%)
Haemorrhage in pregnancy	2/477 (0.4%)		3/479 (0.6%)		0/445 (0%)		0/464 (0%)
Hyperemesis gravidarum	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Jaundice neonatal	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Low birth weight baby	0/477 (0%)		0/479 (0%)		3/445 (0.7%)		3/464 (0.6%)
Meconium stain	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Peripartum cardiomyopathy	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Placenta praevia	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Postpartum haemorrhage	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Pre-eclampsia	8/477 (1.7%)		2/479 (0.4%)		0/445 (0%)		0/464 (0%)
Premature baby	0/477 (0%)		0/479 (0%)		10/445 (2.2%)		12/464 (2.6%)
Premature delivery	3/477 (0.6%)		2/479 (0.4%)		0/445 (0%)		0/464 (0%)
Premature labour	2/477 (0.4%)		6/479 (1.3%)		0/445 (0%)		0/464 (0%)
Premature rupture of membranes	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Premature separation of placenta	2/477 (0.4%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Preterm premature rupture of membranes	1/477 (0.2%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Prolonged rupture of membranes	2/477 (0.4%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Small for dates baby	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Stillbirth	5/477 (1%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Threatened labour	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Uterine inversion	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Psychiatric disorders
Confusional state	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Intentional self-injury	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Major depression	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Renal and urinary disorders
Urinary retention	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Reproductive system and breast disorders
Uterine atony	0/477 (0%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Vaginal discharge	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Dyspnoea	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Meconium aspiration syndrome	0/477 (0%)		0/479 (0%)		6/445 (1.3%)		3/464 (0.6%)
Neonatal asphyxia	0/477 (0%)		0/479 (0%)		5/445 (1.1%)		3/464 (0.6%)
Neonatal respiratory distress	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		2/464 (0.4%)
Neonatal respiratory distress syndrome	0/477 (0%)		0/479 (0%)		5/445 (1.1%)		5/464 (1.1%)
Respiratory disorder	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		0/464 (0%)
Transient tachypnoea of the newborn	0/477 (0%)		0/479 (0%)		1/445 (0.2%)		2/464 (0.4%)
Skin and subcutaneous tissue disorders
Drug eruption	0/477 (0%)		0/479 (0%)		0/445 (0%)		1/464 (0.2%)
Surgical and medical procedures
Abortion induced	1/477 (0.2%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Vascular disorders
Hypertension	1/477 (0.2%)		1/479 (0.2%)		0/445 (0%)		0/464 (0%)
Hypotension	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Venous thrombosis	1/477 (0.2%)		0/479 (0%)		0/445 (0%)		0/464 (0%)
Other (Not Including Serious) Adverse Events
	Mother/Immediate INH		Mother/Deferred INH		Infant/Immediate INH		Infant/Deferred INH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	438/477 (91.8%)		449/479 (93.7%)		417/445 (93.7%)		430/464 (92.7%)
Congenital, familial and genetic disorders
Congenital umbilical hernia	0/477 (0%)		0/479 (0%)		36/445 (8.1%)		41/464 (8.8%)
Gastrointestinal disorders
Abdominal pain	24/477 (5%)		15/479 (3.1%)		2/445 (0.4%)		0/464 (0%)
Diarrhoea	37/477 (7.8%)		25/479 (5.2%)		79/445 (17.8%)		83/464 (17.9%)
General disorders
Pyrexia	12/477 (2.5%)		11/479 (2.3%)		51/445 (11.5%)		57/464 (12.3%)
Infections and infestations
Conjunctivitis	17/477 (3.6%)		14/479 (2.9%)		29/445 (6.5%)		26/464 (5.6%)
Gastroenteritis	25/477 (5.2%)		20/479 (4.2%)		58/445 (13%)		50/464 (10.8%)
Oral candidiasis	1/477 (0.2%)		1/479 (0.2%)		25/445 (5.6%)		24/464 (5.2%)
Upper respiratory tract infection	15/477 (3.1%)		23/479 (4.8%)		45/445 (10.1%)		48/464 (10.3%)
Urinary tract infection	55/477 (11.5%)		51/479 (10.6%)		2/445 (0.4%)		2/464 (0.4%)
Vulvovaginal candidiasis	52/477 (10.9%)		47/479 (9.8%)		0/445 (0%)		0/464 (0%)
Investigations
Alanine aminotransferase increased	187/477 (39.2%)		206/479 (43%)		31/445 (7%)		31/464 (6.7%)
Aspartate aminotransferase increased	141/477 (29.6%)		151/479 (31.5%)		9/445 (2%)		2/464 (0.4%)
Blood alkaline phosphatase increased	12/477 (2.5%)		26/479 (5.4%)		2/445 (0.4%)		1/464 (0.2%)
Blood glucose decreased	144/477 (30.2%)		128/479 (26.7%)		1/445 (0.2%)		1/464 (0.2%)
Blood glucose increased	40/477 (8.4%)		47/479 (9.8%)		0/445 (0%)		0/464 (0%)
Haemoglobin decreased	199/477 (41.7%)		191/479 (39.9%)		353/445 (79.3%)		365/464 (78.7%)
Neutrophil count decreased	81/477 (17%)		87/479 (18.2%)		270/445 (60.7%)		264/464 (56.9%)
Platelet count decreased	22/477 (4.6%)		10/479 (2.1%)		23/445 (5.2%)		26/464 (5.6%)
Weight decreased	96/477 (20.1%)		97/479 (20.3%)		15/445 (3.4%)		12/464 (2.6%)
Metabolism and nutrition disorders
Failure to thrive	0/477 (0%)		0/479 (0%)		23/445 (5.2%)		23/464 (5%)
Musculoskeletal and connective tissue disorders
Growth failure	0/477 (0%)		0/479 (0%)		47/445 (10.6%)		38/464 (8.2%)
Nervous system disorders
Neuropathy peripheral	94/477 (19.7%)		109/479 (22.8%)		0/445 (0%)		0/464 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	46/477 (9.6%)		35/479 (7.3%)		66/445 (14.8%)		87/464 (18.8%)
Vascular disorders
Hypertension	40/477 (8.4%)		37/479 (7.7%)		0/445 (0%)		0/464 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.